US3444160A

US3444160A - Protection of delta**4-3-ketosteroids by the formation of protonated 3-enamines

Info

Publication number: US3444160A
Application number: US627671A
Authority: US
Inventors: Bradford H Walker
Original assignee: Upjohn Co
Current assignee: Pharmacia and Upjohn Co
Priority date: 1967-04-03
Filing date: 1967-04-03
Publication date: 1969-05-13
Anticipated expiration: 1986-05-13
Also published as: NL6804347A; FR1573154A; DE1768115A1

Description

United States Patent U.S. Cl. 260239.5 Claims ABSTRACT OF THE DISCLOSURE The use of protonated 3-enamines as protective groups for the A,B-ring system during electrophilic attack on the C,D-ring system and the 17-side chain of A -3-ketosteroids.

BACKGROUND OF THE INVENTION This invention relates to a novel method for the protection of the A -3-keto function in steroids against electrophilic attack. More particularly this invention relates to the use of a protonated 3-enamine of a A -3-ketosteroid as a protective group for the A,B-ring system during electrophilic attack on the C,D-ring system and the l7-side chain of A -3-ketosteroids.

Electrophilic attack is the attack on a reactive center of a molecule by a positively charged species. See for example Advanced Organic Chemistry, R. C. Fuson, John Wiley and Sons, Inc., New York (1950), page 1, and Organic Chemistry, Donald J. Cram and George S. Hammond, McGraw-Hill Book Co., New York (1964), Chapters 18 and 19.

Heretofore, A -3-ketosteroids could not be subjected to electrophilic attack on the C,D-ring system or on the 17- side chain without concomitant and undesirable attack on the A,B-ring system of the steroid. Ordinary 3-keto protective groups such as ketals, enol ethers, non-protonated B-enamines and the like, are either uneffective or at best only partially effective in preventing undesirable side reactions on the A,B-ring system, since they leave one or two double bonds exposed to electrophilic attack. Ketals and enol ethers have an additional disadvantage in that they are sensitive to acid, i.e., they are easily hydrolyzed under acid conditions.

SUMMARY OF THE INVENTION The process of this invention comprises forming a 3- enamine of a A -3-ketosteroid; treating said 3-enamine with an acid to obtain the corresponding protonated 3- enamine and subjecting the protonated S-enamine thus obtained, to reaction with an electrophilic reagent.

The use of protonated 3-enamines in accordance with the process of this invention, provides a novel method for protecting the A,B-ring system without giving rise to numerous side reactions caused by oxidation or acylation of the A,B-ring system.

The process of this invention is useful for the preparation of known and useful hormones such as 17fi-acetoxyandrostenes, which are useful anabolic-androgenic agents and the 17a-hydroxyprogesterones, which are useful oral progestational agents.

DETAILED DESCRIPTION OF THE INVENTION In carrying out the process of this invention a 3-enamine of a A -3-ketosteroid is converted to a protonated 3-enamine (an acid addition salt thereof) by reaction with an acid in the usual manner for the production of amine acid addition salts as disclosed in US. Patent 2,920,085. Thus, for example, a 3-enamine of a A -3-ketosteroid is treated with an acid which does not react with the particular electrophilic reagent to be used. Acids which can be used for protonation of the enamine are, for example, alkyl and aryl sul-fonic, sulfuric, perchloric, hydrofluoric, fluoroboric, nitric and phosphoric acids, lower hydrocarbon carboxylic acids such as formic, acetic, propio'nic, butyric, chloroacetic, benzoic, trichlorobenzoic, trifiuoroacetic and the like. The protonation can be carried out in any convenient manner. The enamine can be dissolved in a suitable solvent and treated with the selected acid or the enamine can be treated with the acid without the use of a solvent. When a solvent is used it should be one which is reasonably inert under the subsequent reaction conditions, for example, halogenated hydrocarbons, esters, ethers, hydrocarbons, sulfones and substituted amides can be used.

