Патент USA US3080408код для вставки
B?b??gg United gtates I '? atent Patented Mar. 5, 1963 2 1 drosten compounds by a method illustrated by the fol 3,080,3% lowing equation: _ 2~HALOMETHYL-M-ANDROSTENES AND ' DERIVATIVES THEREGF Albert Bowers, John Edwards, and .iarnes C. Orr, allot ' Mexico City, Mexico, assignors to Syntax 8A., Mexico City, Mexico, a corporation of Mexico No Drawing. Filed Apr. 13, 1962, Ser. No. 187,222 ' 18 Claims. (Cl. zeta-397.4) The present invention relates to certain new cyclopen 10 tanophenantrene derivatives and to the method for mak ing the same. More particularly it relates to the novel 2-halomethyl Az-androstenes, which may be further substituted at C-l7zx by an alkyl, alkenyl or alkynyl group as well as 15 to the 19-nor derivatives and the esters thereof. The present invention relates also to a new method for making Za-halomethyl-androstan and l9-nor-androstan l7?-ol-3-one derivatives, which have been described in R our copending application Serial No. 107,039, ?led on 20 May 2, 1961. The novel compounds object of our invention are potent anabolic agents with a favorable anabolic-andro FHiC-I o : OR2 (IV) I ?R R .XlHzC /\ i i I Is” (III) In the above formula R, R1 and R2 have the same genic ratio, lower the blood cholesterol level, relieve pre menstrual tension and exhibit anti-estrogenic and anti 25 meaning as heretofore set forth; X1 represents chlorine gonadotrophio activities. The 17a-alkenyl and alkynyl or bromine. _ , In practicing the process set forth above Z-hydroxy compounds are also progestational agents. The novel compounds of the invention are represented methyl-M-androsten-175-01, 2 - hydroxymethyl-19-nor-A2 by the following formula: androsten-17?-ol, the esters thereof or the corresponding 30 170t-SllbSlltl1ted derivatives (I) is treated with thionyl chloride in benzene solution. The reaction is effected at room temperature, for a period of time in the order of OR2 5 minutes to 1 hour, thus producing the 3B-chloro-2 methylene derivatives (II: X1=chlorine) which upon 35 heating with lithium chloride in dimethylformamide, for a period of time of 18 to 24 hours at 90° C. give rise to the corresponding 2-chloromethyl-Az-androstenes and 19-nor-androstenes (III: X1=chlorine). In a similar manner, but using thionyl bromide and lithium bromide 40 instead of the corresponding chlorides, there are pro In thev above formula R represents hydrogen or meth duced SB-bromo-Z-methylene and 2-,brornomethyl-A2-an yl, R1 represents hydrogen or a lower alkyl, alkenyl or drostenes and 19-nor-androstenes (II and III: X1=bro alkynyl group containing up to 8 carbon atoms; X rep mine). ' _ resents chlorine, bromine or ?uorine and R2 represents In order to obtain the 2‘?uoromethyl-nz-androstenes hydrogen or a hydrocarbon carboxylic acyl radical of 45 object of the present invention, a‘ Z-hydroxymethyl de~ less than 12 carbon atoms. rivative of Ag-androsten-1718-01-l9p-nor-Az-androsten-17B The acyl group is derived from hydrocarbon carboxylic ol, the corresponding 17ot-alkyl, alkenyl or alkynyl de acids containing less- than 12 carbon atoms which may rivatives or esters thereof is reacted with anhydrous hy be saturated or unsaturated, of straight, branched, cyclic drogen ?uoride in mixture with methylene chloride or cyclic-aliphatic chain, aromatic and may be substi 50 tetrahydrofuran, at low temperature, preferably between tuted by functional groups such as hydroXy, alkoxy con -—70° and‘ 0° C. for a period of time in the order of 15 taining up to 5 carbon atoms, acyloxy containing up to 12 to 24 hours preferably for 18 hours, thus producing the carbon‘ atoms, nitro, amino or halogen. Typical ester 2-?uorornethyl-Az-androsten compounds (IV). groups are the acetate, propionate, enanthate, benzoate, Alternatively, the esters of the 2-halomethyl-A2-andro trirnethylacetate, t-butylacetate, phenoxyacetate, cyclo 55 stenes object of the present invention may be obtained by pentylpropionate, aminoacetate and ?