Study On The Synthesis Of Biotin Intermediate

In order to solve the environmental and safe problems in the fumaric acid synthesis route which need Thio reaction and Grignard reaction,and discover economical and green synthetic process,in this study,the synthesis of biotin intermediate(Z)-5-[(3aS,6aR)-1,3-dipenzyl-2-oxo-Hexahydro-4H-thieno[3,4-d]imidazole-4-alkenyl]-pentanoic acid(Target product)was optimized according to the currently used and of other proposed technologies which use L-cysteine hydrochloride as the starting material.The effects of molar ratio of raw materials,reaction temperature,reaction time and stirring rate were investigated in detail.At the same time,some auxiliary raw materials substituted for conventional reagents which can simplify the synthesis method of biotin and make the reaction more simple and stable.The results showed that by adopting multi-step oxidization,the best synthetic technique was as follows: Firstly the intermediate(7RS,7AR)-3-phenyl-6benzyl-7-(5-carboxypentanol)-7,7adihydro-1H,3H-imidazo[1,5-c]-thiazol-5,(6H)-one ? was synthesized from(3S,7S,7AR)-6benzyl-7-(2-oxocyclohexyl)-3-phenyltetrahydro-5H-imidazo[1,5-c][1,3]thiazol-5-one with 40% peracetic acid as oxidant in NaOH methanol solution at-10 ?;and then 3.7% NHPI was oxidized with pure oxygen in acetonitrile solution to obtain the intermediate(7RS,7AR)-3-phenyl-6benzyl-7-(5-carboxypentanoyl)-7,7a-dihydro-1H,3H-imidazo-5,(6H)-one ?;finally the reaction was maintained 16 h at 100 ? in mixed solvents containing 3-fold zinc powder and 10-time acetic acid and piperdine to obtain the target product.The total yield coefficient can reach 58.4% by the use of these optimal steps which will provide critical information useful for the industrial synthesis of biotin.It is feasible to substitute 40% peracetic acid for peroxybenzoic acid after the optimization.The most important thing is one-step synthesis of(5Z)-5-[(3aS,6aR)-1,3-dipenzyl-2-oxo-Hexahydro-4H-thieno[3,4-d] imidazole-4-alkenyl]pentanoic acid was realized from the intermediate(7RS,7AR)-3-phenyl-6benzyl-7-(5-carboxypentanoyl)-7,7a-dihydro-1H,3H-imidazo-5,(6H)-one ?.Furthermore,this reaction process is very simple without esterification and saponification.