CN108640903A - 一种达比加群酯中间体的制备方法 - Google Patents
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
本发明属于医药制备技术领域，特别涉及一种达比加群酯中间体的制备方法。本发明所采用的化合物6具有性质稳定、无刺激性气味，价格便宜等特点。克服了现有达比加群酯中间体合成路线采用酸酐或者酰氯类化合物的缺陷，这类化合物的缺点是有刺激性气味、有吸湿性，对反应体系的无水要求高。本发明的反应过程更易操作和控制，选择性高、收率稳定。
Description
技术领域
本发明属于医药制备技术领域，特别涉及一种达比加群酯中间体的制备方法。
背景技术
达比加群酯是由德国勃林格殷格翰公司研制开发的一种新型直接凝血酶抑制剂，它是达比加群的前体药物，属非肽类的凝血酶抑制剂。达比加群酯在2008年4月在德国和英国率先上市，同年8月获得欧盟委员会的许可，在欧盟27个成员国上市，2010年11月该药在美国上市，商品名为Pradaxa，它也成为了继华发林之后50年来第一个在美国上市的直接口服性抗凝血类新药。达比加群酯的结构式如图1所示，它是一种新型的合成的直接凝血酶抑制剂，“新型”是指其作用机制不同于以往的抗凝类药物，不像华法林那样抑制维生素K与凝血因子的结合来阻碍凝血酶的产生，也不像肝素、利伐沙班等药物那样通过抑制凝血因子来阻碍凝血酶的合成，而是直接作用于凝血酶纤维蛋白，发挥抗凝作用。达比加群酯的上市是抗凝血治疗领域和潜在致死性血栓预防领域的一项重大进展，具有里程碑意义。达比加群酯代替华法林的进度是相当快的，市场估计达比加群酯有成为重磅炸弹的潜力，预计最高销售收入将达到90亿美元左右。因此，对达比加群酯项目的开发具有重大的现实意义。
2011年勃林格殷格翰首次公布了合成达比加群酯的路线(US2011/275824)，如图2所示，该路线具有选择性高、易操作等优点。该路线中通过使用化合物2关环得到关键中间体3，化合物2在该专利中涵盖了以下试剂：氯乙酸酐、氯乙酸、氯乙酰氯。中国专利CN104447697中，报道了用氯乙酸乙酯也可以关环得到关键中间体3。
但上述合成路线都采用了酸酐或者酰氯类化合物，这类化合物的特点是有刺激性气味、有吸湿性，对反应体系的无水要求高。
发明内容
本发明的目的在于克服现有技术的不足，提供一种选择性高、收率稳定、易操作，同时反应原料性质稳定、无刺激性气味，价格便宜的达比加群酯中间体的制备方法。
为了达到上述目的，本发明所设计的一种达比加群酯中间体的制备方法，其合成路线如下：
其中：化合物6中的X指氯、溴、碘、TsO、MsO等易被亲核试剂进攻的离去基团；R指的是一个碳至六个碳的直链、支链或含环状的烷基，进一步R指的是甲基、乙基、正丙基、异丙基、正丁基或环己基，更进一步R指的是甲基或乙基。
作为优选，反应溶剂为DMF、DMSO、NMP、THF、二氯甲烷、二氧六环、甲醇、乙醇、异丙醇、丙酮和水中的一种或者几种的混合溶剂。
作为优选，反应温度为-15℃～100℃，进一步是15℃～40℃。
作为优选，反应催化剂为对甲苯磺酸的一水合物或者无水物、乙酸、三氟乙酸、盐酸、硫酸等。
作为优选，反应时间为6～24小时。
本发明所采用的化合物6具有性质稳定、无刺激性气味，价格便宜等特点。克服了现有达比加群酯中间体合成路线采用酸酐或者酰氯类化合物的缺陷，这类化合物的缺点是有刺激性气味、有吸湿性，对反应体系的无水要求高。本发明的反应过程更易操作和控制，选择性高、收率稳定。
能够对本发明的反应机理作出解释的参考文献为：J.Med.Chem.,2015,58(22),8877–8895,WO2006/20415，WO2006/96444。
附图说明
图1为达比加群酯的结构式。
图2为勃林格殷格翰公布的合成达比加群酯的路线。
图3为本发明实施例1-3合成达比加群酯中间体的路线。
具体实施方式
实施例1
如图3所示，一种达比加群酯中间体的制备方法，具体工艺步骤如下：
将化合物8(5.0g,14.60mmol)溶于二氯甲烷(50mL)，加入化合物5(2-氯原乙酸三甲酯，6.77g,43.81mmol)、对甲苯磺酸(251mg,1.46mmol)；加料完毕后，反应体系在20～25℃下反应11～12小时；反应完毕，加入纯化水(30mL)，分液萃取，水相再用二氯甲烷萃取(20mL X 2)；合并有机相，用饱和食盐水(40mL)洗涤；有机相用无水硫酸钠干燥，过滤、减压浓缩得粗品，经柱层析(洗脱剂：二氯甲烷:甲醇＝15:1)得到化合物9(4.7g,收率:80.3％)。
其核磁共振谱图数据如下：1H NMR(400MHz,CDCl3)δ8.43-8.41(m,1H),7.70(s,1H),7.38-7.32(m,2H),7.16(d,J＝8.48Hz,1H),7.00-6.96(m,1H),6.70(d,J＝8.04Hz,1H),4.78(s,2H),4.42(t,J＝7.24Hz,2H),4.06(q,J＝7.12Hz,2H),3.81(s,3H),2.80(t,J＝7.32Hz,2H),1.20(t,J＝7.12Hz,2H)。
实施例2
如图3所示，一种达比加群酯中间体的制备方法，具体工艺步骤如下：
