WO2006032970A2

WO2006032970A2 - PROCESS FOR PREPARING 7α-ALKOXYCARBONYL SUBSTITUTED STEROIDS

Info

Publication number: WO2006032970A2
Application number: PCT/IB2005/002757
Authority: WO
Inventors: S. Zaheer Abbas; Michael Bauer; Marlon V. Carlos; Paul David; Thaddeus Franczyk; Chung C. Kim; Jon P. Lawson; Keith D. Maisto; David Mckenzie; Mark Pozzo; Joseph Wieczorek
Original assignee: Pharmacia Corporation
Priority date: 2004-09-09
Filing date: 2005-08-25
Publication date: 2006-03-30
Also published as: EP1794177A2; BRPI0515106A; JP2008512439A; CA2579954A1; TW200617020A; WO2006032970A3; AR050632A1; MX2007002846A

Abstract

Processes are described for the conversion of a steroid substrate having a 4,7-carbonyl bridge to a structure comprising a 7α-alkoxycarbonyl substituent by reaction of the substrate with an alkoxy group source, preferably in the presence of a base. Several optional process modifications are described. The reaction may be conducted at a temperature greater than about 70°C, with substantially shorter residence times than are required at lower temperatures. A saponification target may be incorporated into the reaction medium to consume free hydroxide compounds. The product 7α-alkoxycarbonyl compound may be recovered by crystallization, residual steroid values may be recovered from the crystallization mother liquor by extraction, and the extract may be processed to produce a repulp solution wherein the steroids may be re-equilibrated to produce additional 7α-alkoxycarbonyl substituted steroid product. Alternatively, the repulp solution may be recycled to a primary reactor wherein 4,7-carbonyl bridge substrate is converted to 7α-alkoxycarbonyl product. The process is particularly useful in the preparation of eplerenone, wherein a diketone intermediate comprising a 4,7-carbonyl bridge is reacted with an alkali metal methoxide to yield an 11α-hydroxy-7α-methoxycarbonyl compound (hydroxyester), the 11α-hydroxy group is converted to a leaving group which is then abstracted to produce a Δ-9,11 enester, and the enester is epoxidized to eplerenone. Also disclosed is an epoxidation reaction conducted at relatively low hydrogen peroxide to enester substrate ratio.

Description

PROCESS FOR PREPARING 7α-ALKOXYCARBONYI_ SUBSTITUTED STEROIDS

CROSS REFERENCE TO RELATED PATENTS AND PATENT APPLICATIONS [0001] This application is a continuation-in-part of United States provisional application Serial No. 60/608,425, filed September 9, 2004; United States provisional patent application Serial No. 60/612,133, filed September 22, 2005, both of which are incorporated herein by reference in their entireties.

[ 0001] This application relates to the preparation of steroid intermediates and more particularly to processes for converting a diketone compound corresponding to Formula 6000 as described hereinbelow to a 7-alkoxycarbonyl compound of Formula 5000, as further described below.

BACKGROUND OF THE INVENTION

[ 0002 ] US patents 5,981 ,744, 6,331 ,622 and 6,586,591 describe a process for converting compounds of Formula Vl:

Formula Vl

to a 7-alkoxycarbonyl compound of Formula V:

Formula V

[ 0003 ] wherein

[ 0004 ] R¹² is selected from the group consisting of hydrogen, halo, haloalkyl, hydroxy, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, cyano and aryloxy;

[ 0005 ] -A-A- represents the group -CHR¹-CHR²- or -CR¹=CR²-;

[ 0006] where R¹ , R² and R¹² are independently selected from the group consisting of hydrogen, halo, hydroxy, alkyl, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, cyano and aryloxy;

[ 0007 ] -B-B- represents the group -CHR¹⁵-CHR¹⁶-, -CR¹⁵=CR¹⁶- or an α- or β- oriented group:

,16

CH- -CH — CH-CH₂-CH — .

where R¹⁵ and R¹⁶ are independently selected from the group consisting of hydrogen, halo, alkyl, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, and aryloxy;

[ 0008 ] R^17a and R^17b are independently selected from the group consisting of hydrogen, hydroxy, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, acyloxyalkyl, cyano an aryloxy, or R^17a and R^17b comprise a carbocyclic or heterocyclic ring structure, or R^17a and R^17b together with R¹⁵ and R¹⁶ comprise a carbocyclic or heterocyclic ring structure fused to the pentacyclic D ring; and

[ 0009 ] R⁷ comprises alkoxycarbonyl, more preferably, 7α-alkoxycarbonyl.

[ 0010 ] According to the process as described in the aforesaid patents the diketone of Formula Vl is reacted with a base, preferably a metal alkoxide, to open up the ketone bridge between the 4 and 7 positions, cleave the bond between the carbonyl group and the 4-carbon, and form an α-oriented alkoxycarbonyl substitutent at the 7 position while eliminating cyanide at the 5-carbon. [ 0011] The conversion of a compound of Formula Vl to a compound of Formula V is described in the aforesaid patents as step in any of several schemes for the preparation of eplerenone or related 7α-alkoxycarbonyl steroids. Typically, the yields for this step are not consistently as high as would be desired. In certain of the schemes, preparation of the Formula Vl intermediate involves two or more process steps, as a consequence of which it has substantial -value -based on its cost of preparation. ^*As^"a resultrpoor yields in the conversion of this intermediate to the compound of Formula V represent a substantial economic penalty in the overall manufacturing costs.

[ 0012 ] Thus, there is potential value in a process which is capable of providing improved yields in this step.

SUMMARY OF THE INVENTION

[ 0013 ] In accordance with the present invention, a compound as defined in Formula 6000, as described hereinbelow, is converted to a compound of Formula 5000, as further described below, by reaction with a source of an alkoxy group in the presence of a base. The compounds of Formulae Vl and V are fully within the scope of Formulae 6000 and 5000, respectively but, as may be seen below, the latter definitions are broader in certain respects. In various preferred embodiments, the process is capable of providing enhanced yields of the compound of Formula 5000 as compared to the process as described in the aforesaid patents 5,981 ,744, 6,331 ,622 and 6,586,591 , and/or other advantages with regard to the implementation of those processes.

[ 0014 ] Modifications of the process of the aforesaid US patents, as described herein, relate to either the conditions of the reaction, the preparation of a metal alkoxide reagent, the procedures for recovery of the compound of Formula 5000 where desired, and/or any combination of such modifications. In various embodiments of the process, such modifications provide operational and economic advantages. Processes of the invention further include oxidation of a Δ-9,11 steroid to a 9,11 -epoxy steroid, and may optionally comprise other steps in the preparation of 3-keto-7α-alkoxycarbonyl-Δ^9p11-17-spirolactone steroid such as eplerenone.

[ 0015 ] Among the various aspects of the present invention is a process for the preparation of a compound corresponding to the formula 5000:

5000 In the formula 5000 structure, R⁷ represents an alpha-oriented lower alkoxycarbonyl or hydroxycarbonyl radical. The substituents R¹⁰, R¹² and R¹³ are independently selected from the igroup consisting of hydrogen, halo, haloalkyl, hydroxy, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, cyano and aryloxy. Substituents R^17a and R^17b are independently selected from the group consisting of hydrogen, hydroxy, halo, lower alkoxy; acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, acyloxyalkyl, cyano, aryloxy, or R^17a and R^17b together form an oxo, or R^17a and R^17b together with the C(17) carbon comprise a carbocyclic or heterocyclic ring structure, or R^17a or R^17b together with R¹⁵ or R¹⁶ (as defined below) comprise a carbocyclic or heterocyclic ring structure fused to the pentacyclic D ring. The structure -A-A- represents the group -CHR¹-CHR²- or -CR¹=CR²- and substituents R¹ and R² are independently selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy or R¹ and R² together with the carbons of the steroid nucleus to which they are attached form a (saturated) cycloalkylene group. The structure -B-B- represents the group -CHR¹⁵-CHR¹⁶-, - . CR¹⁵=CR¹⁶- or an α- or β-oriented group:

_R15 ^_R16

CH CH

I I CH — CHg — CH

and substituents R¹⁵ and R¹⁶ are independently selected from the group consisting of hydrogen, halo, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, and aryloxy; or R¹⁵ and R¹⁶, together with the C-15 and C-16 carbons of the steroid nucleus to which R¹⁵ and R¹⁶ are respectively attached, form a cycloalkylene group. The structure -G-J- represents the group

CR⁹-CHR¹¹— "^C=CR¹¹ or ' ; and R⁹ and R¹¹ are independently selected from the group consisting of hydrogen, hydroxy, protected hydroxy, halo, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy or R⁹ and R¹¹ together form an epoxy group. Finally, the structure -C-C- is represented by the groups

I -CH=C- or

CH [ 0016] The process for the preparation of above defined formula 5000 comprises reacting a compound of Formula 6000 with a source of an alkoxy group at a temperature above about 70⁰C, where the alkoxy group corresponds to R⁷¹O- and R⁷¹O- corresponds to the alkoxy substituent of R⁷. The compound of Formula 6000 has the following structure:

The identity of R¹, R², R^3a, R^3b, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁵, R¹⁶, -A-A-, -B-B- and -G-J- are defined as above for Formula 5000.

[ 0017 ] Another aspect of the present invention comprises a process for the preparation of a compound of Formula 5000 wherein the process comprises contacting a compound of Formula 6000 with a reagent comprising an alkali metal or alkaline earth metal alkoxide. Free alkali metal or alkaline earth metal hydroxide (that may be contained or formed in the above reagent, and/or contained or formed in a reaction medium in which the compound of Formula 6000 is contacted with the reagent) is reacted with a sacrificial saponification target compound, which inhibits saponification of the product of Formula 5000. The alkali metal or alkaline earth metal alkoxide has the formula (R⁷¹O)_xM wherein M is alkali metal or alkaline earth metal, x is 1 where M is alkali metal, x is 2 where M is alkaline earth metal, and R⁷¹O- corresponds to the alkoxy substituent of R⁷. The compounds corresponding to Formulae 5000 and 6000 are described hereinabove.

[ 0018 ] A further aspect of the present invention com prises a process for the preparation of a compound of Formula 5000 wherein the process comprises contacting a compound of Formula 6000 with an alkali metal or alkaline earth metal alkoxide in a reaction medium containing not more than 0.2 equivalents free alkali metal or alkaline earth metal hydroxide per mole of the compound of Formula 6000 converted in the reaction.

[ 0019 ] Yet another aspect of the present invention comprises a process for the preparation of a compound corresponding to the formula 5000 wherein the process comprises continuously or intermittently introducing a compound of Formula 6000 and a source of an alkoxy group into a continuous reaction zone, and continuously or intermittently withdrawing a reaction mixture comprising said compound of Formula 5000 from the reaction zone. [0020] Still another aspect of the present invention comprises a process for the preparation of a compound having the structure of Formula 5000 wherein the process comprises contacting a compound of Formula 6000 with a source of an alkoxy group in the presence of a base. The resulting reaction produces a reaction mixture comprising the compound of Formula 5000, other steroid components and a cyanide compound. The product compound of Formula 5ΘOΘ-is-reeovered by-er-ystalii-zing-it-from-a-erystallization-medium-which eontains-the Formula

5000 product produced in the reaction mixture, other steroid components, the cyanide compound, and a crystallization solvent. The crystalline product is separated from the crystallization mother liquor. The mother liquor comprises retained steroid values and the cyanide compound, wherein retained steroid values comprise the compound of Formula 5000 and other steroids that may be converted to the compound of Formula 5000. The process further comprises contacting a substantially water-immiscible solution which comprises the retained steroid values with an aqueous extraction medium in a liquid/liquid extraction zone. This step produces a two-phase extraction mixture which comprises an aqueous raffinate phase containing cyanide ion and an organic extract phase comprising the compound of Formula 5000 and the other steroids. Further, the process comprises separating the organic extract and aqueous raffinate phases and recovering steroid values from the organic extract phase.

[ 0021] A further aspect of the present invention comprises a process for the preparation of a compound corresponding to the formula 5600:

The substituent R⁷ represents a lower alkoxycarbonyl or hydroxycarbonyl radical. The structure - A-A- represents the group -CHR¹-CHR²- or -CR¹=CR²- and R¹ and R² are independently selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, cyano and aryloxy. The substituent R¹² is selected from the group consisting of hydrogen, halo, haloalkyl, hydroxy, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, cyano and aryloxy. The process comprises reacting a compound corresponding to formula 6600 with a source of an alkoxy group in the presence of a base at a temperature above about 7O⁰C. The alkoxy group corresponds to R⁷¹O- where R⁷¹O- corresponds to the alkoxy substituent of R⁷. The compound corresponding to formula 6600 has the structure:

wherein R¹, R², R¹² and -A-A- are defined as above for Formula 5600.

[ 0022 ] Yet another aspect of the present invention comprises a process for the preparation of a compound corresponding to the formula 5600 wherein the process comprises contacting a compound corresponding to Formula 6600 with a source of an alkoxy group in the presence of a base. The resulting reaction produces a reaction mixture which comprises the compound corresponding to formula 5600, other steroid components and a cyanide compound. Following production, the compound of formula 5600 is crystallized from a crystallization medium. The crystallization medium comprises the formula 5600 product produced in said reaction mixture, the other steroid components, the cyanide compound and a crystallization solvent. Further, the compound of formula 5600 is separated from the crystallization mother liquor. The mother liquor contains retained steroid values and the cyanide compound. The retained steroid values comprise the compound of formula 5600 and other steroids that may be converted to the compound of Formula 5000. A substantially water-immiscible solution comprising the retained steroid values is contacted with an aqueous extraction medium in a liquid/liquid extraction zone. This step produces a two-phase extraction mixture comprising an aqueous raffinate phase containing cyanide ion and an organic extract phase comprising the compound corresponding to formula 5600 and the other steroids. The two-phase extraction mixture is separated into organic extract and aqueous raffinate phases and steroid values are recovered from the organic extract phase.

[0023 ] Still another aspect of the present invention comprises a process for the preparation of a compound corresponding to the formula 5600 wherein the process comprises contact of a compound corresponding to formula 6600 with a reagent comprising an alkali metal or alkaline earth metal alkoxide. The free alkali metal or alkaline earth metal hydroxide contained or formed in the reagent, and/or in a reaction medium in which the compound corresponding to formula 6600 is contacted with the reagent is reacted with a sacrificial saponification target compound. This reaction inhibits saponification of the product corresponding to formula 5600. The alkali metal or alkaline earth metal alkoxide is as defined above.

[ 0024 ] A further aspect of the present invention is a process for the preparation of a compound corresponding to the formula 1600:

The substituent R⁷ represents a lower alkoxycarbonyl or hydroxycarbonyl radical. The structure A-A- represents the group -CHR¹ -CHR²- or -CR¹=CR²- and R¹ and R² are independently selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, cyano and aryloxy. The substituent R¹² is selected from the group consisting of hydrogen, halo, haloalkyl, hydroxy, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, cyano and aryloxy. The process comprises contacting a steroid substrate of formula 2600 with a peroxide compound in an epoxidation reaction zone in the presence of a peroxide activator. The peroxide compound and the steroid substrate are introduced into the reaction zone in a ratio from about one to about 7 moles peroxide compound per mole steroid substrate. The peroxide compound is reacted with the steroid substrate in the reaction zone to produce a reaction mixture, which comprises an epoxy steroid. The steroid substrate of formula 2600 corresponds to the following structure:

wherein -A-A-, R⁷ and R¹² are defined as above for formula 1600.

[ 0025] Still a further aspect of the present invention is a process for the preparation of a compound corresponding to the formula 1600 wherein the process comprises contact of a Δ⁹'¹¹ steroid substrate of formula 2600 with a peroxide compound in a liquid reaction medium. The peroxide compound is reacted with the steroid substrate in the reaction medium to produce a reaction mixture, which comprises a 9,11 -epoxy steroid of formula 1600. The steroid substrate and peroxide compound are contacted in absolute and relative proportions, and at a temperature, such that the decomposition of the peroxide content of the reaction medium, which is in excess of that stoichiometrically equivalent to the steroid substrate, does not produce an exotherm effective to cause an uncontrolled autocatalytic decomposition of peroxide compound.

[ 0026] Another aspect of the present invention com prises a process for the preparation of a compound corresponding to the formula 1600 wherein the process comprises contact of a Δ⁹'¹¹ steroid substrate of formula 2600 with hydrogen peroxide in a liquid reaction medium. The steroid substrate is reacted with hydrogen peroxide in the liquid reaction medium to produce a reaction mixture, which comprises a 9,11-epoxy steroid of formula 1600, and water is added to the reaction mixture to produce a water-diluted reaction mixture. The composition of the water-diluted reaction mixture being such that decomposition of all the unreacted peroxide compound contained in the reaction mixture cannot produce an exotherm effective to cause an uncontrolled autocatalytic decomposition of peroxide compound.

BRIEF DESCRIPTION OF THE DRAWINGS

[ 0027 ] Fig. 1 is a schematic flowsheet illustrating a process for recovery of steroid values from the mother liquor obtained upon crystallization of the hydroxyester of Formula 5000 from the reaction mass obtained upon reaction of the diketone substrate of Formula 6000 with an alkali metal alkoxide;

[ 0028 ] Fig. 2 is a plot of the rate of formation of the hydroxyester of Formula V-1 by reaction of the diketone of Formula VI-1 with potassium methoxide at various reaction temperatures as described in Example 2;

[ 0029 ] Fig. 3 is plot of the concentration profiles of various steroid components during the progress of the reaction of diketone of Formula VI-1 with potassium methoxide as described in Example 9; and

[ 0030] Fig. 4 is a plot of concentration profiles of steroid components of the reaction mixture during the progress of the reaction of Example 11.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[ 0031] Various schemes are described in US 5,981 ,744, US 6,331 ,622 and US 6,586,591 for the preparation of eplerenone. Several of these schemes involve conversion of a compound of Formula 6000 to a compound of Formula 5000. The process of the present invention comprises modifications to the processes generally described in the 744, '622 and '591 patents for preparation of compounds of Formula 5000 and/or to the steps therein described for recovery of the Formula 5000 compound from the reaction mixture. Such modifications are capable of enhancing productivity, yield, or other performance characteristics. In certain applications, e.g., in a process for the preparation of eplerenone, the process modifications as described herein may provide savings in yield on a high value intermediate of Formula 6000, the preparation of which may typically require two or more ancillary process operations.

[ 0032] In the preferred embodiments of the process for preparation of the compound of Formula 5000, the diketone of Formula 6000 is reacted with a source of an alkoxy group thereby opening up the ketone bridge between the 4 and 7 positions, cleaving the bond between the carbonyl group and the 4-carbon, and forming an α-oriented alkoxycarbonyl substitutent at the 7-position while eliminating cyanide at the 5-carbon. Alternatively, the process may be operated under conditions wherein the ketone bridge is opened and the 7α- alkoxycarbonyl group is formed, but the cyano group remains bonded to the 5-carbon.

[ 0033 ] The reaction is preferably conducted in the presence of a base. In various preferred embodiments, the alkoxy group source comprises a metal alkoxide, which also functions as a base, and which is conveniently supplied in a reagent wherein it is dissolved or dispersed in an alcohol solvent. In such embodiments, the alkoxy moiety of the alkoxycarbonyl group corresponds to the alkoxide component of the metal alkoxide reagent, and the metal alkoxide reagent serves two function in the reaction, i.e., it both comprises a source of an alkoxy group and supplies the base in the presence of which the reaction proceeds. Thus, e.g., in order to form a methoxycarbonyl group at C-7, the compound of Formula 6000 is reacted with a metal methoxide, preferably an alkali metal methoxide such as K methoxide, which is preferably provided in a reagent comprising a solution of K methoxide in methanol.

[0034] Without limiting this disclosure to a particular theory, it is understood that the formation of the compound of Formula 5000 by reaction of a compound of Formula 6000 with metal alkoxide is reversible; and complicated by certain intermediate and side reactions which also are or may be reversible. For example, in the specific case of eplerenone, it has been postulated that the overall reaction mechanism can be represented by the following:

Enolate Simplified Reaction Equilibrium

Although the equilibrium illustrated above is for the preparation of the depicted 3-keto-Δ⁴'⁵-11 α- hydroxy-17-spiro-butyrolactone intermediate that is typically used in the synthesis of eplerenone in accordance with Reaction Scheme 1 of US 5,981 ,744, it will be understood that a comparable equilibrium generally prevails where there are other substituents at the 12- and 17-carbons, other structures -A-A- and/or -B-B- of the generic formulae as set forth above, and/or esters other than the methyl ester formed at the 7-carbon. Moreover, the equilibrium between the Δ-4,5 and 5β-cyano species is understood to depend in significant part on the excess of alkoxy source supplied to the reaction medium.

[ 0035 ] The reaction may be carried out in a liquid organic solvent medium, preferably comprising the alcohol corresponding to the alkoxy group of R⁷, i.e., R⁷¹OH, e.g., methanol if the base reagent is an alkali metal methoxide. The reaction equilibrium is understood to be more favorable at low concentrations, so the process is preferably run at high dilution, e.g., as high as 40:1 wherein the reagent is Na methoxide, or in the range of 20:1 in the case of K methoxide (expressed in liters solvent per kg Formula 6000 substrate). As described in the reference patents, the reverse cyanidation reaction may be inhibited by conducting the reaction in the presence of a precipitating agent for cyanide such as ZnI, Fe₂(SO₄)_S, or halide, sulfate or other salt of an alkaline earth or transition metal that is more soluble than the corresponding cyanide.

[ 0036 ] As described in the aforesaid US patents, the temperature of the reaction is said not to be critical, conveniently atmospheric reflux temperature. The working examples illustrate reaction under atmospheric reflux at 67^CC. Certain embodiments of the present invention encompass operation at temperatures in this relatively low temperature range. Other embodiments achieve significant improvement by conducting the reaction at higher temperature.

[ 0037 ] It has been found that product recovery may be conveniently effected by straightforward cooling of the reaction medium until the product of Formula 5000 forms a crystalline precipitate. Recovery by crystallization from the reaction mixture is described in further detail herein below.

[ 0038 ] As described in the aforesaid US patents, other options for product recovery are available, and can be used. For example, the reaction solution containing the product of Formula 5000 may be quenched with mineral acid, e.g., with concentrated HCI, typically 4N HCI. The acidified reaction mixture may be cooled to ambient temperature, and the Formula 5000 reaction product extracted with an organic solvent such as methylene chloride or ethyl acetate. This and other schemes for recovering Formula 5000 product from the reaction mixture are described in further detail hereinbelow.

[ 0039 ] In other preferred embodiments as described hereinbelow, distillation for removal of HCN is unnecessary and preferably eliminated.

[ 0040 ] A 3-keto-Δ^4l5-7α-methoxycarbonyl intermediate of Formula 5000 can be used directly in the next process step of reaction scheme 1 for the preparation of eplerenone as described in the aforesaid patents, i.e., conversion of the compound of Formula 5000 to the compound designated herein as Formula 4000:

[ 0041] wherein

[ 0042 ] R¹⁰, R¹² and R¹³ are independently selected from the group consisting of hydrogen, halo, haloalkyl, hydroxy, alky], alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, cyano and aryloxy;

[ 0043 ] -A-A- represents the group -CHR¹-CHR²- or -CR¹=CR²-;

[ 0044 ] where R¹ and R² are independently selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy or R¹ and R² together with the carbons of the steroid nucleus to which they are attached form a (saturated) cycloalkylene group;

[ 0045] -B-B- represents the group -CHR¹⁵-CHR¹⁶-, -CR¹⁵=CR¹⁶- or an α- or β- oriented group:

R 15 R 16

\

CH- -CH

-CH — CH₂-CH-

,16

[ 0046] where R¹⁵ and R^1b are independently selected from the group consisting of hydrogen, halo, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, and aryloxy;

[ 0047 ] or R¹⁵ and R¹⁶, together with the C-15 and C-16 carbons of the steroid nucleus to which R¹⁵ and R¹⁶ are respectively attached, form a cycloalkylene group;

[ 0048 ] R^17a and R^17b are independently selected from the group consisting of hydrogen, hydroxy, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, acyloxyalkyl, cyano and aryloxy, or R^17a and R^17b together form an oxo, or R^17a and R^17b together with the C(17) carbon comprise a carbocyclic or heterocyclic ring structure, or R^17a and R^17b together with R¹⁵ and R¹⁶ comprise a carbocyclic or heterocyclic ring structure fused to the pentacyclic D ring; and

[ 0049 ] R⁷ represents an alpha-oriented lower alkoxycarbonyl or hydroxycarbonyl radical; and

[0050 ] R¹¹ represents a leaving group.

