The subject-matter of the invention is a process for the stereoselective preparation of a compound of general formula I
##STR00001##
by stereoselective displacement by a nitrogenous nucleophilic compound of the activated alcohol functional group present at this 4″ position in a corresponding derivative of formula ii.
|
wherein:
P2 is a hydrogen atom or a protective group;
R is a hydrogen atom or a c1-c10 alkyl, c2-c10 alkenyl or c6-c12 arylsulphonyl group, optionally substituted; and
OR1 is a leaving group.
wherein:
P2 is a hydrogen atom or a protective group;
R is a hydrogen atom or a c1-c10 alkyl, c2-c10 alkenyl or c6-c12 arylsulphonyl group, optionally substituted; and
A, each of which is identical or different, is
a nitrogen atom, optionally substituted, or
a c1-c4 alkyl group, which is optionally substituted by one or more aryl groups, which are, in turn, optionally substituted, wherein A is not a hydrogen atom or a R2CO or R2SO2 group, with R2 being a hydrogen atom, a c1-c8 alkyl group or an aryl group, which are, optionally substituted.
1. A process for the stereoselective preparation of a compound of formula I
##STR00014##
wherein:
R is a hydrogen atom or a c1-c10 alkyl, c2-c10 alkenyl or c6-c12 arylsulphonyl group, optionally substituted;
A, each of which is identical or different, is
a hydrogen atom,
a nitrogen atom, optionally substituted,
a c1-c4 alkyl group, which is optionally substituted by one or more aryl groups, which are, in turn, optionally substituted,
an R2CO or R2SO2 group, with R2 being a hydrogen atom, a c1-c8 alkyl group or an aryl group, which are, optionally substituted; and
∇ indicates that the c in the 4″ position has undergone an inversion of configuration
with respect to the formula ii, from a compound of formula ii:
##STR00015##
wherein:
R as defined in formula I and
P1 is a protective group for the hydroxyl functional group at the 2′ position, comprising the steps of:
(i) activating the hydroxyl functional group at the 4″ position in the compound of formula ii, in order to obtain a compound of formula iii:
##STR00016##
wherein:
R and P1 are as defined in formulae I and ii and
OR1 is a leaving group;
(ii) contacting the compound of formula iii with a nitrogenous nucleophilic derivative under conditions which are sufficient to allow the stereoselective displacement of the hydroxyl functional group activated by the said nitrogenous nucleophile; and
(iii) deprotecting the hydroxyl functional group at the 2′ position.
wherein A and R are as defined in
wherein R and P1 are as defined in
3. The process according to
4. The process according to
5. The process according to
BSO2X or (BSO2)2O IVA or IVB wherein:
X is a halogen atom or a nitrogenous heterocycle; and
B is a c1-c20 alkyl, c5-c6 aryl or heteroaryl, or c6-c26 alkylaryl group, which is optionally substituted by one or more halogen atoms and/or a nitro, cyano or trifluoromethyl group.
6. The process according to
7. The process according to
8. The process to
9. The process according to
activating the compound of formula ii with a compound of formula IVA or IVB
BSO2X or IVA (BSO2)2O IVB wherein:
X is a halogen atom or a nitrogenous heterocycle; and
B is a c1-c20 alkyl, c5-c6 aryl or heteroaryl or c6-c26 alkylaryl group, which are optionally substituted by one or more halogen atoms and/or a nitro, cyano or trifluoromethyl group; and
contacting the compound of formula iii with an organic organosoluble azide in order to result, by stereoselective nucleophilic displacement, in a compound of formula V
##STR00019##
wherein R and P1 are as defined in formula I and ∇ indicates that the c in the 4″ position has undergone an inversion of configuration with respect to the formula ii.
