CN1146538C - 佐芬普利钙盐的制备方法 - Google Patents
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Abstract
基本上为纯净形式的佐芬普利钙盐的多晶型物A的制备方法，该方法包括：a)S(-)-3-苯甲酰硫基-2-甲基丙酰氯与顺式-4-苯硫基-L-脯氨酸在pH9.0-9.5的水中反应，回收酸形式的佐芬普利；b)酸式佐芬普利与钾盐在醇溶液中成盐，回收所得钾盐；c)在70-90℃下，向CaCl2水溶液中加入佐芬普利钾盐水溶液，同时放入晶种以促进多晶型物A的沉淀，由此导致钾盐向钙盐的转化。
Description
发明领域
本发明涉及佐芬普利钙盐的新颖的制备方法。据报道，该化合物能够以至少两种固态多晶型物存在，被称为A和B；根据本发明的新合成方法得到仅以多晶型物A存在的佐芬普利钙盐，基本上不含多晶型物B。
现有技术
佐芬普利((4S)-(2S)-3-(苯甲酰硫基)-2-甲基丙酰-4-(苯硫基)-L-脯氨酸)钙盐具有下式I结构：
佐芬普利和其它类似物已被描述于US 4,316,906中。用于获得钙盐的合成法见流程I，基本包括三个步骤：
a)顺式-4-苯硫基-L-脯氨酸与D-3-(苯甲酰硫基)-2-甲基丙酰氯在水溶液中缩合，并通过加入5N氢氧化钠保持pH值为8-8.5；之后用HCl酸化，用乙酸异丁酯萃取和浓缩萃取液，用盐水溶液洗涤，得到(4S)-1-[(2S)-3-(苯甲酰硫基)-2-甲基丙酰]-4-(苯硫基)-L-脯氨酸；
b)前步树脂性物质的异丙醇溶液用2-乙基己酸钾处理，得到相应的钾盐；
c)钾盐溶解在水中至浓度为57％，非常缓慢地加入轻微过量的2N氯化钙水溶液，同时放入晶种，沉淀出所需的钙盐。所得产物用水彻底洗涤，在相对高温的真空下干燥，得到所需钙盐的干燥粉末；熔点约为250℃。
或者：
d)将(4S)-1-[(2S)-3-(苯甲酰硫基)-2-甲基丙酰]-4-(苯硫基)-L-脯氨酸溶于乙醇，用含有一当量CaO的等体积含水悬浮体处理；除去乙醇后用乙醚洗涤，将含水悬浮体冷冻干燥，得到熔点为235-237℃(分解)的钙盐。
佐芬普利钙盐多晶型物的存在在《药物与生物医学分析杂志》，1994，Vol 12，pp.173-177中已有明确的定义，其中阐明用多晶型物A或多晶型物B制备的佐芬普利钙盐片剂根据它们的溶解率是不能加以区分的，但是没有报道这两种多晶型物的化学-物理特征。不过，同质多晶现象的存在难以使所制备的不同批次的佐芬普利钙总是具有相同的化学-物理特征，而这对确保出于科学、管理和治疗目的的最大程度的再现性来说却是不可缺少的。
已发现多晶型物A比多晶型物B更耐压缩和/或耐微粉化，因此，多晶型物A比多晶型物B更适合于固体药物制剂、例如片剂的工业生产；同样明显的是，鉴于上述，基本上不含多晶型物B的多晶型物A是工业上优选的。
另一方面，以前所掌握的佐芬普利钙盐的制备方法不能提供不含多晶型物B的、足够纯的多晶型物A。事实上，US 4,316,906中所述合成法(见上述a，b，c点中)主要得到多晶型物A，但同时多晶型物B所占百分比也是非常不确定的，而且从不低于20％；此外，US4,316,906中所述的替代合成法(见上述d点中)得到部分无定形产物，具有非常不确定的特征，其中多晶型物A(如果存在的话)的浓度大大低于前述方法。
这些问题已经被本发明方法解决了，使制备仅存在且总是存在多晶型物A的产物成为可能，它基本上是纯净的，不含多晶型物B。
发明概述
从佐芬普利钙盐制备基本上纯净的多晶型物A的方法包括：
a)S(-)-3-苯甲酰硫基-2-甲基丙酰氯与顺式-4-苯硫基-L-脯氨酸在pH值在9.0-9.5之间的水中反应，回收酸形式的佐芬普利；
b)酸式佐芬普利与钾盐在醇溶液中成盐，回收所得钾盐；
c)在70-90℃下，向CaCl2水溶液中加入佐芬普利钾盐水溶液，同时放入晶种以促进多晶型物A的沉淀，由此导致钾盐向钙盐的转化。
发明的详细公开
本发明方法以下列流程图表示。
