This disclosure describes certain 15-deoxy prostanoic acid derivatives having a hydroxy group further along in the beta-chain, useful as bronchodilators; hypotensive agents, anti-ulcer agents, or as intermediates.

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Patent
   RE29469
Priority
Jul 24 1972
Filed
May 03 1976
Issued
Nov 08 1977
Expiry
Nov 08 1994
Inventors
Schaub, Ro…
Assg.orig
American C…
Assg.curr
American C…
Entity
unknown
Referenced by
1
References
1
Maint.:
EXPIRED
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1. An optically active compound of the formula: ##STR57## or a racemic compound of that formula and the mirror image thereof wherein R1 is selected from the group consisting of hydroxy, lower alkoxy, tetrahydropyranyloxy, lower alkanoyloxy, methoxy, ethoxy and ω-hydroxy substituted lower alkoxy and ω-tetrahydropyranyloxy substituted lower alkoxy having from 2 to 4 carbon atoms; R2 is a moiety selected from the group consisting of those of the formulae: ##STR58## wherein R' is selected from the group consisting of a straight chain alkyl group having from 2 to 10 carbon atoms and a straight chain alkyl group having from 2 to 6 carbon atoms and having one branched alkyl group of from 1 to 3 carbon atoms n-propyl, n-butyl and n-pentyl, and R" is a moiety selected from the group consisting of a straight chain alkyl group having from 2 to 10 carbon atoms and substituted with an hydroxy group, a straight chain alkyl group having from 2 to 6 carbon atoms and having one branched alkyl group of from 1 to 3 carbon atoms and substituted with an hydroxy group, a straight chain alkenyl group having from 2 to 10 carbon atoms and substituted with an hydroxy group and a straight chain alkenyl group having from 2 to 6 carbon atoms and having one branched alkyl group of from 1 to 3 carbon atoms and substituted with an hydroxy group; those of the formulae: ##STR59## wherein m is an integer from 3 to 5, inclusive, p is an integer from 1 to 3, inclusive, q is zero, 1 or 2, and y is ##STR60## R3 is selected from the group consisting of hydroxy , and alkoxy having from 1 to 12 4 carbon atoms and tetrahydropyranyloxy; and Z is a divalent radical selected from the group consisting of those of the formulae: ##STR61## wherein n is an integer from 3 6 to 8, inclusive , R4 is an alkyl group having up to 3 carbon atoms, and R5 is selected from the group consisting of an alkyl group having up to 3 carbon atoms, a fluorine atom and a phenyl group; and the pharmacologically acceptable cationic salts thereof when R3 is hydroxy.
2. The optically active compound according to claim 1 wherein R1 is hydroxy, R2 is ##STR62## R3 is hydroxy, and Z is --(CH2)6 --; l-9-oxo-11α,20-dihydroxy-13-trans-prostenoic acid.
3. The racemic compound according to claim 1 wherein R1 is hydroxy, R2 is ##STR63## R3 is hydroxy, and Z is --(CH2)6 --; dl-9-oxo-11α,20-dihydroxy-13-trans-prostenoic acid.
4. The optically active compound according to claim 1 wherein R1 is hydroxy, R2 is ##STR64## R3 is hydroxy, and Z is --(CH2)6 --; l-9-oxo-11α,16(S)-dihydroxy-13-trans-prostenoic acid.
5. The racemic compound according to claim 1 wherein R1 is hydroxy, R2 is ##STR65## R3 is hydroxy, and Z is --(CH2)6 --; dl-9-oxo-11α,16(S)-dihydroxy-13-trans-prostenoic acid.
6. The mixture of the two racemic compounds according to claim 1 wherein R1 is hydroxy, R2 is ##STR66## R3 is hydroxy, and Z is --(CH2)6 --; 9-oxo-11α,16-dihydroxy-13-trans-prostenoic acid.
7. The optically active compound according to claim 1 wherein R1 is hydroxy, R2 is ##STR67## R3 is hydroxy, and Z is --(CH2)6 --; l-9-oxo-11α,16(R)-dihydroxy-13-trans-prostenoic acid.
8. The racemic compound according to claim 1 wherein R1 is hydroxy, R2 is ##STR68## R3 is hydroxy, and Z is --(CH2)6 --; dl-9-oxo-11α,16-epidihydroxy(R)-dihydroxy-13-tr ans-prostenoic acid.
9. The optically active compound according to claim 1 wherein R1 is hydroxy, R2 is ##STR69## R3 is hydroxy, and Z is --(CH2)6 ; l-9-oxo-11α,16(S)-dihydroxy-20-methyl-13-trans-prostenoic acid.
10. The racemic compound according to claim 1 wherein R1 is hydroxy, R2 is ##STR70## R3 is hydroxy, and Z is --(CH2)6 --; dl-9-oxo-11α,16(S)-dihydroxy-20-methyl-13-trans-prost enoic acid.
11. The mixture of the two racemic compounds according to claim 1 wherein R1 is hydroxy, R2 is ##STR71## R3 is hydroxy, and Z is --(CH2)6 --; 9-oxo-11α,16-dihydroxy-20-methyl-13-trans-prostenoic acid.
12. The optically active compound according to claim 1 wherein R1 is hydroxy, R2 is ##STR72## R3 is hydroxy, and Z is --(CH2)6 --; l-9-oxo-11α,16(R)-dihydroxy-20-methyl-13-trans-prostenoic acid.
13. The racemic compound according to claim 1 wherein R1 is hydroxy, R2 is ##STR73## R3 is hydroxy, and Z is --(CH2)6 --; dl-9-oxo-11α,16(R)-epi-dihydroxy-20-methyl-13-t rans-prostenoic acid.
14. The optically active compound according to claim 1 wherein R1 is hydroxy, R2 is ##STR74## R3 is hydroxy, and Z is --(CH2)6 --; l-9-oxo-11α,16(S)-dihydroxy-20-ethyl-13-trans-prostenoic acid.
15. The racemic compound according to claim 1 wherein R1 is hydroxy, R2 is ##STR75## R3 is hydroxy, and Z is --(CH2)6 --; dl-9-oxo-11α,16(S)-dihydroxy-20-ethyl-13-trans-proste noic acid.
16. The mixture of the two racemic compounds according to claim 1 wherein R1 is hydroxy, R2 is ##STR76## R3 is hydroxy, and Z is --(CH2)6 --; 9-oxo-11α,16-dihydroxy-20-ethyl-13-trans-prostenoic acid.
17. The optically active compound according to claim 1 wherein R1 is hydroxy, R2 is ##STR77## R3 is hydroxy, and Z is --(CH2)6 --; l-9-oxo-11α,16(R)-dihydroxy-20-ethyl-13-trans-prostenoic acid.
18. The racemic compound according to claim 1 wherein R1 is hydroxy, R2 is ##STR78## R3 is hydroxy, and Z is --(CH2)6 --; dl-9-oxo-11α,16-epidihydroxy(R)-dihydroxy-20-et hyl-13-trans-prostenoic acid.
19. The optically active compound according to claim 1 wherein R1 is hydroxy, R2 is ##STR79## R3 is hydroxy, and Z is --(CH2)6 --; l-9-oxo-11α,16(S)-dihydroxy-20-methyl-13-trans,17-trans-prostadienoi c acid.
20. The racemic compound according to claim 1 wherein R1 is hydroxy, R2 is ##STR80## R3 is hydroxy, and Z is --(CH2)6 --; dl-9-oxo-11α,16(S)-dihydroxy-20-methyl-13-trans,17-trans-prostadieno ic acid.
21. The mixture of the two racemic compounds according to claim 1 wherein R1 is hydroxy, R2 is ##STR81## R3 is hydroxy, and Z is --(CH2)6 --; 9-oxo-11α,16-dihydroxy-20-methyl-13-trans,17-trans-prostadienoic acid.
22. The optically active compound according to claim 1 wherein R1 is hydroxy, R2 is ##STR82## R3 is hydroxy, and Z is --(CH2)6 --; l-9-oxo-11α,16(R)-dihydroxy-20-methyl-13-trans,17-trans-prostadienoi c acid.
23. The racemic compound according to claim 1 wherein R1 is hydroxy, R2 is ##STR83## R3 is hydroxy, and Z is --(CH2)6 --; dl-9-oxo-11α,16-epi-dihydroxy-20-methyl-13-trans,17-trans-prostadien oic acid.
24. The optically active compound according to claim 1 wherein R1 is hydroxy, R2 is ##STR84## R3 is hydroxy, and Z is --(CH2)6 --; l-9-oxo-11α,17(S)-dihydroxy-13-trans-prostenoic acid.
25. The racemic compound according to claim 1 wherein R1 is hydroxy, R2 is ##STR85## R3 is hydroxy, and Z is --(CH2)6 --; dl-9-oxo-11α,17-dihydroxy-13-trans-prostenoic acid.
26. The optically active compound according to claim 1 wherein R1 is hydroxy, R2 is ##STR86## R3 is hydroxy, and Z is --(CH2)6 --; l-9-oxo-11α,17(R)-dihydroxy-13-trans-prostenoic acid.
27. The racemic compound according to claim 1 wherein R1 is hydroxy, R2 is ##STR87## R3 is hydroxy, and Z is --(CH2)6 --; dl-9-oxo-11α,17-epi-dihydroxy-13-trans-prostenoic acid.
28. The mixture of the two racemic compounds according to claim 1 wherein R1 is hydroxy, R2 is ##STR88## R3 is hydroxy, and Z is --(CH2)6 --; 9-oxo-11α,17-dihydroxy-13-trans-prostenoic acid.
29. The optically active compound according to claim 1 wherein R1 is hydroxy, R2 is ##STR89## R3 is hydroxy, and Z is --(CH2)6 --; l-9-oxo-11α-hydroxy-15(S)-hydroxymethyl-13-trans-prostenoic acid.
30. The racemic compound according to claim 1 wherein R1 is hydroxy, R2 is ##STR90## R3 is hydroxy, and Z is --(CH2)6 --; dl-9-oxo-11α-hydroxy-15-hydroxymethyl-13-trans-prostenoic acid.
31. The mixture of the two racemic compounds according to claim 1 wherein R1 is hydroxy, R2 is ##STR91## R3 is hydroxy, and Z is --(CH2)6 --; 9-oxo-11α-hydroxy-15-hydroxymethyl-13-trans-prostenoic acid.
32. The optically active compound according to claim 1 wherein R1 is hydroxy, R2 is ##STR92## R3 is hydroxy, and Z is --(CH2)6 --; l-9-oxo-11α-hydroxy-15(R)-hydroxymethyl-13-trans-prostenoic acid.
33. The racemic compound according to claim 1 wherein R1 is hydroxy, R2 is ##STR93## R3 is hydroxy, and Z is --(CH2)6 --; dl-9-oxo-11α-hydroxy-15-epi-hydroxymethyl-13-trans-prostenoic acid.
34. The optically active compound according to claim 1 wherein R1 is hydroxy, R2 is ##STR94## R3 is hydroxy, and Z is --(CH2)4 --O--CH2 --; l-9-oxo-11α,16(S)-dihydroxy-3-oxa-13-trans-prostenoic acid.
35. The racemic compound according to claim 1 wherein R1 is hydroxy, R2 is ##STR95## R3 is hydroxy, and Z is --(CH2)4 --O--CH2 --; dl-9-oxo-11α,16(S)-dihydroxy-3-oxa-13-trans-prostenoic acid.
36. The mixture of the two racemic compounds according to claim 1 wherein R1 is hydroxy, R2 is ##STR96## R3 is hydroxy, and Z is --(CH2)4 --O--CH2 --; 9-oxo-11α,16-dihydroxy-3-oxa-13-trans-prostenoic acid.
37. The optically active compound according to claim 1 wherein R1 is hydroxy, R2 is ##STR97## R3 is hydroxy, and Z is --(CH2)4 --O--CH2 --; l-9-oxo-11α,16(R)-dihydroxy-3-oxa-13-trans-prostenoic acid.
38. The racemic compound according to claim 1 wherein R1 is hydroxy, R2 is ##STR98## R3 is hydroxy, and Z is --(CH2)4 --O--CH2 --; dl-9-oxo-11α,16(R)-dihydroxy-3-oxa-13-trans-prostenoic acid.
39. The optically active compound according to claim 1 wherein R1 is hydroxy, R2 is ##STR99## R3 is ethoxy, and Z is --(CH2)6 --; l-ethyl 9-oxo-11α,16(S)-dihydroxy-20-methyl-13-trans,18-cis-prostadienoate.
40. The mixture of the two racemic compounds according to claim 1 wherein R1 is hydroxy, R2 is ##STR100## R3 is ethoxy, and Z is --(CH2)6 --; ethyl 9-oxo-11α,16-dihydroxy-20-methyl-13-trans,18-cis-prostadienoate.
41. The optically active compound ethyl l-9-oxo-11α,16-dihydroxy-17-methyl-13-transprostenoate. 42. The racemic compound ethyl dl-9-oxo-11α,16-dihydroxy-17-methyl-13-transprostenoate. 43. The optically active compound l-9-oxo-11α,16-dihydroxy-17-methyl-13-trans-prostenoic acid. 44. The racemic compound dl-9-oxo-11α,16-dihydroxy-17-methyl-13-trans-prostenoic acid. 45. The optically active compound l-9-oxo-11α-hydroxy-16-hydroxy-17-methyl-19,20-dinor-13-trans-proste noic acid. 46. The racemic compound dl-9-oxo-11α-hydroxy-16-hydroxy-17-methyl-19,20-dinor-13-trans-prost enoic acid. 47. The optically active compound l-9-oxo-11α-hydroxy-16-hydroxy-17-ethyl-20-nor-13-trans-prostenoic
acid. 48. The racemic compound dl-9-oxo-11α-hydroxy-16-hydroxy-17-ethyl-20-nor-13-trans-prostenoic acid.
CROSS REFERENCE TO RELATED descried described hereinabove then provides the corresponding 9α-hydroxy or 9β-hydroxy diastereomer (CIV) or (CV). Among the optically active reagents useful for ketone derivatization are 1-α-aminoxy-α -methylpentanoic acid hydrochloride [E. Testa et al., Helv. Chemica Acta, 47 (3), 766 (1973)], methylhydrazine, and 4-α-methylbenzylsemicarbazide. A useful procedure for the cleavage of oximes such as (CXIV) and (CXV) involves treatment of the oxime at about 60°C for about 4 hours in 1:2 aqueous-tetrahydrofuran buffered with ammonium acetate and containing titanium trichloride. ##STR55##

Other useful ketone derivatizing agents are optically active 1,2-glycols, e.g., D(-)-2,3-butanediol, or 1,2-dithiols, e.g., L(+)-2,3-butanedithiol. These are used to convert the 9-oxo derivative to 9,9-alkylenedioxa or 9,9-alkylenedithia derivatives, separation of diastereomers by chromatographic procedures followed by regeneration of the individual 9-oxo diastereomer by ketal cleavage all by procedures well-known in the art. Both ketalization and deketalization would have to be accomplished by procedures which would not disrupt the 11-oxo-9-keto system, which of course, is not a problem in the 11-unsubstituted series.

An alternative procedure for the conversion of substituted 1-alkyne (CXVI) to product (CXX) (formulae XXXIII and XXXVIII respectively of Flowsheet E) proceeds via vinyl lithium reagent (CXVII) (formula XXXIXc of Flowsheet F). ##STR56## In this procedure (CXVII) is reacted with the complex of cuprous iodide-tri-n-butylphosphine is an ether solvent at very low temperatures, e.g., -78°C, to provide a divinyl lithio cuprate species (CXIX). This reagent (CXIX) is reacted with cyclopentenone (CXVIII) (XXXVII of Flowsheet E) in ether-hydrocarbon solvent at -78°C to 0° C. to provide product (CXX), after workup with aqueous ammonium chloride.

The novel compounds of the present invention have potential utility as hypotensive agents, anti-ulcer agents, agents for the treatment of gastric hypersecretion and gastric erosion, agents to provide protection against the ulcerogenic and other gastric difficulties associated with the use of various non-sterodial antiinflammatory agents, e.g. indomethacin, aspirin, and phenylbutazone, bronchodilators, antimicrobial agents, anticonvulsants, abortifacients, agents for the induction of labor, agents for the induction of menses, fertility-controlling agents, central nervous system regulatory agents, salt and water-retention regulatory agents, diuretics, fat metabolic regulatory agents and as serum-cholesterol lowering agents. Certain of the novel compounds of this invention possess utility as intermediates for the preparation of other of the novel compounds of this invention.

Anti-ulcerogenic Effect of Indomethacin

The compounds of this invention also provide protection against the ulcerogenic properties of indomethacin. This assay was carried out in the following manner.

Rats were starved for 48 hours (water was given ad libitum). Indomethacin (20 mg./kg. of body weight) was administered by the subcutaneous route and one-half the dose of the test compound was administered by gavage at the same time. After 3 hours, the second half of the test compound was administered also by gavage. Five hours after the administration of indomethacin the animals were decapitated and the stomachs removed. The stomachs were washed with distilled water, blotted on gauze, cut along the larger curvature, and the contents rinsed with distilled water. The stomachs were spread out, pinned on a cork and visualized under magnifying glass for ulcers. The criteria for scoring of ulers ulcers was as previously reported. [Abdel-Galil et al. Brit. J. Pharmac. Chemotherapy 33:1-14 (1968)].

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SCORE
0- Normal Stomach
1- Petechial hemorrhage or pin point ulcers
2- 1 or 2 small ulcers
3- Many ulcers, a few large
4- Many ulcers, mainly large
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A difference of at least 0.7 unit between the scores for control animals (treated with indomethacin but not test compound) and animals treated with indomethacin and test compound is considered indicative of activity for the test compound. (Control animals treated with neither indomethacin nor test compound give scores of about 0.5-0.8.) The results obtained in this assay with typical compounds of the present invention are set forth in Table I below.

TABLE I
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Total oral
dose: mg./kg
Score
Compound of body weight
treated control
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9-oxo-16-hydroxy-
13-trans-pro-
stenoic acid 50 1.2 2.3
9-oxo-16-hydroxy-
prostenoic acid
50 1.3 2.3
9-oxo-11α,16-di-
12.5 1.0 3.0
hydroxy-13-trans-
4.4 1.0 3.0
prostenoic acid
1.56 1.0 2.5
0.78 1.5 3.0
0.39 2.0 3.0
0.18 2.5 3.0
9-oxo-11α,17-di-
hydroxy-13-trans-
25 1.3 2.7
prostenoic acid
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The novel compounds of the present invention are also effective inhibitors of gastric acid secretion and of ulcer development in experimental animals, and thus are potentially valuable as agents for the control of gastric acid secretion and of gastric erosion and as anti-ulcer agents. Gastric acid secretion inhibitory action is usually measure by the "Shay rat" procedure(1,2) with some modifications as follows.

(footnote) 1. Shay et al., Gastroenterology, 5, 43 (1945).

(footnote) 2. Shay et al., Gastroenterology, 26, 906 (1954).

The rats (male, CFE strain) were starved for 48 hours (water was given ad libitum) to permit evacuation of stomach contents. On the morning of the experiment, under ether anesthesia, the abdominal region was shaved and a midline incision (1-11/2 inches) was made with a scapel. With the help of a closed curved hemostate the duodenum was picked up. Upon getting the duodenum into view, fingers were used to pull the stomach through the opening, the stomach was then gently manipulated with fingers to rid the stomach of air and residual matter which were pushed through the pylorus. Two-5 inch sutures were drawn under the pyloric-duodenal puncture. A ligature, at the juncture, was formed with one of the threads. The second ligature was also formed but not tightened.

The test compound and the vehicle, usually 1 ml./100 g. body weight, were injected into the duodenum as close as possible to the first ligature. After injection the second ligature was tightened below the injection site to minimize leakage. The stomach was placed back through the opening into the abdominal cavity, the area of incision was washed with saline and the incision was closed with autoclips. (Occasionally, instead of an intraduodenal injection, animals were dosed by the oral or subcutaneous route. In the latter case, dosing was done 30 to 60 minutes before the operation.)

Three hours later, the rats were decapitated and exanguinated, taking care that blood did not drain into the esophagus. The abdominal cavity was exposed by cutting with scissors and the esophagus close to the stomach was clamped off with a hemostat, the stomach was removed by cutting above the hemostat (the espphagus esophagus was cut) and between the two sutures. Extraneous tisue tissue was removed, the stomach washed with saline and blotted on gauze. A slit was carefully made in the stomach which was held over a funnel and the contents were collected in a centrifuge tube. The stomach was further cut along the outside edge and turned inside out. Two ml. H2 O were used to wash the stomach contents into the respective centrifuged tube. The combined stomach contents and wash were then centrifuged out for 10 min. in the International Size 2 Centrifuge (setting at 30). The supernatant was collected, volume measured and recorded, 2 drops of a phenylphthalein indicator (1% in 95% ethanol) were added and the solution was titrated with 0.02N NaOH (or with 0.04N NaOH when large volumes of stomach contents were encountered to pH 8.4 (because of usual coloring of the stomach contents, phenolphthalein was only used to permit visual indication that the end point was near) and the amount of acid present was calculated.

Compounds inducing inhibition of gastric acid secretion of 20% or more were considered active. In a representative operation, and merely by way of illustration, the results obtained with this assay with typical compounds of the present invention are given in Table II below.

Table II
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Intraduodenal
dose, mg./kg Percent
Compound of body weight
Inhibition
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9-oxo-16-hydroxy-13-
trans-prostenoic
acid 50 67
9-oxo-16-hydroxy
prostanoic acid 50 58
9-oxo-20-hydroxy
13-trans-prostenoic
acid 100 56
9-oxo-18/19-hydroxy-
13-trans-prostenoic
acid 100 28
9-oxo-18-hydroxy-19,
20-dinor-13-trans-
prostenoic acid 50 21
Ethyl 9-oxo-18-hy-
droxy-19,20-dinor-
13-trans-prostenoate
100 49
9-oxo-11α,16-dihy-
1.6* 79
droxy-13-trans-pro-
0.8* 53
stenoic acid 0.4* 27
9-oxo-11α,17-dihy-
droxy-13-trans-pro-
stenoic acid 50 73
9-oxo-20-hydroxy-10,
13-trans-prosta- 50 91
dienoic acid
______________________________________

Bronchodilator activity was determined in guinea pigs against bronchospasms elicited by intravenous injections of 5-hydroxytryptamine, histamine or acetylcholine by the Konzett procedure, [See J. Lulling, P. Lievens, F. El Sayed and J. Prignot, Arzneimittel-Forschung, 18, 995 (1968).]

In the Table which follows bronchodilator activity for representative compounds of this invention against one or more of the three spasmogenic agents is expressed as an ED50 determined from the results obtained with three logarithemic cumulative intravenous dose.

TABLE III
__________________________________________________________________________
Bronchodilator Activity (Konzett Assays)
__________________________________________________________________________
ED50 mg./kg.
Spasmorgenic Agent
5-hydroxy-
Compound
tryptamine histamine choline
__________________________________________________________________________
9-oxo-20-hydroxy-13-
trans-prostenoic
117 × 10-3
30 × 10-3
2.16
acid
9-oxo-18-hydroxy-
19,20-dinor-13-
2.85 2.22 10.0
trans-prostenoic
acid
9-oxo-16-hydroxy-
13-trans-prostenoic
277 × 10-a
34.6 × 10-3
455 × 10-3
acid
9-oxo-16-hydroxy-
prostanoic acid
92.7 × 10-3
477 × 10-a
1.13
9-oxo-18/19-hydroxy-
13-trans-prostenoic
1.19 1.04
acid
9-oxo-11α,16-dihy-
droxy-13-trans-
.607 × 10-3
166 × 10-3
.420 × 10-3
prostenoic acid
9-oxo-11α,17-dihy-
droxy-13-trans-pro-
0.235 0.45 0.518
stenoic acid
9-oxo-11α,20-dihy-
droxy-13-trans-
0.377 0.077 2.34
prostenoic acid
9-oxo-20-hydroxy-10,
13-trans-prosta-
1.32 2.28
dienoic acid
__________________________________________________________________________

This invention will be described in greater detail in conjunction with the following specific examples.

EXAMPLE 1
PAC Preparation of 2-carbalkoxy(methyl/ethyl)-2-(4-carbethoxybutyl)cyclopentan-1-one

To a stirred solution of the sodium cyclopentanone carboxylate enolate in dimethoxyethane, prepared from 187 g. (1.248 moles) of 2-cyclopentanone carboxylate (mixed methyl and ethyl esters), 52.4 g. (1.248 moles) sodium hydride (57.2% in mineral oil) and 1.6 l. of dimethoxyethane, is added dropwise 309 g. (1.212 moles) of ethyl 5-iodovalerate. The reaction mixture is stirred and heated at reflux for 18 hours. The mixture is cooled and filtered. The solvent is removed from the filtrate by evaporation and the residue is poured into dilute hydrochloric acid and extracted with ether. The combined extracts are washed with water and saline, dried over magnesium sulfate and evaporated to give an oil. The oil is distilled under reduced pressure to give 274 g. of a light yellow oil, b.p. 140°-143°C (0.17 mm).

EXAMPLE 2
PAC Preparation of 2-(4-carboxybutyl)cyclopentan-1-one

A stirred mixture of 274 g. of 2-carbalkoxy(mixed methyl and ethyl esters)-2-(4-carbethoxybutyl)cyclopentan-1-one (Example 1), 600 ml. of 20% hydrochloric acid and 325 ml. of acetic acid is heated at reflux for 20 hours. Solution occurs in approximately one-half hour. The solution is cooled and diluted with water and extracted with ether. The combined extracts are washed with salline saline and dried over magnesium sulfate and evaporated. The residue is evaporated twice with toluene to give 144 g. of an oil.

EXAMPLE 3
PAC Preparation of 2-(4-carbethoxybutyl)cyclopentan-1-one

A stirred solution of 124 g. (0.673 mole) of 2-(4-carboxybutyl)cyclopentan-1-one (Example 2), 800 ml. of ethanol and 1 g. of p-toluenesulfonic acid monohydrate is heated at reflux for 18 hours. The solvent is evaporated and the residue is dissolved in ether. The ether solution is washed with saline, dilute sodium bicarbonate solution and again with saline, dried over magnesium sulfate and evaporated. The oil is distilled under reduced pressure to give 149 g. of a colorless oil, b.p. 106°-109°C (0.23 mm).

EXAMPLE 4
PAC Preparation of 2-carbalkoxy(methyl/ethyl)-2-(3-carbethoxypropyl)cyclopentan-1-one

In the manner described in Example 1, treatment of 2-cyclopentanone carboxylate (mixed methyl and ethyl esters) with sodium hydride in dimethoxyethane followed by ethyl 4-iodobutyrate gives a yellow oil, b.p. 136°-137°C (0.16 mm).

EXAMPLE 5
PAC Preparation of 2-(3-carboxypropyl)cyclopentan-1-one

In the manner described in Example 2, treatment of 2-carbalkoxy(mixed methyl and ethyl esters)-2-(3-carbethoxypropyl)cyclopentan-1-one (Example 4) with a 20% hydrochloric acid and acetic acid mixture gives a yellow oil.

EXAMPLE 6
PAC Preparation of 2-(3-carbethoxypropyl)cyclopentan-1-one

In the manner described in Example 3, treatment of 2-(3-carboxypropyl)cyclopentan-1-one (Example 5) with p-toluenesulfonic acid monohydrate in ethanol gives a colorless oil, b.p. 93°C (0.10 mm).

EXAMPLE 7
PAC Preparation of ethyl and methyl 2-(6-carbethoxyhexyl)-1-cyclopentanon-2-carboxylate

In the manner described in Example 1, ethyl and methyl 2-cyclopentanone carboxylate is reacted with ethyl 7-bromoheptanoate to furnish the subject product, b.p. 147°C (0.09 mm).

EXAMPLE 8
PAC Preparation of 2-(6-carboxyhexyl)cyclopentan-1-one

In the manner described in Example 2, ethyl and methyl 2-(6-carbethoxyhexyl)-1-cyclopentanone-2-carboxylate (Example 7) is hydrolyzed to furnish the subject product, b.p. 143°C (0.05 mm).

EXAMPLE 9
PAC Preparation of 2-(6-carbethoxyhexyl)cyclopentan-1-one

In the manner described in Example 3, 2-(6-carboxyhexyl)cyclopentan-1-one (Example 8) is esterified to furnish the subject product, b.p. 110° C. (0.03 mm).

EXAMPLE 10
PAC Preparation of 1-acetoxy-2-(6-carbethoxyhexyl)cyclopent-1-ene

A stirred solution of 100 g. of 2-(6-carbethoxyhexyl)cyclopentan-1-one (Example 9) in 250 ml. of acetic anhydride containing 0.940 g. of p-toluenesulfonic acid monohydrate is heated to boiling under partial reflux allowing distillate at 118°C or less (i.e., acetic acid) to escape through a Vigreux column equipped with a condenser to collect the distillate. After 16 hours, during which period acetic anhydride is added in portions in order to keep the solvent level at at least 100 ml., the solution is cooled and poured cautiously into a stirred cold mixture of saturated sodium bicarbonate solution (400 ml.) and hexane (250 ml.). The resulting mixture is stirred for an additional 30 minutes during which period solid sodium bicarbonate is added periodically to insure a basic solution. The hexane layer is separated and washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness. Distillation of the residual oil gives 102 g. (87%) of pale yellow oil, b.p. 118°C (0.07 mm).

EXAMPLE 11
PAC Preparation of 1-acetoxy-2-(3-carbethoxypropyl)cyclopent-1-ene

In the manner described in Example 10, treatment of 2-(3-carbethoxypropyl)cyclopentan-1-one (Example 6) with acetic anhydride and p-toluenesulfonic acid monohydrate gives a yellow oil, b.p. 98° -103°C (0.35 mm).

EXAMPLE 12
PAC Preparation of 1-acetoxy-2-(4-carbethoxybutyl)cyclopent-1-ene

In the manner described in Example 10, treatment of 2-(4-carbethoxybutyl)cyclopentan-1-one (Example 3) with acetic anhydride and p-toluenesulfonic acid monohydrate gives a yellow oil, b.p. 109°-110°C (0.37 mm).

EXAMPLE 13
PAC Preparation of 2-(6-carbethoxyhexyl)cyclopent-2-en-1-one

To a rapidly stirred mixture of 50 g. of 1-acetoxy-2-(6-carbethoxyhexyl)cyclopent-1-ene (Example 10) in 150 ml. of chloroform, 200 ml. of water and 18.8 g. of calcium carbonate, cooled in an ice bath, is added dropwise over a period of about 30 minutes, a solution of 30 g. of bromine in 50 ml. of carbon tetrachloride. After stirring for an additional 45 minutes the chloroform layer is separated and washed successively with dilute sodium thiosulfate solution, saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness under reduced pressure.

The residual oil is dissolved in 50 ml. of N,N-dimethylformamide and added to a mixture of 33 g. of lithium bromide and 32 g. of lithium carbonate in 375 ml. of N,N-dimethylformamide, previously dried by refluxing with 375 ml. of benzene under a Dean-Stark apparatus followed by distillation of the benzene. The mixture is stirred at the reflux temperature for 30 minutes, then cooled and poured into 850 ml. of ice-cold water. The resulting mixture is acidified (cautiously) with 4N hydrochloric acid and extracted with ether three times. The combined ether extracts are washed with saturated sodium chloride solution dried with anhydrous magnesium sulfate and taken to dryness under reduced pressure to afford 41.5 g. of an amber oil. In order to convert any isomeric material to the desired product, 41.5 g. of the above material is treated with 0.500 g. of p-toluenesulfonic acid monohydrate in 450 ml. of absolute alcohol at the reflux temperature for 18 hours. The solution is taken to dryness under reduced pressure. The resulting gum is dissolved in ether and washed with saturated sodium bicarbonate solution, saturatd sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness under reduced pressure. The residual oil is distilled to give 30.2 g. of product; b.p. 118°C (0.05 mm); λmaxMeOH 229 mμ (ε9950); λmax 5.75, 5.85, 6.15, 8.45 μ; vapor phase chromatography shows 99% product, containing 1% 2-(6-carbethoxyhexyl)cyclopentan-1-one.