10. The process according to
activating the compound of formula ii with a compound of formula IVA or IVB
BSO2X or IVA (BSO2)2O IVB wherein:
X is a halogen atom or a nitrogenous heterocycle, and
B is a c1-c20 alkyl, c5-c6 aryl or heteroaryl or c6-c26 alkylaryl group, optionally substituted by one or more halogen atoms and/or a nitro, cyano or trifluoromethyl group;
contacting the compound of formula iii with an organic organosoluble azide resulting, by stereoselective nucleophilic displacement, in a compound of formula V:
##STR00020##
wherein:
R and P1 are as defined in formula I and ∇ means that the c in the 4″ position has undergone an inversion of configuration with respect to the formula ii; and
reducing the compound of formula V, so as to obtain a compound of formula I in which A is a hydrogen atom.
11. The process according to
activating the compound of formula ii with the c-4″ carbon having S configuration with a compound of formula IVA or IVB
BSO2X or IVA (BSO2)2O IVB wherein:
X is a halogen atom or a nitrogenous heterocycle, and
B is a c1-c20 alkyl, c5-c6 aryl or heteroaryl or c6-c26 alkylaryl group, optionally substituted by one or more halogen atoms and/or a nitro, cyano or trifluoromethyl group;
contacting the compound of formula iii with an organic organosoluble azide in order to result, by stereoselective nucleophilic displacement, in a compound of formula V
##STR00021##
wherein R and P1 are as defined in formula I, the c-4″ carbon has a R configuration and ∇ indicates that the c in the 4″ position has undergone an inversion of configuration with respect to the formula ii.
12. The process according to
13. The process according to
14. The process according to
15. The process according to
16. The process according to
18. The compound of formula vi according to
19. The compound of formula vi according to
21. The compound of formula vii according to
22. The compound of formula vi according to
31. The process according to
32. The process according to
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This application claims priority from U.S. application Ser. No. 60/127,400, filed, Apr. 1, 1999 and from French Application 99 00459, filed Jan. 18, 1999. Reference is also made to U.S. Provisional patent application Ser. No. 60/128,383, filed, Apr. 8, 1999 and French application 99 03885, filed Mar. 29, 1999. Each of these applications, and each document cited or referenced in each of these applications is hereby incorporated herein by reference. It is hereby stated that the inventive entity of each of U.S. Provisional patent application Ser. No. 60/128,383, filed, Apr. 8, 1999, French application 99 03885, filed Mar. 29, 1999 and any full U.S. utility application claiming priority from either or both of U.S. Provisional patent application Ser. No. 60/128,383, filed, Apr. 8, 1999 and French application 99 03885, filed Mar. 29, 1999 is not “another” or “others” as to the inventive entity of this application, and vice versa. In addition, each document cited herein (“herein cited documents”) and each document referenced or cited in herein cited documents are hereby incorporated by reference.
The subject-matter of the present invention is a process of use in converting the 4″ (S)-OH functional group of the cladinose unit of an azamacrolide to 4″ (R)—NH2.
The present invention relates more particularly to the field of macrolide antibiotics of erythromycin type and more particularly their azamacrolide derivatives which form the subject-matter of Patent EP 508,699 and which correspond to the following general formula:
##STR00002##
in which R is a hydrogen atom or a C1-C10 alkyl, C2-C10 alkenyl or C6-C12 arylsulphonyl group, which are, if appropriate, substituted.
These compounds are obtained from erythromycin and their synthesis involves two major stages:
In fact, the route currently used to provide for this conversion of the 4″ (S)-OH to 4″ (R)-NH2 is not completely suitable for production on an industrial scale.
It involves, successively, an oxidation of the hydroxyl functional group at the 4″ position to a ketone functional group and then the conversion of this ketone to an oxime, which, by reduction, results in an approximately 1 to 1 mixture of the expected amino derivative and of its 4″ epimer.
This synthetic route consequently has the major disadvantage of requiring the formation of sp2 C-4″ intermediates and thus of losing the stereochemical information initially present at the sp3 C-4″ of the cladinose unit. This result is all the more of a nuisance since the isomers, acquired on conclusion of this synthetic route, are obtained with a low yield of about 20% and are in addition difficult to separate. Thus, for a crude reaction yield of about 20%, only approximately 7% of the amino derivative with inversion of configuration is obtained.
