MX2007002846A - Process for preparing 7 -alkoxycarbonyl substituted steroids. - Google Patents

Abstract

Processes are described for the conversion of a steroid substrate having a 4,7-carbonyl bridge to a structure comprising a 7 -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 7 -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 7 -alkoxycarbonyl substituted steroid product. Alternatively, the repulp solution may be recycled to a primary reactor wherein 4,7- carbonyl bridge substrate is converted to 7 -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 11 -hydroxy-7 -methoxycarbonyl compound (hydroxyester), the 11 -hydroxy group is converted to a leaving group which is then abstracted to produce a -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

PROCEDURE FOR PREPARING STEROIDS SUBSTITUTED WITH 7ALFA-ALCOXICARBONYL CROSS REFERENCE TO PATENTS AND REQUESTS FOR RELATED PATENTS This request is a continuation in part of the Request for United States Provisional Patent with serial number 60 / 608,425, filed September 9, 2004; US Provisional Patent Application Serial No. 60 / 612,133, filed September 22, 2005, both incorporated herein by reference in their entirety. This application relates to the preparation of steroidal intermediates and more particularly to processes for converting a diketone compound corresponding to formula 6000 as described hereinafter in a 7-alkoxycarbonyl compound of Formula 5000, as described below.

BACKGROUND OF THE INVENTION U.S. Patents 5,981, 744, 6,331, 622 and 6,586,591 describe a process for converting compounds of Formula VI: Formula VI in a 7-alkoxycarbonyl compound of Formula V: Formula V wherein R12 is selected from the group consisting of hydrogen, , alkyl, hydroxy, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, cyano and aryloxy; -A-A- represents the group -CHR1-CHR2- or -CR1 = CR2-; where R1, R2 and R2 are independently selected from the group consisting of hydrogen, , hydroxy, alkyl, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, cyano and aryloxy; -B-B- represents the group -CHR15-CHR16-, -CR15 = CR16- or an a- or ß-oriented group: wherein R 5 and R 16 are independently selected from the group consisting of hydrogen, , alkyl, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, and aryloxy; R17a and R7b are independently selected from the group consisting of hydrogen, hydroxy, , lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, acyloxyalkyl, cyano and aryloxy, or R17a and R17b comprise a carbocyclic or heterocyclic ring structure , or R17a and R17b together with R15 and R16 comprise a carbocyclic or heterocyclic ring structure fused to the pentacyclic ring D; and R7 comprises alkoxycarbonyl, more preferably, 7-alkoxycarbonyl. According to the process described in the patents mentioned above, the diketone of Formula VI is reacted with a base, preferably a metal alkoxide, to open the ketone bridge bond between positions 4 and 7, to cleave the bond between the carbonyl group and carbon 4 and forming an a-oriented alkoxycarbonyl substituent at the 7-position by removing the cyanide at carbon 5. The conversion of a compound of Formula VI into a compound of Formula V is described in the aforementioned patents as a step in any of the various schemes for the preparation of eplerenone or related 7a-alkoxycarbonyl steroids. Typically, the yields of this stage are not consistently as high as would be desired. In some of the schemes, the preparation of the intermediate of Formula VI involves two or more process steps, as a result of which it has an important value based on its preparation cost. As a result, a low yield in the conversion of this intermediate into the compound of Formula V represents a significant economic disadvantage in the total manufacturing costs. In this way, there is a potential value in a procedure that can provide better performance at this stage.

BRIEF DESCRIPTION OF THE INVENTION According to the present invention, a compound as defined in Formula 6000, as defined hereinafter, is converted to a compound of Formula 5000, as described hereinafter, by reaction with a source of an alkoxy group in the presence of a base. The compounds of Formulas VI and V are completely within the scope of formulas 6000 and 5000, respectively, but, as can be seen below, the latter definitions are more general in certain aspects. In various preferred embodiments, the process can provide better yields of the compound of Formula 5000 compared to the process described in the aforementioned patents 5,981, 744, 6,331, 622 and 6,586,591, and / or other advantages with respect to the implementation of those procedures. . The process modifications of the aforementioned US patents, described herein, relate to the conditions of the reaction, to the preparation of a metal alkoxide reagent, to the processes for the recovery of the compound of Formula 5000 when desired, and / or any combination of such modifications. In various embodiments of the process, such modifications provide economic and operational advantages. The methods of the invention additionally include the oxidation of a steroid -9.1 1 to give a steroid 9, H-epoxy, and may optionally comprise other steps in the preparation of the steroid 3-keto-7a-alkoxycarbonyl-? 0.11" 17-spirolactone such as eplerenone Among the various aspects of the present invention is a process for the preparation of a compound corresponding to the formula 5000: in the structure of formula 5000, R 'represents a lower alkoxycarbonyl radical or alpha-oriented hydroxycarbonyl radical. The substituents R10, R12 and R13 are independently selected from the group consisting of hydrogen, halo, haloalkyl, hydroxy, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, cyano and aryloxy. The substituents R17a and R17b are independently selected from the group consisting of hydrogen, hydroxy, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, acyloxyalkyl, cyano, aryloxy, or R17a and R17b together form an oxo, or R17a and R17b together with carbon C (17) comprise a carbocyclic or heterocyclic ring structure, or R17a or R17b together with R15 or R16 (as defined below) comprise a carbocyclic or heterocyclic ring structure fused to the pentacyclic ring D. The structure -AA- represents the group -CHR1-CHR2- or -CR1 = CR2- and the 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 steroidal nucleus to which they are coupled form a cycloalkylene (saturated) group . The structure -B-B- represents the group -CHR15-CHR16-, -CR 5 = CR16- or an a- or β-oriented group: R15 ^ R16 CH CH1 I CH- CH2-CH and the 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 R6, together with the C-15 and C-16 carbons of the steroidal nucleus to which R15 and R16 are respectively bound, form a cycloalkylene group. The structure -G-J- represents the group RT-CHR11- ^ C = CR11 - / o; 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 the process for the preparation of the formula 5000 defined above comprises reacting a compound of Formula 6000 with a source of an alkoxy group at a temperature above about 70 ° C, where the alkoxy group corresponds to R710- and R710- corresponds to the alkoxy substituent of R7. The compound of Formula 6000 has The following structure: the identity of R1, R2, R3a, R3b, R9, R10, R11, R12, R13, R15, R16, -AA-, -BB- and -GJ- is defined as above for Formula 5000. 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. The alkali metal hydroxide or free alkaline earth metal (which 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 target compound for sacrificial saponification, which inhibits the saponification of the product of Formula 5000. The alkoxide of the alkali metal or alkaline earth metal has the formula (R710) xM wherein M is alkali metal or alkaline earth metal, x is 1 when M is alkali metal, x is 2 when M is alkaline earth metal and R710-corresponds to the alkoxy substituent of R7. The compounds corresponding to Formulas 5000 and 6000 have been described previously herein.

A further 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 an alkali metal or alkaline earth metal alkoxide in a reaction medium containing not more than 0.2 equivalents of alkali metal hydroxide or free alkaline earth metal per mole of the compound of Formula 6000 converted to the reaction. Yet another aspect of the present invention comprises a process for the preparation of a compound corresponding to formula 5000 wherein the process comprises continuously or intermittently introducing a compound of Formula 6000 and a source of an alkoxy group into an area of continuous reaction and continuously or intermittently withdrawing a reaction mixture comprising said compound of Formula 5000 from the reaction zone. Yet 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 steroidal components and a cyanide compound. The compound of the product of Formula 5000 is recovered by crystallizing it in a crystallization medium containing the product of Formula 5000 produced in the reaction mixture, other steroidal components, the cyanide compound and a crystallization solvent. The crystalline product is separated from the mother liquor of crystallization. The mother liquors comprise retained steroidal indices and the cyanide compound, wherein the retained steroid indices comprise the compound of Formula 5000 and other steroids which can be converted to the compound of Formula 5000. The process further comprises contacting a solution substantially immiscible with water. comprising the steroid indices retained with an aqueous extraction medium in a liquid / liquid extraction zone. This step produces a biphasic extraction mixture comprising an aqueous refining phase containing cyanide ion and an organic extract phase comprising the compound of Formula 5000 and the other steroids. In addition, the process comprises separating the phases of organic extract and aqueous refining and recovering the steroid indices of the organic extract phase. A further aspect of the present invention comprises a process for the preparation of a compound corresponding to formula 5600: the substituent R7 represents a lower alkoxycarbonyl radical 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 R12 substituent 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 70 ° C. The alkoxy group corresponds to R710- where R710-corresponds to the alkoxy substituent of R7. The compound that corresponds to formula 6600 has the structure: wherein R1, R2, R12 and -AA- are defined as above for Formula 5600. Yet another aspect of the present invention comprises a process for the preparation of a compound corresponding to Formula 5600 wherein the method comprises in contact 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 comprising the compound corresponding to formula 5600, other steroidal components and a cyanide compound. After production, the compound of formula 5600 is crystallized in a crystallization medium. The crystallization medium comprises the product of formula 5600 produced in said reaction mixture, the other steroidal components, the cyanide compound and a crystallization solvent. In addition, the compound of formula 5600 is separated from the mother liquor of crystallization. The mother liquors contain retained steroid indices and the cyanide compound. The retained steroid indices comprise the compound of formula 5600 and other steroids which can be converted to the compound of Formula 5000. A substantially water-insoluble solution comprising the retained steroid indices is contacted with an aqueous extraction medium in an area of liquid / liquid extraction. This step produces a biphasic extraction mixture comprising an aqueous refining phase containing cyanide ion and an organic extract phase comprising the compound corresponding to formula 5600 and the other steroids. The biphasic extraction mixture is separated into organic extract and aqueous refining phases and the steroid indices are recovered from the organic extract phase. Yet another aspect of the present invention comprises a process for the preparation of a compound corresponding to formula 5600 wherein the process comprises contacting a compound corresponding to formula 6600 with a reagent comprising an alkali metal alkoxide or alkaline earth metal. The hydroxide of the alkali metal or free alkaline earth metal 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 target compound for Saponification of sacrifice. This reaction inhibits the saponification of the product corresponding to formula 5600. The alkali metal or alkaline earth metal alkoxide is as defined above. A further aspect of the present invention is a process for the preparation of a compound corresponding to formula 1600: the substituent R7 represents a lower alkoxycarbonyl radical 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 method comprises contacting a steroidal 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 steroidal substrate are introduced into the reaction zone in a ratio of about 1 to about 7 moles of the peroxide compound per mole of steroidal substrate. The peroxide compound is reacted with the steroidal substrate in the reaction zone producing a reaction mixture comprising a steroid epoxy. The steroidal substrate of formula 2600 corresponds to the following structure: wherein -AA-, R7 and R12 are defined as above for formula 1600. Yet another aspect of the present invention is a process for the preparation of a compound corresponding to formula 1600 wherein the method comprises contacting a steroid substrate 9 11 of formula 2600 with a peroxide compound in a liquid reaction medium. The peroxide compound is reacted with the steroidal substrate in the reaction medium to produce a reaction mixture comprising a steroid 9, H-epoxy of formula 1600. The steroidal substrate and the peroxide compound are contacted in absolute and relative proportions, and at a temperature, so that the decomposition of the peroxide content of the reaction medium, which is in excess of the stoichiometrically equivalent to the steroidal substrate, does not produce an effective exotherm to cause an uncontrolled autocatalytic decomposition of the peroxide compound. Another aspect of the present invention comprises a process for the preparation of a compound corresponding to formula 1600 wherein the process comprises contacting a steroid substrate 9 11 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, comprising a steroid 9, 11-epoxy of formula 1600, and water is added to the reaction mixture to produce a reaction mixture. diluted in water. The composition of the reaction mixture diluted in water is such that the decomposition of all the unreacted peroxide compound contained in the reaction mixture can not produce an effective exotherm to cause an uncontrolled autocatalytic decomposition of the peroxide compound.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a schematic diagram illustrating a process for recovering steroid indices from the mother liquor obtained after crystallization of the hydroxyester from Formula 5000 in the reaction mass obtained after the reaction of the diketone substrate of Formula 6000 with an alkali metal alkoxide; Fig. 2 is a graph 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; Fig. 3 is a graph of the concentration profiles of various steroidal components during the progress of the reaction of the diketone of Formula VI-1 with potassium methoxide as described in Example 9; and Fig. 4 is a graph of concentration profiles of steroidal components of the reaction mixture during the progress of the reaction of Example 11.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES In US 5,981, 744, US 6,331, 622 and US 6,586,591, various schemes for the preparation of eplerenone are described. Several of these schemes involve the conversion of a compound of Formula 6000 to a compound of Formula 5000. The process of the present invention comprises modifications of the processes generally described in patents 744, 622 and 591 for the preparation of Formula 5000 and / or of the steps described in those documents for the recovery of the compound of Formula 5000 from the reaction mixture. Such modifications can improve productivity, performance or other performance characteristics. In certain applications, for example, in a process for the preparation of eplerenone, modifications of the method as described herein may provide performance savings in a high-value intermediate of Formula 6000, the preparation of which may typically require two or more operations. of complementary procedures. In preferred embodiments of the process for the preparation of the compound of Formula 5000, the diketone of Formula 6000 is reacted with a source of an alkoxy group thereby opening the ketone bridge bond between positions 4 and 7, cleaving the bond between the carbonyl group and the carbon 4 and forming an a-oriented alkoxycarbonyl substituent. in position 7 while the cyanide is removed in carbon 5. Alternatively, the process can be carried out under conditions in which the ketone bridge bond is opened and the 7a-alkoxycarbonyl group is formed, but the cyano group remains attached to the carbon 5. The reaction is preferably carried out in the presence of a base. In various preferred embodiments, the source of an alkoxy group comprises a metal alkoxide, which also functions as a base and which is conveniently provided 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 reactant and the metal alkoxide reactant performs two functions in the reaction, ie, it comprises a source of an alkoxy group and provides the base in the presence of the which is the reaction. Thus, for example, 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 methoxide K, which is preferably provided in a reagent comprising a solution of methoxide K in methanol. Without limiting this description 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 a metal alkoxide is reversible; and complicated by certain intermediates and secondary reactions that are also or may be reversible. For example, in the specific case of epierenone, it has been postulated that the total reaction mechanism can be represented by the following: although the equilibrium illustrated above is for the preparation of intermediate 3-keto-? J 4.5 -11a-hydroxy-17-spiro-butyrolactone which is typically used in the synthesis of epierenone according to Reaction Scheme 1 of US Pat. No. 5,981,744, it will be understood that a comparable equilibrium generally prevails when there are other substituents in the carbons 12 and 17, other structures -AA- and / or -BB- of the generic formulas described above and / or esters other than the methyl ester formed on carbon 7. Furthermore, it will be understood that the balance between the species? -4.5 and 5β-cyano depends significantly on the excess of alkoxy source that is provided to the reaction medium. The reaction can be carried out in a liquid organic solvent medium preferably comprising the alcohol corresponding to the alkoxy group of R7, ie, R71OH, for example, methanol if the base reagent is an alkali metal methoxide. It will be understood that the reaction equilibrium is more favorable at low concentrations, so that the process is preferably performed at high dilution, for example, as high as 40: 1 where the reactant is methoxide Na, or in the range of 20: 1 in the case of methoxide K (expressed in liters of solvent per kg of substrate of Formula 6000). As described in the reference patents, the reverse cyanurization reaction can be inhibited by performing the reaction in the presence of a precipitation agent for cyanide such as Znl, Fe2 (S04) 3, or halide, sulfate or other salt of an alkaline earth metal or transition metal that is more soluble than the corresponding cyanide. As described in the aforementioned US Patents, it is mentioned that the reaction temperature is not critical, conveniently atmospheric reflux temperature. The working examples illustrate a reaction to atmospheric reflux at 67 ° C. Certain embodiments of the present invention encompass operation at certain temperatures in this relatively low temperature range. Other embodiments achieve a significant improvement by performing the reaction at higher temperatures. It has been found that recovery of the product can be conveniently effected by simply cooling the reaction medium until the product of Formula 5000 forms a crystalline precipitate. The recovery by crystallization in the reaction mixture is described in more detail later in this document. As described in the aforementioned US Patents, other options for product recovery are available and can be used. For example, the reaction solution containing the product of Formula 5000 can be inactivated with mineral acid, for example with concentrated HCl, typically 4N HCl. The acidified reaction mixture can be cooled to room temperature and the reaction product of Formula 5000 can extracted with an organic solvent such as methylene chloride or ethyl acetate. These and other schemes for recovering the product of Formula 5000 from the reaction mixture are described in more detail later in this document.

In other preferred embodiments described hereinafter, distillation for the removal of HCN is unnecessary and is preferably eliminated. An intermediate 3-keto-? 4-5a-methoxycarbonyl of Formula 5000 can be used directly in the next step of the process of reaction scheme 1 for the preparation of epierenone as described in the aforementioned patents, i.e., compound conversion of Formula 5000 in the compound designated herein as Formula 4000: wherein 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-; wherein 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 steroidal nucleus at which are joined form a cycloalkylene (saturated) group; -B-B- represents the group -CHR15-CHR16-, -CR15 = CR16- or an a- or ß-oriented group: R1B R1ß \ CH CH I I CH- CH2-CH. wherein 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 R6, together with the C-15 and C-16 carbons of the steroidal nucleus to which R15 and R16 are respectively bound, form a cycloalkylene group; pi7a and pi7b are independently separated from the group consisting of hydrogen, hydroxy, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, acyloxyalkyl, cyano and aryloxy, or R17a and R17b together form an oxo, or R17a and R17b together with carbon C (17) comprise a carbocyclic or heterocyclic ring structure, or R17a and R17b together with R15 and R6 comprise a carbocyclic or heterocyclic ring structure fused to the pentacyclic ring D; and R7 represents a lower alkoxycarbonyl radical or alpha-oriented hydroxycarbonyl radical; and R11 represents a leaving group. U.S. Patents 5,981, 744, 6,331, 622 and 6,586,591 are expressly incorporated by reference herein. See especially cabbage. 31, line 33 to col. 34, line 14 of US 5,981, 744. It can be seen that Examples 59-61 of these patents describe a process in which the diketone substrate comprises a group 9, H-epoxy, and the product of the reaction is the corresponding 5-cyano-7a-alkoxycarbonyl-9,11 compound -epox! Under the conditions of these examples, the 5-cyano group is not cleaved from the core of the 9,11-epoxy substrate. In the various embodiments of the process described herein, the reaction conditions and / or processing of the reaction solution vary with the purpose of increasing the productivity of the reaction and / or providing a base for increasing the performance on the steroidal substrate.

Reaction at high temperature In a modification, the reaction of a source of an alkoxy group with the substrate of Formula 6000 is carried out at a temperature that is high, preferably substantially high, compared to the temperatures described in US Pat. No. 5,981, 744, 6,331, 622 or 6,586,591. The reaction is carried out at more than 70 ° C, for example, between about 70 ° C and about 150 ° C. From the point of view of reaction equilibria and reaction rate, the preferred reaction temperature is significantly higher than 70 ° C, for example, > 80 ° C, more preferably > 90 ° C. However, as discussed below, the optimum temperature may depend on the ability to rapidly cool the reaction mixture and thus may vary with the facilities available for the latter purpose. In many industrial applications, the optimum temperature will be in the range of between about 80 ° C and about 95 ° C. Where a very rapid cooling is feasible, as may be the case, for example, in continuous reaction facilities as described below, the optimum reaction temperature may be in a relatively larger range, such as from about 90 ° C to about 120 ° C. In carrying out the process, the substrate of Formula 6000 can be charged to a reaction vessel together with a solvent such as methanol, ethanol, n-propanol or n-butanol, in relative proportions so that the resulting liquid reaction medium initially contains between about 1 and about 10% by weight, more typically between about 2 and about 3% by weight, of the steroidal substrate. Preferably, the solvent comprises an alcohol corresponding to the formula R71OH wherein R710- is as defined above, ie, 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 formula (R710) M M wherein M is an alkali metal, in which case x = 1, or an alkaline earth metal, in which case x = 2. The alkoxide of metal is preferably introduced in the form of a solution or dispersion in an alcohol corresponding to the formula R71OH. Such a solution or dispersion can serve as a source of the R710- alkoxy group. Without being limited to any particular theory, it is believed that the R7 alkoxy moiety can be obtained primarily from the metal alkoxide component, although a portion of the alkoxy substituent can also be obtained from the R71OH alcohol. In any case, the metal alkoxide also serves as a base, thereby providing two functions in the reaction mechanism. For most applications, the base component preferably comprises an alkali metal alkoxide such as NaOR71 or, preferably, KOR71. However, the reaction can be carried out alternatively in the presence of an alkaline earth metal alkoxide, such as Ca (OR71) 2, Mg (OR71) 2 or Ba (OR71) 2. As described above, an alkali metal or alkaline earth metal alkoxide also serves as a source of an alkoxy group and as a base. According to a further alternative, the reaction can be carried out in the presence of an organic nitrogen base such as triethylamine, pyridine or? / - cyclohexyl -? /,? /,? / "? /" - tetramethylguanidine . In the latter embodiments, the source of an alkoxy group may be primarily or exclusively constituted by the alcohol R71OH, although the metal alkoxide (R710) ΔM may also be included, if desired. When an alcohol serves as the main solvent for the reaction and an organic nitrogen compound as the main base, a large amount of the alkoxy group source can be removed from the excess solvent that is normally provided to achieve the preferably high dilution ratio described herein. document.

