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Uit States 3,047,591 EQQ Patented July 31, 1962 1 2 methylenepregn-4-ene-3,20-diones having the general 3 047,591 Formula I above, wherein R is a carboxylic acid residue containing not more than 10 carbon atoms, which process PREPARATION OF lion-ACYLOXY-?w-METHYL-lti METHYLENEPREGN-4-ENE-3,20-DIONES comprises oxidising a 3,8-hydroxy or 3?-acyloxy-6,16-di Vladimir Petr-0w and David Morton Williamson, London, England, assignors to The British Drug Houses Limited No Drawing. Filed Aug. 25, 1960, Ser. No. 51,801 Claims priority, application Great Britain Aug. 31, 195% \ 6 Claims. methylpregna-S,l6-dien-20-one having the general formula Me OOCHa /\ (Cl. 260-4974) l0 This invention is for improvements in or relating to the at erence to the preparation of compounds originally be lieved to be 17ot-acyloxy-6a,l6-dimethylpregn-4~ene~3,20 diones but now believed to be 17a-acyloxy-‘6u-methyl-16 [-Me Me preparation of organic compounds and has particular ref 15 R’O— methy-lenepregn-4-ene-3,20'diones having the general For Me (11) mula I below. Our co-pending application No. 829,234 describes a (wherein R’ is hydrogen or a carboxylic acid residue con process for the preparation of a hydroxy dione originally taining up to 10 carbon atoms) to the corresponding 16a, believed to be rl7a-hydroxy~6u,16-dimethylpregn-4-ene-3, 20 17a-epoxide derivative having the general formula 20-dione but now believed to be 17a-hydroXy-6a-methyl-; Me 16-metl1ylenepregn-4-ene-3,20-dione which process com o 0 CH3 prises ‘oxidising 3/3-hydroXy-6,16-dimethylpregna-5,l6 I x 0i dien-20—one by the Oppenauer procedure to give 6G,16‘ldi' methylpregna-4,16-diene-3,20‘~dione, reacting the 6a,16 dimethylpregna-4,16-diene-3,20-dione with alkaline hy drogen peroxide to give the corresponding 16,17-epoxide, 25 /\ qLMe Me treating the cpoxide with a hydrogen halide and submit H ting the resultant product to treatment with Raney nickel. The resulting compound, ‘originally believed to be ‘17a 30 R'O hydroxye6a,16-dimethylpregn-4-ene-3,ZO-dione but now believed to be 17a-hydroxy-6u-methyl-l6-methylenepregn Me (III) 4-ene-3,20~dione, may be acylated to give a product origi (Where R’ has the same meaning as above), acylating the nally believed to be 17a-acyloXy-6a,16-dimethylpregn-4 I ene-3,20-dione, but now believed to be l7a-acyloXy-6a 35 16u,17a-epoxide derivative in cases where R'=H, react methyl-16-methylenepregn-4-ene-3,20-‘dione having the ing the 160:,17oc-61J0Xid6 derivative with a hydrogen halide formula or with sulphuric or perchloric acid in dioXan, to form a 3/3-acyloxy-l7u-hydroXy-6-metl1yl - 16-methylenepregn-5 Me en-20-one having the general formula C 0 CH3 40 I-"OR Me _CH9 COCHa /\ ""011 "'CH: Me I Me R70 (I) Where R is a carboxylic acid residue containing up to 10 carbon atoms for reasons which have been ‘fully described 50 in our co-pending application No. 829,234. It is further shown in our co-pending application No. 829,234 that Me (IV) (wherein R’ is a carboxylic acid residue containing up to 10 carbon atoms), acylating the l7m-hydroxyl group to l7a-acyloxya6a-methyl - 16 - methylenepregn-4-ene-3,20 diones (I; where R has the same meaning as above) rep resent a novel family of progestational agents of excep tional potency. 1'1 55 give a 3p,17a-diacyloxy~6-methyl-16-methylenepregn-5 en-ZO-one having the general formula Me It is an object of the present invention to provide a new process for the preparation of the compounds originally belived to be -17a-acyloXy-6a,l6-dimethylpregn-4-ene-3, 20-diones but now believed to be 17a-acyl0Xy-6oc-methy1 COOHa 60 16-methylenepregn-4-ene-3,20-diones having the general formula I above where R is a carboxylic acid residue con taining up to 10 carbons, which are of value on account of H their progestational properties. According to the present invention there is provided a 65 process for the preparation of 17a-acyloxy-6a-methyl-16 (V) 3,047,591 A oxide such as aluminium tert.