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3,057,883 United States Patent O??ce Patented Oct. 9, 1962 1 2 3357,8831 tenes, 2-hydroxymethyl-17/3-hydroxy-A2-androstenes, 2a and Z?-hydroxymethyl-17,8-hydroxy-androstanes, of their Z-CARBOXY-ANDROSTANE DERIVATIVES AND 17ot-alkyl, alkenyl and alkynyl substituted derivatives as PROCESS THEREOF Albert Bowers, John Edwards, and James C. Orr, all of 5 Well as of their corresponding 19-nor-analogs. In copending patent application Serial No. 128,974, Mexico City, Mexico, assignors to Syntex Corporation, ?led August 3, 1961, there is described the preparation of a corporation of Panama 2-formyl-A2-androstenes starting from 2-alkoxymethylene No Drawing. Filed Oct. 20, 1961, Ser. No. 146,456 Claims priority, appiication Mexico Apr. 4, 1961 23 Claims. (Cl. 260—397.1) The present invention relates to certain new cyclo pentanoperhydrophenanthrene derivatives and to a meth od for the preparation of the same. More particularly, our invention relates to the novel derivatives of dihydroallotestosterone, 19-nor-dihydroallo testosterone and of their l7a-alkyl, alkenyl or alkynyl 10 substituted derivatives, which upon reduction with a double metal hydride afford the corresponding 2-hydroxy~ methyl compounds which, by acid treatment, give rise to the formation of the 2-f0rmyl-A2-androstenes and 19-nor androstenes. 20: and ZB-carboxy derivaives of androstan-17?-ol, and 15 By reduction of these compounds with lithium in liquid to 2-carboxy-A2-androsten-175-01 which may further ammonia there are obtained the Za-hYdI‘OXYm?thYl possess a 17a-alkyl, alkenyl or alkynyl group; it also com androstanes and 19-nor-androstanes. By catalytic hydro prises the preparation of the esters of such compounds genation of the 2-formyl—A2-androstenes and 19-nor-an and the corresponding 19-nor derivatives. drostenes, there are obtained the 2,3-hydroxymethyl com Such compounds are powerful anabolic agents having 20 pounds, as has been described in detail in copending patent a favorable anabolic-androgenic ratio; they stimulate the application Serial No. 128,972, ?led August 3, 1961. appetite, help to increase the protein metabolism and the The 2 ~ hydroxymethyl - 17B _ hydroxy~A2-androstenes deposition of calcium in the bone tissue; they further show which may also be employed as starting materials for anti-estrogenic activity, lower the chloesterol level in the the preparation of the 2-carboxy-androstenes object of blood, inhibit the scretion of gonadotrophins by the pit 25 our present invention, are obtained by reducing the 2 uitary gland and exhibit depressant action on the central formyl-Az-androstenes with sodium borohydride, such as nervous system. has been described in the patent application Serial No. The 17a-alkenyl and l7a-alkynyl compounds further 146,455 ?led of even date. possess progestational activity. The novel compounds object of our invention are ob 30 The novel compounds object of our present invention tained by the method illustrated by the following series are represented by the following formulas: of reactions: OR’ |_..Rg R j 35 N51“ A __) Brow-Ll tr R R3000 I 40 H 1 OR’ n LnRg R i 45 OR‘ OR! LR, |__-R, R3000 M 50 a In the above formulas, R represents hydrogen or methyl, R1 represents hydrogen or an acyl group derived from a carboxylic acid of 1 to 12 carbon atoms; R2 rep— 55 resents hydrogen, a lower alkyl, alkenyl or alkynyl group such as methyl, ethyl, propyl, vinyl, ethynyl or propynyl, R3O0O—- R R3000 R i a... i : H IV H In In the above formulas, R, R1, R2 and R3 have the same meaning set forth previously. and R3 represents hydrogen or a lower alkyl group such as methyl, ethyl or propyl. The wavy line at C-2 indi In practicing the process outlined above, an ester of 2 formyl-Az-androsten-175-01 or a 170t-S1lbSlIltllt6d deriva tive thereof (I; R==methyl) or an ester of the latter is cates the ot or [3 con?guration for the substituent at such position. The acyl groups referred to above derive from a car boxylic acid of less than 12 carbon atoms, saturated or subjected to direct oxidation with oxygen in the presence of platinum oxide as catalyst to produce the 2-carboxy unsaturated, of straight, branched, cyclic or mixed ali compounds (II; R=methyl, R3=hydrogen). Adequate phatic-cyclic chain, substituted or not with hydroxyl, 6 UK solvents for this oxidation are ethyl acetate, hexane, methoxy, amino, halogen or other groups; typical such butyl acetate or any other similar organic ester. The re esters are the acetate, propionate, butyrate, valerate, hemi action is preferably conducted at room temperature and succinate, enanthate, caproate, benzoate, undecenoate, atmospheric pressure, for a period of time between 72 trimethylacetate, phenoxyacetate, cyclopentylpropionate and ,B-chloropropionate. The novel compounds object of our invention are ob tained by oxidation of 2-forrnyl-17B-hydroxy-A2-andros and 100 hours or under pressure for 24 to 36 hours. 70 Alternatively, such oxidation may be carried out with chromium trioxide in acetic acid or in acetone in sulfuric acid medium. ~ 3,057,883 3 4 chromic acid (prepared in 23% sulfuric acid) and the The ester group at C-175 may be saponi?ed to give mixture was kept for 1 hour at 0° C. At the end of this time the mixture was poured into water and the precipi tate formed was collected and washed with water. Crys the corresponding l7?-alcohol (II; R, R1 and R3=hydro gen), which may be esteri?ed with another acid anhydride or chloride in pyridine solution for the unsubstituted com pounds, or in benzene solution and in the presence of p tallization from acetone a?orded 2-carboxy-l7m-methyl A2-androsten-17B-ol. toluenesulfonic acid for the 17a-alkyl, alkenyl and alkynyl A mixture of 250 mg. of the above compound, 10 cc. of acetic acid, 5 cc. of acetic anhydride and 250 mg. of p-toluenesulfonic acid was kept at room temperature for stones, in the presence of a palladium catalyst, such as 5 % palladium on charcoal, palladium on barium sulfate or 10 1 hour, poured into water, heated on the steam bath for 30 minutes to hoydrolyze the excess of reagent and the 10% palladium on calcium carbonate, and using as sol precipitate formed was collected and washed with water vents ethyl acetate, methanol, ethanol, there are obtained substituted derivatives. By catalytic hydrogenation of the 2-carboxy-A2-andro to neutral, thus giving the acetate of 2-carb0xy-17a the ZB-carboxy derivatives (III; R=methyl; R1 and methyl-Az-androsten-173-01. R3=hydrogen). By esteri?cation of the 2-carboxy compounds of For mulas I1 and Ill (R=methyl; R1 and R3=hydrogen) Example III A solution of 1 g. of 2-carboxy-A2-androsten-173-01, obtained in Example I, in 15 cc. of methanol was cooled with a diazoalkane, such as diazomethane or diazoethane, there are obtained the 2-carbalkoxy compounds (II and to 0-5° C. and treated with an excess of an ether solution of diazomethane, prepared from 5 g. of nitrosomethyl 20 esteri?cation with an acid anhydride or chloride, by the III; R:=methyl, R1=hydrogen, R3=rnethyl or ethyl). By urea; the mixture was kept overnight at 0° C., the excess of diazomethane was destroyed with a few drops of acetic acid and the solution was poured into water and extracted methods set forth above, there are obtained the diesters. By alkaline treatment of the Z?-carbalkoxy compounds, there are obtained the Za-carbalkoxy derivatives (IV; with methylene chloride; the organic phase was washed to R=methyl, R3=methyl, ethyl) neutral, dried and evaporated to dryness. Crystallization In the same manner, the method just described is ap of the residue from acetone-hexane yielded Z-carbometh plied to the 2-formyl-l9-nor-A2-androstenes, thus produc ing the 17-esters of Z-carboxy-19-nor-A2-androsten-17B ol, the 17-esters of 2?