This product can be purified by the following procedure. A mixture of 120 g. of 2-(6-carbethoxyhexyl)-2-cyclopentenone, containing approximately 5% of the saturated analogue, and 7.67 g (10 mole percent) of p-carboxyphenylhydrazine in 400 ml. of absolute ethanol is stirred at ambient temperatures for 18 hours and is then refluxed for 1 hour. The mixture is cooled, the solvent is evaporated, and the residue is taken up into 150 ml. of chloroform and passed through a column of 450 g. of aluminum oxide (Merck). The fltrate filtrate is evaporated to yield a colorless oil containing <0.5% of the saturated impurity.

EXAMPLE 14
PAC Preparation of 2-(3-carbethoxypropyl)cyclopent-2-en-1-one

In the manner described in Example 13, bromination of 1-acetoxy-2-(3-carbethoxypropyl)cyclopent-1-ene (Example 11) followed by dehydrobromination with lithium bromide and lithium carbonate is productive of the subject compound.

EXAMPLE 15
PAC Preparation of 2-(4-carbethoxybutyl)cyclopent-2-en-1-one

In the manner described in Example 13, treatment of 1-acetoxy-2-(4-carbethoxybutyl)cyclopent-1-ene (Example 12) with bromine and subsequent treatment of the brominated product with a mixture of lithium bromide and lithium carbonate in N,N-dimethylformamide is productive of the subject compound. Treatment of this product with p-carboxyphenylhydrazine by the procedure of Example 13 furnishes a product which contains less than 0.5% of the corresponding saturated ketone.

EXAMPLE 16
PAC Preparation of 1-methoximino-2-(6-carbethoxyhexyl)-2-cyclopentene

To a mixture of 35.97 g. (0.151 mole) or of 2-(6-carbethoxyhexyl)-2-cycopentenone (Example 13) and 15.0 g. (0.180 mole) of methoxyamine hydrochloride in 300 ml. of absolute ethanol is added 25 ml. of pyridine and the resulting solution is stirred for 20 hours at ambient temperatures. The solvent is evaporated and the residue is partitioned between water and diethyl ether. The organic phase is washed with water and saturated brine, dried (Na2 SO4), and the solvent is evaporated to yeild an oil. Distillation yields 38.7 g. of a colorless oil, b.p. 115°-118°C (0.075 mm). IR (film): 1740, 1627, 1053, 890 cm-1. λmax (MeOH) 243 (13,000). NMRδ(CDCl3): 3.89.

EXAMPLE 17
PAC Preparation of 1-methoximino-2-(7-hydroxyheptyl)-2-cyclopentene

To an ice cooled solution of 34.10 g. (0.128 mole) of 1-methoximino-2-(6-carbethoxyhexyl)-2-cyclopentene (Example 16) in 200 ml. of benzene under nitrogen is added dropwise 225 ml. of a 25% solution of diisobutyl aluminum hydride in hexane. The resulting solution is stirred for 2 hours at 0°-5°C, poured onto ice and dilute hydrochloric acid, and the aqueous phase is saturated with sodium chloride. The organic phase is separated, washed with saturated brine, dried (Na2 SO4), and evaporated to yield an oil. The latter is dissolved in 100 ml. of hot hexane and cooled to yield 24.3 g. of crystals, m.p. 62°-64°C IR (KBr) 3260, 1630, 1059, 893 cm-1. λmax 243 (14,200). NMR (CDCl3)δ: 2.37.

EXAMPLE 18
PAC Preparation of 1-methoximino-2-(7-p-toluenesulfonyloxyheptyl)-2-cyclopentene

To a solution of 5.00 g. (0.222 mole) of 1-methoximino-2-(7-hydroxyheptyl)-2-cyclopentene (Example 17) in 50 ml. of dry pyridine at 0°C is added 8.45 g. (0.0444 mole) of p-toluenesulfonyl chloride and the resulting solution is chilled at 5°C overnight. The mixture is partitioned between 300 ml. of ice water and diethyl ether. The organic phase is washed with 1:1 ice cold hydrochloric acid, cold water, and cold saturated brine, dried (NaSO4 /K2 CO3), and evaporated under reduced pressure at room temperature to yield an oil. The latter is dissolved in 600 ml. of hexane, treated with 0.5 g. of Darco, filtered and evaporated to yeild 7.7 g. of colorless oil. IR (film) 1600, 1192, 1182, 1053, 890 cm-1. λmax (MeOH) 228 and 243.

EXAMPLE 19
PAC Preparation of 1-methoximino-2-(8,8-dicarbethoxyoctyl)-2cyclopentene

To an alcoholic solution of sodiodiethyl malonate, prepared from 0.847 g. (0.0368 g. atoms) of sodium, 100 ml. of absolute ethanol, and 7.05 g. (0.0440 mole) of diethyl malonate is added 7.7 g. of the tosylate of Example 18 and the mixture is refluxed for 2 hours under a nitrogen atmosphere. The mixture is partitioned between cold dilute hydrochloric acid and diethyl ether, and the organic phase is washed with water and saturated brine, dried (Na2 SO4), and evaporated to yield an oil. The excess diethyl malonate is distilled off under reduced pressure to yield 6.45 g. of a yellowish oil. IR (film) 1755, 1728, 1625, 1054, 890 cm-1.

EXAMPLE 20
PAC Preparation of 1-methoximino-2-(8,8-dicarboxyoctyl)-2-cyclopentene

A mixture of 6.45 g. of the diester of Example 19 and 6.72 g. of potassium hydroxide in 150 ml. of 1:1 aqueous methanol is refluxed for 1 hour, cooled, and is partitioned between water and diethyl ether. The aqueous phase is acidified with hydrochloric acid, extracted with ether, and the organic phase is washed with water and saturated brine, dried (Na2 SO4) and evaporated to yield a solid. The solid is crystallized from benzene to yield 4.15 g. of tan crystals, m.p. 135°-137°C (--CO2).

EXAMPLE 21
PAC Preparation of 1-methoximino-2-(8-carboxyoctyl)-2-cyclopentene

A solution of 3.926 g. (0.0126 mole) of the diacid of Example 20 in 20 ml. of xylene is refluxed for 1.5 hours, cooled and evaporated to yield a tan solid. IR (KBr) 1720, 1618, 1179, 1050,, 1050, 986 cm-1.

EXAMPLE 22
PAC Preparation of 2-(8-carboxyoctyl)cyclopent-2-en-1-one

The acid methoxime from Example 21 is refluxed for 5 hours with 55 ml. of acetone and 20 ml. of 2N hydrochloric acid. The mixture is cooled, the solvent is evaporated, and the residue is partitioned between water and diethyl ether. The organic phase is washed with water and saturated brine, dried (Na2 SO4), and evaporated to yield a tan solid. IR (KBr) 1745, 1665 cm-1. λmax (MeOH) 228 (12,600).

EXAMPLE 23
PAC Preparation of 2-(8-carbethoxyoctyl)cyclopent-2-en-1-one

The acid ketone from Example 22 is Fisher esterfied with 100 ml. of absolute ethanol, 100 ml. of benzene, and 20 mg. of p-toluenesulfonic acid for 6 hours, cooled, and the solvent is evaporated. The resulting oil is dissolved in 3:1 benzene-ether and the solution is passed through a column of 100 g. of Florisil. The filtrate is evaporated and the residue is distilled to yield 2.97 g. of a colorless oil, b.p. 137°-139°C (0.05 Torr).

EXAMPLE 24
PAC Preparation of 2-(4-carbethoxybutyl)-2-cyclopentenone methoxime

Treatment of 2-(4-carbethoxybutyl)-2-cyclopentenone (Example 15) with methoxyamine hydrochloride in the manner described in Example 16 gives an oil, b.p. 107°-109°C (0.05 mm). IR (film): 1740, 1628, 1050, 885 cm-1. λmax (MeOH) 243 (13,600).

EXAMPLE 25
PAC Preparation of 2-(5-hydroxypentyl)-2-cyclopentenone methoxime

Treatment of 2-(4-carbethoxybutyl)-2-cyclopentenomethoxime (Example 24) with diisobutyl aluminum hydride in the manner described in Example 17 gives crystals, m.p. 33°-35°C IR (KBr) 3420, 1630, 1050, 886 cm-1. λmaxMeOH 243 (12,020).

EXAMPLE 26
PAC Preparation of 2-(5-p-toluenesulfonyloxypentyl)-2-cyclopentenone methoxime

Treatment of 2-(5-hydroxypentyl)-2-cyclopentenone methoxime (Example 25) with p-toluenesulfonyl chloride in pyridine in the manner described in Example 18 gives a colorless oil. IR (film) 1600, 1190, 1180, 1050, 885 cm-1.

EXAMPLE 27
PAC Preparation of 2-(6,6-dicarbethoxyoctyl)-2-cyclopentenone methoxime

To a solution of sodio diethyl ethylmalonate, prepared from 1.63 g. (0.0387 mole) of sodium hydride in mineral oil (57.2%), 100 ml. of ethylene glycol dimethyl ether and 8.5 g. (0.0452 mole) of ethyl diethyl malonate, is added 7.5 g. of tosylate from Example 26 in 20 ml. of ethylene glycol dimethyl ether and the mixture is refluxed for 3 hours and then allowed to stand at room temperature for 18 hours under nitrogen atmosphere. The reaction mixture is filtered and most of the solvent is removed. The mixture is partitioned between cold dilute hydrochloric acid and diethyl ether, and the organic phase is washed with water and saturated brine, dried (MgSO4), and evaporated to yield an oil. The excess ethyl diethyl malonate is distilled off under reduced pressure to yield 6.7 g. of a yellow oil. IR (film) 1755, 1728, 1627, 1050, 885 cm-1.

EXAMPLE 28
PAC Preparation of 2-(6,6-dicarboxyoctyl)-2-cyclopentenone methoxime

Treatment of 2-(6,6-dicarbethoxyoctyl)-2-cyclopentene methoxime (Example 26) with potassium hydroxide, and 1:1 aqueous methanol in the manner described in Example 20 gives a light yellow oil.

EXAMPLE 29
PAC Preparation of 2-(6-carboxyoctyl)-2-cyclopentenone methoxime

In the manner described in Example 21, treatment of 2-(6,6-dicarboxyoctyl)-2-cyclopentenone methoxime (Example 28) with xylene at reflux for 18 hours gives a yellow oil.

EXAMPLE 30
PAC Preparation of 2-(6-carboxyoctyl)-2-cyclopentenone

Treatment of 2-(6-carboxyoctyl)-2-cyclopentenone methoxime (Example 29) with acetone and 2N hydrochloric acid in the manner described in Example 22 gives a light yellow oil.

EXAMPLE 31
PAC Preparation of 2-(6-carbethoxyoctyl)-2-cyclopentenone

Treatment of 2-(6-carboxyoctyl)-2-cyclopentenone (Example 30) with thionyl chloride and then treatment of the acid chloride with ethanol in the usual manner gives an amber oil. The oil is placed on a magnesia-silica gel column and eluted with 3:1 benzene:ether. The solvent is removed and the residue is distilled, b.p. 122°C (0.06 mm).

EXAMPLE 32
PAC Preparation of diethyl 1,1-dimethyl-5-tetrahydropyranylpentylmalonate

To 486 mg. (0.02 g.-atoms) of magnesium in 5 ml. of toluene containing one molar equivalent of tetrahydrofuran per equivalent of magnesium and one percent iodine (calculated in weight of magnesium) is added dropwise 3.86 g. (0.02 mole) of 4-chloro-1-tetrahydropyranyloxybutane over a period of one hour with stirring, under nitrogen at 70°C The reaction mixture is stirred at 70°C for four hours. This reagent is then added dropwise to 3 g. (0.015 mole) of ethyl isopropylidenemalonate in 40 ml. of tetrahydrofuran containing 392 mg. of tetrakis [iodo(tri-n-butylphosphine)copper (I)] and stirred at room temperature for 2 hours. The reaction mixture is poured into cold dilute hydrochloric acid and extracted with ether. The ether extract is dried over magnesium sulfate and concentrated to give 5.92 g. of subject product as an oil.

EXAMPLE 33
PAC Preparation of diethyl 1,1-dimethyl-5-hydroxypentylmalonate

A solution of 3.5 g. (0.01 mole) of diethyl 1,1-dimethyl-5-tetrahydrofuranyloxypentylamalonate in 70 ml. of ethanol containing 3 ml. of hydrochloric acid is allowed to stir at room temperature for 18 hours. The solution is concentrated, diluted with water and extracted with ether. The ether extract is washed with water, dried over magnesium sulfate and concentrated to give 3.262 g. of a light yellow oil. The oil is purified by distillation, b.p. 116°- 117° C. (0.05 mm).

EXAMPLE 34
PAC Preparation of 3,3-dimethyl-7-hydroxyheptanoic acid

A mixture of 32 g. (0.117 mole) of diethyl 1,1-dimethyl-5-hydroxypentylmalonate, 25 g. of potassium hydroxide and 600 ml. of methanol-water (1:1) is heated at reflux for 8 hours and then allowed to stand at room temperature for 18 hours. The methanol is removed, diluted with water and the reaction mixture is acidified with concentrated hydrochloric acid. The mixture is extracted with ether. The extract is washed with water and saline, dried over anhydrous magnesium sulfate and concentrated to give 27 g. of 1,1-dimethyl-5-hydroxypentylmalonic acid. This crude oil is dissolved in 200 ml. of bis-(2-methoxyethyl)ether and is heated at reflux for 4 hours and then allowed to stand at room temperature overnight. The solvent is removed and the reaction mixture is diluted with water and extracted with ether. The organic solution is washed with saline, dried over magnesium sulfate and concentrated to give 18 g. of product as an oil.

EXAMPLE 35
PAC Preparation of ethyl 3,3-dimethyl-7-chloroheptanoate

To a solution of 3.484 g. (0.02 mole) of 3,3-dimethyl-7-hydroxyheptanoic acid in 25 ml. of chloroform containing 3 drops of dimethylformamide is added 5.8 ml. (0.08 mole) of thionyl chloride and the solution is then heated at reflux for 3-4 hours. The solution is concentated to give the intermediate 3,3-dimethyl-7-chloro-1-heptanoyl chloride. The acid chloride is dissolved in a minimum amount of benzene and added slowly to 20 ml. benzene, 10 ml. of ethanol and 2.65 ml. of collidine. The solution is heated at reflux for one hour and then concentrated. The residue is dissolved in ether, washed with water, dilute sodium bicarbonate solution and saline. The organic solution is dried over magnesium sulfate and concentrated to give 3.57 g. of product as a yellow oil.

EXAMPLE 36
PAC Preparation of ethyl 3,3-dimethyl-7-iodoheptanoate

To a solution of 3.57 g. (0.0162 mole) of ethyl 3,3-dimethyl-7-chloroheptanoate in 100 ml. of methyl ethyl ketone is added 4 g. of sodium iodide and the mixture heated at reflux for 18 hours. The reaction mixture is cooled, filtered and concentrated. The residue is partitioned between ether and water. The aqueous phase is extracted several times with ether. The extract is washed with sodium bisulfite solution, water and saline. The organic solution is dried over magnesium sulfate and concentrated to give 4.182 g. of a yellow oil. The material is purified by distillation, b.p. 86°-87°C (0.18 Torr).

EXAMPLE 37
PAC Preparation of 2-carbalkoxy(methyl/ethyl)-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopentan-1 -one

This compound is prepared by treatment of sodiocyclopentanone carboxylate enolate with ethyl 3,3-dimethyl-7-iodoheptanoate by the procedure described in Example 1.

EXAMPLE 38
PAC Preparation of 2-(6-carboxy-5,5-dimethylhexyl)cyclopentan-1-one

This compound is prepared by decarbalkoxylation of 2-carbalkoxy (mixed methyl and ethyl ester)-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopentan-1-one by the procedure described in Example 2.

EXAMPLE 39
PAC Preparation of 2-(6-carbethoxy-5,5-dimethylhexyl)cyclopentan-1-one

Esterification of 2-(6-carboxy-5,5-dimethylhexyl)cyclopentan-1-one with ethanol by the procedure described in Example 3 is productive of the subject compound.

EXAMPLE 40
PAC Preparation of 1-acetoxy-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopent-1-one

This compound is prepared from 2-(6-carbethoxy-5,5-dimethylhexyl)cyclopentan-1-one and acetic anhydride by the process described in Example 10.

EXAMPLE 41
PAC Preparation of 2-(6-carbethoxy-5,5-dimethylhexyl)cyclopent-2-en-1-one

This compound is prepared from 1-acetoxy-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopent-1-ene via bromination and dehydrobromination according to the procedure described in Example 13.

EXAMPLE 42
PAC Preparation of 2-(3-carbethoxypropyl)-1-methoximino-2-cyclopentene

In the manner described for the preparation of the compound of Example 16, 2-(3-carbethoxypropyl)-1-methoximino-2-cyclopentene is prepared from 2-(3-carbethoxypropyl)-2-cyclopentenone (Example 14) and methoxyamine hydrochloride.

EXAMPLE 43
PAC Preparation of 2-(4-hydroxybutyl)-1-methoximino-2-cyclopentene

In the manner described for the preparation of the compound of Example 17, 2-(4-hydroxybutyl)-1-methoximino-2-cyclopentene is prepared from 2-(3-carbethoxypropyl)-1-methoximino-2-cyclopentene and diisobutylaluminum hydride.

EXAMPLE 44
PAC Preparation of 2-(6-carbethoxy-5-oxahexyl)-1-methoximino-2-cyclopentene

To an ice cold solution of 4.833 g. (0.0266 mole) of 2-(4-hydroxypentane)-1-methoximino-2-cyclopentene in 50 ml. of dry tetrahydrofuran under nitrogen is added 16.7 ml. of 1.6 molar n-butyl lithium in hexane, dropwise. The reaction mixture is stirred for 0.5 hour and then 4.85 g. (0.029 mole) of ethyl bromoacetate is added dropwise. The reaction mixture is stirred overnight at room temperature and then refluxed for 1.5 hours. The reaction is cooled and poured into water and extracted several times with ether. The ether extracts are washed with saline, dried over magnesium sulfate, and concentrated. The residue is placed on an alumina column, chloroform being used as a wash solvent. The combined washings are concentrated to dryness to give 4.903 g. of product an a yellow oil.

EXAMPLE 45
PAC Preparation of 2-(6-carboxy-5-oxahexyl)-2-cyclopentenone

In the manner described in Example 22, treatment of 2-(6-carbethoxy-5-oxahexyl)-1-methoximino-2-cyclopentene with acetone and 2N hydrochloric acid at reflux gives the subject compound as a yellow oil.

EXAMPLE 46
PAC Preparation of 2-(6-carbethoxy-5-oxahexyl)-2-cyclopentenone

In the manner described in Example 23, treatment of 2-(6-carboxy-5-oxahexyl)-2-cyclopentenone with p-toluenesulfonic acid in ethanol produces the subject product as a light yellow oil.

EXAMPLE 47
PAC Preparation of 2-(6-carboxy-5-oxahexyl)-1-methoximino-2-cyclopente

To an ice cold solution of 3.66 g. (0.02 mole) of 2-(4-hydroxybutyl)-1-methoximino-2-cyclopentene (Example 43) in 50 ml. of 1,2-dimethoxyethane under nitrogen is added dropwise 17 ml. of 1.6 M n-butyl lithium in hexane. The reaction mixture is stirred for half an hour and then the lithium salt of chloroacetic acid, prepared from 1.89 g. (0.02 mole) of chloroacetic acid and 16 ml. of 1.6M n-butyl lithium in 20 ml. of dimethoxyethane, is added and the reaction mixture is heated at reflux for 48 hours. The solvent is evaporated and the residue is partitioned between ether and water. The aqueous phase is acidified with hydrochloric acid and extracted with ether. The organic phase is washed with water and saturated saline solution, dried (MgSO4), and evaporated to give 3.35 g. of a yellow oil.

EXAMPLE 48
PAC Preparation of 2-(6-carboxy-5-oxahexyl)-2-cyclopenten-1-one

In the manner described in Example 22, treatment of 2-(6-carboxy-5-oxahexyl)-1-methoximino-2-cyclopentene (Example 47) with acetone and 2N hydrochloric acid at reflux gives the subject compound as a yellow oil.

EXAMPLE 49
PAC Preparation of 1-methoximino-2-(4-methanesulfonyloxybutyl)-2-cyclopentene

To a solution of 1.83 g. (0.01 mole) of 1-methoximino-2-(4-hydroxybutyl)-2-cyclopentene (Example 43) in 10 ml. of methylene chloride containing 1.52 g. (0.015 mole) of triethylamine is added 1.265 g. (0.011 mole) of methanesulfonyl chloride over a period of 5-10 minutes at -10°-0°C Stirring is continued for 15 minutes and the solution is then washed with cold water cold 10% hydrochloric acid, cold sodium bicarbonate solution, and cold saline solution. The organic phase is dried (MgSO4) and concentrated to give an oil which solidifies upon cooling. Crystallization from ether-petroleum ether (30°-60°C) gives 1.797 g. of white crystals, m.p. 67°-68°C

EXAMPLE 50
PAC Preparation of 1-methoximino-2-(5-cyanopentyl)-2-cyclopentene

A mixture of 2.75 g. (0.01 mole) of 1-methoximino-2-(5-methanesulfonyloxypentyl)-2-cyclopentene (Example 60) and 1.47 g. (0.03 mole) of sodium cyanide in 20 ml. of dry N,N-dimethylformamide is heated at 65°-70°C for 3 hours. The cooled reaction mixture is poured into water and extracted with diethyl ether. The organic phase is washed with water and saturated saline solution, dried (MgSO4), and evaporated to give 1.89 g. of a light yellow oil.

EXAMPLE 51
PAC Preparation of 1-methoximino-2-(5-carboxypentyl)-2-cyclopentene

A mixture of 1.89 g. (0.0092 mole) of 1-methoximino-2-(5-cyanopentyl)-2-cyclopentene (Example 50) and 1 g. (0.025 mole) of sodium hydroxide in 50 ml. of 1:1 aqueous-ethanol is refluxed for 48 hours, coled, and partitioned between water and diethyl ether. The aqueous phase is acidified with hydrochloric acid, extracted with diethyl ether, and the organic phase is washed with water and saturated saline solution, dried (MgSO4), and evaporated to give 1.86 g. of a yellow oil.

EXAMPLE 52
PAC Preparation of 2-(5-carboxypentyl)-2-cyclopentenone

A solution of 1.86 g. (0.00825 mole) 1-methoximino-2-(5-carboxypentyl)-2-cyclopentene (Example 51) in 44 ml. of acetone and 13.1 ml. of 2N hydrochloric acid is refluxed for 5 hours. The solvent is partially evaporated and a solid precipitates and is collected. The residue is extracted with diethyl ether and the organic phase is washed with saturated saline solution, dried (MgSO4), and evaporated to yield additional solid. The combined solid material is crystallized from ether/pet ether (30°-60° C) to yield crystalline material, m.p. 70°-72°C

EXAMPLE 53
PAC Preparation of 2-(5-carbethoxypentyl)-2-cyclopentenone

A solution of 1.309 g. (0.00668 mole) of 2-(5-carboxypentyl)-2-cyclopentenone (Example 52) and 90 mg. of p-toluenesulfonic acid in 150 ml. of ethanol is refluxed for 18 hours. The solvent is evaporated and the residue is dissolved in ether. The organic phase is washed with water, sodium bicarbonate solution, and saturated saline solution, dried (MgSO4), and evaporated to give 1.371 g. of light yellow oil.

EXAMPLE 54
PAC Preparation of 2-(5-acetoxypentyl-2-carbomethoxy/carbethoxy-cyclopentanone

A mixture of sodiocyclopentanone carboxylate, prepared from 1200 g. (8.0 moles) of cyclopentanone carboxylate (methyl and ethyl esters) and 200 g. (8.3 moles) of mineral oil free sodium hydride in 10 l. of 1,2-dimethoxyethane, 1320 g. (8.0 moles) of 5-chloro-1-amyl acetate [M.E. Synerholm, Journ. Amer. Chem. Soc., 69, 2681 (1947)], and 1200 g. (8.0 moles) of sodium iodide is refluxed under nitrogen for 18 hours. The mixture is cooled, connected to 4 l. and partitioned between dilute hydrochloric acid and diethyl ether. The organic phase is washed with water and saturated brine, dried (MgSO4), and evaporated to yield 1920 g. of an oil.

EXAMPLE 55
PAC Preparation of 2-(5-hydroxypentyl)cyclopentanone/2-(5-acetoxypentyl)-cyclopentanone

A mixture of 4,500 g. (16.2 moles) of 2-(5-acetoxypentyl)-2-carbomethoxy/carboethoxy-cyclopentanone (Example 54), 2.2 l. of glacial acetic acid, 1 l. of concentrated hydrochloric acid, and 1 l. of water is refluxed for 18 hours, cooled, and partitioned between saturated brine and benzene. The organic phase is washed with saturated brine, dried (MgSO4), and evaporated in vacuo to yield 3155 g. of an oil.

EXAMPLE 56
PAC Preparation of 1-acetoxy-2-(5-acetoxypentyl)-1-cyclopentene

A solution of 400 g. (2.04 moles) of a mixture of 2-(5-hydroxypentyl)cyclopentanone and 2-(5-acetoxypentyl)cyclopentanone (Example 55) and 4.0 g. of p-toluenesulfonic acid monohydrate in 11 l. of acetic anhydride is refluxed acetic a rate to maintain a steady distillation of acetic acid from the reaction through a relix-packed fractionation column. The reaction is continued with the addition of acetic anhydride to maintain a constant volume until complete conversion of starting materials to product is evident. The mixture is cooled and partitioned between 2 l. of hexane and 3 l. of cold water containing solid sodium bicarbonate to maintain a neutral pH. The organic phase is washed with saturated brine, dried (MgSO4), and evaporated to yield 452 g. of an oil.

EXAMPLE 57
PAC Preparation of 2-(5-acetoxypentyl)-2-cyclopentenone

To a well stirred mixture of 405 g. (4.05 moles) of calcium carbonate, 3 l. of water, and 2.5 l. of chloroform cooled to 5°C is added simultaneously 1016 g. (4.0 moles) of 1-acetoxy-2-(5-acetoxy-pentyl)-1-cyclopentene (Example 56) and a solution of 648 g. (4.05 moles) of bromine in 500 ml. of carbon tetrachloride at a rate to maintain a temperature below 10°C The mixture is stirred for half an hour after addition of the reagents and the phases are then separated. The organic phase is washed with 2% sodium thiosulfate solution, water, and saturated brine, dried (MgSO4), and evaporated in vacuo to an oil. The oil is immediately added to a refluxing slurry of 500 g. (5.0 moles) of calcium carbonate in 2.5 l. of N,N-dimethylacetamide under nitrogen and the mixture is then refluxed for 30 minutes. The mixture is cooled, filtered, and partitioned between water and diethyl ether. The organic phase is washed with water and saturated brine, dried (MgSO4), and evaporated to yield 757 g. of an oil, b.p. 116°-118°C (0.25 mm.).

EXAMPLE 58
PAC Preparation of 1-methoximino-2-(5-acetoxypentyl)-2-cyclopentene

In the manner described for Example 16, 2-(5-acetoxypentyl)-2-cyclopentenone (Example 57) is treated with methoxyamine hydrochloride in pyridine and ethanol to yield the subject compound, b.p. 101°-103°C (0.20 mm.).

EXAMPLE 59
PAC Preparation of 1-methoximino-2-(5-hydroxypentyl)-2-cyclopentene

A mixture of 74 g. (0.22 mole) of 1-methoximino-2-(5-acetoxypentyl)-2-cyclopentene (Example 58) and 56 g. (1.0 mole) of potassium hydroxide in 300 ml. of 1:1 aqueous methanol is refluxed for 2 hours and then cooled. The solvent is partially removed in vacuo and the residue is partitioned between saturated brine and diethyl ether. The organic phase is washed with saturated brine, dried (MgSO4), and evaporated to yield an oil which crystallized, m.p. 35°-36°C

EXAMPLE 60
PAC Preparation of 1-methoximino-2-(5-methanesulfonyloxypentyl)-2-cyclopentene

To a cold solution of 9.85 g. (0.05 mole) of 1-methoximino-2-(5-hydroxypentyl)-2-cyclopentene (Example 59) and 7.6 g. (0.075 mole) of triethylamine in 100 ml. of methylene chloride at -10°C is added 6.3 g. (0.055 mole) of methanesulfonyl chloride at a rate to maintain a temperature of -10°C The mixture is then stirred for 15 minutes and then poured into ice water. The organic phase is washed with cold 10% hydrochloric acid, cold saturated sodium bicarbonate solution, and cold saturated brine, dried (MgSO4), and evaporated to yield a solid, m.p. 78°-80°C

EXAMPLE 61
PAC Preparation of 1-methoximino-2-(6,6-dicarbethoxyhexyl)-2-cyclopentene

To a suspension of sodiodiethylmalonate in 1,2-dimethoxyethane, prepared from 248 g. (1.55 moles) of diethyl malonate and 17.2 g. (0.95 mole) of mineral oil free sodium hydride in 1 l. of 1,2-dimethoxyethane under nitrogen, is added 170 g. (0.62 mole) of 1-methoximino-2-(5-methanesulfonyloxypentyl)-2-cyclopentene (Example 60) in 1.5 l. of 1,2-dimethoxyethane and the mixture is refluxed for 5 hours. The mixture is cooled, filtered, and the solvent is evaporated. The residue is partitioned between cold dilute hydrochloric acid and water, and the organic phase is washed with saturated brine, dried (MgSO4), and evaporated to remove solvent and excess diethyl malonate to yield 209 g. of an oil.

EXAMPLE 62
PAC Preparation of 1-methoximino-2-(6,6-dicarboxyhexyl)-2-cyclopentene

In the manner described in Example 20, 1-methoximino-2-(6,6-dicarbethoxyhexyl)-2-cyclopentene is treated with potassium hydroxide in 1:1 aqueous methanol and then hydrochloric acid to yield the desired compound as crystals from diethyl ether, m.p. 110°-115°C

EXAMPLE 63
PAC Preparation of 1-methoximino-2-(6-carboxyhexyl)-2-cyclopentene

A solution of 141 g. (0.50 mole) of 1-methoximino-2-(6,6-dicarboxyhexyl)-2-cyclopentene in 500 ml. of bis-(2-methoxyethyl) ether is refluxed for 2 hours, cooled, and evaporated to yeild an oil. The latter is crystallized from hexane to yield 92 g. of solid, m.p. 70°-72°C

EXAMPLE 64
PAC Preparation of 2-(6-carboxyhexyl)-2-cyclopentenone

In the manner described in Example 22, treatment of 1-methoximino-2-(6-carboxyhexyl)-2-cyclopentene (Example 63) with acetone and 2N hydrochloric acid at reflux provides the subject compound.

EXAMPLE 65
PAC Preparation of 2-(6-carbethoxyhexyl)-2-cyclopentenone

Fischer estification of 2-(6-carboxyhexyl)-2-cyclopentenone (Example 64) in the manner of Example 23 provides the subject compound.

