生物素中间体合成的研究
发布时间：2018-07-25 16:08
【摘要】：为解决富马酸合成路线需要硫代和格氏反应在环保、安全上面临的挑战,寻找更加绿色的合成工艺,本论文对目前公开的以L-半胱氨酸盐酸盐为起始原料合成生物素中间体(5Z)-5-[(3aS,6aR)]-1,3-二苄基-2-酮基-六氢-4H-噻吩并[3,4-d]咪唑-4-烯基]-戊酸(4)的工艺路线进行了优化研究,主要研究了投料比、反应温度、反应时间、搅拌速度等参数对反应的影响;同时将一些辅料进行了常规试剂的替换,对原工艺进行了简化,使反应变得更加简单稳定。实验结果表明,采取分步氧化法的最佳合成工艺是:用40%的过氧乙酸作为氧化剂在NaOH甲醇溶液中,反应温度为-10℃,氧化(3S,7S,7aR)-3-苯基-7-(2-酮基环己基)-咪唑并[1,5-c]噻唑-5(1H,3H,6H)-酮(1),得到6-[(3S,7S,7aR)-3-苯基-5-酮基-6-苄基-四氢咪唑并[1,5-c]噻唑-7-基]-6-羟基己酸(2),然后用3.7%wt 6-[(3S,7S,7aR)-3-苯基-5-酮基-6-苄基-四氢咪唑并[1,5-c]噻唑-7-基]-6-羟基己酸(2)量的N-羟基邻苯二甲酰亚胺在乙腈溶剂中使用纯氧气常压进行氧化得到6-[(3S,7S,7aR)-3-苯基-5-酮基-6-苄基-四氢咪唑并[1,5-c]噻唑-7-基]-6-酮基己酸(3),再用3倍摩尔量的锌粉,10倍乙酸和哌啶混合溶剂,在100℃条件下反应16 h,一步反应得到(5Z)-5-[(3aS,6aR)]-1,3-二苄基-2-酮基-六氢-4H-噻吩并[3,4-d]咪唑-4-烯基]-戊酸(4),总收率可以达到58.4%。优化后的合成工艺能为生物素的工业化合成提供新的方法,通过改进,氧化试剂可以使用较为常规的40%过氧乙酸代替过氧苯甲酸;真正实现了从6-[(3S,7aR)-3-苯基-5-酮基-6-苄基-四氢-1H-咪唑并[1,5-c]噻唑-7基]-6-酮基己酸(3)到(5Z)-5-[(3aS,6aR)-1,3-二苄基-2-酮基-六氢-4H-噻吩并[3,4-d]咪唑-4-烯基]-戊酸(4)的一步合成,并省去了酯化和皂化反应以及后处理,简化了操作过程。
[Abstract]:In order to solve the challenge of thio- and Grignard reaction in environmental protection and safety in order to solve the synthesis route of fumaric acid, a greener synthetic process is sought. In this paper, the process of synthesizing biotin intermediate (5Z) -5- [(3aSh 6aR)] -1o 3-dibenzyl-2-keto-hexahydro-4H-thiopheno [34-d] imidazole-4-enyl] -pentanoic acid (4) from L- cysteine salt was studied. The effects of reaction temperature, reaction time and stirring speed on the reaction were also discussed, and some excipients were replaced by conventional reagents, the original process was simplified to make the reaction more simple and stable. The experimental results show that the optimum synthesis process is that 40% peracetic acid is used as oxidant in NaOH methanol solution, and the reaction temperature is -10 鈩，
本文编号：2144346
[Abstract]:In order to solve the challenge of thio- and Grignard reaction in environmental protection and safety in order to solve the synthesis route of fumaric acid, a greener synthetic process is sought. In this paper, the process of synthesizing biotin intermediate (5Z) -5- [(3aSh 6aR)] -1o 3-dibenzyl-2-keto-hexahydro-4H-thiopheno [34-d] imidazole-4-enyl] -pentanoic acid (4) from L- cysteine salt was studied. The effects of reaction temperature, reaction time and stirring speed on the reaction were also discussed, and some excipients were replaced by conventional reagents, the original process was simplified to make the reaction more simple and stable. The experimental results show that the optimum synthesis process is that 40% peracetic acid is used as oxidant in NaOH methanol solution, and the reaction temperature is -10 鈩，
本文编号：2144346
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