CN102649785B - 一种伊玛替尼甲烷磺酸盐β晶型的制备方法 - Google Patents
一种伊玛替尼甲烷磺酸盐β晶型的制备方法 Download PDFInfo
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Abstract
本发明提供了一种伊玛替尼甲烷磺酸盐β晶型新的制备方法，即将伊玛替尼悬浮于酯类有机溶剂中，然后加入甲烷磺酸，得到上述伊玛替尼甲烷磺酸盐的β晶型。
Description
技术领域
本发明设计涉及多晶型药物制备技术领域，更具体的为涉及一种伊玛替尼甲烷磺酸盐β晶型的制备方法
发明背景
伊玛替尼甲烷磺酸盐，又叫4-[(4-甲基-1-哌嗪基)甲基]-N-[4-甲基-3-[4-(3-吡啶基)-2-嘧啶基]氨基]-苯基]苯甲酰胺甲烷磺酸盐，其结构式如式I所示：
式I
伊玛替尼甲烷磺酸盐是由瑞士诺华公司开发的一种蛋白质-酪氨酸激酶抑制剂，其在各类型癌症的治疗中特别有效，目前广泛用于治疗慢性粒细胞白血病(CML)急变期、加速期或α-干扰素治疗失败后的慢性期患者；不能手术切除或发生转移的恶性胃肠道间质肿瘤(GIST)患者，通常以口服形式给药，市场需求较大。
到目前为止，根据文献报道，伊玛替尼甲烷磺酸盐共有α、β、δ、ε、α2、H1、Ⅰ、Ⅱ、F、G、K、H、I、K、Ⅳ、Ⅴ、Ⅵ、Ⅶ、Ⅷ、Ⅸ、Ⅹ、Ⅺ、ⅩⅢ、ⅩⅣ、XV、XVI、无定形，共27种晶型，其中β晶型理化性质最为稳定，并作为上市晶型受到广泛的关注和研究。最早在WO9903854中，将非β晶型伊玛替尼甲烷磺酸盐悬浮于极性溶剂中，通过打浆或高温回流冷却后加入β晶种诱导析晶等方法制备获得，该方法需要事先制备亚稳态的伊玛替尼甲烷磺酸盐晶型，且有混晶型现象，重复性和操作性不好；WO2005077933和WO2006054314中提及以丙酮、乙腈、甲醇/异丙醇等极性溶剂为成盐溶剂，直接滴加甲烷磺酸，通过室温打浆或高温回流冷却析晶等方法获得，该方法收率不高，且重复性也不好，有混晶现象。以上三篇专利申请介绍的方法，主要存在有混晶现象，重复性和操作性不好问题，所以导致其在工业化过程中受到一定限制。
发明内容
本发明在大量试验的基础上发现，把伊玛替尼悬浮于酯类溶剂中，在相对较高的温度范围内加入甲烷磺酸一步成盐，再加入少量β晶种诱导析晶制得伊玛替尼甲烷磺酸盐β晶型。该方法成本低、收率高、重复性好、可操作性强，具有很好的工业应用价值。
本发明涉及的反应如式II所示：
式II
将伊玛替尼悬浮于有机溶剂与水的混合溶剂中，然后加入甲烷磺酸，得到上述伊玛替尼甲烷磺酸盐的β晶型。
进一步地，采取的具体方案如下：
将伊玛替尼悬浮于酯类有机溶剂中，使温度维持在40℃～100℃，然后加入甲烷磺酸或甲烷磺酸溶液，继续保持40℃～100℃反应，加入β晶型伊玛替尼甲烷磺酸盐作引发晶种，降温析晶。其中所述的酯类有机溶剂选自C1-4脂肪酸与C1-4脂肪醇缩合的酯中的一种或任意比例混合的多种。
优选地将伊玛替尼悬浮于酯类有机溶剂中，使温度维持在50℃～100℃，然后加入甲烷磺酸或甲烷磺酸溶液，继续保持50℃～100℃反应0.5h～4h，加入0.1％～2％β晶型伊玛替尼甲烷磺酸盐作引发晶种，降温至-10℃～30℃搅拌1h～24h析晶，过滤，干燥，得到伊玛替尼甲烷磺酸盐β晶型。其中所述的酯类有机溶剂选自甲酸甲酯、甲酸乙酯、甲酸丙酯、甲酸异丙酯、甲酸丁酯、甲酸仲丁酯、甲酸异丁酯、甲酸叔丁酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸异丙酯、乙酸丁酯、乙酸仲丁酯、乙酸异丁酯、乙酸叔丁酯、丙酸甲酯、丙酸乙酯、丙酸丙酯、丙酸异丙酯、丙酸丁酯、丙酸仲丁酯、丙酸异丁酯、丙酸叔丁酯、丁酸甲酯、丁酸乙酯、丁酸丙酯、丁酸异丙酯、丁酸丁酯、丁酸仲丁酯、丁酸异丁酯、丁酸叔丁酯、异丁酸甲酯、异丁酸乙酯、异丁酸丙酯、异丁酸异丙酯、异丁酸丁酯、异丁酸仲丁酯、异丁酸异丁酯、异丁酸叔丁酯中的一种或任意比例混合的两种或任意比例混合的三种。