Starting materials for the process of this invention are 3-enamines of A -3ketosteroids which contain functional groups susceptible to electrophilic attack on the C,D-ring system or the 17-side chain. The starting S-enamines for the process of this invention are prepared from the selected A -3-ketosteroid and a secondary amine in accordance with methods known in the art, for example, US. Patents 2,781,342 and 2,886,564 and Heyl and Herr, I. Am. Chem. Soc. 75, pages 1913 and 5927 (1953). The starting 3-enamines are prepared from steroid compounds which have the A -3-keto structure in the A-ring of the steroid nucleus. The steroid may have other substituents, such as ketone, hydroxy, acyloxy, carbalkoxy, halogen, alkyl and the like attached at one or more of the other carbon atoms of the nucleus, such as 2, 4, 6, 7, 11, 12, 16, 17 and other positions.

Representative secondary amines which can be employed to form the desired 3-enamines include, for example, dialkylamines such as diethylamine, dipropylamine, diisopropylamine, dibutylamine, dihexylamine, dioctylamine, and didodecylamine; cycloalkylamines such as dicyclohexylamine and the like; cyclic amines such as piperidine, pyrrolidine, tetrahydroquinoline, oxazolidine (tetra-hydrooxazole), morpholine, homomorpholine, C- alkyl-substituted pyrrolidines, e.g., 2,.4-dimethylpyrrolidine, 3-isopropylpyrrolidine, and 3,3-dimethylpyrrolidine, and the like; aralkylalkylamines such as N-methylbenzylamine, N-ethylbenzylamine and the like; substituted dialkylamines such as diethanolamine and the like; and arylalkylamines such as N-methylaniline, N-methyltoluidine, N-methylanisidine, and the like.

In the practice of this invention, the secondary cyclic amines are preferred, especially those having the formula:

our-0H2 2-(CH2)n' wherein n and n are each whole numbers from 1 to 2, inclusive.

In carrying out the invention a 3-enamine of a N6- keto-steroid is protonated by treatment with an acid and subjected to electrophilic attack on the C,D-ring system or the 17-side chain, leaving the A,B-ring system uneffected and intact. If desired, the enamine group can then be removed by hydrolysis in accordance with known methods (Hogg et al., J. Am. Chem. Soc. 77, page 4436 (1955)) to regenerate the A -3-keto system in the Aring of the steroid.

Protonated B-enamines as protective groups for A -3- ketosteroids are especially useful for the conversion of compounds having the progesterone side chain to obtain the corresponding 17B-acetoxyandrostenes using the Beayer Villiger reaction. In carrying out the Baeyer Villiger reaction a protonated 3-enamine is subjected to electrophilic attack with a peracid, such as peroxytrifiuoroacetic, m-chloroperbenzoic, p-nitroperbenzoic, perphthalic, peracetic, perpropionic, performic, peroxysulfuric, permaleic and the like, in accordance with methods known in the art, see for example Steroid Reactions, Carl Djerassi, Holden-Day, Inc., San Francisco, pages 409-411. The reaction is preferably carried out under acid conditions using an excess of peracid at a temperature of from about to 40 C., although higher or lower temperatures can be used, lower temperatures tend to slow the reaction, while higher temperatures can result in decomposition of the peracid. The time required for completion of the reaction can range from minutes to several hours, depending in part on the temperature at which the reaction is carried out, the amount of oxidant employed and the particular steroid being oxidized. The 17fl-acetate thus obtained can be hydrolyzed by known methods, for example, alkaline hydrolysis with dilute aqueous sodium hydroxide solution to obtain the corresponding free 17,8- hydroxyandrost-4-ene-3-one. Alkaline hydrolysis serves to hydrolyze the 17B-acetate group and to concomitantly hydrolyze the 3-enamine protective group thus regenerating the A -3-keto ring system. If desired, the 3-enamine protective group can be removed under acidic conditions, for example, using sodium acetate-acetic acid hydrolysis leaving the 17B-acetate group intact. The hydrolyzed products can be recovered from the reaction mixture and purified by conventional methods such as chromatography and/or crystallization from a suitable solvent, such as acetone, methylene chloride, hexanes, mixtures thereof and the like. The 17fi-acetoxyandrostenes and the corresponding l7fi-hydroxyandrostenes which are obtained are well known male hormones, many of which also are active anabolic and androgenic agents.

