CN105218482B - 沃替西汀氢溴酸盐β晶型的制备方法 - Google Patents
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Abstract
本发明提供了一种沃替西汀氢溴酸盐β晶型的制备方法，所述制备方法包括以下步骤：使沃替西汀在有机溶剂中与氢溴酸成盐得到浆料，或将沃替西汀氢溴酸盐非β晶型于有机溶剂中悬浮搅拌形成浆料，然后室温搅拌6～24小时，过滤、滤饼用有机溶剂洗涤、干燥得到沃替西汀氢溴酸盐β晶型；所述的有机溶剂选自下列一种或者任意几种的组合：甲醇、乙醇、无水乙醇、正丙醇、丁醇、仲丁醇、N,N‑二甲基甲酰胺、N,N‑二甲基乙酰胺、环己烷、庚烷、硝基甲烷。本发明提供的沃替西汀氢溴酸盐β晶型的制备方法操作简单，重现性好，不会出现溶剂化物，收率高，非常有利于工业化生产。
Description
技术领域
本发明属于药物化学合成技术领域，涉及一种沃替西汀氢溴酸盐β晶型的制备方法。
背景技术
沃替西汀，属于新一代抗抑郁药，被认为通过两种作用机制发挥作用：受体活性调节和再摄取抑制。体外研究表明，沃替西汀是5-HT3和5-HT7受体拮抗剂、5-HT1B受体部分激动剂、5-HT1A受体激动剂、5-羟色胺转运蛋白(SERT)抑制剂。体内非临床研究表明，沃替西汀可提高大脑特定区域神经递质——血清素、去甲肾上腺素、多巴胺、乙酰胆碱、组胺的水平。沃替西汀的多模式作用属性(multimodal activity profile)有望为那些使用现有药物未能充分控制症状的重度抑郁症患者带来临床收益。灵北公司称，在此前的一项研究中，沃替西汀的疗效被证明优于阿戈美拉汀，并希望在该公司现有的抗抑郁药物Cipralex(来士普)的专利到期后，抗抑郁新药能够提供新的收益来源。
专利CN101472906A保护了沃替西汀氢溴酸盐β晶型，并提供了沃替西汀氢溴酸盐β晶型的制备方法，本申请发明人重复了其中的制备步骤：沃替西汀溶解于乙酸乙酯中，加入48％-wt的HBr(aq)。该添加操作形成了浓稠的浆料，将该浆料在室温(25℃)下搅拌过夜。过滤，并在真空下干燥(50℃)过夜，得到产物。所得产物的XRD图谱见图9，根据XRD图谱，发明人发现根据上述工艺制备得到的产物为α晶型和乙酸乙酯溶剂化物，可见该工艺重现性不好，工艺很不稳定，并且收率低，仅为47％。
发明内容
本发明的目的在于提供一种工艺稳定、重现性好、收率高的的沃替西汀氢溴酸盐β晶型的制备方法。
为实现上述发明目的，本发明采用了如下技术方案：
本发明所述的沃替西汀氢溴酸盐β晶型的制备方法，包括以下步骤：
使沃替西汀在有机溶剂中与氢溴酸成盐得到浆料，或将沃替西汀氢溴酸盐非β晶型于有机溶剂中悬浮搅拌形成浆料，然后继续搅拌6～24小时，再经过滤、滤饼用有机溶剂洗涤、干燥得到沃替西汀氢溴酸盐β晶型；所述的有机溶剂选自下列一种或者任意几种的组合：甲醇、乙醇、无水乙醇、正丙醇、丁醇、仲丁醇、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、环己烷、庚烷、硝基甲烷。
本发明中，沃替西汀氢溴酸盐非β晶型可以是各种晶型，如CN101472906A所阐述的α晶型，乙酸乙酯化物或它们的混合物等。
本发明中，所述的有机溶剂优选为无水乙醇、N,N-二甲基乙酰胺或硝基甲烷，最优选为无水乙醇。
本发明中，有机溶剂的体积用量以沃替西汀或沃替西汀氢溴酸盐非β晶型的重量计为1～100mL/g，优选2～50mL/g，更优选3～10mL/g，再更进一步优选为5～10mL/g，最优选为10mL/g。
本发明中，对反应体系的温度没有特别的要求，在低于溶剂的回流温度的范围内均可，可以在0～100℃范围内选择任意一个温度范围，优选为室温，最优选常温。
本发明的一个典型实施例是将沃替西汀溶解于无水乙醇中，滴加入48wt.％的HBr水溶液，固体立即析出，滴加完毕后，室温搅拌过夜，过滤，滤饼用乙醇洗涤，鼓风干燥过夜得到沃替西汀氢溴酸盐β晶型。
本发明的的另一个典型实施例是将沃替西汀氢溴酸盐非β晶型在无水乙醇中悬浮搅拌过夜，过滤，滤饼用乙醇洗涤，鼓风干燥过夜得到沃替西汀氢溴酸盐β晶型。
与现有技术相比，本发明提供的沃替西汀氢溴酸盐β晶型的制备方法，使得工艺能稳定地获得目标晶型，并且工艺重现性好，目标晶型收率大大提高。
附图说明
图1：实施例1所得沃替西汀氢溴酸盐β晶型的XRPD。