更优选地将伊玛替尼悬浮于酯类有机溶剂中，使温度维持在60℃～95℃，然后加入甲烷磺酸或甲烷磺酸溶液，继续保持55℃～90℃反应0.5h～2h，加入0.1％～2％β晶型伊玛替尼甲烷磺酸盐作引发晶种，缓慢降温至0℃～20℃，然后以50rpm～400rpm 的转速保温搅拌10h～20h析晶，过滤，干燥，得到伊玛替尼甲烷磺酸盐β晶型。其中所述干燥为普通加热干燥或20℃～60℃真空干燥；优选20℃～50℃真空干燥。所述的酯类有机溶剂选自甲酸甲酯、甲酸乙酯、甲酸丙酯、甲酸异丙酯、甲酸丁酯、甲酸仲丁酯、甲酸异丁酯、甲酸叔丁酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸异丙酯、乙酸丁酯、乙酸仲丁酯、乙酸异丁酯、乙酸叔丁酯、丙酸甲酯、丙酸乙酯、丙酸丙酯、丙酸异丙酯、丙酸丁酯、丙酸仲丁酯、丙酸异丁酯、丙酸叔丁酯、丁酸甲酯、丁酸乙酯、丁酸丙酯、丁酸异丙酯、丁酸丁酯、丁酸仲丁酯、丁酸异丁酯、丁酸叔丁酯、异丁酸甲酯、异丁酸乙酯、异丁酸丙酯、异丁酸异丙酯、异丁酸丁酯、异丁酸仲丁酯、异丁酸异丁酯、异丁酸叔丁酯中的一种。
最优选地将伊玛替尼悬浮于酯类有机溶剂中，使温度维持在65℃～90℃，然后加入甲烷磺酸或甲烷磺酸溶液，继续保持65℃～90℃反应0.5h～1.5h，加入0.1％～2％β晶型伊玛替尼甲烷磺酸盐作引发晶种，缓慢降温至0℃～20℃，然后以50rpm～400rpm的转速保温搅拌10h～20h析晶，过滤，干燥，得到伊玛替尼甲烷磺酸盐β晶型。其中所述干燥为20℃～50℃真空干燥；所述的酯类有机溶剂选自乙酸乙酯、乙酸异丙酯、乙酸丁酯、乙酸异丁酯中的一种；伊玛替尼与甲烷磺酸的投料摩尔比例为1∶0.95～1∶1.05。
伊玛替尼与酯类溶剂的质量比为1∶8～1∶40，优选地为1∶11～1∶34，更优选地为1∶14～1∶28，进一步优选地为1∶16～1∶24。
伊玛替尼与甲烷磺酸的投料摩尔比例为1∶0.9～1∶1.1，优选地为1∶0.95～1∶1.05，更优选地为1∶0.98～1∶1.02。
本申请中所述的C1-4脂肪酸与C1-4脂肪醇缩合的酯为R1C(O)OR2，其中R1为C1-4烷基或环烷基，R2为C1-4烷基或环烷基；包括但不限于酸甲酯、甲酸乙酯、甲酸丙酯、甲酸异丙酯、甲酸丁酯、甲酸仲丁酯、甲酸异丁酯、甲酸叔丁酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸异丙酯、乙酸丁酯、乙酸仲丁酯、乙酸异丁酯、乙酸叔丁酯、丙酸甲酯、丙酸乙酯、丙酸丙酯、丙酸异丙酯、丙酸丁酯、丙酸仲丁酯、丙酸异丁酯、丙酸叔丁酯、丁酸甲酯、丁酸乙酯、丁酸丙酯、丁酸异丙酯、丁酸丁酯、丁酸仲丁酯、丁酸异丁酯、丁酸叔丁酯、异丁酸甲酯、异丁酸乙酯、异丁酸丙酯、异丁酸异丙酯、异丁酸丁酯、异丁酸仲丁酯、异丁酸异丁酯、异丁酸叔丁酯。
附图说明
图1为实施例1制取伊玛替尼甲烷磺酸盐β晶型的XRPD图谱。
图2为实施例2制取伊玛替尼甲烷磺酸盐β晶型的XRPD图谱。
图3为实施例3制取伊玛替尼甲烷磺酸盐β晶型的XRPD图谱。
图4为实施例4制取伊玛替尼甲烷磺酸盐β晶型的XRPD图谱。