When the base consists mainly of an alkali metal alkoxide corresponding to the formula (R710) M, it is preferably introduced into the reaction medium in a proportion greater than about 1.25 moles per mole of substrate, more preferably greater than about 1.5 moles. per mole of substrate, although in embodiments where the goal is to avoid hydrolysis of the 5-nitrile group and produce the 5-CN-7a-alkoxycarbonyl product ("cyanoester") in its place, proportions lower than 1.25 may be favored. In a batch reaction system, preferably at least 0.5 moles of the metal alkoxide reagent per mole of substrate is introduced into the reaction medium at the beginning of the reaction cycle and any remaining metal alkoxide charge is introduced continuously or in increments intermittent during the course of the reaction. In many cases, it may be desirable to control the amount and time of additions of metal alkoxide to the reaction medium so as to avoid the substantial presence of undissolved metal alkoxide in the medium. As discussed in more detail below with respect to another of the modifications of the present invention, the alkoxide solution introduced into the liquid reaction medium is preferably substantially anhydrous and is substantially free of hydroxyl, alkali metal hydroxide or alkoxide. of partially hydrated alkaline earth metal. Technically, it is understood that the reaction medium is electrically anhydrous because any moisture that enters the medium reacts essentially instantaneously with the metal alkoxide producing a metal hydroxide, or a hydrated metal alkoxide, i.e., (R710) M (OH), in the case that M is an alkaline earth metal. However, it is important, if possible, to minimize or prevent the entry of moisture because the metal hydroxide, including any partially hydrated alkaline earth metal alkoxide, generated by contact with moisture or obtained from another source, has a detrimental effect on the product of Formula 5000 causing a hydrolytic dealkylation of 7a-alkoxycarbonyl to give the 7a-carboxylic acid. Considering that the hydroxide includes both the free hydroxyl ion and the undissociated metal hydroxide, the total hydroxide content of the reaction medium is preferably not greater than about 0.05% by weight, more preferably not more than about 0.03% by weight , still more preferably not greater than about 0.01% by weight at any time during the reaction cycle. To control the hydroxide content of the reaction medium, the total metal hydroxide content of a solution or dispersion of the metal alkoxide reactant is not greater than about 0.12 equivalents per equivalent of metal alkoxide. More preferably, the metal hydroxide content of the reagent solution or dispersion is not greater than about 0.035 equivalents per equivalent of metal alkoxide, even more preferably not greater than about 0.012 equivalents per equivalent of metal alkoxide, more preferably not is greater than about 0.006 molar equivalents per equivalent of metal alkoxide. With respect to the weight for most reagents, this value does not reach more than about 10% by weight, more preferably not more than about 3% by weight, even more preferably not more than about 1.5% by weight of hydroxide of metal, with respect to the metal alkoxide. Thus, for example in a 25-32% by weight solution of methoxide K in methanol, the KOH content is preferably not more than about 3% by weight, more preferably not more than about 1% by weight, even more preferably not greater than about 0.5% by weight. These preferred% weight limitations are also generally applied to alcohol solutions or dispersions of other metal alkoxides, for example, methoxide Na, ethoxide K, ethoxide Na, Mg (OMe) 2, Ca (OEt) 2, etc. To avoid moisture and oxygen, the reaction is preferably carried out in an inert atmosphere, such as a nitrogen gas layer. When the reaction is carried out above the atmospheric boiling point of the solvent medium, the reaction can be initiated in a nitrogen layer which is substantially displaced by the solvent vapor as the reaction proceeds. The liquid reaction medium comprising the substrate of Formula 6000 is heated to an elevated temperature, i.e. a temperature >70 ° C. Preferably, the medium containing the steroidal substrate is brought to > 70 ° C before the addition of the alkali metal alkoxide, although heating to the desired reaction temperature may take place, if desired, during or after the addition. In any case, the temperature is preferably maintained at a level above 70 ° C substantially throughout the course of the reaction. Preferably, the temperature is maintained above 70 ° C to at least 60%, more preferably to at least 80% of the reaction cycle, even more preferably substantially throughout the reaction cycle. However, because of the importance of cooling the reaction mixture after completion of the reaction, as described below, it may be useful in a particular installation to act according to a program in which the reaction temperature changes as a function of time during a discontinuous reaction cycle, or along the flow path of a continuous reaction system. When R7 of the reaction product of Formula 5000 is methoxycarbonyl, ethoxycarbonyl or isopropoxycarbonyl, and the solvent for the reaction comprises mainly the corresponding alcohol, the pressure in the reaction vessel can significantly exceed the atmospheric pressure. For example, when the solvent is methanol, the reaction pressure at 100 ° C is about 60 psig (414 kPa). In a reservoir reactor, the desired reaction temperature can be established and maintained by supplying heat from a heat transfer fluid flowing through a coating on the reactor or through coils immersed in the reaction mass. Alternatively, the reaction mass can be circulated through an external heat exchanger. As the conversion of the compound of Formula 6000 into that of Formula 5000 is moderately endothermic, the temperature control in a reservoir reactor can be conveniently performed by working at reflux temperature while controlling the reaction pressure. To facilitate bringing the reaction medium to the desired reaction temperature, an inert atmosphere can initially be established in the upper reactor space, after which the desired reaction temperature can be established and maintained by controlling the reactor pressure. The pressure of the reactor can be controlled by regulating the air flow of the reflux condenser. When the substrate solution of Formula 6000 is brought to the preferred high reaction temperature before the introduction of the alkali metal alkoxide into a liquid reaction medium comprising mainly a lower alcohol (for example, from Ci to C), it has been It has been discovered that the charge of M (OR71) x / R71OH can be introduced at once without causing the reaction product to precipitate. As the conversion of the compound of Formula 6000 into the compound of Formula 5000 is understood as a reaction in equilibrium with an equilibrium constant that increases with temperature, the performances improve working at elevated temperature. A high reaction temperature also very substantially accelerates the rate at which the reaction progresses. In this way, a batch reaction cycle can be shortened very substantially compared to 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, the reaction of a Vl-I compound (as described hereinafter) with methoxide K in methanol required 16 hours to complete the reaction at 67 ° C. In comparison, under equivalent conditions of reagent selection, reagent concentration, reagent-substrate ratio and substrate steroid concentration, it has now been discovered that a discontinuous reaction can be completed in about 6 hours at 72 ° C, in about 4 hours at 85 ° C, in about 1.5 hours at 90 ° C, or in about 0.5 hours at 100 ° C, considering the reaction cycle as the period of time from the time the compound of Formula 6000 has contacted the metal alkoxide at a mole ratio of alkoxide / substrate of at least 0.5 (which for a batch reaction is the time when the metal alkoxide has been added to the reaction medium in a ratio to the substrate of at least 0.5 moles / mol) until the desired conversion is achieved and / or cooling begins. Normally, the desired conversion means at least 95% substrate consumption. More generally, considering the wide range of conditions contemplated for the reaction and a range of target conversions that equate 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 of about 100 ° C.

As described in WO 98/25948, the reaction equilibrium is also favored by a high dilution, for example, at a weight ratio between solvent and substrate of about 40: 1; but operating at the relatively low temperatures described in WO 98/25948, the performance benefit associated with high dilution comes with a productivity disadvantage. To achieve satisfactory productivity, the optimum dilution for a reaction performed in the range of 50 ° C to 65 ° C may more typically be about 20: 1, especially, for example, when the alkali metal alkoxide is potassium methoxide. Due to the favorable effect of a higher temperature on the reaction equilibria and the strong dependence of the reaction rate with respect to the reaction temperature, the reaction at high temperature provides alternative opportunities that contrast with respect to the solvent / steroid dilution ratio . An alternative is to take advantage of the radically foreshortened reaction times by working with a higher dilution, thus gaining the favorable effect of temperature and dilution in the conversion of the substrate balance of Formula 6000 into a Formula 5000 product, without sacrificing productivity. . In fact, if the reaction is carried out with a solvent to steroid ratio in the range of between about liters of solvent per kg of steroidal substrate and about 60: 1, typically to at least about 40: 1, the effect on the productivity of a lower concentration of the product per unit in volume of reaction mass (which results in a lower payload of the batch reactor) is more than compensated by the shortening of discontinuous cycles; so that both productivity and yield can be improved compared to the reaction in the temperature range of the prior art of about 65 ° C. An opposite alternative is to take advantage of the higher solubility of the steroids at high temperature and to work with a lower dilution than that illustrated in the description of WO 98/25948. According to this alternative, the relationship between solvent and spheroid can be as low as 15: 1, or even lower. For example, the operation can be performed at a dilution ratio in the range between about 10: 1 and about 18: 1. The disadvantage in the reaction equilibrium that is suffered with such high steroidal concentrations is substantially compensated by the favorable effect of the temperature on the equilibrium. The productivity is substantially increased by the combined effect of high temperature reaction rates and high concentration of the product of Formula 5000 in the reaction mixture., which results in high discontinuous reaction payloads and in a high effluent flow of the continuous reactor product. The performance of the insulation can also be improved. In a given solubility of the product of Formula 5000 in the solvent medium, a larger fraction of the product of Formula 5000 contained in the reaction mixture can be recovered by crystallization at any given crystallization temperature. Generally, the ratio between solvent and steroid can be selected based on an optimum economic balance between productivity, favored by a relatively low ratio between solvent and steroid, versus selectivity for a compound of Formula 5000, favored by a higher ratio between solvent and steroid . However, the penalty of error in the choice of the dilution ratio is attenuated by working at high temperature, which leads to a favorable reaction balance and ensures high productivity. To avoid unnecessary deterioration of performance due to the conversion of the Formula 5000 product into by-products or to its consumption by other reactions, the reaction cycle preferably does not extend beyond the period required to achieve a satisfactory yield. In any case, it is preferred that the reaction cycle be terminated before the final yield, at the end of the reaction cycle, has deteriorated excessively with respect to the maximum yield achieved during the reaction. Preferably, the reaction is terminated before the final reaction yield has deteriorated by more than 10% with respect to the maximum achieved during the course of the reaction, more preferably before the final reaction yield has deteriorated more than 5% with respect to the maximum achieved. In some operations, it may be advantageous to provide a series analyzer, for example, infrared spectroscopy with Fourier transform, to monitor the progress of the reaction and end at or near optimum reaction performance. Alternatively, or additionally, the reaction cycle can be controlled by reference to a ratio established to predict the conversion of the substrate of Formula 6000 and the yield of the product of Formula 5000 as a function of time and temperature. For example, it may be useful in some operations to establish an algorithm that relates the optimal conversion with time and reaction temperature, and to end the reaction cycle at or near the point of optimal performance as projected by the algorithm. Those skilled in the art can develop such an algorithm based on experimental reaction data. Useful algorithms can be completely empirical or incorporate equations of kinetics and equilibrium, or they can comprise some combination of both empirical and theoretical relationships. For many combinations of substrate, solvent, metal alkoxide reactant and concentrations thereof, the most favorable overall yield can be achieved at a reaction temperature in the range of about 95 ° C to about 115 ° C. In this temperature range, a reaction cycle that reaches 95% substrate conversion may typically be between about 0.25 and about 2 hours, more typically between about 20 minutes and about 40 minutes. After completion of the reaction cycle, the reaction mixture is preferably rapidly cooled to a temperature below about 60 ° C. Preferably, the cooling rate is sufficient so that the yield of the product of Formula 5000 in the cold reaction mass (final yield) is not deteriorated with respect to the final yield achieved at the end of the reaction cycle by more than about 10%, preferably not more than about 5%. Preferably, the reaction mixture is cooled to below 60 ° C at an integrated average speed of at least 1.25 degrees Centigrade per minute, more preferably at a speed of at least 2 degrees Centigrade per minute. Even more favorable final yields can be achieved if the average integrated cooling rate is greater than about 4 degrees Celsius, 5 degrees Celsius, 10 degrees Celsius or even 20 degrees Celsius, per minute. However, in any given application of the method of the invention, improvements in performance that can be achieved at any given cooling speed against the equipment, the operation and maintenance costs associated with obtaining that cooling rate are weighed. Those skilled in the art can easily determine an optimal cooling speed based on these and other factors that may be specific to the product to be produced, the costs of the raw materials, energy, labor and capital, the value of the product, the site in the that the manufacturing and available facilities are carried out. Taking into account any deterioration in performance due to an excessive prolongation of the reaction cycle plus the loss of cooling performance, the reaction is preferably terminated and the reaction mixture is cooled at a sufficient rate so that the final yield after cooling not more than 15% less, preferably not more than 10% less, more preferably not more than 5% less than the maximum yield achieved during the course of the reaction. Based on the present description of the pronounced increase in the reaction rate as a function of the temperature above 70 ° C, and the consequent radical shortening of the reaction cycle, one skilled in the art can easily reach a reaction cycle. optimal for simple test error, being able to help in its accuracy through an on-line analysis such as infrared spectroscopy with Fourier transform or an off-line analysis such as HPLC. Depending on the capacity of the heat exchange system available to cool the reaction mixture, the temperature program of the reaction can be optimized to approximate or achieve optimum performance for the system the reaction / heat transfer system combination, taking into account factors such as reagent concentrations, achievable cooling speed and desired conversion. For example, when the process is implemented in an existing facility with a limited heat transfer capacity, it may be advantageous to perform the reaction at less than the theoretical optimum, for example, at 80 ° C or at 90 ° C, although the maximum yield more High during the reaction cycle would be achieved at 100 ° C, or perhaps even at 110 ° C or 120 ° C. In some applications, especially when the solvent is methanol or ethanol and the reaction is carried out in a closed vessel at a temperature above the atmospheric boiling point of the solvent, a substantial ultrafast cooling can be achieved by releasing the reaction pressure. Additional ultra-fast cooling can be effected by imposing a vacuum on the reaction vessel. The rapid reaction rates that can be achieved at high temperature also make it feasible to perform the reaction continuously with a relatively short contact time period between the substrate of Formula 6000 and the metal alkoxide, or other source of the alkoxy and base group. The continuous reaction is advantageous because it facilitates rapid cooling of the reaction product mixture at a temperature at which inverse reactions and side reactions are substantially inactivated. In a continuous process, the substrate of Formula 6000 and the metal alkoxide are introduced continuously or intermittently into a continuous reaction zone and a reaction mixture comprising the product of Formula 5000 is continuously or intermittently removed from the zone of reaction and is passed to an ultra-fast cooler and / or surface heat exchanger. In such procedure, a given reduction in the temperature of the reaction system can be obtained in a specified period of time ("increase in cooling temperature") with an instantaneous cooling load much lower than the instantaneous cooling load required to achieve the same increase of the cooling temperature for the entire volume of reaction mixture produced in a batch reaction system. As a result, the same overall productivity of the reactor can be carried out with the same increase in refrigeration using a refrigeration system having a cooling capacity that is only a fraction of what is required for a batch reaction system. The continuous reaction can be carried out in a flow or stirred tank reactor. Since the conversion of the substrate of Formula 6000 to the product of Formula 5000 is different from the zero order, a reaction system comprising only a single continuous stirred tank reactor will require a reaction residence time significantly longer than the cycle of a reaction discontinuous Accordingly, the use of a continuous backmixing reactor could result in a performance sacrifice due to degradation of the reaction product from prolonged exposure to high temperature. The necessary total residence time of the reaction can be reduced by continuous cascade stirred reactors in series cascade. Since the reaction is endothermic but the net energy input requirements are small, the reaction in piston flow is also feasible. For the purposes of this description, it will be understood that "piston flow" means flow through a tube, column or other longitudinal flow path without substantial axial back-mixing. In industrial applications, limited axial backmixing may not be completely avoided, as for example in pipe elbows, column stuffing and the like, but it is not sufficient to significantly compensate for the advantages provided by the flow reaction. The flow reaction is particularly attractive because the residence times need not be longer than the batch reaction cycles so that the integrated driving force with respect to time for inverse reactions and by-products is minimized. Since the energy requirements are small, the heat of the endothermic reaction can be provided by simply coating a tubular reactor. In addition, a heat transfer fluid can be passed through the coating at a temperature only slightly warmer than the temperature of the reaction mixture, thereby preventing degradation of the product which can otherwise result in excessive temperature of the product. wall in the procedure. Operating in continuous reaction mode also reduces the dependence of productivity on the volume of the reactor and, in this way, facilitates the operation in high dilutions, for example, dilutions greater than 30: 1, 40: 1 or even 60: 1 liters of solvent per kg of substrate of Formula 5000. In this way, in a continuous reaction system, the additional benefit of a high dilution in the reaction equilibrium can be realized without an excessive impact on economic requirements or on maintenance costs. Those skilled in the art will appreciate that, for optimal operation, the selection of the reaction temperature depends on the relative effect of the temperature on the reaction equilibria, the rate of conversion of the substrate of Formula 6000 into the product of Formula 5000 and the rate of reactions of by-products such as dealkylation of 7a-alkoxycarbonyl by reaction with CNJ ion byproduct. The optimum reaction temperature may also depend on the available instantaneous cooling capacity. In this way, in an installation where a relatively sharp increase in the cooling temperature can be achieved, the optimum reaction temperature may be somewhat higher than in an installation in which the instantaneous cooling capacity is not so great. The optimum temperature may also vary between discontinuous and continuous reaction and between continuous backmix reaction and continuous flow reaction, both as a function of the reaction equilibria and the kinetics per se, and as a function of the selection of the reaction mode in the increase of the cooling temperature that can be achieved. However, irrespective of the combination of the reaction mode and the installation for the cooling of the reaction masses, it has been found that the preferred reaction temperatures, as described above, have the ability to generally provide better product yields. of Formula 5000 with substantially improved productivity. For example, in a series of reactions, it was discovered that in the discontinuous conversion of: in the product: Formula VI an increase in the reaction temperature from 62 ° C to 100 ° C increased the yield of the Formula 5000 product from 64% to 73% and shortened the reaction cycle from 10 hours to about 30 minutes. LOW CONTENT OF WATER AND HYDROXIDE; SAPONIFICATION DIANA Regardless of the temperature at which the reaction is performed, it is further preferred that the substrate of Formula 6000 is converted to the product of Formula 5000 in a reaction medium containing not more than about 0.2 equivalents of the hydroxide compound per mole of the substrate of Formula 6000 that is converted during the course of the reaction. Typically, the content of the hydroxide compound comprises the sum of the alkali metal hydroxide and the alkaline earth metal hydroxide. In some cases, the hydroxide component may include hydrated alkaline earth metal alkoxide, ie, (R710) M (OH). Water is also classified as unwanted hydroxide compound and, as discussed below, is often the source of other hydroxides but is rapidly consumed in its formations by hydrolysis of metal alkoxide.

More preferably, the reaction medium contains no more than about 0.08 equivalents, still more preferably no more than about 0.02 equivalents of the total hydroxide compound per mole of the substrate of Formula 6000 converted to the reaction. It is also preferred that the ratio between the content of the hydroxide compound and the metal alkoxide content of the reaction medium and the metal alkoxide reactant be maintained within the ranges indicated hereinabove. When the reaction medium or the solution of the metal alkoxide reagent is contaminated with water, the water reacts with the metal alkoxide releasing the alcohol and producing the free metal hydroxide compound. This reaction is typically rapid. Whether it has been generated by reaction of the alkoxide with water, or whether it is present due to the incomplete reaction of the metal hydroxide and alcohol in the initial formation of the alkoxide, the metal hydroxide compound can react with the product of Formula 5000, the substrate of Formula 6000 or any of the various intermediates generating unwanted byproducts. A particularly disadvantageous effect of the free metal hydroxide is the saponification of the desired 7a-alkoxycarbonyl to give the free 7a-carboxylic acid or its salt To exclude the moisture from the reaction medium, the metal alkoxide reactant is preferably prepared in an inert anhydrous atmosphere , and such an atmosphere is maintained in the reaction zone in which the reagent is mixed with or introduced into a reaction medium comprising the substrate of Formula 6000. Additionally, it is preferred that an inert atmosphere be maintained in the recovery stages. of the product as described in more detail below. Except in those steps where water is used as an anti-solvent for the extraction or crystallization of the product of Formula 5000, it is also preferred that the product recovery steps are carried out under anhydrous conditions. In various preferred embodiments, the presence of free metal hydroxide in the reaction medium can be minimized by the use of a sacrificial saponification target that efficiently cleaves 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. The saponification target reacts with the free metal hydroxide producing 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, this is consumed by converting the metal alkoxide into metal hydroxide which in turn is consumed by reaction with the saponification target compound. Preferably, the saponification target is introduced into the reagent comprising the metal alkoxide reactant, so that all moisture and free metal hydroxide have been removed from the reagent before it is contacted with the substrate of Formula 6000. However, it is further preferred that a saponification target is also present in the reaction medium in which the substrate of Formula 6000 is reacted with the metal alkoxide, to treat any moisture that is introduced into the medium through the solvent , the source of the compound of Formula 6000, or otherwise, and more particularly, to remove the metal hydroxide that is formed when such moisture comes into contact with the metal hydroxide reagent. Preferably, the saponification target comprises an ester of the alcohol corresponding to the alkoxycarbonyl group R7, ie, the saponification target is preferably an ester of R71OH. The carboxylate component of the ester is preferably formate or orthoformate. Thus, for example, in the preparation of epierenone, the saponification target is more preferably methyl formate or trimethyl orthoformate. Preferably, a solution or dispersion of reagent is prepared by contacting an alkali metal hydroxide with an alcohol in an effective ratio to produce a solution of metal alkoxide in alcohol. Preferably, the reaction is carried out under substantially anhydrous conditions. Conveniently, the resulting concentration of metal alkoxide in the reagent solution is between about 7 and about 25 mole%, typically about 15 to about 50% by weight. In this way, an excess of alcohol is used with respect to the metal hydroxide to ensure that the hydroxide reacts completely. Preferably, the proportion of alcohol is also sufficient for the alkoxide to be substantially or completely solubilized. After completing the alcoholysis reaction, methyl formate or another saponification target compound can be introduced into the alkoxide solution or dispersion. Alternatively, or additionally, the saponification target compound can be introduced separately into the reaction medium in which the substrate compound of Formula 6000 is contacted with the metal alkoxide reagent. In any case, the saponification target is preferably introduced in stoichiometric excess relative to the hydroxide residue obtained from any and all sources, either from the incomplete reaction of the alcohol and the metal hydroxide, from the moisture introduced by the hydroxide of metal, alcohol and / or other sources in the preparation of the reagent solution, the moisture in the steroid and / or solvent from which the reaction medium is prepared, or the entry of moisture from the environment . An excess of saponification target of 50% with respect to the hydroxide from all sources may be preferred to ensure complete consumption of all the free hydroxide. When using anhydrous metal hydroxide and alcohol sources, it is usually sufficient to introduce a saponification target in a ratio between about 2% and about 25% by weight, more typically between about 5% and 15% by weight , depending on the metal alkoxide content of the reagent solution.

