Patent GB-615798-A (GB)
Title: Improvements in or relating to imidazolido thiophanes and method of preparing same
Filed: 1946-08-08
Abstract: Imidazolido thiophanes of the general formula <FORM:0615798/IV(b)/1> wherein X is hydrogen or an aromatic or aliphatic radical and R and R1 represent hydrogen or N-aromatic or N-aliphatic substituted carbamidoalkyl radicals, are prepared by mixing a compound of the general formula <FORM:0615798/IV(b)/2> wherein X, R and R1 have the above significance, with a nitrite in the presence of an acid, e.g. hydrochloric acid, and a solvent, e.g. alcohol, The reaction is preferably effected by heating the mixture at a temperature of from about 60 DEG  to 100 DEG  C, from about half-an-hour to about three hours, Nitrous acid itself may be employed in the reaction or alkyl nitrites such as methyl, ethyl, amyl or amyl nitrite or salts of nitrous acid such as sodium, potassium or ammonium nitrite and an acid may be added during the course of the reaction, suitable starting materials are 2-(delta-carbanilidobutyl) -, 2 - (delta - methylcarbamidobutyl) - and 2 - (delta - ethylcarbamidobutyl-4 - uranilinothiophane - 3 - cis - carboxhydrazides, 2 - (delta - carbanilidobutyl) -, 2 - (delta-methylcarbamidobutyl) - and 2 - (deltaethylcarbamidobutyl) - 4 - methyluramidothiophane-3 - cis - carboxhydrazides, 3 - uranilinothiophane -, 3 - methyluramidothiophane -, 2-(delta - carbanilidobutyl) - 3 - uranilinothiophane - and 2 - (delta - carbanilidobutyl) - 3-methyluramido - thiophane - 3 - cis - carboxhydrazide, The imidazolido thiophanes having in the 2-position a carbamidobutyl or a substituted carbamidobutyl group can be heated with barium hydroxide to yield 2-(delta-carboxybutyl) - 3 : 4 - cis - diaminothiophane which when treated with phosgene gives dl-biotin, In examples: (1) 2-(delta-carbanilidobutyl) - 5 - keto - 6 - carbanilidoimidazololido [4, 5, c, cis] thiophane is prepared and by treatment with barium hydroxide and then sulphuric acid is converted to 2-(delta-carboxybutyl) - 3 : 4 - cis - diaminothiophane sulphate which on further treatment with potassium carbonate and phosgene yields dl-biotin; (2) 4 - carbanilido - 5 - ketoimidazolido [4, 5, c, cis] thiophane is prepared and by refluxing with hydrobromic acid is converted to cis-3 : 4-diaminothiophane dihydrobromide which on being treated with sodium bicarbonate and phosgene yields 5-ketoimidazolido [4, 5, c, cis] thiophane; (3) and (4) 2-(delta-carbanilidobutyl) - 5 - keto - 6 - carbanilidoimidazolido [4, 5, c, cis] thiophane is prepared,  2 - (delta - carbonilidobutyl) - 4 - uranilinothiophane - 3 - cis - carboxhydrazide is prepared from 2 - (delta - carbomethoxybutyl) - 3 - keto-4-carbomethoxythiophone by a synthesis which involves the preparation of the following intermediates (in order of preparation): 2-(delta - carbomethoxybutyl) - 3 - hydroxy - 3-cyano - 4 - carbomethoxythiophane, 2 - (delta-carbomethoxybutyl) - 3 - cyano - 4 - carbomethoxy - 4 : 5 - dihydrothiophene, 2 - (delta-carboxybutyl) - 4 : 5 - dihydrothiophene-3 : 4 - dicarboxylic acid, 2-(delta - carboxybutylthiophane) - 3 : 4 - trans - dicarboxylic acid, 2 - (delta - carbomethoxybutyl) - 3 : 4-trans - dicarbomethoxythiophane, 2 - (delta-carbomethoxybutyl) - 3 - carbomethoxythiophane - 4 - carboxylic acid, 2 - (delta - carboxybutyl) - 4 - uranilinothiophane - trans - 3 - carboxylic acid dimethyl ester, 2-(delta-carboxybutyl) - 4 - uranilinothiophane - trans - 3-carboxylic acid, 3 - phenyl - 6 - (delta - carboxybutyl) - 5 : 6 : 8 : 9 - tetrahydrothieno [3, 4, c, cis] uracil, 3-phenyl-6-(delta-carbanilidobutyl) - 5 : 6 : 8 : 9 - tetrahydrothieno [3, 4, c, cis] uracil and then by treatment with hydrazine hydrate the desired 2-(delta-carbanilidobutyl)-4 - uranilinothiophane - cis - 3 - carboxhydrazide is obtained.