在步骤a)中，在质子惰性有机溶剂中，在-10℃到+50℃的温度下，优选为20-25℃，将S-(-)-3-苯甲酰硫基-2-甲基丙酸用氯化剂处理，优选为草酰氯或亚硫酰氯，得到相应的酰基氯。在真空下除去反应混合物的挥发性组分，将所得油溶于质子惰性有机溶剂，优选为二氯甲烷、乙酸乙酯、乙酸异丁酯，在-10℃到+50℃的温度下，优选为20-25℃，缓慢加入到pH为9-9.5、优选为9.5的顺式-4-苯硫基-L-脯氨酸水溶液中。加入氢氧化钠溶液保持pH在所需的值。
在加入完成后，该混合物在室温下搅拌15分钟到4小时，优选为30分钟，并保持pH在所需的值(9-9.5)。反应混合物然后用浓盐酸酸化，用有机溶剂萃取，随后蒸发除去该溶剂，得到佐芬普利的游离酸。
发生缩合反应的pH值应当作为合成法的关键参数加以考虑，因为它显著影响终产物的纯度和佐芬普利钾盐的总收率(步骤b)：事实上人们己经注意到当pH值小于9时收率降低，当其大于9.5时硫代酸酯的苯甲酰基水解。
此外，所选择的pH值不会危及原料和所得佐芬普利的异构纯度，因此佐芬普利游离酸的立体异构组成取决于原料的立体异构纯度。
在步骤b)中，将上述所得酸溶于醇性溶剂，优选为异丙醇，并用含有等量有机钾盐的相同醇溶液处理，优选为2-乙基己酸钾。佐芬普利钾盐用离心法收集，洗涤并干燥。
佐芬普利钾盐是非常重要的中间体，由于最终佐芬普利钙盐的不溶性，其纯度显著依赖于对应钾盐的纯度。
事实上，在佐芬普利含有不可接受的高含量化学和/或立体异构杂质的情况下，它的钾盐能够通过从异丙醇/水中的选择性结晶加以纯化。
最后在步骤c)中，将钾盐溶于水，加入到氯化钙水溶液中，保持温度在70-90℃，优选为80-85℃。放入晶种发生沉淀现象。钙盐用离心法收集，用去离子水彻底洗涤，根据AgNO3试验或电导率测量法，直到洗涤后的水基本上不含氯离子为止。
所述合成法得到不同批次的佐芬普利钙盐的多晶型物A，基本上是纯净的，不含多晶型物B，或者即使有的话，后者所占百分比也在检测限的下限左右(低于7％)。
按照本发明方法所得佐芬普利钙盐样本是稳定的，并没有显示与多晶型物B的互变现象；事实上，在25℃和60％相对湿度下贮藏3年的样本或在40℃和75％相对湿度下贮藏6个月的样本的多晶型物B百分比可以忽略不计(低于7％)，且不随时间而变化。
本发明的进一步目的因此是药物组合物，该组合物含有基本上纯净的佐芬普利钙盐的多晶型物A作为活性成分，例如多晶型物B的残余百分比低于15％，优选为低于7％。
本发明阐述在下列实施例中。
实施例1
a)佐芬普利：在催化量DMF的存在下，将(S)-3-苯甲酰硫基-2-甲基丙酸(6.0kg；28.8M)溶于二氯甲烷。向该溶液缓慢加入草酰氯(2.79L)，保持温度在20-25℃。加入完成后，反应混合物在35-38℃下加热至少1.5小时。然后将溶液在35-45℃真空下浓缩，然后在氮气氛下冷却至15-20℃。将所得油(S)-3-苯甲酰硫基-2-甲基丙酰氯溶于乙酸异丁酯，缓慢加入到含有顺式-4-苯硫基-L-脯氨酸(6.5kg；29.1M)的水溶液中，连续加入20％氢氧化钠溶液保持pH为9-9.5。在加入期间，将温度稳定地保持在20-25℃。在加入结束时，混合物在pH9.5下搅拌1/2小时，从而完成反应。反应混合物用浓盐酸酸化至pH为1.8-2.0，分为两相。蒸发除去有机相，得到佐芬普利游离酸。
b)佐芬普利钾盐：在58-60℃下，将上述所得游离酸溶于极少量异丙醇中，加入2-乙基己酸钾(5.3kg；29.1M)的异丙醇浓溶液。混合物保持搅拌不少于8小时，这期间温度缓慢降低至20-25℃。所沉淀出来的佐芬普利钾盐用离心法收集，用异丙醇洗涤，在45-50℃真空下干燥至少8小时。收率为96％。
c)佐芬普利钙盐，多晶型物A：将23.32kg佐芬普利钾盐溶于180L水。所得溶液过滤净化，另用19L水洗涤所有所用仪器，然后加入到上述溶液中。将7.4kg CaCl2二水合物溶于324L水。溶液过滤净化，另用137L水洗涤所有所用仪器，然后加入到过滤后的溶液中。将CaCl2溶液加热到80-85℃，加入6.5L佐芬普利钾盐溶液，放入晶种，即上述所得佐芬普利钙的多晶型物A晶体。所得悬浮液搅拌30分钟，在2.50小时内加入剩余佐芬普利钾盐溶液，保持温度在80-85℃。在加入结束时，悬浮液搅拌30分钟并趁热离心。固体残余物用水洗涤，直到根据AgNO3试验或电导率测量结果，洗出液中检测的氯离子浓度可以忽略不计为止。残余物然后在40℃真空下干燥至含水量为小于3％。收率高于96％。产物中检测不到多晶型物B。
