右旋雷贝拉唑钠的合成工艺优化
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摘要
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 H_2O/acetone at room temperature. Then 2-[[[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl]thio]-1 H-benzo[d]imidazole was obtained by simply workup 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 sodium 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.
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 H_2O/acetone at room temperature. Then 2-[[[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl]thio]-1 H-benzo[d]imidazole was obtained by simply workup 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 sodium 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.
引文
[1] PRAKASH A,FAULDS D. Rabeprazole[J]. Drugs,1998,55(2):261-267.
[2]张春来,罗宏军,姜琦,等.右旋雷贝拉唑钠的制备工艺改进[J].中国药科大学学报,2018, 49(3):291-294.
[3]肖艳华,冯睿杰.雷贝拉唑合成研究进展[J].武汉工程大学学报,2012, 34(1):14-18.
[4]赵志全.S-泮托拉唑及其盐的制备方法:中国,101597277[P]. 2009-12-09.
[5]徐宝财,刘家胜,周雅文,等.(R)-2-{[4-(3-甲氧基丙氧基)-3-甲基吡啶-2-基]甲基亚硫酰基}-1H-苯并咪唑的合成[J].有机化学,2008, 28(12):2155-2158.
[6]刘俊华,吴婷,胡鸿雨.右旋雷贝拉唑钠合成工艺研究[J].海峡药学,2018, 30(7):44-46.
[2]张春来,罗宏军,姜琦,等.右旋雷贝拉唑钠的制备工艺改进[J].中国药科大学学报,2018, 49(3):291-294.
[3]肖艳华,冯睿杰.雷贝拉唑合成研究进展[J].武汉工程大学学报,2012, 34(1):14-18.
[4]赵志全.S-泮托拉唑及其盐的制备方法:中国,101597277[P]. 2009-12-09.
[5]徐宝财,刘家胜,周雅文,等.(R)-2-{[4-(3-甲氧基丙氧基)-3-甲基吡啶-2-基]甲基亚硫酰基}-1H-苯并咪唑的合成[J].有机化学,2008, 28(12):2155-2158.
[6]刘俊华,吴婷,胡鸿雨.右旋雷贝拉唑钠合成工艺研究[J].海峡药学,2018, 30(7):44-46.