具体实施方法
通过下述实施例子将有助于理解本发明，但不限制本发明的内容
实施例1：伊玛替尼甲烷磺酸盐β晶型的制备
称取伊玛替尼10g(2.02mmol，1.0eq)，悬浮于250mL乙酸乙酯中，升温至70℃，以1mL/min的速度滴加1.3mL(2.0mmol，0.99eq)甲烷磺酸溶液，滴加完毕反应液呈橘黄色混浊状，维持75℃继续搅拌反应1h，趁热加入0.1g(1％)伊玛替尼甲烷磺酸盐β晶型作引发晶种，缓慢降温至10℃，以200rpm转速保温搅拌15h，过滤，滤饼用50mL乙酸乙酯冲洗，45℃真空干燥，得到伊玛替尼甲烷磺酸盐β晶型11.5g，收率96％。
实施例2：伊玛替尼甲烷磺酸盐β晶型的制备
称取伊玛替尼10g(2.02mmol，1.0eq)，悬浮于250mL乙酸异丙酯中，升温至70℃，以1mL/min的速度滴加1.3mL(2.0mmol，0.99eq)甲烷磺酸溶液，滴加完毕反应液呈橘黄色混浊状，维持75℃继续搅拌反应1h，趁热加入0.1g(1％)伊玛替尼甲烷磺酸盐β晶型作引发晶种，缓慢降温至10℃，以200rpm转速保温搅拌15h，过滤，滤饼用50mL乙酸乙酯冲洗，45℃真空干燥，得到伊玛替尼甲烷磺酸盐β晶型11.6g，收率97％。
实施例3：伊玛替尼甲烷磺酸盐β晶型的制备
称取伊玛替尼10g(2.02mmol，1.0eq)，悬浮于250mL乙酸丁酯中，升温至70℃，以1mL/min的速度滴加1.3mL(2.0mmol，0.99eq)甲烷磺酸溶液，滴加完毕反应液呈橘黄色混浊状，维持75℃继续搅拌反应1h，趁热加入0.1g(1％)伊玛替尼甲烷磺酸盐β晶型作引发晶种，缓慢降温至10℃，以200rpm转速保温搅拌15h，过滤，滤饼用50mL乙酸乙酯冲洗，45℃真空干燥，得到伊玛替尼甲烷磺酸盐β晶型11.7g，收率98％。
实施例4：伊玛替尼甲烷磺酸盐β晶型的制备
称取伊玛替尼10g(2.02mmol，1.0eq)，悬浮于250mL乙酸异丁酯中，升温至70℃，以1mL/min的速度滴加1.3mL(2.0mmol，0.99eq)甲烷磺酸溶液，滴加完毕反应液呈橘黄色混浊状，维持75℃继续搅拌反应1h，趁热加入0.1g(1％)伊玛替尼甲烷磺酸盐β晶型作引发晶种，缓慢降温至0℃，以200rpm转速保温搅拌15h，过滤，滤饼用50mL乙酸乙酯冲洗，45℃真空干燥，得到伊玛替尼甲烷磺酸盐β晶型11.7g，收率98％。
Claims (4)
1.一种伊玛替尼甲烷磺酸盐β晶型的制备方法，其特征在于，将伊玛替尼悬浮于酯类有机溶剂中，使温度维持在55℃～90℃，然后加入甲烷磺酸或甲烷磺酸溶液，继续保持55℃～90℃反应0.5h～2h，加入0.1％～2％β晶型伊玛替尼甲烷磺酸盐作引发晶种，缓慢降温至0℃～20℃，然后以50rpm～400rpm的转速保温搅拌10h～20h析晶，过滤，干燥，得到伊玛替尼甲烷磺酸盐β晶型；其中伊玛替尼与甲烷磺酸的投料摩尔比例为1:0.95～1:1.05，所述的酯类有机溶剂选自乙酸乙酯、乙酸仲丁酯、乙酸异丁酯、乙酸丙酯、乙酸丁酯、乙酸异丙酯、乙酸叔丁酯中的一种。
2.根据权利要求1所述的制备方法，其特征在于所述干燥为普通加热干燥或20℃～60℃真空干燥。
3.根据权利要求2所述的制备方法，其特征在于所述干燥为20℃～50℃真空干燥。
4.根据权利要求1～3中任一项所述的制备方法，其特征在于所述的酯类有机溶剂选自乙酸乙酯、乙酸异丙酯、乙酸丁酯、乙酸异丁酯中的一种。
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