Патент USA US3068236код для вставки
.i‘trnt nice Patented Dec. 11, 1962 2 As starting materials in the present process, there are 3 968,226 employed 1,6-lower alkyl-Aw-steroids represented by the partial formula: PR?CESd FUR THE PiREPARATION 0F Iii-METH YLENE CGMPGUNDEE 0F HE PREGNANE SERIES David Tani), Metnchen, Norman L. Wendler, Summit, and Robert D. Hoti’sommer, in, Metuchen, Ni, assignors to Merck Sr (10., line, Railway, Psi-3., a corporation of New Jersey No Drawing. Filed Dee. 22, 1961, Ser. No. 161,396 16 Ciaims. (Ci. 26ti-—239.55) This invention relates to an improved process for the preparation of lo-alkylene steroids of the pregnane series CH2 0B. 10 wherein R1 is lower alkyl and P represents an unsaturated pregnane ring nucleus having an oxygen substituent, such novel two-step process for the conversion of 16-lower 15 as keto or hydroxyl at 0-11, hydrogen or halogen at G9, a keto group at C—3 and unsaturation in the A ring at alkyl-Al?-steroids of the pregnane series to the correspond as well as the l6-lower alkyl-16,17-oxido intermediates thereof. More particularly, this invention relates to a C-4 or C-1 and C-4. The R group may be hydrogen but it is preferably an ester group derived from an organic ing 16~alkylene compounds whereby both the l6~alkylene end product and l6-lower alkyl 16,17-oxido intermediate carboxylic acid, especially such acids as formic, ‘acetic, are formed in high yield. This application is a continuation-in-part of copending 20 propionic, benzoic and the like. Typical ‘examples of suitable 16-lower aIkyLAIG-steroid starting materials are: applications Serial No. 801,429, ?led March 24, 1959, and Serial No. 818,017, ?led June 4, 1959. The 16-alkylene steroids produced in accordance with the present invention possess extermely high anti-in?am 16-methyl-2l-hydroxy-4,16-pregnadiene-3,l 1,20-trione 21 acetate, matory activity and are especially effective for the treat 25 ment of arthritis and related diseases since they can be administered for their cortisone-like action in low dosage thereby minimizing undesired side effects. 16-,methyl-11?,21-dihydroxy-4,16-pregnadiene-3,20rdi one Zl-acetate, 9a-?uoro-16-methyl-21-hydroxy~4,16-pregnadiene-37,1‘l, ZO-trione 21-acetate, 9oc-?l101‘O-l6-m6thYl-l 1,8,21-dihydroxy-4,16-pregnadienc One method which has been employed to convert 16 lower alkyl-A16-steroids to the corresponding 16~alkylene 30 compounds has been to react the 16—lower alkyl-A16~steroid starting material with an alkaline solution of hydrogen ‘peroxide or with an alkyl hydroperoxide in the presence of a strong base, as for example, hydrogen peroxide in the presence of sodium hydroxide, to obtain the corre 35 sponding 16-lower alkyl-16,l7-oxido compound, which, 3,20—dione 21-acetate, 16-methyl-21-hydroxy-1,4,16-pregnatriene~3,11,20-tri one ZI-acetate, 16-rnethyl-11,8,21-dihydroxy-1,4,16-pregnatriene-3,20-di one 21-acetate, 9a-fiuoro-l6-methyl-2l-hydroxy-1,4,16-pregnatricne43 11,20-trione 21-acetate, 9a-?uoro-16-methyl-1 l}8,21-dihydroXy-1,4,16-pregnatri upon contact with a hydrohalic acid such as hydrochloric ene-3,20-dione ZI-acetate, and the like. In the ?rst step of the present process, the ,16-lowcr compound. The primary disadvantages of having to use a strong 40 alkyl-16,-l7-oxido compounds are prepared by reacting the l6-lower alkyl-Aw-starting material with an organic per base in the ?rst step of this process are (1) the resulting acid of a strong carboxylic acid. Thus, peracids ‘of alkaline hydrolysis of any 21-ester groups present