EXAMPLE 66
PAC Preparation of 1-methoximino-2-(6-fluoro-6,6-dicarbethoxyhexyl)-2-cyclopentene

To a solution of sodiodiethyl fluoromalonate, prepared from 2.062 g. (0.0491 mole) of sodium hydride in mineral oil (57.2%), 40 ml. of dry N,N-dimethylformamide and 8.174 g. (0.0458 mole) of diethyl fluoromalonate is added dropwise 11.32 g. (0.0413 mole) of 1-methoximino-2-(5-methylsulfonyloxypentyl)-2-cyclopentene (Example 60) in 60 ml. of N,N-dimethylformamide. The mixture is refluxed for 2 hours under a nitrogen atmosphere. The mixture is concentrated and partitioned between cold dilute hydrochloric acid and diethyl ether, and the organic phase is washed with saturated brine, dried (MgSO4), and evaporated to yield 13.631 g. (92%) of a yellow oil.

EXAMPLE 67
PAC Preparation of 1-methoximino-2-(6fluoro,6,6-dicarboxyhexyl)-2-cyclopentene

A mixture of 13.631 g. of the diester of Example 66 and 16 g. of potassium hydroxide in 364 ml. of 1:1 aqueous methanol is refluxed for 5 hours, cooled, concentrated, and is partitioned between water and diethyl ether. The aqueous phase is acidified with hydrochloric acid, extracted with ether, and the organic phase is washed with saturated brine, dried (MgSO4), and evaporated to yield a solid. The solid is crystallized free diethyl ether petroleum ether (30°-60°C) to give 10 g. (90%) of white crystals, m.p. 143°-145°C (--CO2).

EXAMPLE 68
PAC Preparation of 1-methoximino-2-(6-fluoro-6-carboxyhexyl)-2-cyclopentene

A solution of 10 g. of the diacid of Example 67 in 60 ml. of 2-methoxyethyl ether is refluxed for 7 hours, cooled, and evaporated to yield 8.5 g. (95%) of a tan solid. A sample is crystallized from diethyl ether-petroleum ether (30°-60°C) to give white crystals, m.p. 98°-100°C

EXAMPLE 69
PAC Preparation of 2-(6-fluoro-6-carboxyhexyl)cyclopent-2-en-1-one

The acid methoxime (8.5 g.) from Example 68 is refluxed for 5 hours with 180 ml. of acetone and 64 ml. of 2N hydrochloric acid. The mixture is cooled, the solvent is evaporated, and the residue is partitioned between water and diethyl ether. The organic phase is washed with saturated brine, dried (MgSO4), and evaporated to yield 7.4 g. (98%) of a light yellow oil.

EXAMPLE 70
PAC Preparation of 2-(6-fluoro-6-carbethoxyhexyl)cyclopent-2-en-1-one

The acid ketone (7.4 g.) from Example 69 is Fisher esterified with 300 ml. of absolute ethanol and 400 mg. of p-toluenesulfonic acid for 18 hours, cooled and the solvent is evaporated. The resulting oil is dissolved in ether, washed with dilute sodium bicarbonate solution, and saline, dried (MgSO4) and evaporated to give 7.306 g. (86%) of a light yellow oil.

EXAMPLE 71
PAC Preparation of 2-(7-cyanoheptyl)-1-methoximino-2-cyclopentene

Treatment of 1-methoximino-2-(7-p-toluenesulfonyloxy)-2-cyclopentene (Example 18) with sodium cyanide in the manner of Example 50 is productive of the subject compound.

EXAMPLE 72
PAC Preparation of 2-(7-carboxyheptyl)-1-methoximino-2-cyclopentene

Alkaline hydroylsis of 2-(7-cyanoheptyl)-1-methoximino-2-cyclopentene (Example 71) of th eprocedure of Example 51 is productive of the subject compound.

EXAMPLE 73
PAC Preparation of
2-(7-carboxyheptyl)-2-cyclopenten-1-one

Hydrolysis of the methoxime of Example 72 with acetone-hydrochloric acid by the procedure of Example 52 is productive of the subject compound.

EXAMPLE 74
PAC Preparation of 2-(7-carbethoxyheptyl)-2-cyclopenten-1-one

Fisher esterification of the carboxylic acid of Example 73 by the procedure of Example 53 is productive of the subject compound.

EXAMPLE 75
PAC Preparation of 2-(6,6-dicarbethoxy-6-phenylhexyl)-1-methoximino-2-cyclopentene

Treatment of 1-methoximino-2-(5-methanesulfonyloxypentyl)-2-cyclopentene (Example 60) with sodio diethyl phenylmalonate by the procedure of Example 61 is productive of the subject compound.

EXAMPLE 76
PAC Preparation of 2-(6,6-dicarboxy-6-phenylhexyl)-1-methoximino-2-cyclopentene

Alkaline hydrolysis of 2-(6,6-dicarbethoxy-6-phenylhexyl)-1-methoximino-2-cyclopentene (Example 75) by the procedure of Example 20 is productive of the subject diacid.

EXAMPLE 77
PAC Preparation of 2-(6-carboxy-6-phenylhexyl)-1-methoximino-2-cyclopentene-dicarbethoxy

Decarboxylation of 2-(6,6-dicarboxy-6-phenylhexyl)-1-methoximino-2-cyclopentene (Example 76) by the procedure of Example 63 is productive of the subject compound.

EXAMPLE 78
PAC Preparation of 2-(6-carboxy-6-phenylhexyl)-2-cyclopentene-1-one

Methoxime cleavage of 2-(6-carboxy-6-phenylhexyl)-1-methoximino-2-cyclopentene (Example 77) in the manner of Example 69 is productive of the subject ketone.

EXAMPLE 79
PAC Preparation of 2-(6-carbethoxy-6-phenylhexyl)-2-cyclopentene-1-one

Fisher esterification of the carboxylic acid of Example 78 in the manner of Example 70 is productive of the subject keto-ester.

EXAMPLE 80
PAC Preparation of 2-(6-fluoro-6,6-dicarbethoxyhexyl)-1-methoximino-2-cyclopentene

An ethanolic solution of sodium ethoxide, prepared from 0.389 g. of sodium and 40 ml. of absolute ethanol, is treated at ambient temperatures with 5.05 g. of 2-(6,6-dicarbethoxyhexyl)-1-methoximino-2-cyclopentene (Example 61). The resulting solution is cooled to -20°C and then treated with a stream of perchloryl fluoride until the mixture becomes neutral. The excess perchloryl fluoride is removed with a stream of nitrogen and the mixture is retreated with 10 ml. of an ethanol solution of sodium ethoxide (from 0.350 g. of sodium) and then with perchloryl fluoride until the mixture becomes neutral. The excess perchloryl fluoride is removed with a stream of nitrogen and the mixture is filtered an evaporated to an oil. The latter is partitioned between ether and water and the organic phase is washed with saturated saline, dried (Na2 SO4) and evaporated to afford the subject compound.

EXAMPLE 81
PAC Preparation of 2-(6-carbo-n-butoxyhexyl)cyclopent-2-en-1-one

A solution of 50 g. of 2-(6-carboxyhexyl)cyclopent-2-en-1-one [Bagli et al., Tertrahedron Letters, No. 5, 465 (1966)] in 400 ml. of n-butanol containing 2.7 g. of p-toluenesulfonic acid monohydrate is allowed to stand at room temperature in a stoppered flask for about 24 hours. The solution is taken to dryness. The residue is taken up in ether and the ethereal solution is washed several times with saline solution, dried with anhydrous magnesium sulfate, and taken to dryness to afford the subject butyl ester.

EXAMPLES 82-84

Treatment of 2-(6-carboxyhexyl)cyclopent-2-en-1-one by the procedure of Example 81 with the appropriate alcohol affords the esters of the following table.

TABLE IV
______________________________________
Example
Alcohol Product Ester
______________________________________
82 isopropanol
2-(6-carboisopropoxyhexyl)cyclopent-2-
en-1-one
83 methanol 2-(6-carbomethyoxyhexyl)cyclopent-2-en-
1-one
84 1-hydroxy-
2-(6-carbo-n-decyloxyhexyl)cyclopent-2-
n-decane en-1-one
______________________________________
EXAMPLE 85
PAC Preparation of diethyl (5-chloro-1,1-dimethylpentyl)malonate

To magnesium (71 g. 2.92 moles) under 1 l. of ether containing a few crystals of iodine is added dropwise 1-chloro-4-bromobutane (500 g., 2.92 moles) over a period of 30 minutes with stirring under nitrogen. The reaction is maintained at a temperature of 0°C to 5°C by immersing in an acetone-Dry Ice bath periodically. After stirring for 30 minutes at room temperature, the solution is chilled to below 0°C and is then transferred to a dropping funnel from which it is added dropwise to diethyl isopropylidene malonate (440 g., 2.19 moles) [A.C. Cope and E. M. Hancock, J.A.C.S. 60, 2644 (1938)] dissolved in 1000 ml. of ether containing the tri(n-butyl)phosphine complex of copper (I) iodide (57 g.) [G. B. Kaufman and L. A. Teter, Inorganic Synthesis, 7, 9(1963)] at -10°C with stirring under nitrogen over a period of 2 hours. After stirring at room temperature for 4 hours, the reaction mixture is poured into cold dilute hydrochloric acid and is extracted with ether. The combined ether extracts are washed with saline solution, dried over magnesium sulfate, and concentrated in vacuo to give 700 g. of crude amber oil, which is distilled under vacuum to yield two fractions: 212.4 g. with b.p. at 110° - 135°C at 0.3 mm. and 100.0 g. with b.p. at 135° -145°C at 0.3 mm. The total yield is 312.4 g. (49%).

EXAMPLE 86
PAC Preparation of 3,3-dimethyl-7-chloroheptanoic acid

A mixture containing diethyl 5-(5-chloro-1,1-dimethylpentyl)malonate (648 g., 2.22 moles) potassium hydroxide (460 g. and eight liters of 1:1 isopropanol:water is stirred at room temperature overnight. Most of the isopropanol is distilled and the residue is diluted with water, and then carefully acidified with conc. hydrochloric acid. The mixture is extracted with ether and the extracts are washed with water and saline, dried over magnesium sulfate and concentrated in vacuo to give 548 g. of crude oil. The oil is dissolved in three liters of diglyme which is heated under reflux for sixteen hours. About 2.7 l. of solvent is distilled, and the remainder is diluted with water and extracted with ether. The extracts are washed with saline, dried over magnesium sulfate and concentrated in vacuo to give 428 g. of crude oil (99%).

EXAMPLE 87
PAC Preparation of ethyl 3,3-dimethyl-7-chloroheptanoate

To a solution of 3,3-dimethyl-7-chloroheptanoic acid (428 g., 2.21 moles) in 3 l. of chloroform containing 3 ml. of N,N-dimethylformamide is added 500 ml. of thionyl chloride and the resulting solution is tested under reflux for 3 hours. The reaction solution then is concentrated in vacuo and the residual acid chloride is dissolved in a minimum amount of benzene and added slowly to a solution containing 1260 ml. of 95% ethanol and 2520 ml. of benzene and 390 ml. of collidine. After heating under reflux for one hour, the solution is concentrated and the residue is dissolved in ether washed with water, dilute sodium bicarbonate solution and saline solution, dried over magnesium sulfate and concentrated to give 415 g. of crude oil, which is distilled under vacuum to yield two fraction 46.6 g. boiling at 75°C (0.3 mm.) and 236.7 g. boiling at 75° -80°C (0.3 mm). The total yield is 283.3 g. (60%) and the product is indicated to be 95% pure by g.l.c.

EXAMPLE 88
PAC Preparation of methyl/ethyl 2-(6-carbethoxy-5,5-dimethylhexyl) cyclopentanone-2-carboxylate

Sodium hydride (67 g., 1.55 moles) is placed in a three l. round-bottom flask and to this is added 1.1 liters of glyme from a dropping funnel under nitrogen flow and with stirring. To the resulting grayish mixture is added the 2-carbalkoxycyclopentanone (mixed methyl and ethyl esters) dropwise over a period of 45 minutes with nitrogen flow whilst the temperature is maintained in the range of 40°-55° . Ethyl 3,3-dimethyl-7-chloroheptanoate (283 g., 1.28 moles) and potassium iodide (195 g., 1.32 moles) are added and the mixture is heated at reflux overnight. After most of the solvent is distilled, the residue is made acidic with dilute hydrochloric acid and is then extracted with ether. The ether extracts are washed with water and saline solution, dried over magnesium sulfate, and concentrated in vacuo to 500 g. of crude yellow oil, which is distilled to give 405 g. (94% yield) of oil with b.p. 140°-180° (0.8 mm).

EXAMPLE 89
PAC Preparation of 7-(2-cyclopentanone)-3,3 -dimethylheptanoic acid

Methyl/Ethyl 2-(6-carbethoxy-5,5-dimethylhexyl) cyclopentanone-2-carboxylate (200 g., 0.6 moles), glacial acetic acid (180 ml) and 240 ml. of diluted hydrochloric acid, prepared from 100 ml. of conc. hydrochloric acid and 300 ml. of water, are placed in a 2 l. flask, containing a reflux condenser and a magnetic stirrer. The mixture then is stirred at reflux for 24 hours. The reaction mixture is cooled, 1 l. of water is added and the mixture is extracted several times with benzene. The organic extracts are combind, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to an oil (173.5 g.). The oil is rendered basic with sodium hydroxide solution, extracted with benzene and made acidic with hydrochloric acid and reextracted with benzene several times. The benzene layers are combined and washed with water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to yield 109.8 g. (78%) of crude oil, which was used without further purification in the next step.

EXAMPLE 90
PAC Preparation of ethyl 7-(2-cyclopentanone)-3,3-dimethylheptanoate

To a solution of 7-(2-cyclopentanone)-3,3-dimethylheptanoic acid (45 g., 0.22 mol.) in 285 ml. of chloroform containing three drops of N,N-dimethylformamide is added dropwise 25 ml. of thionyl chloride. The solution is stirred at room temperature for 20 minutes, the solvent is removed at reduced pressure and the residual acid chloride is dissolved in a minimum amount of benzene and added slowly to a solution containing 115 ml. of ethanol, 230 ml. benzene and 30 ml. of collodine. This solution is heated under reflux for 15 minutes and then concentrated. The residue is dissolved in ether, washed with water, diluted sodium bicarbonate solution and saline solution, dried over magnesium sulfate and concentrated to give 51 g. of crude oil. Distillation gives 40 g. (67%) b.p. 135-145 (0.1 mm.) of oil.

EXAMPLE 91
PAC Preparation of 1-acetoxy-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopent-1-ene

A solution of ethyl 7-(2-cyclopentanone)-3,3-dimethylheptanoate (90g., 0.336 mol.) and p-toluenesulfonic acid (0.94 g.) in 250 ml. of acetic anhydride is heated to boiling under partial reflux, allowing distillate at 118° or less (i.e. acetic acid) to escape thru a Vigreux column equipped with a condenser to collect the distillate. After ten hours 130 ml. of distillate is collected. Another 50 ml. of acetic anhydride is added and the reaction is heated for 5 more hours; an additional 125 ml. of acetic anhydride is added, the reaction is heated for 7 more hours; finally another 50 ml. of acetic anhydride is added and heating is continued for 4 more hours. The solution is cooled and poured (cautiously) into a cold (0°-5°) mixture of saturated aqueous sodium bicarbonate (400 ml.) and hexane (250 ml.). The resulting cold mixture is stirred for 30 minutes during which time portions of solid sodium bicarbonate are added periodically until carbon dioxide evalution ceases. The hexane layer is separated and washed with saturated sodium chloride solution until the washings are neutral, dried over magnesium sulfate and treated with Darco decolorizing charcoal for clarification and then evaporated to dryness leaving an amber colored oil (87.5 g., 84%).

EXAMPLE 92
PAC Preparation of 2-(6 -carboxy-5,5-dimethylhexyl)cyclopent-2-en-1-one

To a rapidly stirred mixture of 1-acetoxy-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopent-1-ene (35 g., 0.113 mole) chloroform (95 ml.), water (125 ml.) and calcium carbonate (11.8 g.) cooled in an ice-bath is added dropwise over a period of thirty minutes a solution of bromine (18.8 g.) in carbon tetrachloride (31 ml.). After stirring in the cold for an additional 45 minutes the orange colored chloroform layer is separated and washed with dilute sodium bisulfite and saturated saline solution, dried over magnesium sulfate and taken to dryness in vacuo (bath temperature: 35°-40°) leaving an amber colored oil. A slurry of 100 ml. of N,N-dimethylacetamide and 16.5 g. of CaCO3 is stirred and heated to reflux under nitrogen flow. The above dried oil is added from a dropping funnel rapidly, maintaining reflux and nitrogen flow for 30 minutes. The cooled reaction mixture is filtered, and the precipitate is washed with ether. The filtrate is poured into two liters ice-cold water and is extracted with ether. The combined extracts and washing is washed with water, saturated saline, treated with decolorizing charcoal, filtered. The solvent evaporated in vacuo to give 24 g. (77%) of subject product.

EXAMPLE 93
PAC Preparation of 4-bromo-2-(6-carboxyhexyl)cyclopent-2-en-1-one

A stirred mixture of 35.9 g. (0.171 moles) of 2-(6-carboxyhexyl)cyclopent-2-en-1-one [Bagli et al., Tetrahedron Letters, No. 5, 465 (1966)], 35.0 g. (0.197 moles) of N-bromosuccinimide, and 600 ml. of carbon tetrachloride is refluxed for 35 minutes. The mixture is cooled to 5°C and filtered. The filtrate is washed with cold water, dried over magnesium sulfate, and taken to dryness to give an oil, λ max.MeOH = 225 mμ (8850); ν max. = 1705 (carbonyl groups) and 1625. cm-1 (olefin group).

EXAMPLES 94-118

In the manner of the preceding Example 93, the various cyclopentenones of Table V, which follows, are converted to the corresponding 4-bromo derivatives.

TABLE V
______________________________________
Starting
Cyclopentenone
Ex. of Example Product 4-Bromocyclopentenone
______________________________________
94 13 4-bromo-2-(6-carbethoxyhexyl)-
cyclopent-2-en-1-one
95 83 4-bromo-2-(6-carbomethoxyhexyl)-
cyclopent-2-en-1-one
96 15 4-bromo-2-(4-carbethoxybutyl)-
cyclopent-2-en-1-one
97 14 4-bromo-2-(3-carbethoxypropyl)-
cyclopent-2-en-1-one
98 2 4-bromo-2-(4-carboxybutyl)cyclo-
pent-2-en-1-one
99 5 4-bromo-2-(3-carboxypropyl)cyclo-
pent-2-en-1-one
100 22 4-bromo-2-(8-carboxyoctyl)cyclo-
pent-2-en-1-one
101 23 4-bromo-2-(8-carbethoxyoctyl)cyclo-
pent-2-en-1-one
102 30 4-bromo-2-(6-carboxyoctyl)cyclo-
pent-2-en-1-one
103 31 4-bromo-2-(6-carbethoxyoctyl)cy-
clopent-2-en-1-one
104 92 4-bromo-2-(6-carboxy-5,5-dimethyl-
hexyl)cyclopent-2-en-1-one
105 41 4-bromo-2-(6-carbethoxy-5,5-di-
methylhexyl)cyclopent-2-en-1-one
106 45 4-bromo-2-(6-carboxy-5-oxahexyl)-
cyclopent-2-en-1-one
107 46 4-bromo-2-(6-carbethoxy-5-oxahexyl)-
cyclopent-2-en-1-one
108 69 4-bromo-2-(6-carboxy-6-fluorohexyl)-
cyclopent-2-en-1-one
109 70 4-bromo-2-(6-carbethoxy-6-fluoro-
hexyl)cyclopent-2-en-1-one
110 52 4-bromo-2-(5-carboxypentyl)cyclo-
pent-2-en-1-one
111 53 4-bromo-2-(5-carbethoxypentyl)cy-
clopent-2-en-1-one
112 73 4-bromo-2-(7-carboxyheptyl)cyclo-
pent-2-en-1-one
113 74 4-bromo-2-(7-carbethoxyheptyl)-
cyclopent-2-en-1-one
114 78 4-bromo-2-(6-carboxy-6-phenyl-
hexyl)cyclopent-2-en-1-one
115 79 4-bromo-2-(6-carbethoxy-6-phenyl-
hexyl)cyclopent-2-en-1-one
116 81 4-bromo-2-(6-carbo-n-butoxyhexyl)-
cyclopent-2-en-1-one
117 82 4-bromo-2-(6-carbo-isopropoxy-
hexyl)-cyclopent-2-en-1-one
118 84 4-bromo-2-(6-carbo-n-decyloxy-
hexyl)cyclopent-2-en-1-one
118a 272 4-bromo-2-(6-carboxyheptyl)-cyclo-
pent-2-en-1-one
______________________________________
EXAMPLE 119
PAC Preparation of 4-hydroxy-2-(8-carboxyoctyl)cyclopent-2-en-1-one

To a stirred solution of 57.2 g. of crude 4-bromo-2-(8-carboxyoctyl)cyclopent-2-en-1-one (Example 100) in 500 ml. of acetone and 325 ml. of water at 3°C is added 44.1 g. (0.226 moles) of silver fluoborate during a 15 minute period. The mixture is stirred at 0°-3°C for 2 hours and filtered. The filtrate is diluted with water, saturated with solid sodium chloride, and extracted with ether. The extract is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. Partition chromatography of the residue on Celite gives white crystals, m.p. 58°-66° C., λ max.MeOH = 223 mμ (7800); ν max (KBR) = 3340 (hydroxyl groups), 1705 (carbonyl groups), and 1625 cm-1 (olefin group).

EXAMPLE 120
PAC Preparation of 4-acetoxy-2-(6-carbethoxyhexyl)cyclopent-2-en-1-one

A mixture of 51.6 g. (0.137 moles) of crude 4-bromo-2-(6-carbethoxyhexyl)cyclopent-2-en-1-one (Example 94), 27 g. (0.162 moles) of silver acetate, and 200 ml. of glacial acetic acid is stirred at reflux for 4.5 hours. The mixture is cooled, and solids are removed by filtration. The filtrate is concentrated and extracted with hot hexane. The extract is washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated to give an oil. The crude product is distilled at reduced pressure to give a liquid, b.p. 152°-163°C (0.01 mm); λ max.MeOH = 223 mμ (10700); ν max. = 1745 (ester carbonyl groups), 1725 (ketone carbonyl groups), and 1235 cm-1 (acetoxy group).

EXAMPLE 121
PAC Preparation of 4-hydroxy-2-(6-carboxyhexyl)cyclopent-2-en-1-one

To a stirred solution of 6.91 g. (50 mmoles) of potassium carbonate in 1400 ml. of methanol and 1400 ml. of water containing 100 mg. of hydroquinone is added 14.8 g. (50 mmoles) of 4-acetoxy-2-(6-carbethoxyhexyl)cyclopent-2-en-1-one (Example 120) during one minute at room temperature under nitrogen. The solution is stirred for 90 minutes and at this stage it contains 4-hydroxy-2-(6-carbethoxyhexyl)cyclopent-2-en-1-one. It is then treated with 23.6 g. (75 mmoles) of barium hydroxide octahydrate during one minute. The mixture is stirred for 60 minutes and then is concentrated at reduced pressure to a volume of 1800 ml. during one hour. The solution is diluted with 300 ml. of water, saturated with sodium chloride, and stirred with 400 ml. of ether while 70 ml. of 4N hydrochloric acid is added. The aqueous phase is extracted with additional ether, and the combined organic phases are washed with saturated sodium chloride solution. The extract is dried over magnesium sulfate. The crude product obtained after evaporation of the solvents is purified by chromatography on silica gel to give an oil, λ max.MeOH = 223 mμ (7360); ν max. = 3380 (hydroxyl groups), 1710 (carbonyl groups), and 1632 cm-1 (olefin group).

EXAMPLE 122
PAC Preparation of 2-(6-carboxyhexyl)-4-hydroxy-cyclopent-2-en-1-one

To a stirred solution of 10.6 g. (ca. 34 mmoles) of crude 4-bromo-2-(6-carboxyhexyl)cyclopent-2-en-1-one (Example 93) in 100 ml. of acetone and 65 ml. of water is added 8.80 g. (45.2 mmoles) of silver fluoborate during 2 minutes. The temperature is maintained at 25°-30°C by external cooling. The mixture is stirred for 90 minutes, filtered, saturated with sodium chloride, and extracted with ether. The extract is extracted with half saturated sodium bicarbonate solutions. The basic solutions is reacidified with dilute hydrochloric acid, saturated with sodium chloride, and extracted with ether. The extract is washed with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The crude product is purified by partition chromatography on Celite to give an oil with the properties described in Example 121.

EXAMPLES 123-146

By the procedure of the preceding Example 122 the various 4-bromocyclopentenones of the following Table VI are solvolyzed in acetone-water in the presence of silver fluoborate to provide the 4-hydroxycyclopentenones of the Table.

TABLE VI
______________________________________
Starting
cyclopentenones
Product
Example
of Example 4-hydroxycyclopente-2-en-ones
______________________________________
123 94 4-hydroxy-2-(6-carbethoxyhexyl)-
cyclopent-2-en-1-one
124 95 4-hydroxy-2(6-carbomethoxyhexyl)-
cyclopent-2-en-1-one
125 96 4-hydroxy-2-(4-carbethoxybutyl)-
cyclopent-2-en-1-one
126 97 4-hydroxy-2-(3-carbethoxypropyl)-
cyclopent-2-en-1-one
127 98 4-hydroxy-2-(4-carboxybutyl)-
cyclopent-2-en-1-one
128 99 4-hydroxy-2-(3-carboxypropyl)-
cyclopent-2-en-1-one
129 101 4-hydroxy-2-(8-carbethoxyoctyl)-
cyclopent-2-en-1-one
130 102 4-hydroxy-2-(6-carboxyoctyl)-
cyclopent-2-en-1-one
131 103 4-hydroxy-2-(6-carbethoxyoctyl)-
cyclopent-2-en-1-one
132 104 4-hydroxy-2-(6-carboxy-5,5-di-
methylhexyl)cyclopent-2-en-1-one
133 105 4-hydroxy-2-(6-carbethoxy-5,5-
dimethylhexyl)cyclopent-2-en-1-
one
134 106 4-hydroxy-2-(6-carboxy-5-oxa-
hexyl)cyclopent-2-en-1-one
135 107 4-hydroxy-2-(6-carbethoxy-5-oxa-
hexyl)cyclopent-2-en-1-one
136 108 4-hydroxy-2-(6-carboxy-6-fluoro-
hexyl)cyclopent-2-en-1-one
137 109 4-hydroxy-2-(6-carbethoxy-6-
fluorohexyl)cyclopent-2-en-1-one
138 110 4-hydroxy-2-(5-carboxypentyl)-
cyclopent-2-en-1-one
139 111 4-hydroxy-2-(5-carbethoxypentyl)-
cyclopent-2-en-1-one
140 112 4-hydroxy-2-(7-carboxyheptyl)-
cyclopent-2-en-1-one
141 113 4-hydroxy-2-(7-carbethoxyheptyl)-
cyclopent-2-en-1-one
142 114 4-hydroxy-2-(6-carboxy-6-phenyl-
hexyl)cyclopent-2-en-1-one
143 115 4-hydroxy-2-(6-carbethoxy-6-
phenylhexyl)cyclopent-2-en-1-
one
144 116 4-hydroxy-2-(6-carbo-n-butoxy-
hexyl)cyclopent-2-en-1-one
145 117 4-hydroxy-2-(6-carbo-isopropoxy-
hexyl)cyclopent-2-en-1-one
146 118 4-hydroxy-2-(6-carbo-n-decyloxy-
hexyl)cyclopent-2-en-1-one
146a 118a 4-hydroxy-2-(6-carboxyheptyl)-
cyclopent-2-en-1-one
______________________________________
EXAMPLE 147
PAC Preparation of 4-tetrahydropyranyloxy-2-(6-tetrahydropyranylcarboxyhexyl)cylopent-2-en-1- one

To a stirred solution of 5.59 g. (24.6 mmoles) of 4-hydroxy-2-(6-carboxyhexyl)cyclopent- 2-en-1one (Example 122) and 20.7 g. (246 mmoles) of dihydropyran in 100 ml. of methylene chloride at 20°C is added 47 mg. (0.246 mmoles) of p-toluenesulfonic acid monohydrate in one portion. The temperature is maintained at 20°-25°C by cooling and is stirred for one hour at that temperature. The solution is diluted with 200 ml. of ether and poured into a mixture of 40 ml. of saturated sodium bicarbonate solution, 40 ml. of saturated sodium chloride solution, and 80 ml. of water. The phases are seaparated separated , and the aqueous phase is extracted with additional ether. The total extract is washed successively with water and saturated sodium chloride solution, dried over potassium carbonate, and freed of volatile matter by concentration at reduced pressure to give an oil, λ max.MeOH = 223 mμ (9500); ν max. 1730 (ester carbonyl group), 1705 (ketone carbonyl group), and 1030 cm-1 (tetrahydropyranyloxy groups).

EXAMPLES 148-157

By the procedure of Example 147, the various 4-hydroxycyclopentenones of Table VII, which follows, are converted to the tetrahydropyranyl 4-tetrahydropyranyloxycyclopentenone esters of the table.

TABLE VII
______________________________________
Starting Product Tetrahydropyran-2'-
4-hydroxycyclopent-
yl 4-tetrahydropyran-2'-yl'-
Example
enone of Example
oxycyclopent-2-en-1-ones
______________________________________
148 127 4-tetrahydropyran-2'-yloxy-
2-(4-carbotetrahydropyran-
2-'-yloxybutyl)cyclopent-2-
en-1-one
149 128 4-tetrahydropyran-2'-yloxy-
2-(3-carbotetrahydropyran-
2'-yloxypropyl)cyclopent-
2-en-1-one
150 119 4-tetrahydropyran-2'-yloxy-
2-(8-carbotetrahydropyran-
2'-yloxyoctyl)cyclopent-2-
en-1-one
151 130 4-tetrahydropyran-2'-yloxy-
2-(6-carbotetrahydropyran-
2'-yloxyoctyl)cyclopent-2-
en-1-one
152 132 4-tetrahydropyran-2'-yloxy-
2-(6-carbotetrahydropyran-
2'-yloxy-5,5-dimethyl)-
cyclopent-2-en-1-one
153 134 4-tetrahydropyran-2'-yloxy-
2-(6-carbotetrahydropyran-
2'-yloxy-5-oxahexyl)cyclo-
pent-2-en-1-one
154 136 4-tetrahydropyran-2'-yloxy-
2-(6-carbotetrahydropyran-
2'-yloxy-6-fluorohexyl)cy-
clopent-2-en-1-one
155 138 4-tetrahydropyran-2'-yloxy-
2-(5-carbotetrahydropyran-
2'-yloxypentyl)cyclopent-
2-en-1-one
156 140 4-tetrahydropyran-2'-yloxy-
2-(7-carbotetrahydropyran-
2'-yloxyheptyl)cyclopent-
2-en-1-one
157 142 4-tetrahydropyran-2'-yloxy-
2-(6-carbotetrahydropyran-
2'-yloxy-6-phenylhexyl)-
cyclopent-2-en-1-one
157a 146a 4-tetrahydropyran-2'-yloxy-
2-(6-carbotetrahydropyran-
2'-yloxyheptyl)-cyclopent-
2-en-1-one
______________________________________
EXAMPLE 158
PAC Preparation of 4-tetrahydropyranyloxy-2-(6-carbethoxyhexyl)cyclopent-2-en-1-one

To a stirred solution of 674 mg. (2.64 mmoles) of 4-hydroxy-2-(6-carbethoxyhexyl)cyclopent-2-en-1-one (Example 123) and 2.22 g. (26.4 mmoles) of dihydropyran in 2.6 ml. of methylene chloride is added 5.0 mg. (0.026 mmoles) of p-toluenesulfonic acid monohydrate. After stirring for 20 minutes at room temperature the solution is diluted with ether and poured into saturated sodium chloride solution containing a little sodium bicarbonate. The organic phase is separated and washed with saturated sodium chloride solution. The extract is dried over magnesium sulfate, and volatile matter is evaporated at reduced pressure to give an oil, λ max.MeOH = 224 mμ (7950); ν max. = 1735 (ester carbonyl group), 1710 (ketone carbonyl group), and 1030 cm-1 (tetrahydropyranyloxy group).