-chloropropionate. In our copending patent application Serial No. 146,455, conventional esteri?cation of the free compounds (III and IV: R2.=H), that is, by treatment with acid anhy ?led on- October 20, 1961, there is described the method drides or chlorides of less than 12 carbon atoms in pyri for producing 2-hydroxymethyl-A2-androsten-1713-01, the ' dine solution-‘for the 17-unsubstituted 2-halomethyl 17OC-Sllb5tltllt8d derivatives and the corresponding l9-nor compounds by reducing 2-formyl-A2-androstenes and 2 formyl-AF-19-nor-androstenesYwith sodium borohydride‘. The novel 2-halomethyl-dz-compounds of the present invention are obtained from the Z-hydroXymethyl-AZ-an androstenes and l9-nor-androstenes or With acid anhy drldes in benzene solution and in the presence of p toluenesulfonic acid for the 170C-Zi1kyl, alkenyl' and al kynyl derivatives. The new method for producing 2a-halomethyl 17a ‘3,080,398 substituted androstan derivatives is illustrated by the fol lowing sequence of reactions: 9R’ "-33 ‘RR’ "-113 in R i Xroo I . n XHzC / ——' (V) E 01 “ ; (VI) H0 In the above formulas R, R2 and X have the same on: on i __R3 I --R3 15 or lower alkyl. R n Xmo- Kano-- l / (VIII) In practicing the process outlined above, a 2-halomethyl derivative of A2-androsten-17B-ol, which may be further substituted at C-17u by a lower alkyl group, or the cor responding 19-nor derivatives (IX), is treated with a cur 20 rent of diborane in a solvent such as tetrahydroi‘uran. ,_ 0: meaning as heretofore set forth; R4 represents hydrogen no“ , (v11) In the above formulas R, R2 and X have the same meaning as previously set forth; R3 represents a lower alkyl or alkynyl group. In practicing the process set forth above, a Z-halomethyl derivative of A2-androsten-17B-ol, which is further sub Upon subsequent reaction with aqueous alkali and hy drogen peroxide there is formed the 3u-hydroxy-2/3-halo methyl derivative (X) which is converted into the 3-keto compound (XI) upon reaction with chormium trioxide in acetic acid or acetone solution. stituted at C-17ct by an alkyl or alkynyl group, or the The inversion of the steric con?guration of the halo methyl substituent at C-2 is effected by acid treatment, acid in acetone solution or with chromic acid in acetic intended to limit the scope of the present invention. preferably using anhydrous hydrogen chloride in chloro corresponding 19-nor-derivatives (V), is treated with 1.1 molor equivalents of a peracid, preferably monoperph 30 form solution, thus producing 2ot-halomethyl androstan 17?