as well formic acid, trichloroacetic acid, di?uoroacetic acid and as (2) the danger of cleavage of the whole l7-side chain the like may satisfactorily ‘be employed in this process, al with the resulting loss of yield. In the second step of this process, the use of hydrohalic acids is likewise undesirable 45 through peroxytri?uoroacetic acid has been found to be particularly effective in the conversion of the AIS-steroid because of the formation of many unwanted yet closely to ‘the corresponding ‘l6oc,l7oc~0XidO compound. When related steroid by-products from which it is di?icult to peroxytri?uoroacetic acid is employed, the reaction is con separate the desired 16-alkylene product without using veniently carried out by dissolving the l6-1ower .a1kyl-A16 elaborate chromatographic procedures. Thus, for exam ple, the reaction of 9a-?uoro-11B,21-dihydroxy-1GB-meth 50 ‘steroid in an inert organic solvent such as benzene, toluene or the like and preferably methylene chloride, adding ,a yl-l6a,17a-oxido-l,4-pregnadiene-3,20-dione 21 - acetate basic alkaline buffering agent, as for example, disodium with hydrogen chloride results in the production of a mix hydrogen phosphate or sodium bicarbonate and adding to ture of ( 1) 9rx-?uoro-115,17a,21-trihydroxy-lo-rnethylene acid, results in the formation of the 16-alkylene steroid this mixture peroxytrifluoroacetic acid in a compatible 1,4-pregnadiene-3,ZO-dione ZI-acetate, (2) 9a-?uoro-11B, 17c¢,2l-trihydroxy~16-methyl - 1,4,15 — pregnatriene-3,20' dione ZI-acetate, (3) 9a-?uoro-l1/3,21~dihydroxy-l6-meth ly-1,4,l4,l6-pregnatetraene-3,ZO-dione 21-acetate, and (4) 9a - ?uoro-lS-chloro - 11/3,2l-dihydroxy - l6 - methyl-1,4, 55 organic solvent, for example, methylene chloride. The reaction mixture is desirably stirred at a temperature of about 0° C. for a period of about 10-30 minutes .and ‘thereafter for about l~2 hours at room temperature. The 16-pregnatriene~3,ZO-dione 21-acetate. In view of these resulting l6-lower alkyl-16,17-oxido compound is then minimize the formation of by-products and thus enhance the yield of the desired lo-alkylene steroid product. ing the extract. Crystallization of the residue from ,a steroid compounds by reacting the 16-lower alkyl-Am in carrying out thisstep of the process, it has "been ‘found desirable to employ about 1 mole ofiperacid ‘for dit?culties, it Was desirable to ?nd a process which would 60 conveniently recovered by adding Water to the mixture, extracting the solution with methylene chloride and dry suitable solvent such as acetone, ethyl acetate or acetone It has now been found in accordance with the present ether mixtures yields the 16-lower alkyl-16,17-oxido ste invention that 16-lower alkyl~A16-steroids of the pregnane roid. series may be converted to the corresponding lo-alkylene 65 steroid starting material with an organic peracid of a strong carboxylic acid in the presence of an alkaline‘buffer each mole of starting material in order to avoid reaction of the peroxytri?uoroacetic acid with any other double ing agent, and contacting the resulting 16-methyl-l6,17 ‘bonds than the 16:17 double bond which may be‘present 70 oxido compound with a strong carboxylic acid to obtain in the steroid nucleus. the 16-alkylene steroid in high yield. The peroxytri?uoroacetic acid reagent is conveniently 3,068,226 3 prepared by adding tri?uoroacetic anhydride to a stirred solution of 90% hydrogen peroxide dissolved in methylene chloride. A fresh mixture of this reagent is then reacted with the steroid starting