瑞舒地尔关键中间体的合成工艺改进和优化

Synthesis and process optimization of key intermediate of ripasudil

摘要:

以L-氨基丙醇（2）为原料，采用邻硝基苯磺酰氯保护，与3-氨基-1-丙醇进行取代反应，仲氨用叔丁氧甲酰基(Boc)保护后，经分子内Mitsunobu环合反应，用十二硫醇脱去邻硝基苯磺酰基保护基，生成瑞舒地尔关键(S)- 3-甲基-1,4-二氮-1-叔丁氧羰基（1），改进后的工艺路线更为简短，易于操作，总收率从原文献的19%提高到47%，手性异构体杂质含量低于0.1%，已用于中试放大生产。

Abstract:

Using L-aminopropanol (2) as raw material, it was protected by o-nitrobenzenesulfonyl chloride, and substituted with 3-amino-1-propanol, the secondary ammonia was protected with tert-butoxyformyl (Boc). After intramolecular Mitsunobu cyclization reaction, o-nitrobenzenesulfonyl protector was removed with dodecanthiol to produce Ripasudil key intermediate (S)- 3-methyl-1, 4-diazo-1-tert-butylcarbonyl (1). The improved process is shorter and easier to operate, the total yield is increased from 19% to 47%, and the chiral isomer impurity content is less than 0.1%. This improved route has been used in pilot scale production.