依度沙班(1)是口服凝血因子X a(F X a)抑制剂,临床上主要用于治疗接受下肢整形外科术后并发的静脉血栓栓塞.根据逆合成分析,1主要由3个关键中间体组成,分别为[(1R,2S,5S)-2-氨基-5-(二甲基氨基甲酰基)环己基]氨基甲酸叔丁酯(2),5-甲基-4,5,6,7-四氢噻唑并[5,4-c]吡啶-2-羧酸(3),2-[(5-氯吡啶-2-基)氨基]-2-氧代乙酸乙酯(4).其中,2的顺环己二胺片段和3的噻唑环片段合成难度较高.文章归纳整理了以叠氮盐(酯)、光延反应、Burgess试剂和其他起始原料合成顺环己二胺片段的方案,以单氰胺和硫磺、Asinger反应、格氏试剂和三氯乙酮盐合成噻唑环片段的方案,并简要点评了相应的优缺点.
Abstract
Edoxaban(1),an oral inhibitor of coagulation factor X a(F X a),is clinically used for the treatment of venous thromboembolism complicated by undergoing orthopaedic surgery of the lower limbs.According to retrosynthetic analysis,1 is mainly composed of three key intermediates,namely tert-butyl[(1R,2S,5S)-2-amino-5-(dimethylcarbamoyl)-cyclohexyl]carbamate(2),5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid(3),and 2-[(5-chloropyridin-2-yl)amino]-2-oxoethyl acetate(4).Among them,the synthesis of the ciss-cyclohexanediamine fragment of 2 and the thiazole ring fragment of 3 is more difficult.The paper summarizes the schemes for the synthesis of ciss-cyclohexanediamine fragments by azide salts(esters),photo-extension reaction,Burgess reagent and other starting materials,and the synthesis of the thiazole ring fragment by monocyanine and sulphur,Asinger reaction,Grignard reagent and trichloroacetophenonium salts,and briefly comments on the corresponding advantages and disadvantages.
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