The object of the present invention is specifically to provide a new access route to these derivatives, aminated at the 4″ position, which advantageously makes it possible to retain a significant stereoselectivity and provides a satisfactory yield.
More specifically, a first subject-matter of hi the present invention is a process for the preparation of a compound of general formula I
##STR00004##
in which:
The claimed process thus has the significant advantage of not requiring the formation of the sp2 C-4″ intermediate necessarily generated in the prior synthetic route discussed above. It involves only an inversion of configuration at the 4″ position and this inversion is obtained efficiently by displacement by a nitrogenous nucleophile of the activated alcohol functional group present at this 4″ position.
Consequently, the claimed process proves to be particularly advantageous for preparing with a very satisfactory yield, a 4″ (R)-NA2 derivative of general formula I′
##STR00007##
with A and R as defined above from a 4″ (S)-OH azamacrolide derivative of general formula II′
##STR00008##
with R and P1 as defined above.
As regards the leaving group represented by OR1 in general formula III, it is preferably selected from C1-C20 alkyl sulphonates, C5-C6 aryl or heteroaryl sulphonates or C6 to C26 alkylaryl sulphonates, which are substituted, if appropriate, by one or more halogen atoms, preferably fluorine, and/or a nitro, cyano or trifluoromethyl group.
The leaving group represented by OR1 in general formula III is preferably a group selected from mesylate, triflate and tosylate and is more preferably a triflate group.
Use may in particular be made according to the invention, as nitrogenous nucleophilic compound, of compounds of the following types: ammonia, amines which may or may not be substituted by deprotectable groups, such as a benzyl group or one of its derivatives, amides, imides, sulphonamides, sulphonimides, hydrazines or azides.
According to a preferred alternative form of the claimed process, it is more preferably an organic organosoluble azide which can be generated in situ.
The leaving groups deriving from the activation of the hydroxyl functional group at the 4″ position in the general formula II by a compound of formula IVA or IVB
BSO2X or IVA
(BSO2)2O IVB
with:
The compound of general formula III thus obtained is preferably brought into contact with an organosoluble azide in order to result, by stereoselective nucleophilic displacement, in a compound of general formula V
##STR00009##
in which R and P1 are as defined in general formula I and ∇ means that the C in the 4″ position has undergone an inversion of configuration with respect to the formula II,
The C-4″ carbon of the compound II preferably has a S configuration and the C-4″ carbon of the compound V a R configuration.
According to this alternative form of the claimed process, a reduction of the said compound of formula V can additionally be carried out, prior or otherwise to the deprotection of the hydroxyl functional group at the 2′ position, so as to obtain a compound of general formula I in which A is a hydrogen atom. This reduction of the azide functional group can be carried out by any conventional method, such as those described by E. F. V. Scriven et al., Chem. Rev. (1988), 88, 297-368. A catalytic reduction with hydrogen or hydrazine in the presence of palladium-on-charcoal, for example, or of Raney nickel can in particular be carried out.
On conclusion of this reduction, the expected 4″ (R)-NH2 amino derivative, that is to say with inversion of configuration, is thus recovered with a satisfactory yield.
Consequently, this alternative form of the claimed process is very particularly of use in the preparation of the compounds of general formula I″
##STR00010##
in which:
Mention may very particularly be made, as illustration of the azides which are suitable for the present invention, of tetra(C1 to C20 alkyl)ammonium or -phosphonium azide, substituted or unsubstituted triarylsulphoniums and hexa(C1 to C20 alkyl)guanidiniums.
According to a preferred alternative form of the invention, it is a tetraalkylammonium azide and more particularly tetrabutyl- or tetraoctylammonium azide.
In a specific embodiment of the invention, the azide derivative is formed in a two-phase medium and more specifically in solid/liquid phase transfer. In this case, the organosoluble azide is generated in situ from an inorganic azide, such as sodium azide, and from a phase transfer agent in the presence of the compound of general formula III in an organic solvent. The phase transfer agent is preferably a tetra(C1 to C20 alkyl)ammonium or -phosphonium methanesulphonate.
