Crystalline forms of carbapenem antibiotics and methods of preparation

Abstract

A process for preparing a crystalline, carbapenem monosodium salt of formula iia: ##STR00001##
characterized by the steps a) adding about 10 to 30% of an organic solvent to an aqueous solution of the carbapenem, b) cooling the resulting solution to less than −5° C., c) adjusting the pH using a solution containing an acid in an organic solvent to give the appropriate pH for crystallization, and d) crystallizing the compound by adding methanol, and a C_2-5 alcohol at between −5 and −25° C.

Description

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the National Stage of International Application No. PCT/US02/30002 filed on Sep. 20, 2002 which claims the benefit under 35 U.S.C. 119(e) of U.S. Provisional Application No. 60/325,127 filed on Sep. 26, 2001.

BACKGROUND OF THE INVENTION

Carbapenems are a broad class of antibiotic compounds useful for the treatment of infectious diseases, including gram positive and negative, aerobic and anaerobic bacteria. U.S. Pat. No. 5,478,820 to Betts et al, issued Dec. 26, 1995, now assigned to Zeneca Ltd. (incorporated herein by reference thereto), teaches carbapenem compounds, salts and hydrolysable esters thereof, of the general formula I: ##STR00002##
wherein R¹ is 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl, R² and R³ are hydrogen or C_1-4 alkyl, and R⁴ and R⁵ are hydrogen, halo, cyano, nitro, hydroxy, alkylamino, aminosulphonyl, or carbamoyl.

Crystalline forms of carbapenem antibiotics are desirable for improved purity and stability compared with amorphous forms. Crystallization allows isolation of a compound with rejection of impurities, and crystalline forms tend to be more stable than amorphous forms of the same compound. In the present invention, crystalline forms of the carbapenem (4R, 5S,6S,8R,2′S,4′S)-3-[[2-[[(3-carboxyphenyl) amino]carbonyl]pyrrolidin-4-yl]thio]-4-methyl-6-(1-hydroxyethyl)-7-oxo1-azabicyclo [3.2.0]hept-2-en-2-carboxylic acid have been discovered and characterized and the processes for making said forms are disclosed.

The compounds of formula I can generally be synthesized taking into account the disclosure of U.S. Pat. No. 6,063,931 granted May 16, 2000, U.S. Pat. No. 5,648,501 granted Jul. 15, 1997, U.S. Pat. No. 5,478,820 granted Dec. 26, 1995, U.S. Pat. No. 6,180,783 granted Jan. 30, 2001, U.S. Pat. No. 5,872,250 granted Feb. 16, 1999 and U.S. Pat. No. 5,965,747, granted Oct. 12, 1999 (all incorporated herein by reference). See also Bugay, D. E., Pharm. Res., 1993, 10, 317; Harris, R. K., et al., Spectrochimica Acta, 1989, 45A, 465; Byrn, S. R., et al., J. Pharmaceutical Sciences, 1985, 74, 565.

SUMMARY OF INVENTION

Crystalline forms of the carbapenem (4R,5S,6S,8R,2′S,4′S)-3-[[2-[[(3-carboxyphenyl)amino]carbonyl]pyrrolidin-4-yl]thio]-4-methyl-6-(1-hydroxyethyl)-7-oxo1-azabicyclo [3.2.0]hept-2-en-2-carboxylic acid (formula II) and processes for making said forms are disclosed: ##STR00003##

Specifically, crystalline forms, which are solvates and hydrates or mixed solvates/hydrates of the monosodium salt IIa, are disclosed. These crystalline forms are useful in the isolation and purification of the carbapenem of formula IIa in the manufacture of an antibiotic product for the treatment of serious infections. ##STR00004##

BRIEF DESCRIPTION OF DRAWINGS

1 2 is shown in FIG. 3. The solid-state NMR pattern corresponding to Form B is shown in FIG. 4.

This invention also relates to a process for producing a crystalline carbapenem salt of formula IIa: ##STR00007##
comprising adding about 10 to 30% of an organic solvent including but not limited to C₁ to C₅ alcohols to an aqueous solution containing a compound of formula II, its carbamate form (e.g., structural formula 4) and/or salt forms thereof, cooling the resulting solution to below −5° C., adjusting the pH using a solution of an acid such as formic acid, acetic acid, propionic acid, or hydrochloric acid, preferably acetic acid, in an organic solvent including but not limited to C₁ to C₄ alcohols, preferably methanol, to give the pH required for crystallization of the compound of formula IIa (pH of about 5 to about 6). The solution is seeded with a slurry containing Compound IIa (up to about 0.5% relative to Compound IIa going into the crystallization) in a mixture of water, methanol, and 1-propanol (10-30, 5-15, and 3-7 mL/g of Compound IIa charged to make the slurry, respectively). The carbamate form of the compound of formula II is formed at the pyrrolidinone nitrogen.

