Patent GB-685362-A (GB)
Title: Processes relating to the production of 3, 9-epoxy steroid compounds
IPC: C07J75/00
Filed: 1948-02-27
Abstract: Compounds of the formula <FORM:0685362/IV (b)/1> where R is -COOX, -CH(CH3)-COOX, -CH(CH3)-CH2-COOX or -CH(CH3)-CH2-CH2-COOX, X being hydrogen or a C1-C6 alkyl group (produced by treating the corresponding 12-alkoxy compounds with halogen acids), are treated in organic solution with a base to form epoxides <FORM:0685362/IV (b)/2> halogen is added across the double bond of the latter at low temperature and the resulting 11 : 12-dihalogen compound is treated with an oxidizing agent to give the 11-keto-12-halogen compound; finally the halogen is replaced by hydrogen by the action of zinc and acetic acid giving a 3 : 9-epoxy-11-keto-steroid.  If desired the epoxy ring may then be opened (by concentrated hydrohalic acid) and/or the side chain degraded by the usual methods.  Details are given of the following reactions: Desoxycholic acid is esterified with methanol and acetylated in the 3-position.  The 12-hydroxy group is then oxidized to a keto group and the product (1) hydrolysed in alkaline solution to 3(a ) - hydroxy - 12 - keto - cholanic acid, or (2) oxidized with selenium dioxide and hydrolysed to give 3(a )-hydroxy-12-keto-9 : 11-cholenic acid.  In these reactions any aliphatic or aromatic acyl group stable to chromic acid may be used to protect the 3-hydroxyl, e.g. benzoyl or succinyl or phthalyl semi-ester.  The keto-cholenic acid is esterified with methanol, catalytically hydrogenated to give the 12-hydroxy compound, diacetylated for purification and finally hydrolysed to yield 3(a ) : 12-dihydroxy-9 : 11-cholenic acid.  The methyl ester of this acid is methylated in the 12-position and the product treated with concentrated hydrochloric acid to give methyl 3(a ) - hydroxy - 12 - chloro - 9 : 11 - cholenate as starting material for the process of the invention.  Treatment with sodium bicarbonate gives methyl 3 : 9-epoxy-11 : 12-cholenate (which may if desired be hydrolysed to the free acid) followed by bromination to yield two stereo-isomeric methyl 3 : 9-epoxy-11 : 12-dibromocholanates (yield of desired isomer increased by debromination with zinc and rebromination).  The dibromoester is then oxidized with chromium trioxide and silver chromate to the 11-keto-12-bromo-ester and debrominated with zinc and acetic acid to give methyl 3 : 9-epoxy-11-ketocholanate.  Similar reactions may be carried out with compounds containing other side chains in the 17-position, or the existing side chain may be degraded, e.g. by the Wieland-Barbier method.  The epoxy ring may be opened before or after degradation.  Thus methyl 3 : 9-epoxy-11-ketocholanate is converted successively into 3 : 9-epoxy-11-ketonorcholanyl - diphenylcarbinol, 3 : 9-epoxy - 11 - keto - bisnorcholanyl - diphenylethylene, 3 : 9 - epoxy - 11 - ketonorcholanic acid (and methyl ester), 3 : 9-epoxy-11-ketobisnorcholanyl-diphenylcarbinol, 3 : 9 - epoxy-11 - ketopregnanyl - diphenylethylene, 3 : 9-epoxy - 11 - keto - bisnorcholanic acid (and methyl ester), 3 : 9-epoxy-11-ketopregnanyl-diphenylcarbinol, 3 : 9 - epoxy - 11 - ketomethyletiocholanyl - diphenylethylene, 3 : 9-epoxy - 11 : 20 - pregnanedione and 3 : 9-epoxy - 21 - benzal - 11 : 20 - pregnanedione which is ozonized and oxidized to 3 : 9-epoxy-11 - keto - etiocholanic acid (converted into methyl ester). Alternatively, the 3 : 9-epoxy-11 - keto - bisnorcholanyl - diphenylethylene is treated with selenium dioxide to introduce a 22-hydroxyl which is dehydrated to 3 : 9-epoxy - 11 - keto - 24 : 24 - diphenyl - 20 : 22 : 23 : 24-choladiene which can be oxidized directly to 3 : 9-epoxy-11 : 20-pregnanedione.  Similarly, the diphenyl-ethylene derivative can be treated with N-bromosuccinimide.  For opening the epoxide ring, methyl 3 : 9-epoxy-11-keto-cholanate is treated with acetic anhydride and hydrogen bromide giving methyl 3(a ) - acetoxy - 11 - keto - 12 - bromocholanate which is hydrolysed to the 3-hydroxy compound, bromine replaced by hydrogen and the product hydrolysed to the free acid. The 3-acetylation may be omitted but sometimes a 3 : 12-dibromo-derivative results.  In the same way the epoxy ring of 3 : 9-epoxy-11-keto - bisnorcholanyl - diphenylethylene may be opened. The starting material for the invention may also be made from 3(a )-hydroxy-11 : 12-dibromocholanic acid via 3(a ) : 12-dihydroxy-9 : 11-cholenic acid and methyl 3(a )-hydroxy-12-methoxy-9 : 11-cholenate.  According to the Specification as open to inspection under Sect. 91, the 3 : 9-epoxide ring can be formed similarly in all compounds where R in the formula is hydrogen or a monovalent group. Details are given of the degradation of the side-chain after opening the epoxide ring.  Thus 3(a )-acetoxy-11-keto-12-bromo - bisnorcholanyl - diphenylethylene is treated successively with N-bromosuccinimide and sodium acetate to give 3(a )-acetoxy-11-keto - 12 - bromo - 24 - diphenyl - 20 : 22 : 23 : 24-choladiene which is oxidized to 3(a )-acetoxy-12 - bromo - 11 : 20 - pregnanedione. Similarly, 3(a ) - hydroxy - 11 : 20 - pregnanedione is converted into its benzal derivative and ozonized and oxidized to 3(a )-hydroxy - 11-keto-etiocholanic acid.  Dehydrocorticosterone is prepared from the acetyl derivative of the latter via the acid chloride, 3(a )-hydroxy-21-diazo - 11 : 20 - pregnanedione, 3(a ) - hydroxy-21 - acetoxy - 11 : 20 - pregnanedione and 21-acetoxy - 3 : 11 : 20 - pregnanetrione; the 4 : 5-double bond is introduced by bromination followed by dehydrobromination.  This subject-matter does not appear in the Specification as accepted.