CN101973965A - 一种马来酸桂哌齐特的制备方法 - Google Patents
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Abstract
本发明涉及一种马来酸桂哌齐特制备方法，它以1-〔(1-吡咯烷羰基)甲基〕哌嗪和3，4，5-三甲氧基肉桂酰氯为原材料，以甲基异丙基酮为溶剂，不加脱酸剂直接进行N-酰化反应，制得高纯度桂哌齐特游离碱。成马来酸盐是采用桂哌齐特游离碱的乙醇溶液和马来酸的乙醇溶液混合加热反应，然后冷析得到。该制备工艺反应步骤少，反应易于控制，反应产物纯度高，生产成本小，反应收率高，后处理简便易行，排污符合环保要求，可实现工业化生产。
Description
技术领域
本发明属于生物制药领域，具体地说涉及一种马来酸桂哌齐特的制备方法。
背景技术
心脑血管疾病已成为威胁人类健康的主要疾病，严重影响着人类的生存质量，并已明显呈现年轻化、低龄化的趋势，因此急需开发出有效、安全的药物。
马来酸桂哌齐特为新一代的哌嗪类药物，马来酸桂哌齐特化学名称为：化学名：(E)-1-{4-[(3’，4’，5’，-三甲氧基肉桂酰基)]-1-哌嗪}乙酰吡咯啶顺丁烯二酸盐。分子式为C26H35N3O9，英文名为CinepazideMaleate
结构式：
马来酸桂哌齐特为钙离子通道阻滞剂，通过阻止Ca2+跨膜进入血管平滑肌细胞内，使血管平滑肌松弛，脑血管、冠状血管和外周血管扩张，从而缓解血管痉挛、降低血管阻力、增加血流量；能增强腺苷和环磷酸腺苷(cAMP)的作用，降低氧耗；能抑制CAMP磷酸二酯酶，使CAMP数量增加；能提高红细胞的柔韧性和变形性，提高其通过细小血管的能力，降低血液的粘性，改善微循环；通过提高脑血管的血流量，改善脑的代谢。临床上用于治疗：1.脑血管疾病：脑动脉硬化，一过性脑缺血发作，脑血栓形成，脑栓塞，脑出血后遗症和脑外伤后遗症。2.心血管疾病：冠心病、心绞痛，如用于治疗心肌梗塞，应配合有关药物综合治疗。3.外周血管疾病：下肢动脉粥样硬化病、血栓闭塞性脉管炎、动脉炎、雷诺氏病。4.眼科、耳鼻喉科疾病：眼底血管硬化、阻塞、缺血所致的眼病，缺血所致的耳蜗前庭功能失常，突发性耳聋、耳鸣等。5.糖尿病所致的周围血管病变及微循环障碍。
通过对马来酸桂哌齐特制备文献的检索，发现其大致有三条制备路线，具体如下：
(1)、采用N-烷基化反应原理，以N-(3，4，5-三甲氧基肉桂酰)哌嗪为主要中间体，用氯乙酰基吡咯啶进行N-烷基化反应制得桂哌齐特游离碱，然后再与马来酸成盐得到产物。不过，N-(3，4，5-三甲氧基肉桂酰)哌嗪来源于3，4，5-三甲氧基肉桂酰氯和N-甲酰基哌嗪的酰化产物--N-(3，4，5-三甲氧基肉桂酰)-N’-甲酰基哌嗪，由之碱性水解得到。反应式如下：
(2)、采用Wittig反应原理，以哌嗪和乙酰基吡咯啶结合的1-〔(1-吡咯烷羰基)甲基〕哌嗪为起始原料，同氯乙酰氯成酰胺后，再与三苯基膦反应制得膦叶立德，后者与3，4，5-三甲氧基苯甲醛发生Wittig反应得桂哌齐特游离碱，然后再与马来酸成盐得到产物，反应式如下：
(3)、选择N-酰化反应原理，将1-〔(1-吡咯烷羰基)甲基〕哌嗪在碱性介质下用3，4，5-三甲氧基肉桂酰氯酰胺化，反应得到桂哌齐特游离碱，然后再与马来酸成盐制得。反应式如下：