material. In the second step of this process, the l6~lower alkyl 16,17-oxido steroid is reacted with a strong carboxylic acid such as formic, chloroacetic, trichloroacetic, halo genated propionic acid, oxalic acid and the like to form the corresponding l6-methylene steroid. It has been found that tri?uoroacetic acid is particularly effective in 10 carrying out this reaction. Thus, the 16-lower alkyl 16,17-oxido compound is conveniently reacted with tri ?uoroacetic acid at room temperature for a period of about 1-3 hours. In general, while no additional solvent is necessary, it has been found that by carrying out this ‘ contemplates the conversion of the 16-lower alkyl-Am steroids to the corresponding 16-alkylene compound in a single step, thus eliminating the formation and isolation of the'intermediate 16,17-oxido compound. This is ac complished by reacting the 16-1ower alkyl-A1G-steroid dis solved in an inert organic solvent such as methylene chloride with a mixture of a percarboxylic acid and a 16a,17a—oxido-2l-hydroxy-4-pregnene-3,l1,20-trione 21 acetate. In accordance with the foregoing procedure, but start ing with 9st - ?uoro - 16 - methyl-1l/i,2l-dihydroxy-4,l6 pregnadiene-3,20-dione 2l-acetate there is obtained 9a ?uoro - 16,6 - methyl - 16¢,l7a-oxido-11,3,21-dihydroxy-4 pregnene-3,20-dione 21-acetate. Example 3 To a stirred mixture of 2.00 g. of l6-methyl-21-hy droxy-1,4,16-pregnatriene-3,l1,20-trione 2l-acetate and aqueous potassium bicarbonate, saturated sodium chloride and dried over magnesium sulfate. Crystallization of the residue from acetone-ether gives 16,8-methyl-16a,l7a oxido-2l-hydroxy-1,4-pregnadiene-3,l1,20-trione 2l-ace tate. tone, ether or acetone-ether mixtures. In addition to the foregoing two-step process for the production of l6-alkylene steroids, this invention also Crystallization of the residue from acetone-ether gives 9a-?uoro-l6B-rnethyl 30 g. of disodium hydrogen phosphate in 60 ml. of hen zene at 0° C. is added 10 ml. of 2.0 M peroxytri?uoro acetic acid reagent. After 10 minutes at 0° C. and 1 hour at 25° C., water is added and the mixture extracted with benzene. The organic extract is Washed with process in the presence of benzene, a purer product free of any l4,l6~diene by-product is obtained. The 16 alkylene-l7-hydroxy steroid product is conveniently re covered by chromatography over neutral alumina and elution with benzene-chloroform mixtures. Alternatively, the reaction mixture may be extracted with methyl ene chloride, dried, and the residue crystallized from ace 4 dried over magnesium sulfate. In accordance with the foregoing procedure, but start 25 in g with 16-met'nyl-l1?,21-dihydroxy-1,4,16-pregnatriene 3,20-dione 21-acetate there is obtained 165-methyl l6a,17<x - oxido - 115,21-dihydroxy-l,4-pregnadiene-3,20 dione 21-acetate. Example 4 To a stirred mixture of 2.00 g. of 9ct-?uoro-16-methyl 115,21-dihydroxy-L4,l6-pregnatriene-3,20-dione 2l-ace tate and 15 g. of disodium hydrogen phosphate in 40 ml. carboxylic acid, as for example, a mixture of peroxytri of methylene chloride at 0° C. is added 5.0 ml. of 2.0 M ?uoroacetic acid and tri?uoroacetic acid, in the absence of any basic buffering agent. The reaction is conveniently 35 peroxytri?uoroacetic acid (prepared by adding 5.1 ml. of tri?uoroacetic anhydride to a stirred solution of 0.82 ml. carried out by stirring the reaction mixture at 0° C. for 90% hydrogen peroxide in 5 ml. of methylene chloride). about 10-30 minutes followed by further stirring at room After 1 hour at 0° C., water is added and the mixture temperature for 1-2 hours. After extracting the reaction extracted with methylene chloride. The organic extract mixture with methylene chloride and drying, the l6-alkyl ene-l7-hydroxy steroid is readily recovered by chromatog 40 is washed with water and saturated salt solution and dried over magnesium sulfate. Crystallization of the residue raphy or crystallization. from acetone-ether gives 9a-fluoro-16?