[ 0051 ] US patents 5,981 ,744, 6,331 ,622 and 6,586,591 are expressly incorporated herein by reference. See especially col. 31, line 33 to col. 34, line 14 of US 5,981,744. It may be noted that Example 59-61 of these patents describe a process wherein the diketone substrate comprises a 9,11-epoxy group, and the product of the reaction is the corresponding 5-cyano-7α- alkoxycarbonyl-9,11-epoxy compound. Under the conditions of these examples, the 5-cyano group is not cleaved from the nucleus of the 9,11-epoxy substrate.

[ 0052 ] In the various embodiments of the process as described herein, the -~conditions-ofτeaction-and/or processing-of-the-reaetion-solution-are varied for-the purpose of increasing the productivity of the reaction and/or providing a basis for increased yield on steroid substrate.

HIGH TEMPERATURE REACTION

[ 0053 ] In one modification, the reaction of an alkoxy group source with the . substrate of Formula 6000 is conducted at a temperature that is elevated, preferably substantially elevated, as compared to the temperatures disclosed in US 5,981 ,744, 6,331 ,622 or 6,586,591. Reaction is conducted at greater than 70⁰C, e.g., between about 7O⁰C and about 150°. From the standpoint of reaction equilibria and reaction rate, the preferred reaction temperature is significantly higher than 70°, e.g., >80°C, more preferably >90^oC. However, as discussed below, the optimum temperature may depend on the capacity for rapid cooling of the reaction mixture, and may thus vary with facilities available for the latter purpose. In many industrial applications, the optimal temperature may fall in a range between about 80° and about 95⁰C. Where very rapid cooling is feasible, as may be the case for example in continuous reaction facility as described below, the optimal reaction temperature may be in a relatively higher range, such as about 90° to about 120⁰C.

[ 0054 ] In carrying out the process, Formula 6000 substrate may be charged to a reaction vessel together with a solvent such as methanol, ethanol, n-propanol, or n-butanol, in relative proportions such that the resulting liquid reaction medium initially contains between about 1 and about 10 wt.% more typically between about 2 and about 3 wt.%, steroid substrate. Preferably the solvent comprises an alcohol corresponding to the formula R⁷¹OH where R⁷¹O- is as defined above, i.e., if R⁷ is methoxycarbonyl, the alcohol is preferably methanol, if R⁷ is ethoxycarbonyl, the alcohol is preferably ethanol, etc. A base is also introduced into the reaction medium. Conveniently, the base comprises a metal alkoxide corresponding to the formula (R⁷¹O)_xM where M is an alkali metal, in which case x = 1 , or alkaline earth metal, in which case x = 2. The metal alkoxide is preferably introduced as a solution or dispersion in an alcohol corresponding to the formula R⁷¹OH. Such solution or dispersion, may serve as a source of the alkoxy group R⁷¹O-. Without being held to a particular theory, it is believed that the alkoxy moiety of R⁷ may derive primarily from the metal alkoxide component, but a portion of the alkoxy substituent may also ultimately derive from the alcohol R⁷¹OH. In any event, the metal alkoxide also serves as a base, thereby providing two functions in the reaction mechanism.

[ 0055 ] For most applications, the base component preferably comprises an alkali metal alkoxide such as NaOR⁷¹ or, preferably, KOR⁷¹. However, the reaction may alternatively be conducted in the presence of an alkaline earth metal alkoxide, such as Ca(OR⁷¹)₂, Mg(OR⁷¹J₂, or Ba(OR⁷¹)₂. As described above, an alkali metal or alkaline earth metal alkoxide also serves as both an alkoxy group source and a base. According to a further alternative, the reaction may be conducted in the presence of a nitrogenous organic base such as triethyl amine, pyridine, or N- cyclohexyi-N,N',N",N"'-tetramethylguanidine. In the latter embodiments, the alkoxy group source may be primarily or exclusively constituted of the alcohol R⁷¹OH, though metal alkoxide (R⁷¹O)_xM can also be included if desired. Where an alcohol serves as the principal solvent for the reaction and an organic nitrogen compound as the principal base, an ample supply of alkoxy group source may be drawn from the excess of solvent that is ordinarily provided to meet the preferably high dilution ratio described elsewhere herein.

[ 0056] Where the base consists primarily of an alkali metal alkoxide corresponding to the formula (R⁷¹O)M, it is preferably introduced into the reaction medium in a proportion greater than about 1.25 moles per mole substrate, more preferably greater than about 1.5 moles per mole substrate, though proportions lower than 1.25 may be favored in those embodiments where the object is to avoid hydrolysis of the 5-nitrile group but instead to produce the 5-CN-7α- alkoxycarbonyl product ("cyanoester"). In a batch reaction system, at least 0.5 moles metal alkoxide reagent per mole substrate is preferably introduced into the reaction medium at the beginning of the reaction cycle, and any remaining metal alkoxide charge is introduced continuously or in intermittent increments over the course of the reaction. In many cases, it may be desirable to control the amount and timing of metal alkoxide additions to the reaction medium so as to avoid the substantial presence of undissolved metal alkoxide in the medium.

[ 0057 ] As discussed in further detail below with regard to another of the modifications of the present invention, the alkoxide solution as introduced into the liquid reaction medium is preferably substantially anhydrous and substantially free of hydroxyl ion, alkali metal hydroxide or partially hydrated alkaline earth metal alkoxide. Technically, the reaction medium is understood to be inherently anhydrous because any moisture which enters the medium essentially instantly reacts with the metal alkoxide to yield a metal hydroxide, or a hydrated metal alkoxide, i.e., (R⁷¹O)M(OH), in the case where M is an alkaline earth metal. However, it is important, if possible, to minimize or exclude ingress of moisture because the metal hydroxide, including any partially hydrated alkaline earth metal alkoxide, whether generated by contact with moisture or derived from another source, has a deleterious effect on the product of Formula 5000 by causing hydrolytic dealkylation of the 7α-alkoxycarbonyl to the 7α-carboxylic acid. Considering hydroxide to include both free hydroxyl ion and undissociated metal hydroxide, the total hydroxide content of the reaction medium is preferably not greater than about 0.05 wt.%, more preferably not greater than about 0.03 wt.%, still more preferably not greater than about 0.01 wt.% at any time during the reaction cycle. In order to control the hydroxide content of the reaction medium, the total metal hydroxide content of a metal alkoxide reagent solution or . dispersion is not greater than about 0.12 equivalents per equivalent metal alkoxide. More preferably, the metal hydroxide content of the reagent solution or dispersion is not greater than about 0.035 equivalents per equivalent metal alkoxide, still more preferably not greater than about 0.012 equivalents per equivalent metal alkoxide, most preferably not greater than about 0.006 moles equivalents per equivalent metal alkoxide. On a weight basis for most reagents, this works out to not greater than about 10 wt.%, more preferably not greater than about 3 wt.%, still more preferably not greater than about 1.5 wt.% metal hydroxide, basis the metal alkoxide. Thus, for example in a 25-32 wt.% solution of K methoxide in methanol, the KOH content is -— preferably-not greater4han-about-3-wt.%^more preferably-not greater-than-about :-1- wt.%, still- more preferably not greater than about 0.5 wt.%. These preferred wt.% limitations also generally apply to alcohol solutions or dispersions of other metal alkoxides, e.g., Na methoxide, K ethoxide, Na ethoxide, Mg(OMe)₂, Ca(OEt)₂, etc.

[ 0058 ] To exclude both moisture and oxygen, the reaction is preferably conducted under an inert atmosphere, such as a nitrogen gas mantle. Where the reaction is conducted above the atmospheric boiling point of the solvent medium, the reaction may be started up under a nitrogen blanket which is substantially displaced by solvent vapor as the reaction proceeds.

[ 0059 ] The liquid reaction medium comprising the Formula 6000 substrate is heated to an elevated temperature, i.e., a temperature >70^cC. Preferably, the medium containing the steroid substrate is brought to > 70^sC prior to addition of alkali metal alkoxide, but heating to the desired reaction temperature can occur during or after addition if desired. In any event, the temperature is preferably maintained at a level in excess of 70⁰C substantially throughout the course of the reaction. Preferably, the temperature is maintained above 70°C through at least 60%, more preferably through at least 80% of the reaction cycle, still more preferably substantially throughout the reaction cycle. However, because of the importance of cooling the reaction mixture after the reaction is complete, as described below, it may be useful in a particular facility to operate on a schedule under which the reaction temperature changes as a function of time during a batch reaction cycle, or along the flow path of a continuous reaction system. Where R⁷ of the Formula 5000 reaction product is methoxycarbonyl, ethoxycarbonyl or isopropoxycarbonyl, and the solvent for the reaction comprises predominantly the corresponding alcohol, the pressure in the reaction vessel may significantly exceed atmospheric. For example, where the solvent is methanol, the reaction pressure at 100⁰C is about 60 psig (414 kPa).

[ 0060 ] In a tank reactor, the desired temperature of the reaction may be established and maintained by supply of heat from a heat transfer fluid flowing through a jacket on the reactor or through coils immersed in the reaction mass. Alternatively, the reaction mass may be circulated through an external heat exchanger. Because the conversion of the compound of Formula 6000 to that of Formula 5000 is moderately endothermic, temperature control in a tank reactor may be conveniently effected by operating under reflux while controlling the pressure of the reaction. To facilitate bringing the reaction medium up to the desired reaction temperature, an inert atmosphere may be initially established in the reactor head space, after which the desired reaction temperature is established and maintained by controlling the reactor pressure. Reactor pressure may be controlled by regulating the vent flow from the reflux condenser. [ 0061] Where the solution of Formula 6000 substrate is brought to the preferred elevated reaction temperature prior to introduction of the alkali metal alkoxide into a liquid reaction medium comprising predominantly a lower alcohol (e.g., C₁ to C₄), it has been found that the M(OR⁷¹)_X/R⁷¹OH charge can be introduced at once without causing the reaction product to precipitate. [-00-62 ] -Because-conversion of the compound of Form ula-6000-to-the com pound of

Formula 5000 is understood to be an equilibrium reaction with an equilibrium constant that increases with temperature, yields are improved by operation at elevated temperature. Elevated reaction temperature also very substantially accelerates the rate at which the reaction progresses. Thus, a batch reaction cycle may be very substantially shortened as compared with the operation at atmospheric reflux as described in US 5,981 ,744, 6,331 ,622 and 6,586,591. For example, as described in these references, reaction of a compound of Vl-I (as set forth hereinbelow) with K methoxide in methanol required 16 hours to bring the reaction to completion at 67°C. By comparison, under equivalent conditions of reagent selection, reagent concentration, reagent to substrate ratio and substrate steroid concentration, it has now been discovered that a batch reaction can be brought to completion within about 6 hrs. at 72°C, within about 4 hrs. at 85°, within about 1.5 hrs. at 90°, or within about 0.5 hr. at 100°C, considering the reaction cycle as the period between the time at which the compound of Formula 6000 has been contacted with metal alkoxide at an alkoxide/substrate molar ratio of at least 0.5 (which for a batch reaction is the time at which the metal alkoxide has been added to the reaction medium in a ratio to substrate of at least 0.5 moles/mole) until a desired conversion has been achieved and/or cooling is commenced. Normally, the desired conversion equates to at least 95% consumption of substrate. More generally, considering the broader range of conditions contemplated for the reaction, and a range of target conversions equating to substrate consumption in the range of 90 to 95%, the batch reaction cycle is typically between about 0.25 and about 6 hours at temperatures above about 70°C, and between about 20 minutes and about 45 minutes at temperatures about 100°.

[ 0063 ] As described in WO 98/25948, the reaction equilibrium is also favored by high dilution, e.g., at a weight ratio of solvent to substrate of about 40:1 ; but in operation at the relatively low temperatures described in WO 98/25948, the benefit in yield associated with high dilution comes with a penalty in productivity. In order to achieve satisfactory productivity, the optimal dilution for a reaction conducted in the range of 50° to 65°C may more typically be about 20:1 , especially, e.g., where the alkali metal alkoxide is potassium methoxide.

[ 0064 ] Because of the favorable effect of increased temperature on reaction equilibria, and the sharp dependence of reaction rate on reaction temperature, high temperature reaction provides contrasting alternative opportunities with respect to the solvent/steroid dilution ratio. One alternative is to take advantage of the radically foreshortened reaction times by operating at higher dilution, thus gaining the favorable effect of both temperature and dilution on the equilibrium conversion of Formula 6000 substrate to Formula 5000 product, without sacrifice in productivity. In fact, if the reaction is conducted at a ratio of solvent to steroid in the range between about liters solvent per kg steroid substrate and about 60:1 , typically at least about 40:1 , the effect on productivity of lower product concentration per unit volume of reaction mass (resulting in a lower batch reactor payload) is more than offset by the shortening of batch cycles; so that both productivity and yield may be improved by comparison with reaction in the prior art -temperature-range of-about-65°C- — — . — — _

[ 0065] A contrary alternative is to take advantage of the increased solubility of steroids at high temperature and operate at a lower dilution than is exemplified by the disclosure of WO 98/25948. According to this alternative, the ratio of solvent to steroid may be as low as 15:1 , or even lower. For example, operation may be conducted at a dilution ratio in the range between about 10:1 and about 18:1. The penalty in reaction equilibrium that is suffered from such high steroid concentrations is substantially offset by the favorable effect of temperature on the equilibrium. Productivity is substantially enhanced by the combined effect of high temperature on reaction rates and the high concentration of Formula 5000 product in the reaction mixture, translating into high batch reaction payloads, and a high product effluent flux from a continuous reactor. Isolation yield may also be improved. At a given solubility of Formula 5000 product in the solvent medium, a higher fraction of the Formula 5000 product contained in the reaction mixture may be recovered by crystallization at any given crystallization temperature.

[ 0066] Generally, the solvent to steroid ratio may be selected on the basis of an economic optimum balance between productivity, as favored by a relatively low ratio of solvent to steroid, versus selectivity to compound of Formula 5000, as favored by a higher ratio of solvent to steroid. However, the penalty of error in choice of dilution ratio is attenuated by operation at high temperature, which both conduces to a favorable reaction equilibrium and assures high productivity.

[ 0067 ] In order to avoid unnecessary deterioration of yield due to conversion of the product of Formula 5000 to by-products or its consumption by other reactions, the reaction cycle preferably is not prolonged beyond the period required to achieve a satisfactory yield. In any event, it is preferred that the reaction cycle be terminated before the final yield at the end of the reaction cycle has unduly deteriorated from the maximum yield attained during the reaction. Preferably, the reaction is terminated before the final reaction yield has deteriorated by more than 10% from the maximum attained during the course of the reaction, more preferably before the final yield has deteriorated by more than 5% from the maximum attained. In some operations, it may be advantageous to provide an in line analyzer, e.g., Fourier Transform Infrared, to follow the progress of the reaction and terminate at or near optimal reaction yield. Alternatively, or additionally, the reaction cycle may be controlled by reference to an established relationship for predicting the conversion of Formula 6000 substrate and yield of Formula 5000 product as a function of time and temperature. For example, it may be useful in some operations to establish an algorithm relating optimal conversion to time and reaction temperature, and terminate the reaction cycle at or near a point of optimal yield as projected by the algorithm. Such an algorithm may be developed by those skilled in the art based on experimental reaction data. Useful algorithms may be entirely empirical, or incorporate kinetic and equilibrium equations, or comprise some combination of both empirical and theoretical relationships

[ 0068 ] For many combinations of substrate, solvent, metal alkoxide reagent, and concentrations thereof, the most favorable overall performance may be achieved at a reaction temperature in the range of about 95° to about 115°C. In this range of temperature, a reaction cycle extending to-95%-Gonversion of substrate may-be-typically-between about 0.25 and about 2 hours, more typically between about 20 minutes and about 40 minutes.

[ 0069 ] Once the reaction cycle is complete, the reaction mixture is preferably cooled rapidly to a temperature below about 6O⁰C. Preferably, the rate of cooling is sufficient that the yield of Formula 5000 product in the cooled reaction mass (ultimate yield) does not deteriorate from final yield attained at the conclusion of the reaction cycle by more than about 10%, preferably not more than about 5%. Preferably, the reaction mixture is cooled to below 60⁰C at an integrated average rate of at least 1.25 Centigrade degrees per minute, more preferably at a rate of at least 2 Centigrade degrees per minute. Even more favorable ultimate yields are attainable if the integrated average rate of cooling is greater than about 4 Centigrade degrees, 5 Centigrade degrees, 10 Centigrade degrees, or even 20 Centigrade degrees, per minute. However, in any given application of the process of the invention, the yield advantages attainable at any given rate of cooling are balanced against the equipment, operating and maintenance costs associated with achieving that rate of cooling. Those skilled in the art can readily determine an optimum cooling rate based on these and other factors that may be specific to the product being produced, the costs of raw materials, energy, labor, and capital, the value of the product, the site at which manufacturing is conducted and the facilities there available.

[ 0070 ] Taking into consideration any deterioration of yield due to undue prolongation of the reaction cycle plus loss of yield on cooling, the reaction is preferably terminated and the reaction mixture cooled at a sufficient rate so that the ultimate yield after cooling is not more than 15% lower, preferably not more than 10% lower, most preferably not more than 5% lower than the maximum yield attained during the course of the reaction. Based on the instant disclosure of the steep increase in reaction rate as a function of temperature above 70⁰C, and the consequent radical shortening of reaction cycle, one skilled in the art can readily arrive at an optimum reaction cycle by straightforward trial error, which may be aided in its precision by on-line analysis such as Fourier Transform Infrared, or off-line analysis such as HPLC. Depending on the capacity of the heat exchange system available for cooling the reaction mixture, the temperature schedule of the reaction may be optimized to approach or achieve an optimum yield for the combined reaction/heat transfer system, taking into consideration such factors as reactant concentrations, achievable cooling rate, and desired conversion. For example, where the process is implemented in an existing facility with limited heat transfer capacity, it may be advantageous to conduct the reaction at less than the theoretical optimum, e.g., at 80° or 9O⁰C, though the highest maximum yield during the reaction cycle would be achieved at 100⁰C, or perhaps even 110° or 12O⁰C. [ 0071] In some applications, especially where the solvent is methanol or ethanol, and the reaction is conducted in a closed vessel at a temperature above the atmospheric boiling point of the solvent, substantial flash cooling may be achieved by releasing reaction pressure. Additional flash cooling can be effected by imposing a vacuum on the reaction vessel.

[ 0072] The rapid reaction rates attainable at elevated temperature also make it -feasible-tθ Gonduct-the-reaction continuously with relatively short time of contact between the Formula 6000 substrate and the metal alkoxide, or other alkoxy group source and base. Continuous reaction is advantageous because it facilitates rapid cooling of the reaction product mixture to a temperature at which reverse reactions and side reactions are substantially quenched. In a continuous process, the substrate of Formula 6000 substrate and metal alkoxide are continuously or intermittently introduced into a continuous reaction zone, and a reaction mixture comprising the Formula 5000 product is continuously or intermittently withdrawn from the reaction zone and passed into flash cooler and/or surface heat exchanger. In such a process, a given reduction in the temperature of the reaction system within a specified period of time ("cooling temperature ramp") can be obtained at an instantaneous cooling load much less than the instantaneous cooling load required to achieve the same cooling temperature ramp for the entire volume of reaction mixture produced in a batch reaction system. As a consequence, the same overall reactor productivity can be realized with the same cooling ramp using a cooling system having a cooling capacity that is only a fraction of that which is required for a batch reaction system.

[ 0073 ] Continuous reaction can be conducted in either a stirred tank or flow reactor. Because the conversion of Formula 6000 substrate to Formula 5000 product is other than zero order, a reaction system comprising only a single continuous stirred tank reactor would require a reaction residence time significantly longer than the cycle of a batch reaction. Consequently, use of a continuous back mixed reactor could result in a yield sacrifice due to degradation of reaction product from extended exposure to elevated temperature. Requisite total reaction residence time can be reduced by cascading continuous stirred tank reactors in series. Because the reaction is endothermic but the net energy input requirements are modest, reaction in plug flow is also feasible. For purposes of this disclosure, it will be understood that "plug flow" means flow through a pipe, column or other longitudinal flow path without substantial axial back mixing. In industrial application, limited axial back mixing may not be entirely avoided, as for example in pipe elbows, column packing and the like, but is not sufficient to significantly offset the advantages which flow reaction provides. Flow reaction is particularly attractive because residence times need be no longer than batch reaction cycles so that the time integrated driving force for reverse and by-product reactions is minimized. Because energy demands are modest, endothermic reaction heat may be supplied by merely jacketing a tubular reactor. Moreover, a heat transfer fluid may be passed through the jacket at a temperature only moderately warmer than the temperature of the reaction mixture, thereby avoiding product degradation that might otherwise result from an excessive wall temperature on the process side. Operating in a continuous reaction mode also lessens the dependency of productivity on reactor volume, and thus facilitates operation at high dilution, e.g., dilutions greater than 30:1 , 40:1 or even 60:1 liters solvent per kg Formula 5000 substrate. Thus, in a continuous reaction system, the further benefit of high dilution on reaction equilibrium can be realized without an excessive impact on capital requirements or maintenance expense.

[ 0074 ] Those skilled in the art will appreciate that, for optimal operation, selection of -Feaction-temperature-depends-on-the-relative-effeGt-of-temperature-on-the-reaction -equilibria, the rate of conversion of Formula 6000 substrate to the product of Formula 5000, and the rate of by¬ product reactions such as the dealkylation of the 7α-alkoxycarbonyl by reaction with by-product CN^" ion. Optimal reaction temperature can also depend on the available instantaneous cooling capacity. Thus, in a facility wherein a relatively steep cooling temperature ramp can be achieved, the optimal reaction temperature may be somewhat higher than in a facility where the instantaneous cooling capacity is not as great. Optimal temperature may also vary between batch and continuous reaction, and between continuous back mixed and continuous flow reaction, both as a function of reaction equilibria and kinetics per se, and as function of the selection of reaction mode on attainable cooling temperature ramp. However, regardless of the combination of reaction mode and reaction mass cooling facility, it has been found that the preferred reaction temperatures, as described above, have the capability of providing generally improved yields of Formula 5000 product with substantially improved productivity. For example, in one series of reactions, it was found that the batch conversion of:

Formula Vl-I

to the product:

Formula Vl

an increase in reaction temperature from 62°C to 100⁰C increased the yield of Formula 5000 product from 64% to 73% and shortened the reaction cycle from 10 hours to about 30 minutes.

LOW WATER AND HYDROXIDE CONTENT; SAPONIFICATION TARGET

[ 0075] Regardless of the temperature at which the reaction is conducted, it is further preferred that Formula 6000 substrate be converted to Formula 5000 product in a reaction medium which contains not more than about 0.2 equivalents hydroxide compound per mole of Formula 6000 substrate that is converted during the course of the reaction. Typically, the hydroxide compound content comprises the sum of alkali metal hydroxide and alkaline earth metal hydroxide. In some instances, the hydroxide component may include hydrated alkaline earth metal alkoxide, i.e., (R⁷¹O)M(OH). Water also qualifies as an undesired hydroxide compound and, as discussed below, is often the source of other hydroxides but is rapidly consumed in their formation via hydrolysis of metal alkoxide. More preferably, the reaction medium contains not more than about 0.08 equivalents, still more preferably not more than about 0.02 equivalents total hydroxide compound per mole Formula 6000 substrate converted in the reaction. It is also preferred that the relationship between the hydroxide compound content and the metal alkoxide content of the reaction medium and the metal alkoxide reagent be maintained within the ranges stated hereinabove.

