瑞舒地尔关键中间体的合成工艺改进和优化

Synthesis and condition optimization of key intermediate for ripasudil

以L-2-氨基-1-丙醇为原料,用邻硝基苯磺酰氯(NsCl)保护其氨基后,再与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保护基,生成瑞舒地尔关键中间体(S)-3-甲基-1-叔丁氧甲酰基-1,4-二氮杂环庚烷(Ⅰ)。改进后的工艺路线更为简短,易于操作,总收率提高到46.4%,手性异构体杂质HPLC含量<0.1%,已用于中试放大生产。

Key intermediate(S)-3-methyl-1-tert-butylcarbonyl-1, 4-diaza cyclic heptane(Ⅰ) for ripasudil was synthesized from intramolecular Mitsunobu cyclization reaction of intermediates, which was treated with tert-butoxyformyl(Boc) for secondary amine group protection and obtained from substitution reaction of 3-amino-1-propanol with L-2-amino-1-propanol, which was treated with o-nitrobenzenesulfonyl chloride for amino group protection and o-nitrobenzenesulfonyl group protection was later removed by dodecanthiol in the last step. The improved process, with reducing manufacturing time and easier operation, led to total yield increased up to 46.4% and chiral isomer impurity HPLC content less than 0.1%. This improved process had been upscaled for pilot production.