-carboxy-l9-nor-androstan-17f3-ol, oxy-A2-androsten-l7?-ol. A solution of 250 mg. of the above ester in 1 cc. of pyr idine was mixed with 0.5 cc. of benzoyl chloride and heated on the steam bath for 1 hour, cooled and poured into Water; the precipitate formed was collected and re 2-carboxy-17a-alkyl, Not-alkenyl and 17a-a1kynyl-19 nor-Alandrosten - 175 - ol, 2B-carboxy-17a-alkyl, 17a-al kenyl and l7cc-alkynyl-19-nor-androstan-17?-ol, 2a and 25-carbalkoxy-19-nor-androstan-17B-ol, 2a and 2?-carb— alkoxy-l7a-alkyl, Hot-alkenyl and 17a-alkynyl-l9-nor-an crystallized from chloroform-methanol, thus furnishing the beonzoate of 2-carbomethoxy-M-androsten-1713-01. Example I V drostan-l7B-ol, as well as the 17-este1's of the carbalkoxy 35 compounds. A solution of 500 mg. of 2-formyl-17a-ethynyl-19-nor Alternatively, the 20c- and ZB-carboxy derivatives of an A2-androsten-175-o1 was treated with an excess of an 8 N drostan-17B-ol, 19-nor-androstan-17?-ol as well as of their solution of chromic acid in acetone, following the method 17a-alkyl, alkenyl and alkynyl substituted derivatives may of Example II. There was thus obtained 2-carboxy-17a be obtained by oxidation with chromic acid of the corre sponding 2a and 2,8-hydroxymethyl compounds and/ or of 40 their esters. The following examples serve to illustrate but are not intended to limit the scope of the invention: Example I ethynyl»A2-19-nor-androsten-l7?-ol. By treating the above compound with an excess of di azomethane, in accordance with the method of the preced ing example, there was obtained the methyl ester of 2-car boxy-17a-ethynyl-19-nor~A2-androsten-175-01. 45 To a solution of 2.5 g. of the acetate of 2-formyl-A2 androsten-17?-ol, described in copending patent applica tion Serial No. 128,974, ?led August 3, 1961, in 250 cc. of ethyl acetate was added 400 mg. of platinum oxide and the mixture was stirred under an atmosphere of oxygen, at atmospheric pressure and room temperature, for 80 A mixture of 250 mg. of the above methyl ester, 15 cc. of benzene, 1 cc. of acetic anhydride and 500 mg. of p-toluenesulfonic acid was kept at room temperature for 48 hours and then diluted with water; the benzene layer was separated, successively washed with 5% sodium car bonate solution and water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. By chromatography of the residue followed by crystalliza hours. The catalyst was removed by ?ltration through celite and the solvent was evaporated. Crystallization of tion of the solid fractions from acetone-ether, there was obtained the acetate of 2-carbometh0xy-l7a-ethynyl-19 the residue from acetone-ether yielded the acetate of 2-carboxy-A2-androsten-175-01, M.P. 267—68° C., [a]D nor-A2-androsten-17?-ol. +67° (chloroform); 7x max. 218 mp, e 9100. hydrides, there were obtained the caproate, propionate and In the same manner, but using the respective acid an A solution of 3 g. of the above compound in 100 cc. cyclopentylpropionate of 2-carbomethoxy - 17a - ethynyl of methanol was treated with 3 g. of potassium hydroxide 19-nor-A2-andr0sten-175-01. dissolved in 5 cc. of water and 20 cc. of methanol, and the Example V mixture was kept overnight at room temperature, then 60 acidi?ed with acetic acid and concentrated to a small A solution of 500 mg. of the caproate of 2-formyl-17a volume. Water was added until complete precipitation vinyl-az-androsten-176-01 in 65 cc. of ethyl acetate was and the product was collected by ?ltration. Crystalliza stirred for 75 hours under an atmosphere of oxygen and tion from methylene chloride~hexane a?forded 2-carboxy in the presence of 80 mg. of platinum oxide catalyst, at A2-androsten-17?