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United States Patent O?tice r 3,055,920 Patented Sept. 25, 1962 1 2 3,055,920 the 17m-alkyl, alkenyl or alkynyl substituted derivatives, 2~HYDR0XYMETHYL-A2-ANDR0STEN DERIVA TIVES AND PROCESS as Well as of the corresponding l9-nor derivatives, there Albert Bowers, John Edwards, and James C. Orr, all of which upon subsequent esteri?cation produce the cor are obtained the respective Z-hydroxymethyl compounds, exico City, Mexico, assignors, by mesne assignments, No Drawing. Filed Oct. 20, 1961, Ser. No. 146,455 Claims priority, application Mexico Feb. 23, 1961 17 Claims. (Cl. 260-397.5) responding mono- or di-esters. to Syntex Corporation, a corporation of Panama The treatment of the l7-esters of 2-hydroxymethyl-A2 androsten-17?-ol, 2-hydroxymethyl-l9-n0r-A2-androsten 1713-01 or of the Not-substituted derivatives with an etherifying agent gives rise to the formation of the 2 alkoXy and 2-aralkoxy compounds. The present invention relates to certain new cyclo The method described above for preparing the 2-hy pentanoperhydrophenanthrene derivatives and to a droxymethyl and 2-acyloxymethyl derivatives is illustrated method for the preparation of the same. More particularly, our invention relates to the novel by the following sequence of reactions: Z-hydroxymethyl, 2-alkoxymethyl, Z-aralkoxymethyl and 15 2 - acyloxymethyl derivatives of A2 - androsten-U?-ol, which may further possess a 17a-alkyl, alkenyl or alkynyl group; it also comprises the preparation of the esters of such compounds and of the corresponding 19-nor-deriva tives. 7 20 Such compounds are powerful anabolic agents having a favorable anabolic-androgenic ratio; they help to in crease the protein metabolism and the deposition of calcium on the ‘bone tissue; furthermore they show anti ono- I R i H r on OH |---R9 |---R? i Homo m I R a II estrogenic activity, lower the cholesterol level in the blood 25 and inhibit the secretion of gonaldotropins by the pituitary gland. The ?ee-alkenyl and Noe-alkynyl com pounds further exhibit progestational activity. The novel compounds object of our invention are represented by the following formula: 30 mongo- ) OR1 R WORM-L to” 35 R 1'1 III In the above formulas R, R1 and R2 have the same meaning as set forth above; R4 represents and acyl radical of less than 12 carbon atoms. In practicing the process outlined above, Z-formyI-AZ 1'1 40 androsten-17,8~ol or one of the Not-substituted deriva In the above formula R represents hydrogen or methyl; tives thereof (I; R=Me) is subjected to reduction with a R1 represents hydrogen or an acyl group derived from a double metal hydride, such as sodium borohydride or carboxylic acid of l to 12 carbon atoms; R2 represents potassium borohydride, in a solvent inert to the reaction, hydrogen, an alkyl, alkenyl or alkynyl group such as such as methanol, tetrahydrofuran 0r dioxane, at room methyl, ethyl, propyl, vinyl, ethynyl or propynyl, and R3 temperature for a prolonged period of time or under re represents hydrogen, a lower alkyl group, a lower aralkyl ?ux for 1 hour, to produce the corresponding 2-hydroxy methyl derivatives (II, R=Me). Esteri?cation of such group of 1 to 8 carbon atoms or an acyl radical derived from a carboxylic acid of 1 to 12 carbon atoms. compounds with anhydrides or chlorides derived from The acyl groups set forth above derive from carboxylic 50 carboxylic acids of 1 to 12 carbon atoms, in pyridine or acids of less than 12 carbon atoms, saturated or un benzene solution, produces the 2,17-diesters (III; R=Me, R2=hydrogen) or 2-monoesters (III; R=Me, R2=alkyl, saturated, of straight, branched, cyclic or mixed aliphatic cyclic chain, substituted or not with groups such as hy droxy, methoxy, amino, halogen or other