[ 0076] Where the reaction medium or the metal alkoxide reagent solution is contaminated with water, the water reacts with the metal alkoxide to liberate the alcohol and yield the free metal hydroxide compound. This reaction is typically rapid. Whether generated by reaction of the alkoxide with water, or otherwise present due to incomplete reaction of metal hydroxide and alcohol in the initial formation of the alkoxide, the metal hydroxide compound can react with the Formula 5000 product, the Formula 6000 substrate or any of various intermediates to generate undesired by-products. One particularly disadvantageous effect of free metal hydroxide is saponification of the desired 7α-alkoxycarbonyl to the free 7α-carboxylic acid or its salt. — ^»[-0 -0-7-7-] --To-exGlude-moisture-from-ttie-reaGtiQn-medium_T-the-metal-alkoxide-reagent is preferably prepared under an inert anhydrous atmosphere, and such atmosphere is maintained in the reaction zone wherein the reagent is mixed with or introduced into a reaction medium comprising the Formula 6000 substrate. It is further preferred that an inert atmosphere be maintained in the product recovery steps as described in further detail below. Except in those steps wherein water is used as an antisolvent for extraction or crystallization of Formula 5000 product, it is also preferred that the product recovery steps be conducted under anhydrous conditions.

[ 0078 ] In various preferred embodiments, the presence of free metal hydroxide in the reaction medium may be minimized by the use of a sacrificial saponification target that effectively scavenges any free hydroxide in the metal alkoxide reagent and/or the reaction medium. Preferred saponification targets include low molecular weight carboxylic esters such as, for example, methyl formate, ethyl formate, ethyl acetate, methyl acetate, methyl propionate, trimethyl orthoformate and the like.

[ 0079 ] The saponification target reacts with free metal hydroxide to yield the metal salt of the carboxylic moiety of the saponification target plus the free anhydrous alcohol. If water is present in or enters the medium in which the saponification target reacts with the metal hydroxide, it is consumed in converting metal alkoxide to metal hydroxide which in turn is consumed by reaction with the saponification target compound. Preferably, the saponification target is introduced into the reagent which comprises the metal alkoxide reactant, so that all moisture and free metal hydroxide have been eliminated from that reagent before it is contacted with the substrate of Formula 6000. However, it is further preferred that a saponification target also be present in the reaction medium wherein the substrate of Formula 6000 is reacted with the metal alkoxide, in order to deal with any moisture that is introduced into the medium via the solvent, the Formula 6000 compound source, or otherwise, and more particularly to eliminate the metal hydroxide that is formed when such moisture comes into contact with the metal hydroxide reactant.

[ 0080 ] Preferably, the saponification target comprises an ester of the alcohol corresponding to the alkoxycarbonyl group R⁷, i.e., the saponification target is preferably an ester of R⁷¹OH. The carboxylate component of the ester is preferably formate or orthoformate. Thus, e.g., in the preparation of eplerenone, the saponification target is most preferably methyl formate or trimethyl orthoformate.

[ 0081] Preferably, a reagent solution or dispersion is prepared by contacting an alkali metal hydroxide with an alcohol in a ratio effective to produce a solution of metal alkoxide in alcohol. Preferably, the reaction is conducted under substantially anhydrous conditions. Suitably, the resultant metal alkoxide concentration in the reagent solution is between about 7 and about 25 mole%, typically about 15 to about 50 wt.%. Thus, an excess of alcohol relative to metal hydroxide is used so as to assure that the hydroxide is fully reacted. Preferably, the proportion of alcohol is also sufficient so that the alkoxide is substantially or entirely solubilized. After the alcoholysis reaction is complete, methyl formate or other_saponification target compound can be introduced into the alkoxide solution or dispersion. Alternatively, or additionally, the saponification target compound can be separately introduced into the reaction medium in which the Formula 6000 substrate compound is contacted with the metai alkoxide reagent. In any case, the saponification target is preferably introduced in stoichiometric excess relative to the hydroxide moiety as derived from any and all sources, whether from incomplete reaction of alcohol and metal hydroxide, moisture introduced via the metal hydroxide, alcohol and/or other sources in preparation of the reagent solution, moisture in the steroid and/or solvent from which the reaction medium is prepared, or ingress of moisture from the surroundings. A saponification target excess of 50% with respect to hydroxide from all sources may be preferred to assure complete consumption of all free hydroxide. Where anhydrous sources of metal hydroxide and alcohol are used, it is usually sufficient to introduce saponification target in a proportion between about 2% and about 25% by weight, more typically between about 5% and 15% by weight, based on the metal alkoxide content of the reagent solution.

[ 0082] Where the saponification target compound is added to the metal alkoxide reagent solution or dispersion prior to introduction of the reagent into a reaction medium comprising the steroid substrate, the reagent solution/dispersion is preferably held at ambient or moderately elevated temperature for a period of time to scavenge all residual hydroxide that is either contained in the reagent solution as produced, or formed by consumption of moisture over time. Thus, prior to use in conversion of Formula 6000 substrate to Formula 5000, the reagent solution containing saponification target compound is preferably held for at least about 8 hours, more preferably for at least about 24 hours, still more preferably for at least about 48 hours, most preferably for at least about 72 hours, under mild agitation.

[ 0083 ] In carrying out the conversion of the Formula 6000 substrate to the Formula 5000 product, a reaction vessel is preferably charged with steroid substrate and a solvent, preferably an alcohol corresponding to R⁷¹OH, and a reagent solution comprising metal alkoxide in alcohol is added thereto. Advantageously, methyl formate or other saponification target compound is incorporated into the resulting mixture. This effect can be accomplished by using an excess of saponification target in the preparation of the reagent solution and/or by adding a saponification target compound to the reaction medium comprising the solvent that is charged with the Formula 6000 substrate. As described above, the alkali metal alkoxide is preferably added in a molar ratio to Formula 6000 substrate of at least about 1.25, preferably between about 1.5 and about 1.8. The reaction may then be conducted at a temperature from below ambient to 150⁰C, preferably at least about 50⁰C, more preferably at least about 7O⁰C. Most preferably, an elevated reaction temperature is selected within the preferred ranges and according to the governing principles set forth above. As described in WO 98/25948, the metal alkoxide is preferably added in two increments, in a net molar ratio to substrate of about 1.6. The first increment may be added, for example, in a molar ratio to substrate of about 1 ; and about 90 minutes thereafter, a second increment may be added in a molar ration to substrate of about 0.6. However, it has now been found that, if the reaction medium comprising the solvent containing the-Hor.mula-6000-substrate-dissolved.or.dispersed-therein-is.initially-heated-to-elevated- -- temperature in the ranges preferred for the reaction, the entire metal alkoxide charge may be added at once. In any event, alkoxide may typically be added initially in a ratio to substrate of at least about 0.5, and any remaining portion of the charge may be added in increments thereafter. [ 0084] An ester such as methyl formate reacts with KOH to form the salt of the acid from which the ester is derived and release the free alcohol. Thus, where the ester is methyl formate, products of the saponification target reaction are potassium formate and methanol. As discussed below, various schemes are available for recovery of the product of Formula 5000 from the reaction mixture. Most of these ultimately involve crystallization of the Formula 5000 product from a solution thereof. Potassium formate, or other salt of the acid component of the saponification target ester, is retained in the mother liquor and ultimately eliminated in a liquid phase purge. Methanol blends into the liquid phase as well, functioning therein as part of the solvent component. It is also eliminated during processing of the reaction mixture and/or the crystallization mother liquor.

RECOVERY OF FORMULA 5000 PRODUCT FROM THE REACTION MIXTURE

[0085] Product of Formula 5000 is recovered by crystallization. Multiple schemes are available for effecting crystallization and recovery.

[0086] Most straightforwardly, the reaction mixture is cooled to crystallization temperature without any ancillary conditioning steps. To maximize yield, the crystallization is preferably conducted in the cold, e.g., at a temperature below 5^CC, more preferably below about 0°, still more preferably below about -5⁰C. For example, in the case of the 3-keto-11α-7α- methoxycarbonyl-17-spirobutyrolactone ("hydroxyester") intermediate for eplerenone, the crystallization is conveniently conducted between about -25°C and about -10⁰C. The crystalline Formula 5000 product is then separated from the crystallization mother liquor by centrifugation or filtration. The filter cake is preferably washed with an appropriate solvent, conveniently the same solvent that is used for the reaction.

[ 0087 ] Where the Formula 5000 product is crystallized directly from the reaction mixture and recovered by filtration or centrifugation, it has been found that the filter or centrifuge cake is substantially free of cyanide salts and other inorganic contaminants, so that a water wash is not needed for removal of such contaminants. Where anhydrous or substantially anhydrous alcohol is used for washing, the washed cake is substantially free from moisture, which facilitates the drying step and avoids hydrolytic degradation of the cake during drying. It also provides a substantially anhydrous mother liquor, from which steroid values can be recovered by extraction in the manner described below, wherein the steroids can optionally be taken up in a water- immiscible solvent prior to any contact with an aqueous extractant.

[ 0088 ] Various alternative process recovery schemes involve concentration, water addition and/or extraction from the reaction mixture.

[ 0089 ] For example, the compound of Formula 5000 may be isolated by acidifying -the reaction selution.-.e.g.v-with-a mineral aeid-sueh-as- aqueous HCI or sulfuric acid, distilling to concentrate the acidified mixture while stripping off HCN generated by the acidification, and cooling to ambient temperature. Formula 5000 product may then be recovered by further cooling of the stripped concentrate to cause the product to crystallize; or by adding water and an organic solvent such as methylene chloride or ethyl acetate to generate an organic extract comprising the steroid values and an aqueous raffinate comprising the cyanide salts. Alcoholic reaction solvent is typically partitioned significantly to each of the two phases.

[ 0090 ] Where the reaction medium comprises a lower alcohol, product recovery may also be effected by addition of water to a concentrated and acidified reaction mixture to reduce solubility of the Formula 5000 product therein, thereby causing the product to crystallize from the aqueous alcoholic medium. In recovery of the product via this alternative, the reaction solvent (e.g., methanol) and HCN are removed by distillation after the conclusion of the reaction period, with mineral acid (such as hydrochloric acid or sulfuric acid) being added before the distillation and water being added after the distillation. The mineral acid can be added in a single step, in multiple steps or continuously. In a preferred embodiment, mineral acid is continuously added over a period of about 10 to about 40 minutes, more preferably about 15 to about 30 minutes. Likewise, water can be added to the still bottoms in a single step, in multiple steps or continuously. Prior to addition of water, the concentrated reaction mixture is preferably cooled to a temperature between about 50°C to about 7O⁰C, typically between about 6O⁰C to about 70⁰C. Water is then added, preferably continuously over a period of about 15 minutes to about 3 hours, and more preferably over about 60 minutes to about 90 minutes, while the temperature is maintained approximately constant. Product of Formula 5000 begins to crystallize from the still bottoms as the water addition proceeds. After the water has been added to the mixture, the diluted reaction mixture is maintained at about the same temperature for about 1 hour and then cooled to about 15⁰C over an additional period of about 4 to about 5 hours. The mixture is maintained at about 15°C for a period of about 1 to 2 hours. A longer holding period at 15°C causes the equilibrium among steroid species to shift, resulting in an increased yield of the 5-CN- 7α-alkoxycarbonyl species ("cyanoester") in the mixture. This mode of recovery provides a high quality crystalline product without extraction operations.

[ 0091] Where product recovery comprises the use of water as an antisolvent, water and acid may be added before or during the distillation for stripping of HCN. Addition of water and acid before the distillation simplifies operations, but progressive addition during the distillation allows the volume in the still to be maintained substantially constant. Product of Formula 5000 crystallizes from the still bottoms as the distillation proceeds. [ 0092 ] It has been found that multiple solvent extractions for purification of the compound of Formula 5000 are not necessary where the compound of Formula 5000 serves as an intermediate in a process for the preparation of epoxymexrenone, as described herein. In fact, such extractions can often be entirely eliminated. Where solvent extraction is used for product purification, it is desirable to supplement the solvent washes with brihe and caustic -washesv-But where-the-solvent-extractions-are-eliminatedr-the-brine-washes-are too. Eliminating the extractions and washes significantly enhances the productivity of the process, without sacrificing yield or product quality, and also eliminates the need for drying of the washed solution with a desiccant such as sodium sulfate.

RECOVERY OF STEROID VALUES FROM CRYSTALLIZATION MOTHER LIQUOR

[ 0093] As described above, the product of Formula 5000 is preferably recovered from the reaction mixture by crystallization. Prior to crystallization, the reaction solution may optionally acidified and concentrated as described above.

[ 0094 ] Crystallization mother liquor is essentially saturated with the compound of Formula 5000 at the temperature at which the mother liquor is separated from the crystallized solids. In addition to the typically preferred product compound of Formula 5000 wherein the 5- carbon is unsubstituted, the mother liquor contains other steroid values, including unconverted Formula 6000 substrate, and 5β-cyano-7α-alkoxycarbonyl by-product of Formula C, which typically may be in equilibrium with the product of Formula 5000 and residual cyanide ion. Unless these steroid values can be recovered, they represent a substantial penalty in yield on the compound of Formula 6000. According to any of several optional and potentially advantageous embodiments as further described herein, steroid values may be recovered from the mother liquor, and the yield of Formula 5000 product enhanced.

[ 0095 ] Steps for recovering steroid values may be combined with measures for shifting the equilibrium to convert unconverted Formula 6000 substrate, Formula C by-product and/or other intermediates and by-products to the preferred product of Formula 5000 which is unsubstituted at C-5. Among the procedures that may be used to recover steroids and/or shift the equilibrium are: (i) extraction of steroids from the mother liquor; (ii) acidification and addition of water to crystallize steroids in a manner generally comparable to a corresponding primary product recovery scheme as described above; (iii) addition of a ketone for consumption of cyanide ion contained in the mother liquor; (iv) re-equilibration by heating the. mother liquor; and (v) addition of metal compounds for precipitation of cyanide.

MOTHER LIQUOR EXTRACTION

[ 0096] In a preferred embodiment, steroid values retained in the primary crystallization mother liquor are recovered by extraction. This process is effective, for example, where the reaction has been conducted in a water-miscible solvent such as a lower alcohol, and the primary recovery process produces a mother liquor comprising the crystallization solvent and having retained therein components such as a fraction of the product Formula 5000 compound, unreacted Formula 6000 compound, other steroids values that may be converted to the compound of Formula 5000, and cyanide ion. A substantially water-immiscible solution is prepared containing such steroid values. In the extraction step, this water-immiscible solution is contacted with an aqueous extraction medium in a liquid/liquid extraction zone. A two-phase extraction mixture is formed comprising an aqueous raffinate containing cyanide ion and an organic extract phase comprising the compound of Formula 5000, the compound of Formula 6000 and other steroids. A repulp solution is formed, typically by solvent exchange with the extract, comprising a water-miscible solvent and containing steroids obtained from the organic extract. The repulp solution may be processed to recover steroid values contained therein. More particularly, the repulp solution may be processed to convert compound of Formula 6000 to Compound of Formula 5000, and to recover additional Formula 5000 product.

[ 0097 ] For purposes of the extraction, the components retained in the mother liquor are provided in an extraction feed solution typically comprising the mother liquor itself or derived from the mother liquor. In preferred embodiments, the extraction feed solution comprises a concentrate produced by evaporation or distillation of crystallization solvent from the mother liquor. The extraction feed solution is substantially water-miscible itself, but is mixed with a water-immiscible solvent to produce a substantially water-immiscible solution of steroid values that is contacted with an aqueous extraction medium in the extraction zone. The water- immiscible steroid solution is prepared by mixing the water-immiscible solvent with the extraction feed solution either in the presence of the aqueous medium within the extraction zone or prior to contact with the aqueous medium, e.g., in a preliminary mixing step outside the extraction zone. Contact of the water-immiscible steroid solution with the aqueous medium results in transfer of cyanide ion to the aqueous phase and the transfer of steroid values, including compounds of Formula 5000 and Formula 6000 to the organic phase (or retention of such values in the organic phase). The partition coefficient for the typically water-miscible crystallization solvent is such that a significant portion of this solvent is usually distributed to each of the phases. Preferably, the extraction zone is agitated to enhance the rate of mass transfer between the phases. Separation of the phases yields an organic extract containing steroid values and an aqueous raffinate containing cyanide and other salts that may be present.

[ 0098 ] Preferred extraction and steroid recovery schemes are described in more detail hereinbelow.

[ 0099 ] Prior to extraction, the mother liquor is preferably concentrated, by distillation or evaporation, for removal of excess solvent. To maximize recovery of steroids, the mother liquor is preferably concentrated to no more than one half its initial volume, preferably to no more than one third its initial volume, typically to between about one fourth and one sixth of its initial volume, e.g. to minimum stir volume in the still bottoms, i.e., the minimum volume which assures immersion of agitator impeller and/or avoids cavitation or mechanical instabliity of the agitation. However, it is further preferred that the extent to which the mother liquor is concentrated not be sufficient to cause any substantial precipitation of steroid values. To minimize dealkylation of Formula 5000 steroid by cyanide ion, the mother liquor is preferably concentrated under reduced pressure at a temperature less than about 6O⁰C, more preferably less than about 40⁰C, most suitably between about 20° and about 4O⁰C. To effect distillation or evaporation at such temperatures, the mother liquor may be concentrated under reduced pressure. For example, where the crystallization solvent is methanol, concentration of the mother liquor may be — GonduGted-at an-absolute-pressure-in-the-r-ange-between-about-100 and-about 500 mm Hg, more typically in the range between about 200 and about 400 mm Hg. Relatively low temperature distillation reduces the extent of dealkylation of the 7α-alkoxycarbonyl substituent.

[ 0100 ] The concentrated mother liquor may then serve as the source of steroids for the extraction feed solution, and may indeed constitute the extraction feed solution. Typically, . the concentrated mother liquor contains between about 1 and about 3 wt.% Formula 5000 product (unsubstituted at C-5) and between about 0.5 and about 1.5 wt.% other steroid values including, e.g., between about 0.3 and about 0.6 wt.% Formula 6000 substrate and between about 0.2 and about 1.0 wt.% of the 5β-cyano-7α-alkoxycarbonyl by-product of Formula C. It may also typically contain between about 0.5 and about 1.5 wt.% cyanide ion, and about 0.5 wt.% and between about 1.5 wt.% metal M cation.

[ 0101] Preferably, the concentrated mother liquor (extraction feed solution) is mixed with the water-immiscible solvent before either is contacted with an aqueous medium. This preliminary mixing step may conveniently be conducted outside the extraction zone, and the resulting substantially water-immiscible steroid solution may thereafter be introduced into the extraction zone. Preferably the extraction feed solution and water-immiscible solvent are mixed in a volumetric ratio between about 0.2 and about 1.0, more preferably between about 0.3 and about 0.6 parts by volume solvent per part by volume concentrated mother liquor. The resulting water-immiscible solution of steroids typically contains between about 10% and about 80% wt.%, more typically about 25% to about 75%, water-immiscible solvent, between about 20 and about 90 wt.%, more typically between about 30% and about 80% lower alcohol, between 0.5 and about 4 wt.% Formula 5000 product (unsubstituted at C-5) and between about 0.2 and about 3 wt.% other steroid values including, e.g., between about 0.02 and about 0.2 wt.% Formula 6000 substrate and between about 0.03 and about 5.0 wt.% of the 5β-cyano-7α-alkoxycarbonyl by¬ product of Formula C.

[0102] By premixing concentrated mother liquor with water-immiscible solvent, the steroid values may be preferentially partitioned to the organic phase throughout the extraction, thereby protecting them against hydrolytic attack, and particularly against decomposition of the 7α-alkoxycarbonyl to the 7α-carboxy.

[ 0103 ] Alternatively, the extraction feed solution, aqueous extraction medium and water-immiscible solvent may all be directly and independently introduced into the liquid/liquid extraction zone, in which instance the extraction feed solution and water-immiscible solvent are mixed to form the water-immiscible steroid solution within the zone. According to a further though generally less desirable alternative, water and the extraction feed solution may be combined before contact of the resulting mixture with the water-immiscible solvent in the extraction zone. As extraction proceeds, the liquid phase produced by combining extraction feed solution and aqueous medium functions as the aqueous extraction medium, and the water- immiscible steroid solution forms in the extraction zone as mass transfer proceeds. This alternative is ordinarily less preferred because it unnecessarily exposes the steroids to hydrolytic — attack_7--and_can.result in_precipitation of ster.oJds_prLoyo_-αoi3iact₌with-the-wate₌immiscible solvent. However, it remains a feasible approach where extraction proceeds reasonably promptly after the extraction feed solution and aqueous medium are combined, and especially where the extraction is conducted under the conditions described below.

[ 0104 ] Regardless of the mixing sequence, the extraction is preferably conducted in the cold, which helps to minimize hydrolysis of steroids during the extraction. For example, the extraction may be conducted at a temperature below about 15°C, more preferably below about 10⁰C, most preferably below about 5°C, most typically in the range between about -15C° and about 10°C. The aqueous extraction medium is preferably cooled to a temperature in such ranges prior to contact with the water-immiscible steroid solution in the extraction zone. Where the aqueous extraction medium consists of water substantially free of electrolytes, it may optimally be cooled to a temperature just above 0⁰C, e.g., 0.5° to 5°C. Because crystallization solvent and cyanide ion transfers to the aqueous phase during the extraction, it is typically feasible to operate the extraction at a temperature even below 0⁰C, e.g., between 0° and -1O⁰C. It is further preferred that the water-immiscible steroid solution be brought to a temperature within the aforesaid ranges before it contacts the aqueous extraction medium. If the extraction feed solution and water-immiscible solvent are independently introduced into the extraction zone, it is further preferred that each be pre-cooled to a temperature at or about the extraction zone temperature prior to contact therebetweeen in the extraction zone. When the extraction is conducted under preferred conditions, no more than 10% of the compound of Formula 5000 contained in the extraction feed solution is hydrolyzed during the extraction. Typically, the extent of hydrolysis of the compound of Formula 5000 is less than 5%, more typically less than 1%.

[ 0105 ] Only a few minutes of mixing is necessary to effect transfer of steroids to the organic phase and cyanide to the inorganic phase. Preferably, the phases are separated after not more than about 75 minutes, more preferably after not more than an hour, more preferably after not more than one half hour of mixing. Minimizing the contact time further serves to preserve the steroids from hydrolytic attack. Thus, while the extraction feed solution and the water-immiscible solvent are preferably pre-mixed prior to contact with the aqueous extraction medium in the extraction zone, hydrolytic attack on the steroid is generally minimal where the extraction is conducted in the cold within the contact time limitations stated above, even where aqueous extraction medium, water-immiscible solvent and extraction feed solution are independently and simultaneously introduced into the extraction zone.

[ 0106] Water-immiscible solvents that may be used in the extraction include, for example, methylene chloride, ethyl acetate, toluene, and xylene. Methylene chloride is especially effective. To facilitate recovery of steroids from the extract, and especially for the re- equilibration thereof for further conversion to Formula 5000 product, it is preferred that the water- immiscible solvent be more volatile than the lower alcohol solvent in which any subsequent re- equilibrium of steroids is conducted, and also more volatile than the solvent from which the primary crystallization is conducted (and in which the reaction typically also takes place). For example, preferred water-immiscible extraction solvents have a boiling point at atmospheric -pressur-eror-at-a-GonvenieRt-subatmospheric-distillation-pressure.-at-least-i-OSC-lower-i preferably at least about 15°C lower, than the alcohol serving as the medium for the re-equilibration reaction step. Such difference facilitates separation of the water-immiscible solvent from the organic extract as further described hereinbelow. It is particularly preferred that the atmospheric boiling point of the extraction solvent be not greater than about 7O⁰C, preferably not greater than about 50⁰C. To facilitate separation of organic extract from aqueous raffinate, it is further preferred that the specific gravity differential between the water-immiscible solvent and aqueous extraction medium be at least about 0.05, more preferably at least about 0.10, more preferably at least about 0.20.

