Patent GB-1188167-A (GB)
Title: Process for the Preparation of 9alpha-Halogeno-11beta-Substituted Steroids
IPC: C07J1/00
Filed: 1967-05-19
Abstract: 1,188,167. Preparation of 9α-halogeno-11#- substituted steroids. SCHERICO Ltd. 19 May, 1967 [23 May, 1966], No. 23457/67. Heading C2U. The invention comprises a process in which a 9α-halo-11#-X-steroid, wherein X is a leaving group, i.e. a group capable of leaving the 11- carbon atom together with the electrons by which it was bound to it, is treated with an ionized or ionizable reagent YZ, wherein Y is a moiety sufficiently nucleophilic to replace X and is capable of forming an anion Y- and Z is the remainder of the reagent whereby X is replaced by Y and a 9α-halo-11#-Y-steroid is formed. X cannot be iodo when the 9-substituent is iodo. Suitable leaving groups include halo, hydrocarbonsulphonyloxy, alkyl- and aryl-carbonyloxy, -OSO 3 R<SP>1</SP> (R<SP>l</SP>=alkyl, aryl), -OSOCl and OPCl 2 . Z is preferably H, NH 4 , or an alkali or alkaline earth metal and Y is preferably OH, N 3  or halo, but may also be, for example, CN, O alkyl, phosphato, NH 2  which may be substituted, SH, S alkyl and S aryl. In a preferred process a 9α-halo-11#-halo (e.g. Cl) or -hydrocarbonsulphonyloxy steroid is treated with water to give the 11#-ol. In this process an esterified 21-hydroxy group, e.g. a phosphate, alkyl carbonate or alkanoate, in a corticoid side chain may remain intact or may be partly hydrolysed by, for example, the HCl liberated. In the process of the invention a polar solvent is preferably used. If this is a hydroxylic solvent, e.g. water, it may also serve a dual role, as solvent and reagent YZ. Suitable temperatures and pH values are usually in the ranges of 30 to 75 C. and 4 to 8À5 respectively. When the moiety Y is N 3 , the preferred solvent is aqueous methanol, and the 11#-azido product is accompanied by some 11#-ol. This solvent is also preferred when an 11#-sulphonyloxy group is to be replaced by a halogen, e.g. using an alkali metal halide, and may also be used in the conversion of a 9α,11#-dibromo-steroid to the 9α-bromo-11#-chloro compound using, e.g. NaCl . In general, the starting steroid may contain any of the usual substituents and double bonds elsewhere in the molecule. Examples illustrate the above processes, and the hydrolysis and esterification of 21-esters and free 21-ols respectively. 9α - Halo - 11# - p - toluenesulphonyloxysteroids used as starting materials are prepared from the corresponding #<SP>9(11)</SP>-dehydro steroids, p-toluenesulphonic acid in pyridine and N-halosuccinimides. 9α - Bromo - 11# - chloro - 16α - methyl - 1,4- pregnadiene - 17α,21 - diol - 3,20 - dione 21 - disodium phosphate is prepared by hydrolysing 16α - methyl - 1,4,9(11) - pregnatriene - 17α,21- diol - 3,20 - dione 21 - ethoxycarboxylate to the 21-ol, converting this to the 21-methanesulphonate, this to the 21-iodo compound and this to the 21-phosphate, converting this to 9α - bromo - 11# - chloro - 16α - methyl 1,4 - pregnadiene - 17α,21 - diol - 3,20 - dione 21 - phosphate and converting this to the required disodium salt. 16α - Methyl - 1,4,9(11) - pregnatriene - 17α,21- diol - 3,20 - dione 21 - ethoxycarboxylate is prepared from the 21-ol and ethylchlorocarbonate. Other alkoxycarboxylates are prepared similarly.