摘要
通过Zn/TiCl4、H4AlLi/TiCl4、Zn Cu/TiCl3低价钛催化剂比较,选择了稳定的Zn Cu/TiCl3为催化剂,反应制得生物素中间体(6aR) 1,3 二苄基 4 (4 甲氧羰基丁基) 二氢 噻吩并[3,4 d]咪唑 2 酮(Ⅵ)。改用异氰酸苄酯为关环试剂环化合成了(7aR) 3 苯基 6 苄基 1H,3H 咪唑并[1,5 c]噻唑 5,7 二酮(Ⅲ),选用CH3COOH/(CH3CO)2O代替CH3COOH作溶剂,反应时间由17h缩短为3h,产率从75%提高到93%。以L 半胱氨酸盐酸盐为原料,依次以苯甲醛、异氰酸苄酯为关环试剂环化合成Ⅲ,以锌为还原剂于90℃下开环合成了N,N′ 二苄基 L 巯基海因(Ⅳ),经与己二酸单甲酯酰氯于0℃下的酯化反应引入侧链,Zn Cu/TiCl3为催化剂,反应得到Ⅵ,5步反应建立了生物素所需骨架结构,总产率达56%。
A stable Zn-Cu/TiCl_3 system is applied,after being compared with other Mcmurry catalyst systems,to prepare (6aR)-1,3-dibenzyl-4-(4-methoxycarbonylbutyl)-dihydro-thieno[3,4-d] imidazole-2-one(Ⅵ) as a precursor to d-biotin.By treatment of (4R)-carboxy-(2S)-phenylthiazolidine(Ⅱ) with isocyanic acid benzyl ester in CH_3COOH/(CH_3CO)_2O system,the reaction time is shortened from 17 h to 3 h,and the yield of (7aR)-3-phenyl-1H,3H-imidazo[1,5-c] thiazole-(6H, 7aH) 5,7-dione(Ⅲ) is raised from 75% to 93%.Thus,from L-cysteine hydrochloride by treatment with benzaldehyde and isocyanic acid benzyl ester sequentially,Ⅲ is formed and converted into N, N′-dibenzyl-mercaptomethylhydatoin (Ⅳ) via reduction with zinc at 90 ℃.The carboxybutyl chain of biotin is introduced via esterification of Ⅳ with monomethyl adipate chloride to form a compound Ⅴ.Reaction of Ⅴ with Zn-Cu/TiCl_3 system gives readily Ⅵ,and the requisite biotin skeletal structure is established.Overall yield of the five steps reaches 56%.
出处
《精细化工》
EI
CAS
CSCD
北大核心
2005年第2期133-134,148,共3页
Fine Chemicals
