Process for the preparation of 7 α-(methoxycarbonyl)-3-OXO-17alpha-pregn-4,9(11)-dien-21,17-carbolactone, a useful intermediate for the synthesis of molecules with pharmacological activity

Abstract

An improved process for the preparation of intermediate (V) through the elimination of a molecule of water from intermediate (IV) is described. ##STR00001##
Intermediate (V) is a key molecule for the synthesis of eplerenone, a synthetic steroid with pharmacological activity used in the treatment of chronic pathological conditions, including hypertension.

Claims

1. A process for the production of 7-(methoxycarbonyl)-3-oxo-17-pregn-4-9(11)-dien-21,17-carbolactone (V) comprising elimination of a molecule of water from 11-hydroxy-7-(methoxycarbonyl)-3-oxo-17-pregn-4-en-21,17-carbolactone (IV) by reaction with a two component mixture (VI) consisting of (Et).sub.2NCF.sub.2CHFCF.sub.3 and (Et).sub.2NFCCFCF.sub.3, wherein quantities of the two components of said mixture (VI) are variable in ratios such that an observed area of a minority component is not less than 75% than an observed area of a majority component as determined in a gas chromatographic analysis.

2. The process according to claim 1, wherein the amounts of the two components of said mixture (VI) are variable such that an observed area of a minority component is not less than 75% than an observed area of a majority component as determined in a gas chromatographic analysis.

3. The process according to claim 1, in which the elimination of a molecule of water is realized by treating the intermediate (IV) with the mixture (VI) in a chlorinated solvent or in a mixture of solvents in which at least one of the components is a chlorinated solvent.

Description

DETAILED DESCRIPTION OF THE PROCESS

(1) The process of the invention is directed to the preparation of intermediate (V) by elimination of water from intermediate (IV) using as reagent the mixture (VI) (Et).sub.2NCF.sub.2CHFCF.sub.3/(Et).sub.2NFCCFCF.sub.3 obtained by reacting diethylamine with hexafluoropropene.

(2) ##STR00005##

(3) The content of the two components of mixture (VI) is determined with gas chromatographic analysis.

(4) The amounts of the two components of mixture (VI) are variable in such ratios that the area of the minority component is not less than 75%, and preferably not less than 90%, than the area of the majority component.

(5) The reaction solvent is a chlorinated pure solvent or a mixture of solvents containing at least one chlorinated solvent, inert under the reaction conditions, which solubilize intermediate (IV).

(6) Preferably, methylene chloride and/or chloroform are used as chlorinated solvents.

(7) The volume of solvent used is between 5 and 20 ml, preferably between 7.5 and 15 ml, per gram of the steroid used. The reaction temperature is between 0 and 45 C., preferably between 25 and 35 C.

(8) The reaction time is between 12 and 48 hours, preferably between 24 and 36 hours.

(9) The amount of reactive mixture (VI) used (v/w) is between 50 and 100% by volume, preferably between 50 and 75%, with respect to the weight of the reaction steroid.

EXAMPLES

(10) The invention will be further described by the following examples.

(11) The reagents and solvents used, unless otherwise stated, are commercially available from common suppliers of laboratory reagents such as Sigma-Aldrich, Fluka or equivalent.

(12) The Ishikawa reagent used in Example 1, according to the manufacturers indications, consists by more than 90% of N,N-diethyl-1,1,2,3,3,3-hexafluoropropylamine.

(13) The analytical controls by means of thin layer chromatography are carried out using Merck plates code 1.05554.0001.

(14) GC checks are carried out by Agilent gas chromatograph model 7890A.

(15) HPLC checks are carried out using Agilent chromatographs model 1290 Infinity and model 1200.

Example 1

Comparative

(16) This example is representative of the reproduction of the example 18 of WO 03/082895.

(17) 5 g of 11-hydroxy-7-(methoxycarbonyl)-3-oxo-17-pregn-4-ene-21,17-carbolactone (IV) are suspended in 15 mL acetonitrile at room temperature; 2.55 ml Ishikawa reagent (Aldrich 564990) are added, thus obtaining a suspension.

(18) The mixture is heated to 60 C. and after 2.5 hours, the progress of the reaction is checked by TLC: no reaction.

(19) Additional 15 ml acetonitrile and 2.55 ml Ishikawa reagent (Aldrich 564990) are added.

(20) The system is kept at 60 C. and after 1 hour, the progress of the reaction is checked by TLC: minimum formation of intermediate (V), starting intermediate (IV) largely prevalent.

Example 2

(21) 5 g of 11-hydroxy-7-(methoxycarbonyl)-3-oxo-17-pregn-4-ene-21,17-carbolactone (IV) are suspended in 15 mL acetonitrile at room temperature; 2.55 ml Ishikawa reagent (Aldrich 564990) are added, thus obtaining a suspension.

(22) The mixture is heated to 60 C. and after 2.5 hours, the progress of the reaction is checked by TLC: no reaction.

(23) 5 ml methylene chloride (capped reaction flask) are added, thus obtaining a clear solution after 30 minutes.

(24) After 1 additional hour of reaction, the system is cooled to 25 C. checking the progress of the reaction by TLC: minimum formation of intermediate (V), starting intermediate (IV) largely prevalent.

(25) It is left under stirring for 16 hours at 20-25 C. obtaining, after 16 hours, the disappearance of the starting intermediate (IV) with the formation of intermediate (V) plus other stains in the TLC.

(26) The reaction is quenched by adding methanol first and then 15 ml of a basic aqueous solution of water-sodium bicarbonate with pH=8 to the reaction mixture.

(27) The organic fraction is removed by distillation at reduced pressure obtaining a solid (6 g) whose content of intermediate (V), as determined by HPLC analysis, is equal to 3.47 g, corresponding to a yield of 72.5%.

(28) The product is placed under stirring for 10 hours in methyl tert butyl ether (25 ml) at 25 C.

(29) After filtration and drying, 3.5 g of solid are obtained.

(30) The content of intermediate (V) of this solid, as determined by HPLC analysis, is equal to 3.1 g, corresponding to a yield of 66%.

Example 3

(31) 10 g of 11-hydroxy-7-(methoxycarbonyl)-3-oxo-17-pregn-4-ene-21,17-carbolactone (IV) are suspended in 100 mL chloroform at room temperature; 5.1 ml of reagent (VI) are added.

(32) The mixture is stirred at 30 C., checking the progress of the reaction by TLC after 30 hours: reaction ended.

(33) The reaction is quenched by adding methanol first and then 30 ml of a basic aqueous solution of water-sodium bicarbonate with pH=8 to the reaction mixture.

(34) The phases are separated, the organic fraction is eliminated by distillation at reduced pressure, obtaining a yellow solid which is dried at T=45 C. at reduced P to constant weight (9.93 g); the solid is of suitable quality to be used for the next steps.

(35) The content of intermediate (V), as determined by HPLC analysis, is equal to 8.63 g, corresponding to a yield of 90%.

Example 4

(36) This example is representative of the production of reaction mixture (VI).

(37) At room temperature, 100 ml dichloromethane and 17.7 ml diethylamine are loaded in a flask.

(38) It is cooled to T=10 C. and, under stirring, 32.5 g hexafluoropropene are made to be absorbed by the solution over 10 hours.

(39) The GC check shows the complete disappearance of diethylamine from the reaction mixture.

(40) Dichloromethane is distilled at reduced pressure obtaining 33.7 g of reactive mixture (VI) which at the GC check shows the virtually exclusive presence of the two fluorinated components with 49.94 and 48.46% areas.

(41) Such a mixture can be used as such without need for subsequent purifications.