groups; typical such esters are the acetate, propionate, butyrate, valerate, hemiscuccinate, enanthate, caproate, benzoate, undec enoate, trimethylacetate, phenoxyacetate, cyclopentyl propionate and B-chloropropionate. alkenyl or alkynyl). The (3-2 monoesters may be esteri tied at C-17 with the same or a different acid anhydride 55 or chloride of hydrocarbon carboxylic acids of less than 12 carbon atoms, in benzene solution and in the presence of p-toluenesulfonic acid. In the same manner, the process described above is The novel compounds object of our invention are ob tained from the 2-formyl-l7?-hydroxy-A2-androstenes and the corresponding l9-nor derivatives. In our copending patent application Serial No. 128,974, ?led August 3, 1961, there is described the preparation of the Z-forrnyl-M-androstenes starting from a 2-alkoxy methylene derivative of dihydroallotestosterone, 19-nor dihydroallotestosterone or one of the 17a-alkyl, alkenyl or alkynyl substituted derivatives, which by reduction with a double metal hydride furnish the corresponding 3 hydroxy derivatives. By acid treatment of these com applied to the Z-formyl-19-nor-A2-androstenes, thus pro 60 ducing Z-hydroxymethyl-19-nor-A2-androsten-17,8-01 and the corresponding 17a-alkyl, alkenyl and alkynyl deriva tives, as well as the mono- and diesters of such com pounds. Alternatively, there maybe employed as starting mate 65 rial and ester of 2-formyl-A2-androsten-175-01, of 2 formyl-19-nor-A2-androsten-l7B-ol or of the correspond ing Nix-substituted derivatives, which on reduction with a double alkali metal hydride in dioxane or tetrahydro furan under anhydrous conditions, to avoid hydrolysis pounds in the presence of a proton acceptor there are 70 of the acyloxy groups, produce the corresponding 17 obtained the 2-formyl-A2-androstenes. , esters of - 2'-hydroXymethy1-17?-hydroXy-A2-andr0stenes and l9-nor-androstenes. ' ' By reduction of 2-formyl-A2-androsten-175-01, or of The novel 2-alkoxy and 2-aralkoxy compounds object 3,055,920 of our invention are obtained by the method illustrated by the following sequence of reactions: OR1 R HoHtc~ \ 1'1 )2- To a solution of 10 g. of 2-formyl-17a-methyl-A2-an drosten-17l3-ol in 300 cc. of anhydrous tetrahydrofuran was added 10 g. of sodium borohydride and the mixture was stirred at room temperature for 24 hours; at the end of this time the excess of reagent was destroyed with . dim 5 Bionic-A acetic acid, poured into ice water and the precipitate was Crystallization from acetone-ether afforded 2 (/ 1v 4 material, there was obtained 2~hydroxymethyl-19-nor-A2 androsten-17B-ol and its corresponding diacetate. Example 111 10 collected. hydroxymethyl - 17a - methyl - A2-androsten-17B-ol; M.P. 1'1 v 167—169° C.; [a]D+26° (chloroform). In another experiment there was employed anhydrous on mm as solvent, with the same result. 15 dioxane A mixture of 1 g. of Z-hydroxymethyl-17a-methyl-A2 androsten-17?-ol, 10 cc. of pyridine and 1 cc. of acetyl chloride was kept at room temperature for 36 hours and then the solvent was evaporated under vacuum at a tem perature below 60° C. Crystallization of the residue from methylene chloride-hexane furnished 2-acetoxy 20 Bionic ‘/\a methyl-17ot-methyl-A2-androsten-175-01. Example IV 1'1 v1 In accordance with the method of reduction described 25 in the preceding example, there was treated 5 g. of 2 In the above formulas R, R1 and R2 have the same formyl-17a-ethyl-A2-androsten-175-01 with sodium boro hydride using tetrahydrofuran as solvent, thus yielding 2 meaning set forth previously; R5 represents a lower alkyl hydroxymethyl-l7a-ethyl-A2-androsten-176-01. or aralkyl group containing up to 8 carbon atoms. In practicing the process just outlined, a l7-ester of 2-hydroxymethyl-A2-androsten-175-01, which