EXAMPLES 159-172

In the manner of Example 158 the alkyl 4-hydroxycyclopentenone esters of Table VIII, which follows, are converted to the corresponding 4-tetrahydropyranyloxy alkyl esters of the table.

TABLE VIII
______________________________________
Starting 4-
hydroxycyclo-
Product
pentenone Esters
4-tetrahydropyran-2'-yloxy-
Example
of Example cyclopent-2-en-1-one esters
______________________________________
159 124 4-tetrahydropyran-2'-yloxy-2-
(6-carbomethoxyhexyl)cyclopent-
2-en-1-one
160 125 4-tetrahydropyran-2'-yloxy-2-
(4-carbethoxybutyl)cyclopent-
2-en-1-one
161 126 4-tetrahydropyran-2'-yloxy-2-
(3-carbethoxypropyl)cyclo-
pent-2-en-1-one
162 129 4-tetrahydropyran-2'-yloxy-2-
(8-carbethoxyoctyl)cyclopent-
2-en-1-one
163 131 4-tetrahydropyran-2'-yloxy-2-
(6-carbethoxyoctyl)cyclopent-
2-en-1-one
164 133 4-tetrahydropyran-2'-yloxy-2-
(6-carbethoxy-5,5-dimethyl-
hexyl)cyclopent-2-en-1-one
165 135 4-tetrahydropyran-2'-yloxy-2-
(6-carbethoxy-5-oxahexyl)-
cyclopent-2-en-1-one
166 137 4-tetrahydropyran-2'-yloxy-2-
(6-carbethoxy-6-fluorohexyl)-
cyclopent-2-en-1-one
167 139 4-tetrahydropyran-2'-yloxy-2-
(5-carbethoxypentyl)cyclo-
pent-2-en-1-one
168 141 4-tetrahydropyran-2'-yloxy-2-
(7-carbethoxyheptyl)cyclopent-
2-en-1-one
169 143 4-tetrahydropyran-2'-yloxy-2-
(6-carbethoxy-6-phenylhexyl)-
cyclopent-2-en-1-one
170 144 4-tetrahydropyran-2'-yloxy-2-
(6-carbo-n-butoxyhexyl)cyclo-
pent-2-en-1-one
171 145 4-tetrahydropyran-2'-yloxy-2-
(6-carbo-isopropxyhexyl)cyclo-
pent-2-en-1-one
172 146 4-tetrahydropyran-2'-yloxy-2-
(6-carbo-n-decyloxyhexyl)-cyclo
pent-2-en-1-one
______________________________________
EXAMPLE 173
PAC Preparation of 4-methoxy-2-(6-carboxyhexyl)cyclopent-2-en-1-one

(Example 93) in 85 ml. of methanol at 0°-3°C is added 4.40 g. (22.6 mmole) of silver fluoborate in one portion. After 2 minutes, the mixture is treated with 2.66 g. (24.8 mmoles) of 2,6-lutidine. After stirring for 30 minutes at 0°-3°C the mixture is stirred at ambient temperature for 45 minutes. Silver bromide is removed by filtration, and the filtrate is concentrated to a volume of 40 ml. The solution is treated with saturated sodium chloride solution and extracted with ether. The extract is washed successively with 0.5N hydrochloric acid solution, water, and saturated sodium chloride solution; dried over magnesium sulfate; and concentrated. Partition chromatography of the residue on Celite gives an oil, λ max.MeOH = 220 mμ (7450); ν max. = 1715 (carbonyl groups) and 1095 cm-1 (methoxy group).

EXAMPLES 174-202

Alcoholysis with the appropriate alcohol of the 4-bromocyclopentenones listed in Table IX, directly following, in the manner of Example 173 provides the 4-alkoxycyclopentenones of the Table.

TABLE IX
______________________________________
Starting bromo-
cyclopentenone
Product
Example
of example 4-alkoxycyclopent-2-en-ones
______________________________________
174 94 4-ethoxy-2-(6-carbethoxyhexyl)-
cyclopent-2-en-1-one
175 95 4-methoxy-2-(6-carbomethoxyhexyl)-
cyclopent-2-en-1-one
176 96 4-propoxy-2-(4-carbethoxybutyl)-
cyclopent-2-en-1-one
177 97 4-isopropoxy-2-(3-carbethoxypro-
pyl)cyclopent-2-en-1-one
178 98 4-methoxy-2-(4-carboxybutyl)cyclo-
pent-2-en-1-one
179 99 4-ethoxy-2-(3-carboxypropyl)cyclo-
pent-2-en-1-one
180 100 4-methoxy-2-(8-carboxyoctyl)cyclo-
pent-2-en-1-one
181 101 4-isopropoxy-2-(8-carbethoxyoctyl)-
cyclopent-2-en-1-one
182 102 4-methoxy-2-(6-carboxyoctyl)cyclo-
pent-2-en-1-one
183 103 4-n-butoxy-2-(6-carbethoxyoctyl)-
cyclopent-2-en-1-one
184 104 4-methoxy-2-(6-carboxy-5,5-di-
methylhexyl)cyclopent-2-en-1-one
185 105 4-methoxy-2-(6-carbethoxy-5,5-di-
methylhexyl)cyclopent-2-en-1-one
186 106 4-methoxy-2-(6-carboxy-5-oxahexyl)-
cyclopent-2-en-1-one
187 107 4-ethoxy-2-(6-carbethoxy-5-oxa-
hexyl)cyclopent-2-en-1-one
188 108 4-methoxy-2-(6-carboxy-6-fluoro-
hexyl)cyclopent-2-en-1-one
189 109 4-propoxy-2-(6-carbethoxy-6-fluoro-
hexyl)cyclopent-2-en-1-one
190 110 4-methoxy-2-(5-carboxypentyl)cy-
clopent-2-en-1-one
191 111 4-sec-butoxy-2-(5-carbethoxypentyl)-
cyclopent-2-en-1-one
192 112 4-methoxy-2-(7-carboxyheptyl)-
cyclopent-2-en-1-one
193 113 4-methoxy-2-(7-carbethoxyheptyl)-
cyclopent-2-en-1-one
194 114 4-methoxy-2-(6-carboxy-6-phenyl-
hexyl)cyclopent-2-en-1-one
195 115 4-ethoxy-2-(6-carbethoxy-6-phenyl-
hexyl)cyclopent-2-en-1-one
196 116 4-methoxy-2-(6-carbo-n-butoxy-
hexyl)cyclopent-2-en-1-one
197 117 4-methoxy-2-(6-carbo-isopropoxy-
hexyl)cyclopent-2-en-1-one
198 118 1-methoxy-2-(6-carbo-n-decyloxy-
hexyl)cyclopent-2-en-1-one
199 93 4-ethoxy-2-(6-carboxyhexyl)cyclo-
pent-2-en-1-one
200 93 4-propoxy-2-(6-carboxyhexyl)cyclo-
pent-2-en-1-one
201 93 4-isopropoxy-2-(6-carboxyhexyl)-
cyclopent-2-en-1-one
202 93 4-n-butoxy-2-(6-carboxyhexyl)-
cyclopent-2-en-1-one
______________________________________
EXAMPLE 203
PAC Preparation of 4-tert-butoxy-2-(6-carbethoxyhexyl)cyclopent-2-en-1-one

A stirred mixture of 6.35 g. (20 mmoles) of 4-bromo-2-(carbethoxyhexyl)cyclopent-2-en-1-one (Example 94), 3.01 g. (11 moles) of silver carbonate, and 40 ml. of t-butanol is heated at 70°C for 17 hours. The mixture is cooled and filtered. After evaporation of t-butanol the residue is treated with aq. sodium chloride and extracted with 3:1 ether-hexane. The extract is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The crude product is purified by chromatography on silica gel to give, in order of elution; the subject compound as an oil; λ max.MeOH = 219 mμ (8860); ν max. = 1735 (ester carbonyl group), 1725 ketone carbonyl group), and 1365 cm-1 (tert.-butyl group); and 4-hydroxy-2-(6-carbethoxyhexyl)cyclopent-2-en-1-one also as an oil.

EXAMPLE 204
PAC Preparation of 4-(2-hydroxyethyoxy)-2-(6-carboxyhexyl)cyclopent-2-en-1-one

To a stirred solution of 19.1 g. of crude 4-bromo-2-(6-carboxyhexyl)cyclopent-2-en-1-one (Example 93) in 310 ml. of ethylene glycol is added 15.6 g. (80 mmole) of silver fluoborate during 2 minutes. The exothermic reaction is controlled to give a temperature of 29°C, and after 1 minute the mixture is treated during 1 minute with 8.6 g. (80 mmole) of 2,6-lutidine. The mixture is stirred at ambient temperature for 2 hours, diluted with water, and filtered. The filtrate is diluted with saturated sodium chloride solution and extracted with ether. The extract is washed with half-saturated sodium chloride solution containing a little hydrochloric acid and saturated sodium chloride solution. The extract is dried over magnesium sulfate and concentrated. Column chromatograph of the residue on silica gel gives an oil, λ maxMeOH = 216 mμ (8350); ν max = 3340 (hydroxyl groups), 1700 (carbonyl groups), and 1620 cm -1 (olefin group).

EXAMPLES 205-228

By the procedure described in Example 204 the various 4-bromocyclopentenones listed in Table X, which follows, are converted, to the corresponding 4(ω-hydroxyalkyl)cyclopentenones of the table.

TABLE X
______________________________________
Starting 4-bromo-
Product
cyclopentenene
4-(ω-hydroxyalkoxy)cyclopent-
Example
of example 2-en-1-ones
______________________________________
205 94 4-β-hydroxyethoxy-2-(6-car-
bethoxyhexyl)cyclopent-2-en-
1-one
206 95 4-β-hydroxyethoxy-2-(6-carbo-
methoxyhexyl)cyclopent-2-en-
1-one
207 96 4-μ-hydroxypropoxy-2-(4-oar-
bethoxybutyl(cyclopent-2-en-
1-one
208 97 4-β-hydroxyethoxy-2-(3-car-
bethoxypropyl(cyclopent-2-en-
1-one
209 98 4-β-hydroxyethoxy-2-(4-car-
boxybutyl(cyclopent-2-en-1-
one
210 99 4-β-hydroxyethoxy-2-(3-car-
boxypropyl)cyclopent-2-en-1-one
211 100 4-βhydroxyethoxy-2-(8-car-
boxyoctyl)cyclopent-2-en-1-one
212 101 4-β-hydroxyethoxy-2-(8-oar-
bethoxyoctyl)cyclopent-2-en-
1-one
213 102 4-β-hydroxyethoxy-2-(6-oar-
boxyoctyl)cyclopent-2-en-1-one
214 103 4-γ-hydroxypropoxy-2-(6-car-
bethoxyoctyl)cyclopent-2-en-
1-one
215 104 4-β-hydroxyethoxy-2-(6-car-
boxy-5,5-dimethylhexyl)cyclo-
pent-2-en-1-one
216 105 4-β-hydroxyethoxy-2-(6-car-
bethoxy-5,5,-dimethylhexyl)-
cyclopent-2-en-1-one
217 106 4-β-hydroxyethoxy-2-(6-car-
boxy-5-oxahexyl)cyclopent-2-
en-1-one
218 107 4γ-hydroxypropoxy-2-(6-car-
bethoxy-5-oxahexyl)cyclopent-
2-en-1-one
219 108 4-β-hydroxyethoxy-2-(6-car-
boxy-6-fluorohexyl)cyclo-
pent-2-en-1-one
230 109 4-β-hydroxyethoxy-2-(6-car-
bethoxy-6-fluorohexyl)cyclo-
pent-2-en-1-one
221 110 4-β-hydroxyethoxy-2-(5-car-
boxypentyl)cyclopent-2-en-
1-one
222 112 4-β-hydroxyethoxy-2-(7-car-
boxyheptyl)cyclopent-2-en-1-
one
223 114 4-β-hydroxyethoxy-2-(6-car-
boxy-6-phenylhexyl)cyclo-
pent-2-en-1-one
224 115 4-β-hydroxyethoxy-2-(6-car-
bethoxy-6-phenylhexyl)cyclo-
pent-2-en-1-one
225 116 4-β-hydroxyethoxy-2-(6-carbo-
n-butoxyhexyl)cyclopent-2-
en-1-one
236 117 4-β-hydroxyethoxy-2-(carbo-
isopropoxyhexyl)cyclopent-2-
en-1-one
227 118 4-β-hydroxyethoxy-2-(6-carbo-
n-decyloxyhexyl)cyclopent-2-
en-1-one
228 93 4-β-hydroxypropoxy-2-(6-car-
boxyhexyl)cyclopent-2-en-1-
one
______________________________________
EXAMPLES 229-242

By the procedure described in Example 147 the 4-alkoxycyclopentenone carboxylic acis acids listed in Table XI were converted to the corresponding tetrahydropyran-2'-yl esters of the table.

TABLE XI
______________________________________
Starting 4 alkoxy-
cyclopentenone
Product
Ex- carboxylic acid
Tetrahydropyran-2'yl ester
ample of example 4-alkocycyclopent-1-ones
______________________________________
229 178 4-methoxy-2-(4-carbotetra-
hydropyran-2'yloxybutyl)-
cyclopent-2-en-1-one
230 179 4-ethoxy-2-(3-carbotetra-
hydropyran-2'yloxypropyl)-
cyclopent-2-en-1-one
231 180 4-methoxy-2-(8-carbotetra-
hydropyran-2'yloxyoctyl)-
cyclopent-2-en-1-one
232 182 4-methoxy-2-(6-carbotetra-
hydropyran-2'-yloxyoctyl)-
cyclopent-2-en-1-one
233 184 4-methoxy-2-(6-carbotetra-
hydropyran-2'-yloxy-5,5-
dimethylhexyl)cyclopent-2-
en-1-one
234 186 4-methoxy-2-(6-carbotetra-
hydroxypyran-2'-yloxy-5-oxa-
hexyl)cyclopent-2-en-1-one
235 188 4-methoxy-2-(6-carbotetra-
hydropyran-2'-yloxy-6-fluoro-
hexyl)-cyclopent-2-en-1-one
236 190 4-methoxy-2-(5-carbotetra-
hydropyran-2'-yloxy-pentyl)-
cyclopent-2-en-1-one
237 192 4-methoxy-2-(7-carbotetra-
hydropyran-2'-yloxyheptyl)-
cyclopent-2-en-1-one
238 194 4-methoxy-2-(6-carbotetrahydro-
pyran-2'-yloxy-6-phenylhexyl)-
cyclopent-2-en-1-one
239 199 4-ethoxy-2-(6-carbotetrahydro-
pyran-2'-yloxyhexyl)cyclopent-
2-en-1-one
240 200 4-propoxy-2-(6-carbotetrahydro-
pyran-2'-yloxyhexyl)cyclopent-
2-en-1-one
241 201 4-isopropoxy-2-(6-carbotetra-
hydropyran-2'-yloxyhexyl)cyclo-
pent-2-en-1-one
242 202 4-n-butoxy-2-(6-carbotetra-
hydropyran-2'-yloxyhexyl)cyclo-
pent-2-en-1-one
242a 173 4-methoxy-2-(6-carbotetrahydro-
pyran-2'-yloxyhexyl)cyclopent-
2-en-1-one
______________________________________
EXAMPLES 243-266

Treatment of the 4-(ω-hydroxyalkoxy)cyclopentenones of Table XII below with dihydropyran in the manner of Example 147 provides the 4-(ω-tetrahydropyranyloxyalkoxy)-cyclopentenone esters listed in the table.

TABLE XII
______________________________________
Starting 4-(ω-
Product
hydroxyalkoxy)-
4-(ω-tetrahydropyran-2'-yloxy-
cyclopentenone
alkoxy)-cyclopent-2-en-1-one
Example
of example esters
______________________________________
243 205 4-β-tetrahydropyrany-2'-yloxy-
ethoxy-2-(6-carbethoxyhexyl)-
cyclopent-2-en-1-one
244 206 4-β-tetrahydropyrany-2'-yloxy-
ethoxy-2-(6-carbomethoxyhexyl)-
cyclopent-2-en-1-one
245 207 4-γ-tetrahydropyran-2'-yloxy-
propoxy-2-(4-carbethoxybutyl)-
cyclopent-2-en-1-one
246 208 4-β-tetrahydropyran-2'-yloxy-
ethoxy-2-(3-carbethoxypropyl)-
cyclopent-2-en-1-one
247 204 4-β-tetrahydropyran-2'-yloxy-
ethoxy-2-(6-carbotetrahydro-
pyran-2'-yloxyhexyl)cyclopent-
2-en-1-one
248 209 4-β-tetrahydropyran-2'-yloxy-
ethoxy-2-(4-carbotetrahydro-
pyran-2'-yloxybutyl)cyclopent-
2-en-1-one
249 210 4-β-tetrahydropyran-2'-yloxy-
ethoxy-2-(3-carbotetrahydro-
pyran-2'-yloxypropyl)cyclopent-
2-en-1-one
250 212 4-β-tetrahydropyran-2'-yloxy-
ethoxy-2-(8-carbethoxyoctyl)-
cyclopent-2-en-1-one
251 211 4-β-tetrahydropyran-2'-yloxy-
ethoxy-2-(8-carbotetrahydro-
pyran-2'-yloxyoctyl)cyclopent-
2-en-1-one
252 213 4-β-tetrahydropyran-2'-yloxy-
ethoxy-2-(6-carbotetrahydro-
pyran-2'-yloxyoctyl)cyclopent-
2-en-1-one
253 214 4-γ-tetrahydropyran-2'-yloxy-
propoxy-2-(6-carbethoxyoctyl)-
cyclopent-2-en-1-one
254 215 4-β-tetrahydropyran-2'-yloxy-
ethoxy-2-(6-carbotetrahydro-
pyran-2'-yloxy-5,5-dimethyl-
hexyl)cyclopent-2-en-1-one
255 216 4-β-tetrahydropyran-2'-yloxy-
ethoxy-2-(6-carbethoxy-5,5-d-
methylhexyl)cyclopent-2-en-1-one
256 217 4-β-tetrahydropyran-2'-yloxy-
ethoxy-2-(6-carbotetrahydro-
pyran-2-yloxy-5-oxahexyl)cy-
clopent-2-en-1-one
257 218 4-γ-tetrahydropyran-2'-yloxy-
propoxy-2-(6-carbethoxy-5-
oxahexyl(cyclopent-2-en-1-one
258 219 4-β-tetrahydropyran-2'-yloxy-
ethoxy-2-(6-carbotetrahydro-
pyran-2'-yloxy-6-fluorohexyl)-
cyclopent-2-en-1-one
259 220 4-β-tetrahydropyran-2'-yloxy-
ethoxy-2-(6-carbethoxy-6-fluoro-
hexyl)cyclopent-2-en-1-one
260 221 4-β-tetrahydropyran-2'-yloxy-
ethoxy-2-(5-carbotetrahydro-
pyran-2'-yloxpentyl(cyclopent-
2-en-1-one
261 222 4-β-tetrahydropyran-2'-yloxy-
ethoxy-2-(7-carbotetrahydro-
pyran-2'-yloxheptyl)cyclopent-
2-en-1-one
262 223 4-β-tetrahydropyran-2'-yloxy-
ethoxy-2-(6-carbotetrahydro-
pyran-2'-yloxy-6-phenylhexyl)-
cyclopent-2-en-1-one
263 224 4-β-tetrahydropyran-2'-yloxy-
ethoxy-2-(6-carbethoxy-6-phenyl-
hexyl)cyclopent-2-en-1-one
264 225 4-β-tetrahydropyran-2'-yloxy-
ethoxy-2-(6-carbo-n-butoxy-
hexyl)cyclopent-2-en-1-one
265 226 4-β-tetrahydropyran-2'-yloxy-
ethoxy-2-(6-carbo-isopropoxy-
hexyl)cyclopent-2-en-1-one
266 227 4-β-tetrahydropyran-2'-yloxy-
ethoxy-2-(6-carbo-n-decyloxy-
hexyl)cyclopent-2-en-1-one
267 228 4-β-tetrahydropyran-2'-yloxy-
propoxy-2-(6-carbotetrahydro-
pyran-2'-yloxhexyl)cyclopent-
2-en-1-one
______________________________________
EXAMPLE 268
PAC Preparation of 4-(4-hydroxybutoxy)-2-(6-carboxyhexyl)-cyclopent-2-en-1-one

To a stirred solution of 56.0 g. of crude 4-bromo-2-(6-carboxyhexyl)cyclopent-2-en-1-one (Example 93) in 400 ml. of tetrahydrofuran and 133 ml. of water at 3°C is added 44.1 g. (0.226 moles) of silver fluoborate during 25 minutes. The mixture is stirred at 0°-5°C for 60 minutes, diluted with water and ether, and filtered. The aqueous portion of the filtrate is saturated with solid sodium chloride and extracted with additional ether. The combined organic phases and washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. Column chromatography of the residue gives the subject compound as a mixture with 4-hydroxy-2-(6-carboxyhexyl)cyclopent-2-en-1-one. NMR (CDCl3) 3.60 (multiplet, O-methylene hydrogens) and 4.60 f (multiplet, O-methine hydrogen).

EXAMPLE 269
PAC Preparation of 4-(4-tetrahydropyranyloxybutoxy)-2-(6-tetrahydropyranylcarboxyhexyl)cyclop ent-2-en-1-one

In the manner of Example 147 the mixture of 4-hydroxy-2-(6-carboxyhexyl)cyclopent-2-en-1-one and 4-(4-hydroxybutoxy)-2-(6-carboxyhexyl)cyclopent-2-en-1-one (Example 268) is converted to a mixture of the subject compound and 4-tetrahydropyranyloxy-2-(6-tetrahydropyranylcarboxyhexyl)cyclopent-2-en-1 -one with dihydropyran and p-toluenesulfonic acid monohydrate in methylene chloride.

EXAMPLE 270
PAC Preparation of 2-(6,6-dicarbethoxyheptyl)-2-cyclopentenone methoxime

The subject compound is prepared from sodio diethyl methylmalonate and 2-(5-methanesulfonyloxypentyl)-2-cyclopentenone methoxime (Example 60) by the procedure described in Example 61.

EXAMPLE 271
PAC Preparation of 2-(6-carboxyheptyl)-2-cyclopentenone methoxime

Saponification of 2-(6,6-dicarbethoxyheptyl)-2-cyclopentenone methoxime (Example 270) with potassium hydroxide by the method of Example 20 is productive of 2-(6,6-dicarboxyheptyl)-2-cyclopentenone methoxime, decarboxylation of which in the manner of Example 63 provides the subject compound.

EXAMPLE 272
PAC Preparation of 2-(6-carboxyheptyl)-2-cyclopentenone

Methoxime cleavage of 2-(6-carboxyheptyl)-2 (Example 271) in the manner of Example 22 provides the subject ketone.

EXAMPLE 273
PAC Preparation of 2-(6-carbethoxyheptyl)-2-cyclopentenone

Esterification with ethanol of the acid chloride derived from 2-(6-carboxyheptyl)-2-cyclopentenone in the manner of Example 31 is productive of the subject compound.

EXAMPLE 274
PAC Preparation of 2-(6-carbethoxy-5-thiahexyl)-1-methoximino-2-cyclopentene

To a stirred mixture of 1.465 g. (0.0348 mole) of sodium hydride (57.2% in mineral oil) in 50 ml. of dimethoxyethane, under nitrogen, is added slowly 4.8 g. (0.0347 mole) of ethyl-2-mercaptoacetate. The reaction mixture is stirred at room temperature for one hour and then a solution of 7.8 g. (0.0231 mole) of 2-(4p-toluenesulfonyloxybutyl)-1-methoximino-2-cyclopentene in 30 ml. of dimethoxyethane is added dropwise and stirred at room temperature for 18 hours. The solution is heated at reflux for 1 hour, cooled and poured into cold dilute hydrochloric acid and then extracted with ether. The combined ether extracts are washed with saline, dried over magnesium sulfate and evaporated to give 7.6 g. of subject product as a yellow oil.

EXAMPLE 275
PAC Preparation of 2-(6-carboxy-5-thiahexyl)-2-cyclopentenone

In the manner described in Example 22, treatment of 2-(6-carbethoxy-5-thiahexyl)-1-methoximino-2-cyclopentene with acetone and 2N hydrochloric acid at reflux gives the subject product as a yellow oil.

EXAMPLE 276
PAC Preparation of 2-(6-carbethoxy-5-thiahexyl)-2-cyclopentenone

In the manner described in Example 23, treatment of 2-(6-carboxy-5-thiahexyl)-2-cyclopentenone with p-toluenesulfonic acid in ethanol gives the subject ester as a yellow oil.

EXAMPLE 277
PAC Preparation of 1-triphenylmethoxy-5-hexyne

A stirred mixture of 9.81 g. (0.10 moles) of 5-hexyn-1-ol, 33.5 g. (0.12 moles) of triphenylmethyl chloride, and 200 ml. of dry pyridine is refluxed for 60 minutes. The cooled mixture is poured into water and extracted with ether. The extract is washed successively with water, ice-cold N hydrochloric acid, water, saturated sodium bicarbonate solution, and saturated sodium chloride solution. The extract is dried with magnesium sulfate. The crude product obtained after evaporation of the solvent is purified by chromatography on Florisil to give an oil, ν max. 3290 (acetylenic hydrogen), 1600, 1072, and 705 cm-1 (triphenylmethoxy group).

EXAMPLE 278
PAC Preparation of 4-triphenylmethoxy-1-octyne

A mixture of 10 g. (0.08 moles) of 4-hydroxy-1-octyne [L. Crombie and A. G. Jacklin, J. Chem. Soc., 1632 (1957)] and 30.75 g. (0.09 moles) of triphenylmethyl bromide in 85 ml. of dry pyridine is heated on the steam bath for 2 hours. The cooled mixture is treated with water and extracted with ether. The extract is washed successively with ice cold 2% hydrochloric acid, saturated sodium chloride solution, dried with magnesium sulfate, and taken to dryness. Column chromatography of the residue on Florisil affords an oil; λ max 3.01, 4.72 (acetylenic hydrogen), 6.28, 9.65 and 14.25 mμ (triphenylmethoxy group).

EXAMPLE 279
PAC Preparation of 4-triphenylmethoxy-1hexyne

A stirred solution of 9.81 g. (0.10 moles) of 4-hydroxy-1hexyne and 33.5 g. (0.12 moles) of triphenylmethyl chloride in 100 ml. of dry pyridine is heated at reflux for 2 hours. The cooled mixture is treated with water and extracted with a hexane-ether mixture. The extract is washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. Column chromatography of the residue on Florisil gives an oil, ν max. 3290 (acetylenic hydrogen), 1600, 1030, and 705 cm-1 (triphenylmethoxy group).

EXAMPLE 280
PAC Preparation of Tetrahydropyran-2-yl-9-oxo-11α-tetrahydropyranyloxy-20-triphenylmeth oxy-8ξ-13-trans-prostenoate

In the manner described in Example 281, 36.8 g. (100 mmoles) of 8-triphenylmethoxy-1-octyne (Example 304) contained in 50 ml. of benzene is converted to an alanate reagent by treatment with 83.5 ml. of 1.2 M diisobutylaluminum hydride in hexane and 45 ml. of 2.2 M methyl lithium in ether. To the stirred reagent is added 80 mmoles of crude 2-(6-tetrahydropyranylcarboxyhexyl)-4-tetrahydropyranyloxycyclopent-2-en-1 -one (Example 147) in 40 ml. of ether at 5°-10° during 10 minutes. The mixture is stirred at ice temperature for 1 hour and at ambient temperature for 15 hours. The mixture is diluted with ether and poured into a stirred mixture of ice and hydrochloric acid. The organic phase is separated, and the aqueous phase is extracted with ether. The combined extracts are washed with cold N HCl, water, and saturated sodium chloride solution. The extract is dried over magnesium sulfate, and the solvents are evaporated at reduced pressure to give the crude product as an oil, ν max, 1730 (carbonyl groups), 1035 (tetrahydropyranyloxy groups), 975 (trans vinyl group), and 705 cm-1 (triphenylmethoxy group).

EXAMPLE 280 a
PAC Preparation of 11α ,20-dihydroxy-9-oxo-13-trans-prostenoic acid

A 0.05 M solution of crude tetrahydropyran-2-yl-9-oxy-11-tetrahydropyranyloxy-20-triphenylmethoxy-8.x i.-13-trans-prostenoate (Example 280) in glacial acetic acid-tetrahydrofuran-water (4:2:1) is heated at 45° for 7 hours. The solution is diluted with aqueous sodium chloride solution and extracted with ether. The extract is washed with water and concentrated using toluene for azeotropic removal of aqueous acetic acid. The residue is purified by column chromatography on silica gel to give an oil ν max, 1735 (ketone carbonyl group), 1710 (acid carbonyl group), and 967 cm-1 (transvinyl group).

EXAMPLE 281
PAC Preparation of ethyl 20-triphenylmethoxy-9-oxo-18,19-dinor-8-13-trans-prostenoate

A stirred solution of 16.35 g. (48.0 mmoles) of 1-triphenylmethoxy-5-hexyne (Example 277) in 24 ml. of benzene is treated with 40 ml. of 1.2 M diisobutylaluminum hydride in hexane, and the resulting solution is heated at 50° for 2 hours. The solution is cooled, diluted with 35 ml. of ether, and treated at 3°-10° with 27.5 ml. of 1.6 M n-butyl lithium in hexane. After 20 minutes at ambient temperature the alanate solution is cooled to 0° and treated with a solution of 9.53 g. (40 mmoles) of 2-(6-carbethoxyhexyl)-cyclopent-2-en-1-one (Example 13), in 10 ml. of ether. The reaction mixture is stirred at ambient temperature for 18 hours, diluted with ether, and poured into a stirred mixture of ice and 4N hydrochloric acid. The mixture is stirred for 1 hour at ambient temperature, and the ether phase is separated, washed successively with water and saturated sodium chloride solution, and dried over magnesium sulfate. The residue obtained after evaporation of the solvent is purified by chromatography on silica gel to give an oil, ν max. 1735 (carbonyl groups), 968 (trans vinyl group), and 705 cm-1 (triphenylmethoxy group).

EXAMPLE 282
PAC Preparation of ethyl 20-hydroxy-9-oxo-18,19-dinor-13trans-prostenoate

A 0.05 M solution of ethyl 20-triphenyl-methoxy-9-oxo-18,19-dinor-13-trans-prostenoate (Example 281) in glacial acetic acid-tetrahydrofuran-water (4:2:1) is heated at 45° for 9 hours. The residue obtained after evaporation of the solvent is purified by chromatography on silica gel to give an oil, ν max. 3450 (hydroxyl group), 1735 (carbonyl groups), and 967 cm-1 (trans vinyl group).

EXAMPLE 283
PAC Preparation of 20-hydroxy-9-oxo-18,19-dinor-13-trans-prostenoic acid

A solution of 2.54 g. (7.5 mmoles) of ethyl 20-hydroxy-9-oxo- 18,19-dinor-13-trans-prostenoate (Example 282), 1.49 g. (22.5 mmoles) of 85% potassium hydroxide, 45 ml. of water is allowed to stand at room temperature for 20 hours. The solution is concentrated, diluted with water, extracted with ether, acidified with 4N hydrochloric acid, and extracted with ether. The final extract is washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated to give an oil, ν max. 1735 (ketone carbonyl group), 1710 (acid carbonyl group), and 967 cm-1 (trans vinyl group).

