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it fates z 3,067,219 r k atent Fatented Dec. 4, 1962 2 Ii pared by a process illustrated by the following equations: 3,667,219 6-CHLOR0 DERIVATIVES 0F M-PREGNEN-Ua?l DHOL-3,20-D1IONE AND AlA-PREGNADlENE-l’loc, VZJL-DIGlL-E?tl-DEGNE (IJHzOR CHzOR to oo I VIE“ Howard J. Ringoid and Octavio Mancera, Mexico City, Mexico, assignors, by mesne' assignments, to Syntex Corporation, a‘ corporationyof Panama No Drawing. Filed Aug. 29, 1958, Ser. No. 757,939 Claims priority, appiication Mexico Aug. 30, 1957 14 Qlaims. (6i. 26(i--397.47) 1O The present invention relates to novel cyclopenta nophenanthrene compounds. More particularly the present invention relates to 6 or) chloro derivatives of A4-pregnen-17a,21-diol-3,ZO-dione "and A1'4-pregnadien-l7a,21-diol-3,20-dione, the 2l-esters 15 of these compounds of hydrocarbon carboxylic acids of ethylene glycol O and epoxidation l: \ O O, ethyl orthoformate less than 12 carbon atoms, and the 17u,21-diesters of dry H 01 acetic acid (EH20 R these compounds of hydrocarbon carboxylic acids of less OHzO R oo than 12 carbon atoms. Within the foregoing de?nition 20 the 616-chloro compounds to be hereinafter set forth in detail are intermediates for the production of the corre sponding ?a-chloro compounds. The 6a-chloro com pounds above set forth are intermediates for the produc tion of the active cortical hormones, 6a-chloro cortisone 25 and hydrocortisone by well known methods involving the microbiological introduction of an 11,8- or lla-hydroxy _ A] :|— -OH 131mg 5 h0 0': g ‘ :L- OH ('31 group followed (for 6a-chloro cortisone) by oxidation to an ll-keto group. In addition the 17a,21-diesters of the 6a-chloro compounds above set forth are valuable 30 lhypochlorous acid progestational hormones. In accordance with the present invention it has been discovered that 5a,6a-epoxide derivatives of pregnanc 17a,21-diol-20-one having in the C—3 position a ketal or alcohol group upon reaction with hydrogen chloride gave a corresponding 6-chloro derivative. As will be herein after set forth depending on reaction conditions these @etic acid (EH20 R GO /\\ l "OH derivatives were either 6B-chloro or 606-011101'0 com pounds. The novel compounds of the present invention are il 40 lustrated in the following formulas: C—Q‘j o1 CHgOAc 45 ‘ (llHioAo o oo l :L-—O Rs‘ 50 .0? m or) ,. HO peracid -" ' :'-'- o R2' ‘ .. HO . 0i 55 H01 In the above formulas R represents hydrogen or‘ a‘ hydrocarbon carboxylic acid ester group of‘ less than 12 onions or‘noAc unsaturated, of straight or branched chain, cyclic or (I30 IO mixed cyclic-aliphatic, unsubstituted or substituted con i~~0m carbon atoms. These ester groups may be saturated or 60 ventionally asv with methoxy or halogen‘. Examples‘ of such ester groups include acetate, propionate, cyclopent ylpropionate, benzoate, butyrate, etc. R1 represents hy 65 drogen or' a hydrocarbon carboxylic acid ester group of les than 12 carbon atoms when R represents a hydro carbon carboxylic acid ester group of less than 12 car ehromio O —‘ . aci 'd 7 - bon atoms and R1 represents hydrogen when R is hydro gen. X represents a double bond between C—1 and ‘0-2 70 or a saturated linkage between C—1 and C—2. The novel compounds of the present invention are pres Al :- -OR: /Y . HO . l \/ HO l Cl dry ‘n 01 acetic'aci'd 3,067,219 it mild saponi?cation as by reaction with sodium methoxide I at a low temperature gave the corresponding free com CHzOAC . CHzOR to to A I --0 R2 ’ 230 R1 saponi?catlon I ———-----> O: l O: To 17a,21-diol-3,20-dione was reacted with a corresponding acid anhydride in pyridine in a conventional manner. To obtain the 17,21-diesters the same compound is reacted