Патент USA US3079418код для вставки
United States Patent O?ice 3,979,498 Patented Feb. 26, 1953 1 2 =bromo ; 3 - methoxyestra-1,3,5(10)-trien-l6a-ol, respec~ . tively. 3,079,458 3,16-BISOXYGENATED 17-HALOESTRA The 175-halo l6-ketones of this invention can be manu factured also by epimer-ization of the corresponding 17w halo compounds. This process is speci?cally illustrated by the reaction of 17d-bromo-3-methoxyestrae1,3,5(16) trien-16-one with p-toluenesulfonic acid to afford 17a 1,3,5 (1@)-TR§EI\TE§ George P. Mueller, Park Ridge, Ilh, assiguor to G. D. Searle & (30., Chicago, Ill, a corporation of Delaware No Drawing. Filed Apr. 17, 1961, Ser. No. 103,267 7 Claims. (Cl. 2é€i—397.4) bromo-3-methoxyestra-1,3,5(10)-trien-l6-one. The present invention relates to novel 17-halogenated Although the 16,17 - epoxy-3-hydroxyestra-1,3,5(10) steriods, and especially to 3,16-bisoxygenated 17-halo 10 trfenes can be used as such to achieve the instant 3-hy estra-1,3,5(10)-trienes, which can be represented by the droxy compounds, the phenolic moiety is preferably pro structural formula tected by a lower alkanoyl group in order to prevent any possible oxidative decomposition. Thus, 16a-bromo-3 (if; ROI I hydroxyestra-1,3,5(10)-trien-l75-ol is reacted with meth 15 anolic potassium hydroxide to afford 165,175 - epoxy-3 hydroxyestra-1,3,5(10)-triene, which is treated with a low; er alkanoic ac'd anhydride in pyridine to afford the cor responding 3-(lower alkanoate). This ester can be, of course, treated as described in detail supra, to afford the wherein R is ‘selected from the group consisting of hydro 3-hydroxy compounds of this invention. The instant 3,16-di-(lower alkanoates) are preferably manufactured by reaction of the corresponding 3,16-diols gen, lower alkyl, and lower alkanoyl radicals; X is a halogen atom; and Z is selected from the group consist with a lower alkanoi-c acid anhydride in pyridIne. As a speci?c example, 175 _ bromo-3-hydroxyestra-1,3,5(l0) 20 ing of carbonyl, hydroxymethylene, and (lower alkanoyl) 25 trien-l65-o1 is treated with acetic anhydride in pyridine oxy-methylene radicals Lower alkyl radicals represented by R are exempli?ed by methyl, ethyl, propyl, butyl, pentyl, hexyl, and the branched-chain isomers thereof. to yield 3,165 ~ diacetoxy - 175-bromoestra - 1,3,5(10)-' caproyl, and the branched-chain isomers thereof; said groups being the acyl radicals of alkanoic acids contain ing fewer than 7 carbon atoms. 3-(lower alkanoate). triene. On the other hand, treatment of a 3,16-diol of this in vention with a limited quantity of a lower alkanoic acid The lower alkanoyl radicals encompassed by R and Z are, for example, formyl, acetyl, propionyl, butyryl, valeryl, 30 anhydride in pyridine results in production of an instant This application is a continuation-in-part of my co pending application, Serial No. 835,416, ?led August 24, 1959, and now abandoned. 