Process for the esterification of a carbothioic acid

Abstract

A process for preparing compounds of formula [II] ##STR00001##
by esterification of the C-17 hydroxyl group of 6,9-difluoro-11,17-dihydroxy-16-methyl-3-oxoandrosta-1,4-diene-17-carbothioic acid, the compound of formula [I] comprises treating compound [I] with a slight excess of an acyl chloride of general formula RCOCl, where R represents CH2CH3, CH2CH2CH3 or CH(CH3)2, in an inert solvent, in the presence of a tertiary amine. ##STR00002## Preferably the process is carried out using pyridine in the presence of acetone at a temperature of from 5 C. to 20 C.

Claims

1. A process for preparing fluticasone propionate comprising: (i) esterification of the C-17 hydroxyl group of 6,9-difluoro-11,17-dihydroxy-16-methyl-3-oxoandrosta-1,4-diene-17-carbothioic acid, the compound of formula [I]: ##STR00014## (ii) wherein esterification comprises contacting compound [I] with from 1.0 mol to 1.2 moles of an acyl chloride of general formula RCOCl per mol of compound [I], in an inert solvent, in the presence of a tertiary amine at a temperature of from 5 C. to 0 C., where R represents CH.sub.2CH.sub.3, wherein the tertiary amine is pyridine, 2-picoline, 3-picoline, 4-picoline, N-methylimidazole, or N-methylpyrrolidine to produce compound [II], 6,9-difluoro-11-hydroxy-16-methyl-17-propionyloxy-3-oxoandrosta-1,4-diene-17-carbothioic acid: ##STR00015## and (iii) converting compound [II] to fluticasone propionate wherein the fluticasone propionate contains less than 0.3% dimer G ##STR00016##

2. The process according to claim 1 wherein the acyl chloride of general formula RCOCl is propionyl chloride, R representing CH.sub.2CH.sub.3.

3. The process according to claim 1 wherein the tertiary amine is pyridine, or N-methylimidazole.

4. The process according to claim 1 wherein the tertiary amine is pyridine.

5. The process according to claim 1 wherein the inert solvent is acetone.

6. The process according to claim 1 wherein pyridine is used as the tertiary amine and the inert solvent is acetone, tetrahydrofuran, dimethylacetamide, dichloromethane, ethyl acetate, 2-pentanone, 3-pentanone, 4-methyl-2-pentanone or 2-butanone.

7. A process for the preparation of 6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothioic acid S-(2-oxo-tetrahydrofuran-3-yl)-ester which process comprises preparing 6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-3-oxoandrosta-1,4-diene-17-carbothioic acid according to the process of claim 1, and converting said compound to the said S-ester.

8. The process according to claim 2 wherein the tertiary amine is pyridine, or N-methylimidazole.

9. The process according to claim 4 wherein the inert solvent is acetone.

10. The process according to claim 8 wherein the inert solvent is acetone.

11. The process according to claim 1 wherein the process does not comprise an aminolysis step.

12. The process according to claim 1 wherein the process does not comprise an aminolysis step with a primary or secondary amine.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) According to the present invention, there is provided a process for preparing compounds of formula [II]

(2) ##STR00008##
by esterification of the C-17 hydroxyl group of 6,9-difluoro-11,17-dihydroxy-16-methyl-3-oxoandrosta-1,4-diene-17-carbothioic acid, compound of formula [I], which process comprises treating compound [I] with a slight excess of an acyl chloride of general formula RCOCl, where R represents CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3 or CH(CH.sub.3).sub.2, in an inert solvent, in the presence of a tertiary amine. Preferably, the process is carried out at a temperature of from 5 C. to 20 C.

(3) The invention also provides the use of compounds of formula [II] when made according to the process of the invention for the preparation of therapeutically useful medicaments.

(4) The present invention provides an improved and simplified process for the selective 17-esterification of the compound [I], forming negligible amounts of mixed anhydrides of general formula [VII]

(5) ##STR00009##
in which R represents CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3 or CH(CH.sub.3).sub.2, without the need to perform the aminolysis reaction of the corresponding mixed anhydrides.

(6) The process comprises the reaction of compound [I], 6,9-difluoro-11,17-dihydroxy-16-methyl-3-oxoandrosta-1,4-diene-17-carbothioic acid, with a slight excess of an acyl chloride of general formula RCOCl, in which R represents CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3 or CH(CH.sub.3).sub.2, in the presence of an appropriate organic tertiary amine, in an inert solvent, to yield the compounds of general formula [II]

(7) ##STR00010##
in which R represents CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3 or CH(CH.sub.3).sub.2.