When the saponification target compound is added to the solution or dispersion of the metal alkoxide reagent before introducing the reagent into a reaction medium comprising the steroidal substrate, the solution / dispersion of the reagent is preferably maintained at room temperature or at a moderate temperature elevated over a period of time to remove all the residual hydroxide that is contained in the reagent solution, produced or formed by the consumption of moisture over time. Thus, before using in the conversion of the substrate of Formula 6000 in Formula 5000, the reagent solution containing the saponification target compound is preferably maintained for at least about 8 hours, more preferably for at least about 24 hours, still more preferably for at least about 48 hours, and most preferably for at least about 72 hours, with gentle agitation. In carrying out the conversion of the substrate of Formula 6000 to the product of Formula 5000, a reaction vessel with steroidal substrate and a solvent, preferably an alcohol corresponding to R71OH, is preferably charged, and a reagent solution comprising alkoxide is added thereto. of metal in alcohol. Advantageously, methyl formate or another saponification target compound is incorporated into the resulting mixture. This effect can be achieved 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 loaded with the substrate of Formula 6000. As described above, the alkali metal alkoxide is preferably added in a molar ratio to the substrate of Formula 6000 of at least about 1.25, preferably between about 1.5 and about 1.8. Then, the reaction can be carried out at a temperature from below room temperature to 150 ° C, preferably to at least about 50 ° C, more preferably to at least about 70 ° C. More preferably, a high reaction temperature is selected within the preferred ranges and in accordance with the guiding principles described above. As described in WO 98/25948, the metal alkoxide is preferably added in two increments, at a net molar ratio to the substrate of about 1.6. The first increment may be added, for example, in a molar to substrate ratio of about 1; and about 90 minutes later, a second increment in a molar ratio to the substrate of about 0.6 can be added. However, it has been found that, if the reaction medium comprising the solvent containing the substrate of Formula 6000 dissolved or dispersed therein is initially heated at elevated temperature in the preferred ranges for the reaction, the entire charge of metal alkoxide at the same time. In any case, the alkoxide can typically be added initially at a ratio to the substrate of at least about 0.5, and then, any remaining portion of the charge can be added in increments. An ester such as methyl formate reacts with KOH to form the salt of acid from which the ester is obtained and to liberate the free alcohol. In this way, when the ester is methyl formate, products of the saponification target reaction are potassium formate and methanol. As discussed below, various schemes are available for the recovery of the product of Formula 5000 from the reaction mixture. Most of these ultimately involve the crystallization of the Formula 5000 product in a solution thereof. The potassium formate, or other salt of the acid component of the saponification target ester, is retained in the mother liquor and is finally removed in a liquid phase purge. The methanol is also mixed in the liquid phase, functioning therein as part of the solvent component. It is also removed during the processing of the reaction mixture and / or the crystallization mother liquor.

Recovery of the product of formula 5000 from the reaction mixture The product of Formula 5000 is recovered by crystallization. Multiple schemes are available to effect crystallization and recovery. More simply, the reaction mixture is cooled to the crystallization temperature without complementary conditioning steps. To maximize the yield, the crystallization is preferably carried out in cold, for example, at a temperature below 5 ° C, more preferably below about 0 ° C, still more preferably below about -5 ° C. For example, in the case of the intermediate 3-keto-11a-7a-methoxycarbonyl-17-spirobutyrolactone ("hydroxy ester") for epierenone, the crystallization is conveniently carried out between about -25 ° C and about -10 ° C. Then, the crystalline product of Formula 5000 is 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. When the product of Formula 5000 is crystallized directly in the reaction mixture and recovered by filtration or centrifugation, it has been found that the filter cake or the spin cake is substantially free of cyanide salts and other inorganic contaminants, so that a washed with water for the removal of such contaminants. When an anhydrous or substantially anhydrous alcohol is used for washing, the washed cake has substantially no moisture, which facilitates the drying step and prevents the hydrolytic degradation of the cake during drying. Substantially anhydrous mother liquors are also provided, from which the steroid indices can be recovered by extraction in the manner described below, where the steroids can optionally be collected in a water immiscible solvent before any contact with an aqueous extractor. Various recovery schemes of alternative methods involve concentration, addition of water and / or extraction from the reaction mixture. For example, the compound of Formula 5000 can be isolated by acidifying the reaction solution, for example, with a mineral acid such as aqueous HCl or sulfuric acid, distilling to concentrate the acidified mixture while distilling off the HCN generated by acidification and cooling at room temperature. Then, the product of Formula 5000 can be recovered by additionally cooling the distilled concentrate to cause the product to crystallize; or adding water and an organic solvent such as methylene chloride or ethyl acetate to generate an organic extract comprising the steroid indices and an aqueous raffinate comprising the cyanide salts. The alcohol reaction solvent is typically distributed in a significant manner between each of the two phases. When the reaction medium comprises a lower alcohol, the recovery of the product can also be effected by the addition of water to a concentrated and acidified reaction mixture to reduce the solubility of the product of Formula 5000 therein, thereby causing the product to crystallize in the aqueous alcoholic medium. In the recovery of the product by this alternative, the reaction solvent (for example, methanol) and HCN are removed by distillation after the completion of the reaction period, by adding mineral acid (such as hydrochloric acid or sulfuric acid) before distillation and adding water after distillation. The mineral acid can be added in a single step, in multiple stages or continuously. In a preferred embodiment, the mineral acid is added continuously for a period of time from about 10 to about 40 minutes, more preferably from about 15 to about 30 minutes. Likewise, water can be added to the stills in a single stage, in multiple stages or continuously. Before adding water, the concentrated reaction mixture is preferably cooled to a temperature between about 50 ° C and about 70 ° C, typically between about 60 ° C and about 70 ° C. Then, water is added, preferably continuously for a period of about 15 minutes to about 3 hours, and more preferably for about 60 minutes to about 90 minutes, while the temperature remains approximately constant. The product of Formula 5000 begins to crystallize from the still residues while the addition of water is made. After adding the water to the mixture, the diluted reaction mixture is kept at about the same temperature for about 1 hour and then cooled to about 15 ° C for 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 shelf life at 15 ° C causes the equilibrium between the steroid species to shift, which results in a higher yield of the species 5-CN-7a-alkoxycarbonyl ("cyanoester") in the mixture. This recovery mode provides a high quality crystalline product without extraction operations. When the recovery of the product comprises the use of water as an anti-solvent, water and acid can be added before or during the distillation to distill HCN. The addition of water and acid prior to distillation simplifies operations, but the progressive addition during distillation allows the volume in the distiller to remain substantially constant. The product of Formula 5000 crystallizes in the still residues while the distillation takes place. It has been found that multiple solvent extractions are not necessary for the purification of the compound of Formula 5000 when 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 be eliminated normally completely. When solvent extraction is used for the purification of the product, it is desirable to supplement the solvent washes with brine and caustic washes. Although when extractions are eliminated with solvent, washings with brine are also eliminated. By eliminating extractions and washes significantly improves the productivity of the process, without sacrificing the performance or quality of the product and also eliminates the need to dry the solution washed with a desiccant such as sodium sulfate.

Recovery of steroid indices from the crystallization mother liquor As described above, the product of Formula 5000 is preferably recovered from the reaction mixture by crystallization. Prior to crystallization, the reaction solution can optionally be acidified and concentrated as described above. The mother liquor of crystallization 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 compound of the typically preferred product of Formula 5000 in which the carbon 5 is unsubstituted, the mother liquor contains other steroidal indices, including unconverted Formula 6000 substrate, and the 5β-cyano-7a-alkoxycarbonyl by-product of Formula C, which may typically be in equilibrium with the product of Formula 5000 and the residual cyanide ion. Unless these steroid indices can be recovered, they represent a significant disadvantage in the yield of the compound of Formula 6000. According to any of several optional and potentially advantageous embodiments as further described herein, steroid indices can be recovered from the mother liquor. and the performance of the Formula 5000 product can be improved.

The steps to recover the steroidal indices may be combined with measures to shift the equilibrium to convert the unconverted Formula 6000 substrate, the by-product of Formula C and / or other intermediates and by-products into the preferred product of Formula 5000 which is unsubstituted in C -5. Among the procedures that can be used to recover steroids and / or shift balance 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 recovery scheme of corresponding primary products as described above; (iii) addition of a ketone for the consumption of the cyanide ion contained in the mother liquor; (iv) re-balanced by heating the mother liquor; and (v) addition of metal compounds for cyanide precipitation.

Extraction of mother liquor In a preferred embodiment, the steroid indices retained in the primary crystallization mother liquor are recovered by extraction. This method is effective, for example, when the reaction has been carried out in a water-miscible solvent such as a lower alcohol and the primary recovery process produces mother liquors comprising the crystallization solvent and having retained in the same components such as a fraction of the compound of the Formula 5000 product, composed of unreacted Formula 6000, other steroidal indices which can be converted to the compound of Formula 5000, and cyanide ion. A substantially water miscible solution is prepared in water containing such steroidal indices. In the extraction step, this non-miscible solution in water 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 paste solution is formed, typically by exchange of solvent with the extract, which comprises a solvent miscible with water and containing steroids obtained from the organic extract. The paste solution can be processed to recover steroid indices contained in it. More particularly, the paste solution can be processed to convert the compound of Formula 6000 to compound of Formula 5000, and to recover the additional Formula 5000 product. For the purposes of 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 the evaporation or distillation of the crystallization solvent from the mother liquor. The extraction feed solution is itself substantially miscible in water, but is mixed with a non-miscible solvent in water producing a steroid index solution substantially immiscible in water which is contacted with an aqueous extraction medium in the area of extraction. The water-immiscible steroid solution is prepared by mixing the immiscible solvent in water with the extraction feed solution in the presence of the aqueous medium in the extraction zone or before coming into contact with the aqueous medium, for example, in one step preliminary mixing outside the extraction zone. The contact of the non-miscible steroid solution in water with the aqueous medium results in the transfer of cyanide ion to the aqueous phase and the transfer of steroidal indices, including compounds of Formula 5000 and Formula 6000 to the organic phase (or retention of such indices in the organic phase). The partition coefficient for the crystallization solvent typically miscible in water is such that a significant portion of this solvent is normally distributed to each of the phases. Preferably, the extraction zone is stirred to increase the mass transfer rate between the phases. The separation of the phases produces an organic extract that contains steroid indices and an aqueous raffinate containing cyanide and other salts that may be present. More preferred steroid extraction and recovery schemes are described in more detail later in this document. Before extraction, the mother liquors are preferably concentrated, by distillation or evaporation, to remove excess solvent. To maximize the recovery of the steroids, the mother liquors are preferably concentrated to not more than half of their initial volume, preferably not more than one third of their initial volume, typically to between about one quarter and one sixth of their initial volume, for example at a minimum stirring volume in the stills, that is, the minimum volume that ensures the immersion of a driving wheel agitator and / or avoids the cavitation or mechanical instability of the agitation. However, it is further preferred that the degree to which the mother liquor is concentrated is not sufficient to cause any substantial precipitation of steroid indices. To minimize dealkylation of the steroid of Formula 5000 by cyanide ion, the mother liquor is preferably concentrated under reduced pressure at a temperature less than about 60 ° C, more preferably less than about 40 ° C, most conveniently between about 20 ° C. and approximately 40 ° C. To carry out the distillation or evaporation at such temperatures, the mother liquor can be concentrated under reduced pressure. For example, when the crystallization solvent is methanol, the concentration of the mother liquor can be carried out at an absolute pressure in the range between about 100 (13.33 kPa) and about 500 mm Hg (66.66 kPa), more typically in the range between about 200 (26.66 kPa) and approximately 400 mm Hg (53.33 kPa). Distillation at relatively low temperature reduces the degree of dealkylation of the 7a-alkoxycarbonyl substituent. Then, the concentrated mother liquors can serve as a source of steroids for the extraction feed solution and can in fact constitute the extraction feed solution. Typically, the concentrated mother liquors contain between about 1 and about 3% by weight of the product of Formula 5000 (not substituted at C-5) and between about 0.5 and about 1.5% by weight of other steroidal indices including, example, between about 0.3 and about 0.6 wt% of the substrate of Formula 6000 and between about 0.2 and about 1.0 wt% of the 5β-cyano-7a-alkoxycarbonyl byproduct of Formula C. They may also typically contain about 0.5 and about 1.5% by weight of cyanide ion and about 0.5% by weight and between about 1.5% by weight of metal M cation. Preferably, the concentrated mother liquors (extraction feed solution) are mixed with the non-miscible solvent in water before anyone comes into contact with an aqueous medium. This preliminary mixing step can conveniently be carried out outside the extraction zone, and the resulting steroidal solution substantially immiscible with water can then be introduced into the extraction zone. Preferably the extraction feed solution and the non-miscible solvent in water are mixed with a volumetric ratio of between about 0.2 and about 1.0, more preferably between about 0.3 and about 0.6 parts by volume of solvent per part by volume of concentrated mother liquors. The resulting immiscible water-steroid solution typically contains between about 10% and about 80% by weight, more typically from about 25% to about 75%, of non-miscible solvent in water, between about 20 and about 90% by weight, more typically between about 30% and about 80% lower alcohol, between 0.5 and about 4% by weight of the product of Formula 5000 (not substituted at C-5) and between about 0.2 and about 3% by weight of other steroidal indices including, for example, between about 0.02 and about 0.2% by weight of the substrate of Formula 6000 and between about 0.03 and about 5.0% by weight of the 5β-cyano-subproduct. 7a-alkoxycarbonyl of Formula C. By premixing the concentrated mother liquors with water immiscible solvent, the steroidal indices may preferably be distributed in the organic phase to throughout the extraction, thus protecting them against hydrolytic attack and particularly against the decomposition of 7a-alkoxycarbonyl in 7a-carboxy. Alternatively, the extraction feed solution, the aqueous extraction medium and the water immiscible solvent can all be introduced directly and independently into the liquid / liquid extraction zone, in which case the extraction feed solution and the solvent do not miscible in water are mixed forming the steroid solution not miscible in water within the area. According to a further alternative, although generally less desirable, the water and the extraction feed solution can be combined before contacting the resulting mixture with the non-miscible solvent in water in the extraction zone. As the extraction is carried out, the liquid phase produced by combining the extraction feed solution and the aqueous medium functions as the aqueous extraction medium and as the mass transfer takes place the steroid non-miscible solution in water is formed in the extraction area. This alternative is usually preferred less because it unnecessarily exposes steroids to hydrolytic attack and may result in the precipitation of steroids before coming into contact with the water immiscible solvent. However, it remains a possible strategy when the extraction takes place reasonably immediately after combining the extraction feed solution and the aqueous medium, and especially when the extraction is carried out under the conditions described below. Regardless of the mixing sequence, the extraction is preferably carried out cold, which helps to minimize hydrolysis of the steroids during extraction. For example, the extraction can be carried out at a temperature below about 15 ° C, more preferably below about 10 ° C, still more preferably below about 5 ° C, more typically in the range between about -15 ° C and approximately 10 ° C. The aqueous extraction medium is preferably cooled to a temperature in such ranges before coming into contact with the water immiscible steroid solution in the extraction zone. When the aqueous extraction medium consists of water substantially free of electrolytes, it can be cooled optimally at a temperature just above 0 ° C, for example, from 0.5 ° C to 5 ° C. As the crystallization solvent and the cyanide ion are transferred to the aqueous phase during extraction, it is typically feasible to perform the extraction at a temperature even below 0 ° C, for example, between 0 ° C and -10 ° C. It is further preferred that the water immiscible steroid solution be brought to a temperature within the aforementioned ranges before it comes into contact with the aqueous extraction medium. If the extraction feed solution and the water immiscible solvent are introduced independently into the extraction zone, it is further preferred that each one is previously cooled to a temperature at or about the temperature of the extraction zone before coming into contact each other in the extraction zone. When the extraction is carried out under preferred conditions, no more than 10% of the compound of Formula 5000 contained in the extraction feed solution is hydrolyzed during extraction. Typically, the degree of hydrolysis of the compound of Formula 5000 is less than 5%, more typically less than 1%. Only a few minutes of mixing are necessary to carry out the transfer of steroids to the organic phase and of cyanide to the inorganic phase. Preferably, the phases are separated after no more than about 75 minutes, more preferably after no more than one hour, more preferably after no more than half an hour of mixing. The minimization of contact time also serves to protect steroids from hydrolytic attack. Thus, although the extraction feed solution and the non-miscible solvent in water are preferably pre-mixed before coming into contact with the aqueous extraction medium in the extraction zone, the hydrolytic attack on the steroid is generally minimal when the extraction is carried out in the cold in the contact time limitations indicated above, even when the aqueous extraction medium, the non-miscible solvent in water and the extraction feed solution are introduced independently and simultaneously into the extraction zone. Water-immiscible solvents that can be used in the extraction include, for example, methylene chloride, ethyl acetate, toluene and xylene. Methylene chloride is especially effective. In order to facilitate the recovery of steroids from the extract and especially for the rebalancing thereof for the subsequent conversion to the product of Formula 5000, it is preferred that the non-miscible solvent in water be more volatile than the lower alcohol solvent in which any subsequent rebalancing of steroids is performed and also more volatile than the solvent in which the primary crystallization is carried out (and in which the reaction typically also takes place). For example, preferred water-immiscible extraction solvents have a boiling point at atmospheric pressure or a convenient subatmospheric distillation pressure, at least 10 ° C lower, preferably at least about 15 ° C lower, than alcohol which It serves as a means for the reaction stage to rebalance you. Such a difference facilitates the separation of the non-miscible solvent in water from the organic extract as described hereinafter. It is particularly preferred that the atmospheric boiling point of the extraction solvent is not greater than about 70 ° C, preferably not greater than about 50 ° C. To facilitate separation of the organic extract from the aqueous raffinate, it is further preferred that the specific gravity differential between the non-miscible solvent in water and the aqueous extraction medium is at least about 0.05, more preferably at least about EYE, more preferably at least approximately 0.20. Preferably, the relative amounts or proportions of the aqueous extraction medium, extraction feed solution and water-immiscible solvent combined for the purposes of extraction are such that the volumetric ratio between aqueous medium and the sum of the extraction feed solution plus the water immiscible solvent is between about 0.3 and about 1.5, preferably between about 0.4 and about 0.8, and the volume ratio between the aqueous raffinate and the 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 between the non-miscible solvent in water and the extraction feed solution is typically between about 0.3 and about 1.0, the ratio between the aqueous medium and the non-miscible solvent in water is typically between about 1 and about 3, and the ratio between the aqueous medium and the 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 multi-stage countercurrent extraction column. As indicated, the steroid indices in the mother liquors are substantially distributed in the organic phase while the cyanide and other inorganic salts are distributed almost quantitatively in the aqueous phase. When the non-miscible solvent in water is methylene chloride, the partition coefficients for the steroidal indices are typically in the range between about 3 and about 8. The water-miscible crystallization solvent, which normally comprises a lower alcohol, is distributed between the organic and aqueous phases, with a significant component in each phase. When the non-water miscible solvent has properties comparable to those of methylene chloride, the organic extract typically contains between about 10 and about 40% by weight of lower alcohol, less than about 0.3% by weight of cyanide, and between about 0.5 and about 10% by weight of steroid indices, including between about 0.5 and about 8% by weight of the product of Formula 5000 (not substituted at carbon 5), between about OJ and about 1.2% by weight weight of the substrate of Formula 6000, and between about 0.2 and about 5% by weight of the 5β-cyano-7a-alkoxycarbonyl byproduct of Formula C. The organic extract may also contain water dissolved and entrained in a proportion of less than about 1 %. In a single extraction step, the aqueous raffinate typically contains between about 0.3 and about 2% by weight of the cyanide ion and between about 0.3 and about 2% by weight of the M cation. The recovery of steroid indices can be slightly improved by a second extraction step in which the aqueous raffinate is contacted with an additional volume of non-miscible solvent in water. However, the slightly improved steroid recovery value may not overcome the disadvantages that may arise from the presence in the paste solution of impurities that may be extracted from the aqueous raffinate in the second extraction step. If a second extraction step is carried out, it is also preferably carried out in cold with a ratio between water-immiscible solvent and aqueous refining of between about 0.5 and about 1.5. The steroidal content of any second organic extract is generally quite low. By subjecting it or not to one or more additional extraction steps, the aqueous raffinate is removed from the process in the form of a purge of cyanide and other inorganic impurities.