比较上述三条制备路线，路线一以3，4，5-三甲氧基肉桂酰氯和N-甲酰基哌嗪为起始原料先制备出N-(3，4，5-三甲氧基肉桂酰)-N’-甲酰基哌嗪，然后碱性水解得到N-(3，4，5-三甲氧基肉桂酰)哌嗪，将之用氯乙酰基吡咯啶进行N-烷基化反应制得桂哌齐特游离碱，最后再与马来酸成盐得到产物。该制备方法一则反应步骤较长，二则N-甲酰基哌嗪本身不稳定，该产品市场供应不足。采用该方法制备成本较高。路线二制备步骤也较长，并且所用原料三苯基膦和溶剂乙腈均有毒，价格较贵，导致生产成本的增加。路线三则是比较常用的制备路线，采用在碱性介质中，1-〔(1-吡咯烷羰基)甲基〕哌嗪与3，4，5-三甲氧基肉桂酰氯发生反应制备游离碱，但反应溶剂与缚酸剂有所不同。US3634411文献中以苯作为反应溶剂，由于苯为应避免使用的第一类溶剂，其毒性较强，在制药中已经被限制使用。CN1631877(200410009826.0)文献中反应溶剂为二类溶剂二氯甲烷。CN1876646(20061010345.1)文献中溶剂为一类溶剂氯仿。CN200910118902.4报道了以1-〔(1-吡咯烷羰基)甲基〕哌嗪盐酸盐或1-〔(1-吡咯烷羰基)甲基〕哌嗪和3，4，5-三甲氧基肉桂酰基化物(酰基卤化物、酰基混合磷酸酐和酰基混合磺酸酐)为原材料，制得桂哌齐特游离碱。反应时应加碱(碳酸钠、碳酸钾、吡啶或三乙胺)。CN200910057066.3报道了以1-〔(1-吡咯烷羰基)甲基〕哌嗪盐酸盐和3，4，5-三甲氧基肉桂酰氯为原材料，以二氯甲烷为溶剂进行反应，制得桂哌齐特游离碱。再将游离碱溶于热乙醇，加马来酸成盐。CN200910010912.6报道了以1-〔(1-吡咯烷羰基)甲基〕哌嗪和3，4，5-三甲氧基肉桂酰氯为原材料，加入三乙胺作酸吸收剂，以丙酮为溶剂进行室温反应，制得桂哌齐特游离碱。
这些制备方法中，桂哌齐特游离碱的制备在碱性介质中进行，反应副产物较多，不利于游离碱纯度的控制。同时反应溶剂绝大多数为二类(包括二类)以上溶剂，安全性较差。
本制备工艺采用甲基异丙基酮(三类溶剂)替代无水苯(一类毒性溶剂)和二氯甲烷(二类溶剂)作反应溶剂，不加脱酸剂而直接反应，将1-〔(1-吡咯烷羰基)甲基〕哌嗪用3，4，5-三甲氧基肉桂酰氯进行N-酰化反应，制成桂哌齐特游离碱，然后再与马来酸中和成盐得高纯度马来酸桂哌齐特。经检测，HPLC纯度＞99.8％，熔点为170-175℃。符合国家原料标准要求。至于马来酸桂哌齐特的精制则采用乙醇重结晶法，不同文献对此工艺均有报道。此路线反应步骤少，易于控制，反应收率较高，后处理简便易行，排污达到环保要求，成本低，适合工业化生产。
发明内容
本发明的目的是提供一种反应步骤少，反应过程严格可控，产物收率高，纯度高，成本较低，可适合大规模工业化生产的马来酸桂哌齐特制备方法。
本发明所述的制备过程为：
本发明提供的马来酸桂哌齐特制备方法的特征如下：
1、以1-〔(1-吡咯烷羰基)甲基〕哌嗪和3，4，5-三甲氧基肉桂酰氯为起始原料，不加脱酸剂，在反应溶剂中由两原料在一定温度下直接进行(N-酰化)反应来制备桂哌齐特游离碱。再由桂哌齐特游离碱与马来酸成盐，制备马来酸桂哌齐特。
2、制备桂派齐特游离碱反应溶剂优选为甲基异丙基酮。
3、所述反应温度为30-45℃，优选温度为40℃。
4、桂哌齐特游离碱的制备过程中，3，4，5-三甲氧基肉桂酰氯与1-〔(1-吡咯烷羰基)甲基)哌嗪的投料比(重量比)控制在1.2-1.6。
5、桂哌齐特游离碱的后处理包括提取、析晶。提取相为二氯甲烷，析晶溶剂使用丁酮。
6、马来酸成盐是采用桂哌齐特游离碱的乙醇溶液和马来酸的乙醇溶液混合于25-35℃左右反应，然后冷析得高纯度稳定产品，HPLC纯度＞99.8％，熔点为170-175℃。
本发明工艺所达到的效果是：
1、步骤少，反应简单，更适合工业化生产