(8) A particularly preferred embodiment of the present invention is to provide an improved process for the preparation of 6,9-difluoro-11-hydroxy-16-methyl-17-propionyloxy-3-oxoandrosta-1,4-diene-17-carbothioic acid, compound of formula [III], comprising of reacting 6,9-difluoro-11,17-dihydroxy-16-methyl-3-oxoandrosta-1,4-diene-17-carbothioic acid [II] with a slight excess of propionyl chloride, in the presence of an appropriate tertiary amine, in an inert solvent.

(9) The compound of formula [III] is a known intermediate useful in the preparation of anti-inflamatory steroids such as fluticasone propionate of formula [A] (described in U.S. Pat. No. 4,335,121), highly effective in the treatment of inflammatory diseases like asthma and chronic obstructive pulmonary disease (COPD), and in the preparation of the related 6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothioic acid S-(2-oxo-tetrahydro-furan-3-yl) ester of formula [B] (described in the application WO 97/24365), possessing a useful anti-inflammatory activity and having little or no systemic activity.

(10) ##STR00011##

(11) Accordingly, the invention also provides a process for preparing fluticasone propionate which process comprises preparing 6,9-difluoro-11-hydroxy-16-methyl-17-propionyloxy-3-oxoandrosta-1,4-diene-17-carbothioic acid according to the process of the invention and converting the said compound to fluticasone propionate.

(12) There is also provided a process for the preparation of 6-9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothioic acid S-(2-oxo-tetrahydrofuran-3-yl) ester which process comprises preparing 6, 9-difluoro-11-hydroxy-16-methyl-17-propionyloxy-3-oxoandrosta-1,4-diene-17-carbothioic acid according to the process of the invention and converting said compound to the said S-ester.

(13) The present invention provides an advantageous process for the preparation of 6,9-difluoro-11-hydroxy-16-methyl-17-propionyloxy-3-oxoandrosta-1,4-diene-17-carbothioic acid, compound of formula [III] comprising of treating the compound [I], 6,9-difluoro-11,17-dihydroxy-16-methyl-3-oxoandrosta-1,4-diene-17-carbothioic acid, with a slight excess of propionyl chloride, in the presence of an appropriate tertiary amine, in an inert solvent, at a temperature between 5 C. and 20 C.

(14) The acyl chloride of general formula RCOCl is preferably used in the process of the present invention in a molar ratio of from 1.0 to 1.2 moles of acyl chloride per mol of starting compound [I], preferably in an amount within this range.

(15) Inert solvents for the 17-acylation process of the present invention include acetone, tetrahydrofuran, dimethylacetamide, dichloromethane, ethyl acetate, 2-pentanone, 3-pentanone, 4-methyl-2-pentanone and 2-butanone. Acetone is the preferred solvent.

(16) Appropriate tertiary amines to carry out the selective 17-propionylation include pyridine, 2-picoline 3-picoline, 4-picoline, N-methylimidazole, and N-methylpyrrolidine.

(17) The 17-acylation reaction of the invention is preferably performed at a temperature of from 5 C. to 20 C.

(18) The use of the tertiary amines defined above as adequate for the process of the patent, present advantages over other bases previously described in the prior art such as triethylamine, tripropylamine, ethyldiisopropylamine, N,N-dimethylaniline, N,N-dimethylcyclohexylamine, inorganic carbonates such as e.g. sodium hydrogen carbonate, potassium carbonate and sodium carbonate. When using these bases the formation of high levels of the mixed anhydride compound [IV] or incomplete consumption of compound [I] or the formation of high levels of impurities as is the case when sodium hydrogen carbonate is avoided.

(19) Under the preferred conditions of the process of the present invention, 17-esterification goes to completion with 1.0 to 1.2 moles of propionyl chloride per mole of compound [I], in the presence of pyridine, and the levels of mixed anhydride formed during the reaction are below 3% (in area, by HPLC). With these low levels of mixed anhydride, the aminolysis reaction is not required and compound [III] is isolated with a high degree of purity, on work-up of the propionylation reaction.

(20) Under the conditions described in the prior art when compound [III] is prepared via the mixed anhydride, partial degradation of compound [III] may occur during the aminolysis reaction. This degradation is especially problematic when prolonged reaction times take place, which is to be expected on an industrial scale. Under the conditions disclosed in the present invention, this in situ degradation of compound [III] is avoided.

(21) We have found that by following the prior art a precursor (G precursor) to an impurity (impurity G) is formed.