In preparation for the recovery of steroids, any secondary organic extract is preferably combined with the primary organic extract. The organic extract, of a single or combined stage, is distilled to remove the organic solvent immiscible with water and to produce a concentrate comprising the steroid indices in a medium comprising mainly a water miscible solvent. When the organic extract contains more than a negligible fraction of the crystallization solvent, as is normally the case, the component of the water-miscible solvent of the concentrate comprises the crystallization solvent. Preferably, the distillation of the organic extract is carried out at a temperature that is not higher than about 50 ° C, more preferably not greater than about 40 ° C. For example, when the primary crystallization solvent is methanol and the non-miscible solvent in water is methylene chloride (or the volatilities of the two solvents are comparable with methanol and methylene chloride, respectively), the distillation is preferably carried out at a pressure of head in the range of between about 300 mm Hg (40 kPa) and atmospheric pressure and at a temperature of the lower part in the range of between about 20 and about 40 ° C. A direct acquisition distillation is effective for the required separation. No rectification is required. In this sense, the distillation stage can be equivalent to a simple evaporation. Distillation can also be effective to distill residual moisture from the organic extract. Although some of the preferred solvents used in the process, such as methanol and methylene dichloride, are heated to 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 in removing residual moisture from the extract. Optionally, a water-miscible solvent is introduced into the organic extract before distillation, or into the fractions of the distillation residue during distillation after removing a portion of the non-miscible solvent in water. Such water-miscible solvent preferably has a lower volatility than that of the non-miscible solvent in water. Methanol is particularly suitable. If the water-miscible solvent is introduced after removing a portion of the non-miscible solvent in water, the initial distillation may be suitably continued until the minimum stirring volume of the immiscible solvent in water and the steroid residue in the receptacle have been reached. distillation. Then, the water-miscible solvent can be added and the distillation can be resumed until the water-miscible solvent appears as a significant fraction of the distillate, typically at about the point where the temperature of the vessel reaches the boiling point of the solvent miscible with water. water at the prevailing pressure (conveniently atmospheric pressure in those embodiments in which the solvent not miscible with water comprises methylene chloride). After completing the distillation, the fraction of the distillation residue can then be a paste solution subjected to further processing for the recovery of steroid indices. Preferably, the water-miscible solvent added before or during the distillation is the same as the primary crystallization solvent, which in turn is preferably the same as the reaction solvent. In particularly preferred embodiments of the invention, the water-miscible solvent comprises in each case methanol and the non-miscible extraction solvent in water comprises methylene chloride. The distillation can be continued appropriately until the ratio between the water-miscible solvent and the steroid indices in the fraction of the distillation residues is adequate for the re-balancing of steroids to generate additional product of Formula 5000. For example, the water miscible solvent can be removed until the ratio between solvent and steroid in the residue is in a range of between about 10: 1 and about 30: 1, preferably between about 15: 1 and about 22: 1 (liters of solvent per kg of total steroid indices). If the solvent / steroid ratio in the distiller vessel has been reduced to a level below that desired for steroid rebalancing, water miscible solvent may be added again to provide a paste solution of appropriate composition. The condensate from the distillation of the extract can be recycled for use in extraction. Optionally, it is cooled and passed directly to the extraction zone or to a pre-mix stage where it is mixed with the extraction feed solution to produce a non-miscible solution in water of steroid indices which can then be contacted with the extraction medium. aqueous in the extraction zone. According to a further alternative for solvent exchange, the fraction of the distillation residue from the distillation of the organic extract can be diluted with more solvent miscible with water and can be subjected to a second distillation operation to ensure a more complete removal of the solvent not miscible in water of the residue. In the application of this alternative, it is not essential that all steroids remain in solution in the residue of the initial distillation of the organic extract. If desired, substantially all of the solvent may be removed in the first distillation operation and water-miscible solvent may be added to the residue to be put back into solution. When a second distillation operation is carried out, the solvent can be removed again as desired. If the remaining solvent is sufficient to preserve the steroids in solution, the fraction of the distillation residue from the second distillation can serve as a paste solution for the further processing of the steroids. If not, a paste solution can be prepared by adding water-miscible solvent to the residue. The steroid indices contained in the paste solution can be recycled as part of the steroid entry to the reaction stage or they can be subjected to a rebalancing step to increase the yield of the product of Formula 5000. In any case, the solution of The paste may typically contain between about 1 and about 10% by weight of steroids, including between about 0.5 and about 6% by weight of the product of Formula 5000 (in which carbon 5 is not substituted), between about 0J and about 5% by weight of the substrate of Formula 6000 and between about 0.01 and about 5% by weight of the 5β-cyano-7a-alkoxycarbonyl intermediate of Formula C. In certain preferred embodiments, when the primary crystallization solvent is a lower alcohol, the recovery of steroids can be determined from the following algorithm: R = KpD / (1 + D (Kp-1)) where: Cm = concentration of usable steroids in mother liquors M = volume of mother liquor f = fraction of lower alcohol removed in the concentration of mother liquor d = volume of non-miscible solvent in water added h = volume of aqueous extraction medium added Cmfh = concentration of usable steroids in the phase of concentrated mother liquors with respect to water Cd = concentration of steroids usable in the organic extract phase after phase separation Kp = partition coefficient; equilibrium ratio between the concentration of steroids usable in the organic extract phase and that of the aqueous phase R = recovery percentage = moles of steroids in the organic extract phase / (moles of steroids in mother liquor); and Mf = h + dm / f = f Kp = Cd / Cmfh (M (1-f) + h) Cmfh + dCd = Mcm D = d / MH = h / M Based on this algorithm, the fraction of volume of the lower alcohol removed in the mother liquor concentration and the volume fractions of water and non-miscible solvent in water mixed with the extraction feed solution to provide a substantially maximum recovery (R). RE-BALANCED The paste solution can be processed to convert steroids contained therein into the compound of Formula 5000, preferably into a species of Formula 5000 that is not substituted on carbon 5. The most remarkable of the steroidal components that can be converted from this form is the compound of Formula 6000 and the cyanoester of Formula C. Although this pulp processing is described herein as a rebalancing, it usually involves or requires the addition of alkoxy and base source to the pulp solution. to effect the conversion of steroid indices into the compound of Formula 5000. Preferably, the paste solution is mixed with the source of the fresh alkoxy group to promote conversion of the unreacted Formula 6000 substrate into the product of Formula 5000. If the source of the alkoxy group is different from a base, a base is also usually added to the paste solution, since the base The primary reaction in the primary reaction has been removed in the extraction procedure or has been consumed in the primary reaction stage. Preferably, a solution of the metal alkoxide reagent is added to the pulp solution in relative proportions which may depend on the composition of the pulp solution. The composition of the metal alkoxide reactant solution is conveniently the same as or similar to that described above for use in the initial conversion of the substrate of Formula 6000 into the Product of Formula 5000. The alkoxide reactant is preferably charged into the paste solution in a ratio of at least about 1.25 equivalents, more preferably at least about 1.5 equivalents of metal alkoxide to the sum of equivalents of the substrate of Formula 6000 plus 5-cyanohydroxyester in the solution. The rebalancing is preferably performed at a temperature greater than 50 ° C, more preferably at least about 70 ° C, more typically between about 80 ° C and about 95 ° C for a period between about 0.5 and about 6, varying the reaction period inversely with temperature as discussed above with reference to the primary stage of the reaction. After having reached a new equilibrium, the solution of the paste rebalancing reaction is cooled and more product of Formula 5000 crystallized therein. Cooling is preferably performed at the high speeds described hereinabove for the primary reaction step, to minimize the reverse reaction of the product of Formula 5000 to substrate of Formula 6000 during the cooling step. The crystallization is also carried out substantially in the manner described above for the recovery of the product of Formula 5000 from the original reaction mixture. Optionally, the product of the rebalancing can be crystallized from a derivative of the pulp reaction solution, for example, a concentrate thereof. Optionally, a sacrificial saponification target compound is incorporated into the paste solution to remove any free hydroxide that may have been incorporated into the solution as a contaminant of the metal alkoxide reagent or otherwise. For example, the moisture contained in the organic extract from the extraction stage may not be completely eliminated in the concentration stage of the extract, especially if the water-miscible 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 paste rebalancing solution are preferably approximately the same as those described above for the primary reaction stage. Particularly preferred are methyl formate and trimethyl orthoformate. According to an alternative steroid recovery scheme, the paste solution can be recycled to the initial reaction step for further conversion of steroidal indices into the product of Formula 5000. In this case, the general procedure comprises an initial reaction step. wherein the compound of formula 6000 is contacted with a source of the alkoxy group in a primary reaction zone. The recovered steroid indices are recycled in a paste solution to the primary reaction zone where more compound of Formula 5000 (unsubstituted at C-5) is produced by conversion of the compound of Formula 6000, or compound of Formula C, contained in the recovered steroid indices. In a variant of this embodiment, the reaction can be carried out only until partial conversion in the primary reaction zone, ie, the reaction is terminated before the conversion of the compound of Formula 6000 has progressed to equilibrium at the temperature in the that the reaction is over. The product of Formula 5000 is recovered from the reaction solution according to any of the recovery schemes described above, preferably by direct crystallization in the reaction solution without acidification. Then, the unreacted Formula 6000 compound and other steroidal indices are recovered from the crystallization mother liquor, typically according to the above-described mother liquor extraction process.; and the steroid indices are recovered from the organic extract, preferably by solvent exchange in which the non-miscible extraction solvent in water is replaced by a water-miscible solvent, preferably the same solvent as is used in the primary reaction zone. The resulting paste solution can be recycled to the primary reaction zone for conversion of the unreacted Formula 6000 substrate into the product of Formula 5000 as described above. The partial conversion can be effected advantageously in a continuous primary reaction zone, in which the substrate of Formula 6000, the base and the source of alkoxy groups are introduced continuously or intermittently, and from which the reaction mixture of Formula 5000 can be withdrawn continuously or intermittently. A piston flow reactor can be used for the conversion, that is, the primary reaction zone comprises a piston flow reaction path. The source of alkoxy groups preferably comprises an esterification reagent comprising a metal alkoxide in a corresponding alcohol solvent. The composition of the esterification reagent is preferably equal to or comparable to that described above for the primary reaction step, and the ratio between metal alkoxide and substrate of Formula 6000 is also preferably in the range described above for the primary reaction. The conversion of the substrate of Formula 6000 to the Product of Formula 5000 is preferably carried out at an elevated temperature in the ranges described above for the primary reaction. The reaction is preferably terminated before the final yield of the reaction has worsened by more than 10% with respect to 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 case, at a sufficient rate so that the final yield of the reaction after cooling is not more than 10% lower than the final yield at the end of the reaction. As described above, a plug flow reactor or other continuous reactor can be operated to complete the conversion to equilibrium instead of partial conversion. In any case, the steroid indices can be recovered from the mother liquor in the manner described above. The recovered steroid indices may be rebalanced in the pulp solution or the pulp solution may be recycled to the primary reaction zone for the conversion of the substrate of Formula 6000 and other steroidal indices into the compound of the product of Formula 5000.

DESCRIPTION OF THE PROCESS DEVELOPMENT SCHEME Fig. 1 depicts a work-up diagram illustrating a process incorporating the improvements described herein into the conversion of a diketone intermediate to a hydroxyester intermediate which is useful in the preparation of epierenone or related compounds .

A solution comprising a diketone in a reaction medium comprising methanol is prepared. The diketone may typically correspond to Formula VI-1: The solution is introduced into a primary reaction vessel 1 which 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 container can circulate. Then, an esterification reagent comprising a solution or dispersion of potassium methoxide in methanol is introduced into the reaction medium within the primary reaction vessel 1 and the reaction medium is heated to a temperature above 70 ° C, more typically between about 80 ° C and about 110 ° C. 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. The heat for the reaction is provided through the coils and / or from the external heat exchanger. Periodic HPLC analyzes are conveniently followed by the progress of the reaction. When the conversion substantially reaches equilibrium, typically in less than 2 hours when the temperature is 85 ° C to 90 ° C, or in approximately 30 to 45 minutes when the temperature is 95 ° C to 110 ° C, the reaction is it ends by cooling the reaction mass as rapidly as possible at a temperature no greater than about 60 ° C. When an autogenous pressure is generated at the reaction temperature, a part of the cooling is obtained by the release of the pressure and subsequent instantaneous vaporization of methanol. A cooling fluid is provided instead of steam or other heating fluid to the coils and / or to the external heat exchanger to lower the temperature to the desired level. The cold reaction mass is passed to a primary crystallizer 7 in which it is further cooled to a temperature below about 15 ° C, preferably between about -5 ° C and about 5 ° C, causing the crystallization of the hydroxy ester reaction product which corresponds to the formula V-1: and precipitation of the hydroxy ester from the solution. The resulting suspension is transferred to a centrifuge 9 where the crystalline product is separated from the mother liquor of crystallization. The centrifuge cake is preferably washed with fresh methanol and the washing solution is combined with the mother liquor. The crystalline hydroxyester product is removed and may be subjected to further processing as described in another section of this document for conversion to epierenone. The mother liquors discharged from the centrifuge are introduced into a distiller or evaporator 11 in which the methanol is removed, thus concentrating the mother liquor to not more than half of its original volume. Typically, the mother liquor is concentrated four or five times. However, the degree of concentration is preferably insufficient to cause the precipitation of steroids from the liquid phase. Methylene chloride or other water immiscible solvent is added to the mother liquor concentrate in a pre-mix container with solvent adjustment 13, thereby producing a steroid solution immiscible with water which is transferred to the extraction zone of a vessel. Extraction 15. To facilitate the recovery of the steroid indices of the organic extract, the water immiscible solvent is preferably more volatile than the water-miscible solvent used for the reaction and crystallization steps. Optionally, the extraction vessel 15 may comprise a multistage extraction column countercurrent or with the currents in the same direction. In the extraction system, the steroids are preferably distributed in the organic phase, and the cyanide and other inorganic materials are distributed in the aqueous phase. The methanol is substantially divided between the phases. The aqueous refining of the extraction, comprising cyanide ion, potassium ion and a methanol fraction, is purged from the process. The organic extract contains steroidal indices including unreacted diketone, residual hydroxyester product, 5β-cyanohydroxyester (corresponding to formula C), and other steroidal indices. The extract also contains a significant fraction of methanol. The organic extract withdrawn from the extraction system 15 is subjected to a solvent exchange to remove the immiscible solvent in water and produce a paste solution of steroid indices in a water-miscible solvent, preferably methanol. For this purpose, the organic extract is first introduced into a distiller or evaporator 17 in which the extraction solvent immiscible with water is substantially removed. When the extract contains a significant fraction of methanol or another water-immiscible crystallization solvent, the fraction of the distillation residues from the distillation of the extract may constitute a suitable paste solution directly for the subsequent treatment of the recovered steroid indices. Alternatively, as discussed above, the distillation residues may comprise a steroid suspension or a substantially solid steroid residue to which is added methanol or other water miscible solvent to redissolve the steroids. The resulting solution may be subjected to further distillation for the removal of the residual methylene chloride or other non-miscible solvent in water. According to additional alternatives, also discussed above, methanol or other water-miscible solvent may be added during the distillation. When the solvent of the extraction is methylene chloride, the moisture dissolved or entrained in the organic extract can be removed in the form of a water azeotrope / methylene chloride of low boiling point during the distillation of the extract. The headers of the distiller or evaporator 17 are condensed in a header condenser 19 and the condensate is discharged into a manifold 21. The condensate, comprising methylene chloride or another non-miscible solvent in water, can be recycled to the extraction stage, typically by transfer to the premix vessel 13. Fig. 1 illustrates the transfer of the fraction of the distillation residues from the extract, either solution, suspension or wet solid, to a paste tank 23 where water-miscible solvent is added, preferably methanol, producing a paste solution of steroid indices. The pulp solution is preferably transferred to a secondary reaction vessel 25. A solution of potassium methoxide in methanol is added to the secondary reaction vessel and a balancing reaction takes place in which the unreacted diketone, 5β-hydroxyester compound and others Steroid indices can be converted into the desired hydroxy ester product. The rebalancing reaction is carried out under conditions comparable to those of the primary reaction in reactor 1. Methyl formate or another saponification target may optionally be included in the potassium methoxide / methanol solution and / or introduced into the reaction vessel high school. After rebalancing, the paste reaction mass is transferred to a secondary crystallizer 27 where it is cooled to crystallize the hydroxyester. The resulting suspension is transferred to a centrifuge 29 for separation of the secondary hydroxy ester crystallization culture from the secondary mother liquor. A methanol wash of the centrifuge cake is combined with the secondary mother liquor. Secondary mother liquors including wash waters are recycled and combined with the primary mother liquor for extraction. If desired, a fraction of the secondary mother liquor can be purged for the removal of organic impurities. According to an additional option, the paste solution can be recycled to the primary reaction vessel for the conversion of steroidal indices contained in the paste solution into the desired hydroxyester. However, the use of a different secondary reactor is preferred to avoid recycling of organic impurities or residual cyanide ion to the primary reaction zone.

REACTION SCHEME 1 A 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 may begin with androstenedione or a related starting material). wherein -A-A- represents the group -CHR1-CHR2- or -CR1 = CR2-; wherein 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, hydroxycarbonyl, cyano, and aryloxy. Using a bioconversion procedure, a targeting 11-hydroxy group is introduced into the compound of Formula 13600, thereby producing a compound of Formula 8600: wherein R 2 and -A-A- are as defined above for formula 13600.