EXAMPLE 284
PAC Preparation of ethyl 16-triphenylmethoxy-9-oxo-8ξ -13-trans-prostenoate

Treatment of the alanate solution, prepared by the addition of 24 ml. (0.05 moles) of 2.1 M methyl lithium in ether to a solution of 18.4 g. (0.05 moles) of 4-triphenylmethoxy-1-octyne (Example 278) in 25 ml. of dry benzene treated with 34.6 ml. (0.05 moles) of 1.45 M diisobutyl aluminum hydride in benzene, with 9.5 g. (0.04 moles) of 2-(6-carbethoxyhexyl)-cyclopent-2-en-1one (Example 13) according to the procedure, except for chromatography, described in Example 281 gave 27.65 g. of oily material; λ max. 5.78 (carbonyl groups), 10.25 (trans vinyl group), and 14.20 (triphenyl-methoxy group).

EXAMPLE 285
PAC Preparation of ethyl 16-hydroxy-9-oxo-13-trans-prostenoate

A solution of 26.65 g. of ethyl 16-triphenylmethoxy-9-oxo-8ξ-13-trans-prostenoate (Example 284) in glacial acetic acid-tetrahydrofuran-water (4:2:1) is heated at 45° C for 3.5 hours. The residue obtained after evaporation of the solvent is partially purified by chromatography on silica gel. Total purification by partition chromatography affords an oil; ν max. 2.88 (hydroxyl group), 5.77 (carbonyl group), and 10.25 (trans vinyl group).

EXAMPLE 286
PAC Preparation of 16-hydroxy-9-oxo-13-trans-prostenoic acid

Treatment of 3.2 g. of ethyl 16-hydroxy-9-oxo-13-trans-prostenoate (Example 285) in 50 ml. of methanol water (1:1) containing 1.37 g. of potassium hydroxide according to the procedure described in Example 283 gives 2.76 g. of oil; 5.80 (carbonyl groups) and 10.25 M (trans vinyl group).

EXAMPLES 287-303

The triphenylmethoxy substituted 1-alkynes listed in the table below are prepared by the method of Example 278 from triphenylmethyl bromide and the corresponding hydroxy substituted 1-alkynes, appropriate literature references to which are provided in the table.

TABLE 13
______________________________________
Reference to starting
hydroxy substituted
Product triphenylmethoxy
Example
1-alkyne substituted 1-alkyne
______________________________________
287 Reference 1 4-triphenylmethoxy-1-
pentyne
288 Reference 1 4-triphenylmethoxy-1-
heptyne
289 Reference 1 4-triphenylmethoxy-5-
methyl-1-hexyne
290 Reference 2 4-triphenylmethoxy-1-
nonyne
291 Reference 3 4-triphenylmethoxy-1-decyne
292 Reference 4 5-triphenylmethoxy-1-pentyne
293 Reference 5 7-triphenylmethoxy-1-heptyne
294 Reference 6 9-triphenylmethoxy-1-nonyne
295 Reference 7 10-triphenylmethoxy-1-
decyne
296 Reference 8 11-triphenylmethoxy-1-
undecyne
297 Reference 9 5-triphenylmethoxy-1-hexyne
298 Reference 10 4-triphenylmethoxy-7-methyl-
1-octyne
299 Reference 10 4-triphenylmethoxy-5-ethyl-
1-heptyne
300 Reference 11 5-triphenylmethoxy-4-methyl-
1-pentyne
301 Reference 11 5-triphenylmethoxy-4-ethyl-
1-pentyne
302 Reference 11 5-triphenylmethoxy-4-methyl-
1-hexyne
303 Reference 11 5-triphenylmethoxy-4-ethyl-
1-hexyne
______________________________________

References:

1. G. Fontaine et al., Bull. Soc. Chem. France, 1447 (1963).

2. S. Abe and K. Sato, Bull. Chem. Soc. Japan, 29, 88 (1956); Chem. Abstr., 50, 13737 (1956).

3. L. Crombie and A. G. Jacklin, J. Chem. Soc., 1622 (1957); 1740 (1955).

4. R. Paul and S. Tehelitcheff, Compt, rend., 232, 2230 (1951).

5. C. Crisan, Ann. Chim (Paris), [13] 1, 436 (1956).

6. R. Riemschneider, G. Kasang, and C. Boehme, Montashefte Chem., 96, 1766 (1965).

7. Ames, J. Chem. Soc. (C), 1556 (1967).

8. l. d. bergel' son et al., Zh. Obschei Khim., 32, 58 (1962); Chem. Abstr., 57, 14930a (1962).

9. N. V. Egorov and A. S. Atavin, Chem. Abstr., 71, 61473 u (1969).

10. Nobuharra Akio, Agr. Biol. Chem. (Tokyo), 32, 1016 (1968); Chem. Abstr., 70, 3219j (1969).

11. J. Colonge and R. Gelin, Bull. Soc. Chem., France, 799 (1954).

EXAMPLE 304
PAC Preparation of 8-triphenylmethoxy-1octyne

To a stirred suspension of 68.1 g. (0.18 moles) of 1-chloro-6-triphenymethoxyhexane, prepared from 1-chloro-6-hydroxyhexane and triphenylmethyl chloride in the manner of Example 277, in 60 ml. of dimethylsulfoxide is added a solution of 19.9 g. (0.216 moles) of lithium acetylideethylenediamine complex in 120 ml. of dimethylsulfoxide during 20 minutes. The temperature is maintained at 25°C with an ice bath during the addition, after which the mixture is stirred at ambient temperature for 3.5 hours and then at 30°C for 15 minutes. The mixture is diluted with 100 ml. of ether and treated dropwise with 150 ml. of water with ice bath cooling. The mixture is diluted with 400 ml. of water and 250 ml. of 2:1 ether-pet ether and acidified with 120 ml. of 4N hydrochloric acid in the ice bath. The phases are separated, and the aqueous phase is extracted with 3:1 ether-pet ether. The combined extracts are washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. Column chromatography of the residue on Florisil affords the subject compound as white crystals, m.p. 43°-45°C after recrystallization from pet-ether, ν max 3300 (acetylenic hydrogen), 2360 (triple bond), 1600, 1068, and 706 cm-1 (triphenylmethoxy group).

EXAMPLES 305-450

Conjugate addition of the alanates obtained by treatment of the triphenylmethoxy (trityloxy)-1-alkyne (indicated in the following table) with diisobutylaluminum hydride followed by methyl lithium, to the cyclopentenones of the table according to the method described in Example 280 followed by de-O-tritylation of the intermediate triphenylmethoxyprostenoates according to the method of Example 280a is productive of the prostenoic acids and esters of the table.

Those compounds isolated and identified in the table as prostenoic acids are prepared via the corresponding tetrahydropyran-2-yl esters and these compounds bearing a free hydroxy function at the 11α-position or as part of an 11α-(ω-hydroxyalkoxy) moiety are prepared via the corresponding tetrahydropyran-2-yl ethers. The hydroxy function in the β-side chain (that portion of the molecule deriving from the triphenylmethoxy-1-alkyne) of all compounds in the table are initially present in the molecule as the corresponding triphenylmethyl ethers. During the acetic acid treatment (de-O-tritylation step) the triphenylmethyl ether as well as the tetrahydropyran-2-yl ethers and esters functions are hydrolyzed to provide the corresponding free hydroxy and carboxylic acid groups of the compounds listed in the table.

TABLE 14
__________________________________________________________________________
Starting cyclo-
Starting trityloxy-
pentenone of
1-alkyne of
Product
Example
Example Example Hydroxy Prostenoic Acid or Ester
__________________________________________________________________________
305 13 304 Ethyl 9-oxo-20-hydroxy-13-trans-prostenoate
306 13 288 Ethyl 9-oxo-16-hydroxy-20-nor-13-trans-
prostenoate
307 13 290 Ethyl 9-oxo-16-hydroxy-20-methyl-13-trans-
prostenoate
308 13 297 Ethyl 9-oxo-17-hydroxy-19,20-dinor-13-trans-
prostenoate
309 13 294 Ethyl 9-oxo-20-hydroxymethyl-13-trans-
prostenoate
310 81 298 Butyl 9-oxo-16-hydroxy-19-methyl-13-trans-
prostenoate
311 82 303 Isopropyl 9-oxo-17-hydroxy-16-ethyl-13-trans-
prostenoate
312 83 296 Methyl 9-oxo-20-(3-hydroxypropyl)-13-trans-
prostenoate
313 84 278 Decyl 9-oxo-16-hydroxy-13-trans-prostenoate
314 14 295 Ethyl 5,6,7-trinor-9-oxo-20-(2-hydroxy-
ethyl)-13-trans-prostenoate
315 23 278 Ethyl 7a,7b-bishomo-9-oxo-16-hydroxy-13-
trans-prostenoate
316 23 279 Ethyl 7a,7b-bishomo-9-oxo-19,20-dinor-16-
hydroxy-13-trans-prostenoate
317 41 291 Ethyl 3,3-dimethyl-9-oxo-16-hydroxy-20-
ethyl-13-trans-prostenoate
318 46 278 Ethyl 3-oxo-9-oxo-16-hydroxy-13-trans-
prostenoate
319 46 293 Ethyl 3-oxa-9-oxo-19-hydroxy-20-nor-13
trans-prostenoate
320 53 278 Ethyl 7-nor-9-oxo-16-hydroxy-13-trans-
prostenoate
321 53 300 Ethyl 7-nor-9-oxo-16-methyl-17-hydroxy-18,19,
20-trinor-13-trans-prostenoate
322 70 278 Ethyl 2-fluoro-9-oxo-16-hydroxy-13-trans-
prostenoate
323 74 277 Ethyl 7-a-homo-9-oxo-18-hydroxy-19,20-dinor-
13-trans-prostenoate
324 74 278 Ethyl 7a-homo-9-oxo-16-hydroxy-13-trans-
prostenoate
325 79 278 Ethyl 2-phenyl-9-oxo-16-hydroxy-13-trans-
prostenoate
326 79 299 Ethyl 2-phenyl-9-oxo-16-hydroxy-17-ethyl-20-
nor-13-trans-prostenoate
327 31 304 Ethyl 2-ethyl-9-oxo-20-hydroxy-13-trans-
prostenoate
328 273 278 Ethyl 2-methyl-9-oxo-16-hydroxy-13-trans-
prostenoate
329 276 278 Ethyl 3-thia-9-oxo-16-hydroxy-13-trans-
prostenoate
330 276 304 Ethyl 3-thia-9-oxo-20-hyroxy-13-trans-
prostenoate
331 276 302 Ethyl 3 thia-9-oxo-17-hydroxy-16-methyl-19,20-
dinor-13-trans-prostenoate
332 174 278 Ethyl 9-oxo-11α-ethoxy-16-hydroxy-13-trans-
prostenoate
333 175 278 Methyl 9-oxo-11α-methoxy-16-hydroxy-13-tran
s-
prostenoate
334 175 304 Methyl 9-oxo-11α-methoxy-20-hydroxy-13-tran
s-
prostenoate
335 175 292 Ethyl 9-oxo-11α-propoxy-6,7,18,19,20-pentan
or-
17-hydroxy-13-trans-prostenoate
336 177 289 Ethyl 9-oxo-11α-isopropoxy-5,6,7,19,20-pent
a-
nor-16-hydroxy-17-methyl-13-trans-prostenoate
337 181 287 Ethyl-9-oxo-7a,7b-bishomo-11α-isopropoxy-16
-
hydroxy-18,19,20-trinor-13-trans-prostenoate
338 183 301 Ethyl 2-ethyl-9-oxo-11α-butoxy-16-ethyl-17-
hydroxy-18,19,20-trinor-13-trans-prostenoate
339 185 304 Ethyl 3,3-dimethyl-9-oxo-11α-methoxy-20-
hydroxy-13-trans:prostenoate
340 187 278 Ethyl 3-oxa-9-oxo-11α-ethoxy-16-hydroxy-13-
trans-prostenoate
341 189 293 Ethyl 2-fluoro-9-oxo-11α-propoxy-19-hydroxy
-20-
nor-13-trans-prostenoate
342 191 298 Ethyl 7-nor-9-oxo-11α-sec-butoxy-16-hydroxy
-
19-methyl-13-trans-prostenoate
343 193 297 Ethyl 7a-homo-9-oxo-11α-methoxy-17-hydroxy-
19,
20-dinor-13-trans-prostenoate
344 195 290 Ethyl 2-phenyl-9-oxo-11α-ethoxy-16-hydroxy-
20-methyl-13-trans-prostenoate
345 196 278 Butyl 9-oxo-11α-methoxy-16-hydroxy-13-trans
-
prostenoate
346 197 278 Isopropyl 9-oxo-11α-methoxy-16-hydroxy-13-
trans-prostenoate
347 198 278 Decyl 9-oxo-11α-methoxy-16-hydroxy-13-trans
-
prostenoate
348 242a 278 9-oxo-11α-methoxy-16-hydroxy-13-trans-pro-
stenoic acid
349 242a 340 9-oxo-11α-methoxy-20-hydroxy-13-trans-pro-
stenoic acid
350 229 291 6,7-dinor-9-oxo-11α-methoxy-16-hydroxy-20-
ethyl-13-trans-prostenoic acid
351 230 294 5,6,7-trinor-9-oxo-11α-ethoxy-20-hydroxymet
hyl-
13-trans-prostenoic acid
352 231 302 7a,7b-bishomo-9-oxo-11α-methoxy-16-methyl-1
7-
hydroxy-19,20-dinor-13-trans-prostenoic acid
353 232 288 2-ethyl-9-oxo-11α-methoxy-16-hydroxy-20-nor
-
13-trans-prostenoic acid
354 233 293 3,3-dimethyl-9-oxo-11α-methoxy-19-hydroxy-2
0-
nor-13-trans-prostenoic acid
355 234 278 3-oxa-9-oxo-11α-methoxy-16-hydroxy-13-trans
-
prostenoic acid
356 235 295 2-fluoro-9-oxo-11α-methoxy-20-(2-hydroxyeth
yl)-
13-trans-prostenoic acid
357 236 296 7-nor-9-oxo-11α-methoxy-20-(3-hydroxypropyl
)-
13-trans-prostenoic acid
358 237 298 7a-homo-9-oxo-11α-methoxy-16-hydroxy-19-met
hyl-
13-trans-prostenoic acid
359 238 303 2-phenyl-9-oxo-11α-methoxy-16-ethyl-17-hydr
oxy-
19,20-dinor-13-trans-prostenoic acid
360 239 278 9-oxo-11α-ethoxy-16-hydroxy-13-trans-
prostenoic acid
361 240 278 9-oxo-11α-propoxy-16-hydroxy-13-trans-pro-
stenoic acid
362 241 304 9-oxo-11α-isopropoxy-20-hydroxy-13-trans-
prostenoic acid
363 242 279 9-oxo-11α-n-butoxy-16-hydroxy-19,20-dinor-1
3-
trans-prostenoic acid
364 147 278 9-oxo-11α-hydroxy-16-hydroxy-13-trans-pro-
stenoic acid
365 147 288 9-oxo-11α-hydroxy-16-hydroxy-20-nor-13-tran
s-
prostenoic acid
366 147 289 9-oxo-11α-hydroxy-16-hydroxy-17-methyl-19,2
0-
dinor-13-trans-prostenoic acid
367 147 297 9-oxo-11α-hydroxy-17-hydroxy-19,20-dinor-13
-
trans-prostenoic acid
368 147 298 9-oxo-11α-hydroxy-16-hydroxy-19-methyl-13-
trans-prostenoic acid
369 147 299 9-oxo-11α-hydroxy-16-hydroxy-17-ethyl-20-no
r-
13-trans-prostenoic acid
370 147 277 9-oxo-11α-hydroxy-18-hydroxy-19,20-dinor-13
-
trans-prostenoic acid
371 147 293 9-oxo-11α-hydroxy-19-hydroxy-20-nor-13-tran
s-
prostenoic acid
372 147 294 9-oxo-11α-hydroxy-20-hydroxymethyl-13-trans
-
prostenoic acid
373 147 296 9-oxo-11α-hydroxy-20-(3-hydroxypropyl)-13-
trans-prostenoic acid
374 147 302 9-oxo-11α-hydroxy-16-methyl-17-hydroxy-19,2
0-
dinor-13-trans-prostenoic acid
375 148 291 9-oxo-11α-hydroxy-6,7-dinor-16-hydroxy-20-
ethyl-13-trans-prostenoic acid
376 149 304 9-oxo-11α-hydroxy-5,6,7-trinor-20-hydroxy-1
3-
trans-prostenoic acid
377 150 278 9-oxo-11α-hydroxy-7a,7b-bishomo-16-hydroxy-
13-
trans-prostenoic acid
378 150 304 9-oxo-11α-hydroxy-7a,7b-bishomo-20-hydroxy-
13-
trans-prostenoic acid
379 150 294 9-oxo-11α-hydroxy-7a,7b-bishomo-20-hydroxym
ethyl-
13-trans-prostenoic acid
380 151 287 9-oxo-11α-hydroxy-2-ethyl-16-hydroxy-18,19,
20-
trinor-13-trans-prostenoic acid
381 152 278 9-oxo-11α-hydroxy-3,3-dimethyl-16-hydroyx-1
3-
trans-prostenoic acid
382 152 304 9-oxo-11α-hydroxy-3,3-dimethyl-20-hydroxy-1
3-
trans-prostenoic acid
383 153 278 9-oxo-11α-hydroxy-3-oxa-16-hydroxy-13-trans
-
prostenoic acid
384 154 300 9-oxo-11α-hydroxy-2-fluoro-16-methyl-17-hyd
roxy-
18,19,20-trinor-13-trans-prostenoic acid
385 155 278 9-oxo-11α-hydroxy-7-nor-16-hydroxy-13-trans
-
prostenoic acid
386 156 278 9-oxo-11α-hydroxy-7a-homo-16-hydroxy-13-tra
ns-
prostenoic acid
387 157 291 9-oxo-11α-hydroxy-2-phenyl-16-hydroxy-20-
ethyl-13-trans-prostenoic acid
388 157a 278 9-oxo-11α-hydroxy-2-methyl-16-hydroxy-13-
trans-prostenoic acid
389 157a 304 9-oxo-11α-hydroxy-2-methyl-20-hydroxy-13-
trans-prostenoic acid
390 158 278 Ethyl 9-oxo-11α-hydroxy-16-hydroxy-13-trans
-
prostenoate
391 158 304 Ethyl 9-oxo-11α-hydroxy-20-hydroxy-13-trans
-
prostenoate
392 159 278 Methyl 9-oxo-11α-hydroxy-16-hydroxy-13-tran
s-
prostenoate
393 160 294 Ethyl 9-oxo-11α-hydroxy-6,7-dinor-20-hydrox
y-
methyl-13-trans-prostenoate
394 161 298 Ethyl 9-oxo-11αhydroxy-5,6,7-trinor 16-
hydroxy-19-methyl-13-trans-prostenoate
395 162 293 Ethyl 9-oxo-11α-hydroxy-7a,7b-bishomo-19-
hydroxy-20-nor-13-trans-prostenoate
396 163 299 Ethyl 9-oxo-11α-hydroxy-2-ethyl-16-hydroxy-
17-ethyl-20-nor-13-trans-prostenoate
397 164 297 Ethyl 9-oxo-11α-hydroxy-3,3-dimethyl-17-
hydroxy-19,20-dinor-13-trans-prostenoate
398 165 294 Ethyl 9-oxo-11α-hydroxy-3-oxa-20-hydroxy-
methyl-13-trans-prostenoate
399 166 304 Ethyl 9-oxo-11α-hydroxy-2-fluoro-20-hydroxy
-
13-trans-prostenoate
400 167 290 Ethyl 9-oxo-11α-hydroxy-7-nor-16-hydroxy-20
-
methyl-13-trans-prostenoate
401 168 289 Ethyl 9-oxo-11α-hydroxy-7a-homo-16-hydroxy-
17-methyl-19,20-dinor-13-trans-prostenoate
402 169 297 Ethyl 9-oxo-11α-hydroxy-2-phenyl-17-hydroxy
-
19,20-dinor-13-trans-prostenoate
403 170 278 Butyl 9-oxo-11α-hydroxy-16-hydroxy-13-trans
-
prostenoate
404 170 304 Butyl-9-oxo-11α-hydroxy-20-hydroxy-13-trans
-
prostenoate
405 171 278 Isopropyl 9-oxo-11α-hydroxy-16-hydroxy-13-
trans-prostenoate
406 171 304 Isopropyl 9-oxo-11α-hydroxy-20-hydroxy-13-
trans-prostenoate
407 172 278 Decyl 9-oxo-11α-hydroxy-16-hydroxy-13-trans
-
prostenoate
408 172 304 Decyl 9-oxo-11α-hydroxy-20-hydroxy-13-trans
-
prostenoate
409 203 278 Ethyl 9-oxo-11α-t-butyloxy-16-hydroxy-13-tr
ans-
prostenoate
410 243 278 Ethyl 9-oxo-11α(β-hydroxyethyoxy)-16-h
ydroxy-
13-trans-prostenoate
411 244 304 Methyl 9-oxo-11α(β-hydroxyethoxy)-20-h
ydroxy-
13-trans-prostenoate
412 245 294 Ethyl 9-oxo-11α(γ-hydroxypropoxy)-6,7
-dinor-
20-hydroxymethyl-13-trans-prostenoate
413 246 298 Ethyl 9-oxo-11α(β-hydroxyethoxy)-5,6,7
-trinor-
16-hydroxy-19-methyl-13-trans-prostenoate
414 247 278 9-oxo-11α-(β-hydroxyethoxy)-16-hydroxy
-13-
trans-prostenoate
415 247 304 9-oxo-11α-(β-hydroxyethoxy)-20-hydroxy
-13-
trans-prostenoic acid
416 247 292 9-oxo-11α(β-hydroxyethoxy)-17-hydroxy-
18,19,
20-trinor-13-trans-prostenoic acid
417 247 293 9-oxo-11α(βhydroxyethoxy)-19-hydroxy-2
0-
nor-13-trans-prostenoic acid
418 247 294 9-oxo-11α-(β-hydroethoxy)-20-hydroxyme
thyl-
13-trans-prostenoic acid
419 247 298 9-oxo-11α-(β-hydroxyethoxy)-16-hydroxy
-19,
methyl-13-trans-prostenoic acid
420 248 296 9-oxo-11α-(β-hydroxyethoxy)-6,7-dinor-
20-
(3-hydroxypropyl)-13-trans-prostenoic acid
421 249 299 9-oxo-11α-(β-hydroxyethoxy)-5,6,7,20-t
etranor-
16-hydroxy-17-ethyl-13-trans-prostenoic acid
422 251 278 9-oxo-11α-(β-hydroxyethoxy)-7a,7b-bish
omo-16-
hydroxy-13-trans-prostenoic acid
423 251 277 9-oxo-11α-(β-hydroxyethoxy)-7a,7b-bish
omo-18-
hydroxy-19,20-dinor-13-trans-prostenoic acid
424 250 297 Ethyl 9-oxo-11α-(β-hydroxyethoxy)-7a,7
b-bis-
homo-17-hydroxy-19,20-dinor-13-trans-
prostenoate
425 253 287 Ethyl 9-oxo-11α(γ-hydroxypropoxy)-2-e
thyl-
16-hydroxy-18,19,20-trinor-13-trans-
prostenoate
426 252 278 9-oxo-11α-(β-hydroxyethoxy)-2-ethyl-16
-hydroxy-
13-trans-prostenoic acid
427 252 304 9-oxo-11α-(β-hydroxyethoxy)-2-ethyl-20
-hydroxy-
13-trans-prostenoic acid
428 254 278 9-oxo-11α-(βhydroxyethoxy)-3,3-dimethy
l-16-
hydroxy-13-trans-prostenoic acid
429 254 297 9-oxo-11α-(β-hydroxyethoxy)-3,5-dimeth
yl-17-
hydroxy-19,20-dinor-13-trans-prostenoic acid
430 255 293 Ethyl 9-oxo-11α-(β-hydroxyethoxy)-3,3-
dimethyl-
19-hydroxy-20-nor-13-trans-prostenoate
431 257 302 Ethyl 9-oxo-11α-(γ-hydroxypropoxy)-3-
oxa-16-
methyl-17-hydroxy-19,20-dinor-13-trans-
prostenoate
432 256 278 9-oxo-11α-(β-hyddroxyethoxy)-3-oxa-16-
hydroxy-
13-trans-prostenoic acid j -433 258 278 9-oxo-
11α-(β-hyd
roxyethoxy)-2-fluoro-
16-hydroxy-
13-trans-prostenoic acid
434 258 304 9-oxo-11α-(β-hydroxyethoxy)-2-fluoro-2
0-
hydroxy-13-trans-prostenoic acid
435 258 291 9-oxo-11α-(β-hydroxyethoxy)-2-fluoro-1
6-
hydroxy-20-ethyl-13-trans-prostenoic acid
436 259 295 Ethyl 9-oxo-11α-(β-hydroxyethoxy)-2-fl
uoro-
20-(2-hydroxyethyl)-13-trans-prostenoate
437 260 290 9-oxo-11α-(β-hydroxyethoxy)-7-nor-16-h
ydroxy-
20-methyl-13-trans-prostenoic acid
438 261 278 9-oxo-11α-(β-hydroxyethoxy)-7a-homo-16
-hydroxy-
13-trans-prostenoic acid
439 262 293 9-oxo-11α-8β-hydroxyethoxy)-2-phenyl-1
9-
hydroxy-20-nor-13-trans-prostenoic acid
440 263 278 Ethyl 9-oxo-11α-(β-hydroxyethoxy)-2-ph
enyl-16-
hydroxy-13-trans-prostenoate
441 264 278 Butyl 9-oxo-11α-(β-hydroxyethoxy)-16-h
ydroxy-
13-trans-prostenoate
442 264 304 Butyl 9-oxo-11α-(β-hydroxyethoxy)-20-h
ydroxy-
13-trans-prostenoate
443 265 278 Isopropyl 9-oxo-11α-(βhydroxtyethoxy)-
16-hydroxy-
13-trans-prostenoate
444 265 304 Isopropyl 9-oxo-11α-(β-hydroxyethoxy)-
20-
hydroxy-13-trans-prostenoate
445 266 278 Decyl 9-oxo-11α-(β-hydroxyethoxy)-16-
hydroxy-13-trans-prostenoate
446 266 304 Decyl 9-oxo-11α-(β-hydroxyethoxy)-20-h
ydroxy-
13-trans-prostenoate
447 267 278 9-oxo-11α-(β-hydroxypropoxy)-16-hydrox
y-13-
trans-prostenoic acid
448 267 304 9-oxo-11α-(β-hydroxypropoxy)-20-hydrox
y-13-
trans-prostenoic acid
449 267 303 9-oxo-11α-(β-hydroxypropoxy)-16-ethyl-
17-
hydroxy-19,20-dinor-13-trans-prostenoic acid
450 269 278 9-oxo-11α-(4-hydroxybutoxy)-16-hydroxy-3-
trans-prostenoic acid
451 269 304 9-oxo-11α-(4-hydroxybutoxy)-20-hydroxy-13-t
rans-
prostenoic acid
__________________________________________________________________________
EXAMPLES 451a-474

Saponification of the alkyl esters listed in Table 15 below by the method described in Example 283 is productive of the prostenoic acids of the table.

TABLE 15
______________________________________
Starting alkyl
prostenoate of
Product
Example
Example Hydroxy Prostenoic Acid
______________________________________
151a 305 9-oxo-20-hydroxy-13-trans- j - prostenoic acid
452 306 9-oxo-16-hydroxy-20-nor-13-
trans-prostenoic acid
453 307 9-oxo-16-hydroxy-20-methyl-
13-trans-prostenoic acid
454 308 9-oxo-17-hydroxy-19,20-dinor-
13-trans-prostenoic acid
455 309 9-oxo-20-hydroxymethyl-13-
trans-prostenoic acid
456 312 9-oxo-20-(3-hydroxypropyl)-
13-trans-prostenoic acid
457 314 5,6,7-trinor-9-oxo-20-(2-
hydroxyethyl)-13-trans-pro-
stenoic acid
458 315 7a,7b-bishomo-9-oxo-16-hydroxy-
13-trans-prostenoic acid
459 316 7a,7b-bishomo-9-oxo-19,20-
dinor-16-hydroxy-13-trans-
prostenoic acid
460 317 3,3-dimethyl-9-oxo-16-hydroxy-
20-ethyl-13-trans-prostenoic
acid
461 318 3-oxa-9-oxo-16-hydroxy-13-
trans-prostenoc acid
462 319 3-oxa-9-oxo-19-hydroxy-20-nor-
13-trans-prostenoic acid
463 320 7-nor-9-oxo-16-hydroxy-13-
trans-prostenoic acid
464 321 7-nor-9-oxo-16-methyl-17-
hydroxy-18,19,20-trinor-13-
trans-prostenoic acid
465 322 2-fluoro-9-oxo-16-hydroxy-13-
trans-prostenoic acid
466 323 7a-homo-9-oxo-18-hydroxy-19,
20-dinor-13-trans-prostenoic
acid
467 324 7a-homo-9-oxo-16-hydroxy-13-
trans-prostenoic acid
468 325 2-phenyl-9-oxo-16-hydroxy-13-
trans-prostenoic acid
469 326 2-phenyl-9-oxo-16-hydroxy-17-
ethyl-20-nor-13-trans-
prostenoic acid
470 327 2-ethyl-9-oxo-20-hydroxy-13-
trans-prostenoic acid
471 328 2-methyl-9-oxo-16-hydroxy-13-
trans-prostenoic acid
472 329 3 thia-9-oxo-16-hydroxy-13-
trans-prostenoic acid
473 330 3-thia-9-oxo-20-hydroxy-13-
trans-prostenoic acid
474 331 3-thia-9-oxo-17-hydroxy-16-
methyl-19,20-dinor-13-trans-
prostenoic acid
______________________________________
EXAMPLE 475
PAC Preparation of 16-hydroxy-9-oxo-prostanoic acid

A solution containing 1.4 g. (4.3 mmoles) of 16-hydroxy-9-oxo-13-trans-prostenoic acid (Example 286) in 45 ml. of absolute ethanol is hydrogenated using 650 mg. of 10% palladium or carbon. Filtration followed by evaporation of the solvent gives 1.31 g. of subject compound as an oil; ν max 5.78 (ketone carbonyl group) and 5.82 mμ (acid carbonyl group).

EXAMPLES 476-574

Hydrogenation of the 13-prostenoic acids and esters listed in the table below by the procedure described in Example 475 is productive of the prostanoic acids and esters of the table.

