摘要
本研究对孟鲁司特钠(1)的合成工艺进行了优化。2-[(3S)-[3-[2-(7-氯-2-喹啉基)乙烯基]苯基]-3-羟基丙基]-苯甲酸甲酯(2)与甲基氯化镁反应后,经甲基磺酰氯转化羟基得2-[2-[(3S)-[3-[2-(7-氯-2-喹啉基)乙烯基]苯基]-3-(甲基磺酰氧基)丙基]苯基]-2-丙醇(4),4不经纯化,直接与1-(巯甲基)环丙乙酸二钠盐在四丁基溴化铵催化下发生取代反应并酸化得1-[[[(1R)-[3-[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]硫基]甲基]环丙乙酸(6),采用乙醇/水对6进行精制,可除去孟鲁司特的特定杂质,其他杂质含量亦可控制<0.1%;手性纯度99.83%,收率85%。然后6与氢氧化钠反应得目标化合物1,总收率69.3%(以2计)。本工艺已经过中试验证。
An improved synthetic process of montelukast sodium （1） was reported. Methyl 2-[（3S）-[3-[2-（7-chloro-2-quinolinyl）vinyl]phenyl]-3-hydroxypropyl]benzoate （2） was subjected to the Grignard reaction with methyl magnesium chloride, followed by the hydroxy transformation with methanesulfonyl chloride to give 2-[2-[（3S）-[3-[2-（7-chloro-2-quinolinyl）vinyl]phenyl]-3-（methylsulfonyloxy）propyl] phenyl]-2-propanol （4）. Then compound 4 reacted with sodium 1-（mercaptomethyl）cyclopropyl acetate in the presence of tetrabutyl ammonium bromide to afford 1-[[[（1R）-[3-[2-（7-chloro-2-quinolinyl）vinyl]phenyl]-3-[2-（1-hydroxy-1-methylethyl）phenyl]propyl]thio]methyl]cyclopropyl acetic acid （6）. The latter was recrystallized in ethanol ∶ H2O （9 ∶ 1） so that the specific impurity of montelukast was removed and other impurities was controlled to less than 0.1%. In addition, the chiral purity of 6 reached to 99.83%. Then the target compound was obtained via a salification of compound 6 with a total yield of 69.3% （based on 2）.
出处
《中国医药工业杂志》
CAS
CSCD
北大核心
2017年第12期1721-1725,共5页
Chinese Journal of Pharmaceuticals
关键词
孟鲁司特钠
抗哮喘
相转移催化剂
合成
montelukast sodium
anti-asthma
phase transfer catalyst
synthesis