prolonged period or under re?ux. The acid condition may be produced by an excess of anhydride or by p-toluene sulfonic acid for example. To form a 17,21-mixed di i ester the 2l-mono-esters are further esteri?ed with a differ Cl CH2O R C1120 R <50 to ht‘ to“ Le I / l diesters having the same or different ester groups. form the 21-monoesters the free 6a-chloro-A4-pregnen 10 under acid ‘conditions either at room temperature for a reesteritication O 01 pound. The free compound was then reesteri?ed either to form the 21-monoesters previously described or 17,21 dehydrogenation O_ ent acid anhydride under conditions as set forth for 17,21 diester formation. As indicated in the third equation above the 2l-mono esters or 17,20-diesters of 6a-chloro-A4-pregnen-17a,21 diol-3,20-dione are dehydrogenated to the corresponding Aid-compounds. For this reaction the preferred agent is selenium dioxide in the presence of tertiary butanol and pyridine. The‘same dehydrogenation may however be performed by known microbiological methods. The esters of 6tx-chloro-A1A-pregnadien-l7u,21-diol - 3,20 - dione are In the above equations R and R1 represent the same transformed to the free compound by conventional sapon i?cation. The following speci?c examples serve to illustrate the groups as heretofore set forth. Ac represents acetate. Et present invention but are not intended to limit the same. a $1 represents ethyl. R2 represents hydrogen or acetate. Referring to the ?rst of the above equations Reichsteins substance “S” Zl-acetate (A‘l-pregnen-17a,21-diol-3,20 dione 21-acetate) is conventionally converted as known in the art to 3-ethylenedioxy-5a,6ot-oxido-pregnan-17a,21 diol-ZO-one 21-acetate or to the ZI-acetate of 3-ethoxy Example I 5 g. of the 2l-acetate of 3-ethylenedioxy-5a,6a-oxido pregnan-l7a,2l-diol-20-one was dissolved in 250 cc. of glacial acetic acid and a slow stream of dry hydrogen chlo ride was introduced into the solution, for a period of 2 A3'5-pregnadien-l7m21-diol-20-one, by reaction with eth 35 hours, maintaining the temperature of the mixture below ylene glycol followed by epoxidation with a per acid, or 18° C. It was then poured into ice water and the reaction by reaction with ethyl orthoformate. Reaction of the 21 product was extracted with methylene dichloride, washed acetate of 3 - ethylenedioxy-Sa,6a-oxido-pregnan-1704,21 diol-ZO-one with dry HCl in acetic acid gave the 2l-ace tate of 6a-chloro-A4-pregnan-17a,2l-diol-ZO-one. If an other ester of substance S is used as the starting material of the character set forth previously the ?nal product is with 5% sodium carbonate solution and water to neutral, dried over anhydrous sodium sulfate, ?ltered and evap orated to dryness. Crystallization of the residue from acetone-‘hexane afforded the 2l-acetate of 6zx-ChlO1'0-A4 ester of 3-ethoxy-A3'5-pregnadien-17a,21-dio1-20-0ne by reacting these compounds with hypochlorous acid. The pregnen-l7u,21-diol-3,20—dione with M.P. l85~l86° C., [u]D+99.5° (chloroform), A max., 238 my. (log E 4.17). Example II When in the previous example the 21-acetate of 3-ethy1 hypochlorous acid for the reaction is obtained in situ as by treatment with n-chlorosuccinimide in acetone solu substituted by the Zl-acetate of 3-propylenedioxy-5a,6a tion in the presence of sodium acetate and acetic acid. In oxido-pregnan-17oz,21-diol-20-one, there was also obtained the corresponding ester. As indicated the same com pounds may also be prepared from the 21-acetate or other enedioxy - 5:1,6ot - oxido-pregnene-l7a,2l-diol-20-one was place of the n-chlorosuccinimide other N-chloro-imides or the 2l-acetate of 6a-chloro-A4-pregnen-17a,21-diol-3,20 N-chloro-amides may be used such as N-chloroacetamide or