7 Suitable starting materials for the manufacture of the instant compounds are the appropriately 3-oxygenated 16,17 - epoxyestra - 1,3,5 (10) - trienes. , Dehydrobromi The compounds of this invention are useful as result of the'r valuable pharmacological properties. They are, for example, estrogens in consequence of their ability to 35 promote uterine growth and to produce characteristic changes in the vaginal epithelium. The invention will appear more fully from the exam ples which follow. These examples are set forth by Way of illustration only and it will be understood that the nation of the 3-oxygenated l6a,175_-halohydrins, prepared 40 invention is not to be construed as limited in spirit or by the method disclosed at J. Org. Chem. 23, 1190 (1958), affords the 5-epoxides, as typi?ed by the reaction of 16a-bromo-3-methoxyestra-1,3,5(10) - trien-l75 - 01 in scope of the details contained therein, as many modi ?cations in materials and methods will be apparent from this disclosure to those skilled in the art. In these ex respectively. 3 -_yrnethoxyestra - 1,31,5(10) - triene, With methanolic potassium hydroxide to afford 3-meth 45 amples temperatures are given in degrees Centigrade (°' C.). Quantities of materials are expressed in parts oxy - 165,l75-epoxyestra-1,3,5(l0) - triene. Reaction of by weight except where otherwise noted. these 5-epoxides with a hydrohalogen acid results in the instant l7a,~l65-halodydrins. One the other hand, reac Example I tion of the u-epoxides, prepared by epoxidation of the cor A solution of 6 parts of potassium hydroxide and 4.3 responding l6-dehydro derivatives with perbenzoic acid, 50 parts of l6ct-bromo-3-methoxyestra-1,3,5(10)-trien-l75-ol with a hydrohalogen acid produces 175,l6cx-halohydrins in 150 parts of methanol is heated at re?ux for about 19 of this invention. Speci?c examples of these processes hours. The solution is cooled and diluted with water, and are the reaction of hydrogen ?uoride in tetrahydrofuran the resulting crystalline product washed Well with water with 165,175-epoxy-3-methoxyestra-1,3,5 ( 10) - triene or with 160:,l7a-6POXY - 3 - methoxyestra~1,3,5(10)-triene 55 and dried. This substance is puri?ed by adsorption on silica gel, elution with 25% benzene in hexane, and re‘ to a?ord 17a-?uoro-3-methoxyestra-1,3,5(10)-trien-165 crystallization from ether to afford pure 1,65,,175-ep0xy 01 and l75-tluoro~3-methoxyestra-1,3,5(10)-trien-16u-ol, Oxidation of the aforementioned halohydrins, typical MP. 116-1l6.5°; [a]D=+1l5° (chloroform). By substituting an equivalent quantity of 3-n-propoxy ly with chromium trioxide in pyrid'ne, results in the cor 60 165-bro1noestra-1,3,5 (10)-trie‘n-175-ol or 3-acetoxy-l6oc responding 17-halo 16-ketones. For example, the reac brornoestra-l,3,5(lO)~trien-175-ol ‘ and otherwise pro tion of l7a-bromo-3-methoxyestra-1,3,5(10)-trien - 165 01 with chromium trioXide in pyridine, affords 17a-bromo 3-rnethoxyestra-l,3,5 ( 10) -trien-l6-one. ceeding according to the herein described processes, 165, 175-epoxy-3-n-propoxyestra-l,3,5(10)-triene and 165,175 Reaction of the aforementioned 17-halo l6-ketones with 65 epoxy-3-hydroxyes‘tra-1,3,5(10)-triene are obtained. a suitable reducing agent produces the halohydrins of Example 2 this invention wherein the con?gurations of the halogen To a solution of vone part of 165,175-epoxy-3-methoxy and hydroxy substituents are the same. Thus, treatment estra-1,3,5(10)~triene in 38 parts of chloroform is added of 17u-bro-mo-3-methoxyestra-1,3,5(10)-trien - 16 - one or at 0—5°, 15 parts of 48% aqueous hydrobromic acid, and 175 - bromo-3-methoxyestra-l,3,5(10)-trien-16-one with the mixture stirred for about 5 minutes‘. The chloroform lithium aluminum hydride in tetrahydrofuran affords 17a 70 layer is separated, washed with water, dried over anhy bromo-3-methoxyestra-1,3,5(l0) - trien-l6a-ol and 175 drous magnesium sulfate and evaporated to dryness in 8,079,408 tract clari?ed by centrifugation, then evaporated to dry: ness in vacuo to yield l7a-bromo-3-methoxyestra-1,3,J pentane yields pure 17tx-bromo-3-methoxyestra-1,3,5 ( 10) tl‘iEIl-l6cx-Ol, MP. 125-126.5°; [a]D=—|—7.9° (chloro ('10)-trien-l6,6-ol. This bromohydrin displays an infra-' red maximum at 2.77 microns. By substituting equivalent quantities of 16,8,17/8-epoxy form). 