-ol-3-one, 2ot-halomethyl-l7a-alkyl androstan-l75-ol thalic or perbenzoic acid, to give the corresponding 2,8 3-one and the corresponding l9-nor compounds and esters halomethyl-2a,3a-oxido compounds (Vi). Upon treat (XII). ment of these epoxides with lithium aluminum hydride The novel compounds represented by Formulas VIII in tetrahydrofuran solution at re?ux temperature and for a prolonged period of time, preferably during 18 hours, 35 and XII are potent anabolic agents having a favorable anabolic-androgenic ratio; exhibit anti-estrogenic and the epoxide ring is opened, thus producing the Zea-halo anti-gonadotrophic activities; relieve premenstrual ten methyl-3a-hydroxy derivatives (VII), with concomitant sion, lower the blood cholesterol and have anti-?brilla saponi?cation at C-17, when an ester has been used as tory properties. ‘the starting material. Oxidation of the above compounds with 8 N chromic 40 The following examples serve to illustrate but are not acid produce the corresponding 3-ketone (‘Villz R2=hy PREPARATION 1 To a solution of 5 g. of Z-hydroxymethyl-Not-methyl methyl 17ot-alkyl and l7a-alkynyl-androstan-175-01-3 45 A2-androsten-l7?-ol in 100 cc. of anhydrous benzene there were added 1 g. of p-toluenesulfonic acid and 15 one and the esters of 2a-halomethyl~17a-alkyl and 17a cc. of acetic anhydride and the mixture was allowed to alkynyl-19-nor-androstan-l7r3-ol-3-one (VII: R2=acyl). stand for 24 hours at room temperature, poured into ice By partial hydrogenation of the 2-halornethyl-17a and Water, and the resulting mixture stirred to effect allrynyl compounds (VH1: R3=alkynyl) using 2% pal ladium on calcium carbonate as catalyst and in pyridine 50 hydrolysis of the excess anhydride. The benzene layer was separated and washed with 10% sodium carbonate solution there are obtained the 2ot-halornethyl-17a-alkenyl , solution and water. Drying, evaporation and crystalliza derivatives. drogen), which are then esteri?ed by the methods herein above set forth, thus producing the esters of Zea-halo Thus for example, starting from Z-chloromethyl-lh ethynyl-dg-androsten-l75-01 acetate there are obtained tion of the residue from ether-hexane produced Z-acetoxy methyl-17a-rnethyl-A2-androsten-17,6-ol-acetate. successively 2,8-chloromethyl-2a,3ot-oXido-l7a-ethynyl-an A mixture of 2 g. of the above compound and 20 cc. drostan-17B-ol acetate, 2ot-chloromethyl-17ot-ethynyl-an 2a-chlorornethyl-l7a-ethynyl-andro stan-17,6-ol-3-oue and Za-chlommethyl-l7a-vinyl-andro stan-l7?-ol-3-one. of a 1% potassium hydroxide solution was stirred for 1 hour at 0° C.; it was then poured into water and the chloromethyl, Za-bromomethyl and 2a-fluoromethyl-an PREPARATION 2 formed precipitate collected by ?ltration, thus giving 2 hydroxymethyl - 17a - methyl - A2 - androsten - 17,8 - ol In another aspect of the present invention the 20: 60 acetate. drostan-l7?-ol-3-one, the 17a-alkyl substituted derivatives and the corresponding 19-nor compounds are obtained by the method illustrated by the following equation: By the same method of Preparation 1, Z-hydroxy methyl-17a~methy1-19-nor-A2—androsten-17,8-01, 2-hydroxy methyl-l7a-ethyl-Az-androsten-175-01, 2-hydroxymethyl~ 17ct-vinyl-A2—19-norandrosten-l7B-ol, 2 - hydroxymethyl l7a-ethinyl-A2-androsten-17,8 - 01 and 2 - hydroxymethylv l7a-ethinyl-A2-19-nor-androsten-17/3-ol were converted into the corresponding 17-acetates, namely 2-hydroxy 70 methyl-l7a-rnethyl-19-nor-A2-androsten-17,3-01-acetate, 2 hydroxy-methyl-l7a-ethyl-Az-androsten-17/3-ol-acetate, 2 hydroxy-methyl-17a-vinyl-A2-19-nor-androsten-17/3-ol ace tate, 2-hydroxymethyl-17u-ethinyl-A2-androsten - 1713 - ol acetate and 2-hydroxymethyl-l7ot-ethinylal9-nor-Az-an 75 drosten-17?-ol acetate. 