GB608969A - Biotin and its analogues and methods for obtaining the same - Google Patents

Abstract

Biotin and its analogues (21-keto-3,4-imidazolido-2-o -substituted alkyl thiophenes) are made by hydrogenating, in the presence of a sulphide of p molybdenum, nickel, cobalt, tin or iron, a compound of formula <FORM:0608969/IV(b)/1> where n=1 to 8 and the alkylene residue -CnH2nis straight or branched, and where R1 is -COOH, -COOM, -COOR1, alkoxy, aralkoxy or aryloxy, R1 being lower alkyl and M representing a salt-forming group or metal such as sodium or other alkali metal, alkaline earth metal, ammonium or substituted ammonium. The reaction may be carried out in a solvent consisting of dioxane, a lower monohydroxy or polyhydroxy alcohol, or their lower molecular weight ethers. In examples: (1) a mixture of 2,3,4,5-tetradehydrobiotin, dioxane and molybdenum trisulphide-alumina gel catalyst is hydrogenated to yield dl-biotin; (2) a mixture of 21-keto-3,4-imidazolido-2-g -phenoxypropylthiophene, alcohol and molybdenum trisulphide-alumina gel catalyst is hydrogenated to yield mainly 21-keto-3,4-imidazolido-2-g -cyclohexyloxypropyl - tetrahydrothiophene. Similarly, a compound of the formula <FORM:0608969/IV(b)/2> is obtained by hydrogenating 21-keto-3,4-imidazolido-2-g -benzyloxypropylthiophene. 2,3,4,5-Tetradehydrobiotin is prepared by the following series of reactions: Ethyl 3-chloropropyl malonate, obtained from trimethylene chlorobromide and ethyl malonate, is converted to ethyl 5-chloro-valerate by hydrolysis, decarboxylation and esterification, and is then combined with ethyl malonate to give ethyl pentane-1,1,5-tricarboxylate. Hydrolysis, treatment with sulphuryl chloride, and heating to decarboxylate at the 1-carbon atom gives a -chloropimelic acid which, by reacting with the sodium salt of b -mercaptopropionic acid and esterifying, is converted to 2-carbethoxyethyl-11,51-dicarbethoxyamyl sulphide. Cyclization by the Dieckmann reaction gives ethyl - 4 - carbethoxy - 3 - keto - tetrahydrothiophenevalerate which is converted through its oxime to ethyl 3-amino-4-carbethoxyl-2-thiophenevalerate by treatment with dry HCl followed by decomposition of the resulting amine hydrochloride. The di-ester is selectively hydrolysed to 3 - amino - 4 - carbethoxy - 2 - thio - phenevaleric acid which by treatment with benzoyl chloride followed by Curtius degradation through the hydrazide and azide, and refluxing of the azide with alcohol, gives 3 - benzoylamino - 4 - carbethoxyamino - 2 - thio - phenevaleric acid. This is hydrolysed to the free diamine and treated with phosgene to give 2,3,4,5-tetradehydrobiotin. 21 - Keto - 3,4 - imidazolido - 2 - g - phenoxypropyl-thiophene is prepared from diethyl ester of g -phenoxypropylmalonic acid by the same series of reactions as shown for ethyl pentane-1,1,5-tricarboxylate above.