3-hydroxyestra-1,3,5 ( l0)-triene or 165,1713-epoxy-3-n propoxyestra-l,3,5(10)-triene and otherwise proceeding 3,5(l0)~trien-16-one, 5 parts of p-toluenesulfonic acid, 10 and 100 parts of acetic acid is heated at re?ux for about propoxyestra-1,3,S(l0)-trien-l6,8-ol are obtained. Example 3 To a solution of one part of 163,17B-epoxy-3-methoxy estra-l,3,5(10)~triene in 38 parts of chloroform is added, at 0-5 °, 24 parts of concentrated hydrochloric acid and the mixture shaken for about 15 minutes. The chloro form layer is separated, washed with Water, dried over an hydrous magnesium sulfate and evaporated to dryness in vacuo. Example 7 A mixture of 2 parts of 17a-bromo-3~methoxyestra-1, according to the herein described processes, 17a-bromo-3 hydroxyestra-l,3,5 ( 10) -trien-l6,8-ol and 17a-bromo-3-n 4 sorbed on fuller’s earth and eluted with 40% benzene in heptane. Evaporation of the eluate a?ords an oil which crystallizes on standing. Recrystallization from acetone vacuo. The residue is extracted with ether and the ex The residue is extracted with ether and the ex 68 hours. The reaction mixture is diluted with water and extracted with benzene. The organic layer is separated, washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness at reduced pressure. A ben zene solution of the residue is chromatographed on silica gel. Elution of the column with 1% ethyl acetate in ben zene and concentration of the eluate to dryness aifords a solid residue which is recrystallized ?rst from methylene chloride-methanol, then from methanol to afford 17,3 tract clarified by centrifugation, then evaporated to dry ness in vacuo to yield 17a-chloro-3~methoxyestra- 1,3,5 (10) -trien-l6}3-ol, which exhibits a maximum in the in— irared at 2.77 microns. bromo-3-methoxyestra-1,3,5( lO)-trien-16-one, M.P. about 226-229"; [a]D=—100“. Example 8 The substitution of an equivalent quantity of 17a: By substituting an equivalent quantity of concentrated 25 chloro-3-methoxyestra—l,3,5(lO)-trien - 16 - one in the hydriodic acid and otherwise proceeding according to the process of Example 7 results in 17?-chloro-3-methoxy herein described processes, 17a-iodo-3-methoxyestra-l,3, estra-l,3,5(l0)-trien-16-one, Ml’. about 211-213"; 5(l0)-trien-16§-ol, which displays an infrared maximum [a]D=‘—-92°. at 2.77 microns, is obtained. Example 9 30 Example 4 To a stirred solution of 7 parts of lithium aluminum To a solution of 3 parts of anhydrous hydrogen fluoride in 7.5 parts of tetrahydrofuran is added at —70°, with stirring, a solution of one part of l6;8,l7?