将化合物8(5.0g,14.60mmol)溶于二氯甲烷(50mL)，加入化合物5(2-氯原乙酸三乙酯，8.62g,43.81mmol)、对甲苯磺酸(251mg,1.46mmol)；加料完毕后，反应体系在20～25℃下反应11～12小时；反应完毕，加入纯化水(30mL)，分液萃取，水相再用二氯甲烷萃取(20mL X 2)；合并有机相，用饱和食盐水(40mL)洗涤；有机相用无水硫酸钠干燥，过滤、减压浓缩得粗品，经柱层析(洗脱剂：二氯甲烷:甲醇＝15:1)得到化合物9(4.3g,收率:73.5％)。
其核磁共振谱图数据如下：1H NMR(400MHz,CDCl3)δ8.43-8.41(m,1H),7.70(s,1H),7.38-7.32(m,2H),7.16(d,J＝8.48Hz,1H),7.00-6.96(m,1H),6.70(d,J＝8.04Hz,1H),4.78(s,2H),4.42(t,J＝7.24Hz,2H),4.06(q,J＝7.12Hz,2H),3.81(s,3H),2.80(t,J＝7.32Hz,2H),1.20(t,J＝7.12Hz,2H)。
实施例3
如图3所示，一种达比加群酯中间体的制备方法，具体工艺步骤如下：
将化合物8(5.0g,14.60mmol)溶于二氯甲烷(50mL)，加入化合物5(2-溴原乙酸三甲酯，8.72g,43.81mmol)、对甲苯磺酸(251mg,1.46mmol)；加料完毕后，反应体系在20～25℃下反应11～12小时；反应完毕，加入纯化水(30mL)，分液萃取，水相再用二氯甲烷萃取(20mL X 2)；合并有机相，用饱和食盐水(40mL)洗涤；有机相用无水硫酸钠干燥，过滤、减压浓缩得粗品，经柱层析(洗脱剂：二氯甲烷:甲醇＝15:1)得到化合物9(5.1g,收率:78.4％)。
其核磁共振谱图数据如下：1H NMR(400MHz,CDCl3)δ8.43-8.41(m,1H),7.70(s,1H),7.38-7.32(m,2H),7.16(d,J＝8.48Hz,1H),7.00-6.96(m,1H),6.70(d,J＝8.04Hz,1H),4.65(s,2H),4.42(t,J＝7.24Hz,2H),4.06(q,J＝7.12Hz,2H),3.81(s,3H),2.80(t,J＝7.32Hz,2H),1.20(t,J＝7.12Hz,2H)。
Claims (8)
1.一种达比加群酯中间体的制备方法，其特征在于：其合成路线如下：
其中：化合物6中的X指氯、溴、碘、TsO、MsO等易被亲核试剂进攻的离去基团；R指的是一个碳至六个碳的直链、支链或含环状的烷基。
2.根据权利要求1所述的一种达比加群酯中间体的制备方法，其特征在于：R指的是甲基、乙基、正丙基、异丙基、正丁基或环己基。
3.根据权利要求2所述的一种达比加群酯中间体的制备方法，其特征在于：R指的是甲基或乙基。
4.根据权利要求1所述的一种达比加群酯中间体的制备方法，其特征在于：反应溶剂为DMF、DMSO、NMP、THF、二氯甲烷、二氧六环、甲醇、乙醇、异丙醇、丙酮和水中的一种或者几种的混合溶剂。
5.根据权利要求1所述的一种达比加群酯中间体的制备方法，其特征在于：反应温度为-15℃～100℃。
6.根据权利要求5所述的一种达比加群酯中间体的制备方法，其特征在于：反应温度为15℃～40℃。
7.根据权利要求1所述的一种达比加群酯中间体的制备方法，其特征在于：反应催化剂为对甲苯磺酸的一水合物或者无水物、乙酸、三氟乙酸、盐酸、硫酸中的一种。
8.根据权利要求1所述的一种达比加群酯中间体的制备方法，其特征在于：反应时间为6～24小时。
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Citations (3)
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| CN101454292A (zh) * | 2006-03-31 | 2009-06-10 | 阿斯利康(瑞典)有限公司 | 双环苯并咪唑化合物及其作为代谢型谷氨酸受体增效剂的用途 |
| US20110275824A1 (en) * | 2009-11-18 | 2011-11-10 | Boehringer Ingelheim International Gmbh | Process for the manufacture of dabigatran etexilate |
| CN102850325A (zh) * | 2012-06-19 | 2013-01-02 | 上海现代制药海门有限公司 | 一种达比加群酯关键中间体的制备方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101454292A (zh) * | 2006-03-31 | 2009-06-10 | 阿斯利康(瑞典)有限公司 | 双环苯并咪唑化合物及其作为代谢型谷氨酸受体增效剂的用途 |
| US20110275824A1 (en) * | 2009-11-18 | 2011-11-10 | Boehringer Ingelheim International Gmbh | Process for the manufacture of dabigatran etexilate |
| CN102850325A (zh) * | 2012-06-19 | 2013-01-02 | 上海现代制药海门有限公司 | 一种达比加群酯关键中间体的制备方法 |
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