may further From a solution of 1 g. of the above compound in 130 cc. of benzene free of thiophene there was distilled ap proximately 30 co. in order to remove moisture; there was then added 0.52 cc. of pyridine and 1.5 cc. of un decenoyl chloride and the mixture was re?uxed for 1 30 possess a substituent at C—l7oc of the type set forth above, or ‘from the corresponding 19-nor derivatives (IV), is allowed to react at room temperature with an excess of an ether solution of a diazoalkane, such as diazomethane or diazoethane, and in the presence of a catalyst, such as boron tri?uoride or aluminum chloride, to produce the 35 hour; after evaporating to dryness under vacuum the residue was chromatographed on 30 g. of washed alumina, thus yielding Z-undecenoyloxymethyl-17a-ethyl-A2-an drosten-17?-ol. Z-methoxymethyl or 2-ethoxymethyl derivatives (V; R5==methyl, ethyl). Saponi?cation of these compounds by conventional methods produces the corresponding free ethers (VI; R5=methyl, ethyl). Example V By following the method of reduction described in Ex 40 ample I, 2-formyl~17a-ethynyl-A2-andr0sten-175-01, 2 Alternatively, the etheri?cation may be effected by reacting at the re?ux temperature the 2-hydroxymethyl formyl-l7a-vinyl-A2-androsten-175-01, 2-formy1-17a-vinyl 19-nor-A2-androsten-17?-ol and 2-formyl-17a-ethynyl-19 compounds of Formula IV with an alkyl or aralkyl halide, preferably with an alkyl or aralkyl iodide, in an organic 45 nor-A2-androsten-17B-ol were respectively converted into 2-hydroxymethyl-17a-ethynyl-dz-androsten-1713-01, 2-hy solvent such as acetone and in the presence of a base, droxymethyl - 17u-vinyl-A2-androsten-17,8-01, Z-hydroxy such as potassium carbonate, or by treatment with an methyl - 17a - vinyl-19-nor-A2-androsten-17,6-01 and 2-hy alkyl sulfate in acetone solution and in the presence of droxymethyl-17wethynyl-19-nor-A2-androsten-175-01. a base, preferably potassium hydroxide, at room tempera Example VI ture. 50 ' The following examples serve to illustrate but are not intended to limit the present invention. A solution of 500 mg. of 2-hydroxymethyl-A2-andro sten-17B-ol in 2 cc. of pyridine was treated with 1 cc. of caproic anhydride and the mixture was kept over night at room temperature; it was then poured into water A solution of 5 g. of Z-formyl-M-androsten-1713-01 in 55 and the precipitate formed was collected by ?ltration, 200 cc. of methanol was cooled to —5° C., treated with thus affording the caproate of 2-capronoxyrnethyl-A2 1.5 g. of sodium borohydride in 30 cc. of methanol and androsten-17?-ol. the mixture was kept at room temperature for 1 hour By the same method, but using propionic, valeric and under anhydrous conditions; at the end of this time it cyclopentylpropionic anhydride as esterifying agents, Example I was cooled, the excess of reagent was destroyed with a 60 there were obtained the corresponding diesters of 2-hy few drops of glacial acetic acid and water was added droxymethyl-A2-androsten-175-01. until complete precipitation; the precipitate formed was collected by ?ltration, washed and dried, thus yielding Example VII 2-hydroxymethyl-A2-androsten-175-01; M.P. 193—194° C., [ethyl-65° (chloroform). A mixture of 1 g. of the above compound, 4 cc. of pyridine and 2 cc. of acetic anhydride was heated on the steam bath for 1 hour, poured into water and the precipitate formed was collected, washed with water to neutral and dried. By crystallization from acetone hexane there was obtained 2-acetoxymethyl-Alandrosten 175-01 acetate. Example 11 By following the method of the preceding example, A mixture of 1 g. of 2-hydroxymethyl-17a-methyl-A2 65 androsten-l7i-3-ol, 50 cc. of benzene, 2 cc. of acetic an hydride 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, consecutively washed with 5% sodium carbonate solution and with 70 water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. By chromatography of the residue and crystallization of the but using 2-formyl-19-nor-A2-androsten-173-01 as starting 75 solid fractions from acetone-ether there was obtained the agetatle of 2 - acetoxymethyl-17a-rnethyl-A2-androsten 5,055,926 . . 