图2：实施例1所得沃替西汀氢溴酸盐β晶型的HPLC。
图3：实施例2所得沃替西汀氢溴酸盐β晶型的XRPD。
图4：实施例3所得沃替西汀氢溴酸盐β晶型的XRPD。
图5：实施例4所得沃替西汀氢溴酸盐β晶型的XRPD。
图6：实施例5所得沃替西汀氢溴酸盐β晶型的XRPD。
图7：实施例6所得沃替西汀氢溴酸盐β晶型的XRPD。
图8：实施例7所得沃替西汀氢溴酸盐β晶型的XRPD。
图9：重复专利CN101472906沃替西汀氢溴酸盐β晶型的制备方法所得产品的XRPD。
具体实施方式
通过下述实施例有助于理解本发明，但不限制本发明内容。
实施例1
将5.90g沃替西汀溶解于30mL无水乙醇中，25℃下加入2.5mL48wt.％的HBr(aq)。该添加操作形成了浆料，将该浆料在25℃下搅拌16小时过滤，滤饼用乙醇洗涤，再在40℃鼓风干燥箱干燥过夜，生成6.72g产物，收率为89.6％，纯度99.33％。
实施例2
将5.01g沃替西汀氢溴酸盐(α晶型和乙酸乙酯溶剂化物)悬浮于50mL无水乙醇中，形成的浆液，20℃搅拌16小时。过滤，滤饼用乙醇洗涤，再在40℃鼓风干燥箱干燥过夜，生成4.62g产物，收率为92.0％，纯度99.22％。
实施例3
将5.00g沃替西汀氢溴酸盐(α晶型和乙酸乙酯溶剂化物)悬浮于15mL N,N-二甲基乙酰胺中，形成的浆液，16℃搅拌16小时。过滤，滤饼用N,N-二甲基乙酰胺洗涤，再在40℃鼓风干燥箱干燥过夜，生成4.05g产物，收率为81.0％，纯度为97.65％。
实施例4
将5.02g沃替西汀氢溴酸盐(α晶型和乙酸乙酯溶剂化物)悬浮于50mL硝基甲烷中，形成的浆液，16℃搅拌16小时。过滤，滤饼用硝基甲烷洗涤，再在40℃鼓风干燥箱干燥过夜，生成4.81g产物，收率为95.8％，纯度为96.05％。
实施例5
将5.00g沃替西汀氢溴酸盐(α晶型)悬浮于50mL无水乙醇中，形成的浆液，50℃搅拌16小时。过滤，滤饼用乙醇洗涤，再在40℃鼓风干燥箱干燥过夜，生成4.32g产物，收率为86.4％，纯度99.61％。
实施例6
将5.00g沃替西汀氢溴酸盐(α晶型和乙酸乙酯溶剂化物)悬浮于50mL无水乙醇中，形成的浆液，20℃搅拌4小时。过滤，滤饼用乙醇洗涤，再在40℃鼓风干燥箱干燥过夜，生成4.44g产物，收率为88.8％，纯度99.42％。
实施例7
将5.00g沃替西汀氢溴酸盐(α晶型和乙酸乙酯溶剂化物)悬浮于50mL无水乙醇中，形成的浆液，20℃搅拌8小时。过滤，滤饼用乙醇洗涤，再在40℃鼓风干燥箱干燥过夜，生成4.53g产物，收率为90.6％，纯度99.32％。
Claims (6)
1.一种沃替西汀氢溴酸盐β晶型的制备方法，包括以下步骤：将沃替西汀溶解于无水乙醇中，滴加入48wt.％的HBr水溶液，固体立即析出，滴加完毕后，室温搅拌过夜，过滤，滤饼用乙醇洗涤，鼓风干燥过夜得到沃替西汀氢溴酸盐β晶型；
有机溶剂的体积用量以沃替西汀重量计为5～10mL/g。
2.一种沃替西汀氢溴酸盐β晶型的制备方法，包括以下步骤：将沃替西汀氢溴酸盐非β晶型于有机溶剂中悬浮搅拌形成浆料，然后继续搅拌6～24小时，再过滤、滤饼用有机溶剂洗涤、干燥得到沃替西汀氢溴酸盐β晶型；
所述有机溶剂为无水乙醇、N,N-二甲基乙酰胺或硝基甲烷；
有机溶剂的体积用量以沃替西汀氢溴酸盐非β晶型的重量计为3～10mL/g；
搅拌温度为16～50℃。
3.根据权利要求2所述的制备方法，其特征在于：所述有机溶剂为无水乙醇。
4.根据权利要求3所述的制备方法，其特征在于：有机溶剂的体积用量以沃替西汀氢溴酸盐非β晶型的重量计为5～10mL/g。
5.根据权利要求4所述的制备方法，其特征在于：有机溶剂的体积用量以沃替西汀氢溴酸盐非β晶型的重量计为10mL/g。
6.根据权利要求2所述的制备方法，其特征在于所述的制备方法按照如下进行：将沃替西汀氢溴酸盐非β晶型在无水乙醇中悬浮搅拌过夜，过滤，滤饼用乙醇洗涤，鼓风干燥过夜得到沃替西汀氢溴酸盐β晶型。
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| CN102317272A (zh) * | 2009-02-17 | 2012-01-11 | H.隆德贝克有限公司 | 1-[2-(2,4-二甲基苯基硫基)苯基]哌嗪的提纯 |
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