N-chloro-benzenesulfonamide. Alkali metal or alkaline earth metal hypochlorites may also be used such as so dione, identical to the ?nal compound ‘obtained by the method of Example I. dium or calcium hypochlorite. The compounds obtained after this last step are the corersponding 21-esters of 618 Example III A mixture of 2 g. of the 2l-acteate of 3-ethoxy-A3’5 pregnadien-l7a,21-diol-20-one, 40 cc. of acetone, 8 cc. of pounds are then converted to the corresponding 6a-chloro Water and 800 mg. of sodium acetate was cooled to 0° C. compounds by treatment with dry HCl in acetic acid. and treated with 800 mg. of N-chlorosuccinimide and then In the second equation above the starting material is a with 0.8 cc. of glacial acetic acid. The mixture was stirred 2l-acetate or a 17,2l-diacetate of A5-pregnen-3/8,17u,21 60 for 1 hour at 0° C. and then poured into water; the pre triol-20-one. Treatment of these compounds with a per cipitate was collected, dried and recrystallized from ether, chloro-A4-pregnen-17a,21-diol - 3,20 - dione. These com acid such as m-onoperphthalic acid gave the corersponding 5a,6a-oxido compounds. Treatment of these oxido com pounds With hydrogen chloride in chloroform gave the corresponding acetates of 6/3-chloro~pregnan-35,5a,17a, 21-tetrol-20-one. Upon treating these tetrols with chromic acid the 3B-hydroxy group was oxidized to a 3-keto group to give the 21-acetate or 17,2l-diacetate of 6,8-chloro-preg nan-5a,17a,21-triol-20-one. Treatment of these last com pounds with dry hydrogen chloride in acetic acid dehy drated the compounds and inverted the GB-chloro to 6m chloro to, give the 2l-acetate or 17,21-diacetate of 6a chloro-‘i-pregnen-l7a,2l-diol-3,20-dione. ‘Both these ace tates and the 21-esters of 6zx-chloro-A4-pregnen-170:,21 thus yielding the crude 21-acetate of 6/3-chloro-A4-preg nen-l7a,2l-diol-3,20-dione which was puri?ed by recrys tallization from acetone-hexane; M.P. l93—l94° C., k max. 240 mp, log E 4.15, [a]D+4.13° (chloroform). Example IV In the previous example N-chlorosuccinimide was sub stituted by N-chloroacetamide with the same ?nal result. Example V In the methods of Examples III and IV, the 21-acetate of 3-ethoxy-A3'5-pregnadien-l7a,2l-diol-20-one was sub stituted by the 2l-acetate of 3~methoxy-A3-5-pregnadien diol-3,20-dione, previously described, upon conventional 75 17a,21-diol-20-one with the same ?nal result. 3,067,219 5 % Example VI 0° C. and then the mixture was diluted with water and extracted‘ with ether. The extract was washed, dried over 1 g. of the 21-acetate of ?p-chloro-A‘l-pregnen-17a-21 diol-3,20-dione obtained by any of the methods of Exam ples III to V, was [dissolved in 50 cc. of glacial acetic acid ness. Recrystallization oi; the residue from acetone yield~ ed the 21-acetate of 6p-chloro-pregnan-5a,17a,21-triol and a slow stream of dry hydrogen chloride was intro 3,20-dione. duced into the solution for 2 hours maintaining the tem perature below 18° C. The reaction product was worked anhydrous sodium sulfate, ?ltered and evaporated to dry 2 g. of the 21-acet'ate of 6B-chloro-pregnan-5a,170:,21 triol-3,20-dione was dissolved in 80 cc. of glacial acetic up as described in Example I. There was thus obtained acid and a slow stream of dry hydrogen chloride was the 21-acetate of 6a-chloro-A4-pregnen-l7a,2l-diol-3,20 10 passed into the solution for 2 hours at a temperature dione, identical to that obtained in such example. around 18° C. The mixture was diluted with water and they product was extracted with ethyl acetate, washed with water, 5% sodium carbonate solution and water, dried A suspension of 1 g. of the Zl-acetate of 6a-chloro-A4 over anhydrous sodium sulfate and evaporated to dryness. pregnen-17a-21-diol-3,20-dione