-butoxide or iso-propoxide 3 (wherein R’ is a carboxylic acid residue containing up to 10 carbon atoms and R has the same meaning as above) in suitable proportions. Following is a description by way of example of meth ods of carrying the invention into eifect. preferentially hydrolysing the 3?-acyloxy group to give an acyloxy-hydroxyketone having the general formula Example 1 Me 3B-ACE~TOXY>6,1G-DIMETHYL-l?a,17a-EPOXYPREGN-5 OOCH; L-"OR Me ' EN-20-ONE (III; R':AC) Ai Ton, 3?-acetoxy - 6,16 - dimethylpregn-5,16-dien-20-one (6.3 g.) dissolved in boiling ethanol (50 ml.) under re?ux, was treated with 40% aqueous sodium hydroxide solution (3 ml.) followed by 30% hydrogen peroxide (8.5 ml.) and the mixture boiled for 30 minutes. The reaction mixture was cooled and the crystalline product collected, HO (VI, dried and acetylated with acetic anhydride/pyridine at 100° C. for 1 hour, and puri?ed from methanol to give (wherein R has the same meaning as above) and oxidising the 3,8-hydroxyl group of the acyloxyhydroxy ketone with isomerisation of the 5,6-double bond to the conjugate 4,5 one, needles, M.P. 118 to 120° C. [(111323 —49° (c., 0.654 in chloroform). 5H, position. 3 ,8—aceltoxy - 6,16 - dirnethyl-16a,17a-epoxypregn-5-en-20 20 In carrying out the process according to the present in vention, it is preferable to employ 3B-acetoxy-6,16-di methylpregna-S,16-dien-20-one (II; R’=Ac) as starting 3?-ACETOXY-17a-HYDROXY-G-METHYL-lG-METHYLENE PREGN-5-EN-20-ONE (IV; R'zAc) 3?~acetoxy - 6,16 - dimethyl-16a,17a-epoxypregn-5-en 20-one (8 g.) dissolved in dioxan (200 ml.), cooled in material, the preparation of which has been described an ice/water bath, was treated with a 50% solution of in our co-pending application No. 824,961, now Patent No. 3,028,381. Oxidation of this material to the 16a, 17a hydrogen bromide in acetic acid (4 ml.) for 15 minutes. epoxide (III; R’=Ac) may be effected by treating com pound II wherein R"=Ac, with tenL-butyl hydroperoxide in alkaline solution or preferably with hydrogen peroxide The dioxan was diluted with water and the product iso lated with ether. The residue, after evaporation of the ether, was ‘dissolved in acetone (200 ml.) and stirred vigorously with Raney nickel (20 g.) at room tempera in an alcoholic solution made alkaline with a hydroxide such as sodium or potassium hydroxide. The reaction ture, for 4 hours. The Raney nickel was ?ltered off and washed well with methylene chloride. The ?ltrate was proceeds readily at 0° C., but may be accelerated by using temperatures up to the boiling point of the alcohol used as solvent. Complete saponi?cation of the 3|8-ace~ hexane to give 313 - acetoxy - 17a - hydroxy-6-methyl-16 toxy group occurs during this reaction and the product [@1324 —161° (c., 0.306 in chloroform). is acetylated \to give 3?-acetoxy-16u,17a-epoxy-6,l6-di methyl-pregn-S-en-ZO-one (III; R’=Ac). evaporated to dryness and the residue crystallised from methylenepregn-5-ene-20-one needles M.P. 126 to 128° C., In an alternative method 3,8-acetoxy-6,16-dimethyl The epoxy derivative (III; R’=Ac) so obtained is then 16a,l7a-epoxypregn-5-en-20-one (5 g.) dissolved in dioxan (200 ml.) containing concentrated sulphuric acid (0.5 ml.) treated in a solvent such as dioxan, acetic acid or benzene, was left overnight at room temperature (20° C.). The with a hydrogen halide which is preferably hydrogen bro reaction mixture was poured into water and the precipi tated solids were collected by ?ltration and washed with water and dried. Crystallisation of the solid from hexane mide at a temperature at or below 25° C. and preferably within the range 0° C. to 10° C. The product so ob tained may contain residual halogen which may be re moved, if desired, by treatment with Raney nickel in an organic solvent such as ethanol or acetone at or about room temperature to give 3 B - acetoxy - 17a - hydroxy-6 methyl-l6-methylenepregn-5-en-20-one (IV; R’=Ac). Alternatively, the epoxy derivative (III; R’=Ac) may be treated with sulphuric acid or perchloric \acid in a solvent such as dioxan, preferably at or about room tem perature to give the 16-methylene compound (IV; R’=Ac) directly. Acylation of the tertiary 17u-hydroxyl group present in the latter compound may be achieved by methods well-known to those skilled in the art. Such methods include, for example, treatment of the compound with an acid anhydride, such as acetic anhydride, or acid chloride and a catalytic quantity of toluene-p-sulphonic acid at a temperature of about 20° C. for 8 hour. Acylat gave 3,8 - acetoxy-l7a-hydroxy - 6 - methyl-16-methylene pregn-5-en-20-one, M.P. 126 to 128° C. 36,17a-DIACE'I‘OXY-6-METHYL-lG-METHYLENEPREGN 5<EN—20-ONE (V; RzR’zAc) 318 - acetoxy-17a-hydroxy-6-methyl-l6-methylenepregn 5-en-20-one (IV; R’=Ac) (l g.) and toluene-p-sulphonic 50 acid monohydrate (150 mg.) were suspended in acetic anhydride (35 ml.) and left at room temperature over night. The clear solution was poured into water, and the product isolated with ether. The residue from the ether extracts crystallised from hexane in plates to give 318,170: diacetoxy-G-methyl-16-methylenepregn-5-en-one, M.P. 166 to 168° C., [@1325 —l78° (c., 0.882 in chloroform). 17a-ACETOXY-3e-HYDROXY-G-METHYIAGMETHYLENE PREGN-5-EN»20‘-ONE (VI; RzAc) The foregoing diacetoxyketone (V; R=R'=Ac) (1 g.) ing agents that can be employed include the anhydrides and chlorides derived from the following acids, acetic, 60 was heated under re?ux in methanol (100 ml.) contain ing concentrated hydrochloric acid (1 ml.) for 1 hour. pnopionic, butyric, valeric, caproic, oenanthic, cyclopentyl The mixture was poured into water, and the precipitate propionic, cyclohexanecarboxylic, benzoic, hexahydro collected and crystallised from aqueous methanol to give benzoic, toluic, B-phenylpropionic, nicotinic, furoic and thiophene 1carboxylic. Partial hydrolysis of the resulting 3,8-acyloxy - 17a - acyloxy-6-methyl-16-methylenepregn-5 en-20-one (V; R’=Ac, Rzacyl) may be best effected with hot ethanolic or methanolic hydrochloric acid, when 17a-acyloxy-3?-hydroxy-6-methyl - 16 - rnethylenepregn-S en-20-one (VI; R-=acyl) is obtained. Conversion of this latter compound into the required 17a-acyloxy-6a-rnethyl 16-methylenepregn - 4 - ene-3,20-dione (I; R=acyl) may 17a - acetoxy - 3B - hydroxy - 6 - methyl - 16 - methylene pregn-5-en-20-one, needles, M.P. 163 to 165° C., [@1325 ~175° (c., 0.334 in chloroform). 17a-ACETOXY-Ga-METHYL-lG-METHYLENEPREGN-‘i‘ ENE-3,20-DIONE (I; RzAc) The foregoing acetoxyhydroxyketone (VI; R=Ac) (1 g). in cyclohexanone (24 ml.) was heated under re?ux with aluminium tert.-butoxide (1 g.) in dry toluene (16 ml.) for 1 hour. Rochelle salt solution was added to conveniently be achieved by an oxidation of the Oppenauer the mixture which was then steam distilled for 6 hours. type, employing for example, toluene as solvent, cyclo hexanone as hydrogen acceptor and an aluminium alk 75 The product was isolated with ether, and the residue from 3,047,591 5 6 the ether extracts was crystallised from aqueous methanol to 10 carbon atoms) with alkaline hydrogen peroxide to to give 17a-acetoXy-6a-methyl-16-methylenepregn-4-ene 3,20-di0ne (I; R=Ac), needles, M.P. 206 to 208° C., [@1322 —99° (c., 0.214 in chloroform), form the corresponding 16a,17a-epoxide Me 0 0 CH: 0 A523,“ 240 mp, log 6 4.19 I i ENEPREGN-5-EN-20-ONE (V; R:CO.CeH5; R'=Ac) l '—Me /\ Example 2 3l3-ACETOXY-l7a-CAPROYLOXY-6-METHYL-1G-METHYL Me 10 /, H 33 - acetoxy - 17a - hydroxy - 6 - methyl - 16 - methyl enepregn-S-en-ZO-one (IV; R'=Ac) (l g.) and toluene R'o' p-sulphonic anhydride monohydrate (150 mg.) were sus pended in caproic anhydride (30 ml.) and the mixture left at room temperature for 4 days. Pyridine (10 ml.) 15 Me (III) (where R’ has the same meaning as above), acylating the l6u,l7a-epoxide derivative in cases where R'=H by reaction with an acylating agent providing a residue of a hydrocarbon carboxylic acid containing up to 10 car was then added and the mixture steam-distilled until no more organic matter was present in the distillate, when the product was extracted from the residual liquor with ether, and was obtained as a gum after removal of the ether. 