Патент USA US3028391код для вставки
United States Patent 0 " lC€ 3,028,381 Patented Apr. 3, 1962 2 1 (2' : 3' - diazacyclopent-2’-eno ) -pregn-5-en-20-one R=H or acyl) 3,028,381 ?-METHYL STEROID DERIVATIVES AND PROCESSES 0F PREPARING SAME Vladimir Petrow and David Morton Williamson, London, England, assignors to The British Drug Houses Limited, London, England, a British company No Drawing. Filed July 6, 1959, Ser. No. 824,961 Claims priority, application Great Britain July 9, 1958 6 Claims. (Cl. 260-2395) (III; Me 0 OMe LuNzl? : 1- - —CH2 Me I . r‘: 10 This invention is for improvements in or relating to R0 organic compounds and has particular reference to the Me preparation of new 6:16-dimethylpregnane derivatives which are of value as intermediates in the preparation of ~ (III) According to the present invention there is provided a for the preparation of 3?-hydroxy and 3f3-acyl 17a-hydroxy- and 17a-acyloxy 6:16-dimethyl derivatives 15 process oxy-6: l6-dimethylpregna-5 : l6-dien-20-one which proc ess comprises reacting the corresponding B?-acyloxy or In particular l7a-acetoxy-6a,IG-dimethylprogesterone 313-hydroxy-6-methylpregna-5z l6-dien-20-one (IV) where is found to be ‘100 times more potent than dimethisterone of pregnane which are valuable as progrestational agents. R=H or an acyl group containing up to 10 carbon atoms (6a,2l - dimethylethisterone; 60:,21 - dimethylanhydrohy Me droxyprogesterone) in the Clauberg assay. As dimethi 20 sterone (6a,21-dimethylethisterone) is known to be slight ly more than 10 times as active as anhydrohydroxyproge sterone (ethisterone) in the Clauberg assay (David, Hart ley, 'Millson ‘and Petrow, J. Pharm. Pharmacol, 1957, 9, i A 929), it will be apparent to those skilled in the art that 25 l7a-acetoxy-6al6-dimethylprogesterone is a proges-tation a1 agent of quite unexpected and remarkable potency, and its preparation a matter of importance. B0 Me It is an object of the present invention to provide the '(IV) new compounds 3,8-hydroxy- and 3?-acyloxy- 6: 16-dimeth 30 with diazomethane to yield the corresponding 16a,17u ylpregna-5z16-dien-20-one (I; R=H or an acyl group con taining up to 10 carbon atoms) . methylene diazo derivative (III) or pyrazoline and ther mally decomposing the pyrazoline. Me OOMe A 35 e i of the residue. ‘Decomposition of the pyrazoline (III) to yield the 6: l6-dimethylpregnane derivative (1) may readily be per formed by heating the pyrazoline under re?ux in an inert RO Me (I) organic solvent of B.P. approximately the same as the MP. of the pyrazoline, such as dibutyl ether, for 3 to 5 The above compounds are valuable and convenient starting materials for the preparation of the potent pro hours. p-Cymene and ethylene glycol are other solvents suitable for e?ecting this thermal decomposition. ‘Conversion of I (‘where R=acyl) into I (where R=H) may readily be effected by alkaline hydrolysis, for exam ple by heating the acyl derivative with the carbonate or ges-tational agent 17a-acetoxy-6a,16-dimethylprogesterone. Their conversion into this progestational agent may be accomplished by converting compound I into the 3-oxo derivative, 60:: 16-dimethylpregna-4: l6-dien-3 :20-dione Me 50 hydroxide of an ‘alkali metal in an aqueous/ organic sol O OMe p such as diethyl ether and the reaction mixture allowed to stand at room temperature for periods of 16 to 40 hours, and the pyrazoline subsequently isolated by re moval of the solvent by evaporation and crystallisation Me Me Addition of diazomethane to the starting material (IV) is preferably performed in an unreactive organic solvent vent mixture such ‘as aqueous acetone or aqueous tert.~ butanol. Following is a description ‘by way of example of meth ods of carrying the invention into effect. 55 Example 1 3p - ~acetoxy-6-methy-l-16: 17-(2’ : 3'-diazacyclopent-2’ 8 H 0_ eno)-pregn-5-en-20-one (III; R=Ac): 3?acetoxy-6-meth lite (n) forming the 16a,17u-epoxide, converting this 1641,17“ epoxide into ‘a 17a-hydroxy-16,8-halo-16a-methyl inter mediate by reaction with a halohydrin, reductively re 60 lypregna-5:l6-dien-20-one (IV) (20 gm.) was treated with a solution of diazomethane prepared from N-methyl N-nitroso-toluene-p-sulphonamide (125 gm.) in diethyl ether (750 mls.) and the mixture was allowed to stand at room temperature overnight (16 hours). Excess di moving the halogen atom and acetylatnig the tert.