As regards the compound of general formula II, it is generally obtained beforehand by protection of the hydroxyl functional group at the 2′ position in the corresponding derivative. Of course, this protection is carried out conventionally using a conventional protective group for the hydroxyl functional group, such as those which appear in “Protective Groups in Organic Synthesis”, Second Edition, Theodora W. Greene and P. G. Wuts, Wiley Intersciences, p. 10-142. The procedures for carrying out the protecting and deprotecting operations are also described in the work referred to above.
Following this protection of the hydroxyl functional group at the 2′ position, the hydroxyl functional group at the 4″ position is activated. This activation of the compound of general formula II is also carried out under conventional operating conditions, such as those described in “Protective Groups in Organic Synthesis”, Second Edition, Theodora W. Greene and P. G. M. Wuts, Wiley Intersciences, p. 117-118. The examples submitted below describe a detailed procedure for the activation of the 4″ hydroxyl functional group with triflic anhydride.
As regards the nucleophilic substitution reaction, it is carried out in an organic solvent, preferably an anhydrous organic solvent. In the preferred alternative form of the invention employing an organosoluble azide, aromatic solvents, such as benzene and toluene, or ethers, such as THF or methyl tert-butyl ether, are suitable in particular as solvents.
The nitrogenous nucleophilic compound, preferably the azide, is used in a proportion of approximately 1 to 30 equivalents with respect to the compound of formula III and preferably in a proportion of approximately 1 to 5 equivalents.
The temperature is conventionally between −20 and 180° C. As a general rule, it is adjusted so as to favour the kinetics of the reaction without harming the stability of the compounds.
According to a preferred alternative form of the invention, in the first stage, the hydroxyl functional group at the 4″ position is activated by a trifluoromethanesulphonate group and the nucleophilic substitution is carried out with inversion of configuration with tetrabutyl- or tetraoctylammonium azide in toluene at room temperature.
According to a preferred alternative form of the invention, R is a methyl group in the general formula I, I′, II′, II″, III and V and A a hydrogen atom in the general formula I and I′.
Another subject-matter of the present invention is the compounds of general formula VI
##STR00011##
in which
More preferably, R is a methyl group and OR1 is a triflate group and more preferably the C-4″ carbon has a R configuration.
The present invention also relates to the compounds of general formula VII
##STR00012##
in which
More preferably, R is a methyl group and NA2 an N3 group and more preferably, the C-4″ carbon has a R configuration.
The examples which appear below are presented by way of illustration and without implied limitation of the present invention.
The synthetic scheme used is as follows: ##STR00013##
All the tests are carried out under an inert atmosphere.
Pyridine (39.5 mg, 0.51 mmol, 5 equiv.) is added to a solution of alcohol 2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A (0.1 g, 0.12 mmol, 1 equiv.) in anhydrous dichloromethane (0.4 ml). The solution is cooled to 0° C. and then a solution of triflic anhydride (42.3 mg, 0.15 mmol, 1.2 equiv.) is added dropwise. The solution is stirred for 1 h at 0° C. and then 30 min at room temperature. After diluting the reaction mixture with anhydrous dichloromethane (10 ml), the reaction mixture is cooled to 0° C. and then hydrolysed by addition of a saturated aqueous sodium bicarbonate solution (10 ml). The organic phase is separated and then washed with distilled water (10 ml), dried over magnesium sulphate and evaporated. The crude product is taken up in heptane (10 ml) in order to remove any trace of residual pyridine by azeotropic distillation. 110.4 mg of 4″ (S)-trifluoromethylsulphonyl-2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homo-erythromycin A are obtained with a purity greater of than or equal to 90%. The structure is confirmed by NMR and MS analysis.