-epoxy-3-meth oxyestra-l,3,5 (10)-triene in 40 parts of chloroform. Stir ring is continued at -—70° for about 30 minutes, then at —30° for about one hour. The reaction mixture is treated with excess aqueous potassium carbonate and the organic layer separated, washed with water, dried over anhydrous magnesium sulfate, and concentrated to dry hydride in 700 parts of ether is added, at —5° over a period of several minutes, a solution of 15 parts of 175 bromo-3-methoxyestra-1,3,5(10)-trien-l6-one in 355 parts of tetrahydrofuran. The reaction mixture is treated suc~ cessively with 50 parts of water and 10 parts of 10% aqueous sodium hydroxide, ?ltered through a bed of anhydrous magnesium sulfate containing a ?lter aid and evaporated to dryness at reduced pressure. The result ness in vacuo, to yield l7a-?uoro-34methoxyestra-1,3,5 ing residue is recrystallized from acetone-petroleum ether, then from petroleum ether to produce 1713-bromo-3 (10)-trien-16;S-ol, M.P. about 146-149". methoxyestra-l,3,5(l0)-trien-l6;9-ol, M.P. about 150 151"; [a]D=+7O°. Example 5 To a suspension of 2.4 parts of chromium trioxide in 24 parts of pyridine is added, with stirring, a solution of 45 1.2 parts of 17wbromo-3-methoxyestra-1,3,5(10)-trien 165-01 in 12 parts of pyridine. Stirring at room tempera Example 10 A mixture of one part of 17a-bromo-3-hydroxyestra 1,3,5 (10)-trien-l6p’-ol, 10 parts of acetic anhydride, and 20 parts of pyridine is warmed on the steam bath to achieve homogeneity, then allowed to stand at room temperature for about 16 hours. The reaction mixture rated, washed successively with water, dilute hydrochloric 50 is diluted with water and extracted with ether. The organic solution is washed successively with aqueous acid, water and saturated aqueous sodium chloride; then sodium bicarbonate and water, dried over anhydrous dried over anhydrous magnesium sulfate and concentrated magnesium sulfate, and evaporated to dryness in vacuo to an oil in vacuo. This oil is adsorbed on silica gel, ture is continued for about 3 hours, then water added and the mixture extracted with ether. The ether layer is sepa eluted with chloroform, and the eluate evaporated to yield to yield 3,16,8-diacetoxy-l7ot-bromoestra-l,3,5 (10)-triene. (10)-trien-l6-one, butyroxy-17a-bromoestra-1,3,S(10)-triene. Substitution of an equivalent quantity of n-butyric an oil which crystallizes on standing. Recrystallization 55 anhydride in the instant process results in 3,l6?-di-n-. from ether affords pure 17a-bromo-3-methoxyestra-1,3,5 MP. 133.5-l36.5°; [a]D=—5° Example 11 (chloroform) . The substitution of an equivalent quantity of 170: chloro-3-methoxyestra-l,3,5(10)-trien-l6B-ol in the in 60 To a solution of 6 parts of l7a-bromo-3-hydroxyestra 1,3,5(l0)~trien-l6;8-ol in 800 parts of acetone is added stant process results in pure 17cc-chloro-3-methoxyestra dropwise, at 10-15", 5.5 parts by volume of an aqueous 1,3,5(10)-trien-l6-one, M.P. 11l.1-1l2.5°; [a]D=—49° solution containing 1.47 parts of chromium trioxide and (chloroform) . 2.34 parts of concentrated sulfuric acid. The reaction Example 6 mixture is stirred for about 5 minutes, then diluted with water and extracted with benzene. The benzene solu-. To a stirred solution of one part of lithium aluminum tion is washed successively with water and aqueous po hydride in 70 parts of dry ether is added, at 0° over a tassium bicarbonate, dried over anhydrous magnesium period of about 10 minutes, a solution of 6.45 parts of 17a-bromo-3-methoxyestra-1,3,5(10)-trien-16-one in 54 sulfate and evaporated to dryness in vacuo. Recrystal parts of tetrahydrofuran. The reaction mixture is treated lization from acetone-hexane altords pure 17a-bromo-3 successively with water and excess dilute hydrochloric hydroxyestra-1,3,5(l0)-trien-16-one, which exhibits in acid, then extracted with