20 bon atoms, reacting the 16a,17u-epoxide derivative with an acid selected from the group consisting of a hydrogen halide, sulphuric and perchloric acid to form a 3?-acyl 17a-CAPROYLOXY-3?-HYDROXY-G-METHYL-ISFMETHYL ENEPREGN-5-EN-20-ONE- (VI; R: CO.C5H11) oxy - 17a - hydroxy - 6 - methyl - 16 - methylenepregn The foregoing crude product was heated under re?ux with methanol (100 ml.) and concentrated hydrochloric 25 acid (1 ml.) for 1 hour, poured into water and the prod uct isolated with ether. 17a-CAPROYLOXY-6a-METHYL-lB-METHYLENEPREGN 4-ENE-3,20-DIONE (I; R=CO.CsH11) 5-en-20-one having the general formula Me O 0 CH3 30 The foregoing crude product in cyclohexanone (20 ml.) and dry toluene (20 ml.) was heated under re?ux with aluminium tert.-butoxide (l g.) for 1 hour, then Rochelle salt (20 g.) was added and the mixture steam distilled for 6 hours. The product, isolated with ether Me was a gum which after chromatography on alumina (30 g.) alforded 17a - caproyloxy - 6a - methyl - 16 - methyl enepregn-4-ene-3,20-dione as a low-melting solid. We claim: 1. A process for the preparation of 17a-acyloxy-6a (IV) (wherein R’ is a carboxylic acid residue containing up to 10 carbon atoms), acylating the l7a-hydroxyl group by reaction with an acylating agent providing a residue of a 40 hydrocarbon carboxylic acid containing up to 10 carbon atoms to give a 3J8,17a-diacyloxy-6-methyl-16-methylene pregn-S-en-ZO-one having ‘the general formula methyl - 16 ~ methylenepregn - 4 - ene - 3,20 - diones having the general formula Me COCH: Me 0 0 CH: /\ LHOR 45 CH; /\ i’ R OH; Me Me I 50 H 0: Me 5 Me (I) wherein R is a carboxylic acid residue containing up to 10 carbon atoms, which process comprises oxidising a steroid selected from the group consisting of a 3p-hydroxy Me O 0 CH3 60 /\ ' Ln]: 2H2 Me i) 0 CH3 Me /\/\ Me Me (V) preferentially hydrolysing the 3,8-acyloxy group to give an acyloxyhydroxyketone having the general formula and 3p - acyloxy - 6,16 - dimethylpregna - 5,16 - dien - 20 one having the general formula . (wherein R’ is a carboxylic acid residue containing up to 55 10 carbon atoms and R has the same meaning as above) ‘J I_ I a 65 HO 1% CH3 (VI) 70 (wherein R has the same meaning as above) and sub R’0—— jecting said acyloxyhydroxyketone to Oppenauer oxida Me (11) tion to oxidise the 3?-hydroxyl group with isomerisation of the 5,6-double bond to the conjugate 4,5 position there (wherein R’ is a group selected from the class consisting by providing a compound having the Formula I above. of hydrogen and a carboxylic acid residue containing up 75 2. A process as claimed in claim 1 wherein B?-acetoxy 3,047,591 8 6,l6-dimethylpregna-5,l6-dien-20-one is oxidised with hy drogen peroxide in alkaline alcoholic solution. 3. A process as claimed in claim 1 wherein said 16oz, l7a-epoxide derivative is treated in a solvent with hydro gen bromide. 4. A process as claimed in claim 1 wherein the prefer ential hydrolysis of the 3,8-acyloxy group is effected with hot methanolic hydrochloric acid. 5. A process as claimed in claim 1 wherein oxidation 6. A process as claimed in claim 5 wherein said hydro gen acceptor is cyclohexanone. References Cited in the ?le of this patent UNITED STATES PATENTS 2,876,237 2,892,851 2,954,386 Julian et al. __________ __ Mar. 3, 1959 Bergstrom et al. ______ __ June 30, 1959 Beyler ______________ __ Sept. 27, 1960 OTHER REFERENCES of the 3p-hydroxyl group of said acyloxydioxydione is 10 Fieser and Fieser: Steroids (Reinhold, N.Y.), June 25, e?ected by the use of an aluminium alkoxide in toluene in the presence of a hydrogen acceptor. 1959, page 570.