3,080,398 5 Example I vented into the 2-chloromethyl-Az-androsten derivatives . (I11). A solution of 2.5 g. of 2-hydroxymethyl-A2-androsten 175-01 in 250 cc. of dry benzene thiofene free was treated with 2.5 cc. of freshly distilled thionyl chloride and the reaction mixture was kept at room temperature during I 2-hydroxymethyl- 1 hour. It was then diluted with water and the organic layer washed well with 5% sodium carbonate solution chloro-19-nor- androstan17?-ol- 2-hydroxymethyl- l7a-methyl-A2orated to dryness under vacuo. The residue was ?ltered through a column of 100 g. of acetic acid washed alumina 10 androsten-H?-ol. 2-hydroxymethylusing 500 ‘cc. of benzene-hexane 1:1 as solvent. The 17a-vmyl-Ncrystalline fractions were combined and recrystallized androsten-U?-ol- caproate. 2-hydroxymethyl17a-ethiny1-A2- from methanol, thus affording 1 g. of 3?-chloro-2-methyl ene-androstan-17B-ol. ' A mixture of the above compound (1 g.), 1 g. of 2-mcthylene-3B- 19-n0r-A2- androsten-17?-olacetate. and water, dried over anhydrous sodium sulfate and evap II androsten-WB-ol. acetate. 2-methylene-35Gh10l‘O-17a- ir;gtl11yl-androstan -0 . 2-methylene-3B- ehlor0-17aviuyl-androstan17/3-ol-eapr0ate. 2-methylene-3?011lOI‘0-17ixethinyl-androstan III 2eh1oromethyl-19 nor-A?-androsten 17B-0l-acetate. 2-chl0r0methyl-17a methyl-N-androsten 1718-01. 2-ehloromethyl-17a viuyl-Aa-androsten 1713-01-capr0ate. 2-chloromethyl-l7a ethinyl-Az-androsten 176-01. ' 175-01. lithium chloride and 100 cc. of dimethyl formamide Was heated on the steam bath for 18 hours. Water was added Example V By following the method of Example II, 5 g. of 2 and the formed precipitate collected by ?ltration, thus giving the crude 2-chloromethyl-A2-androsten-175-01 which was puri?ed by recrystallization from methanol 20 hydroxymethyl-17a-methyl-A2-androsten-17,8-ol were con water. verted into 2-fluoromethyl - 17a - methyl-Az-androsten A mixture of 1 g. of the latter compound, 4 cc. of pyr idine and 2 cc. of acetic anhydride was kept at room 175-01. temperature overnight. It was then poured into water, and the formed precipitate collected by ?ltration, thus producing the acetate of 2-chloromethyl-Az-androsten of anhydrous benzene there were added 200 mg. of p toiuenesulfonic acid and 2 cc. of acetic anhydride and the mixture was allowed to stand for 24 hours at room 1713-01. temperature, poured into ice and water, and the resulting hydrogen fluoride and 144 g. of tetrahydrofuran pre viously cooled to —70° C. in a Dry Ice-acetone bath. evaporation and crystallization of the residue from ether-hexane produced the acetate of 2-fluoromethyl-17u The mixture was kept standing at —-10° C. for 18 hours. It was then carefully poured into water and the excess methyl-Alandrosten-175-01. To a solution of 1 g. of the latter compound in 20 cc. A solution of 2 g. of 2-hydroxy-methyl-A2-androsten mixture stirred to e?'ect hydrolysis of the excess anhy 1713-01 in 80 cc. of methylene chloride was cooled to dride. The benzene layer was separated and washed 30 --70° C. and added to a mixture of 8 g. of anhydrous with 10% sodium carbonate solution and water. Drying, Example VI of hydrogen ?uoride decomposed by adding 50 g. of , In accordance with the esteri?cation method of th sodium carbonate. The product was then extracted with methylene chloride and the organic extract washed to neutral, dried over anhydrous sodium sulfate and evap orated to dryness under reduced pressure. The crude preceding example 2 - chloromethyl - 17a - methyl-A2 .androsten-lm-ol was converted into the corresponding product was dissolved in 100 cc. of hexane-benzene (1:1) 40 and ?ltered rapidly through a column of 50 g. of acetic acid washed alumina. The