A 0.58M solution of tetrabutylammonium azide in toluene (4.5 ml; app. 1.3 equiv.) is added to unpurified 4″ (S)-trifluoromethylsulphonyl-2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A from the preceding stage (1.84 g, 2.0 mmol, 1 equiv.) at room temperature. The reaction mixture is stirred for 3 days at room temperature and then diluted with toluene (25 ml). This solution is washed three times with distilled water (3×10 ml), then dried over magnesium sulphate and evaporated. 1.63 g of 4″-dehydroxy-4″(R)-azido-2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homo-erythromycin A are obtained with a purity of 70%. The structure is confirmed by NMR and MS analysis.
Raney nickel (200 mg) is added to a solution in isopropanol (5 ml) of unpurified 4″-dehydroxy-4″(R)-azido-2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homo-erythromycin A from the preceding stage (250.0 mg, 0.30 mmol, 1 equiv.). Hydrazine monohydrate (30 microliters, 0.6 mmol, 2 equiv.) is added every 30 minutes. The reaction time is 2 h. The reaction mixture is diluted with ethyl acetate (10 ml) and filtered. The filtrate is washed with a saturated aqueous sodium bicarbonate solution (10 ml) and then with water (10 ml). After drying over magnesium sulphate, the filtrate is evaporated. 230 mg of 4″-dehydroxy-4″ (R)-amino-2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A are obtained with a purity of 60%. The structure is confirmed by NMR and MS analysis.
Tetraoctylammonium azide (190.3 ml, 0.5 mmol, 5 equiv.) is added at room temperature to a solution of 4″ (S)-trifluoromethylsulphonyl-2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A (92.3 mg, 0.1 mmol, 1 equiv.) in toluene (0.2 ml). After stirring for two days at room temperature, tetraoctylammonium azide (58 mg, 0.15 mmol, 1.5 equiv.) is again added. After stirring for an additional two days at room temperature, the reaction mixture is diluted with toluene (10 ml) and washed with water (10 ml). The organic phase is separated and dried over sodium sulphate. After evaporating the solvents, 1H NMR analysis shows the predominant presence of the compound 4″-dehydroxy-4″ (R)-azido-2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A.
Tetrabutylphosphonium methanesulphonate (355 mg, 1 mmol, 5 equiv.) and then sodium azide (325 mg, 5 mmol, 25 equiv.) are successively added to a solution of 4″ (S)-trifluoromethylsulphonyl-2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A (185 mg, 0.2 mmol, 1 equiv.) in toluene (0.4 ml) at room temperature. After stirring for three days at room temperature, the reaction mixture is diluted with toluene (10 ml) and washed with water (10 ml). The organic phase is separated and dried over sodium sulphate. After evaporating the solvents, 1H NMR analysis shows the predominant presence of the compound 4″-dehydroxy-4″ (R)-azido-2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A.
Tetraoctylammonium methanesulphonate (217 mg, 0.38 mmol, 3.8 equiv.) and then tetrabutylammonium azide (158 mg, 2.5 mmol, 25 equiv.) are successively added to a solution of 4″ (S)-trifluoromethylsulphonyl-2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A (92 mg, 0.1 mmol, 1 equiv.) in toluene (0.25 ml) at room temperature. After reacting for 4 days at room temperature, the reaction mixture is diluted with toluene (10 ml) and washed with water (10 ml). The organic phase is separated and dried over sodium sulphate. After evaporating the solvents, 1 H NMR analysis shows the predominant presence of the compound 4″-dehydroxy-4″ (R)-azido-2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A.
A solution of 4″ (S)-trifluoromethylsulphonyl-2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A (21.4 mg, 0.023 mmol) in N-methylpyrrolidinone is saturated with gaseous ammonia. This solution is stirred for 48 h at room temperature. The reaction mixture is subsequently diluted with ethyl acetate (10 ml) and washed with water (15 ml). The organic, phase is separated, dried over sodium sulphate and evaporated. LC/MS analysis shows the formation of 22%, by internal standardization, of 4″-dehydroxy-4″ (R)-amino-2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A.
Leon, Patrick, Garel, Laurent, Oddon, Gilles, Lhermitte, Frederic, Pauze, Denis, Guevel, Ronan
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