[ 0107 ] Preferably, the relative amounts or proportions of aqueous extraction medium, extraction feed solution and water-immiscible solvent combined for purposes of the extraction are such that the volumetric ratio of aqueous medium to the sum of the extraction feed solution plus water-immiscible solvent is between about 0.3 and about 1.5, preferably between about 0.4 and about 0.8, and the volumetric ratio of aqueous raffinate to organic extract is between about 0.5 and about 5, typically between about 0.8 and about 3, more typically between about 1 and about 2.5. For this purpose, the ratio of water-immiscible solvent to extraction feed solution is typically between about 0.3 and about 1.0, the ratio of aqueous medium to water- immiscible solvent is typically between about 1 and about 3, and the ratio of aqueous medium to extraction feed solution is typically between about 0.5 and about 1.5. The extraction zone may comprise a stirred tank mixer or other liquid/liquid contacting means such as, for example, a countercurrent multistage extraction column.

[ 0108 ] As noted, steroid values in the mother liquor partition substantially to the organic phase while cyanide and other inorganic salts partition nearly quantitatively to the aqueous phase. Where the water-immiscible solvent is methylene chloride, partition coefficients for steroid values are typically in the range between about 3 and about 8. The water-miscible crystallization solvent, usually comprising a lower alcohol, is distributed between the organic and aqueous phases, with a significant component in each phase. Where the water-immiscible solvent has properties comparable to those of methylene chloride, the organic extract typically contains between about 10 and about 40 wt.% lower alcohol, less than about 0.3 wt% cyanide, and between about 0.5 and about 10 wt.% steroid values, including between about 0.5 and about 8 wt.% Formula 5000 product (unsubstituted at the 5-carbon), between about 0.1 and about 1.2 wt.% Formula 6000 substrate, and between about 0.2 and about 5 wt.% 5β-cyano-7α- alkoxycarbonyl by-product of Formula C. The organic extract may also contain dissolved and entrained water in a proportion less than about 1%. [0109] In a single stage extraction, the aqueous raffinate typically contains between about 0.3 and about 2 wt.% cyanide ion and between about 0.3 and about 2 wt.% M cation. Recovery of steroid values can be marginally improved by a second extraction step in which the aqueous raffinate is contacted with an additional volume of water-immiscible solvent. However, the value of the marginally improved steroid recovery may not outweigh the disadvantages that -can-arise-from the presence in the repulp solution of impurities that may be extracted from the aqueous raffinate in the second stage of extraction. If a second extraction step is conducted, it is also preferably conducted in the cold at a ratio of water-immiscible solvent to aqueous raffinate between about 0.5 and about 1.5. Steroid content of any second organic extract is generally quite low. With or without subjecting it to one or more additional extraction stages, the aqueous raffinate is removed from the process as a purge of cyanide and other inorganic impurities.

[ 0110 ] Preparatory to recovery of steroids, any secondary organic extract is preferably combined with the primary organic extract. The organic extract, whether single stage or combined, is distilled to remove water-immiscible organic solvent, and produce a concentrate comprising the steroid values in a medium primarily comprising a water-miscible solvent. Where the organic extract contains more than an insignificant fraction of the crystallization solvent, as it ordinarily does, the water-miscible solvent component of the concentrate comprises the crystallization solvent. Preferably, distillation of the organic extract is conducted at a temperature not greater than about 5O⁰C, more preferably not greater than about 40°C. For example, where the primary crystallization solvent is methanol and the water-immiscible solvent is methylene chloride (or the volatilities of the two solvents are comparable to methanol and methylene chloride, respectively), distillation is preferably conducted at a head pressure in the range between about 300 mm Hg and atmospheric, and a bottoms temperature in the range between about 20 and about 4O⁰C. A straight takeover distillation is effective for the requisite separation. No rectification is required. In this respect, the distillation step may be equated to a simple evaporation.

[0111] Distillation may also be effective to strip residual moisture from the organic . extract. Although certain of the preferred solvents used in the process, such as methanol and methylene dichloride, boil at temperatures below the boiling point of water at atmospheric pressure, certain solvents such as methylene chloride form low boiling azeotropes with water, which are effective for removing residual moisture from the extract.

[ 0112 ] Optionally, a water-miscible solvent is introduced into the organic extract prior to the distillation, or into the bottoms fraction during the distillation after a portion of the water-immiscible solvent has been removed. Such water-miscible solvent is preferably of lesser volatility than the water-immiscible solvent. Methanol is particularly suitable. If the water- . miscible solvent is introduced after a portion of the water-immiscible solvent has been removed, the initial distillation may suitably be continued until the minimum stir volume of water-immiscible solvent and steroid residue in the distillation vessel has been reached. Water-miscible solvent may then be added and distillation resumed until the water-miscible solvent appears as a significant fraction of the distillate, typically at approximately the point where the pot temperature reaches the boiling point of the water-miscible solvent at the prevailing pressure (conveniently atmospheric in those embodiments wherein the water-immiscible solvent comprises methylene chloride). After distillation is complete, the bottoms fraction may then constitute a repulp solution subject to further processing for recovery of steroid values. Preferably, the water-miscible -solvent added prior- to-or-during-the-distillation is the-same-as the primary-erystallization-solvent, which in turn is preferably the same as the reaction solvent. In particularly preferred embodiments of the invention, the water-miscible solvent in each case comprises methanol and the water-immiscible extraction solvent comprises methylene chloride.

[ 0113 ] Distillation may appropriately be continued until the ratio of water-miscible solvent to steroid values in the bottoms fraction is suitable for re-equilibration of steroid to generate additional product of Formula 5000. For example, water-miscible solvent may be removed until the ratio of solvent to steroid in the residue is in a range between about 10:1 and about 30:1 , preferably between about 15:1 and about 22:1 (liters solvent per kg total steroid values). If the solvent/steroid ratio in the still pot has been reduced to a level below that desired for steroid re-equilibration, water-miscible solvent may be added back to provide a repulp solution of appropriate composition.

[ 0114 ] Condensate from the extract distillation may be recycled for use in the extraction. Optionally, it is cooled and passed directly to the extraction zone, or to a premixing step where it is mixed with the extraction feed solution to produce a water-immiscible solution of steroid values that may then be contacted with the aqueous extraction medium in the extraction zone.

[ 0115 ] According to a further alternative for conducting the solvent exchange, the bottoms fraction from the organic extract distillation may be diluted with additional water-miscible solvent and subjected to a second distillation operation to assure more complete removal of water-immiscible solvent from the residue. In the implementation of this alternative, it is not essential that the steroids all remain in solution in the residue of the initial distillation of the organic extract. If desired, substantially all solvent can removed in the first distillation operation, and water-miscible solvent added to the residue to bring it back into solution. Where a second distillation operation is conducted, solvent can again be removed to whatever extent may be desired. If the remaining solvent is sufficient to preserve the steroids in solution, the bottom fraction of the second distillation can serve as a repulp solution for further processing of steroids. If not, a repulp solution may be prepared by adding water-miscible solvent to the residue.

[ 0116] Steroid values contained in the repulp solution may be either recycled as part of the steroid feed to the reaction step, or subjected to a re-equilibration step to increase the yield of Formula 5000 product. In either case, the repulp solution may typically contain between about 1 and about 10 wt.% steroids, including between about 0.5 and about 6 wt.% Formula 5000 product (wherein the 5-carbon is unsubstituted), between about 0.1 and about 5 wt.% Formula 6000 substrate and between about 0.01 and about 5 wt.% 5β-cyano-7α-alkoxycarbonyl intermediate of Formula C.

10117 ] In certain preferred embodiments, where the primary crystallization solvent is a lower alcohol, the steroid recovery is determinable from the algorithm:

.. ^R =3PJS1⁺3^K?-VΪ _.. _ ._ where:

C_m = concentration of usable steroids in the mother liquor

M = volume of mother liquor f = fraction of lower alcohol removed in concentrating mother liquor d = volume of water-immiscible solvent added h = volume of aqueous extraction medium added

C_mfh = concentration of usable steroids in the water-concentrated mother liquor phase

C_d = concentration of usable steroids in the organic extract phase after phase separation

K_p = partition coefficient; equilibrium ratio of concentration of usable steroids in the organic extract phase to that in the aqueous phase

R = percent recovery = moles of steroid in the organic extract phase/(moles of steroid in the mother liquor); and

Mf = h + d C_m/f = C_mf

(M(1-f)+h)C_mfh + dC_d = Mcm D = d/M

H = h/M

[ 0118 ] Based on this algorithm, the volume fraction of lower alcohol removed in concentrating the mother liquor, and the volume fractions of water and water-immiscible solvent mixed with the extraction feed solution are selected to provide a substantially maximum recovery (R).

RE-EQUILIBRATION

[ 0119 ] The repulp solution may be processed to convert steroids contained therein to the compound of Formula 5000, preferably to a species of Formula 5000 that is unsubstituted at the 5-carbon. Most prominent of the steroid components that may be so converted are the compound of Formula 6000 and the cyanoester of Formula C. While this repulp processing is described herein as a re-equilibration, it normally involves or requires addition of alkoxy source and base to the repulp solution to effect conversion of steroid values to the compound of Formula 5000.

[ 0120 ] Preferably, the repulp solution is mixed with fresh alkoxy group source to promote the conversion of unreacted Formula 6000 substrate to Formula 5000 product. If the alkoxy group source is other than a base, a base is normally added to the repulp solution as well, sinceineώase. introduced-inloJhe.primary. reactioruhas. oxdiøariJy_baeπ_remo-ved in-the extraction process or consumed in the primary reaction step. Preferably, a metal alkoxide reagent solution is added to the repulp solution in relative proportions that may depend on the composition of the repulp solution. The composition of the metal alkoxide reagent solution is conveniently the same as or similar to that described above for use in the initial conversion of Formula 6000 substrate to Formula 5000 product. The alkoxide reagent is preferably charged to the repulp solution jn a ratio of at least about 1.25 equivalents, more preferably at least about 1.5 equivalents metal alkoxide to the sum of equivalents of Formula 6000 substrate plus 5-cyano hydroxyester in the solution. Re-equilibration is preferably conducted at temperature greater than 50⁰C, more preferably at least about 70⁰C, most typically between about 80⁰C and about 95⁰C for a period between about 0.5 and about 6, the reaction period varying inversely with the temperature as discussed above with reference to the primary reaction step.

[0121] After a new equilibrium has been reached, the repulp re-equilibration reaction solution is cooled and additional Formula 5000 product crystallized therefrom. Cooling is preferably conducted at the rapid rates described hereinabove for the primary reaction step, so as to minimize the reverse reaction of Formula 5000 product to Formula 6000 substrate during the cooling step. Crystallization is also conducted substantially in the manner described above for recovery of Formula 5000 product from the original reaction mixture. Optionally, the product of the re-equilibration can be crystallized from a derivative of the repulp reaction solution, e.g., a concentrate thereof.

[ 0122 ] A sacrificial saponification target compound is optionally incorporated into the repulp solution to scavenge any free hydroxide that may have been incorporated into the solution as a contaminant of the metal alkoxide reagent or otherwise. For example, moisture entrained in the organic extract from the extraction step might not be entirely eliminated in the extract concentration step, especially if the water-immiscible solvent selected does not form a low boiling azeotrope with water. The sacrificial saponification targets that can be used are the same as those described above with respect to the primary reaction step, and the concentrations in the repulp re-equilibration solution are preferably approximately the same as described above for the primary reaction step. Methyl formate and trimethyl orthoformate are particulary preferred.

[ 0123 ] According to a further alternative steroid recovery scheme, the repulp solution may be recycled to the initial reaction step for further conversion of the steroid values to Formula 5000 product. In this instance, the overall process comprises an initial reaction step in . which the Formula 6000 compound is contacted with an alkoxy group source in a primary reaction zone. Recovered steroid values are recycled in a repulp solution to the primary reaction zone where additional compound of Formula 5000 (unsubstituted at C-5) is produced by conversion of compound of Formula 6000, or compound of Formula C, contained in the recovered steroid values. In a variant of this embodiment, the reaction may be run to only partial conversion in the primary reaction zone, i.e., the reaction is terminated before the conversion of the Formula 6000 compound has progressed to equilibrium at the temperature at which the reaction is terminated. The Formula 5000 product is recovered from the reaction solution according to any of the recovery schemes described above, preferably by direct crystallization from the reaction solution without acidification. Unreacted Formula 6000 compound and other steroid values are then recovered from the crystallization mother liquor, typically according to the mother liquor extraction process described above; and the steroid values are recovered from the organic extract, preferably by solvent exchange in which the water-immiscible extraction solvent is replaced by a water-miscible solvent, preferably the same solvent that is used in the primary reaction zone. The resulting repulp solution may be recycled to the primary reaction zone for conversion of unreacted Formula 6000 substrate to Formula 5000 product as described above.

[ 0124 ] Partial conversion may advantageously be effected in a continuous primary reaction zone, into which the Formula 6000 substrate, base, and alkoxy group source are continuously or intermittently introduced, and from which the Formula 5000 reaction mixture may be continuously or intermittently removed. A plug flow reactor may be used for the conversion, i.e., the primary reaction zone comprises a plug flow reaction path. The alkoxy group source preferably comprises an esterification reagent comprising a metal alkoxide in a corresponding alcohol solvent. Composition of the esterification reagent is preferably the same as or comparable to that described above for the primary reaction step, and the ratio of metal alkoxide to Formula 6000 substrate is also preferably in the range described above for the primary reaction. The conversion of Formula 6000 substrate to Formula 5000 product is preferably conducted at an elevated temperature in the ranges described above for the primary reaction. The reaction is preferably terminated before the final reaction yield has deteriorated by more than 10% from the maximum yield achieved during the course of the reaction; and the reaction mixture is preferably cooled rapidly at the rates described for the primary reaction, and in any event at a rate sufficient such that the ultimate reaction yield after cooling is not more than 10% lower than the final yield at the end of the reaction.

[ 0125 ] As described above, a plug flow or other continuous ractor can be operated to complete equilibrium conversion rather than partial conversion. In either case, steroid values may be recovered from the mother liquor in the manner described above. Recovered steroid values may be re-equilibrated in the repulp solution, or the repulp solution may be recycled to the primary reaction zone for conversion of Formula 6000 substrate and other steroid values to Formula 5000 product compound,

DESCRIPTION OF PROCESS FLOWSHEET [ 0126] Fig. 1 depicts a flowsheet illustrating a process which incorporates the improvements described herein in the conversion of a diketone intermediate to a hydroxyester intermediate that is a useful in the preparation of eplerenone or related compounds. ! [ 0127 ] A solution is prepared comprising a diketone in a reaction medium comprising methanol. The diketone may typically correspond to Formula Vl-I :

[ 0128 ] The solution is introduced into a primary reaction vessel 1 that is provided with a reflux condenser 3 and internal cooling coils (not shown) or an external heat exchanger 5 through which the contents of the vessel can be circulated. An esterification reagent comprising a solution or dispersion of potassium methoxide in methanol is then introduced into the reaction medium within primary reaction vessel 1 and the reaction medium heated to a temperature above 70⁰C, most typically between about 80° and about 110⁰C. Optionally methyl formate, trimethyl orthoformate or other saponification target is incorporated into the esterification reagent and/or added to the reaction mixture in reactor 1. Heat for the reaction is supplied through the coils and/or external heat exchanger. Progress of the reaction is conveniently followed by. periodic HPLC analysis. When conversion substantially reaches equilibrium, typically in less than 2 hours when the temperature is 85^s to 90^QC, or within about 30 to 45 minutes when the temperature is 95^s to 110^eC, the reaction is terminated by cooling the reaction mass as rapidly as practicable to a temperature not greater than about 60⁰C. Where autogenous pressure is generated at the reaction temperature, a portion of the cooling is achieved by release of pressure and consequent flashing of methanol. Cooling fluid instead of steam or other heating fluid is supplied to the coils and/or external heat exchanger to bring the temperature down to the desired level.

[ 0129] The cooled reaction mass is transferred to a primary crystallizer 7 wherein it is further cooled to a temperature below about 15°C, preferably between about -5° and about 5°C causing crystallization of the hydroxyester reaction product corresponding to Formula V-1 :

and precipitation of the hydroxyester from the solution.

[0130] The resulting slurry is transferred to a centrifuge 9 where the crystalline product is separated from the crystallization mother liquor. The centrifuge cake is preferably washed with fresh methanol, and the wash solution is combined with the mother liquor. The crystalline hydroxyester product is removed and may be subjected to further processing as described elsewhere herein for conversion to eplerenone.

[ 0131] Mother liquor discharged from centrifuge is introduced into a still or evaporator 11 wherein methanol is removed, thereby concentrating the mother liquor to not more than half its original volume. Typically, the mother liquor is concentrated four fold or five fold. However, the extent of concentration is preferably not enough to cause precipitation of steroids from the liquid phase.

[ 0132 ] Methylene chloride or other water-immiscible solvent is added to the mother liquor concentrate in a solvent adjustment pre-mix vessel 13, thereby producing a water- immiscible solution of steroids which is transferred to the extraction zone of an extraction vessel 15. To facilitate recovery of steroid values from the organic extract, the water-immiscible solvent is preferably more volatile than the water-miscible solvent used for the reaction and crystallization steps. Optionally, extraction vessel 15 may comprise a multi-stage countercurrent or cocurrent extraction column. In the extraction system, steroids are preferentially partitioned to the organic phase, and cyanide and other inorganics are partitioned to the aqueous phase. Methanol is substantially divided between the phases. Aqueous raffinate from the extraction, comprising cyanide ion, potassium ion and a fraction of the methanol, is purged from the process. The organic extract contains steroid values including unreacted diketone, residual product hydroxyester, 5β-cyano hydroxyester (corresponding to Formula C), and other steroid values. The extract also contains a significant fraction of methanol.

[ 0133 ] The organic extract removed from extraction system 15 is subjected to solvent exchange to remove water-immiscible solvent and produce a repulp solution of steroid values in a water-miscible solvent, preferably methanol. For this purpose, the organic extract is first introduced into a still or evaporator 17 wherein the water-immiscible extraction solvent is substantially removed. Where the extract contains a significant fraction of methanol or other water-immiscible crystallization solvent, the bottoms fraction of the extract distillation may constitute a repulp solution directly suitable for further processing of recovered steroid values. Alternatively, as discussed above, the distillation bottoms may comprise a steroid slurry or substantially solid steroid residue to which methanol or other water-miscible solvent is added to redissolve the steroids. The resulting solution may be subjected to further distillation for removal of residual methylene chloride or other water-immiscible solvent. According to further alternatives, as also discussed above, methanol or other water-miscible solvent may be added during the distillation. Where the extraction solvent is methylene chloride, moisture dissolved or entrained in the organic extract may be removed as a low boiling water/m ethylene chloride azeotrope during the extract distillation.

[ 0134 ] Overheads from the still or evaporator 17 are condensed in an overheads condenser 19 and the condensate is discharged to a receiver 21. The condensate, comprising methylene chloride or other water-immiscible solvent, may be recycled to the extraction step, typically by transfer to premix vessel 13.

[ 0135] Fig. 1 illustrates transfer of the extract distillation bottoms fraction, whether solution, slurry or wet solid, to a repulp tank 23 where water-miscible solvent, preferably methanol, is added to produce a repulp solution of steroid values. The repulp solution is preferably transferred to secondary reaction vessel 25. A solution of potassium methoxide in methanol is added to the secondary reaction vessel and an equilibration reaction takes place in which unreacted diketone compound, 5β-hydroxyester and other steroid values may be converted to the desired hydroxyester product. The re-equilibration reaction is conducted under conditions comparable to those of the primary reaction in reactor 1. Methyl formate or other saponification target may optionally be included in the potassium methoxide/methanol solution and/or introduced into the secondary reaction veseel. After re-equilibration, the repulp reaction mass is transferred to a secondary crystallizer 27 where it is cooled to crystallize hydroxyester. The resulting slurry is transferred to a centrifuge 29 for separation of the secondary hydroxyester crystallization crop from the secondary mother liquor. A methanol wash of the centrifuge cake is combined with the secondary mother liquor. The secondary mother liquor including the wash liquor is recycled and combined with the primary mother liquor for extraction. If desired, a fraction of the secondary mother liquor may be purged for removal of organic impurities.

[ 0136] According to a further option, the repulp solution may recycled to the primary reaction vessel for conversion of steroid values contained in the repulp solution to the desired hydroxyester. However, the use of a separate secondary reactor is preferred in order to avoid recycle of organic impurities or residual cyanide ion to the primary reaction zone.

REACTION SCHEME 1

[ 0137 ] One preferred process scheme for the preparation of compounds of Formula I advantageously begins with canrenone or a related starting material corresponding to Formula 13600 (or, alternatively, the process can begin with androstenedione or a related starting material)

[0138] wherein

[ 0139] -A-A- represents the group -CHR¹-CHR²- or -CR¹=CR²-;

[ 0140 ] where R¹ and R² are independently selected from the group consisting of hydrogen, halo, hydroxy, alky!, alkoxy, cyano and aryloxy; and

[ 0141] R¹² is selected from the group consisting of hydrogen, halo, haloalkyl, hydroxy, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, cyano and aryloxy.

[ 0142 ] Using a byconversion process, an 11-hydroxy group of α-orientation is introduced in the compound of Formula 13600, thereby producing a compound of Formula 8600:

[ 0143 ] where R¹² and -A-A- are as defined above for formula 13600.

[ 0144 ] The preferred organisms that can be used in this hydroxylation step and conditions for the bioconversion are described in U.S. Patent No. 5,981 ,744, which is herein incorporated by reference in its entirety.

[0145] Preferably, the compounds of Formula 13600 and 8600 correspond to Formula VIIIA in which -A-A- is -CH₂-CH₂- and R¹² is hydrogen, lower alkyl or lower alkoxy.

[ 0146] Further in accordance with the process of scheme 1 , the compound of Formula 8600 is reacted under alkaline conditions with a source of cyanide ion to produce an enamine compound of Formula 7600

[ 0147 ] wherein -A-A-, and R D1¹2* are as defined above for formula 13600.

[ 0148 ] Cyanidation of the 11 α-hydroxyl substrate of Formula 8600 may be carried out by reacting it with a cyanide ion source such as a ketone cyanohydrin, most preferably acetone cyanohydrin, in the presence of a base and a alkali metal salt, most preferably LiCI. Alternatively, cyanidation can be effected without a cyanohydrin by using an alkali metal cyanide in the presence of an acid.

[ 0149 ] Preferably, the compounds correspond to Formula 7600. wherein -A-A- is - CH₂-CH₂- and R¹² is hydrogen, lower alkyl or lower alkoxy.

[ 0150 ] Most preferably the compound of Formula 7600 is 5'R(5'α),7'β-20¹- Aminohexadecahydro-11'β-hydroxy-10'α,13'α-dimethyl-3',5-dioxospiro[furan-2(3H),17'α(5Η)- ^.^metheno^HlcyclopentataJphenanthrene^δ'-carbonitrile.

[ 0151] In the next step of the Scheme 1 synthesis, the enamine of Formula 7600 is hydrolyzed to produce a diketone compound of Formula 6600

[0152 ] where -A-A- and R¹² are as defined in Formula 13600. Any aqueous organic or mineral acid can be used for the hydrolysis. Hydrochloric acid is preferred. To enhance productivity, a water-miscible organic solvent, such as a lower alkanol, is preferably used as a cosolvent. Preferably, the compounds correspond to Formula 6600 wherein -A-A- is -CH₂-CH₂- and R¹² is hydrogen, lower alkyl or lower alkoxy.

[ 0153 ] Most preferably, the compound of Formula 6600 is 4'S(4'α),7'α- Hexadecahydro-H'α-hydroxy-IO'β.iS'β-dimethyl-S'.δ^O'-trioxospirotfuran^SHJ.^'β- [4,7]methano[17H]cyclopenta[a]phenanthrene]-5'β(2'H)-carbonitrile. [ 0154 ] In a particularly preferred embodiment of the invention, the product enamine of Formula 7600 is produced from the compound of Formula 8600 in the manner described in U.S. Patent No. 5,981 ,744, and converted in situ to the diketone of Formula 6600.