In contrast, when the Baeyer Villiger reaction is carried out using the same A -3-ketosteroids which are not protected by the presence of a protonated 3-enamine (Strojny et al., US. Patent No. 2,844,603), the reaction results in oxidation and/or degradation of the A,B-ring system giving rise to numerous undesirable side reactions. The desired 17p-acetoxyandrostenes are obtained, if at all, only in low yields and only in the presence of undesirable by-products which make separation and purification of the desired l7fl-acetoxyandrostenes extremely difficult.

In addition to the Baeyer Villiger reaction, protonated S-enamines of A -3-ketosteroids as protective groups for the A,B-ring system against electrophilic attack are applicable to any electrophilic reaction wherein modification of the C,D-ring system or the 17-side chain is desired. Representative examples of electrophilic reactions wherein protonated 3-enamines can be effectively used are as follows:

(1) The preparation of 17(20)-enol acylates of 4- pregnene-3,20-diones is illustratively represented by the following flow diagram of partial structural formulae:

CH I

=0 (ll-OR wherein R is the acyl radical of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid of 2 to 8 carbon atoms, inclusive, the 17(20)-enol acylates are prepared by subjecting the selected A -3-ketoprogesterone which has been protected by a protonated 3-enamine group as hereinbefore described, to enol acylation with an acylating agent in the presence of an acid catalyst, suitable acylating agents are acid halides and acid anhydrides of organic carboxylic acids, the acid anhydrides are preferred. Acylating agents which are especially suitable are those containing the acyl residue of a hydrocarbon carboxylic acid of 2 to 8 carbon atoms, inclusive, such as acetic, propionic, butyric, valeric, hexanoic, heptanoic, octanoic, benzoic, toluic, isomeric forms thereof, and the like. The acids may also contain substituents such as halogen, alkyl, methoxy and others which are non-reactive under the conditions employed. Acid catalysts which can be used include, for example, strong acids such as sulfuric acid, perchloric acid, arylsulfonic acids, i.e., benzenesulfonic and p-toluenesulfonic, and the like, of these perchloric acid and p-toluenesnlfonic are preferred. The enol acylation is carried out in accordance with methods known in the art, see for example, US. Patent 2,668,817. When an lla-hydroxy group is present it will be converted to lla-acyloxy during the enol acylation reaction. In carrying out the enol acylation using a protonated Z-enamine as a protective group for the M6- keto ring system, it is preferable to protonate the enamine with an excess of an acid which will also act as a catalyst for the enol acylation, such as those hereinbefore named. However, the enamine can be protonated first by any of the suitable acids hereinbefore named, followed by addition of a sufiicient quantity of an acid which will act as a catalyst for the enol acylation.

(2) The epoxidation of steroidal double bonds present in the l7-side chain of steroids and/or those present in the C and D-rings of steroids such as those occurring in such positions as 9(11),11(12),14(15),16(17),17(20), 20(21) and the like, The following flow diagrams of partial structural formulae are illustrative:

| OR 0 R2 I I wherein R is hydrogen or acyl, in which acyl is the acyl radical of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid, R is acyl as defined above, and the wavy lines above, and elsewhere in the application, designate the u-configuration, the B-configuration and mixtures thereof. The above epoxidations are carried out by subjecting a 3-enamine of a A -3-ketosteroid which also has double bonds present in the C,D-ring system or the 17-side chain to protonation with a strong acid as hereinbefore described, followed by epoxidation with a peracid in accordance with procedures well known in the art, for example, Steroid Reaction supra, pages 597- 604, peracids which can be used are, for example, perbenzoic, perphthalic, peracetic, and others hereinbefore listed. The epoxidation reaction is preferably conducted in an inert organic solvent such as tetrahydrofuran, chloroform, methylene chloride, benzene, ether, diglyme, and the like, at temperatures ranging from 0 to 100 C. for from about 1 to hours. When the reaction is com lete Mon the excess peracid is decomposed, the enamine removed by hydrolysis as hereinbefore described, and the desired epoxides are separated and recovered by conventional methods such as chromatography and/or crystallization. These epoxides are well known in the art as valuable intermediates.