5 ,1. . In the same manner, but employing propionic, caproic, undecenoic and cyclopentylpropionic anhydrides as esteri fying agents (the latter two being employed in twice the amount), there were obtained the propionate of Z-propion . I 6 Example XI To a solution of 10 g. of 2-formyl-A2-androsten-17?-ol in 40 cc. of pyridine was added 10 cc. of benzoyl chloride and the mixture was heated on the steam bath for 1 hour, cooled and poured into water; the precipitate formed was oxymethyl-l7a-methyl-A2-androsten-17,6-01, the caproate of 2 - capronoxymethyl - 17a-methyl-A2-and-rosten-175-01, the undecenoate of Z-undecenoyloxymethyl-l7a-methyl~ collected and recrystallized from chloroform-methanol, A2-androsten-17/3-ol and the cyclopentylpropionate of 2 thus yielding the benzoate of 2-formyl-A2-androsten 17,6-01. cyclopentylpropionoxymethyl - 17a-methyl-A2-androsten 1718-01. 10 Example VIII To a solution of 5 g. of the above benzoate in 100 cc. out anhydrous dioxane was added 5 g. of potassium boro hydride and :the mixture was stirred overnight at room 2 g. of 2-formyl-Not-methyl-19-nor-A2-androsten-1718-01 temperature and under anhydrous conditions; the excess was reduced with sodium borohydride in tetrahydrofuran, of reagent was destroyed with acetic acid, the mixture following the method described in Example I; there was 15 was poured into water and the product extracted with thus obtained 2-hydroxymethyl-17u-methyl-l9-nor-A2 ethyl acetate. The organic extract was washed to neu androsten-17/8-ol. tral, dried and evaporated to dryness under vacuum. The above compound was dissolved in 10 cc. of pyri dine and 5 cc. of acetic anhydride, heated for 1 hour on benzoate of 2~hydroxymethyI-AZ-androsten-175-01. Crystallization from chloroform-methanol furnished the the steam bath and poured into ice water; the precipi 20 By subsequent treatment with an excess of diazometh tate Iformed was collected, thus giving Z-acetoxy-methyl ane, in accordance with the method of Example X, there Hot-methyl-19-nor-A2-androsten-l75-01. was obtained the benzoate of 2-methoxymethyl-A2-andos~ 500 mg. of the latter compound was treated with 1 cc. ten-17?-ol. ' -- a - of cyclopentylpropionic anhydride in benzene solution and A solution of 500 mg. of the above compound in 25 in the presence of p-toluenesulfonic acid, in accordance 25 cc. of 2% methanolic potassium hydroxide solution was with the method described in Example VII; there was thus re?uxed for 2 hours, then neutralized with acetic acid, obtained the cyclopentylpropionate of 2-acetoxymethyl concentrated under vacuum to a small volume and poured l7a-methyl-19-nor-androsten-1713-01. into ice cold salt water; the precipitate formed was col— lected, washed and dried, thus giving 2-methoxymethyl Example IX 30 A2-androsten-17,B~ol. A mixture of 5 g. of Z-formyl-17a-methyl-A2-androsten Example XII 17,8-01, 200 cc. of acetic acid, 100 cc. of acetic anhy dride and 5 g. of p-toluenesulfonic acid was kept at room temperature for 1 hour, poured into water, stirred for 30 minutes to hydrolyze the excess of anhydride and ex tracted several times with methylene chloride; the com~ There was repeated the process of the preceding exam ple, but using the acetate of 2-formyl-19-nor-A2-andro sten-17/3-o1 as starting material. There were thus suc 35 - cessively obtained: the acetate of 2-hydroxymethyl-19~ bined extract was washed to neutral, dried over anhydrous nor-A2-androsten-17/8-ol, the acetate of 2~methoxymethyl sodium sulfate and evaporated to dryness. The residue was dissolved in 100 cc. of 1% methanolic potassium hy droxide, ‘kept at 0-10° C. for 1 hour, poured into Water and extracted with ethyl acetate; the extract was washed with water to neutral, dried over anhydrous sodium sul fate and evaporated to dryness under vacuum. By crys tallization ‘from acetone~hexane there was obtained the A2-androsten-l7-ol. acetate of 2-formyl-17m-mcthyl-nz-androsten-l7,8-01. 