TabLE 16
______________________________________
Starting 13-pro-
stenoic acid or
Product
Example
ester of example
Prostanoic acid or ester
______________________________________
476 318 Ethyl 3-oxa-9-oxo-16-hydroxy-
prostanoate
477 319 Ethyl 3-oxa-9-oxo-19-hydroxy-
20-nor-prostanoate
478 320 Ethyl 7-nor-9-oxo-16-hydroxy-
prostanoate
479 321 Ethyl 7-nor-9-oxo-16-methyl-
17-hydroxy-18,19,20-trinor-
prostanoate
480 322 Ethyl 2-fluoro-9-oxo-16-
hydroxy-prostanoate
481 324 Ethyl 7a-homo-9-oxo-16-
hydroxy-prostanoate
482 325 Ethyl 2-phenyl-9-oxo-16-
hydroxy-prostanoate
483 327 Ethyl 2-ethyl-9-oxo-20-
hydroxy-prostanoate
484 328 Ethyl 2-methyl-9-oxo-16-
hydroxy-prostanoate
485 305 Ethyl 9-oxo-20-hydroxy-
prostanoate
486 306 Ethyl 9-oxo-16-hydroxy-20-
nor-prostanoate
487 307 Ethyl 9-oxo-16-hydroxy-20-
methyl-prostanoate
488 308 Ethyl 9-oxo-17-hydroxy-19,20-
dinor-13-prostanoate
489 309 Ethyl 9-oxo-20-hydroxymethyl-
prostanoate
490 310 Butyl 9-oxo-16-hydroxy-19-
methyl-prostanoate
491 311 Isopropyl 9-oxo-17-hydroxy-16-
ethyl-prostanoate
492 312 Methyl 9-oxo-20-(3-hydroxy-
propyl)-prostanoate
493 313 Decyl 9-oxo-16-hydroxy-
prostanoate
494 314 Ethyl 5,6,7-trinor-9-oxo-
20-(2-hydroxyethyl)-
prostanoate
495 315 Ethyl 7a,7b-bishomo-9-oxo-
16-hydroxy-prostanoate
496 316 Ethyl 7a,7b-bishomo-9-oxo-
19,20-dinor-16-hydroxy-
prostanoate
497 317 Ethyl 3,3-dimethyl-9-oxo-16-
hydroxy-20-ethyl-prostanoate
498 332 Ethyl 9-oxo-11α-ethoxy-16-
hydroxy-prostanoate
499 333 Methyl 9-oxo-11α-methoxy-16-
hydroxy-prostanoate
500 337 Ethyl 9-oxo-7a,7b-bishomo-11α-
isopropoxy-16-hydroxy-18,19,
20-trinor-prostanoate
501 338 Ethyl 2-ethyl-9-oxo-11α-
butoxy-16-ethyl-17-hydroxy-
18,19,20-rinor-prostanoate
502 339 Ethyl 3,3-dimethyl-9-oxo-11α-
methoxy-20-hydroxy-prostanoate
503 340 Ethyl 3-oxa-9-oxo-11α-ethoxy-
16-hydroxy-prostanoate
504 341 Ethyl 2-fluoro-9-oxo-11α-
propoxy-19-hydroxy-20-nor-
prostanoate
505 342 Ethyl 7-nor-9-oxo-11α-sec-
butoxy-16-hydroxy-19-methyl-
prostanoate
506 347 Decyl 9-oxo-11α-methoxy-16-
hydroxy-prostanoate
507 348 9-oxo-11α-methoxy-16-hydroxy-
prostanoic acid
508 349 9-oxo-11α-methoxy-20-hydroxy-
prostanoic acid
509 352 7a,7b-bishomo-9-oxo-11α-
methoxy-16-methyl-17-hydroxy-
19,20-dinor-prostanoic acid
510 353 2-ethyl-9-oxo-11α-methoxy-16-
hydroxy-20-nor-prostanoic acid
511 354 3,3-dimethyl9-oxo-11α-methoxy-
19-hydroxy-20-nor-prostanoic
acid
512 355 3-oxa-9-oxo-11α-methoxy-16-
hydroxy-prostanoic acid
513 356 2-fluoro-9-oxo-11α-methoxy-
20-(2-hydroxyethyl)
prostanoic acid
514 357 7-nor-9-oxo-11α-methoxy-20-
(3-hydroxypropyl)-prostanoic
acid
515 358 7a-homo-9-oxo-11α-methoxy-16-
hydroxy-19-methyl-prostanoic
acid
516 359 2-phenyl-9-oxo-11α-methoxy-
16-ethyl-17-hydroxy-19,20-
dinor-prostanoic acid
517 360 9-oxo-11α-ethoxy-16-hydroxy-
prostanoic acid
518 361 9-oxo-11α-propoxy-17-hydroxy-
prostanoic acid
519 362 9-oxo-11α-isopropoxy-20-
hydroxy-prostanoic acid
520 363 9-oxo-11α-n-butoxy-16-hydroxy-
19,20-dinor-prostanoic acid
521 364 9-oxo-11α-hydroxy-16-hydroxy-
prostanoic acid
522 365 9-oxo-11α-hydroxy-16-hydroxy-
20-nor-prostanoic acid
523 367 9-oxo-11α-hydroxy-17-hydroxy-
19,20-dinor-prostanoic acid
4524 368 9-oxo-11α-hydroxy-16-hydroxy-
19-methyl-prostanoic acid
525 370 9-oxo-11α-hydroxy-18-hydroxy-
19,20-dinor-prostanoic acid
526 371 9-oxo-11α-hydroxy-19-hydroxy-
20-nor-prostanoic acid
527 372 9-oxo-11α-hydroxy-20-hydroxy-
methyl-prostanoic acid
528 373 9-oxo-11α-hydroxy-20-(3-
hydroxypropyl)-prostanoic
acid
529 374 9-oxo-11α-hydroxy-16-methyl-
17-hydroxy-19,20-dinor-pro-
stanoic acid
530 375 9-oxo-11α-hydroxy-6,7-dinor-
16-hydroxy-20-ethyl-prostanoic
acid
531 377 9-oxo-11α-hydroxy-7a,7b-
bishomo-16-hydroxy-prostanoic
acid
532 378 9-oxo-11α-hydroxy-7a,7b-
bishomo-20-hydroxy-prostanoic
533 381 9-oxo-11α-hydroxy-3,3-dimethyl-
16-hydroxy-prostanoic acid
534 382 9-oxo-11α-hydroxy-3,3-dimethyl-
20-hydroxy-prostanoic acid
535 383 9-oxo-11α-hydroxy-3-oxa-16-
hydroxy-prostanoic acid
536 384 9-oxo-11α-hydroxy-2-fluoro-
16-methyl-17-hydroxy-18,19,
20-trinor-prostanoic acid
537 385 9-oxo-11α-hydroxy-7-nor-16-
hydroxy-prostanoic acid
538 386 9-oxo-11α-hydroxy-7a-homo-
16-hydroxy-prostanoic acid
539 387 9-oxo-11α-hydroxy-2phenyl-
16-hydroxy-20-ethyl-prostanoic
acid
540 388 9-oxo-11α-hydroxy-2-methyl-16-
hydroxy-prostanoic
acid
541 389 9-oxo-11α-hydroxy-2-methyl-20-
hydroxy-prostanoic acid
542 390 Ethyl 9-oxo-11α-hydroxy-16-
hydroxy-prostanoate
543 391 Ethyl 9-oxo-11α-hydroxy-20-
hydroxy-prostanoate
544 400 Ethyl 9-oxo-11α-hydroxy-7-nor-
16-hydroxy-20-methyl-
prostanoate
546 403 Butyl 9-oxo-11α-hydroxy-16-
hydroxy-prostanoate
547 407 Decyl 9-oxo-11α-hydroxy-16-
hydroxy-prostanoate
548 408 Decyl 9-oxo-11α-hydroxy-20-
hydroxy-prostanoate
549 409 Ethyl 9-oxo-11α-t-butoxy-16-
hydroxy-prostanoate
550 410 Ethyl 9-oxo-11α-(β-hydroxy-
ethoxy)-16-hydroxy-prostanoate
551 411 Methyl 9-oxo-11α-(β-hydroxy-
ethoxy-20-hydroxy-prostanoate
552 414 9-oxo-11α-(β-hydroxyethoxy)-
16-hydroxy-prostanoic acid
553 415 9-oxo-11α-(β-hydroxyethoxy)-
20-hydroxy-prostanoic acid
554 417 9-oxo-11α-(β-hydroxyethoxy)-19-
hydroxy-20-nor-prostenoic acid
555 419 9-oxo-11α-(β-hydroxyethoxy-
16-hydroxy-19-methyl-
prostanoic acid
556 422 9-oxo-11α-(β-hydroxyethoxy)-
7a,7b-bishomo-16-hydroxy-
prostanoic acid
557 423 9-oxo-11α-(β-hydroxyethoxy-
7a,7b-bishomo-18-hydroxy-
29,20-dinor-prostanoic acid
558 424 Ethyl 9-oxo-11α-(β-hydroxy-
ethoxy)-7a,7b-bishomo-17-
hydroxy-19,20-dinor-prostanoate
559 426 9-oxo-11α-(β-hydroxyethoxy)-
2-ethyl-16-hydroxy-prostanoic
acid
560 427 9-oxo-11α-(β-hydroxyethoxy)-
2-ethyl-20-hydroxy-pro-
stanoic acid
561 428 9-oxo-11α-(β-hydroxyethoxy)-
3,3-dimethyl-16-hydroxy-
prostanoic acid
562 429 9-oxo-11α-(β-hydroxyethoxy)-
3,3-dimethyl-17-hydroxy-19,20-
dinor-prostanoic acid
563 432 9-oxo-11α-(β-hydroxyethoxy)-3-
oxa-16-hydroxy-prostanoic
acid
564 433 9-oxo-11α-(β -hydroxyethoxy)-2-
fluoro-16-hydroxy-prostanoic
acid
565 434 9-oxo-11α-(β-hydroxyethoxy)-2-
fluoro-20-hydroxy-prostanoic
acid
566 437 9-oxo-11α-(β-hydroxyethoxy)-7-
nor-16-hydroxy-20-methyl-
prostanoic acid
567 438 9-oxo-11α-(β-hydroxyethoxy)-
7a-homo-16-hydroxy-
prostanoic acid
568 439 9-oxo-11α-(β-hydroxyethoxy)-
2-phenyl-19-hydroxy-20-nor-
prostanoic acid
569 445 Decyl 9-oxo-11α-(β-hydroxy-
ethoxy)-16-hydroxy-
prostanoate
570 446 Decyl 9-oxo-11α-(β-hydroxy-
ethoxy)-20-hydroxy-
prostanoate
571 447 9-oxo-11α-(β-hydroxypropoxy)-
16-hydroxy-prostanoic acid
572 448 9-oxo-11α-(β-hydroxypropoxy)-
20-hydroxy-prostanoic acid
573 450 9-oxo-11α-(4-hydroxybutoxy)-
16-hydroxy-prostanoic acid
574 451 9-oxo-11α-(4-hydroxybutoxy)-
20-hydroxy-prostanoic acid
______________________________________
EXAMPLE 575
PAC Preparation of 9α ,11α ,20-trihydroxy-13-trans-prostenoic acid

To a stirred solution of 459 mg. (1.29 mmoles) of 11α ,20-dihydroxy-9-oxo-13-trans-prostenoic acid (Example 280a) in 4.0 ml. of tetrahydrofuran is added 5.2 ml. of a 0.65M solution of lithium perhydro 9b-boraphenalyl hydride in tetrahydrofuran at -78°C under nitrogen. The solution is stirred at -78°C for 45 minutes and at ambient temperatures for 15 minutes. The solution is diluted with 10 ml. of water and extracted with ether. The extract is back-extracted with N/4 sodium bicarbonate solution. The combined aqueous phases are acidified with 4N hydrochloric acid, saturated with sodium chloride, and extracted with ether. The extract is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The residue is purified by thin layer chromatography on silica gel to give a colorless oil, ν max. = 3310 (hydroxyl groups), 1705 (acid carbonyl group), and 970 cm-1 (trans-vinyl group).

EXAMPLES 576-678 a

Reduction of the 9-oxo derivative listed in the table below with lithium perhydro-9β-boraphenyalyl hydride by the method described in Example 575 is productive of the 9α-hydroxy derivative of the table.

When the starting 9-oxo-derivative is an ester, the original ether extract is washed with brine, dried over magnesium sulfate, and concentrated. Chromatography of the residue on silica gel to separate the boron-containing compounds affords the product esters of the table.

TABLE 17
______________________________________
Starting 9-oxo
derivative of
Product
Example
Example 9α-hydroxy Derivative
______________________________________
576 305 Ethyl 9α,20-dihydroxy-13-
trans-prostenoate
577 306 Ethyl 9α,16-dihydrox-20-nor-
13-trans-prostenoate
578 307 Ethyl 9α,16-dihydroxy-20-
methyl-13-trans-prostenoate
579 308 Ethyl 9α,17-dihydroxy-19,20-
dinor-13-trans-prostenoate
580 309 Ethyl 9αhydroxy-20-hydroxy-
methyl-13-trans-prostenoate
581 310 Butyl 9α,16-dihydroxy-19-
meythyl-13-trans-prostenoate
582 311 Isopropyl 9α,17-dihydroxy-16-
ethyl-13-trans-prostenoate
583 313 Decyl 9α,16-dihydroxy-13-
trans-prostenoate
584 315 Ethyl 7a,7b-bishomo-9α,16-
dihydroxy-13-trans-prostenoate
585 317 Ethyl 3,3-dimethyl-9α,16-di-
hydroxy-20-ethyl-13-trans-
prostenoate
586 318 Ethyl 3-oxa-9α,16-dihydroxy-
13-trans-prostenoate
587 320 Ethyl 7-nor-9α,16-dihydroxy-
13-trans-prostenoate
588 323 Ethyl 7a-homo-9α,18-dihydroxy-
19,20-dinor-13-trans-
prostenoate
589 324 Ethyl 7a-homo-9α,16-dihydroxy-
13-trans-prostenoate
590 326 Ethyl 2-phenyl-9α,16-dihydroxy-
17-ethyl-20-nor-13-trans-
prostenoate
591 328 Ethy l2-methyl-9α,16-dihydroxy-
13-trans-prostenoate
592 329 Ethyl 3-thia-9α,16-dihydroxy-
13-trans-prostenoate
593 330 Ethyl 3-thia-9α,20-dihydroxy-
13-trans-prostenoate
594 332 Ethyl 11α-ethoxy-9α,16-di-
hydroxy-13-trans-prostenoate
595 333 methyl 11α-methoxy-9α,16-
dihydroxy-13-trans-
prostenoate
596 334 Methyl 11α-methoxy-9α,20-di-
hydroxy-13-trans-prostenoate
597 337 Ethyl 7a,7b-bishomo-11α-iso-
propoxy-9α,16-dihydroxy-18,19,
20-trinor-13-transprostenoate
598 338 Ethyl 2-ethyl-11α-butoxy-16-
ethyl-9α,17-dihdroxy-18,19,
20-trinor-13-trans-prostenoate
599 339 Ethyl 3,3-dimethyl-11α-methoxy-
9α,20-dihydroxy-13-trans-
prostenoate
600 341 Ethyl 2-fluoro-9-oxo-11α-pro-
poxy-9α,19-dihydroxy-20-
nor-13-trans-prostenoate
601 342 Ethyl 7-nor-11α-sec-butoxy-9α,
16-dihydroxy-19-methyl-13-
trans-prostenoate
602 343 Ethyl 7a-homo-11α-methoxy-9α,
17-dihydroxy-19,20-dinor-13-
trans-prostenoate
603 347 Decyl 11α-metoxy-9α,16-di-
hydroxy-13-trans-prostenoate
604 348 11α-methyl-9α,16-dihydroxy-
13-trans prostenoic acid
605 349 11α-methoxy-9α,20-dihydroxy-
13-trans-prostenoic acid
606 351 5,6,7-trinor-9α-hydroxy-11α-
ethoxy-20-hydroxymethyl-13-
trans-prostenoic acid
607 352 7a,7b-bishomo-11α-methoxy-16-
methyl-9α,17-dihydroxy-19,20-
dinor-13-trans-prostenoic
acid
608 353 2-ethyl-11α-methoxy-9α,16-di-
hydroxy-20-nor-13-trans-
prostenoic acid
609 355 3-oxa-11α-methoxy-9α,16-di-
hydroxy-13-trans-prostenoic
acid
610 356 2-fluoro-9α-hydroxy-11α-
methoxy-20-(2-hydroxyethyl)-
13-trans-prostenoic acid
611 357 7-nor-9α-hydroxy-11α-methoxy-
20-(3-hydroxypropyl)-13-
trans-prostenoic acid
612 358 7a-homo-9-oxo-11α-methoxy-9α,
16-dihydroxy-19-methyl-13-
trans-prostenoic acid
613 360 11α-ethoxy-9α,16-dihydroxy-
13-trans-prostenoic acid
614 361 11α-propoxy-9α,16-dihydroxy-
13-trans-prostenoic acid
615 362 11α-isopropoxy-9α,20-dihydroxy-
13-trans-prostenoic acid
616 363 11α-n-butoxy-9α,16-dihydroxy-
19,20-dinor-13-trans-
prostenoic acid
617 364 9α,11α,16-trihydroxy-13-trans-
prostenoic acid
618 365 9α,11α,16-trihydroxy-20-nor-
13-trans-prostenoic acid
619 366 9α,11α,16-trihydroxy-17-
methyl-19,120-dinor-13-trans-
prostenoic acid
620 367 9α,11α,17-trihydroxy-19,20-
dinor-13-trans-prostenoic
acid
621 368 9α,11α,16-trihydroxy-19-methyl-
13-trans-prostenoic acid
622 369 9α,11α,16-trihydroxy-17-
ethyl-20-nor-13-trans-
prostenoic acid
623 370 9α,11α,18-trihydroxy-19,20-
dinor-13-trans-prostenoic
acid
624 371 9α,11α,19-trihydroxy-20-nor-
13-trans-prostenoic acid
625 372 9α,11α-dihydroxy-20-hydroxy-
methyl-13-trans-prostenoic
acid
626 373 9α,11α-dihydroxy-20-(3-hydroxy-
propyl)-13-trans-prostenoic
acid
627 374 9α,11α,1l7-trihydroxy-16-
methyl-19,20-dinor-13-trans-
prostenoic acid
628 375 9α,11α,16-trihydroxy-6,7-
dinor-20-ethyl-13-trans-
prostenoic acid
629 376 9α,11α,20-trihydroxy-5,6,7-
trinor-13-trans-prostenoic
acid
630 377 9α,11α,16-trihydroxy-7a,7b-
bishomo-13-trans-prostenoic
acid
631 378 9α,11α,20-trihydroxy-7a,7b-
bishomo-13-trans-prostenoic
acid
632 380 9α,11,16-trihydroxy-2-ethyl-
18,19,20-trinor-13-trans-
prostenoic acid
633 381 9α,11α,16-trihydroxy-3,3-di-
methyl-13-trans-prostenoic
acid
634 382 9α,11α,20-trihydroxy-3,3-di-
methyl-13-trans-prostenoic
acid
635 383 9α,11α,16-trihydroxy-3-oxa-
13-trans-prostenoic acid
636 384 9α,11α,17-trihydroxy-2-fluoro-
16-methyl-18,19,20-trinor-
13-trans-prostenoic acid
637 385 9α,11α,16-trihydroxy-7-nor-13-
trans-prostenoic acid
638 386 9α,11α,16-trihydroxy-7a-homo-
13-trans-prostenoic acid
639 387 9α,11α,16-trihydroxy-2-phenyl-
20-ethyl-13-trans-prostenoic-
acid
640 388 9α,11α,16-trihydroxy-2-methyl-
13-trans-prostenoic acid
641 389 9α,11α,20-trihydroxy-2-methyl-
13-trans-prostenoic acid
642 390 Ethyl 9α,11α,16-trihydroxy-
13-trans-prostenoate
643 391 Ethyl 9α,11α,20-trihydroxy-
13-trans-prostenoate
644 403 Butyl 9α,11α,16-trihydroxy-
13-trans-prostenoate
645 407 Decyl 9α,11α,16-trihydroxy-
13-trans-prostenoate
646 408 Decyl9α.11α.20-trihydroxo-
13-trans-prostenoate
647 409 Ethyl 11α-t-butoxy-9α.15-
dihydroxy-13-trans-
prostenoic acid
648 410 Ethyl 11α-(β-hydroxyethoxy)-
9α16-dihydroxy-13-trans-
prostenoate
649 411 Methyl 11α-(β-hydroxyethoxy)-
9α.20-dihydroxy-13-trans-
prostenoate
650 414 9α.16-dihydroxy-11α-(β-
hydroxyethoxy)-13-trans-
prostenoic acid
651 415 9α.20-dihydroxy-11-60 -(β-hydroxy-
ethoxy)-13-trans-prostenoic
acid
652 416 9α,17-dihydroxy-(β-hydroxy-
ethoxy)-18,19,20-trinor-13-
trans-prostenoic acid
653 417 9α.19-dihydroxy-(β-hydroxy-
ethoxy)-20-nor-13-trans-
prostenoic acid
654 418 9α-hydroxy-(β-hydroxyethoxy)-
20-hydroxymethyl-13-trans-
prostenoic acid
655 419 9α,16-dihydroxy-(β-hydroxy-
ethoxy)-19-methyl-13-trans-
prostenoic acid
656 422 9α.16-dihydroxy-(β-hydroxy-
ethoxy)-7a, 7b-bishomo-13-
trans-prostenoic acid
657 426 9α,16-dihydroxy-11α-(β-hydroxy-
ethoxy)-2-ethyl-13-trans-
prostenoic acid
658 427 9α,20-dihydroxy-11α-(β-hydroxy-
etoxy)-2-ethyl-13-trans-
prostenoic acid
659 428 9α,16-dihydroxy-11α-(β-hydroxy-
ethoxy)-3,3-dimethyl-13-
trans-prostenoic acid
660 432 9α,16-dihydroxy-11α-(β-hydroxy-
ethoxy)-3-oxa-13-trans-
prostenoic acid
661 433 9α,16-dihydroxy-11α-(β-hydroxy-
ethoxy)-2-fluoro-13-trans-
prostenoic acid
662 437 9α,16-dihydroxy-11α-(β-hydroxy-
ethoxy)-7-nor-20-methyl-13-
trans-prostenoic acid
663 438 9α.16-dihydroxy-11α-(β-hydroxy-
ethoxy)-7a-homo-13-trans-
prostenoic acid
664 440 Ethyl9α,16-dihydroxy-11-α-(β-
hydroxyethoxy)-2-phenyl-13-
trans-prostenoic acid
665 443 Isoproyl 9α,16-dihydroxy-11α-
β-hydroxyethoxy)-13-trans-
prostenoic acid
666 445 Decyl 9α.16-dihydroxy-11-60 -
(β-hydroxyethoxy)-13-trans-
prostenoic acid
667 446 Decyl 9α-20-dihydroxy-11α-
(β-Hydroxyethoxy)-13-trans-
prostenoic acid
668 447 9α.16-dihydroxy-11α-(β-hydroxy-
propoxy)-13-trns-prostenoic
acid
669 450 9α.16-dihydroxy-11-60 -(4-hydroxy-
butoxy)-13-trans-prostenoic
acid
670 507 9α.16-dihydroxy-11α-methoxy-
prostanoic acid
671 511 9α.19-dihyroxy-3,3-dimethyl-
11α-methoxy-20-nor-
prostanoate
672 531 9α,11α,16-trihydroxy-7a, 7b-
bishomo-prostanoic acid
673 527 9α,11α-dihydroxy-20-hydroxy-
methyl-prostanoic acid
674 534 9α,11α,20-trihydroxy-3,3-di-
methyl-prostanoic acid
675 538 9α,11α,6-trihydroxy-7a-homo-
prostanoic acid
676 547 Decyl 9α,11α,16-trihydroxy-
prostanoate
677 558
hydroxyethoxy) prostanoic
acid
678 560 9α,20-dihydroxy-2-ethyl-11α-
(β-hydroxyethoxy)-prostaoic
acid
678a 745 9α,20-dihydroxy-13-trans-
prostenoic acid
______________________________________
EXAMPLE 679
PAC Preparation of 9α/9β,11,20-trihydroxy-13-trans-prostenoic acid

To a stirred, ice-cold solution of 355 mg. (1.00 mmoles) of 11α ,20-dihydroxy-9-oxo-13-trans-prostenoic acid (Example 280a) in 50 ml. of ethanol is added 409 mg. (10.8 mmoles) of sodium borohydride in small portions during 1 minute. The mixture is stirred at 0°C for 5 minutes and at ambient temperature for 1.5 hour. The bulk of the ethanol is evaporated at room temperature, and the residue is treated with ether followed by dilute hydrochloric acid while cooling in an ice bath. The organic phase is separated and washed with water and saturated sodium chloride solution. The solution is dried over magnesium sulfate and concentrated. The residue is purified by thin layer chromatography on silica gel to give an oil, ν max. 3310 (hydroxyl groups), 1705 (acid carbonyl group), and 970 cm-1 (trans vinyl group).

EXAMPLES 680-685

Treatment of the 9-oxo-derivatives listed in the table below with sodium borohydride in accordance with the procedure described in Example 674 is productive of the 9-hydroxy derivatives of the table. Each of these derivatives represents a mixture of 9α- and 9β-hydroxy compounds.

TABLE 18
______________________________________
Startng 9-oxo-
derivative of
Product
Example
Example 9α/9β-hydroxy derivative
______________________________________
680 305 Ethyl9α/9β,20-dihydroxy-13-
trans-prostenoate
681 329 Ethyl9α/9β,16-dihydroxy-3-
thia-13-trans-prostenoate
682 355 3-oxa 9α/9β16-dihyroxy-11α-
methoxy-13-trans-prostanoic
acid
683 364 9α/9β,11α,16-trihydroxy-13-
trans-prostenoic acid
684 378 9α/9β,11α20-trihydroxy-7a,7b-
bisheo-13-trans-prostenoic
acid
685 414 9α/9β16-dihydroxy-11-60 -(β-
hydroxyethoxy)-13-trans-
prostenoic acid
______________________________________
EXAMPLE 686
PAC Preparation of 20-hydroxy-9-oxo-10,13-trans-prostadienoic acid

A solution of 355 mg. (1.00 mmoles) of 11α ,20-dihydroxy-9-oxo-13-trans-prostenoic acid (Example 280a) in 6.67 ml. of 1.5N hydrochloric acid and 13.3 ml. of tetrahydrofuran is allowed to stand at room temperature for 70 hours. The solution is treated with saturated sodium chloride solution and extracted with ether. The extract is washed successively with water and saturated sodium chloride solution and dried over magnesium sulfate. The crude product obtained after evaporation of the solvent is purified by chromatography on silica gel to give an oil, ν max MeOH = 217 mμ (9500); ν max = 1700 (acid carbonyl group), 1690 (ketone carbonyl group), 1585 (conjugated olefin group), and 965 cm-1 (trans vinyl group).

EXAMPLES 687-737

Acid treatment by the procedure described in Example 686 of the 11α-hydroxy-9-oxo derivatives listed in the table below is productive of the Δ10 derivatives of the table.

TABLE 19
______________________________________
Starting 11α-
hydroxy-9-oxo- Product
derivative of 9-0x0-10-prostenoic acids and
Example
Example esters
______________________________________
687 387 9-oxo-2-phenyl-16-hydroxy-20-
ethyl-10,13-trans-prostadienoic
acid
688 388 9-oxo-methyl-15-hydroxy-10,13-
trans-prostadienoic acid
689 389 9-oxo-2-methyl-20-hydroxy-10,13-
trans-prostadienoic acid
690 390 Ethyl 9-oxo-16-hydroxy-10,13-
trans-prostadienoate
691 391 Ethyl 9-oxo-20 hydroxy-10,13-
trans-prostadienoate
692 392 Methyl 9-oxo-16-hydroxy-10,13-
trans-prostadienoate
693 393 Ethyl9-oxo-6,7-dinor-20-hydroxy-
methyl-10,13-trans-prostadienoate
694 394 Ethyl-9-oxo-5,6,7-trnor-16-
hydroxy-19-methyl-10,13-trans-
prostadienoate
695 395 Ethyl 9-oxo-7a,7b-bishomo-19-
hydroxy-20-nor-10,13-trans-
prostadienoate
696 396 Ethyl 9-oxo-2-ethyl-16-hydroxy-
17-ethyl-20-nor-10,13-trans-
prostadienoate
697 397 Ethyl 9-oxo-3,3-dimethyl-17-
hydroxy-19,20-dinor-10,13-trans-
prostadienoate
698 398 Ethyl 9-oxo-3-oxa-20-hydroxy-
methyl-10,13-trans-prostadienoate
699 399 Ethyl 9-oxo-2-fluoro-20-hydroxy-
10,13-trans-prostadienoate
700 400 Ethyl 9-oxo-7-nor-16-hydroxy-
20-methyl-10,13-trans-
prostadienoate
701 401 EThyl9-oxo-7a,homo-16-hydroxy-
17-methyl-19,20-dinor-10,13-
trans-prostadienoate
702 402 Ethyl 9-oxo-2-phenyl-17-hydroxy-
19,20-dinor-10,13-trans-
prostadienoate
703 403 Butyl 9-oxo-16-hydroxy-10,13-
trans-prostadienoate
704 404 Butyl 9-oxo-20-hyroxy-10,13-
trans-prostadienoate
705 405 Isopropyl 9-oxo-16-hydroxy-
10,13-trans-prostadienoate
706 406 Isopropyl 9-oxo-20-hydroxy-10,
13-trans-prostadienoate
707 407 Decyl 9-oxo-16-hydroxy-10,13-
trans-prostadienoate
708 408 Decyl 9-oxo-20-hydroxy-10,13-
trans-prostadienoate
709 364 9-oxo-16-hyroxy-10,13-trans-
prostadienoic acid
710 365 9-oxo-16-hydroxy-20-nor-10,13-
trans-prostadienoic acid
711 366 9-oxo-16-hydroxy-17-methyl-19-
20-dinor-10,13-trans-prosta-
dienoic acid
712 367 9-oxo-17-hydroxy-19,20-dinor-
10,13-trans-prostadienoic acid
713 368 9-oxo16-hydroxy-19-methyl-10-
13-trans-prostadienoic acid
714 369 9-oxo-16-hyroxy-17-ethyl-20-
nor-10,13-trans-prostadienoic
acid
715 370 9-oxo-18-hydroxy-10,20-dinor-
10,13-trans-prostadienoic acid
716 371 9-oxo-19-hydroxy-nor-10,13-
trans-prostadienoic acid
717 372 9-oxo-20-hyroxymethyl-10,13-
trans-prostadienoic acid
718 373 9-oxo-20-(3-hydroxypropyl)-10-
13-trans-prostadienoic acid
719 374 9-oxo-16-methyl-17-hydroxy-19-
20-dinor-10,13-trans-prosta-
dienoic acid
720 375 9-oxo-6,7-dinor-16-hydroxy-20-
ethyl-10,13-trans-prostadienoic
acid
721 376 9-oxo-5,6,7-trinor-20-hyroxy-
10,13-trans-prostadienoic acid
722 377 9-oxo-7a,7b-bishomo-16-hydroxy-
10,13-trans-prostadienoic acid
723 378 9-oxo-7a,7b-bishomo-20-hydroxy-
10,13-trans-prostadienoic acid
724 380 9-oxo-2-ethyl-16-hydroxy-18,19.
20-trinor-10,13-trans-prost-
dienoic acid
725 381 9-oxo-3,3-dimethyl-16-hyroxy-
10,13-trans-prostadienoic acid
726 382 9-oxo-3,3-dimethyl-20-hydroxy-
10,13-trans-prostadienoic acid
727 383 9-oxo-3-oxa-16-hydroxy-10,13-
trans-protadienoic acid
728 384 9-oxo-2-fluoro-16-methyl-17-
hydroxy-18,19,20-trinor-10,13-
trans-prostadienoic acid
729 385 9-oxo-7-nor-16-hyroxy-10,13-
trans-oprostadienoic acid
730 386 9-oxo-7a-homo-16-hydroxy-10,13-
trans-prostadienoic acid
731 521 9-oxo-16-hydroxy-10-prostenoic
acid
732 523 9-oxo-17-hydroxy-10,20-dinor-
10-prostenoic acid
733 526 9-oxo-19-hydroxy-20-nor-10-
prostenoic acid
734 529 9-oxo-17-hydroxy-16-methyl-10-
20-dinor-10-prostenoic acid
735 531 9-oxo-16-hydroxy 7a,7b-bishomo-
10-prostenoic acid
736 534 9-oxo-20-hydroxy-3,3-dimethy-
10-prostenoic acid
737 535 9-oxo-16-hydroxy-3-oxa-10-
prostenoic acid
______________________________________
EXAMPLE 738
PAC Preparation of ethyl 9-oxo-13-trans-prostenoate

A solution of 1.102 g. of 1-octyne in 2 ml. of benzene is treated with 11.5 ml. of 15% diisobutylaluminum hydride in toluene and the solution is heated to 50°C for 2 hours. The solution is cooled, its solvent is removed in vacuo, and the resulting oil is treated with 5.45 ml. of 5.10% methyl lithium in diethyl ether with ice cooling. To the resulting solution is added 1.830 g. of 2-(6-carbethoxyhexyl)-2-cyclopentenone (Example 13) and the solution is stirred at ambient temperatures for 18 hours. The solution is poured onto ice and dilute hydrochloric acid, and the mixture is extracted with diethyl ether. The organic phase is washed with dilute sodium bicarbonate, water, and saturated brine, dried, and evaporated. The residue is purified by chromatography on Florisil and distilltion to yield 1.878 g. of an oil, IR 1736 cm-1 (ester and ketone carbonyls) 969 cm-1 (trans vinyl group); NMR (CDCl3) δ 5.14-5.87 (multiplet, 2H, vinyl protons, J trans=15 Hz); Mass Spectrum, parent peak at 350 mμ.