(3) The bromination of progesterones to obtain the corresponding dibromoketones, as illustratively represented by the following flow diagram of partial structural formulae:

The bromination is carried out by subjecting the 3-enamine of a A -3-ketosteroid having the progesterone side chain to protonation with an acid followed by bromination in accordance with known methods, Steroid Reactions supra, pages 406-407. For example, the protonated 3-enamine steroid is subjected to bromination with bromine and hydrobromic acid in the presence of acetic acid preferably between 0 C. and 50 C. After bromination the reaction mixture is neutralized and treated with a base, for example, alcoholic potassium hydroxide; the protective enamine group is thus hydrolyzed to regenerate the A -3-keto ring system and the bromine is removed to give the corresponding A -2l-pregneoic acid, which can be recovered from the reaction mixture by conventional methods such as chromatography and/ or crystallization. These A -21-pregneoic acids are known valuable intermediates for the production of compounds having the full cortical side chain and for the production of the corresponding 4-androstene-3,17-diones. Alternatively, the protonated B-enamine group can be removed by hydrolysis under acidic conditions without removing the attached 17,2l-dibromo substituents.

(4) The preparation of 16aand l6 3-hydroxy or acyloxy 17-ketosteroids, as illustratively represented by the following flow diagram of partial structural formulae:

wherein R is acyl as hereinbefore defined. The 17-ketol6-acylates are prepared by subjecting a 3-enamine of the selected l7 3-acyloxy-4,l6-androstadiene-3-one to protonation with acid as hereinbefore described, followed by oxidation with a lead tetraacylate, lead tetraacetate is preferred, to obtain the corresponding 17-keto-16aor 16fl-acylate, for example, see Steroid Reactions supra, page 562. The enamine protective group is removed by hydrolysis under basic conditions as hereinbefore described and the corresponding 16-hydroxy-4-androstene- 3,17-dione thus obtained is recovered by conventional methods. Alternatively, the hydrolysis can be carried out under acid conditions as hereinbefore described to obtain the corresponding 16-acyloxy-4-androstene-3,17-dione.

The addition of hypohalous acids to steroidal double bonds, for example, to 17(20)-enol acylates to form whaloketones as illustratively represented by the following flow diagram of partial structural formulae:

wherein X is chlorine or bromine and R has the meaning hereinbefore given. Hypobromous or hypochlorous acids are readily added to 20-enol acylates of A -3-pregnenes which have been protected by a protonated S-enamine group as hereinbefore described. The hypohalous acid addition is carried out in accordance with known methods, for example, Lyttle et al., J. Org. Chem. 20, 1709 (1955) using N-chlorosuccinamide or N-bromosuccinamide, in the presence of an acid such as acetic acid, as a source of hypohalous acid. The protective enamine group can be removed by hydrolysis under mildly alkaline or acid conditions, as hereinbefore described, to regenerate the A -3-keto-A,B-ring system. The a-haloketones thus obtained, can be dehydrohalogenated if desired, either before or after removal of the protective enamine group, for example, using collidine, pyridine or with lithium salts in dimethylformamide to obtain, for example, the corresponding 4,16-pregnadiene-3,20-diones; these compounds which are known in the art are useful per se and are also useful as intermediates for the production of known biologically active 16-substituted steroids.

The following preparations and examples are for the purpose of illustrating the best mode contemplated for carrying out the invention and to supplement the foregoing disclosure of the invention with additional descriptions of the manner and process of carrying out the invention so as further to enable workers skilled in the art to do so.

PREPARATION 1 Peroxytrifluoroacetic acid To 28.00 g. of trifiuoroacetic anhydride cooled in an ice bath to ca. 2 C. was added with vigorous stirring 2.91 ml. of 85% hydrogen peroxide. The rate of hydrogen peroxide addition was controlled so that the temperature was maintained at less than 13 C. After mixing, the solution was stirred for an additional period of about 1 hour with ice bath cooling to give peroxytrifiuoroacetic acid.