19-nor-A2-androsten-17a-o1 and 2-methoxymethyl-19-nor Example XIII 1 g. of the caproate of Z-formyl-17a-vinyl-A2-andro sten-17?-ol was reduced with sodium borohydride in di oxane solution, in accordance with the method of Exam 45 The above compound was reduced with sodium boro ple III, to produce the caproate of 2-hydroxymethyl-17a vinyl-nz-androstend7,8-01. A solution of 500 mg. of the above compound in 75 hydride in tetrahydrofuran, in accordance with the meth od of Example III, to produce the acetate of 2-hydroxy cc. of ether was treated with an ether solution of diazo ethyl-Az-androsten-175-01. androsten-17?-ol. methane and 10 mg. of aluminum chloride; the mixture was kept at room temperature for 1 hour, the excess of By the same method 2-formyl~17a-ethyl-A2-androsten 50 diazomethane was destroyed by the addition of a ‘few 1718-01 was converted into the respective acetate which on drops of acetic acid and evaporated to dryness, thus fur reduction afforded the acetate of 2-hydroxymethyl-17a nishing the caproate of Z-methoxymethyl-17a-vinyl-A3 methyl-1 7a-methyl-A2-androsten-175-01. Example X Exam‘ple XIV v55 There was repeated the method of the preceding exam A solution of 1 g. of the acetate of Z-hydroxymethyl 17a-methyl-A2-androsten-17,8-01 in 100 cc. of ether was cooled to 0~5° C. and treated with an ether solution of ple, but using as starting materials the acetate of 2-formyl diazomethane (prepared from 5 g. of nitrosomethylurea) 60 and 3 drops of recently distilled boron tri?uoride etherate. 17a-ethynyl-A2-androsten-17,8-01 acetate, 2-methoxymeth~ yl-17ot-ethnyl~2-androsten-l7,8-01 acetate, 2-hydroxymeth 17a-ethynyl~A2-androsten-1713-01 and its corresponding 19-nor analog, thus giving respectively 2-hydroxymethyl The mixture was kept at room temperature for 1 hour, treated with a few drops of acetic acid to destroy the ex 2 - methoxymethyl - 17oz - cess of diazomethane and then evaporated to dryness; sten~17,B-ol acetate. yl-l7ac-ethynyl-19-nor-A,2 androsten-17B-ol acetate and there was thus obtained 2-methoxymethyl-17a-methyl-A2 65 androsten-lZB-ol, acetate. ethynyl f 19 - nor - A2 - andro-' Example XV There was repeated the method of Example X, but em ploying an ether solution of diazoethane instead of vdiazo A solution of 500 mg. of the above compound in 50 cc. of methanol was treated with 500 mg. of potassium hy methane, thus obtaining the acetate of 2-ethoxymethyl droxide dissolved in 1 cc. of water and 5 cc. of methanol and the mixture was kept overnight at room temperature; 70 l7a-methyl-A2-androsten-175-01 and then the correspond ing free compound. it was then neutralized with acetic acid, concentrated to a small volume and diluted with water until complete pre Example XVI cipitation. The product was collected by ?ltration and A mixture of 2 g. of the acetate of Z-hydroxymethyl crystallized from methylene chloride-hexane, thus afford ing 2-methoxymethyl-l7a-methyl-A2~androsten-17/3-01. 