Preferred organisms that can be used in this hydroxylation step and conditions for bioconversion are described in U.S. Patent No. 5,981, 744, which is incorporated herein by reference in its entirety. Preferably, the compounds of Formula 13600 and 8600 correspond to the Formula VINA wherein -A-A- is -CH2-CH2- and R12 is hydrogen, lower alkyl or lower alkoxy. In further accordance with the procedure of scheme 1, the compound of Formula 8600 is reacted under alkaline conditions with a cyanide ion source producing an enamine compound of Formula 7600 wherein -AA-, and R12 are as defined above for formula 13600. Cyanurization of the 11a-hydroxy substrate of Formula 8600 can be performed by reacting it with a cyanide ion source such as a ketone cyanohydrin, plus preferably acetone cyanohydrin, in the presence of a base and an alkali metal salt, most preferably LiCl. Alternatively, the cyanurization can be performed without a cyanohydrin using an alkali metal cyanide in the presence of an acid. Preferably, the compounds correspond to Formula 7600 wherein -A-A- is -CH-CH2- and R 2 is hydrogen, lower alkyl or lower alkoxy. Still more preferably the compound of Formula 7600 is 5'R (5'a) .7'ß-20'-aminohexadecahydro-11 'ß-hydroxy-10'a.13'a-dimethyl-3J5-dioxoespiro [furan-2 (3 / - /) J7'a (5 '/ - /) - [7.4] methane [4H] cyclopenta [a] phenanthrene] -5'-carbonitrile. In the next step of the synthesis of Scheme 1, the enamine of Formula 7600 is hydrolyzed to produce a diketone compound of Formula 6600 wherein -A-A- and R12 are as defined in Formula 13600. Any aqueous mineral or organic acid can be used for hydrolysis. Hydrochloric acid is preferred. To improve productivity, a water miscible organic solvent, such as a lower alkanol, is preferably used as a cosolvent. Preferably, the compounds correspond to Formula 6600 where -A-A- is -CH-CH2- and R12 is hydrogen, lower alkyl or lower alkoxy. More preferably, the compound of Formula 6600 is 4'S (4'a) .7'a-Hexadecahydro-11 'a-hydroxy-10'ß.1 S'ß-dimethyl-S'.d ^ O'-trioxoespyr [furan-2 (3H) J 7'ß- [4.7] methane [17H] c'clopenta [a] phenanthrene] -5'β (2'H) -carbonyltriol. In a particularly preferred embodiment of the invention, the enamine product of Formula 7600 is produced from the compound of Formula 8600 in the manner described in U.S. Patent No. 5,981,744, and is converted in situ to the diketone in Formula 6600. In the next step of the synthesis of Scheme 1, the diketone compound of Formula 6600 is reacted with a metal alkoxide to open the ketone bridge link between positions 4 and 7, cleave the bond between the carbonyl group and the carbon 4, form an a-oriented alkoxycarbonyl substituent in the 7-position and remove the cyanide in the carbon 5. The product of this reaction is a hydroxyester compound corresponding to the formula 5600 wherein R7 represents a lower alkoxycarbonyl radical or hydroxycarbonyl; and -AA- and R12 are as defined in Formula 13600. The particular reaction conditions for this reaction are described hereinbefore in the sections describing the improvements at high temperature, extraction conditions of mother liquor and the use of methyl formate. Preferably, the compounds correspond to Formula 5600 wherein -A-A- is -CH2-CH-, R12 is hydrogen, lower alkyl or lower alkoxy and R7 is lower alkoxycarbonyl. More preferably, the compound of Formula 5600 is Methyl hydrogen 11aJ7a-Dihydroxy-3-oxopregn-4-en-7a.21-dicarboxylate,? -lactone. The compound of Formula 5600 can be isolated by the methods described hereinabove for compounds of Formula 5000. The crude 11a-hydroxy-7a-alkanoyloxycarbonyl product is collected again in the solvent for the next reaction step of the process, which is the conversion of the 11-hydroxy group into a good leaving group at the 11-position thereby producing a compound of Formula 4600: wherein R111 is lower arylsulfonyloxy, alkylsulfonyloxy, acyloxy or halide; -A and R12 are as defined in Formula 13600, R7 is as defined in Formula 5600. Preferably, 11a-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 of Formula 5600. This reaction is described in more detail in U.S. Patent No. 5,981,744. Preferably, the compounds correspond to the Formula 4600 wherein -A-A- is -CH2-CH2- and R12 is hydrogen, lower alkyl or lower alkoxy. More preferably, the compound of Formula 4600 is Methyl hydrogen 17a-Hydroxy-11 a- (methylsulfonyl) oxy-3-oxopregn-4-en-7a.21 -dicarboxylate,? -lactone. When an acyloxy leaving group is desired, the compound of Formula 4600 is preferably 7-methyl hydrogen 17-hydroxy-3-oxo-l 1a- (2.2.2-trifluoro-1-oxoethoxy) -17a-pregn-4-en- 7a.21 -dicarboxylate,? -lactone; or 7-methyl-11a- (acetyloxy) -17-hydroxyo-3-oxo-17a-pregn-4-en-7a.21-dicarboxylate,? -lactone. In an alternative and preferred embodiment of the invention, the compound of Formula 4600 is crudely recovered as a concentrated solution by removal of a portion of the solvent. This concentrated solution is used directly in the next step of the process, which is the removal of the leaving group 11a of the compound of Formula 4600, thereby producing an ester of Formula 2600: wherein -AA- and R12 are as defined in Formula 13600, and R7 is as defined in Formula 5600. For the purposes of this reaction, the R 11 substituent of the compound of Formula 4600 can be any leaving group whose removal is effective to generate a double bond between carbon atoms. and 11. 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 may be used, but lower alkanoic acids are preferred. Advantageously, the reactant for the reaction additionally includes an alkali metal salt of the alkanoic acid used. It is particularly preferred that the leaving group comprises mesyloxy and the reactant for the reaction comprises formic acid or acetic acid and an alkali metal salt of one of these acids or another lower alkanoic acid. When the leaving group is mesyloxy and the removal reagent is formic acid and potassium formate, a relatively high proportion of olefin 9.11 is observed with respect to 11.12. The conversion of the substrate of Formula 2600 into the product of Formula 1600 can be performed 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 then. In another embodiment of the invention, the hydroxy ester of Formula 5600 can be converted to the ester of Formula 2600 without isolation of the intermediate compound of Formula 4600. In this process, the hydroxyester is taken up in an organic solvent such as methylene chloride; and an acylating agent, for example, methanesulfonyl chloride, or a halogenating agent, for example, sulfuryl chloride, is added to the solution. The mixture is stirred and, when halogenation is involved, an HCl scavenger such as imidazole is added. This series of chemical transformations may be performed using the methods described herein or in U.S. Patent 5,981,744. 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 wherein -AA- and R12 are as defined above for formula 13600 and R7 is as defined above for Formula 5600. This epoxidation reaction can be carried out using the procedure described in 5,981,744 or using the improved epoxidation processes described herein and is very useful as the final stage of the synthesis of Scheme 1. In many of the various embodiments, the method of the present invention can combine the improvements described for step 3, which involves the transformation of a compound of Formula 6600 in a compound of Formula 5600 and the improvements described for the epoxidation step, which involves the transformation of a compound of Formula 2600 into a compound of Formula 1600. In the general procedure for converting a compound of Formula 13600, in particular canrenone, in a compound of Formula 1600, in particular epierenone, each of the improvements of the process of Stage 3 can be combined individually or collectively with the improvements of the epoxidation stage. In a particularly preferred embodiment, the general procedure of Scheme 1 is performed as indicated below.

Improved epoxidation process The epoxidation according to the process described herein can be performed at an unsaturation site in the steroid core. As described herein, the process is especially advantageous in the epoxidation of trisubstituted bonds such as a 9,11-olefin. Substrates 9 1 that are useful in the process of this invention can include, for example: 1599 wherein 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; -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, cyano, and aryloxy, or R1 and R2 together with the carbons of the structure steroid to which they are attached form a cycloalkyl group; -B-B- represents the group -CHR15-CHR16-, -CR15 = CR16 or an a- or β-oriented group: 316, 16 V CH CH I I -CH-CH2-CH- wherein 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 steroidal nucleus to which they are coupled, form a cycloalkylene group, (e.g., cyclopropylene). 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 structure of carbocyclic or heterocyclic ring, or R8 and R9 together with R6 or R7 comprise a carbocyclic or heterocyclic ring structure condensed with the pentacyclic ring D; -G-J- represents the group mcR11- wherein R11 is selected from the group consisting of hydrogen, alkyl, substituted alkyl and aryl; -D-D- represents the group: -CHR4-CR! \ -CR4 = C J wherein R 4 and R 5 are independently selected from the group consisting of hydrogen, halo, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, and aryloxy or R 4 and R 5 together with the carbons of the steroid structure at which are linked form a cycloalkyl group; -E-E- represents the group -CHR6-CHR7- or -CR6 = CR7-; where R6 is selected from the group consisting of hydrogen, halo, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, and aryloxy; and R7 is selected from the group consisting of hydrogen, hydroxy, protected hydroxy, halo, alkyl, cycloalkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, aryloxy, heteroaryl, heterocyclyl, acetylthio, furyl and furyl substituted, or R6 and R7, together with the carbon atoms C-6 and C-7 of the steroidal nucleus to which R6 and R7 are respectively coupled, form a cycloalkylene group, or R5 and R7, together with the carbon atoms C-5, C- 6 and C-7 of the steroidal nucleus form a pentacyclic ring fused with the steroidal nucleus and comprising a 5.7-lactol, 5.7-hemiacetal or 5.7-lactone corresponding to the structure: wherein R72 comprises = CH (OH), = CH (OR73) or = CH = 0. R11 is preferably hydrogen but may also be alkyl, substituted alkyl or aryl. When R 11 is substituted alkyl, the substituents may include halides and other moieties that do not destabilize the epoxide ring.

When R11 is aryl, it may include substituents that are not strongly electron attractants. 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, butyl and propyl straight chain, branched or cyclic; methoxy, ethoxy, propoxy, butoxy, hydroxymethyl, hydroxyethyl, hydroxyethyl, hydroxybutyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, butoxymethyl, butoxyethyl, butoxybutyl, butoxybutyl, hydroxycarbonyl, cyano, phenoxy, benzyloxy; -A-A- represents the group -CHR1-CHR2- or -CR1 = CR2-; where R1 and R2 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, butoxybutyl, butoxybutyl, hydroxycarbonyl, methoxycarbonyl, propoxycarbonyl, butoxycarbonyl, acetoxymethyl, acetoxyethyl, acetoxypropyl , acetoxybutyl, propionyloxymethyl, propionyloxyethyl, butyryloxymethyl, butyryloxyethyl, cyano, phenoxy and benzoxy; or R and R2 together with the carbons of the steroidal nucleus to which they are coupled form a cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene or cycloheptylene (saturated) group; -B-B- represents the group -CHR15-CHR16 -, - CR15 = CR16- or an a- or ß-oriented group: 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, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, butoxymethyl, butoxyethyl, butoxybutyl, butoxybutyl, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, acetoxymethyl, acetoxyethyl, acetoxypropyl, acetoxybutyl, propionyloxymethyl, propionyloxyethyl, butyryloxymethyl, butyryloxyethyl, cyano, phenoxy and benzoxy; or R15 and R16, together with the C-15 and C-16 carbons of the steroidal nucleus to which R15 and R16 are coupled respectively form a cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene group; -D-D- represents the group 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, acetoxletilo , acetoxypropyl, acetoxybutyl, propionyloxymethyl, propionyloxyethyl, butyryloxymethyl, butyryloxyethyl, cyano, phenoxy and benzoxy; or R4 and R5 together with the carbons of the steroid skeleton to which they are attached form a cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene group; : CR 11 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; -EE- represents the group -CHR6-CHR7- or -CR6 = CR7-, where 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, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybuthyl, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, acetoxymethyl, acetoxyethyl, acetoxypropyl, acetoxybutyl, propionyloxymethyl, propionyloxyethyl, butyryloxymethyl, butyryloxyethyl, cyano, phenoxy and benzoxy; and 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, hydroxyethyl, hydroxybutyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxybutyl, 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, thiazole, pyridyl, pyrimidyl, oxazolyl, acetylthio, furyl, substituted furyl, thienyl and substituted thienyl; or R6 and R7, together with the carbons C-6 and C-7 of the steroid nucleus to which R6 and R7 are coupled respectively, form a cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene (saturated) group. In many embodiments, 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, butyl and propyl linear, branched or cyclic; methoxy, ethoxy, propoxy, butoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, and cyano; R10 and R13 are methyl, typically β-methyl; -A-A- represents the group -CH2-CH2- or -CH = CH-; -B-B- represents the group -CHR15-CHR16 -, - CR15 = CR16- or an a- or ß-orylated group: wherein 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 cyan; or R 5 and R 16, together with the C-15 and C-16 carbons of the steroidal nucleus to which R 15 and R 16 are respectively coupled, form a cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene group; -D-D- represents the group where R and R 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; -EE- represents the group -CHR6-CHR7- or -CR6 = CR7-, where 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 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; or R6 and R7, together with the carbons C-6 and C-7 of the steroidal nucleus to which R6 and R7 are respectively coupled, form a cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene (saturated) group. In various preferred embodiments, R 12 is selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, cyano, and aryloxy; R 10 and R 13 are methyl, paularly β-methyl; -A-A- represents the group -CH2-CH2-; -B-B- represents the group -CHR15-CHR16-; where R15 and R16 are hydrogen; or R15 and R16, together with the C-15 and C-16 carbons of the steroidal nucleus to which they are respectively coupled, form a cycloalkylene (saturated) group; -D-D- represents the group: - CR4- c: where R4 is hydrogen; -E-E- represents the group -CHR6-CHR7-; where R6 is hydrogen; wherein R7 is selected from the group consisting of hydrogen, furyl, substituted furyl, thienyl, substituted thienyl and acetylthio; or R6 and R7, together with the carbons C-6 and C-7 of the steroidal nucleus to which they are respectively coupled, form a cycloalkylene (saturated) group; -J-G- represents the group CIZZCR11 - where R11 is hydrogen. Unless otherwise indicated, the organic radicals referred to as "lower" in the present disclosure contain at most 7, and preferably 1 to 4, carbon atoms.

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 tere-butyl; methoxycarbonyl, ethoxycarbonyl and isopropoxycarbonyl are especially preferred. A lower alkoxy radical is preferably one derived from one of the d-C4 alkyl radicals mentioned above, especially from a primary C C alkyl radical; methoxy is especially preferred. A lower alkanoyl radical is preferably one derived from a straight chain alkyl having from 1 to 7 carbon atoms; formyl and acetyl are especially preferred. A methylene bridge bond at position 15.16 is preferably β-oriented. A preferred class of compounds that can be produced according to the methods of the invention are the 20-spiroxane compounds described in U.S. Patent 4,559,332, ie, those corresponding to formula IA: Preferably, the 20-spiroxane compounds produced by the novel processes of the invention are those of Formula I wherein Y1 and Y2 together represent the oxygen bridge bond -O-. Especially preferred are compounds of formula I in which X represents oxo. Of the 20-spiroxane compounds of Formula IA wherein X represents oxo, the most preferred ones are those in which Y1 together with Y2 represent the oxygen bridge bond -O-. Especially preferred compounds of formula I and IA are, for example, the following: 9a, Ha-epoxy-7a-methoxycarbonyl-20-spirox-4-en-3,21-dione, 9a, 11a-epoxy-7a-ethoxycarbonyl- 20-spirox-4-en-3,21-dione, 9a, Ha-epoxy-7a-isopropoxycarbonyl-20-spirox-4-en-3, 21 -dione, and the 1,2-dehydro analogue of each of these compounds; 9a, Ha-epoxy-6a.7a-methylene-20-spirox-4-en-3, 21 -dione, 9a, 11 a-epoxy-6β.7β-methylene-20-spirox-4-en-3, 21 -dione , 9a, Ha-epoxy-6β.7β; 15β.16β-bismethylene-20-spirox-4-en-3,21-dione, and the 1,2-dehydro analog of each of these compounds; 9a, 11a-epoxy-7a-methoxycarbonyl-17β-hydroxy-3-oxo-pregn-4-en-21-carboxylic acid, 9a, 11-epoxy-7a-ethoxycarbonyl-17β-hydroxy-3-oxo-pregn 4-in-21 -carboxylic acid, 9a, 11a-epoxy-7a-isopropoxycarbonyl-17β-hydroxy-3-oxo-pregn-4-en-21 -carboxylic acid, 9a, 11 a-epoxy-17β-hydroxy-6a acid , 7a-methylene-3-oxo-pregn-4-en-21-carboxylic acid, 9a-acid, Ha-epoxy-17β-hydroxy-6β, 7β-methylene-3-oxo-pregn-4-ene-21-carboxylic acid, acid 9a, Ha-epoxy-17β-hydroxy-6β, 7β; 15β, 16β-methyl-3-oxo-pregn-4-en-21-carboxylic acid, and alkali metal salts, especially the potassium salt or ammonium salt of each of these acids and also a corresponding 1, 2-dehydro analogue of each of the above-mentioned carboxylic acids or of a salt thereof; methyl ester, ethyl ester and isopropyl ester of 9a, 11a-epoxy-15β, 16β-methylene-3,21-dioxo-20-spirox-4-en-7a-carboxylic acid ester, methyl ester, ethyl ester and isopropyl ester of acid 9a, Ha-epoxy-15β, 16β-methylene-3,21-dioxo-20-spiroxa-1,4-diene-7a-carboxylic acid, methyl ester, ethyl ester and isopropyl ester of 9a, 11a-epoxy-3-oxo- 20-spirox-4-en-7a-carboxylic acid, 9a, 11 a-epoxy-6β, 6β-methylene-20-spirox-4-en-3-one, 9a, 11a-epoxy-6β, 7β; 15β. 16β-bismethyl-20-pyrrox-4-en-3-one, methyl ester, ethyl ester and isopropyl ester of 9a, 11a-epoxy-17β-hydroxy-17a (3-hydroxy-propyl) -3 -oxo-androst-4-en-7a-carboxylic acid, 9a, 11 a-epoxy-17β-hydroxy-17a- (3-hydroxypropyl) -6a, 7a-methylene-androst-4-en-3-one, 9aJ 1 a-epoxy-17β-hydroxy-17a- (3-hydroxypropyl) -6β, 7β-methylene-androst-4-en-3-one, 9a, Ha-epoxy-17β-hydroxy-17a- (3-hydroxypropyl) - 6ß, 7ß; 15ßJ6ß-bismethylene-androst-4-en-3-one, including 17a- (3-acetoxypropyl) analogues and 17a- (3-formyloxypropyl) of the aforementioned androstane compounds, and also 1,2-dehydro analogues of all the mentioned compounds of the androst-4-en-3-one series and 20-spirox-4-en- 3-one. The chemical names of the compounds of Formulas I and IA, and of analogous compounds having the same structural characteristics, are derived according to the current nomenclature in the following manner: for compounds in which Y1 together with Y2 represents -O-, from 20-spiroxane (for example a compound of Formula IA wherein 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-17a-pregnen-21-carboxylic acid; and for those in which each of Y1 and Y2 represents hydroxy and X represents two hydrogen atoms, from 17β-hydroxy-17a- (3-hydroxypropyl) -androstane. As the cyclic and open-chain forms, ie, lactones and 17β-hydroxy-21-carboxylic acids and their salts, respectively, are so closely related that the latter can be considered merely as a hydrated form of the former, it will be understood hereinafter and as indicated hereinabove, unless otherwise specified, both in the final products of formula I and in the starting materials and intermediates of analogous structure, in each case, all the forms mentioned above joint Illustrative substrates for this reaction include? -9,11-canrenone, and Generally, the epoxidation process of the invention is carried out in accordance with the process described in US 4,559,332, as described more particularly 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. Patent documents 4,559,332, 5,981, 744 and 6,610,844 are expressly incorporated herein by reference. In the epoxidation process described in these references, a solution of the substrate 9 in a suitable solvent is contacted with an aqueous hydrogen peroxide composition in the presence of an activator such as, for example, trichloracetonitrile or, preferably, trichloroacetamide. . In order to ensure complete conversion of the substrate to the 9, H-epoxide, the epoxidation reaction described in the references cited above is typically performed at a molar charge ratio of 10 moles of hydrogen peroxide per mole of steroidal substrate. It has now been found that the epoxidation reaction can be carried out with a significantly lower ratio of hydrogen peroxide to substrate 9 11 than indicated or illustrated in US 4,559,332, 5,981, 744 or in US 6,610,844. Operation at a relatively low ratio between peroxide and substrate provides the option of achieving any of several potential advantages, as described later in this document. In carrying out the reaction, preferably the substrate solution, 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 is added thereto. . Preferably, a solvent for the steroidal substrate is selected in which the solubility of the steroidal substrate and the epoxidized steroidal product is reasonably high, preferably at least about 10% by weight, more preferably at least about 20% by weight, but in wherein the solubility of the water is low, preferably less than about 1% by weight, more preferably less than about 0.5% by weight. In such embodiments, an epoxidation reaction zone comprising a two phase liquid reaction medium, with the substrate in the organic phase and hydrogen peroxide in the aqueous phase is established in the reaction vessel. Epoxidation of the substrate in the biphasic medium produces a reaction mass containing the epoxidized steroidal reaction product substantially within the solvent phase. Without being limited to a particular theory, it is believed that the reaction takes place in the organic phase or at the interface between phases and that a more than very small content of water in the organic phase effectively delays the reaction. After introducing the steroid solution into the reactor, all of the peroxide solution can be added in a short period of time before the reaction begins, for example, from 2 to 30 minutes, more typically from 5 to 20 minutes. When the resistance of the peroxide solution supplied to the reactor is greater than the concentration to be established at the beginning of the reaction, water can be charged and mixed with the organic phase before the addition of peroxide, adding water in a volume that subsequently dilutes the concentration of peroxide at the desired level at the beginning of the reaction. In those embodiments in which hydrogen peroxide is introduced at the start of the reaction cycle, the phase of the solvent and the solution of the added aqueous peroxide are preferably maintained at a relatively low temperature, more preferably, at less than about 25 ° C, typically at less than about 20 ° CJ more typically in the range of about -5 ° C to about 15 ° C, as the peroxide is introduced. Then, the reaction continues with stirring. Preferably the reaction is carried out in an inert atmosphere, preferably by means of a nitrogen purge in the upper space of the reactor. Generically, the peroxide activator can correspond to the formula: R ° C (0) NH2 where R ° is a group that has an electron attraction force (measured by the sigma constant) at least as high as the group monochloromethyl. Preferably, the promoter comprises trieloroacetonitrile, tricloacetamide or a related compound corresponding to the formula: i P '' C- R - C - N H wherein X1, X2, and X3 are independently selected from halo, hydrogen, alkyl, haloalkyl and cyano and cyanoalkyl, and Rp is selected from arylene and - (CX4X5) n-, where n is 0 or 1, with at least one of X1, X2, X3, X4 and X5 halo or perhaloalkyl. When any of X1, X2, X3, X4 or X5 is not halo, it is preferably haloalkyl, more preferably perhaloalkyl. Particularly preferred activators include those in which n is 0 and at least two of X1, X2 and X3 are halo; or wherein all 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, although mixed halides may also be suitable, as may perchloralkyl or perbromoalkyl and combinations thereof. Other suitable promoters include hexafluoroacetone dicyclohexylcarbodiimide. The buffer stabilizes the pH of the reaction mass. Without being bound by a particular theory, it is believed that the buffer also functions as a proton transfer agent to combine the peroxide anion and the promoter in a form that reacts with the substrate 9 11 to form 9, 11-epoxide. Generally, it is desirable that the reaction be carried out at a pH in the range of about 5 to about 8, preferably about 6 to about 7. Suitable compounds that can function both as a buffer and as a proton transfer agent include dimetal phosphates alkaline and alkali metal salts of dibasic organic acids, such as Na citrate or K tartrate. Particularly favorable results are obtained with a buffer comprising dipotassium hydrogen phosphate and / or with a buffer comprising a combination of dipotassium hydrogen phosphate and potassium dihydrogen phosphate in relative proportions between about 1: 4 and about 2: 1, more preferably in the range of about 2: 3. Borate buffers can also be used, but generally give conversions slower than dipotassium phosphate or KH2P0 or mixtures of K2HP04 / KH2P04. Whatever the composition of the buffer, it must provide a pH in the range indicated above. Apart from the general composition of the buffer or the specific pH that it can impart, it has been observed that the reaction proceeds much more efficiently if at least a part of the buffer comprises a dibasic hydrogen phosphate ion. It is believed that this ion can participate essentially as a homogeneous catalyst in the formation of an adduct or complex comprising the hydroperoxide promoter, which generation in turn can be essential for the general epoxidation reaction mechanism. In this way, the quantitative requirement for the dibasic hydrogen phosphate (preferably K2HP04) may be only a small catalytic concentration. Generally, it is preferred that a dibasic hydrogen phosphate be present in a proportion of at least about OJ equivalents, for example, between about OJ and about 0.3 equivalents, per equivalent of substrate. After the addition of the peroxide solution has been substantially completed, the temperature can be increased, for example, in the range of 15 ° C to 50 ° C, more typically 20 ° C to 40 ° C to increase the speed of the reaction and the conversion of the substrate into epoxide. Optionally, the peroxide solution can be added progressively during the course of the reaction, in which case the temperature of the reaction mass is preferably maintained in a range of about 15 ° C to about 50 ° C, more preferably between about 20 ° C and about 40 ° C as the reaction proceeds. In any case, the reaction rate in the two-phase reaction medium is normally limited by mass transfer, requiring modest to vigorous agitation to maintain a satisfactory reaction rate. In a discontinuous reactor, the completion of the reaction may require from 3 to 24 hours, depending on the temperature and intensity of agitation. The decomposition of hydrogen peroxide is an exothermic reaction. At ordinary reaction temperatures, the decomposition rate is low to negligible and the heat generated is easily removed by cooling the reaction mass under a temperature control. However, if the cooling system of the reaction or the temperature control system fails, for example, by loss of agitation, the decomposition rate can be accelerated by the resulting increase in the temperature of the reaction mass, which at its It can accelerate the velocity of autogenous heating of the reaction. When the initial molar ratio between peroxide and steroidal substrate is in the range described in US 4,559,332, US 5,981, 744 or US 6,610,844, that is, in the range of 10: 1 or greater, autogenic heating resulting from the loss Cooling can reach a temperature at which the decomposition becomes autocatalytic and therefore very fast and uncontrolled, resulting in a potential eruption of the reaction mass. If the temperature is high enough, destructive oxidation of the steroid substrate can generate additional heat in the reaction, further accelerating the rate of temperature rise and the severity of the resulting eruption. Other events other than loss of agitation can also potentially destabilize the peroxide and result in an exotherm leading to uncontrolled decomposition. For example, contaminants such as rust or other source of transition metals in the peroxide or substrate solutions can catalyze a rapid or uncontrolled release of oxygen from the aqueous phase. It has now been found that the epoxidation reaction can be carried out with a significantly lower ratio between the peroxide and the substrate 9 1 than that indicated or illustrated in the US documents. 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 found that the reaction can be carried out at a charge ratio of between about 2 and about 7 moles, preferably between about 2 and about 6 moles, more preferably between about 3 and about 5 moles of hydrogen peroxide per mole of the substrate? 9 11. Operation with such relatively low ratios between peroxide and substrate reduces the degree to which the reaction mass can be heated by the autogenous decomposition of the peroxide. Preferably, the ratio between peroxide and substrate is sufficiently low that the maximum temperature that can be reached by autogenous heating is lower than the threshold temperature of the autocatalytic decomposition, which can completely prevent the peroxide decomposition from reaching a level in the that an eruption of the reaction mass could occur. The operation at the load ratios described above makes this possible. When the epoxidation reaction is carried out at a relatively low temperature below the incipient decomposition temperature of the peroxide or when the decomposition rate is relatively low, additional protection against an uncontrolled reaction is provided. In this way, in the case of a disturbance of the process resulting in an accumulation of unreacted hydrogen peroxide can produce a small autogenous heating, at least initially, so that, even after the loss of agitation, the cooling capacity of the reactor remains sufficient under natural circulation to maintain the temperature of the reaction mass in a safe range, or at least the process operators have sufficient time to take corrective measures before reaching uncontrolled autocatalytic decomposition conditions. With this purpose, it is preferred that the epoxidation reaction be carried out at a temperature in the range of about 0 ° C to 50 ° C, more preferably in the range of about 20 ° C to about 40 ° C. Further protection against an uncontrolled reaction is provided by conducting the epoxidation reaction in a liquid reaction medium comprising a solvent having a boiling point at the reaction pressure which is well below the autocatalytic decomposition temperature of the peroxide, and preferably it is only slightly higher than the reaction temperature. Preferably, the boiling point of the organic phase of the reaction mixture is not greater than about 60 ° C, preferably it is not greater than about 50 ° C. Preferably, the selected solvent does not boil from the reaction mass at the reaction temperature, but vaporizes rapidly if the temperature increases by a small increase from about 10 degrees centigrade to about 50 degrees centigrade, so the heat of the Vaporisation serves as a heat sink preventing substantial heating of the reaction mass until the solvent has been substantially removed from the reaction zone. When the reaction is carried out at atmospheric pressure at a temperature in the ranges mentioned above, various solvents are available which meet these criteria and are also suitable for the epoxidation reaction. These include methylene chloride (eg atmospheric = 39.75 ° C), dichloroethane (eg atmospheric = 83 ° C, and methyl-butyl ether (eg = 55 ° C) .The water content of the reaction mass also serves as an important sink. of sensible heat.When the reaction is carried out at, near or below atmospheric pressure, the water content of the aqueous hydrogen peroxide solution serves as potentially much greater heat sink, although it is generally preferred to avoid conditions in which a substantial generation of steam is produced since this can also give rise to an eruption of the reaction mass, although much less violent than that which results from the autocatalytic decomposition of a peroxide compound.Thus, in one aspect, the present invention comprises performing the epoxidation reaction in a liquid reaction medium, preferably comprising a solvent for the steroid, which contains the steroidal substrate and the peroxide in said absolute and relative proportions, and at a relatively modest initial epoxidation reaction temperature, so that the decomposition of the peroxide content of the reaction mass in stoichiometric excess against the substrate loading does not produce, and preferably can not produce , an effective exotherm to initiate the autocatalytic decomposition of the peroxide compound, or at least not cause an uncontrolled autocatalytic decomposition thereof. To protect against uncontrolled decomposition at any time during the epoxidation cycle, it is additionally preferred that the combination of conditions mentioned above be such that the decomposition of the entire peroxide content of the reaction mass, at any time during the course of the the reaction can not produce an effective exotherm to initiate the autocatalytic decomposition of the peroxide compound, or at least does not cause an uncontrolled autocatalytic decomposition thereof. Optimally, the combination of substrate concentration, concentration of the peroxide compound and initial temperature is such that the decomposition of the stoichiometric excess or of the entire peroxide compound charge can not produce sufficient exotherm to initiate autocatalytic decomposition, or at least does not cause an uncontrolled autocatalytic decomposition of the same, even in adiabatic conditions, that is, after the loss of cooling in a well insulated reactor. The peroxide content of the aqueous phase, set at the beginning 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 steroid substrate? 9 in the organic phase it is between about 3% and about 25% by weight, more preferably between about 7% and about 15% by weight. Preferably, the components effective to promote the epoxidation reaction such as, for example, trieloroacetonitrile or trichloroacetamide, together with a phosphate salt such as alkaline dimetal hydrogen phosphate, are charged to the reactor with the steroid solution, before the addition of the aqueous peroxide. . The molar ratio between peroxide and phosphate is preferably maintained in the range of between about 10: 1 to about 100: 1, more preferably between about 20: 1 and about 40: 1. The initial concentration of trichloroacetamide or trieloroacetonitrile is preferably maintained between about 2 and about 5% by weight, more preferably between about 3 and about 4% by weight, in the organic phase; or in a molar ratio to the steroidal substrate of between about 1.1 and about 2.5, more preferably between about 1.2 and about 1.6. The volumetric ratio between the aqueous phase and the organic phase finally 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 limited to a particular theory, it is believed that the epoxidation reaction takes place in the organic phase or at the interface between the phases. In any case, the reaction mass is preferably stirred vigorously to promote the transfer of the peroxide to the organic phase, or at least to the phase. A high mass transfer rate is desired to promote the progress of the reaction, thereby shortening discontinuous reaction cycles and improving productivity, and to minimize the amount of peroxide in the reaction vessel at any given rate of solution addition. aqueous peroxide 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. (from 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 to remove heat from the epoxidation reaction, in addition to any additional heat increase. that results from the decomposition of peroxide. After completion of the epoxidation reaction, the unreacted hydrogen peroxide in the aqueous phase is preferably decomposed under controlled conditions in which the release of molecular oxygen is minimized or completely prevented. A reducing agent such as an alkali metal sulfite or an alkali metal thiosulfate is effective in promoting decomposition. Preferably, the aqueous phase of the final reaction mass, comprising unreacted peroxide, is separated from the organic phase, which comprises a solution of the steroidal product 9, H-epoxidized in the reaction solvent. Then, the aqueous phase can be "inactivated" by contacting the peroxide contained therein with the reducing agent. When the molar charge ratio between the peroxide and the steroidal 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. say, from 25% to 30% by weight in the case of hydrogen peroxide), the aqueous peroxide solution spent 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 can be diluted with water to reduce the concentration of peroxide and therefore the probability and degree of an exotherm that results from decomposition during phase separation and / or transfer of the aqueous phase, such as the transfer to another container for inactivation 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. The inactivation can be carried out 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 an alternative, the organic phase can be transferred to a different container after the separation of the aqueous phase, and the aqueous phase can be left in the reaction vessel. Then, the solution of the reducing agent can be added to the diluted or undiluted aqueous phase in the reaction vessel to effect the reduction of the residual peroxide. Alternatively, the diluted or undiluted peroxide solution may be added over a period of time to a container initially charged with an appropriate volume of reducing agent solution. When the reducing agent is an alkali metal sulphite, the sulphite ion reacts with the peroxide to form an sulphate and water. The decomposition reaction is highly exothermic. The decomposition is preferably carried out at a controlled temperature in the range between about 20 ° C and about 50 ° C by heat transfer from the aqueous mass in which the decomposition is carried out. For this purpose, the quench reactor can be provided with cooling coils, a cooling jacket or an external heat exchanger through which the inactivation reaction mass can circulate, for transferring the heat of the decomposition reaction to a cooling fluid. The inactivation mass is preferably subjected to moderate agitation to maintain a uniform distribution of the reducing agent, a uniform temperature distribution and rapid heat transfer. When the reducing agent is added to the spent peroxide solution, the addition is preferably carried out at a controlled rate to maintain the temperature of the inactivation reaction mass in the aforementioned ranges, so as to effect a controlled decomposition of the peroxide. The alternative procedure, that is, the process in which the peroxide solution is added to the reducing agent solution, avoids the presence of a large amount of peroxide which would otherwise undergo autocatalytic decomposition triggered by the addition of an agent of decomposition to it. However, this alternative requires the transfer of the spent peroxide solution while the inverse alternative allows the peroxide solution to remain in the epoxidation reactor while only the organic phase of the reaction mass and the reducing agent solution need transfer. Regardless of which alternative is followed, the inactivation reaction is preferably carried out in the temperature range specified above.