crystalline fractions were acetate. . In a similar manner, but using capro‘ic and propionic anhydride as esterifying agents, there were produced caproate and the propionate of Z-chloromethyl-lh methyvl-dg-androsten-175-01. combined and recrystallized from methanol, thus giving 0.7 g. of 2-?uoromethyl-A2-androsten-17B-ol. Example VIZ In accordance with the method described in Example A solution of 1 g. of the latter compound in 4 cc. of pyridine was treated with 2 cc. of benzoyl chloride and then heated on the steam bath for 1 hour. The mixture was then poured into ice water and the formed precipitate III, 1 g. of 2-hydroxymethyl-17a-vinyl-A2-androsten-1718 01 Was reacted with thionyl‘ bromide, thus a?ording 3f} collected, washed with water and dried. Recrystallization bromo-2-methylene-17ot-vinyl=androstan - 175-01. Upon from methylene chloride-hexane a?orded the benzoate of 50 treatment of the ‘above compound with lithium bromide 2-?uoromethyl-A2-androsten-1713-01. in dimethyl formamide there was produced 2-bromo methyl-17a-Vinyl-A2-androsten-1716-01. Example III 250 mg. oi the latter compound were esteri?ed with A solution of 5 g. of 2-hydroxymethyl-M-androsten propi-onic anhydride in benzene solution and in the pres 17,8-01- in 500 cc. of dry benzene, thiophene free was 55 ence of p-toluenesulfonic acid; by following ‘the method treated with 5 cc. of freshly distilled thionyl bromide of the preceding example, thus producing the propionate and the mixture kept at room temperature for 1 hour. It ‘ of, Z-bromomethyl-17a-vinyl-A2-androsten-1713-01. was then washed with water, 5% sodium carbonate solu ' 'tion and water to neutral, dried and evaporated to dryness under vacuo. The residue was dissolved in 1 1t. of 60 benzene-hexane 1:1 and ?ltered through a column of 200 g. of acetic acid washed alumina thus producing 318 Example VIII A slow stream of dibonane was passed through ‘a so lution of 10 g. of Z-chlorornethyl - 17a-metl1yl-A’2 =androsten-17/8-ol acetate in 150 cc, of tetrahydrofuran ' bromo~2-rnethylene-androstan-175-01. . for 1 hour. A mixture of 1 g. of the above compound 1 g. of (After 20- minutes the solution became lithium bromide and 100 cc. of dimethyl-formamide was 65 warm and then the temperature slowly sub-sided.) The excess of diborane was decomposed by careful addition heated on the steam bath for 18 hours. It was then of Water. Then 1 it. of water was added and the. formed poured into water and the formed precipitate collected precipitate was ?ltered, washed ‘and dried, thus giving by ?ltration. Recrystallization from methanol gave the pure 2-brornomethyl-A2-androsten-17[3-ol. Example IV By following the method of Example I the compounds listed below under I were treated with thionyl chloride in benzene solution to give the corresponding 3B-chloro . 9.6 g. of the organoboron- compound. 70 This material was dissolved in 200 cc. of tetrahydro furan and treated with 9 g. of sodium hydroxide previ ously dissolved in 25 cc. of water, and 45 cc. of 35% . hydrogen peroxide, stirring and. keeping the temperature around 15° C. The mixture was stirred ‘for 2 hours, Z-methylene compounds (II), which in turn were con 75 after this time, the precipitatedv product was ?ltered, 3,080,898 d 400 mg. of pre-hydrogenated 2% palladium calcium car bonate catalyst. When 1.1 molar equivalent of hydrogen had been ab sorbed, the reaction was stopped, the catalyst separated by ?ltration through celite, washed with ethyl acetate and washed ‘and dried, thus producing 25-chloromethyl-17a methyl androstane-3u,17B-diol-17-acetate. A solution of 2 g. of the above compound in 50 cc. of acetone was cooled to 0° C. and treated under an ‘atmosphere of nitrogen and with stirring, with a solu tion of 8 N chrornic acid (prepared by mixing 26 g. of the combined solutions evaporated to dryness in vacuo, yielding the crude vinyl derivative. This crude product chromium trioxide with 23 cc, of concentrated sulfuric was dissolved in ethyl acetate, the organic solution washed acid and diluting with water to 100 cc.), until the color with dilute hydrochloric acid and Water to neutral, dried of the reagent persisted in the mixture. It was stirred for 5 minutes further at 0~5° C. and diluted with water. 10 and evaporated to dryness. Recrystallization from ace tone gave Za-?uoromethyl-lh-vinyl-19-nor-androstan The precipitate was collected, washed with water and dried under vacuum, thus affording a crude product 17/3-ol-3-one. The above compound was esteri?ed with acetic, propi which upon recrystallization from acetone-hexane gave onic and undecenoic anhydride in benzene solution and ZB-chloromethyl - 17cc - methyl-androstan-l7?-ol-3-one acetate. A solution of 1 g. of the preceding compound in 50 cc. of dry chloroform was treated with 1 cc. of dry chloro form saturated with hydrogen chloride. After 3 hours at 15 in the presence of p-toluenesulfonic acid, thus producing the corresponding esters. Example XII Examples I and IX were repeated but using 2-hydroxy room temperature the reaction mixture was washed with 5% sodium bicarbonate solution and water to neutral, 20 methyl-17e-ethyl-A2-androsten-17?-ol acetate as starting material. There were thus obtained successively 2-meth— dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product after crystallization from ether-pentane a?orded 0.4 g. of 2a ylene - 3,8 - chloro - 17a - ethyl - androstan - 17,8 - ol chloromethyl-l7a-methyl-androstan-l7?-ol-3-one acetate. 1713-01 acetate, 2,8-chloromethyl-2e,3a-oxido-17a-ethyl androstan-17/8-ol acetate, 2ot-chloromethyl-l7u-ethyl-an Example 1X By following the method of Example II, 5 g. of 2-hy droxymethyl-lh-ethinyl-19-nor-A2-androsten-1713-01 was converted into Z-?uoromethyl-17e-ethinyl-19-nor-A2-an dr0sten-175-ol. Esteri?cation of the above compound with acetic anhydride in benzene solution and in the presence of p-toluenesulfonic acid gave the corresponding acetate. A solution of 2.5 g. of 2-?uoromethyl-l7u-ethinyl-19 nor-Az-androsten-17,8-ol-acetate in 100 cc. of chloroform was cooled to 0° C. and mixed with 1.4 g. (1.1 molar equivalents) of monoperphthalic acid in ether solution. The mixture was kept at room temperature for 20 hours, diluted with Water, the organic layer was separated, acetate, 25 2 - chloromethyl - 17a - ethyl - A2 - androsten drostane-3a,17p-diol, Za-chloromethyl-l7a-cthyl-andro stan-17?-ol-3-one and 2a-chloromethyl-l7a-ethyl-andro stan-l7?-ol-3-one propionate. Example XIII 5 g. of 2-chloromethyl-Az-androsten-175-01 were con verted into the corresponding benzoate by treatment with benzoyl chloride in pyridine solution. The above benzoate was then subjected to the reactions 35 described in Example VIII, thus producing Z?-chloro methyl-androstane-f'm,175-diol - 17 - benzoate, Z?-chloro methyl-androstan-17?-ol-3-one benzoate and Z-oc-ChlOIO methyl-androstan-l7?-ol-3-one benzoate. In a similar manner, starting with 2-bromomethyl-A2 washed with aqueous sodium bicarbonate solution and then with water to neutral, dried over anhydrous sodium 40 androsten-N?