-ol, M.P. 243-244° C., A max. 219 11111., room temperature and atmospheric pressure; there was 5 8,700. thus obtained the caproate of 2-carboxy-l7a-vinyl-Az-an In the same manner the propionate of 2-formyl-19-nor A2-androsten-17B-ol was converted into the propionate of 2-carboxy-19-nor-A2-androsten-17(3-01 and then into 2 carboxy-19-nor-A2-androsten-17,8-01. drosten-17g8-ol. By treating the above compound with an excess of di 70 azomethane, there was obtained the caproate of Z-carbo Example 11 A stirred solution of 700 mg. of 2-formyl-l7a-methyl A2-androsten-17?-ol in 10 cc. of pure acetone was cooled to 0° C. and treated with 0.4 cc. of an 8 N solution of 75 methoxy-l7a-vinyl-A2-androsten-175-01. Example VI A stirred solution of 1.4 g. of 2-hydroxymethyl-17a methyl-A2-androsten-1713-01, described in copending patent 3,057,883 5 application Serial No. 146,455 in 25 cc. of pure acetone was collected, thus furnishing the acetate of Zea-carbo was treated with 1.6 cc. of an 8 N solution of chromic methoxy-androstan-175-ol. acid, following the method described in Example II; there By the same method but using caproic, undecenoic and cyclopentylpropionic anhydrides as esterifying agents, was thus obtained Z-carboxy-l7a-methyl-A2-androsten 175-o1, identical with that obtained in such example. By there were obtained the caproate, undecenoate and cyclo esteri?cation with an ether solution of diazoethane, there pentylpropionate of Zea-carbomethoxy-androstan-175-o1. Example XI was obtained 2-car-boethoxy - 17a - methyl-Az-androsten 175-o1. A solution of 1.2 g. of 2a-hydroxymethyl-17a-vinyl-19 Example VII A stirred solution of 1 g. of the acetate of 25-hydroxy 10 nor-androstan-175-ol in 60 cc. of acetic acid was treated with 0.6 g. of chromic acid in 15 cc. of acetic acid, in methylandrostan-175-ol, obtained as described in the accordance with the method of Example VII, thus giv copending patent application Serial No. 128,972, in 50 iug 2a-carboxyl-17tx-vinyl-l9-nor-androstan-175-o1. By cc. of acetic acid was treated dropwise with a solution of esterifying the above compound with acetic anhydride in 500 mg. of chromic acid in 10 cc. of 80% acetic acid, benzene solution and in the presence of p-toluenesulfonic 15 at a temperature between 15 and 20° C. The mixture was kept for 2 hours at room temperature, then poured into ice cold salt water and the precipitate formed was collected and washed with water to neutral, thus giving the acetate of 25-carboxy-androstan-175-o1, which was puri?ed by crystallization from chloroform-methanol. acid, there was obtained the acetate of 2a-carboxy-17a vinyl-19-nor-androstan-175-o1. 20 The above compound was treated with an excess of Example XII By following the method of hydrogenation described in Example X, l g. of 2-carboethoxy-17a-methyl-A2-an drosten-175-ol, obtained as described in Example VI, was diazornethane, thus yielding the respective methyl ester. converted into 25 - carboethoxy - 17a - methyl-androstan 175-ol. Example VIII By following the method of the preceding example, 25 This compound was treated with a mixture of 25 acetic anhydride and acetic acid in the presence of p methyl-l7u-ethynyl-androstan-175-o1, and 25-hydroxy toluenesulfonic acid, in accordance with the method of esteri?cation of Example II, and thus there was obtained the acetate of 25-carboethoxy-17a-methyl-androstan methyl-l7a-ethynyl-19-nor-androstan-175-ol were oxidized 175-o1. hydroxymethyl-l7a-methyl-androstan-175-o1, 25-hydroxy with an excess of chromic acid in acetic acid to produce, 30 respectively, 25-carboxyl-175-methyl-androstan - 175 - ol, 25-carboxy-17a-ethynyl-androstan - 175 - 01, and 25-car boxy-l7a-ethynyl-19-nor-androstan-175-01. Example XIII 2 g. of 2-hydroxymethyl-17a-ethyl-A2-androsten-175-o1 was oxidized with 8 N chromic acid in acetone, in ac By treating cordance with the method of Example VI to produce 2 these compounds