右旋雷贝拉唑钠的合成工艺优化

Improved Synthesis of Dexrabeprazole Sodium

对右旋雷贝拉唑钠的合成工艺进行改进。2-羟甲基-4-(3-甲氧基丙氧基)-3-甲基吡啶盐酸盐与氯化亚砜反应得2-氯甲基-4-(3-甲氧基丙氧基)-3-甲基吡啶盐酸盐;不经分离,其水溶液直接与2-巯基苯并咪唑在水/丙酮中于室温反应2 h,然后经简单的浓缩、过滤、洗涤即得2-[[[4-(3-甲氧基丙氧基)-3-甲基-2-吡啶基]甲基]硫代]-1H-苯并咪唑。避免了柱色谱的使用,简化了操作,收率也提高至93.7%。然后以钛酸四异丙酯和L-酒石酸二乙酯为手性催化剂,以过氧化氢二异丙苯为氧化剂进行不对称氧化,经三次精制得纯度为99.9%的右旋雷贝拉唑。最后与氢氧化钠成盐制得目标产品,纯度99.9%,手性纯度99.9%,总收率83.0%。改进后的工艺反应条件温和、操作简便,已经过中试验证。

The synthetic process of dexrabeprazole sodium was improved.2-(Hydroxymethyl)-4-(3- methoxypropoxy)-3-methylpyridine hydrochloride reacted with sulfoxide chloride to give 2-(chloromethyl)-4-(3-methoxypropoxy)-3-methylpyridine hydrochloride,and then the aqueous solution without purification was directly subjected to a substitution with 2-mercaptobenzimidazole in H2O/acetone at room temperature.Then 2-[[[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl-thio]-1H-benzo [d]imidazole was obtained by simply work-up with a yield of 93.7%.The latter was subjected to an asymmetric oxidation using tetra isopropyl titanate and diethyl L-tartrate as the chiral catalysts,hydroperoxide,bis (1-methylethyl)phenyl as the oxidant to afford dexrabeprazole with a purity of 99.9%after three refining steps.Finally,the target product was prepared via a salification with sodiun hydroxide in an overall yield of 83.0%,a purity of 99.9%,and a chiral purity of 99.9%.This optimized process has mild reaction conditions and simple operation,and it has been tested in pilot scale.