实施例2
多晶型物B的合成
从佐芬普利钾盐开始，例如通过下列方法能够得到不含多晶型物A的、基本上纯净的多晶型物B：将佐芬普利钾盐溶液(0.27M)喷入微温的水(55℃)中，同时加入氯化钙溶液(1.17M)；溶液中佐芬普利钾盐和氯化钙的总量是等摩尔数的。将含有浆状产物的所得悬浮液在85℃下加热12-14小时，完全转化为多晶型物B。在约25℃下冷却后，产物过滤，用水洗涤，直到根据电导率测量结果基本上不含氯离子为止。滤液然后在真空下干燥。收率高于90％。
实施例3
多晶型物的表征
佐芬普利钙盐的多晶型物A和B能够凭借X射线衍射(DXR)和/或扫描电子显微镜(SEM)技术易于区分。
两种多晶型物之间观察不到互变现象。
DRX：使用PW-1710衍射计在从0°到60°的2θ范围内记录两种样本粉末的衍射光谱。将约10mg样品悬浮在石油醚中，放置在玻片上，将玻片放置在仪器的样本夹上。两种多晶型物的衍射图在衍射峰的数量上和光谱的位置上都有明显差异。差异更显著的光谱区域是从2θ＝15到2θ＝25的区间(图1)，在对混合物中两种多晶型物的定量分析时正是根据该区域。
SEM：将样本用金金属化，利用扫描电子显微镜在不同尺寸下拍照。
两种多晶型物在它们的形态和粒径方面都具有不同的特征。
多晶型物A是表面上为层状聚集体的形式，粒径不超过50μm。多晶型物B是球状大聚集体的形式，直径范围从0.2到1.0mm。球体表面放大后显示棱形粒子有明显的玫瑰形生长。
多晶型物A样本中多晶型物B的测定：
多晶型物A样本中多晶型物B的百分比能够通过观察X衍射图(DRX)易于估计。分析所用区域的2θ范围从15到25。在这一区域中，有三个峰，分别是I2θ＝1 8.4、II2θ＝19.2和III2θ＝19.9，测量含有已知量多晶型物B(不超过30％)的不同多晶型物A样本的相对强度I/III和II/III。由此获得回归方程，在峰I和II相对于峰III的强度与样本中所含有的多晶型物B百分比之间建立相互关系。用上述方程所得结果的精密度和准确度是很好的，在置信限度的基础上，多晶型物A中可检测到的极少量多晶型物B可被估计为＜7％。图4报告上述根据回归方程计算所得数值与观测值之间的关系。
多晶型物对微粉化的稳定性
将两种多晶型物在剧烈条件下研磨，在Retsch MM2球形粉碎机内装入200mg样本，以80次振动/分钟操作15分钟，它们在相同的实验条件下显示不同的稳定性。事实上根据DRX，多晶型物A在处理后依然保持晶体结构(图2)，然而多晶型物B完全丧失其晶体结构，变成了完全无定形的固相(图3)。
Claims (14)
1、一种纯净形式的佐芬普利钙盐的多晶型物A的制备方法，该方法包括：
a)S(-)-3-苯甲酰硫基-2-甲基丙酰氯与顺式-4-苯硫基-L-脯氨酸在pH9.0-9.5的水中反应，回收酸形式的佐芬普利；
b)酸式佐芬普利与2-乙基己酸钾在醇溶液中成盐，回收所得钾盐；
c)在70-90℃下，向CaCl2水溶液中加入佐芬普利钾盐水溶液，同时放入晶种以促进多晶型物A的沉淀，由此导致钾盐向钙盐的转化。
2、如权利要求1所要求保护的方法，其特征在于，在步骤a)中，S(-)-3-苯甲酰硫基-2-甲基丙酰氯是通过相应的酸与草酰氯的反应加以制备的，反应在质子惰性有机溶剂中、在-10至+50℃的温度下进行，其特征还在于与顺式-4-苯硫基-L-脯氨酸的反应是这样进行的，在-10至+50℃的温度，将酰氯在质子惰性有机溶剂中的溶液加入到pH为9.0-9.5的顺式-4-苯硫基-L-脯氨酸水溶液中。
3、如权利要求2所要求保护的方法，其中通过加入氢氧化钠使pH保持在9.0至9.5。
4、如权利要求2或3所要求保护的方法，其中pH保持在9.5。
5、根据权利要求2或3的方法，其中该质子惰性有机溶剂是乙酸乙酯、乙酸异丁酯或二氯甲烷。
6、如权利要求1所要求保护的方法，其中该醇是异丙醇。
7、如权利要求1所要求保护的方法，其中步骤c)是在80-85℃的温度下进行的。