with an ether solution of diazomethane, there were obtained the respective methyl esters, which were then esteri?ed with acetic anhydride in benzene solu tion and in the presence of p-toluenesulfonic acid, thus carboxy-17a-ethyl-A2-androsten-175-o1. The above compound was hydrogenated in accordance with the method of Example II, to produce 25-carboxy 17a-ethyl-androstan-175-o1. giving ?nally the acetate of 25-carbomethoxy-l7a-methyl The above compound was treated with an excess of androstan-l75-ol, the acetate of 25-carbomethoxy-17a in ether solution to yield 25-carbomethoxy ethynylandrostan-175-ol and the acetate of 25-carbometh 4.0 diazornethane 17a-ethyl-androstan-175-01. oxy-l7a-ethynyl-l9-nor-androstan-l75-ol. A mixture of 800 mg. of the above methyl ester and 20 cc. of a 1% solution of sodium hydroxide in methanol was kept at room temperature for 30 minutes and then There was repeated the method of Example VI, but poured into ice cold salt water. The product was ex using 2a-hydroxymethyl-l7a-methyl-androstan-175-01 as 45 tracted with methylene chloride and the extract was starting compound, thus obtaining 2u-carboxy-l7a-meth washed with water to neutral, dried over anhydrous sodi Example IX yl-androstan-l75-ol and Zea-carbomethoxy-17a-methyl-an um sulfate and evaporated to dryness, thus affording 2a carbomethoxy-l7u-ethyl-androstan-175-o1. drostan-l75-ol. 500 mg. of the above compound was esteri?ed with By esterifying the above compound with cyclopentyl propionic anhydride in benzene solution and in the pres 50 propionic anhydride in benzene solution and in the pres ence of p-toluenesulfonic acid, by following the method ence of p-toluenesulfonic acid, there was produced the described in Example IV. There was thus obtained the cyclopentylpropionate of 20a - carbomethoxy - 17cc - ethyl propionate of 2-carbomethoxy - 17oz - methyl - androstan 175-o1. Example X androstan-17501. 55 Example XIV By following the method of Example VI, 2a-hydroxy A solution of 2 g. of the benzoate of Z-carbomethoxy A2-androsten-l75-ol, obtained as described in Example methyl-17a-ethynyl-19-nor-androstan-175-ol were oxidized III, in 100 cc. of ethyl acetate was hydrogenated at room with an excess of 8 N chromic acid in acetone, thus pro methyl-17a-ethynyl-androstan - 175 - 01 and 2a - hydroxy temperature and atmospheric pressure in the presence of 60 ducing 2a-carboxy-17a-ethynyl - androstan - 175-01 and its 19-nor derivative. By reacting these compounds with 200 mg. of 5% palladium on charcoal which had been previously reduced. When the equivalent of 1.1 mols of an ether solution of diazoethane, there were obtained the hydrogen had been absorbed, the catalyst was removed corresponding ethyl esters, i.e., 2ot-carboethoxy-17a by ?ltration and the ?ltrate was evaporated to dryness. ethynyl-androstan-175-ol and 2a-carboethoxy-l7a-ethynyl Crystallization of the residue from chloroform-methanol 65 l9-nor-androstan-175-ol. furnished the benzoate of 25-carbomethoxy-androstan 175-01. Example XV A solution of 1 g. of Z-carboxy-l9-nor-A2-androsten The above compound was saponi?ed by following the 175-o1, obtained in Example I, in 75 cc. of methanol was method of Example I, with simultaneous inversion of the carboxyl group at C-2, thus producing Zea-carbometh 70 hydrogenated in the presence of 100 mg. of 5% palladium oxy-androstan-175-ol. on charcoal, following the method of Example X. There A solution of 500 mg. of the above compound in 2 was thus obtained 25-carboxy-19-nor-androstan - 175 - 01, cc. of pyridine was treated with 1 cc. of acetic anhydride and the mixture was kept overnight at room tempera produced 25-corbomethoxy-19-nor - androstan - 175 - ol. ture. After pouring into water, the precipitate formed Acetylation of this compound by conventional methods which upon treatment with an excess of diazomethane 3,057,883 '8 . 