申请人:Chawla Harmander Singh Pal
公开号:US20090182148A1
公开(公告)日:2009-07-16
An improved process for the manufacture of 1-[[[(1R)-1-[3-[(1E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropane acetic acid, sodium salt [montelukast sodium(I)]. It consists of converting a vital intermediate 1-(mercaptomethyl)-cyclopropane acetic acid of formula IX, to a quaternary ammonium salt of formula X, using a suitable base in a suitable solvent at 0° C. to 50° C. followed by monometalation to provide an intermediate of formula XI and subsequent condensation of XI with 2-[2-[3-(S)-[3-[2-(7-chloro-2-quinolinyl)-ethenyl]phenyl]-3-methanesulphonyloxypropyl]phenyl]-2-propanol at 0 to −50° C. to afford 1-[[[(1R)-1-[3-[(1E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropane acetic acid as the quaternary ammonium salt which is filtered, purified by crystallization from a suitable solvent and finally treated with a sodium base in a suitable solvent to generate montelukast sodium which is isolated by trituration with an antisolvent. The invention provides a convenient process for preparing montelukast sodium (I) in good yields and purities.
一种改进的制备1-[[[(1R)-1-[3-[(1E)-2-(7-氯-2-喹啉基)乙烯基]苯基]-3-[2-(1-羟基-1-甲基乙基)苯基]丙基]硫]甲基]环丙烷乙酸钠盐[蒙特卢卡斯钠(I)]的方法。该方法包括将公式IX的关键中间体1-(巯基甲基)-环丙烷乙酸转化为公式X的季铵盐,使用适当的碱在适当的溶剂中在0℃至50℃下进行单金属化反应,形成公式XI的中间体,然后在0℃至-50℃下将XI与2-[2-[3-(S)-[3-[2-(7-氯-2-喹啉基)-乙烯基]苯基]-3-甲磺酰氧基丙基]苯基]-2-丙醇进行缩合反应,得到以季铵盐形式存在的1-[[[(1R)-1-[3-[(1E)-2-(7-氯-2-喹啉基)乙烯基]苯基]-3-[2-(1-羟基-1-甲基乙基)苯基]丙基]硫]甲基]环丙烷乙酸,该季铵盐经过过滤、从适当的溶剂中结晶纯化,最后在适当的溶剂中使用钠碱生成蒙特卢卡斯钠,通过与抗溶剂混合物进行沉淀分离。该发明提供了一种方便的制备蒙特卢卡斯钠(I)的方法,产率和纯度均较高。