For the purposes of stopping the reaction, the aqueous inactivation solution charged in the inactivation reaction zone preferably contains between about 12% by weight and about 24% by weight, more preferably between about 15% by weight and about 20% by weight, of a reducing agent such as sulfite Na, bisulfite Na, sulfite K, bisulfite K, etc. The volume of inactivation solution is preferably sufficient for the reducing agent contained therein to be in stoichiometric excess with respect to the peroxide content of the aqueous phase to be inactivated. The volumetric ratio of the inactivation solution that is mixed with the peroxide solution can typically vary from about 1.2 to about 2.8, more typically from about 1.4 to about 1.9 after dilution with the aqueous water of the spent aqueous peroxide solution. Typically, residual organic solvent may remain in the reactor after the initial phase separation and have been trapped in the aqueous phase during the inactivation reaction. In addition, the inactivated aqueous phase may contain a salt of trichloroacetic acid, formed as a byproduct of the epoxidation reaction when trichloroacetamide is used as the promoter. Before removal of the inactivated aqueous phase, the contained reaction solvent is preferably removed therefrom, for example, by distillation of the solvent. If a solvent such as methylene chloride is entrapped in the inactivation reaction mixture and the aqueous phase thereof contains trichloroacetate, the aqueous phase is preferably heated before distilling the solvent to decarboxylate the trichloroacetate. The decarboxylation of the trichloroacetate can be achieved by heating to a temperature of, for example, 70 ° C or higher. If trichloroacetate is not removed, it can decompose during the distillation of the solvent producing chloroform and carbon dioxide. After separation of the aqueous phase from the reaction mass, the organic phase is preferably washed with water to remove the unreacted peroxide and any inorganic contaminants. For the removal of the residual peroxide, it may be useful for the wash water to contain a reducing agent. For example, the aqueous phase can be contacted with an aqueous wash solution having a pH in the range of 4 to 10 and typically containing 5% OJ in mol of reducing agent, preferably from about 0.2 to about 0.2%. 0.6% mole of reducing agent (such as, for example, aqueous solution of 6 to 18% sulphite Na), in a convenient volumetric ratio between wash solution and organic phase of between about 0.05: 1 to about 0.3: 1. After separation of the washing of the spent reducing agent from the organic phase, the organic phase is preferably washed sequentially with a dilute caustic solution (for example, from 0.2% to 6% by weight of NaOH in a volumetric ratio with respect to the phase organic from about 0J to about 0.3) followed by a wash with water or a solution with dilute acid (for example, a HCl solution of 0.5 to 2% by weight in a volumetric ratio to the organic phase of between about OJ and approximately 0.4). A final wash can also be carried out with more solution of bisulfite Na or metabisulfite Na or sulphite Na. When the R11 substituent of the epoxide product is other than hydrogen, it is generally desirable to avoid a highly acidic wash, such as a wash with HCl which can expose the product to an aqueous phase having a pH of 1 or less. When there is an alkyl substituent on carbon C-11, the epoxy group can be destabilized under highly acidic conditions. If there is a solvent such as methylene chloride in the dilute caustic wash, the aqueous phase thereof contains trichlorosodium acetate produced from the basic hydrolysis of the residual trichloroacetamide., and the aqueous phase is preferably heated before the distillation of the solvent to decarboxylate the trichlorosodium acetate. The decarboxylation of trichlorosodium acetate can be achieved by heating at a temperature of, for example, 70 ° C or higher. The caustic wash can be combined with the inactivated aqueous phase of the reaction mixture for the purposes of decarboxylation and distillation of the residual solvent. The washed organic phase is concentrated by evaporation of the solvent, for example, by atmospheric distillation, which results in the precipitation of steroids forming a relatively thick suspension with from about 40% to about 75% by weight of the contained steroid. When the mother liquors of a recrystallization step are recycled, as described below, the mother liquor can be mixed with the steroid suspension and the solvent component of the mother liquor can be removed under vacuum to again produce a slurry having a concentration of solids typically in the same range as the suspension obtained by removing the reaction solvent. A solvent in which the solubility of the steroidal product is relatively low, for example, a polar solvent such as ethanol, is added to the suspension obtained from the removal of the reaction solvent, or to the second suspension obtained by removing the solvent from the waters mother of recrystallization. Alternative solvents include toluene, acetone, acetonitrile and acetonitrile / water. In this stage, the impurities are digested in the solvent phase, thus retreating the solid phase steroidal product to increase its results in the test. When the digestion solvent is an alcohol such as ethanol, it can be added in a volumetric ratio between ethanol and the steroid content of between 6 and about 20. A portion of ethanol and residual organic solvent is removed from the resulting mixture by distillation, producing a suspension typically containing between about 10% by weight and about 20% by weight of the steroid product, where impurities and by-products are substantially retained in the solvent phase. When the solvent is ethanol, the distillation is preferably carried out at atmospheric pressure or slightly above.

After distillation of the digestion solvent, the solids of the steroidal product are separated from the residual suspension, for example, by filtration. The solid product is preferably washed with the digestion solvent and can be dried yielding a solid product substantially comprising the 9,11-epoxy steroid. Drying can advantageously be performed under pressure or under vacuum using an inert carrier gas at a temperature in the range of about 35 to about 90 ° C. The dry solids, wet filtered solids or the residual suspension obtained after the evaporation of the digestion solvent can be collected in a solvent in which the epoxy steroidal product is moderately soluble, for example, 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 of steroid. The resulting solution can be filtered, if desired, and then evaporated to remove the polar solvent and recrystallized from steroid 9, H-epoxy. When the solvent is 2-butanone, the evaporation is conveniently carried out at atmospheric pressure, although other pressure conditions can be used. The resulting suspension is cooled slowly to crystallize more steroid. For example, the suspension can be cooled relative to the distillation temperature (about 80 ° C in the case of 2-butanone at atmospheric pressure) to a temperature at which the yield of the steroidal product is considered satisfactory. The production of the highly pure steroidal 9,11-epoxy product of a suitable crystalline size can be obtained by cooling in stages and maintaining the temperature for a period between the cooling stages. An illustrative cooling program comprises cooling in a first stage to a temperature in the range of 60 ° C to 70 ° C, cooling in a second stage to a temperature in the range of about 45 ° C to about 55 ° C, cooling in a third stage at a temperature between about 30 ° C and about 40 ° C and cooling in a final stage at a temperature between about 10 ° C and about 20 ° C, with periods of 30 to 120 minutes between the cooling stages in which the temperature is kept substantially constant. Then, the recrystallized product can be recovered by filtration and dried. The drying can be carried out effectively at a temperature close to room temperature. The dried product can remain solvated with the polar solvent previously used in the product recovery protocol, typically ethanol. Drying and desolvation can be completed at elevated temperature under pressure or under vacuum, for example, at a temperature of 75 ° C to 95 ° C. The mother liquors of the recrystallization step can be recycled for use in refining the suspension of the steroid product obtained from the evaporative removal of the epoxidation reaction solvent, as described hereinabove.

At a charge ratio of 7 moles of peroxide per mole of substrate in the oxidation of the precursor 9-11 to epierenone, the decomposition of the peroxide releases only about 280 liters of molecular oxygen per kg of epierenone. With a charge ratio of 4 moles of peroxide per mole of substrate, the oxygen release is only about 160 liters / kg of epierenone. This contrasts with a release of 400 liters / kg of epierenone at a loading ratio of 10 moles of peroxide per mole of substrate. As an additional example, at a charge ratio of 4 moles of peroxide per mole of substrate, a substrate concentration of 12% in a solvent of methylene chloride, a concentration of peroxide in the aqueous phase of 30%, a temperature of initial reaction of 30 ° C, substantially at atmospheric pressure with an inert gas purge and a volume fraction of the upper reactor space of 15%, the maximum internal pressure that can be generated in the epoxidation reactor after the exothermic decomposition of the entire peroxide charge is approximately 682 psig (4706 kPa). In addition, even in this case, the initial exotherm is small enough so that an operator with reasonable experience has plenty of time to safely handle the loss of agitation or other mishap in the procedure that could potentially lead to a reaction not controlled. At the relatively low peroxide-substrate ratios described herein, a significantly lower potential oxygen release can be ensured with the same reactor payload that can be achieved at peroxide / substrate ratios of 10 or more.; or higher payloads in the reactor can be achieved with the same volume of oxygen release. At a constant work volume in an epoxidation reactor, both an increase in the payload and a reduction in the release of oxygen can be achieved. It is to be understood that the epoxidation process as described above has application beyond the various schemes for the preparation of epoxymexrenone, and can in fact be used for the formation of epoxides through 9,11-olefinic double bonds in a wide variety of substrates subjected to reaction in the liquid phase. Illustrative substrates for this reaction include? -9, H-canrenone, and As the reaction proceeds more rapidly and completely with tri-substituted and tetra-substituted double bonds, it is especially effective for selective epoxidation in such double bonds in compounds which may include other double bonds where the olefinic carbons are monosubstituted or even disubstituted. As epoxide preferably the most highly substituted double bonds, for example, 9,11-olefin, with high selectivity, the process of this invention is especially effective to achieve high yields and productivity in the epoxidation steps of the various reaction schemes described in other sections of this document. It has been shown that the improved process has a particularly advantageous application in the preparation of: by epoxidation of: the following examples illustrate the invention.

EXAMPLE 1 A potassium methoxide reagent solution was prepared by dissolving potassium methoxide in methanol at a KOMe concentration of 32% by weight. Methyl formate was added to the reagent solution in a proportion of 10% by weight (for example, pure methyl formate (8 g) was added to a 32% by weight solution (80 g) of KOMe in MeOH). The reagent solution containing methyl formate was maintained at room temperature for three days. An RC1 reactor (HP60, Hastelloy C, Mettler-Toledo, nominally 1400 ml) was charged with methanol (1105 g; <0.005% by weight) and a diketone compound corresponding to formula VI-1 (80.0 g): After VI-I, the reactor was closed and flushed with nitrogen (approximately 1 atm. (101.325 kPa)). The resulting suspension was heated to 62 ° C, after which a first charge of the potassium methoxide reagent solution containing methyl formate (44.4 g, 1 equiv of KOMe) was introduced into the reactor. The reaction medium was stirred under a nitrogen atmosphere and the KOMe was reacted with the compound of Formula VI-1 to produce the compound of Formula V-1: Formula VI-I after continuing the reaction for 1.5 hours, an additional charge of the KOMe solution containing methyl formate (26.7 g, 0.6 equiv of KOMe) was introduced into the reaction medium. The stirring of the reaction mixture at 62 ° C continued for a period of about 10 hours. Then, the reaction solution was cooled to 0 ° C, maintained for at least one hour, then filtered under vacuum through a rugged porous glass filter. The filter cake was washed twice with methanol (100 g each wash). Additional tests were carried out in the manner described above, with the exception that the reaction temperature was maintained at 80 ° C during one test, at 100 ° C during another test, and at 15 ° C in another test. At an elevated temperature, it was possible to add all the KOMe / MeOH reagent in a charge, which was performed at a rate of 48 g / min using a diaphragm pump. The reaction time was greatly reduced as the reaction temperature increased. The reaction at 100 ° C continued for only about 0.5 hours. Cooling from 100 ° C to 60 ° C required approximately four minutes.