10155 ] In the next step of the Scheme 1 synthesis, the diketone compound of Formula 6600 is reacted with a metal alkoxide to open up the ketone bridge between the 4 and 7 positions, cleave the bond between the carbonyl group and the 4-carbon, form an α-oriented alkoxycarbonyl substituent at the 7 position, and eliminate cyanide at the 5-carbon. The product of this reaction is a hydroxyester compound corresponding to Formula 5600

[ 0156] where R⁷ represents a lower alkoxycarbonyl or hydroxycarbonyl radical; and -A-A- and R¹² are as defined in Formula 13600. Particular reaction conditions for this reaction are disclosed hereinabove in the sections reciting high temperature improvements, mother liquor extraction conditions and use of methyl formate.

[ 0157 ] Preferably, the compounds correspond to Formula 5600 in which -A-A- is - CH₂-CH₂-, R¹² is hydrogen, lower alkyl or lower alkoxy, and R⁷ is lower alkoxycarbonyl.

[ 0158 ] Most preferably, the compound of Formula 5600 is Methyl Hydrogen 11α,17α-Dihydroxy-3-oxopregn-4-ene-7α,21-dicarboxylate, γ-Lactone.

[ 0159 ] The compound of Formula 5600 may be isolated by the methods described hereinabove for compounds of Formula 5000.

[ 0160 ] The crude 11 α-hydroxy-7α-alkanoyloxycarbonyl product is taken up again in the solvent for the next reaction step of the process, which is the conversion of the 11 -hydroxy group to a good leaving group at the 11 position thereby producing a compound of Formula 4600:

[ 0161] where R¹¹¹ is lower arylsulfonyloxy, alkylsulfonyloxy, acyloxy or halide; -A-A- and R¹² are as defined in Formula 13600, R⁷ is as defined in Formula 5600. Preferably, the 11α- hydroxyl is esterified by reaction with a lower alkylsulfonyl halide, an acyl halide or an acid anhydride which is added to the solution containing the intermediate product of Formula 5600. This reaction is described in more detail in U.S. Patent No. 5,981 ,744.

[ 0162 ] Preferably, the compounds correspond to Formula 4600 wherein -A-A- is - CH₂-CH₂- and R¹² is hydrogen, lower alkyl or lower alkoxy.

[ 0163 ] Most preferably, the compound of Formula 4600 is Methyl Hydrogen 17α- Hydroxy-11α-(methylsulfonyl)oxy-3-oxopregn-4-ene-7α,21-dicarboxylate, γ-Lactone. Where an acyloxy leaving group is desired, the compound of Formula 4600 is preferably 7-methyl hydrogen 17-hydroxy-3-oxo-11 α-(2,2,2-trif luoro-1 -oxoethoxy)-17α-pregn-4-ene-7α,21 -dicarboxylate, y- lactone; or 7-methyl 11α-(acetyloxy)-17-hydroxy-3-oxo-17α-pregn-4-ene-7α,21 -dicarboxylate, y- lactone.

[ 0164] In an alternative and preferred embodiment of the invention, the product compound of Formula 4600 is recovered in crude form as a concentrated solution by removal of a portion of the solvent. This concentrated solution is used directly in the following step of the process, which is removal of the 11α-leaving group from the compound of Formula 4600, thereby producing an enester of Formula 2600:

[ 0165 ] where -A-A- and R¹² are as defined in Formula 13600, and R⁷ is as defined in Formula 5600. For purposes of this reaction, the R¹¹¹ substituent of the compound of Formula 4600 may be any leaving group the abstraction of which is effective for generating a double bond between the 9- and 11 -carbons. Preferably, the leaving group is a lower alkylsulfonyloxy or acyloxy substituent which is removed by reaction with an acid and an alkali metal salt. Mineral acids can be used, but lower alkanoic acids are preferred. Advantageously, the reagent for the reaction further includes an alkali metal salt of the alkanoic acid utilized. It is particularly preferred that the leaving group comprise mesyloxy and the reagent for the reaction comprise formic acid or acetic acid and an alkali metal salt of one of these acids or another lower alkanoic acid. Where the leaving group is mesyloxy and the removal reagent is formic acid and potassium formate a relatively high ratio of 9,11 to 11 ,12-olefin is observed.

[ 0166 ] Conversion of the substrate of Formula 2600 to the product of Formula 1600 may be conducted in the manner described in U.S. patent 4,559,332 which is expressly incorporated herein by reference, or more preferably by the novel reaction using a haloacetamide promoter as described below.

[ 0167 ] In another embodiment of the invention, the hydroxyester of Formula 5600 may be converted to the enester of Formula 2600 without isolation of the intermediate compound of Formula 4600. In this method, the hydroxyester is taken up in a an organic solvent, such as methylene chloride; and either an acylating agent, e.g., methanesulfonyl chloride, or halogenating reagent, e.g., sulfuryl chloride, is added to the solution. The mixture is agitated and, where halogenation is involved, an HCI scavenger such as imidazole is added. This series of chemical transformations may be made using the methods described herein, or in U.S. patent 5,981 ,744.

_ [-0-16S ]- - In-the last-step of-the-process,-a-compound-of. formula 2600-is-contacted with an epoxidation agent to form a compound corresponding to Formula 1600

[ 0169 ] wherein -A-A- and R¹² are as defined above for Formula 13600 and R⁷ is as defined above for Formula 5600.

[ 0170 ] This epoxidation reaction may be carried out using the method described in U.S. 5,981 ,744 or using the improved epoxidation methods described herein and is highly useful as the concluding step of the synthesis of Scheme 1. In many of the various embodiments, the process of the present invention may combine the improvements described for step 3, which involves the transformation of a compound of Formula 6600 to a compound of Formula 5600 and the improvements described for the epoxidation step, which involves the transformation of a compound of Formula 2600 to a compound of Formula 1600. In the overall process of converting a compound of Formula 13600, in particular canrenone, to a compound of Formula 1600, in particular eplerenone, each of the process improvements to step 3 may be combined individually or collectively with the epoxidation step improvements. In a particularly preferred embodiment, the overall process of Scheme 1 proceeds as follows.

IMPROVED EPOXIDATION PROCESS

[ 0171] Epoxidation according the process described herein may be carried out at a site of unsaturation in the steroid nucleus. As described herein, the process is especially advantageous in the epoxidation of trisubstituted bonds such as a 9,11 -olefin.

[ 0172 ] Δ⁹'¹¹ -Substrates that are useful in the process of this invention may include, for example:

[0173] wherein [ 0174 ] R¹⁰, R¹², and R¹³ are independently selected from the group consisting of hydrogen, halo, hydroxy, lower alkyl, lower alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, cyano, and aryloxy;

[ 0175] -A-A- represents the group -CHR¹-CHR²- or -CR¹=CR²-;

[ 0176 ] where R¹ and R² are independently selected from the group consisting of hydrogen, haloT hydroxyralkylralkoxyracyl.-hydroxyalkylralkOxyalkylr hydroxycarbonyl, alkoxycarbonyl, cyano, and aryloxy, or R¹ and R² together with the carbons of the steroid backbone to which they are attached form a cycloalkyl group;

[ 0177 ] -B-B- represents the group -CHR¹⁵-CHR¹⁶-, -CR¹⁵=CR¹⁶ or an α- or β- oriented group:

^«_N .16

CH- -CH

I I

— CH-CH₂-CH — .

[ 0178 ] where R¹⁵ and R¹⁶ are independently selected from the group consisting of hydrogen, halo, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, and aryloxy; or R¹⁵ and R¹⁶, together with the C-15 and C-16 carbons of the steroid nucleus to which they are attached, form a cycloalkylene group, (e.g., cyclopropylene).

[ 0179 ] R⁸ and R⁹ are independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkynyl, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, acyloxyalkyl, cyano and aryloxy, or R⁸ and R⁹ together comprise a carbocyclic or heterocyclic ring structure, or R⁸ and R⁹ together with R⁶ or R⁷ comprise a carbocyclic or heterocyclic ring structure fused to the pentacyclic D ring;

[ 0180 ] -G-J- represents the group

^C-=CR¹¹-

[0181] where R¹¹ is selected from the group consisting of hydrogen, alkyl, substituted alkyl and aryl;

[0182] -D-D- represents the group:

— CHR⁴-CR^ — CR⁴=C^

^ or ^-

[ 0183 ] where R⁴ and R⁵ are independently selected from the group consisting of hydrogen, halo, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy or R⁴ and R⁵ together with the carbons of the steroid backbone to which they are attached form a cycloalkyl group; [ 0184] -E-E- represents the group -CHR⁶-CHR⁷- or -CR⁶=CR⁷-;

[ 0185] where R⁶ is selected from the group consisting of hydrogen, halo, aikyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano and ;aryloxy; and

[ 0186] R⁷ is selected from the group consisting of hydrogen, hydroxy, protected hydroxy, halo, alkyl, cycloalkyl_ralkoxy_raGylrhydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, aryloxy, heteroaryl, heterocyclyl, acetylthio, furyl and substituted furyl, or

[ 0187 ] R⁶ and R⁷, together with the C-6 and C-7 carbons of the steroidal nucleus to which R⁶ and R⁷ are respectively attached, form a cycloalkylene group,

[ 0188 ] or R⁵ and R⁷, together with the C-5, C-6 and C-7 carbons of the steroid nucleus form a pentacyclic ring fused to the steroid nucleus and comprising a 5,7-lactol, 5,7- hemiacetal or 5,7-lactone corresponding to the structure:

preferably

[ 0189 ] wherein R⁷² comprises =CH(OH), =CH(OR⁷³) or =CH=O.

[ 0190 ] R¹¹ is preferably hydrogen but may also be alkyl, substituted alkyl or aryl. Where R¹¹ is substituted alkyl, substituents may include halides and other moieties which do not destabilize the epoxide ring. Where R¹¹ is aryl, it may include substituents which are not strongly electron withdrawing.

[ 0191] In various preferred embodiments, a 3-keto structure corresponding to formula 1599, R¹², R¹⁰ and R¹³ are independently selected from the group consisting of hydrogen, fluoride, chloride, bromide, iodide, fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, chloromethyl, chloroethyl, chloropropyl, chlorobutyl, bromomethyl, bromoethyl, bromopropyl, bromobutyl, iodomethyl, iodoethyl, iodopropyl, iodobutyl, hydroxy, methyl, ethyl, straight, branched or cyclic propyl and butyl; methoxy, ethoxy, propoxy, butoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxym ethyl, propoxyethyl, propoxypropyl, propoxybutyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, hydroxycarbonyl, cyano, phenoxy, benzyloxy;

[ 0192] -A-A- represents the group -CHR¹ -CHR²- or -CR¹=CR²-;

[ 0193 ] where R¹ and R² are independently selected from the group consisting of hydrogen, fluoride, chloride, bromide, iodide, methyl, ethyi, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, acetyl, propionyl, butyryl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, acetoxym ethyl, acetoxyethyl, acetoxypropyl, acetoxybutyl, propionyloxymethyl, propionyloxyethyl, butyryloxymethyl, butyryloxyethyl, cyano, phenoxy and benzoxy;

are attached form a (saturated) cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene or cycloheptylene group;

[ 0195] -B-B- represents the group -CHR¹⁵-CHR¹⁶-,-CR¹⁵=CR¹⁶- or an α- or β- oriented group:

i15 R 16

\

CH- -CH I I

-CH-CH₂-CH

[0196] where R¹⁵ and R¹⁶ are independently selected from the group consisting of hydrogen, fluoride, chloride, bromide, iodide, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, acetyl, propiόnyl, butyryl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, acetoxymethyl, acetoxyethyl, acetoxypropyl, acetoxybutyl, propionyloxymethyl, propionyloxyethyl, butyryloxymethyl, butyryloxyethyl, cyano, phenoxy and benzoxy;

[ 0197] or R¹⁵ and R¹⁶, together with the C-15 and C-16 carbons of the steroid nucleus to which R¹⁵ and R¹⁶ are respectively attached, form a cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene group;

[ 0198 ] -D-D- represents the group

[ 0199 ] where R⁴ and R⁵ are independently selected from the group consisting of hydrogen, fluoride, chloride, bromide, iodide, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, acetyl, propionyl, butyryl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, acetoxymethyl, acetoxyethyl, acetoxypropyl, acetoxybutyl, propionyloxymethyl, propionyloxyethyl, butyryloxymethyl, butyryloxyethyl, cyano, phenoxy and benzoxy; or R⁴ and R⁵ together with the carbons of the steroid backbone to which they are attached form a cyclopropylene cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene group;

11

:CR

[ 0200 ] where R¹¹ is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, octyl, decyl, 5-fluoropentyl, 6-chlorohexyl, phenyl, p-tolyl, o-tolyl;

[0201] -E-E- represents the group -CHR⁶-CHR⁷- or -CR⁶=CR⁷-, wherein R⁶ is selected from the group consisting of hydrogen, fluoride, chloride, bromide, iodide, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, acetyl, propionyl, butyryl, hydroxy methyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxym ethyl, propoxyethyl, propoxypropyl, propoxybutyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, acetoxymethyl, acetoxyethyl, acetoxypropyl, acetoxybutyl, propionyloxymethyl, propionyloxyethyl, butyryloxymethyl, butyryloxyethyl, cyano, phenoxy and benzoxy; and

[ 0202 ] R⁷ is selected from the group consisting of hydrogen, hydroxyl, protected hydroxyl, fluoride, chloride, bromide, iodide, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methoxy, ethoxy, propoxy, butoxy, acetyl, propionyl, butyryl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, acetoxymethyl, acetoxyethyl, acetoxypropyl, acetoxybutyl, propionyloxymethyl, propionyloxyethyl, butyryloxymethyl, butyryloxyethyl, cyano, phenoxy, benzoxy, pyrrolyl, imidazolyl, thiazolyl, pyridyl, pyrimidyl, oxazolyl, acetylthio, furyl, substituted furyl, thienyl and . . substituted thienyl;

[ 0203 ] or R⁶ and R⁷, together with the C-6 and C-7 carbons of the steroid nucleus to which R⁶ and R⁷ are respectively attached, form a (saturated) cyclopropylene cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene group.

[ 0204 ] In many embodiments,

[ 0205 ] R¹² is selected from the group consisting of hydrogen, fluoride, chloride, bromide, iodide, fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, chloromethyl, chloroethyl, chloropropyl, chlorobutyl, bromomethyl, bromoethyl, bromopropyl, bromobutyl, iodomethyl, iodoethyl, iodopropyl, iodobutyl, hydroxy, methyl, ethyl, straight, branched or cyclic propyl and butyl; methoxy, ethoxy, propoxy, butoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, and cyano;

[ 0206] R¹⁰ and R¹³ are methyl, typically β-methyl; [0207 ] -A-A- represents the group -CH₂-CH₂- Or -CH=CH-; [ 0208 ] -B-B- represents the group -CHR¹⁵-CHR¹⁶-,-CR¹⁵=CR¹⁶- or an α- or β- oriented group:

R 15 ₃16

\

CH= =^CH-

I I -CH — CH₂-CH

[ 0209 ] where R¹⁵ and R¹⁶ are independently selected from the group consisting of hydrogen, fluoride, chloride, bromide, iodide, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, acetyl, propionyl, butyryl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and cyano;

[ 0210 ] or R¹⁵ and R¹⁶, together with the C-15 and C-16 carbons of the steroid nucleus to which R¹⁵ and R¹⁶ are respectively attached, form a cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene group;

[ 0211] -D-D- represents the group

/ / CHR⁴-CR⁵. CR⁴-=C^

^ or ^ ;

[ 0212 ] where R⁴ and R⁵ are independently selected from the group consisting of hydrogen, fluoride, chloride, bromide, iodide, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, acetyl, propionyl, butyryl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and cyano;

[ 0213 ] -E-E- represents the group -CHR⁶-CHR⁷- or -CR⁶=CR⁷-, wherein R⁶ is selected from the group consisting of hydrogen, fluoride, chloride, bromide, iodide, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, acetyl, propionyl, butyryl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and cyano; and

[ 0214 ] R⁷ is selected from the group consisting of hydrogen, hydroxyl, protected hydroxyl, fluoride, chloride, bromide, iodide, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methoxy, ethoxy, propoxy, butoxy, acetyl, propionyl, butyryl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, cyano, furyl, thienyl, substituted furyl and substituted thienyl;

[ 0215] or R⁶ and R⁷, together with the C-6 and C-7 carbons of the steroid nucleus to which R⁶ and R⁷ are respectively attached, form a (saturated) cyclopropylene cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene group.

[ 0216] In various preferred embodiments, R¹² is selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, cyano and aryloxy;

[ 0217 ] R¹⁰ and R¹³ are methyl, particularly β-methyl;

[ 0218 ] -A-A- represents the group -CH₂-CH₂-; [ 0219 ] -B-B- represents the group -CHR¹⁵-CHR¹⁶-; where R¹⁵ and R¹⁶ are hydrogen;

[ 0220 ] or R¹⁵ and R¹⁶, together with the C-15 and C-16 carbons of the steroid nucleus to which they are respectively attached, form a (saturated) cycloalkylene group;

[0221] -D-D- represents the group:

-CR⁴Z=C^

[ 0222 ] where R⁴ is hydrogen;

[ 0223 ] -E-E- represents the group -CHR⁶-CHR⁷-; where R⁶ is hydrogen;

[ 0224 ] where R⁷ is selected from the group consisting of hydrogen, furyl, substituted furyl, thienyl, substituted thienyl and acetylthio;

[ 0225] or R⁶ and R⁷, together with the C-6 and C-7 carbons of the steroid nucleus to which they are respectively attached, form a (saturated) cycloalkylene group;

[ 0226] -J-G- represents the group

:CR¹¹-

[ 0227 ] where R¹¹ is hydrogen.

[0228] Unless stated otherwise, organic radicals referred to as "lower" in the present disclosure contain at most 7, and preferably from 1 to 4, carbon atoms.

[ 0229 ] A lower alkoxycarbonyl radical is preferably one derived from an alkyl radical having from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl and tert.-butyl; especially preferred are methoxycarbonyl, ethoxycarbonyl and isopropoxycarbonyl. A lower alkoxy radical is preferably one derived from one of the above- mentioned C₁-C₄ alkyl radicals, especially from a primary C₁-C₄ alkyl radical; especially preferred is methoxy. A lower alkanoyl radical is preferably one derived from a straight-chain alkyl having from 1 to 7 carbon atoms; especially preferred are formyl and acetyl.

[ 0230] A methylene bridge in the 15, 16-position is preferably β-oriented.

[ 0231] A preferred class of com pounds. that may be produced in accordance with the methods of the invention are the 20-spiroxane compounds described in U.S. Patent No. 4,559,332, i.e., those corresponding to Formula IA:

[ 0232 ] Preferably, 20-spiroxane compounds produced by the novel methods of the invention are those of Formula I in which Y¹ and Y² together represent the oxygen bridge -O-.

[ 0233 ] Especially preferred compounds of the formula I are those in which X represents oxo. Of compounds of the 20-spiroxane compounds of Formula IA in which X represents oxo, there are most especially preferred those in which Y¹ together with Y² represents the oxygen bridge -O-.

[ 0234 ] Especially preferred compounds of the formula I and IA are, for example, the following:

[0235] 9α,11 α-epoxy-7α-methoxycarbonyl-20-spirox-4-ene-3,21 -dione,

[0236] 9α, 11 α-epoxy-7α-ethoxycarbonyl-20-spirox-4-ene-3,21 -dione,

[0237] 9α,11 α-epoxy-7α-isopropoxycarbonyl-20-spirox-4-ene-3,21 -dione,

[0238] and the 1 ,2-dehydro analog of each of the compounds;

[0239] 9α,11 α-epoxy-6α,7α-methylene-20-spirox-4-ene-3,21 -dione,

[0240] 9α,11α-epoxy-6β,7β-methylene-20-spirox-4-ene-3,21 -dione,

[0241] 9α, 11 α-epoxy-6β,7β; 15β, 16β-bismethylene-20-spirox-4-ene-3,21 -dione,

[0242] and the 1 ,2-dehydro analog of each of these compounds;

[ 0243 ] 9α,11α-epoxy-7α-methoxycarbonyl-17β-hydroxy-3-oxo-pregn-4-ene-21- carboxylic acid,

[ 0244 ] 9α,11α-epoxy-7α-ethoxycarbonyl-17β-hydroxy-3-oxo-pregn-4-ene-21- carboxylic acid,

[ 0245] 9α,11 a-epoxy-7a-isopropoxycarbonyl-17β-hydroxy-3-oxo-pregn-4-ene-21 - carboxylic acid,

[ 0246] 9α,11α-epoxy-17β-hydroxy-6α,7α-methylene-3-oxo-pregn-4-ene-2T- carboxylic acid,

[ 0247 ] 9α,11α-epoxy-17β-hydroxy-6β,7β-methylene-3-oxo-pregn-4-ene-21- carboxylic acid, [0248] 9α, 11 α-epoxy- 17β-hydroxy-6β,7β; 15β, 16β-bism ethylene-3-oxo-pregn-4-ene- 21-carboxylic acid,

10249 ] and alkali metal salts, especially the potassium salt or ammonium salt of each of these acids, and also a corresponding 1 ,2-dehydro analog of each of the mentioned carboxylic acids or of a salt thereof;

[ 0250 ] 9α, 11 α-epoxy-15β, 16β-methylene-3,21 -dioxo-20-spirox-4-ene-7α-carboxylic acid methyl ester, ethyl ester and isopropyl ester,

[0251] 9α,11α-epoxy-15β,16β-methylene-3,21-dioxo-20-spiroxa-1,4-diene-7α- carboxylic acid methyl ester, ethyl ester and isopropyl ester,

[ 0252 ] 9α,11α-epoxy-3-oxo-20-spirox-4-ene-7α-carboxylic acid methyl ester, ethyl ester and isopropyl ester,

[ 0253 ] 9α, 11 α-epoxy-6β,6β-methylene-20-spirox-4-en-3-one,

[0254] 9α, 11 α-epoxy-6β,7β; 15β, 16β-bismethylene-20-spirox-4-en-3-one,

[ 0255 ] 9α,11 α-epoxy, 17β-hydroxy- 17α(3-hydroxy-propyl)-3-oxo-androst-4-ene-7α- carboxylic acid methyl ester, ethyl ester and isopropyl ester,

[ 0256 ] 9α,11α-epoxy,17β-hydroxy-17α-(3-hydroxypropyl)-6α,7α-methylene-androst- 4-en-3-one,

[ 0257 ] 9α,11α-epoxy-17β-hydroxy-17α-(3-hydroxypropyl)-6β,7β-methylene-androst- 4-en-3-one,

[0258 ] 9α, 11 α-epoxy- 17β-hydroxy-17α-(3-hydroxypropyl)-6β,7β; 15β, 16β- bismethylene-androst-4-en-3-one,

[ 0259 ] including 17α-(3-acetoxypropyl) and 17α-(3-fromyloxypropyl) analogs of the mentioned androstane compounds,

[ 0260 ] and also 1 ,2-dehydro analogs of all the mentioned compounds of the androst-4-en-3-one and 20-spirox-4-en-3-one series.

[ 0261] The chemical names of the compounds of Formulas I and IA, and of analog compounds having the same characteristic structural features, are derived according to current nomenclature in the following manner: for compounds in which Y¹ together with Y² represents - O-, from 20-spiroxane (for example a compound of the Formula IA in which X represents oxo and Y¹ together with Y² represents -O- is derived from 20-spiroxan-21-one); for those in which each of Y¹ and Y² represents hydroxy and X represents oxo, from 17β-hydroxy-17α-pregnene-21- carboxylic acid; and for those in which each of Y¹ and Y² represents hydroxy and X represents two hydrogen atoms, from 17β-hydroxy-17α-(3-hydroxypropyl)-androstane. Since the cyclic and open-chain forms, that is to say lactones and 17β-hydroxy-21 -carboxylic acids and their salts, respectively, are so closely related to each other that the latter may be considered merely as a hydrated form of the former, there is to be understood hereinbefore and hereinafter, unless specifically stated otherwise, both in end products of the formula I and in starting materials and intermediates of analogous structure, in each case all the mentioned forms together.

