Patent GB-453773-A (GB)
Title: Process for the manufacture of cholenic acid or its lower homologues and their derivatives
IPC: C07J75/00
Filed: 1935-03-14
Abstract: Cholenic acid, its lower homologues and derivatives thereof having the general formula <FORM:0453773/IV/1> where X represents either CH(CH3).CH2.CH2. COOH or CH(CH3).CH2.COOH or CH(CH3).COOH and R is either an (OH) group, or a group which on hydrolysis is convertible into an OH group are prepared by subjecting sterols containing at least a double bond in the nucleus of their cyclopentanopolyhydrophenanthrene system to the action of oxidizing agents capable of splitting single carbon to carbon bonds, and isolated from the acid fraction of the oxidation product.  The nuclear double bond of the sterol is preferably protected during the oxidation by treatment with halogen or hydrohalic acid and the double bond reestablished by treatment with zinc dust, sodium amalgam metallic nickel in the case of halogen protection, or by potassium hydroxide or pyridine in the case of hydrohalic acid protection. This treatment may take place either on the entire acid fraction or on the separated individual acids.  The hydroxyl group of the sterol may also be protected during oxidation by transformation into a group which on hydrolysis can be reconverted into the hydroxyl group.  The isolation of the individual acids from the acid fraction of the oxidation is effected by treatment with compounds capable of forming insoluble salts with the cholenic acids such as alkali salts. Alternatively, the entire acid fraction may be subjected to fractional recrystallization from solvents such as acetone or glacial acetic acid.  Alternatively, the entire acid fraction may be subjected to fractional distillation or sublimation in a high vacuum. Finally, the acid fraction may be esterified by means for instance of diazomethane and the esters so obtained may be subjected to fractional crystallization, sublimation, or distillation.  In examples: (1) cholesterol acetate dibromide is oxidized with chromic acid, the alkali salts separated, decomposed with acid, debrominated with zinc dust and the 3-acetoxy cholenic acid separated and saponified to give 3-hydroxy-cholenic acid; (2) sitosterol acetate-dibromide is oxidized with chromic acid, and worked up as in example (1) to give 3-hydroxy-norcholenic acid; (3) the oxidation mixture obtained by the action of chromic acid on stigmasterol acetate dibromide, is debrominated, and then the alkali salts precipitated, followed by working up as in example (1) to give 3-hydroxy-bisnorcholenic acid; (4) phytosterol acetate, having its nuclear double bond protected by bromine is oxidized with chromic acid, debrominated with zinc dust, the alkali salts precipitated, separated and decomposed by acid.  The mixture of acids so obtained is separated by treatment with a methyl alcoholic solution of barium hydroxide to yield 3-hydroxy norcholenic acid, and 3-hydroxy-bisnorcholenic acid; (5) the product obtained by oxidizing cholesterol acetate dibromide with chromic acid followed by debromination with zinc dust is treated with methyl alcoholic barium hydroxide, then esterified with diazo methane and the product worked up to give on acetylation 3-acetoxy cholenic acid methyl ester and 3-acetoxy-norcholenic acid methyl ester; (6) cholesterol acetate dibromide is oxidized with chromic acid, debrominated with zinc dust and the product after purification directly crystallized from acetone.  3 - Acetoxy - cholenic acid crystallizes first followed by 3 - acetoxy norcholenic acid on the addition of acetic acid; (7) the chromic acid oxidation product of cholesterol acetate dibromide is treated with zinc dust, the alkali salts formed and the 3-acetoxy cholenic acid separated and purified by diazomethane.  In place of the 3-acetyl sterols, the corresponding benzoyl, succinyl, phthaloyl or other acyl compounds, or the methyl ethyl and the like ethers may be employed.  Specification 449,379 is referred to.