-ol there were obtained successively 2-bro momethyl - A2 - androsten - 1713 - ol-benzoate, sulfate and evaporated to dryness. Crystallization from acetone-hexane gave 2,8-?uoromethyl-2a,3a-oxido-17a ethinyl-lQ-nor-androstan-17(3-01 acetate. Z?-bromo 'methyl-androstane-3ot,17,8-diol 17-benzoate, 2,8-bromo methyl-androstan-17/8-ol-3-one benzoate and 2a-bromo methyl-androstan-17,6-01-3-one benzoate. Example XIV A solution of 1 g. of the preceding epoxide in 50 cc. of tetrahydrofuran was added over a 30 minute period to a stirred suspension of 1 g. of lithium aluminum hydride In accordance with the method of Example III, 2 g. of in 50 cc. of anhydrous tetrahydrofuran. The mixture 2 - hydroxymethyl - l7ot-ethinyl-androstan-17?-ol acetate was re?uxed for 18 hours, then cooled and cautiously were treated with thionyl-bromide, to give 3,8-bromo-2 treated with 5 cc. of ethyl acetate and 2 cc. of water. Solid sodium sulfate was added, the inorganic material 50 methylene-17a-ethinyl-androstan-1713-01 acetate, which upon reaction with lithium bromide in dimethyl-forma ?ltered off and thoroughly washed with hot ethyl acetate, mide gave Z-bromethyl-l7a-ethinyl-A2-androsten-1713-01 the combined organic solutions upon evaporation yielded a crude material, which was puri?ed by crystallization from acetone-hexane thus giving 2a-?uoromethyl-l7u ethinyl-19-nor-androstan-3a,l7,8-diol. Upon oxidation of the above diol with 8 N chromic acid in acetone solution, in accordance with the method of Example VIIl there was obtained 2a-?uoromethyl-17ot— ethinyl-l9-nor-androstan-17,8-ol-3-one which was esteri acetate. The latter compound was then converted into 2oz-b1'0m0 55 methyl-l7a-ethinyl-androstan-175-01-3-0116, by following the method of Example IX. ' Example XV 2 g. of 2-chloromethyl-17a-ethinyl-A2-androsten-1713-01 ?ed with propionic anhydride in benzene solution and in 60 acetate were oxidized with monoperphthalic acid, in ac cordance with the method of Example IX, and the result the presence of p-toluenesulfonic acid, to give the corre ing epoxide re?uxed for 18 hours with lithium aluminum sponding propionate. Example X By following the methods of Examples II and VIII, the acetate of 2-hydroxymethyl-l9-nor-A2-androsten-17? 01 was converted successively into 2-?uoromethyl-A2-l9 hydride thus giving 2a-chloromethyl-17a-ethiny1-andro stane-Zia,17?-diol. A solution of 250 mg. of chromic acid in 5 cc. of 80% acetic acid was added dropwise to a stirred solution of 1 g. of 2u-chloromethyl-l7ct-ethinyl-androstan-3a,l7?-diol in nor-androsten-17?-ol-acetate, 2,8-fluoromethyl-l9-nor~an 75 cc. of glacial acetic acid, while the temperature was maintained around 20° C. After 2 hours at room tem drostane-Sor,l7?-diol-l7-acetate and 2a-fluoromethyl-l9 70 perature, the mixture was poured into ice water and the nor-androstan-17,8-ol-3-0ne-acetate. formed precipitate collected, washed with water and re Example XI crystallized trom methanol, thus giving 2a-chloromethyl A solution of 1 g. of 2u-?uoromethyl-17a-ethinyl-19 nor-androstan-17,6-ol-3-one,in 40 cc. of pyridine was hy 17d-ethinyl-androstan-17B-ol-3-one. The above compound was esteri?ed with acetic and drogenated at 25 ° C. and 570 mm. in the presence of 75 cyclopentylpropionic anhydride in benzene solution and 3,080,398 10 7. Z-?uoromethyl-17a-ethynyl-A2-androsten-175-01. in the presence of p-toluenesulfonic acid, to give the ace tate and the cyclopentylpropionate of 2m-chloromethyl 8. The acetate of Z-?uoromethyl-17a-methy1-A2-andro 17a-ethinyl-androstan-17B-ol-3-one. sten-17?