in 10 cc. of absolute meth Crystallization of the residue from acetone-hexane af 15 anol was cooled to 0° C. and mixed under nitrogen with forded the 21-acetate of 6a-chloro-A4-pregnen-1~7a,21-diol a cooled solution of sodium methoxide prepared by dis 3,20-dione, identical with the compound of Example I. solving approximately 60 mg. of sodium in 5 cc. of abso Example XI lute methanol. The mixture was stirred under nitrogen A suspension of 3 g. of the 21-acetate' of 5a,6a-oxido for 1 hour and then poured into a cooled saturated aque . Example VII ous solution of sodium chloride containing 0.3 cc. of 20 pregnan-B?,17a,21-triol-20—onc in 200 cc. of acetone was mixed with 10 cc. of concentrated hydrochloric acid and glacial acetic acid. The precipitate was collected, washed stirred for one and a half hours. It was then poured into with water, dried and crystallized from acetone-hexane, saturated aqueous sodium chloride solution and extracted thus giving 6a-chloro-A4-pregnen-17a,21—diol-3,20-dione. Example VIII By the same method of the previous example, the 21 with three portions of methylene dichloride. The extract 25 was washed with 5% sodium carbonate solution and then with water, dried over anhydrous sodium sulfate and con acetates of 6,8-cliloro-A4-pregnen-17a,21-diol-3,20-dione centrated to 30 cc. The mixture was cooled and the crys was converted into the free 6?-chloro-A4-pregnen-l7a,21 talline precipitate was collected, thus giving the ZI-acetate diol-3,20-dione. of 6,8-chloro-pregnan-313,5a,17a,21-tetrol-20-one, identical Example IX A mixture of 1 g. of 6B-chloro-A4-pregnen-17u,21-diol 3,20-dione, 10 cc. of pyridine and 1 cc. of propionic an hydride was kept overnight at room temperature and with the compound obtained by the method of Example X. Example XII 3 g. of the ZI-acetate of 6a - chloro - pregnan poured into water. The mixture was heated on the steam 35 3e,5a,17a,21-tetrol-20-one dissolved in 100 cc. of acetic bath for half an hour, cooled and the precipitate was col lected. Recrystallization from acetone-hexane yielded the 2l-propionate of 6B-chloro-A4-pregnen-l7a,21-diol 3,20-dione. Similarly, there was prepared the 21-propionate of 6a chloro-A4-pregnen-17a,21-diol-3,20-dione; When propi onic anhydride was substituted by the anhydride or chlo ride of another hydrocarbon‘ carboxylic acid, of up to 12 carbon atoms, there were obtained the corresponding 21 esters. Speci?cally there were obtained in this way the-21 cyclopentylpropionate and the 21-benzoate. Example X A solution of 5 g. of the 21-acetate of A5-pregnen 3?,17a,21-triol-20-one in 100 cc. of chloroform was mixed acid was mixed with 950 mg. of chromic acid previously dissolved in 20 cc. of 80% acetic acid. The reagent was added dropwise to the stirred solution which was kept at a temperature below 15° C. The stirring was continued for 2 hours at 15° C. and the mixture was then diluted 40 with water and the precipitate formed was collected, washed with water, dried and recrystallized from acetone hexane, thus yielding the 21-acetate of 6B-chloro-pregnan 5a,17a,21-triol-3,20-dione, identical with the‘ compound obtained by the method of Example X. 45 Example XIII By the methods of Examples X to XII, the 17,21-di— acetate of A5-pregnen-3?,17a,21-triol-204one was con with 1.5 molar equivalents of monoperphthalic acid in verted into the 17,2l-diacetate of 5u,6a-oxido-pregnan 3a,17a,21-triol-20-one, then into the 17,21-diacetate' of ether solution and the mixture was kept at room tempera ture for 20 hours. It was then diluted with water and the to that of G?-chloro-pregnan-SaJ7a,21-triol-3,20-dione. 