EXAMPLE 1 Baeyer Villiger reaction A solution of 7.34 g. (.02 mole) of the 3-pyrrolidyl enamine of progesterone in 27 ml. of redistilled methylene chloride was cooled in an ice bath and treated slowly with 10 ml. of trifluoroacetic acid, while maintaining the temperature below 15 C., to Obtain the protonated 3-pyrrolidyl enamine of progesterone. Cooling was continued and 5.67 ml. of peroxytrifiuoroacetic acid was added slowly over a period of about 70 minutes. After the addition was complete, stirring was continued for an additional period of about minutes at about 3 C. This reaction mixture, which contained protonated 3- enamine of 17p acetoxytestosterone, was added to a solution of 15 ml. of 50% aqueou sodium hydroxide, 20 ml. of water and 50 ml. of methanol and allowed to stand at room temperature for about 18 hours. Thin layer chromatography showed the absence of any residual enamine of testosterone acetate. The alkaline mixture was then diluted with water and extracted into methylene chloride. The methylene chloride was washed with hydrochloric acid to remove any residual pyrrolidine, filtered over sodium sulfate and concentrated to dryness. The residue thus obtained was dissolved in methylene chloride and chromatographed on 300 g. of Florisil. Elution with 500 ml. fractions of Skellysolve B (hexanes) (hereinafter referred to as Skelly B) containing increasing proportions of acetone, 0 to 10%, gave 4.04 g. of testosterone, which was recrystallized from Skelly B acetone 1:1 to give 3.66 g. of testosterone, M.P. 151 153 C.

EXAMPLE 2 Epoxidation A solution of 10.00 g. of the 3-pyrro1idyl enamine of progesterone was dissolved in 100 ml. of chloroform and cooled to about 7 C. in an ice bath. To the cold solution was added 2.65 ml. of 70% perchloric acid to give the protonated 3-pyrrolidyl enamine of progesterone. With continued cooling 13.05 ml. of acetic anhydride was added. This addition caused the previously heterogenous reaction mixture to become homogeneous and was accompanied by an exothermic reaction. The reaction was allowed to proceed for one hour at room temperature to give the corresponding 17(20)-enol acetate. Water (0.84 ml.) was then added followed by the addition of 4.1 g. of sodium acetate trihydrate to buffer the reaction mixture. The reaction mixture was then treated with 13.8 ml. of peracetic acid and allowed to react at to 5 C. for a period of about 5 to 6 hours to obtain the corresponding 17,20-epoxy 20acetate. The reaction mixture was treated with aqueous sodium hydroxide, the organic phase was separated, washed with saline solution, acid, dilute base and taken to dryness. The residue thus obtained was dissolved in methanol (500 ml.) and treated with 5 ml. of concentrated hydrochloric acid. After neutralization of the acid with dilute aqueous sodium hydroxide solution, water was added, the product extracted with methylene chloride and the methylene chloride solution taken to dryness. The residue thus obtained, was chromatographed on 500 g. Florisil (synthetic magnesium silicate) eluting with Skelly B containing increas ing amounts of acetone. The product fractions .7099 g., on recrystallization from isopropyl alcohol gave .3534 g. of 17a-hydroxyprogesterone, M.P. 208-212 which on further crystallization gave .1943 g. of 17a-hydroxyprogesterone, M.P. 2l3-2l6; [a] +90 (CHCl A max. 240 mu (6 15,900); LR. was identical with a reference standard of 17a-hydroxyprogesterone.

EXAMPLE 3 Epoxidation The 3-pyrrolidyl enamine of progesterone (5.0 g.) was dissolved in 7.5 ml. of acetic acid, 50 ml. of acetic anhydride and 5.05 g. of p-toluenesulfonic acid monohydrate was added. The acetic acid was distilled slowly and was replaced with 50-75 ml. of acetic anhydride over a period of 6.5 hours. The residue anhydride was removed in vacuo and 150 ml. of methylcyclohexane was added and distilled at atmospheric pressure. The last traces of solvent were removed in vacuo at 50 C. The residue thus obtained, comprising the protonated 3-pyrrolidyl enamine of 20 acetoxy 4,17(20) pregnadiene 3 one was dissolved in 50 ml. of chloroform, diluted with 5 ml. of glacial acetic acid and the residual strong acid was neutralized with 4.0 g. of sodium acetate trihydrate. The 20-enol acetate was then treated with 7.0 ml. of 40% peracetic acid at 5 C. and the reaction was allowed to proceed at about 0 C. for a period of about 20 hours. The reaction mixture was then added to a mixture of alkali and ice water (pH ca. 12) and the product extracted with methylene chloride. After evaporating the methylene chloride the residue was dissolved in 80 ml. of chloroform, 140 ml. of methanol and 4 g. of sodium hydroxide dissolved in 60 ml. of water. The hydrolysis was allowed to proceed for one hour at about 35-37 C. Water was then added and the chloroform solution was washed with acid, base and salt solution. The chloroform solution was concentrated to dryness and the residue thus obtained was crystallized from isopropyl alcohol to give 1.3 g. of l7a-hydroxyprogesterone; an analytical sample recrystallized from isopropanol melted at 2l32l. C.