-ol. 9. 2oz - fluoromethyl - 17oz - ethynyl - 19 - nor - an Example XVI By following the method of Example XI, Zwbromo drostan-17?-ol-3-one. methyl-17a-ethinyl-androstan-17B-ol-3-one and Zea-chloro drostan-l7?-ol-3-one. methyl - 17a-ethinyl-androstan-17/3-ol-3~one 10. 2a - ?uoromethyl - 17a - vinyl - 19 - nor - an cyclopentyl 11. 2a - chloromethyl - 17a - ethynyl - androstan - 175 propionate were converted respectively into 2a~bromo methyl-l7a-vinyl-androstan-17/8-ol-3-one and 2a-chloro methyl-17a-viny1-androstan-17?-ol-3-one cyclopentylpro pionate. ol-3-onc. 10 12. 2a - chloromethyl - 17oz - vinyl - androstan - 17B 01-3~one-cyclopenty1propionate. 13. 2a - bromornethyl - 17a - ethynyl - androstan - 1718 ol-3-one. Example X VZI 14. The method ‘for the production of Za-halomethyl In accordance with the methods of Examples II and 1 5 17-substituted androstanes which comprises treating the VIII, 5 g. of 2-hydroxymethy1-17a-methyl-19-nor-A2-an corresponding 2-ha1omethyl-A2-compound with a peracid, drosten-17?-ol acetate were converted successively into reacting the 2a,3a-epoxide thus formed with lithium alu 2-fluoromethyl-17a-methyl - 19 - nor-Az-androsten-??-ol minum hydride in a suitable solvent to give the 2a-halo acetate ZB-?uoro-methyl-17a-methyl-l9-nor-androstan-3a, methyl-3a-hydroxy compound, and oxidizing with chro 17?-diol-17-acetate, Z?-?uoromethyl-17u-methyl~19 - nor 2 0 mium trioxide to form the corresponding 3-keto com pound. androstan 17?-ol-3-one acetate and Za-?HOI‘OmGthYI-I'Ya methyl-19-nor-androstan-17/3-ol-3-one-acetate. 15. The method for the production of a compound se lected from the group consisting of 2oc-halomethyl-an We claim: 1. A compound of the following formula: drostan-l7p-ol-3-one compounds and the corresponding 2 5 17a-al‘kyl derivatives, which comprises treating 'a corre sponding 2-hal0methy1-A2-androstan-17,8-01 with diborane, followed by hydrogen peroxide-alkaline treatment, to give the corresponding 2?-halomethyl-3a-hydroxy compound, oxidizing to the 3-keto and thereafter treating with acid 3 0 to form the corresponding 2a-halomethyl-androstan-175 XHQ l 0l-3-one derivative. 16. The method of claim 15 wherein the 2a-halomethyl derivative is the chloromethyl derivative, the peracid is the monoperphthalic acid, the suitable solvent for the re l I wherein X is selected from the group consisting of chlo rine, bromine and ?uorine, R is selected from the group 3 5 duction is tetrahydrofuran. 17 . The method of claim 15 wherein the 2a-halomethyl consisting of hydrogen and methyl; R1 is selected from derivative is the bromomethyl derivative, the peracid is the group consisting of hydrogen, lower alkyl, lower a1 the monoperphthalic acid, the suitable solvent for the re~ kenyl and lower alkynyl radicals and R2 is selected from duction is tetrahydrofuran. the group consisting of hydrogen and a hydrocarbon car boxylic radical of less than 12 carbon atoms. 40 5. 2-chloromethyl-19-nor-A2-androsten-175-01, acetate. 6. 2-chloromethyl-17a-methy1-M-androsten-1713-01. 18. The method of claim 15 wherein the 2a-halomethyl derivative is the ?uoromethyl derivative, the peracid is ‘the monoperphthalic acid, the suitable solvent for the re duction is tetrahydrofuran. 2. 2-chloromethyl-A2-androsten-175-01. 3. 2-bromornethyl-A2-androsten-175-01. 4. 2-?uoromethyl-A2-androsten-175-01. 5 No references cited.