[0262 ] Exem plary substrates for this reaction include Δ-9, 11 -canrenone, and

[ 0263 ] Generally, the epoxidation process of the invention is conducted in accordance with the procedure describe in US 4,559,332, as more particularly described in US 5,981 ,744, col. 40, line 38 to col. 45, line 15 and in Examples 26-28 and 42-51. See also US 6,610,844. The 4,559,332, 5,981 ,744 and 6,610,844 patent documents are expressly incorporated herein by reference.

[ 0264 ] In the epoxidation process as described in these references, a solution of Δ⁹'¹¹ substrate in a suitable solvent is contacted with an aqueous hydrogen peroxide composition in the presence of an activator such as, for example, trichloracetonitriie or, preferably, trichloroacetamide. With the goal of assuring complete conversion of the substrate to the 9,11- epoxide, the epoxidation reaction as described in the above-cited references is typically conducted at a molar charge ratio of 10 moles hydrogen peroxide per mole steroid substrate.

[ 0265 ] It has now been discovered that the epoxidation reaction can be conducted at a significantly lower ratio of hydrogen peroxide to Δ⁹'¹¹ substrate than is taught or exemplified in US 4,559,332, 5,981 ,744 or US 6,610,844. Operation at a relatively low peroxide to substrate ratio provides the option of achieving any of several potential advantages, as discussed hereinbelow.

[ 0266 ] In carrying out the reaction, preferably the solution of substrate, together with the activator and a buffer are first charged to a reaction vessel comprising an epoxidation reaction zone, and an aqueous solution of hydrogen peroxide added thereto. Preferably, a solvent for the steroid substrate is selected in which the solubility of the steroid substrate and epoxidized steroid product is reasonably high, preferably at least about 10 wt.%, more preferably at least about 20 wt.%, but in which the solubility of water is low, preferably less than about 1 wt.%, more preferably less than about 0.5 wt.%. In such embodiments, an epoxidation reaction zone comprising a two phase liquid reaction medium is established within the reaction vessel, with the substrate in the organic phase and hydrogen peroxide in the aqueous phase. Epoxidation of the substrate in the two phase medium produces a reaction mass containing the epoxidized steroid reaction product substantially within the solvent phase. Without being held to a particular theory, it is believed that the reaction occurs in the organic phase or at the interface between the phases, and that more than a very minor water content in the organic phase effectively retards the reaction.

[ 0267 ] After the solution of steroid is introduced into the reactor, the entire peroxide solution may -be added over-a-short period-of time-before-reaction is eommenced-,-e.g.,-within 2 to 30 minutes, more typically 5 to 20 minutes. Where the strength of the peroxide solution as supplied to the reactor is greater than the concentration to be established at the outset of the reaction, water may be charged and mixed with the organic phase prior to addition of peroxide, water being added in a volume which thereafter dilutes the peroxide concentration to the level desired at the outset of the reaction. In those embodiments wherein hydrogen peroxide is introduced at the beginning of the reaction cycle, the solvent phase and added aqueous peroxide solution are preferably maintained at a relatively low temperature, more preferably, lower than about 25^gC, typically lower than about 20³C, more typically in the range of about -5^s to about 15^SC, as the peroxide is introduced.

[ 0268 ] Reaction then proceeds under agitation. Preferably the reaction is conducted under an inert atmosphere, preferably by means of a nitrogen purge of the reactor head space.

[ 0269 ] Generically, the peroxide activator may correspond to the formula:

R⁰C(O)NH₂

[ 0270] where R⁰ is a group having an electron withdrawing strength (as measured by sigma constant) at least as high as that of the monochloromethyl group. Preferably, the promoter comprises trichloroacetonitrile, trichloracetamide, or a related compound corresponding to the formula:

X O

2 I D ' '

X — C — R - C — N H x³

[ 0271] where X¹, X², and X³ are independently selected from among halo, hydrogen, alkyl, haloalkyl and cyano and cyanoalkyl, and R^p is selected from among arylene and -(CX⁴XV, where n is 0 or 1 , at least one of X¹, X², X³, X⁴ and X⁵ being halo or perhaloalkyl. Where any of X¹, X², X³, X⁴ or X⁵ is not halo, it is preferably haloalkyl, most preferably perhaloalkyl. Particularly preferred activators include those in which n is 0 and at least two of X¹, X² and X³ are halo; or in which all of X¹, X², X³, X⁴ and X⁵ are halo or perhaloalkyl. Each of X¹, X² X³, X⁴ and X⁵ is preferably Cl or F, most preferably Cl, though mixed halides may also be suitable, as may perchloralkyl or perbromoalkyl and combinations thereof.

[ 0272 ] Other suitable promoters include hexafluoroacetone dicyclohexylcarbodiimide.

[ 0273 ] The buffer stabilizes the pH of the reaction mass. Without being bound to a particular theory, the buffer is further believed to function as a proton transfer agent for combining the peroxide anion and promoter in a form which reacts with the Δ⁹'¹¹ substrate to ^■ form the 9,11 -epoxide. It is generally desirable that the reaction be conducted at a pH in the range of about 5 to about 8, preferably about 6 to about 7. Suitable compounds which may function both as a buffer and as a proton transfer agent include dialkali metal phosphates, and alkali metal salts of dibasic organic acids, such as Na citrate or K tartrate.

[ 0274 ] Especially favorable results are obtained with a buffer comprising dipotassium hydrogen phosphate, and/or with a buffer comprising a combination of dipotassium hydrogenphosphate and potassium dihydrogen phosphate in relative proportions of between about 1 :4 and about 2:1 , most preferably in the range of about 2:3. Borate buffers can also be used, but generally give slower conversions than dipotassium phosphate or KH₂PO₄ or K₂HPO₄ZKH₂PO₄ mixtures. Whatever the makeup of the buffer, it should provide a pH in the range indicated above. Aside from the overall composition of the buffer or the precise pH it may impart, it has been observed that the reaction proceeds much more effectively if at least a portion of the buffer is comprised of dibasic hydrogenphosphate ion. It is believed that this ion may participate essentially as a homogeneous catalyst in the formation of an adduct or complex comprising the promoter and hydroperoxide ion, the generation of which may in turn be essential to the overall epoxidation reaction mechanism. Thus, the quantitative requirement for dibasic hydrogenphosphate (preferably from K₂HPO₄) may be only a small catalytic concentration. Generally, it is preferred that a dibasic hydrogenphosphate be present in a proportion of at least about 0.1 equivalents, e.g., between about 0.1 and about 0.3 equivalents, per equivalent substrate.

[ 02751 After addition of the peroxide solution is substantially complete, the temperature may be raised, e.g., into the range of 15^s to 50^QC, more typically 20^Q to 40^sC to enhance the rate of the reaction and the conversion of substrate to epoxide. Optionally, the peroxide solution can be added progressively over the course of the reaction, in which case the temperature of the reaction mass is preferably maintained in a range of about 15° to about 50°C, more preferably between about 20° and about 40⁰C as the reaction progresses. In either case, the reaction rate in the two phase reaction medium is ordinarily mass transfer limited, requiring modest to vigorous agitation to maintain a satisfactory reaction rate. In a batch reactor, completion of the reaction may require from 3 to 24 hours, depending on the temperature and intensity of agitation.

[ 0276] The decomposition of hydrogen peroxide is an exothermic reaction. At ordinary reaction temperatures the rate of decomposition is small to negligible, and the heat generated is readily removed by cooling the reaction mass under temperature control. However, if the reaction cooling system or temperature control system fails, e.g., by loss of agitation, the rate of decomposition can be accelerated by the resulting increase in temperature of the reaction mass, which can in turn accelerate the rate of autogenous reaction heating. Where the initial molar ratio of peroxide to steroid substrate is in the range described in US 4,559,332, US

from loss of cooling can reach a temperature at which the decomposition becomes autocatalytic, and thus very rapid and uncontrolled, resulting in potential eruption of the reaction mass. If the temperature is high enough, destructive oxidation of the steroid substrate may generate additional reaction heat, further accelerating the rate of temperature increase and the severity of the resulting eruption. Events other than loss of agitation can also potentially destabilize the peroxide and result in an exotherm that leads to uncontrolled decomposition. For example, contaminants such as rust or other source of transition metals in the peroxide or substrate solutions may catalyze a rapid or uncontrolled release of oxygen from the aqueous phase.

[ 0277 ] It has now been discovered that the epoxidation reaction can be conducted at a significantly lower ratio of peroxide to Δ⁹'¹¹ substrate than is taught or exemplified in US 4,559,332, 5,981 ,744 or US 6,610,844, thereby reducing the risk of uncontrolled decomposition of the peroxide. More particularly, it has been discovered that the reaction can be conducted at a charge ratio between about 2 and about 7 moles, preferably between about 2 and about 6 moles, more preferably between about 3 and about 5 moles hydrogen peroxide per mole Δ⁹'¹¹ substrate. Operation at such relatively low ratios of peroxide to substrate reduces the extent to which the reaction mass may be heated by autogenous decomposition of the peroxide. Preferably, the peroxide to substrate ratio is low enough so that the maximum temperature attainable by autogenous heating is lower than the threshold temperature for autocatalytic decomposition, which may entirely preclude decomposition of the peroxide from reaching the stage at which an eruption of the reaction mass could result. Operation at the above described charge ratios makes this feasible.

[ 0278 ] Further protection against uncontrolled reaction is provided where the epoxidation reaction is conducted at a relatively modest temperature below the temperature of incipient decomposition of the peroxide, or where the rate of decomposition is relatively slow. Thus, in the event of a process upset which results in accumulation of unreacted hydrogen peroxide, little autogenous heating can occur, at least initially, so that, even after loss of agitation, reactor cooling capacity remains sufficient under natural circulation to maintain the temperature of the reaction mass in a safe range, or at least process operators are afforded ample time to take corrective measures before conditions for an uncontrolled autocatalytic decomposition are approached. For this purpose, it is preferred that the epoxidation reaction be carried out at a temperature in the range of about 0^e to 50^QC, more preferably in the range of about 20^s to about 40^sC.

[ 0279 ] Still further protection against uncontrolled reaction is afforded by conducting the epoxidation reaction in a liquid reaction medium comprising a solvent having a boiling point at the reaction pressure that is well below the autocatalytic decomposition temperature of the peroxide, and preferably only modestly higher than the reaction temperature. Preferably, the boiling point of the organic phase of the reaction mixture is no greater than about 60°C, preferably not greater than about 50⁰C. Preferably, the selected solvent does not boil from the reaction mass at the reaction temperature, but is rapidly vaporized if the temperature increases -by-a-modest-incrementf rom-about 10 centigrade degrees-to-about-50-centigrade-degrees,- - whereby the heat of vaporization serves as a heat sink precluding substantial heating of the reaction mass until the solvent shall have been substantially driven out of the reaction zone. Where the reaction is conducted under atmospheric pressure at a temperature in the aforesaid ranges, a variety of solvents are available which meet these criteria, and are also suitable for the epoxidation reaction. These include methylene chloride (atmos. b.p. = 39.75³C), dichloroethane (atmospheric b.p. = 83°C, and methyl t-butyl ether (b.p. = 55°C).

[ 0280] The water content of the reaction mass also serves as a substantial sensible heat sink. Where the reaction is conducted at, near or below atmospheric pressure, the water content of the aqueous hydrogen peroxide solution serves as a potentially much larger heat sink, though it is generally preferred to avoid conditions under which substantial steam generation occurs since this may also result in eruption of the reaction mass, albeit much less violent than that which results from autocatalytic decomposition of a peroxide compound.

[ 0281] Thus, in one aspect, the present invention comprises conducting the epoxidation reaction in a liquid reaction medium, preferably comprising a solvent for the steroid, which contains the steroid substrate and peroxide in such absolute and relative proportions, and at a relatively modest initial epoxidation reaction temperature, such that the decomposition of the peroxide content of the reaction mass in stoichiometric excess vs. the substrate charge does not, and preferably cannot, produce an exotherm effective to initiate autocatalytic decomposition of peroxide compound, or at least not to cause an uncontrolled autocatalytic decomposition thereof. To protect against an uncontrolled decomposition at any time during the epoxidation cycle, it is further preferred that the aforesaid combination of conditions be such that decomposition of the entire peroxide content of the reaction mass, at any time during the course of the reaction, cannot produce an exotherm effective to initiate autocatalytic decomposition of peroxide compound, or at least not to cause an uncontrolled autocatalytic decomposition thereof. Optimally, the combination of substrate concentration, peroxide compound concentration and initial temperature are such that decomposition of the stoichiometeric excess, or of the entire peroxide compound charge, cannot produce an exotherm sufficient to initiate autocatalytic decomposition, or at least not to cause an uncontrolled autocatalytic decomposition, even under adiabatic conditions, i.e., upon loss of cooling in a well-insulated reactor.

[ 0282 ] The peroxide content of the aqueous phase, as established at the outset of the epoxidation reaction, is preferably between about 25% and about 50% by weight, more preferably between about 25% and about 35% by weight, and the initial concentration of Δ⁹'¹¹ steroid substrate in the organic phase is between about 3% and about 25% by weight, more preferably between about 7% and about 15% by weight. Preferably, components effective to promote the epoxidation reaction such as, for example, trichloroacetonitrile or trichloroacetamide, together with a phosphate salt such as a dialkali metal hydrogen phosphate, are charged to the reactor with the steroid solution, prior to addition of the aqueous peroxide. The molar ratio of peroxide to phosphate is preferably maintained in the range between about 10:1 and about 100:1 , more preferably between about 20:1 and about 40:1. The initial trichloroacetamide or — -triehloroaeetonitrile concentration is preferably maintained at between about 2-and about 5 wt.%, more preferably between about 3 and about 4 wt.%, in the organic phase; or in a molar ratio to the steroid substrate between about 1.1 and about 2.5, more preferably between about 1.2 and about 1.6. The volumetric ratio of the aqueous phase to the organic phase ultimately introduced into the reactor is preferably between about 10:1 and about 0.5:1 , more preferably between about 7:1 and about 4:1. As mentioned above, and again without being held to a particular theory, it is believed that the epoxidation reaction occurs in the organic phase or at the interface between the phases. In any event, the reaction mass is preferably agitated vigorously to promote transfer of peroxide to the organic phase, or at least to the interface. A high rate of mass transfer is desired both to promote the progress of the reaction, thereby shortening batch reaction cycles and enhancing productivity, and to minimize the inventory of peroxide in the reaction vessel at any given rate of addition of aqueous peroxide solution to the reaction mass. Thus, in various preferred embodiments of the invention, the agitation intensity is preferably at least about 10 hp/1000 gal. (about 2 watts/liter), typically from about 15 to about 25 hp/1000 gal. (about 3 to about 5 watts/liter). The epoxidation reactor is also provided with cooling coils, a cooling jacket, or an external heat exchanger through which the reaction mass is circulated for removal of the heat of the epoxidation reaction, plus any further increment of heat resulting from decomposition of the peroxide.

[ 0283 ] After completion of the epoxidation reaction, unreacted hydrogen peroxide in the aqueous phase is preferably decomposed under controlled conditions under which release of molecular oxygen is minimized or entirely avoided. A reducing agent such as an alkali metal sulfite or alkali metal thiosulfate is effective for promoting the decomposition. Preferably, the aqueous phase of the final reaction mass, which comprises unreacted peroxide, is separated from the organic phase, which comprises a solution of 9,11-epoxidized steroid product in the reaction solvent. The aqueous phase may then be "quenched" by contact of the peroxide contained therein with the reducing agent.

[ 0284 ] Where the molar charge ratio of peroxide to steroid substrate is in the range of, for example, 3 to 5, and the initial concentration of a peroxide in the aqueous phase is in the range of about 7 to about 9 molar (i.e., 25% to 30% by weight in the case of hydrogen peroxide), the spent aqueous peroxide solution at the end of the reaction is about 4-6 molar in peroxide (between about 15 and about 21% by weight for hydrogen peroxide). Prior to phase separation, the aqueous phase may be diluted with water to reduce the peroxide concentration and thereby the likelihood and extent of any exotherm resulting from decomposition during the phase separation and/or transfer of the aqueous phase, such as transfer to another vessel for quenching with a reducing agent. For example, sufficient water may be added to reduce the concentration of hydrogen peroxide in the spent aqueous phase to between about .2% and about 10% by weight, more preferably between about 2% and about 5% by weight.

[ 0285] Quenching may be effected by adding the spent aqueous peroxide solution, or a dilution thereof, to a vessel containing an aqueous solution of the reducing agent, or vice- versa. According to one alternative, the organic phase may be transferred to a separate vessel -upon-separation from the-aqueous-phaseVand the-aqueous phase-allowed-to-remain in the reaction vessel. The solution of the reducing agent may then be added to the diluted or undiluted aqueous phase in the reaction vessel to effect reduction of the residual peroxide. Alternatively, the diluted or undiluted peroxide solution may be added over time to a vessel to which an appropriate volume of reducing agent solution has initially been charged. Where the reducing agent is an alkali metal sulfite, the sulfite ion reacts with the peroxide to form sulfate ion and water.

[ 0286 ] The decomposition reaction is highly exothermic. Decomposition is preferably conducted at a temperature controlled in the range of between about 20°C and about 5O⁰C by transfer of heat from the aqueous mass in which the decomposition proceeds. For this purpose, the quenching reactor may be provided with cooling coils, a cooling jacket, or an external heat exchanger through which the quench reaction mass may be circulated, for transfer of decomposition reaction heat to a cooling fluid. The quenching mass is preferably subjected to moderate agitation to maintain uniform distribution of reducing agent, uniform temperature distribution, and rapid heat transfer.

[ 0287 ] Where the reducing agent is added to the spent peroxide solution, addition is preferably carried out at a rate controlled to maintain the temperature of the quench reaction mass in the aforesaid range, thereby to effect controlled decomposition of the peroxide.

[ 0288 ] The alternative process, i.e., the process wherein the peroxide solution is added to the reducing agent solution, avoids the presence of a large inventory of peroxide that might otherwise be subject to autocatalytic decomposition as triggered by the addition of a decomposition agent thereto. However, this alternative requires transfer of the spent peroxide solution while the reverse alternative allows the peroxide solution to be retained in the epoxidation reactor while only the organic phase of the reaction mass and the reducing agent solution need to be transferred. Regardless of which alternative is followed, the quench reaction is preferably conducted in the temperature range specified above.

[ 0289 ] For purposes of the quenching reaction, the aqueous quench solution charged to the quenching reaction zone preferably contains between about 12 wt% and about 24 wt.%, more preferably between about 15 wt% and about 20 wt.%, of a reducing agent such as Na sulfite, Na bisulfite, K sulfite, K bisulfite, etc. The volume of quench solution is preferably sufficient so that the reducing agent contained therein is in stoichiometric excess with respect to the peroxide content of the aqueous phase to be quenched. The volumetric ratio of quench solution that is mixed with the peroxide solution may typically vary from about 1.2 to about 2.8, more typically from about 1.4 to about 1.9 after preliminary water dilution of the spent aqueous peroxide solution.

[ 0290 ] Typically, residual organic solvent may have remained in the reactor after the initial phase separation, and have become entrained in the aqueous phase during the quenching reaction. Also, the quenched aqueous phase may contain a salt of trichloroacetic — acidrformed as-a-by-produet-of-the-epoxidation-reaetion-when-triehloroaeetamide-is-used as a promoter. Before disposal of the quenched aqueous phase, entrained reaction solvent is preferably removed therefrom, e.g., by solvent stripping. If a solvent such as methylene chloride is entrained in the quench reaction mixture, and the aqueous phase thereof contains ^• trichloroacetate, the aqueous phase is preferably heated prior to solvent stripping in order to decarboxylate the trichloroacetate. Decarboxylation of the trichloroacetate may be achieved by heating to a temperature of, e.g., 70°C or higher. If trichloroacetate is not removed, it can decompose during solvent stripping to produce chloroform and carbon dioxide.

[ 0291] After separation from the aqueous phase of the reaction mass, the organic phase is preferably washed with water to remove unreacted peroxide and any inorganic contaminants. For elimination of residual peroxide it may be useful for the wash water to contain a reducing agent. For example, the organic phase may be contacted with an aqueous wash solution having a pH in the range of 4 to 10 and containing typically 0.1 to 5 mole % reducing agent, preferably about 0.2 to about 0.6 mole % reducing agent (such as, e.g., 6 to 18% aqueous solution of Na sulfite), in a convenient volumetric ratio of wash solution to organic phase between about 0.05:1 to about 0.3:1. After separation of the spent reducing agent wash from the organic phase, the organic phase is preferably washed sequentially with a dilute caustic solution (e.g., 0.2% to 6% by weight NaOH in a volumetric ratio to the organic phase between about 0.1 to about 0.3) followed by either a water wash or a dilute acid solution (for example, a 0.5 to 2 wt.% HCI solution in a volumetric ratio to the organic phase between about 0.1 and about 0.4). A final wash with further Na bisulfite or Na metabisulfite or Na sulfite solution may also be conducted.

[ 0292 ] Where the R¹¹ substituent of the product epoxide is other than hydrogen, it is generally desirable to avoid a highly acidic wash, such as an HCI wash which can expose the product to an aqueous phase having a pH of 1 or less. Where there is an alkyl substituent at the C-11 carbon, the epoxy group may destabilize under highly acidic conditions.

[ 0293 ] If a solvent such as methylene chloride is entrained in the dilute caustic wash, the aqueous phase thereof contains trichlorosodiumacetate produced from basic hydrolysis of residual trichloroacetamide, and the aqueous phase is preferably heated prior to solvent stripping in order to decarboxylate the trichlorosodiumacetate. Decarboxylation of the trichlorosodiumacetate may be achieved by heating to a temperature of, e.g., 70^sC or higher. The caustic wash may be combined with the quenched aqueous phase of the reaction mixture for purposes of decarboxylation and residual solvent stripping.

[ 0294 ] The washed organic phase is concentrated by evaporation of solvent, for example, by atmospheric distillation, resulting in precipitation of steroid to form a relatively thick slurry with about 40% to about 75% by weight contained steroid. Where mother liquor from a recrystallization step is recycled, as described below, the mother liquor may be mixed with the steroid slurry, and the solvent component of the mother liquor removed by vacuum to again produce a thick slurry having a solids concentration typically in the same range as the slurry obtained by removing the reaction solvent. A solvent in which the solubility of the steroid product — is-relatively-low, e.-gr_ra-polar~solvent-such-as-ethanol_ris-added-to-the-slurry obtained from removal of reaction solvent, or to the second slurry as obtained by removal of the recrystallization mother liquor solvent. Alternative solvents include toluene, acetone, acetonitrile and acetonitrile/water. In this step, the impurities are digested into the solvent phase, thus refining the solid phase steroid product to increase its assay. Where the digestion solvent is an alcohol such as ethanol, it may be added in a volumetric ratio of ethanol to contained steroid between 6 and about 20. A portion of the ethanol and residual organic solvent are removed from the resulting mixture by distillation, yielding a slurry typically containing between about 10 wt.% and about 20 wt.% steroid product, wherein impurities and by-products are substantially retained in the solvent phase. Where the solvent is ethanol, the distillation is preferably conducted at atmospheric pressure or slightly above.

[ 0295 ] After distillation of the digestion solvent, the steroid product solids are separated from the residual slurry, e.g., by filtration. The solid product is preferably washed with the digestion solvent, and may be dried to yield a solid product substantially comprising the 9,11- epoxy steroid. Drying may advantageously be conducted with pressure or vacuum using an inert carrier gas at a temperature in the range of about 35 to about 90^°C.

