富马酸经溴加成,对甲氧基苄胺化保护,三光气闭环及脱水反应制得(3aS,6aR)-1,3-双(4-甲氧苄基)-二氢-1H-呋喃并[3,4-d]咪唑-2,4,6(6aH)-三酮(12),12经奎宁催化不对称醇解、高区域选择性还原,硫代反应制得(+)-生物素关键中间体(3aS,6aR)-1,3-双(4-甲氧苄基)-四氢-1H-噻吩并[3,4-d]咪唑-2,4-二酮,总收率44%。 (3aS, 6aR) -1,3-bis (4-methoxybenzyl) -dihydro-1H-1,2-benzisothiazole was obtained by bromine addition of fumaric acid, amination of methoxybenzylamine and cyclization of triphosgene. (+) Is obtained by catalytic asymmetric alcoholysis of quinine, selective reduction with high selectivity and thio-reaction with furo [3,4-d] imidazole-2,4,6 (6aH) - biotin key intermediate (3aS, 6aR) -1,3-bis (4-methoxybenzyl) -tetrahydro-1H-thieno [3,4- d] imidazole-2,4- Yield 44%.