-hy 65 azomethane was destroyed by addition of dilute acetic drcxyl group at C17. acid, and the ethereal layer washed with water, sodium The present invention also provides the intermediate pyrazolines 3?-hydroxy- and 3?-acyloxy-6-methyl-l6:17 bicarbonate solution, water and dried. The ether was re 3,028,381 3 4 moved under reduced. pressure and the residue crystal lised from methanol to yield 3,6-acetoxy-6-methyl-16:17 methane in diethyl ether is added to the steroid starting material and the reaction mixture allowedto stand at room temperature for periods of 16 to 40 hours. 3. A process as claimed in claim 1 wherein the 160:, (2': 3' - diazacyclopent - 2’~ eno)-pregn-5-en-20-one (III; R=Ac), plates, M.P. 156 to 158° C. with decomposi tion, [@1323 —l4° (c., 0.44 in chloroform). 5 Not-methylene diazo derivative is decomposed by heat 35 - acetoxy-6:16-dimethylpregna-5:16-dien-20-one (I; R=Ac): The foregoing pyrazoline (III; R=Ac) (20 ing under re?ux in an inert organic solvent of BF. ap proximately the same as the M.P. of the 16a,17oc-m6thyl gm.) was dissolved in dibutyl ether (200 ml.) and the solution heated under re?ux for 3 hours. The dibutyl ene ‘diazo derivative. 4. A process asv ‘claimed in claim 3 wherein the inert ether was removed under reduced pressure and the re 10 organic solvent is dibutyl ether and the heating under re sidue crystallised from methanol to give 3,8-acetoxy-6: l6 ?ux is carried out for 3 to 5 hours. dimethylpregna-S:l6-dien-20-one (I; R=Ac), plates, 5. 3?-hydroxy- and 35-acyloxy-6:16-dimethylpregna M.P. 158 to 160° C., [@1324 —41° (c., 0.654 in chloro 5: 16-dien-20-one form), Me A523? 251 my, e=8650 3 ?-hydroxy-6: 16-dimethylpregna-5 : 16-dien-20-one 15 (IZOMe (I; /\M_e R=H): The foregoing 3/3-acetoxy-6:16-dimethylpregna 5:16-dien-20-one (I; R=Ac) (2 gm.) was hydrolysed by heating under re?ux with potassium hydroxide (2 gm.) in methanol (80 ml.) and water (20 ml.) for 1 hour. Me _ R0 ' The mixture was poured into water and the precipitate 20 ?ltered off, washed with water, dried and crystallised Me (I) from methanol to give 3B-hydroxy-6:16-dimethylpregna 5:16-dien-20-one (I; R=H), plates, M.P. 148 to 149° C., 25 where R=H or an acyl group containing up to 10 carbon atoms. [aJD24 —99° (c., 0.292 in chloroform), 6. 3l3-hydroxy- and 3B-acyloxy-6-methyl-16:17-(2’:3’ R513? 251 to 253 mp, e 8806 diazacyclopent-2’-eno) -pregn-5-en-20-one Example 2 3ii-hydroxy-6: 16-dimethylpregna-5: 16-dien-20-one (I; R=H): Me 30 COMe 3/3 - hydroxy-6-methylpregna-5:16-dien-20-one (IV; R=H) (20 g.) was treated with an ethereal solution of diazomethane in the manner described in Example 1. The crude pyrazoline (III; R=H) thus obtained was dis solved in dibutyl ether (200 ml.) and the solution heated 35 under re?ux for 3 hours. After removal of the dibutyl ether, the residue was crystallised from methanol to give BO 3?éhydroxy-6: 16-dimethylpregna-5: 16-dien ZO-one, M.P. ‘148 to 149.0 (3., identical with a specimen prepared as ‘de scribed above. ‘T ' ‘ ' ' ' ‘ ' " We claim :' 1. 'A process for the preparation of 3?-hydroxy~ and 3,8}acyloxy-6: 16-‘dimethylpr‘egna-5: 16-dien-2'0-one which process comprises reacting the corréspondingBB-acyloxy Me ‘ atoms. “ 2. A process as claimed in claim 1 wherein the diazo~ ' ' References Cited in the ?le of this patent or‘ 3l8-hydroxy-6-methylpregna-5:16ldien-20—one with di ‘.15 2,888,457 azomethane to yield the corresponding 16a,17a-methyl ene diazo derivative and heating to thermally decompose said 1611,1704, methylene diazo derivative. (In) 40 where R=H or an aeyl group containing up to 19 carbon IJNITED STATES PATENTS Beyler et a1. ________ __ May 26, 1959 OTHER REFERENCES Journal of Chemical Society (1957), article by Burn et al., pages 40-94 relied on.