2a~carboxy-19-nor4androstan-175-01. . ZB-carboxy-l9-nor-androstan-17p-ol. . 2u-carbomethoxy-17a-methyl-androstan-175-01. furnished the acetate of ZB-carbomethoxy-19-n0r-andros tan-l7l3-ol. Example XVI A mixture of 500 mg. of 2B-carbomethoxy-19-nor . Z?-carbomethoxy-l9-nor-androstan~175-ol. . 2a-carboethoxy-l7a-ethynyl-androstan-1713-01. . A process for preparing a compound of the follow androstan-l7B-ol and 15‘ cc. of a 1% solution of potas sium hydroxide in methanol was kept at room tempera ture for 1 hour, then poured into water and the precipitate ing formula: formed was collected, thus yielding 2oc-carbomethoxy-l9 10 nor-androstan-l7/3-ol. By esteri?cation of the ‘above compound with benzoyl R HOOCMV ‘ chloride in pyridine, in accordance with the method de scribed in Example III, there was obtained the benzoate of 2or-carbomethoxy-19-nor-androstan-175-01. ‘ 15 We claim: 1. A compound of the following formula: wherein R is selected from the group consisting of hy drogen and methyl; R1 is selected from the group con sisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; and R2 is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl and lower alkynyl, comprising oxidizing a R3000 I C-l7-hydrocarbon carboxylic acid ester of the corre sponding 2-hydroxymethyl-androstan-17,8-01 derivative | and thereafter saponifying the ester group. 23. A process for preparing a compound of the follow wherein R is selected from the group consisting of hy ing formula: drogen and methyl; R1 is selected from the group consist ing of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R2 is selected from the group 30 A I consisting of hydrogen, lower alkyl, lower alkenyl, and lower alkynyl; and R3 is selected from the group con sisting of hydrogen and lower alkyl. 2. 2-carboXy-A2-androsten-175-01. 3. The acetate of 2-carboxy-A2-androsten-175-01. . . . . . . Z-carboxy-l9-nor-A2-androsten-l7?-ol. Z-carboxy-l7a-methyl-A2-androsten-175-01. 2-carboxy-l7a-ethynyl-A2-androsten-173-01. 2-carboxy-17u-vinyl-A2-androsten-1713-01. 2-carbomethoxy-Az-androsten-l713-01. The acetate of Z-carbomethoxy-l7a-ethynyl-A2- an 35 wherein R is selected from the group consisting of hy drogen and methyl; R1 is selected from the group consist 40 ing of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R2 is selected from the group consisting of hydrogen, lower alkyl, lower al drosten-l7/3-ol. kenyl and lower alkynyl ; and R3 is selected from the 10. The acetate of 2-carbomethoxy-l7a-methyl-A2 group consisting of hydrogen and lower alkyl, compris androsten-17/3-ol. ing oxidizing a compound of the following formula: 11. A compound of the following formula: 1mm 50 R3000 MN RI m‘ wherein R is selected from the group consisting of hydro 55 wherein R and R2 have the same meaning as above and R4 represents the hydrocarbon carboxylic acyl group to gen and methyl; R1 is selected from the group consisting form the corresponding 2-carboxy-A2-andr0sten~175-01 of hydrogen and a hydrocarbon carboxylic acyl group of l7-acylate derivative, hydrogenating the latter in the pres less than 12 carbon atoms; R2 is selected from the group ence of a hydrogenation catalyst to produce the corre consisting of hydrogen, lower alkyl, lower alkenyl and lower alkynyl and R3 is selected from the group consisting 60 sponding 2f3-carboxy-androstan-l75-01 compound, es terifying the latter with a diazoalkane to produce the cor of hydrogen and lower alkyl. responding ZB-carboalkoxy-androstan-1713-01 compound and then treating the latter with an alkali to produce the corresponding 2u-carboalkoxy-androstan-173-01. 12. Zu-carboxy-androstan-175-01. 13. Z?-carboxy-androstan-17?-ol. 14. 2u-carboxy-17u-methyl-androstan-175-01. l5. 2a-carboxy-17u-ethynyl-androstan-175-01. l6. 2?-carboxy~17a-ethynyl-androstan-175-01. 65 No references cited.