6,6-chloro-pregnan-3 ,8,5 11,17 a,21-tetrol-20-one and then in The ?nal product was the diacetate of‘ 6a-chloro-A4 organic layer was separated and washed with water, so pregnen-17a,21-diol-3,20-dione. dium bicarbonate solution and again with water to neutral, Example XIV dried over anhydrous sodium sulfate and evaporated to 55 dryness under reduced pressure. The residue crystallized A. suspension of 1 g. of the diacetate of 6a-chloro-A4 from acetone-hexane to give the 21-acetate of 5a, 6a pregnen-17a,21-diol-3,20-dione in 10 cc. of absolute oxido-pregnan-lip,17a,21-triol-20-one. methanol was cooled to 0° C. and mixed with a solu 3 g. of the 2l-acetate of 5a,6a-oxido-pregnan-3,B,17a,21 tion of sodium methoxide prepared by dissolving 120 t'riol-3,20-dione-was dissolved in 100 cc. of chloroform, 60 mg. of sodium metal in‘ 10cc. of absolute methanol; the cooled to 0° C. and then a slow stream of dry hydrogen addition was effected with stirring under an atmosphere chloride was allowed to pass into the solution for 2 of nitrogen. The stirring was continued under nitrogen hours while the temperature was maintained below 10° for 1 hour at 0° C. and the mixture was then poured into C. The mixture was diluted with Water and the chloro 60 cc. of cold saturated aqueous sodium chloride solution 65 form layer was washed with water, dried over anhydrous containing 0.3 cc. of acetic acid. The precipitate formed sodium sulfate and evaporated to dryness. Crystalliza tion of the residue from acetone-furnished the 21-acetate of 6?-chloro-pregnan-3/3,5a,17a,21-tetrol-20-one. was collected, washed with water, dried and recrystal lized from acetone-hexane. There was thus obtained the free 6a-chloro-A4-pregnen-17a,21-diol-3,20-dione, identi A solution of 3 g. of the acetate of 6p-chloro-pregnan cal with the compound of Example I. 3,8,5“,17u21-tetrol-20-one in 150 cc. of acetone was 70 Example‘ XV cooled to 0° C. and mixed with an 8N solution of chro A solution of 1 g. of 6a-chloro-A4-pregnen-17a,21-diol mic acid prepared by mixing 1.7 g. of chromic acid with 3,20-dione in 50 cc. of anhydrous benzene was treated concentrated sulfuric acid and water. The reagent ‘was with 4 cc. of propionic anhydride and 300 mg. of p-tolu added dropwise with stirring and keeping the temperature enesulfonic acid and the mixture was kept standing at below 0° C. The stirring was continued for 1 hour at 8,067,219 8 room temperature for 40 hours. It was then diluted wherein R is selected from the group consisting of hy with water and the organic layer was separated, washed drogen and a hydrocarbon carboxylic ester group of less with water, aqueous sodium bicarbonate solution and than 12 carbon atoms. again with water to neutral, dried over anhydrous sodi um sulfate and the benzene was evaporated. Crystal 5 3. The 21-monoacetate of 6,8-chloro-A4-pregnen-170:,21 lization of the residue from acetone-hexane furnished diol-3,20-dione. 6a-chloro-A4-pregnen-l7a,21 - diol - 3,20 - dione 4. A compound of the following formula: 17,21“ propionate. ~ Example XVI CHzOR By the method of Example XV, 1 g. of the 2l-cyclo 10 pentylpropionate of 6a-chloro-A4-pregnen-l7¢r,21-diol 3,20-dione, in solution in 50 cc. of anhydrous benzene, was treated with 2 cc. of acetic anhydride and 200 mg. XA Cl of p-toluenesulfonic acid, at room temperature for 24 hours. The acetylation product was worked up as above, .r/Jj thus yield yielding 6a-chloro-A4-pregnen-17a,21-diol-3,20 dione 17-acetate-2l-cyclopentylpropionate. Example XVII Following the procedure described in Examples XV and XVI, there were prepared other 17,21-diesters of 6a l chloro—A4-pregnen-l7a,21 - diol - 3,20 - dione, wherein the wherein X is selected from the group consisting of a double bond between C-1 and C-2 and a saturated link age between