Patent GB-883711-A (GB)
Title: Improvements in or relating to steroids and the manufacture therefor
IPC: C07J5/00
Filed: 1958-05-21
Abstract: The invention comprises 11b ,17a -dihydroxy-11a - lower alkyl-pregnane-3,20-dione in which the lower alkyl group contains 1 to 8 carbon atoms, and the preparation thereof by ketalizing 17a -hydroxy-pregnane-3,11,20-trione to form 17a  - hydroxy - pregnane-3, 11, 20 - trione 3, 20 - bis ketal, reacting this compound with a lower alkyl lithium to form 11b ,17a -dihydroxy-11a -lower alkyl-pregnane-3,20-dione 3,20-bis ketal, and hydrolysing this compound e.g., with hydrochloric acid, and by reacting pregnane-3,11,20-trione 3,20-diketal with a lower alkyl lithium to form 11b -hydroxy-11a -lower alkyl-pregnane-3,20-dione 3,20-diketal, hydrolysing this compound to form 11b -hydroxy-11#-lower alkyl-pregnane-3,20-dione and then introducing the 17a -hydroxy group either microbiologically with Cephalothecium roseum, or by halogenating with a molar equivalent of chlorine or bromine to form 4-chloro (or bromo)-11b -hydroxy-11a -methyl-pregnane-3,20-dione, dehydro-halogenating this compound with semicarbazide and pyruvic acid to form 11b -hydroxy-11a -lower alkyl-4-pregnene-3,20-dione, diglyoxylating this compound with methyl or ethyl oxalate and an alkali-metal alkoxide to produce a 2,21-dialkoxy-oxalyl-11b -hydroxy - 11a  - lower alkyl - 4 - pregnene - 3, 20 - dione alkali metal dienolate, trichlorinating or tribrominating this compound to form a 2,21,21-trichloro (or tribromo)-11b -hydroxy-11a -alkyl-4-pregnene-3,20-dione, treating this compound with an alkali metal alkoxide to produce a 2-halo-3-keto - 11b  - hydroxy - 11a  - lower alkyl - 4, 17(20) - cis-pregnadien-21-oic acid alkyl ester, dehalogenating this compound e.g., with zinc and acetic acid, to form 3-keto-11b -hydroxy-11a -lower alkyl-4,17(20)-cis-pregnadien-21-oic acid alkyl ester, converting this compound to an enamine derivative, i.e. 3-keto-11b -hydroxy-11a -lower alkyl-4,17(20)-cis-pregnadien-21-oic acid alkyl ester 3-enamine, reducing this compound with lithium aluminium hydride to form 3-keto-11b ,21-di-hydroxy - 11a  - lower alkyl - 2, 4, 17 (20) - cis - pregnadien-3-one 3-enamine, hydrolysing this compound to form 3-keto-11b ,21-dihydroxy-11a -alkyl-2,4,17(20) -cis-pregnadien-3-one, esterifying this compound to form the corresponding 21-acylate, oxidative hydroxylating the 21-acylate with osmium tetroxide and hydrogen peroxide, with an amine oxide peroxide or with phenyl iodoso acetate forms 11b ,71a ,21-trihydroxy-11a -alkyl-4-pregnene-3,20-dione, hydrolysing this compound forms 11b ,17a ,21-trihydroxy-11a -alkyl-4-pregnene-3,20-dione, tosylating this compound to form the corresponding 21-tosylate, treating the 21-tosylate with sodium iodide to form 11b , 17a  - dihydroxy - 11a - lower alkyl - 21 - iodo-4-pregnene-3,20-dione, reducing this compound with zinc dust to form 11b ,17a -dihydroxy-11a -alkyl-4-pregnene-3,20-dione, and hydrogenating this compound, e.g., in the presence of a palladium catalyst.  In all the above processes the preferred lower alkyl lithium is methyl lithium so that all intermediate and final products contain 11a -methyl group.  The di-ketal group may be a bis ethylene ketal group.  Detailed examples are given. Specifications 738,311, 743,484, 761,490, 761,527, 761,528, 771,344, 779,002, 781,782, 829,476 and 873,605 are referred to.