-methyl-l6a,17a The following examples illustrate methods of carrying 1 oxido - 115,21 - dihydroxy-l,4-pregnadiene-3,20-dione 21 out the present invention, but it is to be understood that acetate. these examples are given for purposes of illustration and In accordance with the foregoing procedure, but start 45 not of limitation. ing with 9oc-?uoro-l6-methyl-2l-hydroxy-1,4,16-pregna Example 1 triene-3,l1,20-trione 21-acetate there is obtained 9a To a stirred mixture of 2.00 g. of 16-methyl-21-hydroxy ?uoro - l6/3-methyl-16a,17u-oxido-2l-hydroxy-l,4-pregna 4,l6-pregnadiene-3,11,20-trione 2l-acetate and 30 g. of di diene-3,11,20-trione 2l-acetate. sodium hydrogen phosphate in 60 ml. of methylene chloride at 0° C. is added 10 ml. of 2.0 M peroxytri?uoro acetic acid reagent (prepared by cautiously adding 5.1 ml. of trifluoroacetic anhydride to a stirred solution of 0.82 Example 5 To 240 mg. of 16?-methyl-16a,l7rx-oxido-2l-hyroxy-4 pregnene-3,ll,20-trione Zl-acetate is added 3 ml. of tri ?uoroacetic acid mixed with 2 ml. of benzene. After 2 chloride). After 10 minutes at 0° C. and 1 hour at 25° 55 hours at 25° C., water is added and the mixture is ex ml. 90% hydrogen peroxide in 5 ml. of methylene C., water is added and the mixture extracted with methyl ene chloride. The organic extract is washed with aqueous potassium bicarbonate, saturated sodium chloride and dried over magnesium sulfate. Crystallization of the residue from acetone-ether gives 16,8-methyl-16a,17a oxido-21-hydroxy-4-pregnene-3,11,20-trione 2 l-acetate. In accordance with the foregoing procedure, but start ing with l6-methyl-l1,8,2l-dihydroxy-4,l6-pregnadiene 3,20-dione 2l-acetate there is obtained 16B-methyl 1611,1701. - oxido - 113,2l-dihydroxy-4-pregnenc-3,20-dione ZI-acetate. Example 2 To a stirred mixture of 2.00 g. of 906-?llOI‘O-16-l'l’l6ii1Yl 21-hydroxy-4,16-pregnadiene-3,l1,20-trione 2l-acetate and tracted with methylene chloride. The organic extract is washed with aqueous potassium bicarbonate, saturated sodium chloride and dried over magnesium sulfate. Crystallization of the residue from acetone-ether gives 16 - methylene - 17a,2l-dihydroxy-4-pregnene-3,11,20-tri one 2l-acetate. In accordance with the foregoing procedure, but start ing with 16B-methyl-l6oc,l7e-oxido-115,21-dihydroxy-4 pregnene-3,20-dione ZI-acetate there is obtained 16 methylene - 1118,170;,21-trihydroxy-4-pregnene-3,20-dione 21-acetate. Example 6 To 240 mg. of 9e-?uoro-16,8-methyl-16a,17e-oxido-21 30 g. of sodium bicarbonate in 60 ml. of methylene 70 hydroxy-4-pregnene-3,l1,20-trione 2l-acetate is added 3 ml. of trichloroacctic acid. After 2 hours at 25° C., chloride at 0° C. is added 10 ml. of 2.0 M performic acid. water is added and the mixture is extracted with methyl After 10 minutes at 0° C. and 1 hour at 25° C., water ene chloride. The organic extract is washed with aqueous is added and the mixture extracted with methylene potassium bicarbonate, saturated sodium chloride and chloride. The organic extract is washed with aqueous potassium bicarbonate, saturated sodium chloride and 75 dried over magnesium sulfate. Crystallization of the resi 5 3,068,226 6 due from acetone-ether gives 9a-?uoro-16-methylene-17a, dium hydrogen phosphate, thereby forming the corre sponding 16?