EXAMPLE 4 Epoxidation A solution of the 3-piperidyl enamine of 17,3-acet0xyandrosta 4,16 diene 3 one in chloroform is protonated by the addition of a slight excess of sulfuric acid and then treated with an excess of perbenzoic acid. The reaction is allowed to proceed at room temperature for a period of about 20 hours to give the corresponding l6a,l7a epoxide. The protective enamine group is removed by hydrolysis with aqueous sodium hydroxide solution in accordance with the procedure of Example 3 above to give 16a,17a-epoxy-l7fl-acetoxyandrost-4-en-3- one.

EXAMPLE 5 Bromination A solution of the 3-pyrrolidyl enamine of progesterone in methylene chloride is protonated by the addition of acetic acid and treated with bromine in the presence of acetic acid at about 40 C. to obtain the corresponding l7u,2l-dibromo derivative. The dibromo compound thus obtained is hydrolyzed by the addition of an excess of me thanolic potassium hydroxide solution to the reaction mixture to give 3 keto 4,l7(20)-pregnadien-2loic acid.

Alternatively, the enamine can be removed under milder conditions, for example with sodium acetate in the presence of acetic acid to obtain 17a,21-dibromo-4-pregnene-3,20-dione.

EXAMPLE 6 Oxidation A solution of 50 mg. of the 3-morpholinyl enamine of 17B acetoxyandrosta 4,16 dien 3 one is acidified by the addition of a slight excess of acetic acid and treated with 0.5 ml. of acetic anhydride and mg. of lead tetraacetate to obtain the protonated 3-morpholinyl enamine of 16a acetoxyandrost 4 ene 3,17 dione, which is hydrolyzed with aqueous sodium hydroxide, in accordance with the procedure of Example 2, above, to obtain l6a-hydroxyandrost-4-ene-3,l7-dione.

EXAMPLE 7 Hypohalous acid addition The 3-pyrrolidyl enamine of progesterone (5.0 g.) is dissolved in 7.5 ml. of acetic acid, 50 ml. of acetic anhydride and 5.05 g. of p-toluenesulfonic acid monohydrate is added. The acetic acid is distilled slowly and replaced with 50-75 ml. of acetic anhydride over a period of about 6.5 hours. The residue anhydride is removed in vacuo and ml. of methylcylcohexane is added and then distilled off at atmospheric pressure. The last traces of solvent are removed in vacuo at about 50 C. The residual protonated 3-pyrrolidyl enamine of 20-acetoxy-4,l7 (20)- pregnadien-3-one thus obtained is dissolved in acetone, treated with a slight excess of hydrochlorus acid and allowed to react for a period of 10 minutes to give the 3- pyrrolidyl enamine of l7a-chloro-4-pregnen3-one. The reaction mixture is then concentrated under vacuum, diluted with water, made strongly basic with sodium hydroxide and allowed to stand at room temperature for about 18 hours. The alkaline reaction mixture is then diluted with water and extracted with methylene chloride. The methylene chloride extract is evaporated to dryness to give 4,l6-pregnadiene-3,ZO-dione.

Alternatively, the hydrolysis can be carried out under mild conditions, for example, using sodium acetate and acetic acid to obtain l7a-chloro-4-pregnene-3,20-dione.

EXAMPLE 8 To a residue, comprising the protonated 3-pyrrolidyl enamine of 20 acetoxy 4,17(20) pregnidien 3 one (prepared in the manner described in Example 3, above) is added about 300 ml. of t-butyl alcohol. The mixture is then treated with a slight excess of hypobromous acid (prepared by dissolving N-bromosuccinamide in tert. butyl alcohol and acidifying with dilute sulfuric acid) and allowed to stand in the dark at room temperature for about 2 hours. A solution of sodium bisulfite in an amount sufiicient to destroy the excess hypobromous acid is then added and the solvents are removed by distillation under reduced pressure. The residue thus obtained comprising the 3-protonated pyrrolidyl enamine of 17a-bromo-4-pregnen- 3-one is hydrolyzed and dehydrobrominated with sodium hydroxide in the manner described in Example 7, above, to give 4,16-pregnadiene-3,20-dione.