ether. The organic layer is sepa frared maxima at 2.77 and 5.70 microns. rated, washed successively with water and aqueous sodium Example 12 bicarbonate, dried over anhydrous magnesium sulfate, and evaporated to an oil in vacuo. The residue is ad 75 A mixture of 2 parts of 17a-bromo-3-hydroxyestra 5 3,079,408 6 1,3,5(10)-trien-16-one, 10 parts of acetic anhydride, and Example 17 20 parts of pyridine is allowed to stand at room tem perature for about 15 hours. The reaction mixture is diluted with water and extracted with benzene. The The substitution of an equivalent quantity of 17a ?uoro-3-methoxyestra-1,3,5(10) - trien - 16,3 - 01 or 17/3 ?uoro-3-methoxyestra-1,3,5(10)-trien~16a—o1 in the pro cedure of Example 4 affords 17a-?uoro-3-methoxyestra 1,3,5 (10)-trien-l6-one, M.P. about 148—l49° organic layer is separated, washed successively with water and aqueous potassium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated to dryness in vacuo. The crude product can be recrystallized from aqueous ethanol to produce pure 3-acetoxy-l7a-brornoestra-1,3, 5(10)-trien~l6-one. This substance displays maxima in 10 and 17B-?uoro-3-methoxyestra-1,3,5 (10)-trien M.P. about 155-156°, respectively. the infrared at 5.70 microns. Example 13 A mixture of 3.5 parts of 17tx-bromo-3-hydroxyestra 1,3,5 (10)-trien-16?-ol, one part of acetic anhydride, and 15 What is claimed is: 1. A member selected from the group consisting of compounds of the structural formulae 13 T Ki 20 parts of pyridine is allowed to stand at room tem perature for about 16 hours. The reaction mixture is diluted with water and the resulting mixture extracted with benzene. The benzene solution is washed succes sively with aqueous potassium bicarbonate solution and 20 water, dried over anhydrous magnesium sulfate, and evaporated to dryness in vacuo. The residue is adsorbed on silica gel and eluted with chloroform to aiford 3 acetoxy-17a-bromoestra-1,3,5(10)-trien-l6B-ol which dis plays infrared maxima at 2.77 and 5.70 microns. and Ito-(l3 25 Example 14 By substituting an equivalent quantity of 17/8-chlor0~ 3-methoxyestra-1,3,S(10)-trien-l6-one and otherwise pro ceeding according to the procedure of Example 9, 17/8 30 chloro-3-methoxyestra-1,3,5(10)-trien-16?-ol is obtained. Example 15 Rods/‘j wherein R is selected from the group consisting of hy drogen, lower alkyl, and lower alkanoyl radicals; X The substitution of an equivalent quantity of 17a: bromo-3-methoxyestra-1,3,5 (10) - trien - 165 - 01 or 175 is a halogen atom, and Z is selected from the group con chloro-3-methoxyestra-1,3,5(10)-trien-16B-ol in the proc sisting of carbonyl, hydroxymethylene, and (lower alka noy1)-oxymethy1ene radicals. 7. 17~bromo-3-methoxyestra-1,3,5 ( 10) -trien-16-one. ess of Example 10 results in l6?-acetoxy-l7u-bromo-3 methoxyestra-l , 3, 5 ( 10)-triene and 16B-acetoxy-17/3-chlo ro-3-methoxyestra-1,3,5(10)-triene. Example 16 16 - one, 40 The substitution of one part of 16a,17a-epoxy-3-meth oxyestra-l,3,5(10)-triene in the process of Example 4 results in 17,6-?uoro-3-methoxyestra-1,3,5(10)-trien-l6a 45 ol, M.P. about 74-76"; [a]D=+18°. . 1 7-ch1oro'3-methoxyestra-1,3,5 ( 10 ) -t.rien-1 6-one. . 17-bromo-3-methoxyestra-1,3,5(10)-trien-l6-o1. . 17-chloro-3-methoxyestra-1,3,5 ( 10) -trien~1 6-01. . 17-f1uoro-3-methoxyestra-1,3,5 ( 10) ~trien-16-one. 17-?uoro-3-rnethoxyestra-1,3,5 ( 10 ) -trien- 1 6-01. No references cited.