-methyl-16a,l7a-oxido-steroid compound and 2l-dihydroxy-4-pregnene-3,11,20-trione 21-acetate. In accordance with the foregoing procedure, but start reacting this compound with tri?uoroacetic acid to obtain ing with 9a-?uoro-l6B-methyl-16a,17o¢~oxido-l1?,21-di 16 - methylene-1If},17a,2l-trihydroxy-4-pregnene-3,20-di one 21-acetate hydroxy-4—pregnene-3,ZO-dione ZI-acetate there is ob tained 9a - fluoro - 16~methylene-1.15,17a,21-trihydroxy-4 3. The process which comprises reacting 9a-?uoro-l6 pregnene-3,20-dione 21-acetate Example 7 To 240 mg. of 165-methyld6a,17a-oxido-21-hydroxy 1,4—pregnadiene-3,11,20~trione Ill-acetate is added 3 ml. 10 responding 16/3-methyl-16a,17a-oxido~steroid compound of oxalic acid. After 2 hours at 25° C., water is added and the mixture is extracted with methylene chloride. obtain 90: - ?uoro-16-methylene-l1,3,17a,21~trihydroxy-4 methyl-1 1?,21-dihydroxy-4,16-pregnadiene-3,20-dione 21 acetate with peroxytri?uoroacetic acid in the presence of disodium hydrogen phosphate, thereby forming the cor and reacting this compound with tri?uoroacetic acid to pregnene-3,20‘-dione 21-acetate. The organic extract is washed with aqueous potassium bicarbonate, saturated sodium chloride and dried over 15 '4. The process which comprises reacting 16-methyl 1118,21 - dihydroxy-1,4,l6-pregnatriene-3,ZO-dione 21-ace magnesium sulfate. Crystallization of the residue from tate with peroxytri?uoroacetic acid in the presence of acetone-ether gives 16-methylene-17a,21-dihydroxy-l,4 disodium hydrogen phosphate, thereby forming the cor pregnadiene-3,l1,20-trione 2l-acetate. responding 16?-methyl-16a,17a-oxido-steroid compound In accordance with the foregoing procedure, but start and reacting this compound with tri?uoroacetic acid to ing with l6?-methyl-16u,17o<-oxido-1lB,21-dihydroxy-l,4 20 obtain 16 - methylene - 11,8,17a,21-trihydroxy-1,4-pregna pregnadiene-3,20-dione 21-acetate there is obtained l6~ diene-3,20-dione 21-acetate. methylene - 11,3,170c,21 - trihydroxy - 1,4 - pregnadiene 3,20-dione 2l-acetate. 5. The process which comprises reacting 9oc-?1101‘0-16 i methyl - 1 1,8,21-dihydroxy-1,4,16-pregnatriene-3,20-dione Example 8 To a stirred solution of 1.00 g. of 9cc-?l10I‘O-16/3-II16111Y1 21-acetate with peroxytri?uoroacetic acid in the presence 25 of disodium hydrogen phosphate, thereby forming the 16cc, l7u-oxido-l15,2l-dihydroxy-l,4-pregnadiene-3,20-di corresponding 16,8 - methyl - 160:,170t-0Xid0-S16f0id com bonate is added and the mixture extracted with ethyl acetate. The organic layer is washed with saturated so dium chloride solution, dried over magnesium sulfate and concentrated to dryness. Crystallization of the solid resi series with a strong percarboxylic acid in the presence of an alkaline buffering agent to form the correspond pound and reacting this compound with tri?uoroacetic one 21-acetate in 20 ml. of benzene at 10° C. is added a acid to obtain 9a-?uoro-16-methylene-11B,17a,2,1-trihy~ mixture of 4 ml. of tri?uoroacetic acid and 10 ml. of ben zene. After 18 hours at 20—25° C. cold 5% sodium car 30 droxy-l,4-pregnadiene-3,20-dione 21-acetate. 6. The process which comprises reacting a 16-lower alkyl-l1,21-bisoxygenated-Al‘i-steroid of the pregnane due from ethyl acetate gives 9a-?uoro-l6-methylene-l113, 35 ing 16,8-lower alkyl-l1,2l-bisoxygenated-l6u,17o¢-oxido steroid compound. 