Alternatively, the hydrolysis can be carried out under mild conditions, for example, using sodium acetate and acetic acid to obtain 17a-bromo-4-pregnene-3,20-dione.

I claim:

1. A method for protecting the A,B-ring system of A 3-ketosteroids during electrophilic attack on the C,D-ring system or the 17-side chain, which comprises forming a 3-enamine of A -3-ket0steroid, protonating the said 3-enamine with an acid and subjecting the protonated 3-enamine to reaction with an electrophilic reagent.

2. A method for protecting the A,B-ring system of a 4- pregnene-3,20-dione during electrophilic attack on the 17- side chain, which comprises reacting said 4-pregnene-3,20- dione with a secondary amine to obtain the corresponding 3-enamine, treating the B-enarnine so obtained with an acid to produce the corresponding protonated 3-enamine and reacting the latter compound with a peracid to obtain the corresponding B-enamine of l7/i-acetoxyandrost-4-ene-3-one.

3. The process of claim 2 wherein the secondary amine is a secondary cyclic amine.

4. The process of claim 2 wherein the secondary amine is pyrrolidine.

5. The process of claim 2 wherein the secondary amine is morpholine.

6. The process of claim 2 wherein the peracid is peroxytrifiuoroacetic acid.

7. The process of claim 2 wherein the starting 4-pregnene-3,20-dione is progesterone.

8. The process which comprises treating the 3-pyrrolidyl enamine of progesterone with an acid to obtain the corresponding protonated 3-enamine, reacting the protonated 3-enamine so obtained with a peracid to obtain the protonated 3-pyrrolidyl enamine of 17,8-acetoxytestosterone and hydrolyzing the latter compound to regenerate the A -3-ket0 structure in the A,B-ring system.

9. The process of claim 7 wherein the hydrolysis is carried out under basic conditions to obtain testosterone.

10. The process of claim 7 wherein the hydrolysis is carried out under acidic conditions to obtain 17fl-acetoxytestosterone.

11. A method for protecting the A,B-ring system of a 4- pregnene-3,20-dione during electrophilic attack on the 17 side chain, which comprises reacting said 4'pregnene-3,20- dione with a secondary amine to obtain the corresponding 3-enamine; treating the 3-enamine so obtained with an acid to produce this corresponding protonated 3-enamine, treating the protonated 3-enamine so obtained, with an acylating agent which contains the acyl residue of a hydrocarbon carboxylic acid of 2 to 8 carbon atoms, inclusive, in the presence of an acid catalyst, to obtain the corresponding 17(20)-enol 20-acylate; treating the 17(20)-enol acylate so obtained with a peracid to obtain the corresponding 17,20-epoxy 20-acylate; and hydrolyzing the latter compound to obtain the corresponding 17a-hydroxy- 4-pregnene-3,20-dione.

12. The process of claim 11 wherein the secondary amine is pyrrolidine.

13. The process of claim 11 wherein the secondary amine is morpholine.

14. The process of claim 11 wherein the acid employed for both protonation and catalysis is p-toluenesulfonic acid.

15. The process of claim 11 wherein the acid employed for both protonation and catalysis is perchloric acid.

16. The process of claim 11 wherein the peracid is peracetic acid.

17. The process of claim 11 wherein the acylating agent is acetic anhydride.

18. The process of claim 11 wherein the starting 4- pregnene-3,20-dione is progesterone and the product obtained is 17a-hydroxyprogester0ne.

19. The process of claim 11 wherein the starting 4- pregnene-3,20-dione is llu-hydroxyprogesterone and the product obtained is 11a,l7m-dihydroxyprogesterone.

20. The process of claim 11 wherein the starting 4- pregnene-3,20-dione is ll-ketoprogesterone and the product obtained is 17a-hydroxy-ll-ketoprogesterone.

References Cited UNITED STATES PATENTS 7/1958 Strojny et al. I/ 1960 Magerlein et al.

HENRY A. FRENCH, Primary Examiner.