17a-methyl-A2-androsten-175-01, 100 cc. of anhydrous 75 acetone, 10 cc. of methyl iodide and 2 g. of anhydrous 3,055,920 8 16. A process for preparing a compound of the fol potassium carbonate was re?uxed for 48 hours. At the end of this time it was poured into water, extracted with ethyl acetate and the organic extract was washed with water, dried over anhydrous sodium sulfate and evapo lowing formula: rd rated to dryness under vacuum. The residue was puri ?ed by chromatography on washed alumina, thus fur nishing the acetate of 2-methoxymethyl—17a-methy1-A2 androsten-17/3-ol, identical with the product obtained in Example X. 10 Example XVII wherein R is selected from the group consisting of hy drogen and methyl; R1 is selected from the group con By following the method of the preceding example, but using ethyl, propyl or benzyl iodide instead of methyl iodide, the acetate of 2-hydroxymethyl-17u-ethyl-A2-an 15 drosten-17B-ol was converted into 2-ethoxymethyl-17a 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 reacting a com ethyl-A2-androsten-17B-ol acetate, 2-propoxymethyl-l7a ethyl-M-androsten-U?-ol acetate and 2-benzoxymethyl 17a-ethyl-A2-androsten-1713-01 acetate. By subsequent pound of the following formula: saponi?cation of these compounds, in accordance with 20 the method of Example X, there were obtained the re spective free compounds. -6193 Exam'ple XVIII By following the method of acetylation described in 25 Example III, 2-hydroxymethyl-17a-vinyl-A2-androsten 1719-01 and Z-hydroxymethyl-17a-ethynyl-A2-androsten 175-01 were respectively converted into 2-acetoxymethyl 17a-vinyl-A2-androsten-175-01 and 2-acetoxymethyl-17a ethynyl-Az-androsten-175-01. wherein R, R1 and R2 have the same meaning as above, 30 with a double metal hydride to form the corresponding Z-hydroxymethyl compound and thereafter esterifying We claim: with a hydrocarbon carboxylic acid of less than 12 car 1. A compound of the following formula: bon atoms. 17. A process for preparing a compound of the fol ORl 35 lowing formula: A. Hi” weak/l1 40 IUOHaC-l wherein R is selected from the group consisting of hydro 45 gen and methyl; R1 is selected from the group consisting wherein R is selected from the group consisting of hy of hydrogen and a hydrocarbon carboxylic acyl group of drogen and methyl; R1 is selected from the Igroup con less than 12 carbon atoms; ‘R2 is selected from the group sisting of hydrogen and a hydrocarbon carboxylic acyl consisting of hydrogen, lower alkyl, lower alkenyl and group of less than 12 carbon atoms; R2 is selected from lower alkynyl, and R3 is selected from the group con the group consisting of hydrogen, lower alkyl, lower sisting of hydrogen, lower alkyl and aralkyl containing up alkenyl and lower alkynyl; and R5 is selected from the group consisting of lower alkyl and aralkyl containing to eight carbon atoms. 2. 2-hydroxymethyl-M-androsten-l76-01. up to 8 carbon atoms comprising reacting a compound 3. 2-hydroxymethyl-17a-methyl-A2-androsten-l718-01. of the following formula: 4. Z-hydroxymethyl-19-nor-A2-androsten-175-01. 5. Z-hydroxymethyl-17a-vinyl-Az-androsten-l75-01. 6. Z-hydroxymethyl-17u-ethynyl-A2-androsten-175-01. 55 l---.Rg 7. 2 - hydroxymethyl - 17a - methyl - 19 - nor - A2 - an drosten-17/3-ol. Ii 60 8. 2 - hydroxymethyl - 17oz - ethynyl - 19 - nor - A2 - an drosten-l7p-ol. ' 9. The propionate of 2-propionoxymethyl-Az-andro H sten-17?-ol. 10. The caproate of Z-capronoxymethyl-M-androsten 175-01. 11. 2-methoxymethyl-A2-androsten-175-01. 12. Z-methoxymethyl-l7a-methyl-A2-androsten-17,6-01. 13. The acetate of 2-111eth0xymethyl-A2-androsten 17/3-01. 14. 2-acetoxymethyl-17a-vinyl-Az-androsten-17,6-01. 15. 2-acetoxymethyl-17a-ethynyl-A2-androsten-1713-01. 65 wherein R and R2 have the same meaning as before and R1 represents the hydrocarbon carboxylic acyl group of less than 12 carbon atoms, with a double metal hydride to form the corresponding 2-hydroxymethyl compound and thereafter reacting the latter compound with an etherfying agent. No references cited.