(22) ##STR00012##

(23) With the process of the present invention, dimer G, which is difficult to remove from the final product, fluticasone propionate, by recrystallization when at levels higher than 0.5%, is formed at levels below 0.3%. Hence, repeated recrystallizations to obtain material of the required purity, which if carried out significantly reduces the overall yield, are avoided.

(24) Another embodiment of this invention is to provide an improved process for the preparation of the compounds 6,9-difluoro-11-hydroxy-16-methyl-17-butyryloxy-3-oxoandrosta-1,4-diene-17-carbothioic acid, compound of formula [VIII] and 6,9-difluoro-11-hydroxy-16-methyl-17-isobutyryloxy-3-oxoandrosta-1,4-diene-17-carbothioic acid of formula [IX].

(25) ##STR00013##
Compounds of formula [VIII] and [IX] are directly prepared from compound [I] by reaction with a slight excess of the corresponding acyl chloride, without the need to perform an aminolysis reaction of the corresponding mixed anhydrides.

(26) According to a preferred aspect of to the present invention, esterification of compound. [I] to obtain compound [VIII], is performed with 1.0 to 1.2 moles of butyryl chloride, in acetone, in the presence of pyridine, at a temperature between 5 C. and 20 C., preferably between 5 C. and 0 C. The esterification of compound [I] to obtain compound [IX] is preferably performed with 1.0 to 1.2 moles of isobutyryl chloride, in acetone, in the presence of pyridine, at a temperature between 5 C. and 20 C., preferably between 5 C. and 0 C.

EXAMPLES

(27) The following examples illustrate the invention and certain preferred embodiments and are exempt of limitative character of the scope of the invention.

Example 1: Preparation of 6,9-difluoro-11-hydroxy-16-methyl-17-propionyloxy-3-oxoandrosta-1,4-diene-17-carbothioic acid

(28) A suspension of compound [I] (10 g, 0.024 moles) in acetone (175 ml) is cooled to 20 C. and treated with pyridine (30 ml) and propionyl chloride (2.3 ml, 0.026 moles), while maintaining the temperature between 20 C. and 15 C. The mixture is stirred at 20 C./15 C. until completion of reaction. A second addition of propionyl chloride (0.02 ml) can be carried out if necessary to complete the reaction. Compound [III] is precipitated by addition of water (240 ml) and concentrated hydrochloric acid (30 ml). The suspension is stirred for 2 hours at a temperature between 0 C. and 5 C., filtered, and the wet cake washed with cold water until neutral pH. The solid is dried at a temperature below 40 C., under vacuum, to give the title compound as a white to off white solid (10.04 g; 88%; Purity, area % by HPLC: 96.1%).

Example 2: Preparation of 6,9-difluoro-11-hydroxy-16-methyl-17-isobutyryloxy-3-oxoandrosta-1,4-diene-17-carbothioic acid

(29) Isobutyryl chloride (0.28 ml, 0.0027 moles) is slowly added to a mixture of acetone (17.5 ml), compound [I] (1 g, 0.0024 moles) and pyridine (3 ml), at temperatures between 5 C. and 0 C., and the mixture is stirred at that temperature range until consumption of compound [I]. Upon completion of the reaction the title compound is precipitated by addition of water (24 ml) and concentrated hydrochloric acid (3 ml). The suspension is stirred for 1 to 2 hours, at a temperature between 0 C. and 5 C., filtered, and the wet cake washed with cold water until neutral pH. The wet solid is dried at a temperature lower than 40 C., under vacuum, to yield the title compound as a white to off white solid (1.09 g; 93%; Purity, area % by HPLC: 94.8%).

Example 3: Preparation of 6,9-difluoro-11-hydroxy-16-methyl-17-propionyloxy-3-oxoandrosta-1,4-diene-17-carbothioic acid

(30) A suspension of compound [I] (1 g, 0.0024 moles) in acetone (17 ml) is cooled to a temperature between 20 C. and 15 C. N-methylimidazole (2.9 ml) and propionyl chloride (0.23 ml, 0.0026 moles) are sequentially added to the solution, maintaining the temperature between 20 C. and 15 C. Upon completion of the reaction, compound [III] is precipitated by addition of water (24 ml) and concentrated hydrochloric acid (3 ml). The suspension is stirred for 2 hours at ca. 0 C., filtered, and the wet cake washed with cold water until neutral pH. The wet solid is dried at a temperature below 40 C., under vacuum, to give the title compound as a white to off white solid (1.0 g; 88%; Purity, area % by HPLC: 96.8%).