2、整个生产过程中使用低毒试剂，原料药品更安全。
3、3，4，5-三甲氧基肉桂酰氯与1-〔(1-吡咯烷羰基)甲基〕哌嗪的投料比(重量比)控制在合适的比例，这样，1-〔(1-吡咯烷羰基)甲基〕哌嗪转化完全，未出现乳化难分离情况，同时后处理又方便。
4、反应产物纯度高，收率高。桂派齐特游离碱的收率73.5％，总收率达60％以上。经分析检测，马来酸桂哌齐特粗品HPLC纯度＞99.5％。
具体实施方式
下述实施步骤只是对本发明方法的进一步说明，并不对本发明作任何限制。
一.制备桂哌齐特
1.桂哌齐特的化学反应过程
在搅拌下将20g1-〔(1-吡咯烷羰基)甲基〕哌嗪溶于122ml甲基异丙基酮液中，加热，溶液呈淡黄色。另取24g3，4，5-三甲氧基肉桂酰氯，加入120ml甲基异丙基酮，热溶，室温静置待用。向1-〔(1-吡咯烷羰基)甲基〕哌嗪/甲基异丙基酮液中(温度控制40℃)加入3，4，5-三甲氧基肉桂酰氯/甲基异丙基酮溶液，搅拌反应完全，采用TCL检测。
2.桂哌齐特的提取过程
反应完毕，用稀盐酸搅拌提取水相，冷却后，滴加NaOH液约75ml，调节反应液PH12-13。加230ml二氯甲烷分次提取水相，合并取二氯甲烷相，加20g无水硫酸镁搅拌干燥过夜。过滤除掉干燥剂，40-45℃水浴减压旋蒸，蒸干二氯甲烷，得黄色油状液约60g。
3.桂哌齐特的结晶过程
取60ml丁酮加入油状液中，热溶后，放冷析晶。过滤，干燥得类白色晶体。收率73.5％。经检测，HPLC纯度＞99.3％。
二.制备马来酸桂哌齐特粗品
取马来酸8.4g加入55ml无水乙醇热溶液中，，另取30g桂哌齐特游离碱加至200ml无水乙醇热溶液中，加热至25-35℃溶解。在游离碱醇溶液中加入马来酸的无水乙醇溶液。搅拌约1-2min后，反应液逐渐变混浊，停止搅拌，析出大量白色晶体。过滤，干燥，得马来酸桂哌齐特成品。经HPLC检测，纯度＞99.5％。
三.马来酸桂哌齐特精制
马来酸桂哌齐特粗品用乙醇重结晶的工艺，不同文献均有报道。只是不同文献乙醇溶液浓度不同。本工艺采用无水乙醇重结晶，得高纯度稳定产品，HPLC纯度＞99.8％，熔点为170-175℃。
Claims (6)
1.马来酸桂哌齐特的制备(制备)方法，其特征在于：以1-〔(1-吡咯烷羰基)甲基)哌嗪和3，4，5-三甲氧基肉桂酰氯为起始原料，不加脱酸剂，在反应溶剂中由两原料在一定温度下直接进行(N-酰化)反应来制备桂哌齐特游离碱。桂哌齐特游离碱经后处理后，再由桂哌齐特游离碱与马来酸成盐，制备马来酸桂哌齐特。
2.根据权利要求1所述的一种马来酸桂哌齐特的制备方法，其特征在于：制备桂派齐特游离碱反应溶剂优选为甲基异丙基酮。
3.根据权利要求1所述的一种马来酸桂哌齐特的制备方法，其特征在于：所述温度为30-45℃，优选温度为40℃。
4.根据权利要求1所述的一种马来酸桂哌齐特的制备方法，其特征在于：桂哌齐特游离碱的制备过程中，3，4，5-三甲氧基肉桂酰氯与1-〔(1-吡咯烷羰基)甲基)哌嗪的投料比(重量比)控制在1.2-1.6。
5.根据权利要求1所述的一种马来酸桂哌齐特的制备方法，其特征在于：桂哌齐特游离碱的后处理包括提取、析晶。提取相为二氯甲烷，析晶溶剂优选丁酮。
6.根据权利要求1所述的一种马来酸桂哌齐特的制备方法，其特征在于：马来酸成盐是采用桂哌齐特游离碱的乙醇溶液和马来酸的乙醇溶液混合于25-35℃左右反应，然后冷析得高纯度稳定产品，HPLC纯度＞99.8％，熔点为170-175℃。
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