C—1 and C—2, R is selected from the group ester groups were identical or di?erent from each other. By this method there were prepared speci?cally the 17,21 dibenzoates, the 17,21-diacetates, the '17,2l-dicyclopentyl propionates, the 17-acetate, 21-butyrate, etc. Example XVIII consisting of hydrogen and a hydrocarbon carboxylic ester group of less than 12 carbon atoms, R1 is hydrogen when R is hydrogen and R1 is selected from the group consisting of hydrogen and a hydrocarbon carboxylic A mixture of 2 g. of 6a-chlor0-A4-pregnen-17a,2l-diol 3,20-dione diacetate, 100 cc. of tertiary butanol, 0.8 g. of recently sublimed selenium dioxide and 0.4 cc. of pyridine hydrocarbon carboxylic ester group of less than 12 car was re?uxed for 72 hours under an atmosphere of nitro bon atoms. gen. ester group of less than 12 carbon atoms when R is a 5. éa-chloro-At-pregnen-17m,21-diol-3,20-dione. The mixture was ?ltered, washing the ?lter with 6. The 2l-hydrocarbon carboxylic mono esters of less than 12 carbon atoms of 6ot-chloro-A4-pregnen-170:,21 40 cc. of hot t-butanol, and the combined ?ltrate and washings was evaporated to dryness under reduced pres sure. The residue was dissolved in acetone, treated with decolorizing charcoal and ?ltered. The acetone was re moved and the residue was chromatographed on neutral than 12 carbon atoms of 6a-chloro-M-pregnen-17¢,21 alumina, thus yielding 6a-chloro-A1r‘l-pregnadien-l7a,21 diol-3,20-dione. diol-3,20~dione. 7. The 17,21-hydrocarbon carboxylic di esters of less 8. The 21-monoacetate of 6a-chloro-A4-pregnen-l7a,21 diol13,20-dione diacetate. 40 diol-3,20-dione. Eample XIX 9. The 17,21-diacetate of éa-chloro-A‘i-pregnen-170:,21 By the method of the previous example, there was de diol-3,20-dione. hydrogenated 6a-chloro-A4-pregnen-17u,21-diol-3,20-dione 1i). 6a-chloro-A114-pregnadien-17a,2l-diol-3,2O-dione. 17-acetate-21-butyrate to produce 60: - chloro - A114 - preg 11. The 21-hydrocarbon carboxylic mono esters of less than 12 carbon atoms of 6a-chloro-A1'4-pregnadien nadien-l7a,2l-diol-3,20-dione 17-acetate-2l-butyrate. Example XX Following the procedure described in Example XVIII, 17a,21-diol-3,20-dione. there was introduced an additional double bond between 12. The 17,21-l1ydrocarbon carboxylic di esters of less than 12 carbon atoms of 6a-chloro-A1’4-pregnadien C-1 and C-2 of other diesters of hydrocarbon carboxylic acids of less than 12 carbon atoms 6a-chloro-A4-pregnen 170:,21-(ll0l~3,20—dl021€. 17a,21-diol-3,20-dione, which esters were formed with identical radicals or different from each other including the other esters referred to in Example XVII. 17a,2l-di0l 3,20-dione. 13. The 2l-rnonoacetate of 6a-chloro-Alr‘i-pregnadien 14. The 17,2l-diacetate of 6a-chloro-Ald-pregnadiem 17a,21-diol-3,20-dione. Example XXI 55 By conventional saponi?cation of the esters of 60a chloro-AL4-pregnadien-l7a,21-diol-3,2O-dione such as the 17,2l-diacetate there was prepared the free 6a-chloro AM-pregnadien-17,21-diol-3,20-dione. We claim: 1. A compound of the following formula: CHzOR I 5w 60 References Cited in the ?le of this patent UNITED STATES PATENTS 2,774,775 2,786,855 2,837,464 2,838,540 2,862,939 2,865,914 Korman et al. ________ __ Dec. 18, Sondheimer et al ______ __ Mar. 26, Nobile _______________ __ June 3, Campbell et al ________ __ June 10, Dodson et al. ________ __ Dec. 2, Schneider et al. _______ __ Dec. 23, 1956 1957 1958 1958 1958 1958 2,934,546 Ringold et al __________ .__ Apr. 26, 1960 OTHER REFERENCES Sondheimer et al.: J. Am. Chem. Soc., vol. 75, Dec. 5, 1953, pp. 5930-593. Meystre et al.: Helv. Chim. Acta, vol. 39, Section III, 1956, No.88, pp. 734-42. Bowers et al.: J. Am. Chem. Soc., vol. 80, Aug 20, 1958, pp. 4423 and 4424.