The compound is crystallized by adding from 0.5 to 2 volumes of methanol relative to the aqueous volume, and a C_2-5 alcohol (from 0.5 to 2.5 volumes relative to the aqueous volume), preferably 1-propanol, at between −5 and −25° C. to give crystalline Form A. The solid is then washed with a mixture of water and 2-propanol (from 5 to 30 mL/g of the compound of formula IIa) with said mixture containing from 5 to 20% water (v/v) to give crystalline Form B.

The crystalline form of formula IIa as crystallized from a solution containing formula IIa in a mixture of water/methanol/1-propanol is also referred to herein as (4R,5S,6S,8R,2′S,4′S)-3-[[2-[[(3-carboxyphenyl)amino]carbonyl]-pyrrolidin-4-yl]thio]4-methyl-6-(1-hydroxyethyl)-7-oxo1-azabicyclo[3.2.0]hept-2-en-2-carboxylic acid monosodium salt.

The crystalline compound of the present invention is used in the manufacture of a drug product that is useful for the treatment of bacterial infections in animal and human subjects. ##STR00008##

The crystalline forms can be produced in accordance with the following non-limiting examples.

EXAMPLE ONE

A hydrogenator is charged with 63 g of 5% Pd on carbon catalyst (dry weight) in 1.8 L of water. The vessel is placed under hydrogen then vented and placed under nitrogen. Sodium hydroxide (68 g, 50%) is charged adjusting the pH to about 7.5 with carbon dioxide.

The enol phosphate (170 g) and the thiol (86 g) are dissolved in 1.3 L of N-ethylpyrrolidinone (NEP). The mixture is cooled to below −40° C. and 1,1,3,3-tetramethylguanidine (109 g) is added. After 3 hours, the reaction mixture is quenched into the hydrogenator at below 15° C. adjusting the pH to about 8 with carbon dioxide. The vessel is placed under hydrogen. When the reaction is complete, the hydrogen is vented and the reaction mixture is treated with activated carbon and filtered. The filtrate is extracted with iso-amyl alcohol containing diphenylphosphoric acid (240 g) and 50% NaOH (44 g). The resulting aqueous solution is further extracted with iso-amyl alcohol to give an aqueous solution containing at least 90 mg/mL of the compound of formula II (predominantly in the stabilized form, 4). Both extractions are performed using two CINC (Costner Industries Nevada Corporation) centrifugal separators set in series for countercurrent extraction. 1-Propanol is added (20% by volume) and the resulting solution is cooled to below −5° C. The pH is adjusted to 5.5 at below −5° C. using a solution of acetic acid in methanol (3 M). Methanol and 1-propanol are respectively added to 0.5 and 0.25 volumes total relative to the aqueous solution from the extraction. The resulting solution is seeded with a slurry containing 0.1 g of the compound of formula IIa in a mixture of water, methanol, and 1-propanol (2, 1, and 0.5 mL, respectively) prepared at −10° C. The product is then crystallized at below −5° C. by adding methanol and 1-propanol to bring the total of each to one volume relative to the aqueous solution from the extraction and isolated by filtration to give the compound of formula IIa as a crystalline solid (Form A).

EXAMPLE TWO

The solid derived by crystallization from a mixture of water, methanol, and 1-propanol (Form A) is washed with a mixture of water and 2-propanol (15:85 v/v, 10 mL/assay g of compound IIa) at below 10° C. to give the compound of formula IIa as a crystalline solid (Form B).

Claims

1. Crystalline solvate (4R,5S,6S,8R,2′S,4′S)-3-[[2-[[(3-carboxyphenyl) amino]carbonyl]pyrrolidin-4-yl]thio]-4-methyl-6-(1-hydroxyethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-en-2-carboxylic acid monosodium salt, formula iia, having an x-ray powder diffraction pattern of form B in accordance with FIG. 3.

2. A process for preparing a crystalline solvate carbapenem monosodium salt of formula iia: ##STR00009##

3. The process according to claim 2, wherein the C_1-5 alcohol is selected from the group consisting of methanol, 1-propanol, 2-propanol, isopropyl alcohol, ethanol, 1-butanol, 2-butanol, isobutyl alcohol, t-butyl alcohol, 1-pentanol, 2-pentanol, 3-pentanol, isopentyl alcohol and mixtures thereof.

4. A process according to claim 2 which is conducted at a temperature of about −5° C. to about −25° C. and wherein the acid is selected from a group consisting of formic acid, acetic acid, propionic acid, and butyric acid.

5. A process according to claim 4 wherein the acid is acetic acid.

6. A process for preparing a crystalline solvate carbapenem monosodium salt of general formula iia, form B: ##STR00011##