EXAMPLE 739
PAC Preparation of ethyl 20-chloro-9-oxo-13-trans-prostenoate

In the manner described in Example 738, 2-(6-carbethoxyhexyl)-2-cyclopentenone (Example 13) is added to the reagent prepared from 8-chloro-1-octyne [W. J. Gensler and G. R. Thomas, J. Amer. Chem. Soc., 73, 4601 (1951)], diisobutylaluminum hydride, and methyl lithium. The crude product obtained by acid hydrolysis is purified by silica gel chromatography to give an oil, IR 1740 cm-1 (ester and ketone carbonyls), 967 cm-1 (trans vinyl group).

EXAMPLE 740
PAC Preparation of ethyl 20-iodo-9-oxo-13-trans-prostenoate

A stirred mixture of 30 g. of ethyl 20-chloro-9-oxo-13-trans-prostenoate (Example 739), 25 g. of sodium iodide and 225 ml. of acetone is refluxed for 12 hours. The reaction mixture is concentrated, diluted with water, and extracted with ether. The extract is washed with saturated sodium chloride, dried, and evaporated to give an oil.

EXAMPLE 741
PAC Preparation of 9-oxo-13-trans-prostenoic acid

A mixture of 0.140 g. of ethyl 9-oxo-13-trans-prostenoate (Example 738) and 0.072 g. of potassium hydroxide in 6 ml. of 1:1 aqueous methanol is stirred at ambient temperature for 17 hours. The resulting solution is acidified with hydrochloric acid, extracted with diethyl ether, and the organic phase is washed with water and saturated brine, dried, and the solvent removed to yield 0.128 g. of an oil, IR 1739 cm-1 (ketone carbonyl) 1706 cm-1 (acid carbonyl), 969 cm-1 (trans vinyl group); NMR (CDCl3) 5.34-5.67 (multiplet, 2H, vinyl protons, J trans=15 Hz), 10.47 (broad singlet, 1H, carboxyl proton, exchangeable); Mass spectrum, parent peak at 322 mμ.

EXAMPLE 742
PAC Preparation of ethyl 9,9-ethylenedioxy-20-iodo-13-trans-prostenoate

A solution of 25.2 g. of ethyl 20-iodo-9-oxo-13-trans-prostenoate (Example 740), 5.6 ml. of ethylene glycol and 110 mg. of p-toluenesulfonic acid monohydrate in 170 ml. of benzene is refluxed for 4 hours with azeotropic removal of water. The solution is concentrated to a volume of 50 ml. Column chromatography of the solution on Florisil with benzene gives a liquid, IR 1740 (ester carbonyl), 967 (trans vinyl group), and 952 cm-1 (ethylene ketal).

EXAMPLE 743
PAC Preparation of ethyl 20-benzoyloxy-9,9-ethylenedioxy-13-trans-prostenoate

A stirred mixture pf 7.80 g. (15 mmoles) of ethyl 9,9-ethylenedioxy-20-iodo-13-trans-prostenoate, (Example 742), 8.65 g. (60 mmoles) of sodium benzoate, and 100 ml. of dry methylformamide is maintained at 115°C for 2 hours. The mixture is cooled, diluted with water and extracted with ether. The extract is washed successively with water, saturated sodium becarbonate solution, and saturated sodium chloride solution. The extract is dried over magnesium sulfate. The crude product obtained by evaporation of the solvent is purified by chromatography on silica gel to give an oil, ν max. 1745 (alkanoate ester group), 1730 (benzoate ester group), 967 (trans vinyl group), and 948 cm-1 (ethylenedioxy group).

EXAMPLE 744
PAC Preparation of ethyl 20-benzoyloxy-9-oxo-13-trans-prostenoate

A solution of 5.35 g. (10.4 mmoles) of ethyl 20-benoyloxy-9,9-ethylenedioxy-13-trans-prostenoate (Example 743), 99 mg. (0.52 mmoles) of p-toluenesulonic acid monohydrate, and 40 ml. of acetone is allowed to stand at room temperature for 41 hours. The acetone is evaporated, and the residue is dissolved in ether. The solution is washed successively with sodium chloride solution, dilute sodium bicarbonate solution, and saturated sodium chloride solution. The solution is dried over magnesium sulfate and concentrated to give an oil, ν max. 1740 (ketone and alkanoate ester groups), 1730 benzoate ester group), and 967 cm-1 (trans vinyl group).

EXAMPLE 745
PAC Preparation of 20-hydroxy-9-oxo-13-trans-prostenoic acid

A solution of 4.75 g. (10.1 mmoles) of ethyl 20-benzoyloxy-9-oxo-13-trans-prostenoate (Example 744), 3.31 g. (50 mmoles) of 85% potassium hydroxide, 90 ml. of methanol, and 9 ml. of water is allowed to stand at room temperature for 24 hours. The solution is concentrated, diluted with water, and extracted with ether. The extract is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. Column chromatography of the crude product on silica gel gives an oil, ν max. 1735 (ketone carbonyl group), 1710 (acid carbonyl group), and 967 cm-1 (trans vinyl group).

EXAMPLE 746
PAC Preparation of 9-oxo-18-hydroxy-19-hydroxy-13-trans-prostenoic acid

Inoculum Preparation:

A typical medium used to grow the inoculum was prepared according to the following formula:

______________________________________
Sodium Nitrate 3 grams
Dipotassium Hydrogen Phosphate
1 gram
Magnesium Sulfate Heptahydrate
5 grams
Potassium Chloride 5 grams
Ferrous Sulfate Heptahydrate
0.01 grams
Sucrose 30 grams
Water to 1000 milliliters
______________________________________

The washed or scraped spores from an agar slant of Lederle Culture V89 (a strain of Diplodia malorum received from Centraalbureau voor Schirnmel cultures Baarn, Netherlands) is used to inoculate a flask containing 50 milliliters of the above medium in a 250 milliliter flask. The flask is placed on a rotary shaker and agitated vigorously for 5 days at 22° C.

Ten milliliters of the above first stage inoculum is introduced into two additional 250 milliliter flasks each containing 50 milliliters of medium, using 5 milliliters per flask. The flasks are incubated from 72 hours under the same conditions described for the first stage inoculum.

The 100 milliliters of second stage inoculum is used to inoculate a 4 liter glass fermentor containing 2 liters of sterile medium. The fermentor is aerated with sterile air while growth is continued for 72 hours at 25°C This 2 liters of inoculum is used to inoculate a 40 liter tank fermentor containing 20 liters of liquid medium.

Fermentation:

A fermentation medium is prepared according to the same formula used for the inoculum medium. The fermentation medium is sterilized at 120° C. with steam at 20 pounds pressure for 45-60 minutes. The pH of the medium after sterilization is 6.6. Twenty liters of sterile medium in a 40 liter tank fermentor is inoculated with 2 liters of inoculum and the fermentation is carried out at 22°C using lard oil, as necessary, as a defoaming agent. Aeration is supplied at the rate of 1.0 liters of sterile air per liter of mash per minute. The mash is agitated by air impeller driven at 400 revolutions per minute. At the end of 42 hours of fermentation time, a 5.15 gram sample of CL82, 680 dissolved in 150 milliliters of acetone is added to the fermentation. The fermentation is continued for an additional 5 hours whereupon the mash is harvested.

Isolation:

Twenty liters of fermentation mash (pH 7.5) is clarified by filtration through Hyflo, and the filtrate is extracted with three one-fifth volumes of chloroform after prior adjustment to pH 2.8 with hydrochloric acid. The combined chloroform extract is concentrated to a residue (4.85 g.) in vacuo, which after trituration with two 100 milliliter portions of cold hexane gives 4.28 g. residue.

This residue is further purified by adsorption chromatography on 100 grams of Davison Grade No. 62 silica gel slurry-packed in chloroform. The residue is dissolved in a small volume of chloroform, applied to the column and the column developed with a linear gradient between 1 liter each of chloroform and 10% ethanol-in-chloroform. Fractions of about 15 milliliters each are collected automatically. The progress of development is followed by monitoring the column effluent at 240 nanometers and also by thin layer chromatography of appropriate fractions. The fractions (47-80) containing the subject product are combined and concentrated to a residue (3.55 g.) in vacuo.

This residue is further purified by means of partition chromatography on 300 grams Celite. The column support is prepared by mixing 0.5 milliliters of the lower phase from the solvent system hexane-ethyl acetate-methanol-water (9:3:2:1) with each 1 gram of Celite. The residue from above, dissolved in 5 milliliters of lower phase is treated similarly and packed on top of the column which is then eluted with this upper phase. Fractions of about 60 milliliters each are collected automatically. The progress of development is followed by monitoring the column effluent at 270 nanometers and also by thin layer chromatography of appropriate fractions. The fractions (16-36) containing the desired compound are combined and concentrated to a residue (2.93 g.) in vacuo. This is dissolved in some chloroform, poured over 50 grams of Davison Grade No. 62 silica gel slurry-packed in chloroform, and, following washing the column with chloroform, it is eluted with 10% ethanol-in-chloroform to give, following evaporation, 2.9 grams product, which by nmr analysis contains a mixture of the 18-hydroxy and 19-hydroxy derivative in a ratio of about 3:1 to 1:1.

EXAMPLE 747
PAC Preparation of 9-oxo-18,19-oxo-13-trans-prostenoic acid

A 1.5 gram sample of the product from Example 746 is dissolved in 20 milliliters of acetone and Jones Reagent (6.68 grams CrO3 in 5.75 milliliters concentrated H2 SO4 diluted to 25 milliliters with water) is added slowly with stirring until the color persist. The reaction mixture is stirred an additional 15 minutes whereupon the excess reagent is destroyed by the addition of methanol. The mixture is diluted to about 200 milliliters with water and extracted with three 50 milliliter portions of chloroform, which is then dried with anhydrous sodium sulfate and evaporated to give 1.5 grams of a pale yellow oil. This dissolved in some chloroform, poured over 30 grams of Davison Grade No. 62 silica gel slurry-packed in chloroform and, following washing the column with chloroform it is eluted with 5% ethanol-in-chloroform to give, following evaporation, 1.46 grams of subject product ketones.

EXAMPLES 748-750

Treatment of the 3-hydroxymethyl-1-alkynes, listed in Table 20 below, with triphenylmethyl bromide by the procedure described in Example 278 is productive of the 3-triphenylmethoxymethyl-1-alkynes of the Table.

TABLE 20
______________________________________
Starting 3-hydroxy-
Product 3-triphenylmethoxy-
Example
methyl-1-alkyne
methyl-1-alkyne
______________________________________
748 3-hydroxymethyl-1-
3-triphenylmethoxymethyl-
hexyne* 1-hexyne
749 3-hydroxymethyl-1-
3-triphenylmethoxymethyl-
heptyne* 1-heptyne
750 3-hydroxymethyl-1-
3-triphenylmethoxymethyl-
octyne* 1-octyne
______________________________________
*A. Schaap, L. Brandsma and J.F. Arens, Rec. trav. chim., 86. 393 (1967).
EXAMPLE 750a
PAC Preparation of 1-chloro-3-triphenylmethoxy hexane

A stirred solution of 27.3 g. (0.20 moles) of 1-chloro-3-hexanol, 77.6 g. (0.24 moles) of triphenylmethyl bromide, 30.0 g. (0.28 moles of 2,6-lutidine, and 200 ml. of chlorobenzene is heated at 95°C for 1 hour. The cooled mixture is treated with water, and the organic phase is washed successively with water and saturated sodium chloride solution. The solution is dried over magnesium sulfate and concentrated. Column chromatography of the residue on Florisil affords the subject compound as an oil, ν max. 1600, 1030, and 705 cm-1 (triphenylmethoxy group).

EXAMPLE 751
PAC Preparation of 5-triphenylmethoxy-1-octyne

To a stirred solution of 32.2 g. (85 mmoles) of 1-chloro-3-triphenylmethoxyhexane (Example 750a) in 25 ml. of dimethylsulfoxide (DMSO) is added a solution of 9.4 g. (102 mmoles) of lithium acetylide-ethylene diamine complex in 60 ml. of DMSO during 10 minutes while maintaining a temperature of 25°-30°C After 3.5 hours the mixture is diluted with ether and treated successively with water and 4N hydrochloric acid while cooling in an ice bath. The phases are separated, and the aqueous phase is extracted with ether-petroleum ether. The combined extracts are washed successively with water and saturated sodium chloride solution dried over magnesium sulfate, and concentrated. The product is then purified by column chromtography of the residue of Florisil.

EXAMPLE 752-775

Conjugate addition of the alanates obtained by treatment of the triphenylmethoxy (trityloxy)-1-alkynes (indicated in the following table) with diisobutylaluminum hydride followed by methyl lithium, to the cyclopentenones of the table according to the method described in Example 280 followed by de-O-tritylation of the intermediate triphenylmethoxyprostenoates according to the method of Example 280a is productive of the prostenoic acids and esters of the table.

Those compounds isolated and identified in the table as prostenoic acids are prepared via the corresponding tetrahydropyran-2-yl esters and these compounds bearing a free hydoxy function at the 11 α-position or as part of an 11α-(ω-hydroxyalkoxy) moiety are prepared via the corresponding tetrahydropyran-2-yl ethers. The hydroxy function in the β-side chain (that portion of the molecule deriving from the triphenylmethoxy-1-alkyne) of all compounds in the table are initially present in the molecule as the corresponding triphenylmethyl ethers. During the acetic acid treatment (de-O-tritylation step) the triphenylmethyl ether as well as the tetrahydropyran-2-yl ethers and esters functions are hydrolyzed to provide the corresponding free hydroxy and carboxylic acid groups of the compounds listed in the table.

TABLE 21
__________________________________________________________________________
Starting cyclo-
Starting trityloxy
pentenones of
1-alkyne of
Product
Example
Example Example Hydroxy Prostenoic Acid or Ester
__________________________________________________________________________
752 13 748 Ethyl 9-oxo-15-hydroxymethyl-19,20-dinor-13-
trans-prostenoate
753 13 749 Ethyl 9-oxo-15-hydroxymethyl-20-nor-13-trans-
prostenoate
754 13 750 Ethyl 9-oxo-15-hydroxymethyl-13-trans-
prostenoate
755 13 751 Ethyl 9-oxo-17-hydroxy-13-trans-prostenoate
756 23 751 Ethyl 9-oxo-17-hydroxy-7a,7b-bishomo-13-
trans-prostenoate
757 41 750 Ethyl 9-oxo-15-hydroxymethyl-3,3-dimethyl-
13-trans-prostenoate
758 276 750 Ethyl 9-oxo-15-hydroxymethyl-3-thia-13-trans-
prostenoate
759 276 751 Ethyl 9-oxo-17-hydroxy-3-thia-13-trans-
prostenoate
760 147 751 9-oxo-11α,17-dihydroxy-13-trans-prostenoic
acid
761 147 748 9-oxo-11α-hydroxy-15-hydroxymethyl-19,20-
dinor-13-trans-prostenoic acid
762 147 749 9-oxo-11α-hydroxy-15-hydroxymethyl-20-nor-
O
13-trans-prostenoic acid
763 147 750 9-oxo-11α-hydroxy-15-hydroxymethyl-13-trans
-
prostenoic acid
764 151 750 9-oxo-11α-hydroxy-15-hydroxymethyl-2-ethyl-
13-trans-prostenoic acid
765 152 751 9-oxo-11α,17-dihydroxy-3,3-dimethyl-13-tran
s-
prostenoic acid
766 153 751 9-oxo-11α,17-dihydroxy-3-oxa-13-trans-
prostenoic acid
767 153 750 9-oxo-11α-hydroxy-15-hydroxymethyl-3-oxa-13
-
trans-prostenoic acid
768 154 750 9-oxo-11α-hydroxy-15-hydroxymethyl-2-fluoro
-
13-trans-prostenoic acid
769 155 749 9-oxo-11α-hydroxymethyl-7,20-dinor-
13-trans-prostenoic acid
770 157 750 9-ox-11α-hydroxy-15-hydroxymethyl-2-phenyl-
N
13-trans-prostenoic acid
771 157a 750 9-oxo-11α-hyddroxy-15-hydroxynethyl-7a-homo
-13-
trans-prostenoic acid
772 242a 750 9-oxo-11α-methoxy-15-hydroxymethyl-13-trans
prostenoic acid
773 242a 751 9-oxo-11α-methoxy-17-hydroxy-13-trans-
prostenoic acid
774 247 750 9-oxo-11α-(2-hydroxyethoxy)-15-hydroxymethy
l-
13-trans-prostenoic acid
775 247 751 9-oxo-11α-(2-hydroxyethoxy)-17-hydroxy-13-
trans-prostenoic acid
__________________________________________________________________________
EXAMPLES 776-783

Saponification of the designated esters in Table 22 below by the method described in Example 283 is productive of the prostenoic acids of the table.

TABLE 22
______________________________________
Starting alkyl
prostenoate of
Example
Example Product Prostenoic Acid
______________________________________
776 752 9-oxo-15-hydroxymethyl-19,20-
dinor-13-trans-prostenoic acid
777 753 9-oxo-15-hydroxymethyl-20-mor-
13-trans-prostenoic acid
778 754 9-oxo-15-hydroxymethyl-13,trans-
prostenoic acid
779 755 9-oxo-17-hydroxy-13-trans-
prostenoic acid
780 756 9-oxo-17-hydroxy-7a,7b-bishomo-
13-trans-prostenoic acid
781 757 9-oxo-15-hydroxymethyl-3,3-
dimethyl-13-trans-prostenoic
acid
782 758 9-oxo-15-hydroxymethyl-3-thia-
13-trans-prostenoic acid
783 759 9-oxo-17-hydroxy-3-thia-13-
trans-prostenoic acid
______________________________________
EXAMPLES 784-815

Hydrogenation of the 13-prostenoic acids and esters listed in Table 23 below furnishes the prostanoic acids and esters of the table.

TABLE 23
______________________________________
Starting
13-prostanoic
Ex- acid or ester
ample of Example Product Prostanoic Acid or Ester
______________________________________
784 752 ethyl 9-oxo-15-hydroxymethyl-
19,20-dinor prostanoate
785 753 ethyl 9-oxo-15-hydroxymethyl-
20-nor-prostanoate
786 754 ethyl 9-oxo-15-hydroxymethyl-
prostanoate
787 755 ethyl 9-oxo-17-hydroxy-
prostanoate
788 757 ethyl 9-oxo-17-hydroxymethyl-
7a,7b-bishomo-prostanoate
789 757 ethyl 9-oxo-15-hydroxymethyl-
3,3-dimethyl-prostanoate
790 758 ethyl 9-oxo-15-hydroxymethyl-
3-thia-prostanoate
791 759 ethyl 9-oxo-17-hydroxy-3-thia-
prostanoate
792 760 9-oxo-11α,17-dihydroxy-prostanoic
acid
793 761 9-oxo-11α-hydroxy-16-hydroxy-
methyl-19,20-dinor-prostanoic
acid
794 762 9-oxo-11α-hydroxy-15-hydroxy-
methyl-20-nor-prostanoic acid
795 763 9-oxo-11α-hydroxy-15-hydroxy-
methyl-prostanoic acid
796 764 9-oxo-11α-hydroxy-15-hydroxy-
methyl-2-ethyl-prostanoic acid
797 765 9-oxo-11α,17-dihydroxy-3,5-
dimethyl-prostanoic acid
798 766 9-oxo-11α,17-dihydroxy-3-oxa-
prostanoic acid
799 767 9-oxo-11α-hydroxy-15-hydroxy-
methyl-3-oxa-prostanoic acid
800 768 9-oxo-11α-hydroxy-15-hydroxymethyl-
2-fluoro-prostanoic acid
801 769 9-oxo-11α-hydroxy-15-hydroxy-
methyl-7,20-dinor prostanoic acid
802 770 9-oxo-11α-hydroxy-15-hydroxymethyl-
2-phenyl-prostanoic acid
803 771 9-oxo-11α-hydroxy-15-hydroxymethyl-
7a-homo-prostanoic acid
804 772 9-oxo-11α-methoxy-15-hydroxymethyl-
prostanoic acid
805 773 9-oxo-11α-methoxy-17-hydroxy-
prostanoic acid
806 774 9-oxo-11α-(2-hydroxyethoxy)-
15-hydroxymethyl-prostanoic acid
807 775 9-oxo-11α-(2-hydroxyethoxy)-
17-hydroxy-prostanoic acid
808 776 9-oxo-15-hydroxymethyl-19,20-
dinor-prostanoic acid
809 777 9-oxo-15-hydroxymethyl-20-nor
810 778 9-oxo-15-hydroxymethyl-prostanoic
acid
811 779 9-oxo-17-hydroxy-prostanoic acid
812 780 9-oxo-17-hydroxy-7a,7b-bishomo-
prostanoic acid
813 781 9-oxo-15-hydroxymethyl-3,3-
dimethyl-prostanoic acid
814 782 9-oxo-15-hydroxymethyl-3-thia-
prostanoic acid
815 783 9-oxo-17-hydroxy-3-thia-prostanoic
acid
______________________________________
EXAMPLES 816-868

Reduction of the 9-oxo-derivatives listed in Table 24 below with lithium perhydro-9β-boraphenalyl hydride by the procedure described in Example 575 is productive of the 9α-hydroxy derivative of the Table.

TABLE 24
______________________________________
Starting 9-oxo
Ex- derivative of
ample Example Product 9α-hydroxy derivative
______________________________________
816 752 Ethyl 9α-hydroxy-15-hydroxy-
methyl-19,20-dinor-13-trans-
prostenoate
817 753 Ethyl 9α-hydroxy-15-hydroxy-
methyl-20-nor-13-trans-
prostenoate
818 754 Ethyl 9α-hydroxy-16-hydroxy-
methyl-13-trans-prostenoate
819 755 Ethyl 9α,17-dihydroxy-13-
trans-prostenoate
820 756 Ethyl 9α,17-dihydroxy 7a,7b-
bishomo-113-trans-prostenoate
821 757 Ethyl 9α-hydroxy-15-hydroxy-
methyl-3,3-dimethyl-13-trans-
prostenoate
822 758 Ethyl 9α-hydroxy-15-hydroxy-
methyl-3-thia-13-trans-
prostenoate
823 759 Ethyl 9α,17-dihydroxy-3-thia-
13-trans-prostenoate
824 760 9α,11α,17-trihydroxy-13-trans-
prostenoic acid
825 761 9α,11α-dihydroxy-15-hydroxy-
methyl-19,20-dinor-13-trans-
prostenoic acid
826 762 9α,11α-dihydroxy-15-hydroxy-
methyl-20-nor-13-trans-
prostenoic acid
827 763 9α,11α-dihydroxy-15-hydroxy-
methyl-13-trans-prostenoic
acid
828 764 9α,11α-dihydroxy-15-hydroxy-
methyl-2-ethyl-13-trans-
prostenoic acid
829 765 9α,11α,17-trihydroxy-3,3-di-
methyl-13-trans-prostenoic acid
830 766 9α,11α,17-trihydroxy-3-oxa-13-
trans-prostenoic acid
831 767 9α,11α-dihydroxy-15-hydroxy-
methyl-3-oxa-13-trans-
prostenoic acid
832 768 9α,11α-dihydroxy-15-hydroxy-
methyl-2-fluoro-13-trans-
prostenoic acid
833 769 9α,11α-dihydroxy-15-hydroxy-
methyl-7,20-dinor-13-trans-
prostenoic acid
834 770 9α,11α-dihydroxy-15-hydroxy-
methyl-2-phenyl-13-trans-
prostenoic acid
835 771 9α,11α-dihydroxy-15-hydroxy-
methyl-7a-homo-13-trans-
prostenoic acid
836 772 9α-hydroxy-11α-methoxy-15-
hydroxymethyl-13-trans-
prostenoic acid
837 773 9α-hydroxy-11α-methoxy-9α,1l7-
dihydroxy-13-trans-prostenoic
acid
838 774 9α-hydroxy-11α-(2-hydroxy-
ethoxy)-15-hydroxymethyl-13-
trans-prostenoic acid
839 775 9α-hydrox-11α-(2-hydroxy-
ethoxy)-17-hydroxy-13-trans-
prostenoic acid
840 776 9α-hydroxy-15-hydroxymethyl-
19,20-dinor-13-trans-
prostenoic acid
841 777 9α-hydroxy-15-hydroxymethyl-
20-nor-13-trans-prostenoic
842 778 9α-hydroxy-15-hydroxymethyl-13-
trans-prostenoic acid
843 779 9α,17-dihydroxy-13-trans-
prostenoic acid
844 780 9α,17-dihydroxy-7a,7b-bishomo-
13-trans-prostenoic acid
845 781 9α-hydroxy-15-hydroxymethyl-
3,3-dimethyl-13-trans-
prostenoic acid
846 782 9α-hydroxy-15-hydroxymethyl-
3-thia-13-trans-prostenoic
acid
847 809 9α-hydroxy-15-hydroxymethyl-
19,20-dinor-prostanoic acid
848 809 9α-hydroxy-15-hydroxymethyl-
20-nor-prostanoic acid
849 810 9α-hydroxy-15-hydroxymethyl-
prostanoic acid
850 811 9α,17-dihydroxy-prostanoic
acid
851 812 9α,17-dihydroxy-7a,7b-bishomo-
prostanoic acid
852 813 9α-hydroxy-15-hydroxymethyl-
3,3-dimethyl-prostanoic acid
853 792 9α,11α,17-trihydroxy-prostanoic
acid
854 793 9α,11-dihydroxy-15-hydroxy-
methyl-19,20-dinor-prostanoic
acid
855 794 9α,11-dihydroxy-15-hydroxy-
methyl-20-nor-prostanoic acid
856 795 9α,11-dihydroxy-15-hydroxy-
methyl-prostanoic acid
857 796 9α,11-dihydroxy-15-hydroxy-
methyl-2-ethyl-prostnoc acid
858 798 9α,11α,17-trihydroxy-3-oxa-
methyl-prostanoic acid
859 798 9α,11α,17-trihydroxy-3-oxa-
prostanoic acid
860 799 9α,11α-dihydroxy-15-hydroxy-
methyl-3-oxa-prostanoic acid
861 800 9α,11α-dihydroxy-15-hydroxy-
methyl-2-fluoro-prostanoic
acid
862 801 9α,11α-dihydroxy-15-hydroxy-
methyl-7,20-dinor-prostanoic
acid
863 802 9α,11α-dihydroxy-15-hydroxy-
methyl-2-phenyl-prostanoic
acid
864 803 9α,11α-dihydroxy-15-hydroxy-
methyl-7a-homo-prostanoic acid
865 804 9α-hydroxy-11α-methoxy-15-
hydroxymethyl-prostanoic acid
866 805 9α-hydroxy-11α-methyl-17-
hydroxy-prostanoic acid
867 806 9α,11α-(2-hydroxyethoxy)-15-
hydroxymethyl-prostanoic acid
868 807 9α,11α-(2-hydroxyethoxy)-17-
hydroxy-prostanoic acid
______________________________________
EXAMPLES 869-893

Acid treatment of the method described in Example 686 of the 11α-hydroxy-9-oxo derivatives listed in the table below furnishes the Δ10 -derivatives of the table.

TABLE 25
______________________________________
Starting 11α-
hydroxy-9-oxo-
derivative of
Product 9-oxo-10-prostenoic noic
Example
Example acids and esters
______________________________________
869 760 9-oxo-17-hydroxy-10,13-trans-
prostadienoic acid
870 761 9-oxo-15-hydroxymethyl-19,20-
dinor-10,13-trans-prostadienoic
acid
871 762 9-oxo-15-hydroxymethyl-20-nor-10,
13-trans-prostadienoic acid
872 763 9-oxo-15-hydroxymethyl-10,13-
trans-prostadienoic acid
873 764 9-oxo-15-hydroxymethyl-2-ethyl-
10,13-trans-prostadienoic acid
874 765 9-oxo-17hydroxy-3,3-dimethyl-
10,13trans-prostadienoic acid
875 766 9-oxo-17-hydroxy-3-oxa-10,13-
trans-prostadienoic acid
876 767 9-oxo-15-hydroxymethyl3-oxa-10,
13-trans-prostadienoic acid
877 768 9-oxo-15-hydroxymethyl-2-fluoro-
10,13-trans-prostadienoic acid
878 770 9-oxo-15-hydroxymethyl-2-phenyl-
10,13-trans-prostandienoic acid
879 770 9-oxo-15-hydroxymethyl-2-phenyl-
10,13-trans prostandienoic acid
880 771 9-oxo-15-hydroxymethyl-7a-homo-
10,13-trans- prostadienoic acid
881 792 9-oxo-17-hydroxy-10-prostenoic
acid
882 793 9-oxo-15-hydroxymethyl-19,20-
dinor-prostenoic acid
883 794 9-oxo-15-hydroxymethyl-20-nor-
prostenoic acid
884 795 9-oxo-15-hydroxymethyl-prostenoic
acid
885 796 9-oxo-15-hydroxymethyl-2-ethyl-
prostenoic acid
886 797 9-oxo-17-hydroxy-3,3-dimethyl-
prostenoic acid
887 798 9-oxo-17-hydroxy-3-oxa-prostenoic
acid
888 799 9-oxo-15-hydroxymethyl-3-oxa-
prostenoc acid
889 800 9-oxo-15-hydroxymethyl-2-fluoro-
prostenoic acid
890 801 9-oxo-15-hydroxymethyl-7,20-
dinor-prostenoic acid
891 802 9-oxo-15-hydroxymethyl-2-phenyl-
prostenoic acid
892 803 9-oxo-15-hydroxymethyl-7a-homo-
prostenoic acid
______________________________________
EXAMPLE 893
PAC Preparation of 4-hydroxy-1-octyne

A suspension of 24.3 g. (1.0 mole) of magnesium in 90 ml of dry ether is stirred at room temperature under nitrogen with 100 mg. of mercuric chloride. The reaction is initiated by the addition of 2 ml. of propargyl bromide and maintained by the dropwise addition of a solution of 119.5 g. (1.0 mole) of propargyl bromide and 107.7 g. (1.25 mole) of valeraldehyde in 300 ml. of dry ether. While the initial reaction is quite vigorous and is maintained at 30°C only by cooling in an ice bath it may become necessary to heat the mixture to reflux temperature after about a third of the ether solution is added in order to maintain the reaction. After the addition is complete the reaction mixture is refluxed until most of the magnesium is dissolved (several hours) and the reaction mixture is decanted from excess magnesium into 1500 ml. of stirred ice-cold ammonium chloride solution. The ether layer is separated and the aqueous layer is extracted three times with 300 ml. portions of ether. The combined ether extract is washed with saturated sodium chloride solution, dried over magnesium sulfate and filtered. Evaporation of the ether under vacuum leaves about 115 mg. of yellow oil, which is distilled through a 15 cm. Vigreaux column at 18 mm. The fraction boiling at 81°-82°C is collected (36 g.) and the higher-boiling and lower-boiling distillates may be redistilled to yield additional product. The infrared absorption spectrum shows at most a trace of allene (5.1 μ) and gas-liquid partition chromatography shows a purity of about 98% for the main fraction.