EXAMPLE 2 Additional reaction assays were performed in the manner described in Example 1 but on a smaller scale. In each assay of this series of reactions, methanol (175 ml) and the compound of Formula VI-1 (9.60 g) were charged in a 175 ml (6 oz.) Fischer-Porter vessel lined with a Parr reactor head. The reaction times were substantially the same as in Example 1, although the reaction mixture at 100 ° C was cooled to 60 ° C in only 3 minutes. In some of the assays, biphenyl sulfone was added as an internal standard and samples were taken during the course of the reaction. The samples were diluted approximately 21-fold with a mobile HPLC phase before analysis using the short HPLC method. At this scale, a solution of the KOMe / MeOH reagent was added using a 10 ml syringe. The relative progress of the reaction at the various reaction temperatures is shown in the profiles described in Fig. 2. After crystallization of the hydroxyester of Formula V-1 in the reaction mixture and filtration of the crystallization mass, the mother liquor was returned to the reactor as a rinse for the residual content of the reactor. The resulting rinse solution was filtered again for further recovery of the hydroxyester.

In Table 1 the yields of the solid hydroxyester product of the crystallization of the reaction masses produced at reaction temperatures of 62 ° C and 100 ° C are shown.

TABLE 1 Improvement of the High Temperature Performance Experiment Test 2-A Test 2-B Test 2-C Test 2-D Temperature (° C) 62 62 100 100 Reaction time (h) 10 10 0.5 0.5 Scale (ml) 175 1400 175 1400 Purity of the solid (% by weight) 95 95 96 97 Yield of the solid (% in mol) 63 65 74 78 Waters (mol%) 10 11 13 10 Washing of the cake (% in mol) 3 2 2 1 Cleaning ( % in mol) NMa 1 NM 1 Total yield (% in mol) 76 78 89 92 a Not measured. It will be appreciated that a reaction at 100 ° C provides an increase 11 percent on the yield of the final crystallization versus a reaction at 62 ° C on a 175 ml scale, and a point increase of thirteen percent on a scale of 1400 ml. Based on a hydroxyester product, the improvement in performance is 17% on a scale of 175 ml and 20% at a scale of 1400 ml. When taking into account the hydroxyester content of the mother liquors, the yields at 100 ° C increase up to the 90% range.

EXAMPLE 3 Additional reaction tests were performed in the manner described in Examples 1 and 2 with the exception that the cooling rate was deliberately reduced to determine the effect of the cooling rate on the final yield. The results are indicated in Table 2.

TABLE 2 Impact of Cooling Rate and Reaction Time on Performance (175 ml Scale) Test Experiment 3-A Test 3-B Test 3-c Test 3-D Time at 100 ° C (min) 30 30 30 120 Time at 60 ° C (min) 3 20 60 3 Purity of the solid (% by weight) 95 95 94 92 Solid yield (mol%) 74 72 66 58 Stem water (% in mol) 12 12 12 20 Washing the cake (% in mol) 3 3 3 3 Cleaning (mol%) 1 0 1 1 Total yield (mol%) 90 87 81 83 It will be noted that the experiment in which the reaction mixture is maintained for 2 hours at 100 ° C showed a significant reduction of the total and isolated reaction yield. Samples of the reaction mixture during the maintenance period showed an increase in the number or concentration of impurities, but not a large reduction in the concentration of the hydroxyester product. It is believed that these data reflect an increase in the concentration of the open lactone (in C (17)), which is more soluble than the hydroxyester of Formula V, but which is analyzed as a hydroxyester of Formula V-1 due to the preparation procedure of acid samples that was used.

EXAMPLE 4 A further reaction and crystallization assay was performed in the manner described in assay C of Example 2 (175 ml scale) with the exception that the loading of the substrate of Formula VI-1 (2 x 6.8%) was twice the used in Example 2. The concentration of KOMe also doubled. The reaction time was extended to one hour because the concentration of the diketone of Formula VI-1 did not appear to immunize rapidly enough for the reaction to be completed in a shorter time. However, the additional reaction time did not materially improve the performance in this case. The isolated yield of the hydroxy ester of Formula V-1 was 65%.

EXAMPLE 5 An additional reaction and crystallization test was performed with a higher substrate loading of Formula VI-1 in the manner described in Example 5 although at a scale of 1400 ml instead of 175 ml and at a temperature of 115 ° C. This assay was performed using an untreated KOMe / MeOH solution, i.e. no methyl formate or other saponification target compound was added to the reagent solution or reaction medium. The isolated crystallization yield was 68%.

EXAMPLE 6 Additional diketone reactions of Formula VI-1 were performed with potassium methoxide in the manner generally described in Example 1. One of these (Test J) was carried out at a reaction temperature of 62 ° C, while the other two (Tests K and L) were carried out at 100 ° C. The J-test was carried out without treatment with methyl formate of the KOMe / MeOH reagent or the reaction medium. In the other tests, the KOMe / MeOH reagent was treated with methyl formate at a level of 10% by weight in the manner generally described in Example 1. Different batches of steroids were used in the various tests. The results are shown in Table 3: TABLE 3 Impact of KOMe Treatment (Recent KOMe, Two Steroid Lots, 1400 ml Scale, Rapid Cooling).

Test Experiment 1- Test 6- Test 1- Test 6- Enamite 6- B A D B C Treatment with KOMe Yes No Yes Yes no Temperature (° C) 62 62 100 100 100 Steroid Lot? 1A '001? 1A' 001 '001 Purity of the solid (% in 95 95 97 98 96 weight) Yield of the Solid (% 65 63 78 78 72 in mol) Waters mother (% in mol) 11 11 10 10 12 Washing the cake (% in 2 2 1 1 2 mol) Cleaning (% in mol) 1 0 1 3 2 Total yield (% in 78 76 92 93 87 mol) EXAMPLE 7 Conversions of diketone of Formula VI-1 were made in hydroxyester of Formula V-1 and crystallizations of the product of Formula V-1 in the manner generally described in the previous examples. Samples of the mother liquors of the crystallizations were kept at controlled temperatures for defined periods of time and then analyzed with respect to the concentration of the product of Formula V-1. No attempt was made to remove the cyanide ion from the mother liquor. In all but one of the experiments, a sample of mother liquor was maintained at a specific temperature for a specified period of time and then analyzed with respect to the hydroxy ester product of Formula V-1. The results are indicated in Table 4. The maintenance time for each entry was 30 minutes, except for the last entry at 60 ° C in which the maintenance time was six hours.

TABLE 4 Experiment Temperature, ° C Formula V-1 as percentage 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 Two observations can be extracted from this data. First, the speed of approach to equilibrium was slow so that a maintenance time of 30 minutes was not enough to reach equilibrium. Second, when the mother liquor sample was maintained at 60 ° C for six hours, there was a material increase (14%) in the concentration of the product of Formula V-1. However, when the balanced mother liquor of the ML-7 assay was attempted to cool, no crystallization was observed. Despite the 14% increase in the assay of the product of Formula V-1, the concentration was not high enough to initiate supersaturation.

EXAMPLE 8 To evaluate the effect of an extraction scheme with methylene dichloride / water on the hydrolytic degradation of the product of Formula V-1, both a representative sample of mother liquor (40 ml) and an amount of water (40 ml) were cooled to 1.5 ° C and then put in contact with each other. The concentration of steroids in the sample was controlled over time. The reduction of usable steroids was only 13.6% during a period of 21 hours.

EXAMPLE 9 A sample of diketone of Formula VI-1 (40 g) was added to anhydrous methanol (700 ml, 131 mM) in a reaction vessel. The resulting mixture was heated to 65 ° C and a solution of potassium hydroxide reagent (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 zero time. The reaction solution was stirred for 8 hours and the samples were periodically removed to measure the steroidal concentration by HPLC. The concentration profiles of the steroidal component versus time are indicated in Fig 3. After 8 hours, the reactor was cooled to -10 ° C with a maintenance time of one night. The solids were filtered and dried.

The yield of the hydroxy ester of Formula V-1 from the solid was 62.6 mol%. A part of the crystallization mother liquor (400 ml) was cooled to 1.5 ° C, methylene chloride (150 ml) was added to the mother liquor and the resultant steroid solution immiscible in water was cooled to 1.5 ° C. Water (330 ml) pre-cooled to 1.5 ° C was added to the steroid solution not miscible in water, the biphasic mixture was stirred for 5 minutes to promote mass transfer between the phases and the phase of the organic extract (methylene chloride) ) was separated from the aqueous refining phase and removed from the lower valve of the reactor. Samples were taken from both phases to determine the steroidal content. The analyzes are indicated in Table 5.

TABLE 5 Sample ID Water Phase Phase% of organic aqueous mother Equilibrium Formula V-1 hydroxy acid 0.9 0.8 0.2 114.1 dealkylated 5-CN-7 -COOH 1.4 1.1 0.0 80.1 Dicetone of Formula VI 2.4 0.9 0.0 38.9 Hydroxyester of Formula V-1 8.6 4.9 3.9 102.3 Cyanoester 2.1 0.0 2.3 1.6.6 Steroid byproduct 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 These data demonstrate that usable steroids can be extracted almost quantitatively from the mother liquor in a methylene chloride phase in a single extraction step. The distribution coefficient (Kp) can be easily calculated from the data: Kp = ([S] 0A / o) / ([Sa] A / a) where: [S] 0 = the concentration of steroid indices in the organic phase V0 = the volume of the organic phase [S] a = the concentration of steroid indices in the aqueous phase; and Va = the volume of the aqueous phase From the data in Table 5, Kp = 5.2. A similar calculation can be made for the cyanide ion, yielding a Kp for the cyanide ion of 93.5 for the aqueous phase. It can be determined that the total recovery of usable steroids in the organic extract is 47.4%, which is equivalent to a point increase of 11.2% of the molar yield against the yield obtained in the crystallization culture of the primary crystallization stage, ie , the crystallization of the hydroxyester of Formula V-1 in the reaction mixture.

EXAMPLE 10 A series of reaction tests were performed at 100 ° C on a scale of 1400 ml, substantially as described in Example 1, and the product of Formula V-1 crystallized in the reaction solution, also substantially as described in that example. The mother liquors were concentrated by vacuum distillation to approximately one fifth of their original volume. The distillation was carried out with a container temperature of about 30 ° C to minimize the dealkylation of the 7a-methoxycarbonyl group of the product of Formula V-1 contained in the mother liquor. The concentrated mother liquors were cooled to 1.5 ° C, mixed with methylene chloride and the resultant non-miscible steroid solution in water was cooled to 1.5 ° C and mixed with water at 1.5 ° C. The resulting biphasic mixture was stirred and then substantially separated as described in Example 9. The data from these reaction, crystallization and extraction tests of the mother liquor concentrate are indicated in Table 6.

TABLE 6 Test Crystallization Conc. Factor Vol. Vol. Kp Recovery Increase of the Stereoidal primary number of medium-yield ML mM conc. water MeCI2 (cale.) in the ML stage (0 (h) (d)% 10-A 63 26.8 0 0.42 0.17 27.6 78.3 14.2 10-B 62.4 32.8 0 0.38 0.17 5.2 47.4 1 1.2 10-C 66.4 24.3 0.5 0.41 0.17 (26.1) 82.8 15.4 10-D 54.4 31.7 0.6 0.4 0.2 (4.9) 44.8 13.7 10-E 65.9 24.1 0.6 0.4 0.2 (3.0) 41.3 7.9 10-F 54.3 40.2 0.6 0.4 0.2 (2.2) 36.5 13.7 10-G 60.3 32.4 0.76 0.4 0.3 (2.0) 45.4 14.1 10-H 44 53.8 0.81 0.16 0.71 (0.8) 62.3 25.6 10-1 61 31.4 0.8 0.36 0.43 (0.7) 33.8 8.1 10-J 60 33.4 0.8 0.25 0.55 (0.9) 30.7 7.8 Half. 59.17 33.08 50.33 13.7 The recovery percentage of Table 6 is calculated with the assumption of achieving an 85% conversion to the hydroxy ester of Formula V-1, diketone of Formula VI-1 and / or cyanoester in a paste solution derived from the organic extract.

It can be seen that increasing the volume of water with respect to the volume of methanol in the extraction feed solution (mother liquor concentrate) increases the partition coefficient in the organic phase (Kp), but also increases the loss fraction of steroid at a given steroid concentration in the aqueous refining phase. Thus, as indicated in Example 11 shown below, there may be a theoretical optimum relationship between the water and the organic solvent immiscible in water with respect to the concentrated mother liquors to which a maximum recovery of steroids is realized. However, in practice, the relationships used can be imposed mainly by the volumetric limitations of the processing vessel and considerations of operational stability and control. The preferred ratios between extraction feed solution, water and water immiscible solvent are substantially as described hereinabove.

EXAMPLE 11 The solids recovered from the mother liquors of the reaction batches of Example 10 were combined (45.9 g total), methanol and potassium methoxide (1.6 equiv. With respect to usable steroids) were added and a re-equilibrated reaction was carried out in the The resulting paste solution was heated at 65 ° C for 8 hours substantially as described in Example 1. The steroidal concentration in the reaction medium was monitored as a function of time by HPLC analysis. The profiles indicated in Fig. 4 show the progress of the reaction and the rebalancing. As the concentration of the hydroxy ester of Formula V-1 in the pulp solution was relatively high, it can be seen that the rebalancing was actually achieved in only about 4 hours. After 8 hours of equilibration, the reaction solution was cooled to -10 ° C and the hydroxy ester of Formula V-1 formed in the equilibrium crystallized in a secondary crystallization stage, separated from the secondary crystallization mother liquor and tested . It was found that the solid product had a purity of 93-95% by weight with respect to the desired hydroxyester. Based on the equations indicated above that describe the operation of the concentration stages of mother liquor and extraction, the recoveries can be calculated as a function of the volume of the mother liquor (M), concentration factor of mother liquor (f), volume of methylene chloride used in the extraction (d), and volume of water used in the extraction (h). These are shown in Table 7 where D = d / M and H = h / M: TABLE 7 Optionally, steroids recovered from the mother liquor can be recycled when used as a starting material for a subsequent reaction batch, thereby reducing the amount of recent diketone required for reactor loading. However, as described hereinabove, it is preferred that the recovered steroids be subjected to a different equilibration reaction instead of being recycled to the primary reaction step.

EXAMPLE 12 Synthesis of Methyl Hydrogen 9.11a-Epoxy-17a-hydroxy-3-oxopregn-4 ° en-7a.21 -dicarboxylate,? -lactone Crude precursor of epierenone 9 11 (1628 g, assaying the 78.7% ester) was added to a reaction vessel with methylene chloride (6890 ml) and stirred. After dissolving the solids, trichloroacetamide (1039 g) and dipotassium phosphate (111.5 g) were added to the mixture. The temperature was adjusted to 25 ° C and the mixture was stirred at 320 RPM for 90 minutes. 30% hydrogen peroxide (1452 g) was added over a period of ten minutes. The reaction mixture was allowed to come to 20 ° C and was stirred at that temperature for 6 hours, at which time the conversion was checked by HPLC. It was determined that the remaining ester was less than 1% by weight. The reaction mixture was added to water (100 ml), the phases were allowed to separate and the methylene chloride phase was removed. Sodium hydroxide (0.5 N, 50 ml) was added to the methylene chloride phase. After 20 minutes, the phases were allowed to separate and HCl (0.5 N, 50 ml) was added to the methylene chloride phase after which the phases were allowed to separate and the organic phase was washed with saturated brine (50 ml) . The methylene chloride phase was dried over anhydrous magnesium sulfate and the solvent was removed. A white solid (5.7 g) was obtained. The aqueous sodium hydroxide phase was acidified and extracted and the extract was treated yielding 0.2 g more of product. The yield of epoxymexrenone was 90.2%.

EXAMPLE 13 One reactor was loaded with crude precursor of? 9.11"eplerenone (1628 g) and methylene chloride (6890 ml) .The mixture was stirred to dissolve the solids and then charged with dipotassium phosphate (111.5 g) and trichloroacetamide. (1039 g) through the opening. Temperature and agitation were adjusted to 25 ° C and 320 RPM, respectively. The mixture was stirred for 90 minutes; then 30% hydrogen peroxide (1452 g) was added over a period of 10-15 minutes. Stirring was continued at 29-31 ° C until less than 4% of the initial charge of epierenone precursor determined by periodic evaluation by HPLC remained. This required approximately 8 hours. At the end of the reaction, water (2400 ml) was added and the methylene chloride portion was separated. The methylene chloride phase 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 approximately 45 minutes to remove unreacted trichloroacetamide. The methylene chloride fraction was washed sequentially with water (2700 ml) and then with a solution of sodium bisulfite (190 g) in water (3060 ml). The methylene chloride solution of epierenone was distilled at atmospheric pressure to a final volume of about 2500 ml. Methyl ethyl ketone (5000 ml) was charged. The mixture was distilled under vacuum and the solvent was removed to a final volume of about 2500 ml. Ethanol (18.0 I) was charged and about 3500 ml was removed by atmospheric distillation. The mixture was cooled to 20 ° C over a period of 3 hours 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 a nitrogen atmosphere for at least 30 minutes. Finally, the solid was dried in a vacuum oven at 75 ° C until an LOD <5.0%. In this way, 1100 g of the semipure epierenone were obtained. Recrystallization of the semi-pure epierenone in 8 volumes of methyl ethyl ketone (based on content) provides pure epinerenone with a recovery of approximately 82%.

EXAMPLE 14 An pie 11-epierenone 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).

Water (25.6 ml) was added to the methylene chloride mixture. The amount was adjusted to accommodate the concentration of hydrogen peroxide introduced in the next operation. In this case, the water was sufficient to dilute the concentration of the aqueous hydrogen peroxide subsequently added (35% by weight) to a desired level of 30% by weight. The mixture of water, steroidal substrate, trichloroacetamide and dipotassium phosphate was stirred at 400 RPM and adjusted at 25 ° C for a period of 30 to 45 minutes with a heating mantle connected to a temperature controller. Subsequently, 35% by weight hydrogen peroxide (138.4 ml) was added in less than 5 minutes. Although this example used 35% hydrogen peroxide, higher concentrations, eg, 50% by weight, can be used. As seen, the introduction of aqueous hydrogen peroxide having a higher potency than that desired for the reaction requires the addition of water, typically in the previous step, to maintain the desired concentration for the start of the reaction. The temperature was maintained at a temperature of 28 to 31 ° C throughout the reaction. Samples were periodically sampled from the organic portion of the reaction mass to control the conversion by evaluation by HPLC at 240 nm. A graph of the disappearance rate of the enters precursor versus time gave a straight line trend with R2 = 0.996. The trend predicted 98% conversion at 712 minutes. The objective of the reaction was a conversion of 95 to 98%. Although the reaction was controlled at 240 nm not all impurities were observed at this wavelength. To obtain a true profile of the reaction and the impurities the test was repeated at 210 nm. 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 to be equal to the volume of other subsequent water loads in the treatment. The addition of water reduced the strength of the peroxide and decreased the reactivity towards the steroid components. However, the potential for the generation of low oxygen levels was still present. The phases were allowed to separate and the lowest phase of methylene chloride was removed (aqueous pH = 6.5-7.0). Typically, hydrogen peroxide was given in the test about 5 to 6% by weight. This level of concentration was correlated with the consumption of 1.5 moles of peroxide per mole of converted esters and 30% of starting concentration. In a preferred mode of operation, the discarded peroxide solution is removed by sulfite inactivation. This operation is very exothermic and is preferably carried out with a slow and controlled combination of the components (direct or reverse inactivation modes can be used) to control the exotherm. The hydrogen peroxide is reduced to give water while the sulfite is oxidized to sulfate during this process. After inactivation with sulfite, the inactive aqueous phase is subjected to a steam distillation operation to remove the contained methylene chloride. Prior to steam distillation, the aqueous phase is heated to decarboxylate the trichloroacetate salt which is produced as a by-product of the conversion of the trichloroacetamide during the course of the epoxidation reaction. Decarboxilation before steam distillation prevents the trichloroacetate from reacting with methylene chloride during the distillation operation, which may result, on the other hand, in the formation of chloroform. The decarboxylation can be effected, for example, by heating the aqueous phase at 100 ° C for a sufficient period of time to substantially eliminate the trichloroacetate salt. The organic phase of the reaction mixture, comprising a methylene chloride solution of epierenone, was washed for about 15 minutes at 25 ° C with an aqueous solution containing Na 2 SO 3 (7.4 g) and water (122.4 ml) (pH 7-8). A negative test of starch iodide (without purple color with Kl paper) was observed in the organic phase at the end of the stirring period. If a positive trial was observed, the treatment would be repeated. The methylene chloride fraction was washed with a dilute aqueous solution of sodium hydroxide prepared from lentils (7.88 g) and water (392 ml). The mixture was stirred for 35 minutes at 25 ° C and then the phases were separated (aqueous pH = 13). With this short contact time, trichloroacetamide is not completely hydrolyzed but is removed as a salt. In this regard, typically at least 2 hours are required to hydrolyze the trichloroacetamide in the corresponding acid salt, with release of ammonia. The methylene chloride portion was subsequently washed with water (392 ml). This was done as a backup wash in case the basic interface was lost. Since trichloroacetamide is not completely hydrolyzed during the contact period of 30 minutes, there is a potential to redistribute it in the organic phase once the pH is adjusted (aqueous pH = 10). 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 period the pH was adjusted to neutral with the addition of a solution prepared from sodium sulfite (12.4 g) and water (40 ml) (pH 6-7). The methylene chloride solution was concentrated by atmospheric distillation to approximate a minimum stirring volume of the vessel (~ 240 ml). Approximately 1024 ml of methylene chloride distillate were collected. As the preparation of this example was a "virgin assay," that is, as there were no recrystallization mother liquors available for recycling, fresh MEK (1000 ml) was added to the solution of epierenone in methylene chloride, in a proportion (1546). ml in this case) intended to mimic the recycling of mother liquor. Again, the solvent was removed by atmospheric distillation to approximate a minimum stirring volume (-240 ml). Alternatively, these distillations could have been performed under vacuum. Ethanol (2440 ml) was added to the residue. The ethanol loading was correlated with 15 ml / g of contained epierenone estimated for a combined raw product with a typical volume of recrystallization mother liquor with MEK (162.7 g). No distinction was made for a virgin lot (144.8 g). Therefore, the virgin trial in a campaign is operated at slightly higher volume ratios than the trials containing the MEK mother liquor for recovery. Ethanol was distilled from the suspension (no homogeneous solution was obtained in this treatment) at atmospheric pressure until 488 ml were removed. The amount of ethanol removed adjusted the isolation ratio to 12 times (not counting the minimum stirring volume of about 1.5 ml / g) the volume of the estimated amount of epierenone compound contained in the crude product. As no distinction was made for the virgin assay, the isolation volume of this assay was slightly increased. The final mixture was maintained at atmospheric reflux for about one hour. The temperature of the mixture in the distillation vessel was reduced to 15 ° C and after stirring for 4 hours at this temperature, the solid was filtered. The transfer was completed with an ethanol rinse. In general, a quantity of 1-2 volumes was used based on the contained epierenone (155 to 310 ml) in the production trials.