[ 0296] Either the dried solids, wet filtered solids or the residual slurry obtained after evaporation of the digestion solvent may be taken up in a solvent in which the epoxy steroid product is moderately soluble, e.g., 2-butanone (methyl ethyl ketone), methanol, isopropanol- water or acetone-water. The resulting solution may typically contain between about 3% and about 20% by weight, more typically between about 5% and about 10% by weight, steroid. The resulting solution may be filtered, if desired, and then evaporated to remove the polar solvent and recrystallize the 9,11 -epoxy steroid. Where the solvent is 2-butanone, evaporation is conveniently conducted at atmospheric pressure, but other pressure conditions may be used. The resulting slurry is cooled slowly to crystallize additional steroid. For example; the slurry may be cooled from the distillation temperature (about 80°C in the case of 2-butanone at atmospheric pressure) to a temperature at which yield of steroid product is deemed satisfactory. Production of a highly pure 9,11 -epoxy steroid product of a suitable crystal size may be obtained by cooling in stages and holding the temperature for a period between cooling stages. An exemplary cooling schedule comprises cooling in a first stage to a temperature in the range of 60° to 70°C, cooling in a second stage to a temperature in the range of about 45° to about 55°C, cooling in a third stage to a temperature between about 30° and about 40°C, and cooling in a final stage to a temperature between about 10° and about 20°C, with substantially constant temperature hold periods of 30 to 120 minutes between cooling stages. [ 0297 ] The recrystallized product may then be recovered by filtration and dried. Drying may be conducted effectively at near ambient temperature. The dried product may remain solvated with the polar solvent used early in the product recovery protocol, typically ethanol. Drying and desolvation may be completed at elevated temperature under pressure or vacuum, e.g., at 75° to 95°C. [-0-2-98-] — Mother-liquor-from-the-recrystallization-step-may-be-reeyeled for use in refining the steroid product slurry obtained from evaporative removal of the epoxidation reaction solvent, as described hereinabove.

[ 0299 ] At a charge ratio of 7 moles peroxide per mole substrate in the oxidation of the Δ⁹'¹¹ precursor to eplerenone, decomposition of the peroxide releases only about 280 liters molecular oxygen per kg eplerenone. At a charge ratio of 4 moles peroxide per mole substrate, the oxygen release is only about 160 liters/kg eplerenone. This contrasts with a release of 400 liters/kg eplerenone at a charge ratio of 10 moles peroxide per mole substrate. By way of further example, at a charge ratio of 4 moles peroxide per mole substrate, a substrate concentration of 12% in a methylene chloride solvent, a peroxide concentration in the aqueous phase of 30%, an initial reaction temperature of 30^sC, substantially at atmospheric pressure under an inert gas purge, and a reactor head space volume fraction of 15%, the maximum internal pressure that can be generated in the epoxidation reactor upon exothermic decomposition of the entire peroxide charge is about 682 psig (4706 kPa). Moreover, even in this instance, the initial exotherm is modest enough that a reasonably skilled operator should have ample time to safely deal with loss of agitation or other process upset that could otherwise potentially lead to uncontrolled reaction.

[ 0300 ] At the relatively low peroxide to substrate ratios described herein, either significantly lesser potential evolution of oxygen can be assured at the same reactor payload that can be achieved at peroxide/substrate ratios of 10 or more; or higher reactor payloads may be achieved at the same volume of oxygen release. At constant working volume in an epoxidation reactor, both an increase in payload and a reduction in oxygen release can be achieved.

[0301] It should be understood that the epoxidation method as described above has application beyond the various schemes for the preparation of epoxymexrenone, and in fact may be used for the formation of epoxides across 9,11-olefinic double bonds in a wide variety of substrates subject to reaction in the liquid phase. Exemplary substrates for this reaction include Δ-9, 11 -canrenone, and

[ 0302 ] Because the reaction proceeds more rapidly and completely with . trisubstituted and tetrasubstituted double bonds, it is especially effective for selective epoxidation across such double bonds in compounds that may include other double bonds where the olefinic carbons are monosubstituted, or even disubstituted.

[ 0303 ] Because it preferentially epoxidizes the more highly substituted double bonds, e.g., the 9,11 -olefin, with high selectivity, the process of this invention is especially effective for achieving high yields and productivity in the epoxidation steps of the various reaction schemes described elsewhere herein.

[0304 ] The improved process has been shown to have particularly advantageous application to the preparation of:

by epoxidation of:

[0305 ] The following examples illustrate the invention.

Example 1 [ 0306] A potassium methoxide reagent solution was prepared by dissolving potassium methoxide in methanol at a KOMe concentration of 32 wt.%. Methyl formate was added to the reagent solution in a proportion of 10 wt.% (e.g., neat methyl formate (8g) was added to a 32 wt.% solution (80 g) of KOMe in MeOH). The reagent solution containing methyl formate was held at room tempreature for three days.

- ~[ 0-30-7 ] An-RG1-reaGtor (HP60-Hastelloy-C,- Mettler-Toledo.-nomiRally -1400 ml) was charged with methanol (1105 g; <0.005 wt.%) and a diketone compound corresponding to Formula VI-1 (80.0 g):

Formula Vl-I

[ 0308 ] The reactor was then closed and flushed with nitrogen (about 1 atm.). The . resulting slurry was heated to 62°C, after which a first charge of the methyl formate-containing potassium methoxide reagent solution (44.4 g; 1 eq. KOMe) was introduced into the reactor. The reaction medium was agitated under a nitrogen atmosphere and the KOMe reacted with the compound of Formula VI-1 to produce the compound of Formula V-1:

Formula Vl-I

[ 0309 ] After reaction had proceeded for 1.5 hours, an additional charge of the methyl formate-containing KOMe solution (26.7 g; 0.6 eq. KOMe) was introduced into the reaction medium. Agitation of the reaction mixture at 62°C was continued for a period of approximately 10 hours.

[ 0310] Thereafter, the reaction solution was cooled to O⁰C, held for at least one hour, then filtered under vacuum through a coarse-fritted glass filter. The filter cake was washed twice with methanol (100 g each wash).

[ 0311] Additional runs were conducted in the manner described above, except that the temperature of the reaction was maintained at 80⁰C for one run, 100°C for another run, and 115°C for still another. At elevated temperature, it was feasible to add all the KOMe/MeOH reagent in one charge, which was effected at a rate of 48 g/min using a diaphragm pump. The reaction time was sharply reduced as the reaction temperature increased. Reaction at 100⁰C was continued for only about 0.5 hours. Cooling from 100⁰C to 6O⁰C required about four minutes.

Example 2

[ 0312 ] Additional reaction runs were carried out in the manner described in Example 1 but on a smaller scale. In each run of this series of reactions, methanol (175 ml) and Formula VI-1 compound (9.60 g) were charged to a jacketed, 175 ml. (6 oz.) Fischer-Porter bottle with a Parr reactor head. Reaction times were substantially the same as in Example 1 , but the 100⁰C reaction mixture was cooled to 6O⁰C in only 3 minutes. In certain of the runs biphenyl sulfone was added as an internal standard and samples taken during the course of the reaction. The samples were diluted approximately 21 -fold with an HPLC mobile phase before analysis using the short HPLC method. At this scale, KOMe/MeOH reagent solution was added using a 10 ml syringe. The relative progress of the reaction at the various reaction temperatures is shown in the profiles set forth in Fig. 2. After crystallization of Formula V- 1 hydroxyester from the reaction mixture and filtration of the crystallization mass, the mother liquor was returned to the reactor as a rinse for the residual reactor contents. The resulting rinse solution was filtered again for further recovery of hydroxyester.

^; [ 0313 ] Set forth in Table 1 are the yields of solid hydroxyester product from crystallization of reaction masses produced at reaction temperatures of 62° and 100⁰C.

Table 1 : Yield Improvement at Elevated Temperature

Experiment Run 2-A Run 2-B Run 2-C Run 2-D

Temperature(°C) 62 62 100 100 Reaction time (h) 10 10 0.5 0.5

Scale (m L) 175 1400 117755 1400

Solid purity (wt%) 95 95 96 97 Solid yield (mol%) 63 65 74 78 Mother liq. (mol%) 10 11 13 10 Cake wash (mol%) 3 2 2 1 Cleaning (mol%) NM^a 1 NM 1

Total yield (mol%) 76 78 89 92 ^aNot measured.

[ 0314 ] It will be seen that 100⁰C reaction affords an 11 percentage point increase in ultimate crystallization yield vs. 62⁰C reaction at the 175 ml scale, and a thirteen percentage point increase at the 1400 ml scale. On a hydroxyester product basis, the improvement in yield is 17% at 175 ml scale and 20% at the 1400 ml scale. When the hydroxyester content of the mother liquor is taken into consideration, yields at 100⁰C increased to the range of 90%.

Example 3

[ 0315 ] Additional reactions runs were conducted in the manner described in Examples 1 and 2 except that the cooling rate was deliberately reduced to determine the effect of cooling rate on ultimate yield. The results are set forth in Table 2.

Table 2: Impact of Cooling Rate and Reaction Time on Yield (175-mL Scale)

Experiment Run 3-A Run 3-B Run 3-C Run 3-D

Time at 100°C (min) 30 30 30 120

Time to 60⁰C (min) 3 20 60 3 Solid Purity (wt%) 95 95 94 92

Solid yield (mol%) 74 72 66 58

Mother liq. (mol%) 12 12 12 20

Cake wash (mol%) 3 3 3 3

Cleaning (mol%) 1 0 1 1

Total yield (mol%) 90 87 81 83

[ 0316 ] It will be noted that the experiment in which the reaction mixture was held for 2 hours at 100⁰C showed a significant decrease in total and isolated reaction yield. Samples of the reaction mixture during the hold period showed an increase in the number or concentration of impurities, but not a large decrease in the product hydroxyester concentration. It is believed that these data reflect an increase in the concentration of the open lactone (at C(17)), which is more soluble than the hydroxyester of Formula V, but which analyzes as Formula V-1 hydroxyester due to the acidic sample preparation method that was used.

Example 4

[ 0317 ] A further reaction and crystallization run was conducted in the manner described in Run C of Example 2 (175 ml scale) except that the loading of Formula VI-1 substrate (2 x 6.8%) was twice that used in Example 2. The KOMe concentration was also doubled. The reaction time was extended to one hour because the Formula VI-1 diketone concentration did not appear to be dropping rapidly enough for the reaction to be completed in a shorter time. However, the additional reaction time did not materially improve the yield in this case. Isolated yield of Formula V-1 hydroxyester was 65%.

Example 5

[ 0318 ] A further reaction and crystallization run was conducted at increased Formula VI-1 substrate loading in the manner described in Example 5 but at the 1400 ml rather than the 175 ml scale and at a temperature of 115°C. This run was conducted using an "untreated" KOMe/MeOH solution, i.e., neither methyl formate nor other saponification target compound was added to the reagent solution or to the reaction medium. Isolated crystallization yield was 68%.

Example 6

[ 0319 ] Further reactions of Formula Vl-1 diketone with potassium methoxide were conducted in the manner generally described in Example 1. One of these (Run J) was carried out at a reaction temperature of 62°C, while the other two (Runs K and L) were at 100°C. Run J was conducted without methyl formate treatment of either the KOMe/MeOH reagent or the reaction medium. In the other runs, the KOMe/MeOH reagent was treated with methyl formate at a 10 wt.% level in the manner generally described in Example 1. Different steroid lots were used in the various runs. The results are set forth in Table 3:

Table 3: Impact of KOMe Treatment (Fresh KOMe, Two Steroid Lots. 1400 mL Scale. Fast

Cooling

Experiment Run 1-B Run 6-A Run 1-D Run 6-B Run 6-C

KOMe treatment yes no yes yes no

Temperature(°C) 62 62 100 100 100

Steroid lot 'A1A O01 Α1A "001 O01

Solid purity(wt%) 95 95 97 98 96

Solid yield(mol%) 65 63 78 78 72

Mother liq.(mol%) 11 11 10 10 12

Cake wash(mol%; I 2 2 1 1 2

Cleaning(mol%) 1 0 1 3

Total yield(mol%) 78 76 92 93 87

Example 7

[ 0320 ] Conversions of Formula VI-1 diketone to Formula V-1 hydroxyester and crystallizations of Formula V-1 product were conducted in the manner generally described in the foregoing examples. Mother liquor samples from the crystallizations were held at controlled temperatures for defined periods of time and then analyzed for concentration of Formula V-1 product. No attempt was made to remove cyanide ion from the mother liquor. In all but one of the experiments, a mother liquor sample was held at a specific temperature for a specified period of time and then analyzed for Formula V-1 hydroxyester product. The results are set forth in Table 4. The hold time for each entry was 30 minutes, except for the last entry at 60⁰C where the hold time was six hours.

Table 4

Experiment Temperature. ⁰C Formula V-1 as percent of usable steroid

ML-1 20 49.5

ML-2 40 46.6

ML-3 60 49.6

ML-4 40 52.9

ML-5 20 57.6

ML-6 0 48.3

ML-7 60 63.8

[0321] Two observations can be drawn from these data. First, the rate of approach to equilibrium was slow so that a 30 minute hold time was not sufficient to achieve equilibrium. Second, where the mother liquor specimen was held at 6O⁰C for six hours, there was a material increase (14%) in Formula V-1 product concentration.

[ 0322 ] However, when an attempt was made to cool the equilibrated mother liquor of run ML-7, no crystallization was observed. In spite of the 14% increase in Formula V-1 product assay, the concentration was not great enough to initiate supersaturation.

Example 8

[ 0323 ] To evaluate the effect of a methylene dichloride/water extraction scheme on the hydrolytic degradation of Formula V-1 product, a representative mother liquor sample (40 ml) and a quantity of water (40 ml) were each cooled to 1.5⁰C and then brought into contact with each other. The concentration of steroids in the sample was monitored over time. The reduction in useable steroids was only 13.6% over a 21 hour period.

Example 9

[ 0324 ] A specimen of Formula VI-1 diketone (40 g) was added to anhydrous methanol (700 ml; 131 mM) in a reaction vessel. The resulting mixture was heated to 65°C and potassium hydroxide reagent solution (12.2 g, comprising 32 wt.% KOMe in MeOH) was added to the reaction medium when the temperature reached 60°C. This was recorded as time zero. The reaction solution was stirred for 8 hours and samples were withdrawn periodically to measure steroid concentration by HPLC. Profiles of steroid component concentration vs. time are set forth in Fig. 3. After 8 hours, the reactor was cooled to -10⁰C with an overnight hold. The solids were filtered and dried. The yield of hydroxyester of Formula V-1 from the solid was 62.6 mol%.

[ 0325 ] A portion of the crystallization mother liquor (400 ml) was cooled to 1.5⁰C, methylene chloride (150 ml) was added to the mother liquor, and the resulting water-immiscible solution of steroids was cooled to 1.5⁰C. Water (330 ml) pre-cooled to 1.5⁰C was added to the water-immiscible steroid solution, the two-phase mixture was agitated for 5 minutes to promote mass transfer between the phases, and the organic extract (methylene chloride) phase was separated from the aqueous raffinate phase and removed form the reactor bottom valve. Both phases were sampled for steroid content. Analyses are set forth in Table 5.

Table 5 Mother Aqueous Organic %

Sample ID Liquor Phase Phase Balance

Hydroxyacid de-

Alkylated Formula V- 1 0.9 0.8 0.2 114.1

5-CN-7α-COOH 1.4 1.1 0.0 80.1

Formula Vl Diketone 2.4 0.9 0.0 38.9

Formula V- 1 Hydroxy-

Ester 8.6 4.9 3.9 102.3

Cyanoester 2.1 0.0 2.3 1.6.6

Steroid by-Product 0.7 0 0.5 74.9

Cyanide 47.0 45.5 0.1 97.1

Total 16.1 7.7 7.0 91.0

[ 0326] These data show that useable steroids can be almost quantitatively extracted from the mother liquor into a methylene chloride phase in a single extraction stage. From the data, the partition coefficient (K_p) can readily be calculated:

K_p = ([Syv_o)/([S_a]/V_a) where:

[S]₀ = the concentration of steroid values in the organic phase

V₀ = the volume of the organic phase

[S]_a = the concentration of steroid values in the aqueous phase; and

V_a = the volume of the aqueous phase

From the data in Table 5, K_p = 5.2. A similar calculation may be carried out for cyanide ion, yielding a K_p for cyanide ion of 93.5 to the aqueous phase. Overall recovery of useable steroid in the organic extract can be determined to be 47.4%, equating to an 11.2 percentage point increase in molar yield vs. the yield obtained in the crystallization crop from the primary crystallization step, i.e., the crystallization of Formula V-1 hydroxyester from the reaction mixture.

Example 10

[ 0327 ] A series of reaction run was carried out at 100⁰C at the 1400 m I scale, substantially as described in Example 1 , and Formula V-1 product crystallized from the reaction solution, also substantially as described therein. The mother liquor was concentrated by distillation under vacuum to approximately one fifth its original volume. The distillation was conducted at a pot temperature of about 30⁰C so as to minimize dealkylation of the 7a- methoxycarbonyl group of the Formula V-1 product contained in the mother liquor. The concentrated mother liquor was cooled to 1.5°C, mixed with methylene chloride, and the resulting water-immiscible steroid solution was cooled to 1.5°C and mixed with 1.5⁰C water. The resulting two phase mixture was agitated and then separated substantially as described in Example 9. Data from these reaction, crystallization and mother liquor concentrate extraction runs are set forth in Table 6.

[ 0329 ] The percentage recovery in Table 6 is calculated on the assumption of achieving a conversion of 85% to Formula V-1 hydroxyester, Formula VI-1 diketone and/or cyanoester in a repulp solution derived from the organic extract.

[ 0330 ] It may be noted that increasing the volume of water relative to the volume of methanol in the extraction feed solution (mother liquor concentrate) increases the partition coefficient to the organic phase (K_p), but also increases the fraction of steroid losses at a given concentration of steroid in the aqueous raffinate phase. Thus, as indicated in Example 11 , below, there may be a theoretical optimum ratio of water to water-immiscible organic solvent to concentrated mother liquor at which a maximum recovery of steroids is realized. However, as a practical matter, the ratios utilized may be dictated primarily by process vessel volume limitations and considerations of operational stability and control. Preferred ratios of extraction feed solution, water, and water-immiscible solvent are substantially as described hereinabove.

Example 11

[ 0331] Solids recovered from the mother liquor of the reaction batches of Example 10 were pooled (45.9 g total), methanol and potassium methoxide (1.6 eq. With respect to useable steroids) were added, and a re-equilibration reaction conducted in the resulting repulp solution at 65°C for 8 hours substantially as described in Example 1. The steroid concentration in the reaction medium was monitored as a function of time by HPLC analyses. The profiles set forth in Fig. 4 show the progress of the reaction and re-equilibration. Because the concentration of Formula V-1 hydroxyester in the repulp solution was relatively high, it may be seen that re- equilibration was actually achieved in only about 4 hours.

[ 0332 ] After 8 hours of equilibration, the reaction solution was cooled to -1O⁰C and the Formula V-1 hydroxyester formed in the equilibration was crystallized in a secondary crystallization step, separated from the secondary crystallization mother liquor, and assayed. The solid product was found to be in the 93-95 wt.% purity range with respect to the desired hydroxyester.

! ; [ 0333 ] Based on the equations set forth above describing the operation of the mother liquor concentration and extraction steps, recoveries may be calculated as a function of the volume of mother liquor (M), mother liquor concentration factor (f), volume of methylene chloride used in the extraction (d), and volume of water used in the extraction (h). These are tabulated in Table 7 wherein D = d/M and H = h/M:

Table 7

[ 0334 ] Optionally, steroids recovered from the mother liquor can be recycled as used as starting material for a subsequent reaction batch, thereby reducing the amount of fresh diketone required for the reactor charge. However, as described hereinabove, it is preferred that the recovered steroids be subjected to a separate equilibration reaction rather than recycled to . the primary reaction step.

Example 12

Synthesis of Methyl Hydrogen 9,11 α-Epoxy-17α-hydroxy-3-oxopregn-4-ene-7α,21 -dicarboxylate, γ-Lactone

[ 0335 ] Crude Δ⁹'¹¹-eplerenone precursor (1628 g, assaying 78.7% enester) was added to a reaction vessel with methylene chloride (6890 ml_) and stirred. After dissolving solids, trichloroacetamide (1039 g) and dipotassium phosphate (111.5 g) were added to the mixture. The temperature was adjusted to 25^SC and the mixture was stirred at 320 RPM for 90 minutes. 30% hydrogen peroxide (1452 g) was added over a ten minute period.

[ 0336 ] The reaction mixture was allowed to come to 20^eC and stirred at that temperature for 6 hrs., at which point conversion was checked by HPLC. Remaining enester was determined to be less than 1% by weight. -[-0-337 ] The reaction mixture was added to water (100 mL),-the phases were allowed to separate, and the methylene chloride layer was removed. Sodium hydroxide (0.5 N; 50 mL) was added to the methylene chloride layer. After 20 min. the phases were allowed to separate and HCI (0.5 N; 50 mL) was added to the methylene chloride layer after which the phases were allowed to separate and the organic phase was washed with saturated brine (50 mL). The methylene chloride layer was dried over anhydrous magnesium sulfate and the solvent removed. A white solid (5.7 g) was obtained. The aqueous sodium hydroxide layer was acidified and extracted and the extract worked up to yield an additional 0.2 g of product. Yield of epoxymexrenone was 90.2%.

Example 13

[ 0338 ] A reactor was charged with crude Δ⁹'¹¹ -eplerenone precursor ( 1628 g) and methylene chloride (6890 mL). The mixture was stirred to dissolve solids, then dipotassium phosphate (111.5 g) and trichloroacetamide (1039 g) were charged through the hatch. The temperature and agitation were adjusted to 25^SC and 320 RPM, respectively. The mixture was stirred for 90 minutes; then 30% hydrogen peroxide (1452 g) was added over a 10-15 minute period. Stirring was continued at 29-31 ^SC until less than 4% of the initial charge of eplerenone precursor remained as determined by periodic HPLC evaluation. This required about 8 hours. At the end of the reaction, water (2400 mL) was added and the methylene chloride portion separated. The methylene chloride layer was washed with a solution of sodium sulfate (72.6 g) in water (1140 mL). After a negative test for peroxide with potassium iodide paper, the methylene chloride fraction was stirred with a caustic solution prepared from 50% sodium hydroxide (256 g) diluted in water (2570 mL) for about 45 minutes in order to remove unreacted trichloroacetamide. The methylene chloride fraction was washed sequentially with water (2700 mL), then with a solution of sodium bisulfite (190 g) in water (3060 mL).

[ 0339 ] The methylene chloride solution of eplerenone was distilled at atmospheric pressure to a final volume of approximately 2500 mL. Methyl ethyl ketone (5000 mL) was charged. The mixture was placed under vacuum distillation and solvent removed to a final volume of approximately 2500 mL. Ethanol (18.0 L) was charged and approximately 3500 mL was removed via atmospheric distillation. The mixture was cooled to 20^sC over a 3-hour period, and then stirred for 4 hours. The solid was collected on a filter and washed twice with 1170 mL of ethanol each time. The solid was dried on the filter under nitrogen for at least 30 minutes. Finally, the solid was dried in a vacuum oven at 75 ⁵C to <5.0% LOD. Thus, 1100 g of the semipure eplerenone was obtained. [ 0340 ] Recrystallization of semipure eplerenone from 8-volumes of methyl ethyl ketone (based on contained) provides pure eplerenone with a recovery of about 82%.

Example 14

[ 0341] Δ⁹'¹¹-eplerenone precursor (160 g crude) was combined with trichloroacetamide (96.1 g), dipotassium~phosphate-(6^9-g)-and-methylene chloride-(1004 ml. or 6.4 ml/g).

[ 0342 ] Water (25.6 ml_) was added to the methylene chloride mixture. The quantity was adjusted to accommodate the concentration of hydrogen peroxide introduced in the following operation. In this case the water was sufficient to dilute the concentration of the subsequently added aqueous hydrogen peroxide (35 wt.%) to a desired level of 30 wt.%.

[ 0343 ] The mixture of water, steroid substrate, trichloroacetamide and dipotassium phosphate was stirred at 400 RPM and adjusted to 25 ^SC over a 30 to 45 minute period with a heating mantle connected to a temperature controller.