8、根据权利要求1-3中任意一项的方法，其特征在于得到多晶型物B含量低于7％的佐芬普利钙盐的多晶型物A。
9、一种抗高血压的药物组合物，含有权利要求1的方法得到的纯净形式的佐芬普利钙盐多晶型物A作为活性成分。
10、根据权利要求的抗高血压的药物组合物，含有多晶型物B含量低于15％的佐芬普利钙盐的多晶型物A作为活性成分。
11、根据权利要求9的抗高血压的药物组合物，含有多晶型物B含量低于7％的佐芬普利钙盐的多晶型物A作为活性成分。
12、权利要求1的方法得到的纯净形式的佐芬普利钙盐多晶型物A在药物制备中的用途，该药物用于原发性高血压、心代偿失调和急性心肌梗塞的治疗。
13、根据权利要求12的用途，其中，所述多晶型物A中的多晶型物B含量低于15％。
14、根据权利要求12的用途，其中，所述多晶型物A中的多晶型物B含量低于7％。
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| IT1998MI001833A IT1301993B1 (it) | 1998-08-04 | 1998-08-04 | Processo per la preparazione di zofenopril sale di calcio. |
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| AU2006264650B2 (en) * | 2005-07-01 | 2012-08-23 | Generics [Uk] Limited | Zofenopril calcium in polymorph form C |
| EA012845B1 (ru) * | 2005-12-09 | 2009-12-30 | Менарини Интернэшнл Оперейшнс Люксембург С. А. | Фармацевтическая композиция, содержащая зофеноприл и hctz, для лечения гипертензии |
| WO2007138352A1 (en) * | 2006-05-26 | 2007-12-06 | Generics (Uk) Limited | Zofenopril calcium |
| GB0715626D0 (en) | 2007-08-10 | 2007-09-19 | Generics Uk Ltd | Crystalline form of zofenopril calcium |
| NZ622549A (en) * | 2008-02-27 | 2015-10-30 | Generics Uk Ltd | Novel crystalline form of zofenopril calcium |
| US8853421B2 (en) | 2008-02-27 | 2014-10-07 | Generics [Uk] Limited | Crystalline forms of zofenopril calcium |
| WO2010084515A2 (en) * | 2009-01-23 | 2010-07-29 | Glenmark Generics Limited | A process for the preparation of zofenopril and its pharmaceutically acceptable salts thereof |
| SI23949A (sl) | 2011-12-19 | 2013-06-28 | Silverstone Pharma | Nove kristalne soli zofenoprila, postopek za njihovo dobivanje in njihova uporaba v terapiji |
| CN104138359B (zh) * | 2013-05-06 | 2016-03-02 | 扬子江药业集团上海海尼药业有限公司 | 佐芬普利钙片的制备方法 |
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