The solid was dried in a vacuum oven at 45 ° C and semi-hard material (150.8 g) was obtained with an 89.2% assay as a virgin assay yield (154.6 g of adjusted assay is the expected yield for the assays including a recovery of recrystallization mother liquor with MEK). Generally, 94-95% of the available epierenone was recovered after this first stage of improvement of the crude product. The designated level of drying allowed the isolation of the semi-pure epierenone in the form of the ethanol solvate. In this sense, the solvate does not readily release ethanol until the temperature reaches approximately 90 ° C. The solvate is preferred for further processing since the desolvated material tends to agglutinate upon mixing with MEK in the next operation. The solid is combined with 2-butanone (MEK) (2164 ml). This amount of MEK corresponds to a volume ratio of 14 ml / g versus the estimate of contained epierenone (includes the MEK mother liquor portion). Preferably a hot filtration of the epierenone in the MEK solution is carried out before recrystallization, but it was not used in the laboratory test. Filtration is usually followed by a wash amount that is in correlation with 2 volumes of MEK based on the epierenone contained, for example, 310 ml. This gives a total volume of MEK of 2474 ml which correlates with 16 ml / g. The hot filtration should not be performed below a ratio of 12 ml / g since this is the estimated saturation level for epierenone in MEK at 80 ° C. MEK was distilled from the solution at atmospheric pressure until 1237 ml was removed. This was correlated with 8 volumes and adjusted the crystallization ratio to a volume of 8 ml / g versus the amount of epierenone estimated in the semi-hard product. The actual remaining volume in the reactor is 8 ml / g plus the voids of the solids estimated in 1-1.5 volumes for a total isolation target volume of 9-9.5 ml / g. The solution (the mixture is supersaturated at this point and nucleation may occur before cooling begins) is cooled according to the following schedule. This stepwise strategy has consistently generated polymorph II. Cool to 65 ° C and keep for 1 hour. Cool to 50 ° C and keep for 1.5 hours. Cool to 35 ° C and keep for 1 hour Cool to 15 ° C and hold for 1 hour, then, the solid is filtered and rinsed with MEK (310 ml). The solid was initially dried on the filter at 25 ° C overnight. Then, drying and desolvation were completed in a vacuum oven at 80-90 ° C for about 4 hours. The expected dry solid weight is 119.7 g for a virgin assay and 134.5 g for a test including MEK mother liquor. The LOD of the final product should be < 0.1%. The filtrate (1546 ml) contained approx. 17.9 g of epierenone. This was correlated with 11.5% by weight of the adjusted entry of epierenone precursor. The mother liquors were saved for recovery by combination with a subsequent treatment with ethanol. The data have indicated that the epierenone product was stable up to 63 days in MEK at 40 ° C. The adjusted weight yield of the overall trial was 76. 9% This total yield is composed of yields of 93, 95 and 87% by weight adjusted for the assay, improvement with ethanol and recrystallization from MEK, respectively. There is a potential for loss of performance of 1 to 2% in relation to the NaOH treatment and the associated aqueous washes. The inclusion of MEK mother liquor in subsequent trials is expected to increase the total yield by 9.5% (11.5 x 0.95 x 0.87) for an adjusted total of 86.4%. The MEK mother liquors can be combined with a methylene chloride solution from the following epoxidation reaction and the process, as described above, can be repeated. In view of the foregoing, it will be noted that the various objects of the invention are achieved and that other advantageous results are achieved. By being able to make various changes in the above methods and compositions without departing from the scope of the invention, it is intended that all the material contained in the above description be interpreted as illustrative and not in a limiting sense.

Claims (15)

NOVELTY OF THE INVENTION CLAIMS

1. - A process for the preparation of a compound corresponding to the formula 5000: and -C-C- is i wherein R7 represents a lower alkoxycarbonyl radical or alpha-oriented hydroxycarbonyl radical; R 0, R 12 and R 13 are independently selected from the group consisting of hydrogen, halo, haloalkyl, hydroxy, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, cyano and aryloxy; R17a and R b are independently selected from the group consisting of hydrogen, hydroxy, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, acyloxyalkyl, cyano, aryloxy, or R7a and R17b together form an oxo, or R17a and R17 together with C (17) comprise a carbocyclic or heterocyclic ring structure, or R17a or R17b together with R15 or R 6 comprise a carbocyclic or heterocyclic ring structure condensed with the pentacyclic ring D; -A-A- represents the group -CHR1-CHR2- or -CR1 = CR2-; where R1 and R2 are selected independently 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 steroidal nucleus to which they are coupled form a cycloalkylene (saturated) group; -B-B- represents the group -CHR15-CHR16-, -CR15 = CR16- or an a- or β-oriented group: CH CH I I CH- CH2-CH wherein 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 respectively R15 and R6, form a cycloalkylene group; -G-J- represents the group RT-CHR11- ^ C I CR11 o; wherein 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 a epoxy group, and -CC- is -CH = C- or the process comprising: reacting a compound of Formula 6000 with a source of an alkoxy group at a temperature above about 70 ° C, said alkoxy group corresponding to the formula R710- wherein R710- corresponds to the R7 alkoxy substituent, said Composed of Formula 6000 structure: 6000 wherein R1, R2, R3a, R3b, R9, R10, R11, R12, R13, R15, R16, R17a, R17b, -AA-, -BBy -GJ- 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 wherein R3a and R3b are independently selected from the group consisting of hydrogen, hydroxy, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, acyloxyalkyl, cyano, aryloxy, or R3a and Rb together with the C-atom -3 to which they are attached form heterocycle, or R3a and R3b together form oxo; R7 represents a lower alkoxycarbonyl radical or alpha-oriented hydroxycarbonyl radical; R 0, R 12 and R 13 are independently selected from the group consisting of hydrogen, halo, haloalkyl, hydroxy, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, cyano and aryloxy; R 7a 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 R17a and R17b together form an oxo, or R17a and R17b together with C (17) comprise a carbocyclic or heterocyclic ring structure, or R17a or R17b together with R15 or R16 comprise a carbocyclic or heterocyclic ring structure fused to the pentacyclic ring D; -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 sterol core to which they are coupled form a cycloalkylene group (saturated); -B-B- represents the group -CHR15-CHR16-, -CR 5 = CR16- or an a- or ß-oriented group: R15 R16 CH CH I I CH- CH2-CH wherein 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 steroidal nucleus to which R15 and R16 are respectively bound, form a cycloalkylene group; M-G-J- represents the group ^ TCF ^ -CHR11- ^ CZ = CR11- where R9 and R1 are independently selected from the group that it consists of hydrogen, hydroxy, protected hydroxy, halo, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy or R9 and R1 together form an epoxy group, and -C-C- is i the method comprising: contacting a compound of Formula 6000 with a reagent comprising an alkaline or alkaline earth metal alkoxide corresponding to formula (R710) xM wherein M is alkali metal or alkaline earth metal, x is 1 when M is alkali metal, x is 2 when M is alkaline earth metal, and R7 0- corresponds to the alkoxy substituent of R7, said compound of Formula 6000 having the structure: 6000 wherein R1, R2, R3a, R3b, R9, R10, R11, R12, R3, R5, R16, R17a, R17b, -A-A-, -B-B- and -G-J- are defined as above for Formula 5000; the free alkaline 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, is reacted with a sacrificial saponification target compound , thus inhibiting the saponification of product of Formula 6000.

3. A process for the preparation of a compound of Formula 5000: and -C-C- is i -CH = C- or wherein R3a and R3b are independently selected from the group consisting of hydrogen, hydroxy, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonylalkyl, alkoxycarbonyl-alkyl, acyloxyalkyl, cyano, aryloxy, or R3a and R3b together with the C-3 atom to which they are attached form heterocycle, or R3a and R3 together form oxo; R7 represents a radical lower alkoxycarbonyl or alpha-oriented hydroxycarbonyl; R10, R12 and R13 are independently selected from the group consisting of hydrogen, halo, haloalkyl, hydroxy, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, cyano and aryloxy; R17a and R17b are independently selected from the group consisting of hydrogen, hydroxy, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, acyloxyalkyl, cyano, aryloxy, or R17a and R17b together form an oxo, or R17a and R17b together with C (17) comprise a ring structure carbocyclic or heterocyclic, or R 7a or R 17b together with R 15 or R 16 comprise carbocyclic or heterocyclic ring structure condensed with the pentacyclic ring D; -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 steroidal nucleus to which they are coupled form a cycloalkylene (saturated) group; -B-B- represents the group -CHR15-CHR16-, -CR15 = CR16- or an a- or ß-oriented group: 'R1 * ^ R16 CH CH | | CH- CH2-CH wherein R15 and R16 are independently selected from the group that It consists of hydrogen, halo, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, and aryloxy; or R15 and R6, together with the C-15 and C-16 carbons of the steroid nucleus to which they are attached respectively R15 and R16, form a cycloalkylene group; -G-J- represents the group wherein 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 a epoxy group, and -CC- is i the method comprising: contacting a compound of Formula 6000 with an alkaline or alkaline earth metal alkoxide corresponding to formula (R710) xM wherein M is alkali metal or alkaline earth metal, x is 1 or 2, and R710- corresponds to the R 'alkoxy substituent, in a reaction medium containing no more than 0.2 equivalents of alkali metal or alkaline earth metal hydroxide per mole of said compound of Formula 6000 converted to the reaction, said compound of Formula 6000 having the structure: wherein R1, R2, R3a, R3b, R9, R10, R11, R12, R13, R15, R16, R17a, R17b, -AA-, -BBy -GJ- are defined as above for Formula 5000. 4.- A process for the preparation of a compound corresponding to the formula 5000: and -C-C- is i -CH = C- or wherein R7 represents a lower alkoxycarbonyl radical or alpha-oriented hydroxycarbonyl radical; R10, R12 and R13 are independently selected from the group consisting of hydrogen, halo, haloalkyl, hydroxy, alkyl, alkoxy, hydroxyalkyl, acoxyalkyl, hydroxycarbonyl, cyano and aryloxy; R17a and R17b are independently selected from the group consisting of hydrogen, hydroxy, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, acyloxyalkyl, cyano, aryloxy, or R17a and R17b together form an oxo, or R17a and R17b together with C (17) comprise a carbocyclic or heterocyclic ring structure, or R17a or R17b together with R15 or R16 comprise a carbocyclic or heterocyclic ring structure fused to the pentacyclic ring D; -A-A- represents the group -CHR-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 steroidal nucleus to which they are coupled form a cycloalkylene (saturated) group; -B-B- represents the group -CHR15-CHR16-, -CR15 = CR16- or an a- or β-oriented group: R15 R16 CH CH I I CH- CH2-CH wherein 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 respectively R15 and R16, form a cycloalkylene group; -G-J- represents the group R'-CHR > 111'- i: CR 11 or wherein R9 and R11 are independently selected from the group consisting of hydrogen, hydroxy, protected hydroxyl, halo, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy or R9 and R11 together form an epoxy group, and -CC- is I comprising the process: continuously or intermittently introducing a compound of Formula 6000 and a source of an alkoxy group into a continuous reaction zone, and withdrawing continuously or intermittently a reaction mixture comprising said compound of Formula 5000 of the reaction zone, said alkoxy group corresponding to Formula R710- wherein R710- corresponds to the alkoxy substituent of R7, said compound of Formula 6000 having the structure: wherein R1, R2, R3a, R3b, R9, R10, R11, R12, R13, R15, R16, R17a, R17b, -AA-, -BBy -GJ- are defined as above for Formula 5000. 5.- A process for the preparation of a compound having the structure of Formula 5000: and -C-C- is l -CH = C- or wherein R7 represents a lower alkoxycarbonyl radical or hydroxycarbonyl radical alpha-oriented; R10, R12 and R13 are independently selected from a group consisting of hydrogen, halo, haloalkyl, hydroxy, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, cyano and aryloxy; R17a and R17b are independently selected from the group consisting of hydrogen, hydroxy, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonylalkyl, alkoxycarbonyl-alkyl, acyloxyalkyl, cyano, aryloxy, or R17a and R17b together form an oxo, or R17a and R17b together with C (17) comprise an carbocyclic or heterocyclic ring structure, or R17a or R17b together with R15 or R 6 comprise a carbocyclic or heterocyclic ring structure condensed with the pentacyclic ring D; -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 steroidal nucleus to which they are coupled form a cycloalkylene (saturated) group; -B-B- represents the group -CHR15-CHR16-, -CR15 = CR16- or an a- or ß-oriented group: R1 * ^ R16 CH CH I I CH- CH2-CH wherein R 5 and R 16 are independently selected from the group consisting of hydrogen, halo, alkyl, alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl, acyloxyalkyl, cyano, and aryloxy; or R 5 and R 16, together with the C-15 and C-16 carbons of the steroidal nucleus to which R 15 and R 16 are respectively attached, form a cycloalkylene group; -G-J- represents the group CRT-CHR11- XR 11 wherein 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 form together an epoxy group, and -CC- is i -CH = C- or The method 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 Formula R710- wherein R O- corresponds to the alkoxy substituent of R7, producing, both, a reaction mixture comprising said compound of Formula 5000, other steroidal components and a cyanide compound; said compound of Formula 6000 having the structure: wherein R1, R2, R3a, R3b, R9, R10, R11, R12, R13, R15, R16, R17a, R17b, -A-A-, -B-B- and -G-J- are defined as above for Formula 5000; crystallizing the product compound of Formula 5000 in a crystallization medium, said crystallization medium comprising the product of Formula 5000 produced in said reaction mixture, said other steroidal components, said cyanide compound, and a crystallization solvent; separating the crystalline product from the crystallization mother liquor, said mother liquor comprising retained steroid indices and said cyanide compound, said retained steroid indices comprising said compound of Formula 5000 and other steroids which can be converted to said compound of Formula 5000; contacting a solution substantially immiscible in water comprising said retained steroid indices with an aqueous extraction medium in a liquid / liquid extraction zone, thereby producing a biphasic extraction mixture comprising an aqueous refining phase containing cyanide ion and an organic extract phase comprising the compound of Formula 5000 and said other steroids; Separate the phases of organic extract and aqueous refining; and recover the steroid indices of the organic extract phase. 6.- A procedure for the preparation of a compound corresponding to the formula 5600: wherein R7 represents a lower alkoxycarbonyl radical or hydroxycarbonyl; -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 R 12 is selected from the group consisting of hydrogen, halo, haloalkyl, hydroxy, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, cyano and aryloxy; the method 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 70 ° C, said alkoxy group corresponding to formula R710- wherein R710- corresponds to the alkoxy substituent of R7, said compound corresponding to formula 6600 having the structure: wherein R71 is lower alkyl; and R1, R2, R12 and -A-A- are defined as above; wherein the 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 according to claim 6, further characterized in that the preparation of said compound corresponding to formula 7600 comprises contacting a compound corresponding to formula 8600 with a source of cyanide in the presence of a salt of alkali metal, said compound corresponding to formula 8600 having the structure: wherein R1, R2, R12 and -A-A- are defined as above. 8. The process according to claim 7, further characterized in that the 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 to introduce a group of -hydroxy in said substrate in orientation a, said substrate corresponding to formula 13600 having the structure: wherein R1, R2, R12 and -A-A- are defined as above. 9. The process according to any of claims 6 to 8, further characterized in that it additionally comprises the 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 the preparation of said compound corresponding to formula 4600 comprises reacting an acylating or lower alkylsulfonylating reagent or a halide generating agent with a compound corresponding to formula 5600. 10. The process according to claim 9, further characterized in that it additionally comprises the preparation of a compound corresponding to formula 2600: wherein -A-A-, R1, R2, R7 and R12 are as defined above; wherein the preparation of said compound corresponding to formula 2600 comprises removing a leaving group 11a of a compound corresponding to formula 4600. 11. The process according to claim 10, further characterized in that it additionally comprises the preparation of a compound that corresponds to the formula 1600: wherein -A-A-, R1, R2, R7 and R12 are as defined above; wherein the preparation of said compound corresponding to formula 1600 comprises contacting an epoxidation agent with a compound corresponding to formula 2600. 12. The process according to any of claims 6 to 11, further characterized because R7 is methoxycarbonyl, R71 is methyl, R11 is methylsulfonyloxy, -AA- is -CH2-CH2- and R12 is hydrogen. 13. The process according to any of claims 6 to 12, further characterized in that the free alkaline 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, it is reacted with a sacrificial saponification target compound, thereby inhibiting the saponification of the product of Formula 6600. 1

4. The process according to any of claims 6 to 13, further characterized in that it further comprises crystallizing the product compound of Formula 5600 in a crystallization medium, said crystallization medium comprising the product of Formula 5600 produced in said reaction mixture, said other steroidal components, said cyanide compound, and a crystallization solvent; separating the crystalline product from the crystallization mother liquor, said mother liquor comprising retained steroid indices and said cyanide compound, said retained steroid indices comprising said compound of Formula 5600 and other steroids which can be converted into said compound of Formula 5600; contacting a solution substantially immiscible in water comprising said retained steroid indices with an aqueous extraction medium in a liquid / liquid extraction zone, thereby producing a biphasic extraction mixture comprising an aqueous refining phase containing cyanide ion and an organic extract phase comprising the compound of Formula 5600 and said other steroids; separate the phases of organic extract and aqueous refining; and recover the steroid indices of the organic extract phase. 1

5. The process according to any of claims 11 to 14, further characterized in that contacting a compound corresponding to formula 2600 with an epoxidation agent comprises: contacting a steroidal substrate of formula 2600 with a compound peroxide in an epoxidation reaction zone in the presence of a peroxide activator, introducing said peroxide compound and said steroidal substrate in said reaction zone in a ratio between about one and about 7 moles of peroxide compound per mole of steroidal substrate; and reacting said peroxide compound with said steroidal substrate in said reaction zone to produce a reaction mixture comprising a steroid epoxy of formula 1600. SUMMARY OF THE INVENTION Processes are described for the conversion of a steroidal substrate that is bonded by 4.7-carbonyl bridges to a structure comprising a 7a-alkoxycarbonyl substituent by reacting the substrate with a source of an alkoxy group, preferably in the presence of a base; several modifications of optional procedures are described; the reaction can be carried out at a temperature greater than about 70 ° C, with residence times substantially shorter than those required at lower temperatures; a saponification target can be incorporated in the reaction medium to consume the free hydroxide compounds; the 7a-alkoxycarbonyl product compound can be recovered by crystallization, residual steroidal indices can be recovered from the crystallization mother liquor by extraction, and the extract can be processed to produce a paste solution in which the steroids can be rebalanced to produce more steroid product substituted with 7a-alkoxycarbonyl; alternatively, the pulp solution can be recycled to a primary reactor in which the 4.7-carbonyl bridging substrate is converted to the 7α-alkoxycarbonyl product; the process is particularly useful in the preparation of epierenone, wherein a diketone intermediate comprising the 4.7-carbonyl bridge bond is reacted with an alkali metal methoxide to produce a 11a-hydroxy-7a-methoxycarbonyl (hydroxyester) compound , the a-hydroxy group is converted into a leaving group which is then extracted to produce an? -9.11 enether, and the enether is epoxidized to give epierenone; An epoxidation reaction performed at a ratio between hydrogen peroxide and relatively low enmester substrate is also described. PFIZER P07 / 207F