17a,2l-trihydroxy-1,4-pregnadiene-3,20-dione Zl-acetate. 7. The process according to claim 6, wherein the percarboxylic acid is peroxytri?uoroacetic acid and the Example 9 buffering agent is disodium hydrogen phosphate. To a stirred mixture of 2.00 g. of 9a-fluoro-l6-rnethyl 8. The process according to claim 6 wherein the 115,21 - dihydroxy-4,16-pregnadiene-3,20-dione ZI-acetate 40 percarboxylic acid is performic acid and the bu?fering in 60. ml. of methylene chloride at 0° C. is added 10 ml. agent is sodium carbonate. of a mixture of peroxytri?uoroacetic acid reagent and tri 9. The process according to claim 6 wherein the ?uoroacetic acid in a ratio of 1:1. After 10 minutes at percarboxylic acid in peroxydi?uoroacetic acid and the 0° C. and 1 hour at 25° 0, water is added and the mix ture extracted with methylene chloride. The organic ex 45 buifering agent is disodium hydrogen phosphate. 10. The process which comprises reacting a 16,8-lower tract is washed with aqueous potassium bicarbonate, sat urated sodium chloride and dried over magnesium sulfate. alkyl-l1,21-bisoxygenated-16u,17o¢-oxido-steroid of the pregnane series with a strong carboxylic acid to obtain Crystallization of the residue from acetone-ether gives 90: the corresponding 16'lower alkylene-17zx-hydroxy-steroid ?uoro - l6-methylene-1 1,8,17a,2l-trihydroxy-4,16-pregna diene-3,20-dione 21-acetate. In accordance with the foregoing procedure, but start ing with 900 - ?uoro-16-methyl-11?,21-dihydroxy-1,4,16 pregnatriene-lZO-dione ZI-acetate there is obtained 90: ?uoro - 16 - methylene-11,8,17a,21-trihydroxy-1,4,16-preg 50 compound. 11. The process according to claim 10 wherein the reaction is carried out in the presence of the organic solvent benzene. 12. The process according to claim 10‘ wherein the natriene~3,20>dione ZI-acetate. 55 carboxylic acid is tri?uoroacetic acid. 13. The process according to claim 101 wherein the Various changes and modi?cations may be made in carboxylic acid is trichloroacetic acid. carrying out the present invention without departing ‘from 14. The process according to claim 10‘ wherein the carboxylic acid is oxalic acid. 15. The process which comprises reacting a 16-lower claims, they are to be considered as part of our invention. 60 alkyl-l1,21-bisoxygenated-A16-steroid of the pregnane We claim: series with a mixture of a strong percarboxylic acid and 1. The process which comprises reacting a l6-lower a strong carboxylic acid thereby forming the correspond alkyl-Aw-steroid of the pregnane series with a strong per ing l6-lower alkylene-17a-hydroxy-steroid compound of carboxylic acid in the presence of an alkaline butfering agent, thereby forming the corresponding 16,8-lower al 65 the pregnane series. 16. The process which comprises reacting 9oc-?110rO-16~ kyl-16oz,17a-0Xid0 steroid compound, and reacting this the spirit and scope thereof. Insofar as these changes and modi?cations are within the purview of the annexed compound with a strong carboxylic acid to obtain the corresponding 16-lower alkylene-17-hydroxy steroid of the pregnane series. methyl -1 16,21- dihydroxy-l,4, 16 - pregnatriene - 3,20-dione 21-acetate with a mixture of pcroxytri?uoroacetic acid and tri?uoroacetic acid thereby forming the correspond 2. The process which comprises reacting 16-methyl 70 ing 9a-?uoro-16-methylene~1 1,8, l7a,21-trihydroxy-1,4,16 pregnatriene-3,20-dione 21-acetate. 11B, 2 l -dihydroxy-4, l 6-pregnadiene-3,20-dione 21-acetate with peroxy tri?uoroacetic acid in the presence of diso No references cited.