[ 0344 ] Thereafter, 35 wt.% hydrogen peroxide (138.4 mL) was added in less than 5 minutes. Although this example utilized 35% hydrogen peroxide, higher concentrations, e.g., 50 wt.%, can be used. As noted, the introduction of aqueous hydrogen peroxide having a strength greater than is desired for the reaction necessitates adding water, typically in the previous step, in order to maintain the desired concentration for the start of the reaction.

[ 0345 ] The temperature was maintained at 28 to 31^SC throughout the reaction.

[ 0346] The organic portion of the reaction mass was periodically sampled in order to monitor the conversion via HPLC evaluation at 240 nm. A plot of the rate of disappearance of the enester precursor vs. time gave a straight line trend with R² = 0.996. The trend predicted a 98% conversion at 712 minutes. The reaction was targeted for a 95 to 98% conversion. Although the reaction was monitored at 240 nm not all of the impurities were observed at this wavelength. In order to get a true profile of the reaction and impurities the assay was re-run at 210 nm.

[ 0347 ] Water (392 mL) was added to the mixture after 660 minutes (97.7% conversion). In the preparation of this example, the total amount of water was chosen so as to equal the volume of other water charges later in the workup. Addition of water reduced the strength of the peroxide and diminished reactivity towards the steroid components. However, the potential for the generation of low levels of oxygen was still present. The layers were allowed to separate and the lower methylene chloride layer removed (aqueous pH = 6.5-7.0). Typically the hydrogen peroxide assayed at about 5 to 6% by weight. This level of concentration correlated with the consumption of 1.5 moles peroxide per mole of enester converted and a 30% starting concentration.

[ 0348 ] In a preferred mode of operation, the waste peroxide solution is disposed of via a sulfite quench. This operation is very exothermic and is preferably carried out with slow, controlled combination of the components (either forward or reverse quench modes can be used) in order to control the exotherm. The hydrogen peroxide is reduced to water while the sulfite is oxidized to sulfate during this procedure. After the sulfite quench, the quenched aqueous phase is subjected to a steam stripping operation in order to remove entrained methylene chloride. Prior to steam stripping, the aqueous phase is heated to decarboxylate the trichloroacetate salt that is produced as a by-product arising from conversion of the trichloroacetamide during the course of-the epoxidation reaction —Decarboxylation prior to- steam stripping-prevents-the trichloroacetate from reacting with methylene chloride during the stripping operation, which can otherwise result in the formation of chloroform. Decarboxylation can be effected, for example, by heating the aqueous phase at 100 ^SC for a time sufficient to substantially eliminate the trichoroacetate salt.

[ 0349 ] The organic phase of the reaction mixture, comprising a methylene chloride solution of eplerenone, was washed for about 15 minutes at 25 ^SC with an aqueous solution containing Na₂SO₃ (7.4 g) and water (122.4 ml.) (pH 7-8). A negative starch iodide test (no purple color with Kl paper) was observed in the organic phase at the end of the stir period. If a positive test were observed, the treatment would be repeated.

[ 0350 ] The methylene chloride fraction was washed with a dilute aqueous sodium hydroxide solution prepared from pellets (7.88 g) and water (392 mL). The mixture was stirred for 35 minutes at 25 ^SC and then the layers separated (aqueous pH = 13). With this short contact time the trichloroacetamide is not completely hydrolyzed but is removed as the salt. In this regard, at least 2 hours is typically required to hydrolyze the trichloroacetamide to the corresponding acid salt, with release of ammonia.

[ 0351] The methylene chloride portion was further washed with water (392 mL). This was intended as a backup wash in case the basic interface was missed. Since the trichloroacetamide is not completely hydrolyzed during the 30-minute contact time, there is a potential for partitioning back into the organic phase once the pH is adjusted (aqueous pH = 10).

[ 0352 ] The methylene chloride portion was washed with a solution of concentrated hydrochloric acid (4.1 mL) in water (352 mL) (pH 1) for about 45 minutes. At the end of this time the pH was adjusted toward neutral with the addition of a solution prepared from sodium sulfite (12.4 g) and water (40 mL) (pH 6-7).

[ 0353 ] The methylene chloride solution was concentrated via atmospheric distillation to approximate a vessel minimum stir volume (~ 240 mL). About 1024 mL of methylene chloride distillate was collected. Because the preparation of this example was a "virgin run," i.e., there was no recrystallization mother liquor available for recycle, fresh MEK (1000 mL) was added to the methylene chloride solution of eplerenone, in a proportion (1546 mL in this case) intended to mimic the recycle of mother liquor. Again, the solvent was removed via atmospheric distillation to approximate a minimum stir volume (-240 mL). Alternatively, these distillations could have been done under vacuum.

[ 0354 ] Ethanol (2440 m L) was added to the residue. The ethanol charge correlated with 15 mL/g of estimated contained eplerenone for a crude product combined with a typical volume of MEK recrystallization mother liquor (162.7 g). No distinction was made for a virgin batch (144.8 g). Consequently, the virgin run in a campaign is operated at slightly higher volume ratios than runs that contained MEK mother liquor for recovery.

[0355] Ethanol was distilled from the slurry (a homogeneous solution was not obtained in this treatment) at atmospheric pressure until 488 ml_ was removed. The quantity of -ethanol-removed-adjusted the-isolation-ratio-to-i≤-volumes^not-countingJhe-minimum stir volume of about 1.5 mL/g) times the estimated quantity of compound eplerenone contained in the crude product. Since no distinction was made for a virgin run, the isolation volume for this run was slightly inflated. The final mixture was maintained at atmospheric reflux for about one hour.

[ 0356 ] The temperature of the mixture in the distillation pot was lowered to 15^SC and, after stirring for 4 hours at this temperature, the solid was filtered. The transfer was completed with an ethanol rinse. In general, a 1-2 volume quantity based on contained eplerenone (155 to 310 mL) was utilized in production runs.

[ 0357 ] The solid was dried in a vacuum oven at 45^SC and semipure material (150.8 g) with an 89.2% assay was obtained as the output of a virgin run (154.6 g assay adjusted is the expected output for runs that include an MEK recrystallization mother liquor recovery). Generally, 94-95% of the available eplerenone was recovered after this first stage upgrade of crude product. The designated level of drying allowed isolation of the semipure eplerenone as the ethanol solvate. In this regard, the solvate does not easily release ethanol until the temperature reaches about 90^sC. The solvate is preferred for further processing since the desolvated material tends to clump upon mixing with MEK in the next operation.

[ 0358 ] The solid is combined with 2-butanone (MEK) (2164 mL). This quantity of MEK corresponds with a volume ratio of 14 mL/g vs. the estimate of contained eplerenone (includes MEK mother liquor portion).

[ 0359 ] A hot filtration of the eplerenone in MEK solution is preferably carried out prior to recrystallization, but was not employed in the laboratory run. The filtration is normally followed with a rinse quantity correlating with 2 volumes of MEK based on contained eplerenone, e.g., 310 mL. This gives a total MEK volume of 2474 mL that correlates with 16 mL/g. The hot filtration should not be operated below a ratio of 12 mL/g since this is the estimated saturation level for eplerenone in MEK at 80⁵C.

[ 0360 ] MEK was distilled from the solution at atmospheric pressure until 1237 mL was removed. This correlated with 8 volumes and adjusted the crystallization ratio to a volume of 8 mL/g vs. the quantity of eplerenone estimated in the semipure product. The actual volume remaining in the reactor is 8 mL/g plus the solid void estimated at i-1.5 volumes for a total isolation target volume of 9-9.5 mL/g.

[ 0361] The solution (the mixture is supersaturated at this point and nucleation may occur before the cool down starts) is cooled according to the following schedule. This stepwise strategy has consistently generated polymorph II. [ 0362 ] Cool to 65^eC and hold for 1 hour.

[ 0363 ] Cool to 50⁵C and hold for 1.5 hours.

[ 0364 ] Cool to 35^SC and hold for 1 hour

[ 0365] Cool to 15³C and hold for 1 hour,

[ 0366] Then the solid is filtered and rinsed with MEK (310 mL).

[ 0367 ] — ThB^*sOlid-was"initially'driexj on theiilterat 25^sC^~OveτnightrThen drying and desolvation were completed in a vacuum oven at 80-90 ^SC for ca. 4 hours. The expected dry solid weight is 119.7 g for a virgin run and 134.5 g for a run with MEK mother liquor inclusion. The LOD of the final product should be < 0.1%. The filtrate (1546 mL) contained ca. 17.9 g of eplerenone. This correlated with 11.5 wt.% of adjusted input of eplerenone precursor. The mother liquor was saved for recovery via combination with a subsequent ethanol treatment. Data have indicated that the product eplerenone was stable up to 63 days in MEK at 40^BC.

[ 0368 ] The overall assay adjusted weight yield was 76.9%. This overall yield is composed of 93, 95 and 87 assay adjusted weight % yields for the reaction, ethanol upgrade and MEK recrystallization, respectively. There is a potential 1 to 2 % yield loss related to the NaOH treatment and associated aqueous washes. Inclusion of the MEK mother liquor in subsequent runs is expected to increase the overall yield by 9.5% (11.5 x 0.95 x 0.87) for an adjusted total of 86.4%.

[ 0369] The MEK mother liquor can be combined with a methylene chloride solution from the next epoxidation reaction and the procedure, as described above, repeated.

[ 0370] In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained. As various changes can be made in the above processes and compositions without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense.

Claims

What is claimed is:

1. A process for the preparation of a compound corresponding to the formula 5000:

and -C-C is

I -CH=C- or

CH

where

R⁷ represents an alpha-oriented lower alkoxycarbonyl or hydroxycarbonyl radical;

R¹⁰, R¹² and R¹³ are independently selected from the group consisting of hydrogen, halo, haloalkyl, hydroxy, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, cyano and aryloxy;

R^17a and R^17b are independently selected from the group consisting of hydrogen, hydroxy, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, acyloxyalkyl, cyano, aryloxy, or R^17a and R^17b together form an oxo, or R^17a and R^17b together with the C(17) comprise a carbocyclic or heterocyclic ring structure, or R^17a or R^17b together with R¹⁵ or R¹⁶ comprise a carbocyclic or heterocyclic ring structure fused to the pentacyclic D ring;

-A-A- represents the group -CHR¹-CHR²- or -CR¹=CR²-; where R¹ and R² are independently selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy or R¹ and R² together with the carbons of the steroid nucleus to which they are attached form a (saturated) cycloalkylene group; -B-B- represents the group -CHR¹⁵-CHR¹⁶-, -CR¹⁵=CR¹⁶- or an α- or β-oriented group:

_R15 ^_R16

CH CH

I I CH — CH₂-CH

^"" where R¹⁵ and R¹⁶ are^'iridependently selecteci from the group consisting ofhydrόgen, halo, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, and aryloxy; or R¹⁵ and R¹⁶, together with the C-15 and C-16 carbons of the steroid nucleus to which R¹⁵ and R¹⁶ are respectively attached, form a cycloalkylene group;

-G-J-, represents the group

CR⁹-CHR¹¹— :CR 11 or where R⁹ and R¹¹ are independently selected from the group consisting of hydrogen, hydroxy, protected hydroxy, halo, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy or R⁹ and R¹¹ together form an epoxy group,

and -C-C is

I -CH=C- or

CH

the process comprising:

reacting a compound of Formula 6000 with a source of an alkoxy group at a temperature above about 70⁰C, said alkoxy group corresponding to the Formula R⁷¹O- where R⁷¹O- corresponds to the alkoxy substituent of R⁷, said compound of Formula 6000 having the structure:

where

R¹, R², R^3a, R^3b, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁵, R¹⁶, R^17a, R^17b, -A-A-, -B-B- and -G-J- are defined as above for Formula 5000.

2. A process for the preparation of a compound of Formula 5000:

and -C-C is

I -CH=C- or

where R^3a and R^3b are independently selected from the group consisting of hydrogen, hydroxy, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, acyloxyalkyl, cyano, aryloxy, or R^3a and R^3b together with the C-3 atom to which they are attached form heterocylo, or R^3a and R^3b together form oxo;

R⁷ represents an alpha-oriented lower alkoxycarbonyl or hydroxycarbbnyl radical;

,.. R¹⁰,.R¹² and RU_arejndependently selected from the group consisting of hydrogen, halo, haloalkyl, hydroxy, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, cyano and aryloxy;

R^17a and R^17b are independently selected from the group consisting of hydrogen, hydroxy, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, acyloxyalkyl, cyano, and aryloxy, or R^17a and R^17b together form an oxo, or R^17a and R^17b together with the C(17) comprise a carbocyclic or heterocyclic ring structure, or R^17a or R^17b together with R¹⁵ or R¹⁶ comprise a carbocyclic or heterocyclic ring structure fused to the pentacyclic D ring;

-A-A- represents the group -CHR¹-CHR²- or -CR¹=CR²-; where R¹ and R² are independently selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy or R¹ and R² together with the carbons of the steroid nucleus to which they are attached form a (saturated) cycloalkylene group;

-B-B- represents the group -CHR¹⁵-CHR¹⁶-, -CR¹⁵=CR¹⁶- or an α- or β-oriented group:

where R¹⁵ and R¹⁶ are independently selected from the group consisting of hydrogen, halo, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, and aryloxy; or R¹⁵ and R¹⁶, together with the C-15 and C-16 carbons of the steroid nucleus to which R¹⁵ and R¹⁶ are respectively attached, form a cycloalkylene group;

-G-J- represents the group

where R⁹ and R¹¹ are independently selected from the group consisting of hydrogen, hydroxy, protected hydroxy, halo, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy or R⁹ and R¹¹ together form an epoxy group,

and -C-C is

I -CH=C- or

CH

the process comprising:

contacting a compound of Formula 6000 with a reagent comprising an alkali metal or alkaline earth metal alkoxide corresponding to the formula (R⁷¹O)_xM wherein M is alkali metal or alkaline earth metal, x is 1 where M is alkali metal, x is 2 where M is alkaline earth metal, and R⁷¹O- corresponds to the alkόxy substituent of R⁷, said compound of Formula 6000 having the structure:

where

R¹, R², R^3a, R^3b, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁵, R¹⁶, R^17a, R^17b, -A-A-, -B-B- and -G-J- are defined as above for Formula 5000;

free alkali metal or alkaline earth metal hydroxide contained or formed in said reagent, and/or in a reaction medium in which said compound of Formula 6000 is contacted with said reagent, being reacted with a sacrificial saponification target compound, thereby inhibiting saponification of the product of Formula 6000.

3. A process for the preparation of a compound of Formula 5000:

and -C-C is

I -CH=C- or

where

R^3a and R^3b are independently selected from the group consisting of hydrogen, hydroxy, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, acyloxyalkyl, cyano, aryloxy, or R^3a and R^3b together with the C-3 atom to which they are attached form heterocylo, or R ,3a and R -,3b : together form oxo;

R and R are independently selected from the group consisting of hydrogen, hydroxy, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, acyloxyalkyl, cyano, aryloxy, or R^17a and R^17b together form an oxo, or R^17a and R^17b together with the C(17) comprise a carbocyclic or heterocyclic ring structure, or R^17a or

R together with R or R comprise a carbocyclic or heterocyclic ring structure fused to the pentacyclic D ring;

CH CH

I I CH — CH₂ ^1-CH

-G-J- represents the group

XR⁹-CHR¹¹— ^C=CR¹¹

' or ^ ; where R⁹ and R¹¹ are independently selected from the group consisting of hydrogen, hydroxy, protected hydroxy, halo, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyaikyl, cyano and aryloxy or R⁹ and R¹¹ together form an epoxy group,

and -C-C is

I -CH=C- or

the process comprising:

contacting a compound of Formula 6000 with an alkali metal or alkaline earth metal alkoxide corresponding to the formula (R⁷¹O)_xM, wherein M is alkali or alkaline earth metal, x is 1 or 2, and R⁷¹O- corresponds to the alkoxy substituent of R⁷, in a reaction medium containing not more than 0.2 equivalents alkali metal or alkaline earth metal hydroxide per mole of said compound of Formula 6000 converted in the reaction, said compound of Formula 6000 having the structure:

where

4. A process for the preparation of a compound corresponding to the formula 5000:

and -C-C is

-CH=C- or

where

R⁷ represents an alpha-oriented lower alkoxycarponyl or hydroxycarbonyl radical; R¹⁰, R¹² and R¹³ are independently selected from the group consisting of hydrogen, halo, haloalkyl, hydroxy, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, cyano and aryloxy;

-A-A- represents the group -CHR¹ -CHR²- or -CR¹=CR²-; where R¹ and R² are independently selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy or R¹ and R² together with the carbons of the steroid nucleus to which they are attached form a (saturated) cycloalkylene group;

_R15 ^_R16

CH α/

I I

CH CHg CH

where R¹⁵ and R¹⁶ are independently selected from, the group consisting of hydrogen, halo, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, and aryloxy; or R¹⁵ and R¹⁶, together with the C-15 and C-16 carbons of the steroid nucleus to which R¹⁵ and R¹⁶ are respectively attached, form a cycloalkylene group;

-G-J- represents the group

^CR⁹-CHR¹¹— ^C=CR¹¹ or where R⁹ and R¹¹ are independently selected from the group consisting of hydrogen, hydroxy, protected hydroxy, halo, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy or R⁹ and R¹¹ together form an epoxy group,

and -C-C is

I -CH=C- or

CH the process comprising:

continuously or intermittently introducing a compound of Formula 6000 and a source of an alkoxy group into a continuous reaction zone, and continuously or intermittently withdrawing a reaction mixture comprising said compound of Formula 5000 from the reaction zone, said alkoxy group corresponding to the Formula R⁷¹O- where R⁷¹O- corresponds to the alkoxy substituent of R⁷, said compound of Formula 6000 having the structure:

where

5. A process for the preparation of a compound having the structure of Formula 5000:

and -C-C is I -CH=C- or

where

_R15 ^_R16

CH α/

I I CH — CH₂-CH

-G-J- represents the group

CR⁹-CHR¹¹— ^C=CR¹¹ or where R⁹ and R¹¹ are independently selected from the group consisting of hydrogen, hydroxy, protected hydroxy, halo, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy or R⁹ and R¹¹ together form an epoxy group, and -C-C is

I -CH=C- or

CH

the process comprising:

contacting a compound of Formula 6000 with a source of an alkoxy group in the presence of a base, said alkoxy group corresponding to the Formula R⁷¹O- where R⁷¹O- corresponds to the alkoxy substituent of R⁷, thereby producing a reaction mixture comprising said compound of Formula 5000, other steroid components and a cyanide compound;

said compound of Formula 6000 having the structure:

where

crystallizing product compound of Formula 5000 from a crystallization medium, said crystallization medium comprising Formula 5000 product produced in said reaction mixture, said other steroid components, said cyanide compound, and a crystallization solvent. separating the crystalline product from the crystallization mother liquor, said mother liquor comprising retained steroid values and said cyanide compound, said retained steroid values comprising said compound of Formula 5000 and other steroids that may be converted to said compound of Formula 5000;

contacting a substantially water-immiscible solution comprising said retained steroid values with an aqueous extraction medium in a liquid/liquid extraction zone, thereby producing a two phase extraction mixture comprising an aqueous raffinate phase containing cyanide ion and an organic extract phase comprising the compound of Formula 5000 and said other steroids;

separating the organic extract and aqueous raffinate phases; and

recovering steroid values from the organic extract phase.

6. A process for the preparation of a compound corresponding to the formula 5600:

wherein

R⁷ represents a lower alkoxycarbonyl or hydroxycarbonyl radical;

-A-A- represents the group -CHR¹ -CHR²- or -CR¹=CR²-; where R¹ and R² are independently selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, cyano and aryloxy; and

R¹² is selected from the group consisting of hydrogen, halo, haloalkyl, hydroxy, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyi, cyano and aryloxy; the process comprising reacting a compound corresponding to formula 6600 with a source of an alkoxy group in the presence of a base at a temperature above about 70⁰C, said alkoxy group corresponding to the Formula R⁷¹O- where R⁷¹O- corresponds to the alkoxy substituent of R⁷, said compound corresponding to formula 6600 having the structure:

->71 :„ wherein Rⁿ is lower alkyl; and R¹, R², R¹² and -A-A- are defined as above; wherein preparation of said compound corresponding to formula 6600 comprises hydrolyzing a compound corresponding to formula 7600, said compound corresponding to formula 7600 having the structure:

wherein R¹, R², R¹² and -A-A- are defined as above.

7. The process of claim 6 wherein preparation of said compound corresponding to formula 7600 comprises contacting a compound corresponding to formula 8600 with a source of cyanide ion in the presence of an alkali metal salt, said compound corresponding to formula 8600 having the structure:

wherein R¹, R², R¹² and -A-A- are defined as above.

8. The process of claim 7 wherein preparation of said compound corresponding to formula 8600 comprises oxidizing a substrate compound corresponding to Formula 13600 by fermentation in the presence of a microorganism effective for introducing an 11 -hydroxy group into said substrate in α-orientation, said substrate corresponding to the formula 13600 having the structure:

wherein R¹, R², R¹² and -A-A- are defined as above.

9. The process of any one of claims 6 to 8 further comprising preparation of a compound corresponding to formula 4600:

wherein R¹¹¹ is lower arylsulfonyloxy, alkylsulfonyloxy, acyloxy or halide; and

R¹, R², R⁷, R¹² and -A-A- are defined as above; wherein preparation of said compound corresponding to formula 4600 comprises reacting a lower alkylsulfonylating or acylating reagent or a halide generating agent with a compound corresponding to formula 5600.

10. The process of claim 9 further comprising preparation of a compound corresponding to formula 2600:

wherein -A-A-, R¹, R², R⁷ and R¹² are as defined above; wherein preparation of said compound corresponding to formula 2600 comprises removing an 11α-leaving group from a compound corresponding to formula 4600.

11. The process of claim 10 further comprising preparation of a compound corresponding to formula 1600:

wherein -A-A-, R¹, R², R⁷ and R¹² are as defined above;

wherein preparation of said compound corresponding to formula 1600 comprises contacting an epoxidation agent with a compound corresponding to the formula 2600.

12. The process of any one of claims 6 to 11 wherein R⁷ is methoxycarbonyl, R⁷¹ is

,111 12 methyl, R is methylsulfonyloxy, -A-A- is -CH₂-CH₂- and R is hydrogen.

13. The process of any one of claims 6 to 12 wherein free alkali metal or alkaline earth metal hydroxide contained or formed in said source of an alkoxy group, and/or in a reaction medium in which said compound of Formula 6600 is contacted with said source of an alkoxy group, being reacted with a sacrificial saponification target compound, thereby inhibiting saponification of the product of Formula 6600.

14. The process of any one of claims 6 to 13 further comprising crystallizing product compound of Formula 5600 from a crystallization medium, said crystallization medium comprising Formula 5600 product produced in said reaction mixture, said other steroid components, said cyanide compound, and a crystallization solvent.

separating the crystalline product from the crystallization mother liquor, said mother liquor comprising retained steroid values and said cyanide compound, said retained steroid values comprising said compound of Formula 5600 and other steroids that may be converted to said compound of Formula 5600;

contacting a substantially water-immiscible solution comprising said retained steroid values with an aqueous extraction medium in a liquid/liquid extraction zone, thereby producing a two phase extraction mixture comprising an aqueous raffinate phase containing cyanide ion and an organic extract phase comprising the compound of Formula 5600 and said other steroids;

separating the organic extract and aqueous raffinate phases; and

recovering steroid values from the organic extract phase.

15. The process of any one of claims 11 to 14 wherein contacting a compound corresponding to the formula 2600 with an epoxidation agent comprises:

contacting a steroid substrate of formula 2600 with a peroxide compound in an epoxidation reaction zone in the presence of a peroxide activator, said peroxide compound and said steroid substrate being introduced into said reaction zone in a ratio from about one to about 7 moles peroxide compound per mole steroid substrate; and

reacting said peroxide compound with said steroid substrate in said reaction zone to produce a reaction mixture comprising an epoxy steroid of formula 1600.