EXAMPLES 894-897

The product 1-alkyn-4-ols of Table 26 below are prepared by treatment of the aldehydes or ketones in Table 26 with propargyl magnesium bromide by the procedure described above in Example 893.

Table 26
______________________________________
Starting Aldehyde
Product 1-Alkyn-
Example or Ketone 4-ol
______________________________________
894 2-trans-hexen- 4-hydroxy-5-
aldehyde trans-ene-1-
nonyne
895 3-cis-hexen- 4-hydroxy-6-cis-
aldehyde* ene-1-nonyne
896 2-methylvaler- 4-hydroxy-5-
aldehyde methyl-1-octyne
897 2-hexanone 4-hydroxy-4-
methyl-1-octyne
______________________________________
*M. Winter, Melv. Chim. Acta, 46, 1792 (1963).
EXAMPLE 898
PAC Preparation of 4-benzoyloxy-1-octyne

To a stirred solution of 63 g. (0.50 moles) of 4-hydroxy-1-octyne (Example 893) in 500 ml. of pyridine is added 77 g. (0.55 moles) of benzoyl chloride. After stirring for 1.5 hours the mixture is treated with 10 ml. of water, allowed to stand for 15 minutes, and concentrated. A solution of the residue in ether is washed successively with ice-cold hydrochloric acid, water, sodium bicarbonate solution, and brine. The solution is dried over magnesium sulfate, filtered through Celite, and concentrated to give an oil, ν max. 3240 (terminal acetylene) and 1730 cm-1 (benzoyloxy group).

EXAMPLE 899
PAC Stereoselective hydrolysis of racemic 4-benzoyloxy-1-octyne by Rhizopus arrhizus

An agar slant of R. arrhizus (MUMF 1638) is used to inoculate 7 shake flasks (250 ml. Erlenmeyer). Each flask contains 50 ml. of a medium consisting of 2% Edamine, 2% glucose, and 0.72% corn steep liquor in water with pH adjusted to 7∅ A total of 14 such flasks are incubated on a rotary shaker at 28°C After 72 hours incubation, 50 mg. of racemic 4-benzoyloxy-1-octyne (Example 898) in 0.1 ml. of acetone is added to each flask. After 28 hours the flasks are harvested and worked up by extraction of the whole mash with an equal volume of chloroform. The combined extracts are dried over magnesium sulfate and concentrated. The resulting oil is chromatographed on a column of silica gel with hexane progressively enriched in ethyl acetate.

From fractions 3-6 is obtained 150 mg. of colorless oil, identical to 4-benzoyloxy-1-octyne, [α]D25 = 5 ± 1.0°(C=0.91, ethyl acetate). This compound has the (S)-configuration.

From fractions 13-20 is obtained 75 mg. of colorless oil, identical to 4-hydroxy-1-octyne, [α]D25 = -17 ± 1.0°(C=0.77, ethyl acetate). This compound has the (R)-configuration.

The strain of R. arrhizus utilized in this experiment is a higher fungus which grows steadily on a variety of artificial media at 20°-25°C In this study of the taxonomic aspects of the culture, Petri dishes of potato-dextrose, malt extract, and cornmeal agars were inoculated and incubated at ambient room temperature for 10 days. Observations of cultural and morphological characteristics are recorded in the description below:

Colonies on Petri dishes of Potato-dextrose agar growing rapidly, covering the agar surface in 3-5 days and producing a thick, loose mat of grayish mycelium. Colony surface characterized by abundant black sporangia. Colony reverse grayish white. Colonies on Malt extract agar growing rapidly, covering the agar surface in 3-5 days. Mycelial mat thick, grayish-yellow. Colony surface becoming brownish-black from masses of sporangia. Colony reverse yellowish. Colonies on Cornmeal Agar very thin, whitish; spreading across agar surface. Cultures transparent with relatively few sporangia produced. Visibility of micromorphology is good on this medium. Rhizoids produced sparingly along stoloniferous hyphae. Generally two to three sporangiophores arose from rhizoids. Walls of sporangiophores olive brown, 14.0-20.0 μM in width at base, tapering slightly to apex; 0.5-1.5 mm in length. Sporangiophores terminated by spherical sporangia, 130-225 μM in diameter. Columellae hemispherical, 3-50 μM high by 50-70 μM wide. Spores brownish when mature, 6.0-8.5 μM × 4.5-6.0 μM. Spore walls conspicuously marked by longitudinal striations.

EXAMPLE 900
PAC Preparation of (S)-4-hydroxy-1-octyne

A solution of 1.15 g. (5.0 mmoles) of (S)-4-benzoyloxy-1-octyne (Example 899) and 1.40 g. (25 mmoles) of potassium hydroxide in 50 ml. of 10:1 methanol-water is allowed to stand at room temperature for 24 hours. The bulk of the methanol is evaporated at room temperature, and the mixture is extracted with ether. The extract is washed with brine, dried over magnesium sulfate, and evaporated to give a colorless oil, identical to 4-hydroxy-1-octyne [α]D25 = +17 ± 1.0°(C=0.77, ethyl acetate). This compound has the (S)-configuration.

EXAMPLE 901
PAC Preparation of 3-bromo-1-octyne

To a stirred suspension of 600 g. of triphenylphosphine in 2000 ml. of acetonitrile, under nitrogen atmosphere, is added dropwise 118 ml. of bromide at a temperature not exceeding 35°C After stirring for an additional hour, the supernatant liquid is decanted and taken to dryness. The solid residue is combined with the previous solid with 1500 ml. of dimethylformamide. The suspension is stirred at -20°C and a solution of 200 g. of 1-octyne-3-ol in 300 ml. of dimethylformamide is added in three portions. The temperature is allowed to warm up slowly to 20°C After 3 hours the solution is extracted with three 1600 ml portions of petroleum ether (b.p. 30°-60°). The combined extracts are washed with saturated sodium chloride solution, saturated sodium bicarbonate solution, and finally with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness (bath 30°-35°C). The residual oil was distilled to give 117 g. (39%) of product, b.p. 66°-68°/9mm.

EXAMPLE 902
PAC Preparation of 3-hydroxymethyl-1-octyne

To a suspension of 2.54 g. of magnesium in 15 ml. of ether containing a few crystals of mercuric chloride, under nitrogen atmosphere, is added a small portion of 3-bromo-1-octyne in 20 ml. of ether. When reaction has set in, the flask is cooled in a 15°C water bath, and the remainder of the halide in ether is added dropwise over a period of about 1 hour. When all of the halide has been added, stirring is continued for 15 minutes. The flask is then fitted with a glass tube which reaches almost to, but not below, the surface of the liquid. This tube connects directly with a round bottom flask containing about 20 mg. of paraformaldehyde which has been previously dried for 2 days in a vacuum desicator over phosphorous pentoxide. This flask contains an inlet tube for nitrogen. The reaction flask is immersed in an ice-bath, and the flask containing the paraformaldehyde is heated in an oil bath at 180°-200°C The formaldehyde formed by depolymerization is carried over into the Grignard reagent by a slow current of dry nitrogen. At the end of 30-40 minutes formaldehyde addition is terminated and the reaction mixture stirred at room temperature for 18 hours.

The reaction mixture is then cooled in an ice-bath and saturated ammonium chloride is added, followed by water and then ether. The mixture is then acidified with 2M sulfuric acid. The organic phase is separated, washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and the solvent removed in vacuo. The residue is distilled to give 4.4 g. of product; b.p. 91°-93°/9mm.

EXAMPLE 903- 905

Treatment of the 3-hydroxymethyl-1-alkynes, listed in Table 27 below, with triphenylmethyl bromide by the procedure described in Example 278 is productive of the 3 -triphenylmethoxymethyl-1-alkynes of the Table.

TABLE 27
______________________________________
Product hexyne1
Ex- Starting 3-hydroxy-
phenylmethoxy-
ample methyl-1-alkyne methyl-1-alkyne
______________________________________
903 3-hydroxymethyl-1-
3-triphenylmeth-
hexyne oxymethyl-1-hexyne
904 3-hydroxymethyl-1-
3-triphenylmeth-
heptyne1 oxymethyl-1-heptyne
905 3-hydroxymethyl-1-
3-triphenylmeth-
octyne1 (Ex. 902)
oxymethyl-1-octyne
______________________________________
1 A. Schaap. L. Brandsma and J.F. Arens. Rec. trav. chim. 86.393
(1967)
EXAMPLE 906
PAC Preparation of 1-chloro-3-triphenylmethoxyhexane

A stirred solution of 27.3 g. (0.20 moles) of 1-chloro-3-hexanol, 77.6 g. (0.24 moles) of triphenylmethyl bromide, 30.0 g. (0.28 moles of 2,6-lutidine, and 200 ml. of chlorobenzene is heated at 95°C for 1 hour. The cooled mixture is treated with water, and the organic phase is washed successively with water and saturated sodium chloride solution. The solution is dried over magnesium sulfate and concentrated. Column chromatography of the residue on Florisil affords the subject compound as an oil, λ max. 1600, 1030, and 705 cm-1 (triphenylmethoxy group).

EXAMPLE 907
PAC Preparation of 5-triphenylmethoxy-1-octyne

To a stirred solution of 32.2 g. (85 mmoles) of 1-chloro-3-triphenylmethoxyhexane (Example 906) in 25 ml. of dimethylsulfoxide (DMSO) is added a solution of 9.4 g. (102 mmoles) of lithium acetylide-ethylene diamine complex in 60 ml. of DMSO during 10 minutes while maintaining a temperature of 25°-30°C After 3.5 hours the mixture is diluted with ether and treated successively with water and 4N hydrochloric acid while cooling in an ice bath. The phases are separated, and the aqueous phase is extracted with ether-petroleum ether. The combined extracts are washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The product is then purified by column chromatography of the residue on Florisil.

EXAMPLES 908- 912

The triphenylmethoxy substituted 1-alkynes listed in Table 28 below are prepared by the method of Example 278 from triphenylmethoxyl bromide and the corresponding hydroxy substituted 1-alkynes of the table.

TABLE 28
______________________________________
Starting hydroxy sub-
Product triphenyl-
Ex- stituted alkyne of
methoxy substituted
ample Example alkyne
______________________________________
908 894 4-triphenylmethoxy-
5-trans-ene-1-
nonyne
909 895 4-triphenylmethoxy-
6-cis-ene-1-nonyne
910 896 4-triphenylmethoxy-
5-methyl-1-octyne
911 899 (R)-4-triphenyl-
methoxy-1-octyne
912 900 (S)-4-triphenyl-
methoxy-1-octyne
______________________________________
EXAMPLE 913
PAC Preparation of 1-iodo-4-triphenylmethoxy-trans-1-octene

To a stirred suspension of 1.78 g. (0.074 mole) of sodium borohydride in 200 ml. of dry glyme at -5°C under nitrogen is added 15.8 g. (0.22 mole) of 2-methyl-2-butene and 16.2 g. (0.11 mole) of boron trifluoride etherate, and the mixture is stirred for 2 hours at -5° to 0°C A solution of 37.5 g. (0.10 mole) of 4-trityloxy-1-octyne (Example 278) in 50 ml. of glyme is added to the cold solution during 5-10 minutes, and the solution is allowed to warm to 20°C during 1.5 hours. The reaction mixture is cooled to 0°C, and 30 g. (0.4 mole) of dry trimethylamine-N-oxide is added during 5 minutes. On removing the cooling bath the temperature rises to 40°C, and the mixture is kept between 30°-40°C for 1.5 hours. The suspension is poured rapidly into 1 liter of ice cold 15% sodium hydroxide solution during good stirring and a solution of 80 g. of iodine in 200 ml. of tetrahydrofuran is added immediately. Stirring is continued for 30 minutes without further cooling and the organic layer is separated. The aqueous layer is extracted with three 200 ml. portions of ether and the combined organic layers are washed successively with water, 5% sodium thiosulfate solution and saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to yield 50 g. of yellow oil. The bulk of the oil is dissolved in hexane and, after decantantation from a gummy solid the hexane solution is percolated through a 5.1 cm. diameter column at 1500 g. of alumina with additional hexane. Fractions containing the desired product are concentrated to a pale yellow oil (33 g.) which has n.m.r. and infrared spectra characteristics of the desired product.

EXAMPLES 914- 922

Treatment of the triphenylmethoxy substituted 1-alkynes listed in Table 29 below with disiamylborane, prepared in situ from 2-methyl-2-butene, boron trifluoride and sodium borohydride, followed by trimethylamine N-oxide, and then sodium hydroxide and iodine all by the procedure described in Example 913 above furnishes the product triphenylmethoxy substituted 1-iodo-1-trans-alkenes of the table.

TABLE 29
______________________________________
Starting triphen-
ylmethoxy sub- Product 1-iodo-tri-
Ex. situted 1-alkyne
phenylmethoxy substi-
ample of Example tuted-1-trans-alkene
______________________________________
914 905 1-iodo-3-triphenylmeth-
oxymethyl-1-trans-
octene
915 907 1-iodo-5-triphenylmeth-
oxy-1-trans-octene
916 290 1-iodo-4-triphenylmeth-
oxy-1-trans-nonene
917 908 1-iodo-4-triphenylmeth-
oxy-1,5-trans.trans-
nonadiene
918 910 1-iodo-4-triphenylmeth-
oxy-5-methyl-1-trans-
oxlene
919 909 1-iodo-4-triphenylmeth-
oxy-1-trans-16-cis-
nonadiene
920 911 (R)-1-iodo-4-triphenyl-
methoxy-1-trans-octene
921 912 (S)-1-iodo-4-triphenyl-
methoxy-1-trans-octene
922 304 1-iodo-8-triphenylmeth-
oxy-1-trans-octene
______________________________________
EXAMPLE 923- 924

Treatment of the 4-hydroxycyclopentenones, listed in Table 30 below, with dihydropyran by the procedure described in Example 158 is productive of the 4-tetrahydropyranyloxycyclopentenones of the table.

TABLE 30
______________________________________
Ex- Starting 4-hydroxy-
Product 4-tetrahydro-
amle cyclopentenone pyranloxycyclopentenone
______________________________________
923 (R)-4-hydroxy-2-
(R)-4-tetrahydropyranyl-
(6-carbomethoxy-
oxy-2-(6-carbomethoxy-
hexyl)cyclopent-
hexyl)cyclopent-2-en-1-
2-en-1-one* one
924 (S)-4-hydroxy-2-
(S)-4-tetrahydropyranyl-
(6-carbomethoxy-
oxy-2-(6-carbomethoxy-
hexyl)cyclopent-
hexyl)cyclopent-2-en-1-
2-en-1-one* one
______________________________________
*R. Pappo et al., Tetrahedron Letters, 1973.943
EXAMPLE 925
PAC Preparation of 9-oxo-11α,17-dihydroxy-13-trans-prostenoic acid

To a stirred solution of the di-i-butylalkenylalane, prepared from 26.5 g. (72 mmoles) of 5-triphenylmethoxy-1-octyne (Example 907) and 60 ml. of 1.2 M di-i-butylaluminum hydride in hexane in 36 ml. of benzene according to the procedure of Example 281 is added 30 ml. of 2.2M methyllithium in ether.

The resulting alanate is reacted with 4-tetrahydropyranyloxy-2-(6-tetrahydropyranylcarboxyhexyl)-cyclopent-2-en- 1-en-1-one (Example 147) according to the method of Example 280. The crude product thereby obtained is deblocking according to the method of Example 280a. The crude product is purified to provide the title compound as an oil, ν max. 1735 (ketone carbonyl group), 1710 (acid carbonyl group), and 967 cm-1 (trans-vinyl group).

EXAMPLE 926
PAC Preparation of 9-oxo-11α ,16-dihydroxy-13-trans-prostenoic acid

To a stirred solution of 25.2 g. (48 mmoles) of 1-iodo-4-triphenylmethoxy-trans-1-octene (Example 913) in 50 ml. of toluene is added 24.0 ml. of 2.0M n-butyllithium in hexane at -70° C. After 1 hour this solution containing 4-triphenylmethoxy-trans-1-octenyl lithium is treated with 31.7 ml. of 1.45M trimethyl-aluminum in hexane at -40°C and the resulting solution is stirred at 0°C for 20 minutes.

To the above solution containing lithio trimethyl-(4-triphenylmethoxy-trans-1-octenyl)alanate is added a solution of 15.4 g. (39 mmoles) of 4-tetrahydropyranyloxy-2-(6-carbotetrahydropyranyloxyhexyl)-cyclopent-2-en -1-one (Example 147) in 50 ml. of ether at 0°-8°C The mixture is stirred at 0°C for 1 hour and 25°C for 20 hours, diluted to 500 ml. with ether, and poured into a stired mixture of ice and 20 ml. of 37% hydrochloric acid. The aqueous phase is separated and extracted with ether. The combined organic phases are washed with water and brine, dried over magnesium sulfate, and concentrated to give an oil.

The crude product is dissolved in 440 ml. of 4:2:1 acetic acid-tetrahydrofuran-water, and the resulting solution is heated at 45°C for 6 hours. The solvents are removed in vacuo at 20° C. to give a mixture of oil and crystals.

The crude product is purified by partition chromatography on acid-washed silica gel using the conjugate phases from benzene-methanol-water (15:5:2), with further purification by silica gel adsorption chromatography if necessary. The prostenoic acid is thereby obtained as an oil, ν max. (film) 3300 (hydroxy), 1735 (cyclopentenone), 1705 (carboxylic acid), and 967 cm-1 (trans-olefin).

EXAMPLE 927
PAC Preparation of ethyl 9-oxo-11α ,16-dihydroxy-17-methyl-13-transprostenoate

To a stirred solution of 10.21 g. (20 mmoles) of iodo-5-methyl-4-triphenylmethoxy-trans-1-octene (Example 918) in 10 ml. of toluene is added 10 ml. of 2.0M n-butyllithium in hexane at -70°C After 2 hours this solution containing 5-methyl-4-triphenylmethoxy-trans-1-octenyl lithium is added during 5 minutes at -75°C to a stirred solution of 3.93 g. (10.0 mmoles) of cuprous iodide-tri-n-butylphoshine complex in 40 ml. of ether. The resulting solution is stirred at -50°C for 30 minutes and then treated with a solution of 3.38 g. (10.0 mmoles) of cuprous iodide-tri-n-butylphosphine complex in 40 ml. of ether. The resulting solution is stirred at -50°C for 30 minutes and then treated with a solution of 3.38 g. (10.0 mmoles) of 4-tetrahydropyranyloxy-2-(6-carbethoxyhexyl)-cyclopent-2-en-1-one (Example 158) in ml. of ether during 10 minutes at -45°C The solution is allowed to warm to -20°C during 1 hour and is stirred at 0°C for 2 hours. The reaction mixture is quenched by pouring into iced ammonium chloride solution, and the product is extracted into ether. The extract is washed with brine, dried over magnesium sulfate, and concentrated to give an oil.

The crude product is dissolved in 100 ml. of 4:2:1 acetic acid-tetrahydrofuran-water, and the resulting solution is heated at 45°C for 8 hours. The solvents are removed in vacuo at 20° C. to give a mixture of oil and crystals.

The crude product is purified by chromatography on acid-washed silica gel using benzene-ethyl acetate gradient elution to provide the title compound as an oil, ν max. 1740 (ketone and ester carbonyl groups) and 967 cm-1 (trans-vinyl group).

EXAMPLE 928- 937

Conjugate addition of the cuprates, obtained by treatment of the triphenylmethoxy (trityloxy)-1-iodo-trans-1-octene (indicated in the following table) with butyldilithium followed by cuprous iodide-tri-n-butylphosphine complex, to the cyclopentenones of the table according to the method described in Example 927 followed by de-O-tritylation of the intermediate triphenylmethoxy prostenoates according to the method of Example 927 is productive of the prostenoic acids or esters of the table.

These compounds isolated and identified in the table as prostenoic acids are prepared via the corresponding tetrahydropyran-2-yl esters and those compounds bearing a free hydroxy function at the 11α-position or as part of an 11α(ω-hydroxyalkoxy) moiety are prepared via the corresponding tetrahydropyran-2-yl ethers. The hydroxy function in the β-chain (that portion of the molecule deriving from the triphenylmethoxy-1-alkylene) of all compounds in the table are initially present in the molecule as the corresponding triphenylmethyl ethers. During the acetic acid treatment (de-O-tritylation step) the triphenylmethyl ether as well as the tetrahydropyran-2-yl ethers and esters functions are hydrolyzed to provide the corresponding free hydroxy and carboxylic acid groups of the compounds listed in the table.

TABLE 3
__________________________________________________________________________
Starting cyclo-
Starting 1-iodo-triphenyl-
pentenone of
methoxy substituted 1-
Product Hydroxy Prostenoic
Example
Example
trans-alkene of Example
Acid or Ester
__________________________________________________________________________
928 243 914 Ethyl 9-oxo-11α-(β-hydroxyethoxy)-
15-
hydroxymethyl-13-trans-prostenoate
929 234 915 3-oxa-9-oxo-11α-methoxy-17-hydroxy-13-
O
trans-prostenoic acid
930 147 916 9-oxo-11α,16-dihydroxy-20-[nor]methyl-1
3-
trans-[prostenoate]prostenoic acid
931 147 917 9-oxo-11α-dihydroxy-20-[nor]methyl-
13,17-trans,trans-prostadienoic acid
932 158 919 Ethyl 9-oxo-11α,16-dihydroxy-20-[nor]
methyl-13-trans-18-cis-prostadienoate
933 147 918 9-oxo-11α,16-dihydroxy-17-methyl-13-
trans-prostenoic acid
934 923 920 Methyl 9-oxo-(11R)11-hydroxy-16(R)-hydroxy-
13-trans-prostenoate
935 923 921 Methyl 9-oxo-(11R)11-hydroxy-16(S)-16-
hydroxy-13-trans-prostenoate
936 9224 920 Methyl 9-oxo-(11S)11-hydroxy-(16R)-hydroxy-
13-trans-prostenoate
937 924 921 Methyl 9-oxo-(11S)11-hydroxy-(16S)16-
hydroxy-13-trans-prostenoate
__________________________________________________________________________
EXAMPLE 938
PAC Preparation of 9α,11α,17-trihydroxy-13-trans-prostenoic acid

To a stirred solution of 1.366 g. of 9-oxo-11α,17-dihydroxy-13-trans-prostenoic acid (Example 925) in 19 ml. of tetrahydrofuran is added 10.0 ml. of a 1.0M solution of lithium tris-(sec-butyl)borohydride in 1:1 tetrahydrofuran pentane at -78° C. under nitrogen. The solution is stirred at -78°C for 45 minutes and then is treated with 5 ml. of water. The mixture is stirred at 30°C for 30 minutes, diluted with dilute sodium bicarbonate solution and extracted with ether. The aqueous phase is acidified with 4N hydrochloric acid, saturated with sodium chloride, and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate and concentrated. The residue is purified by dry column chromatography with silica gel to give a colorless oil, ν max. = 3310 (hydroxyl groups), 1705 (carboxyl group), and 970 cm-1 (trans-olefin group).

EXAMPLE 939
PAC Preparation of methyl 9-oxo-16-hydroxy-8(12),13-trans-prostadienoate

A solution of 69 mg. of potassium carbonate (0.50 mmoles) and 81 mg. (0.25 mmoles) of methyl 9-oxo-11α-methoxy-16-hydroxy-13-trans-prostenoate (Example 333) in 25 ml. of 5:1 methanol-water is allowed to stand at room temperature for 24 hours. The solution is diluted with brine and extracted with ether. The extract is washed with brine, dried over magnesium sulfate and concentrated to give an oil, ν max. = 279 μ.

EXAMPLE 940- 943

Treatment by the method described in Example 939 of the esters listed in the table below furnishes the Δ8(12) -derivatives of the table.

TABLE 32
______________________________________
Ex- Starting ester
Product 9-oxo-8(12)-
ample of Example prostenoate ester
______________________________________
940 430 Ethyl 9-oxo-3,3-di-
methyl-19-hydroxy-20-
nor-8(12),13-trans-
prostadienoate
941 424 Ethyl 9-oxo-7a,7b-bis-
homo-17-hydroxy-19,
20-dinor-8(12),13-
trans-prostadienoate
942 442 Butyl 9-oxo-20-hydroxy-
8(12(,13-trans-prosta-
dienoate
943 344 Ethyl 2-phenyl-9-oxo-
13-hydroxy-20-methyl-
8(12)-13-trans-pro-
stadienoate
______________________________________
EXAMPLE 944
PAC Preparation of 9-oxo-2-methyl-16-hydroxy-8(12),13-transprostadienoic acid

A solution of 0.56 g. (10 mmoles) of potassium hydroxide and 921 mg. (2.5 mmoles) of 9-oxo-11α-hydroxy-2-methyl-13-trans-prostenoic acid (Example 388) in 25 ml. of 10:1 methanol-water is allowed to stand at room temperature for 24 hours. The solution is diluted with brine, acidified with hydrochloric acid, and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, and concentrated to give an oil, ν max. = 279 mμ .

EXAMPLES 945- 948

Treatment by the method described in Example 944 of the esters or acids listed in the Table below furnishes the Δ8(12) prostenoic acids of the table.

TABLE 33
______________________________________
Ex- Starting ester of
Product 9-oxo-8(12)-
ample acid of Example
prostenoic acid
______________________________________
945 536 9-oxo-2-fluoro-16-
methyl-17-hydroxy-
18,19,20-trinor-
8(12)-prostenoic acid
946 363 9-oxo-16-hydroxy-19,
20-dinor-8(12),13-
trans-prostadienoic
acid
947 444 9-oxo-20-hydroxy-
8(12),13-trans-pro-
stadienoic acid
948 876 9-oxo-15-hyroxymethyl-
3-oxa-8(12),13-trans-
prostadienoic acid
______________________________________
EXAMPLES 949- 952

Conjugate addition of alanate obtained by treatment of the trityloxy-1-iodo-trans-1-octene (indicated in the following table) with n-butyllithium followed by trimethyl aluminum, to the cyclopentenones of the table according to the method described in Example 926 followed by the blocking group removal process of Example 926, is production of the prostenoate esters of the table.

TABLE 34
______________________________________
Starting
Starting
1-iodo-tri-
cyclo- phenylmethoxy
tenone substituted-
of 1-trans-akene
Product
Ex. of Ex. of Example
Hydroxy Prostenoate Ester
______________________________________
949 923 920 Methyl 9-oxo-(11R)-hydroxy-
(16R)-hydroxy-13-trans-
prostenoate
950 923 921 Methyl 9-oxo-(11R)-hydroxy-
(16S)16-hydroxy-13-trans-
prostenoate
951 924 920 Methyl 9-oxo-(11S)11-hydroxy-
(16R)16-hydroxy-13-trans-
prostenoate
952 924 921 Methyl 9-oxo-(11S)11-hydroxy-
(16S)16-hydroxy-13-trans-
prostenoate
______________________________________
EXAMPLES 953- 956

Acid treatment by the procedure described in Example 686 of the 11α-hydroxy-9-oxo-derivative listed in the table below in productive of the Δ10 derivatives of the table.

TABLE 35
__________________________________________________________________________
starting 11α-
hydroxy-9-oxo
Ex- derivative of
Product 9-oxo-10-
ample Example Prostenoate ester
__________________________________________________________________________
953 949 Methyl 9-oxo-16(R)-
hydroxy-10,13-trans-
(8R,12R)-prosta-
dienoate
954 950 Methyl 9-oxo-16(S)-
hydroxy-10,13-trans-
(8R,12R)-prosta-
dienoate
955 951 Methyl 9-oxo-16(R)-
hydroxy-10,13-trans-
(8S,12S)-prosta-
dienoate
956 952 Methyl 9-oxo-16(S)-
hydroxy-10,13-trans-
(8S,12S)-prosta-
dienoate
__________________________________________________________________________
EXAMPLES 957- 958

Treatment by the method described in Example 939 of the esters listed in the table below furnishes the Δ8(12) -derivatives of the table.

TABLE 36
______________________________________
Starting 11α-hydroxy-
Ex- 9-oxo derivative of
Product 9-oxo-10-
ample Example prostenoate esters
______________________________________
957 949 (R)-Methyl-9-oxo-16-
hydroxy-8(12),13-
trans-prostadienoate
958 950 (S)-Methyl-9-oxo-16-
hydroxy-8(12),13-
trans-prostadienoate
______________________________________
EXAMPLES 959- 960

Treatment by the method described in Example 944 of the esters listed in the table below furnishes the Δ8(12) prostenoic acids of the table.

TABLE 37
______________________________________
Starting 11α-hydroxy-
Ex- 9-oxo derivative of
Product 9-oxo-10-
ample Example prostenoic acid
______________________________________
959 951 (R)-9-oxo-16-hy-
droxy-8(12),13-
trans-prostadien-
oic acid
960 952 (S)-9-oxo-16-hy-
droxy-8(12),13-
trans-prosta-
dienoic acid
______________________________________
EXAMPLES 962- 964

Reduction of the 9-oxo derivatives listed in the table below with lithium perhydro-9b-borahenalyl hydride by the method described in Example 575 with modification indicated for Example 576 is productive of the 9α-hydroxy derivative of the table.

TABLE -
Starting 9-oxo
Ex- derivative Product
ample of Example 9α-hydroxy derivative
______________________________________
961 949 methyl(9S,11R,16R)-
trihydroxy-13-trans-
prostenoate
962 950 Methyl (9S,11R,16S)-
trihydroxy-13-trans-
prostenoate
963 951 Methyl (9R,11S,16R)-
trihydroxy-13-trans-
prostenoate
964 952 Methyl (9R,11S,16S)-
trihydroxy-13-trans)
prostenoate
______________________________________
EXAMPLES 965- 968

Reduction of the 9-oxo derivatives listed in the table below with sodium borohydride by the method described in Example 679 followed by separation of the 9α- and 9β-hydroxy derivatives by chromatography on silica gel is productive of the named 9β-hydroxy derivatives of the table.

TABLE 39
______________________________________
Starting 9-oxo
Ex- derivative of Product
ample Example 9β-hydroxy derivative
______________________________________
965 (9R,11R,16R)- Methyl - trihydroxy-13-trans-
prostenoate
966 950 Methyl (9R,11R,16S)-
trihydroxy-13-trans-
prostenoate
967 951 Methyl (9S,11S,16R)-
trihydroxy-13-trans-
prostenoate
968 952 Methyl (9S,11S,16S)-
trihydroxy-13-trans-
prostenoate
______________________________________
INVENTORS:

Schaub, Robert Eugene, Floyd, Jr., Middleton Brawner, Weiss, Martin Joseph, McGahren, William James

THIS PATENT IS REFERENCED BY THESE PATENTS:
Patent Priority Assignee Title
5193935, Jan 07 1991 Terex USA, LLC Soil decontamination apparatus and methods of decontaminating soil
THIS PATENT REFERENCES THESE PATENTS:
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3770776,
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