CN100427480C - 阿加曲班水合物的制备方法 - Google Patents

阿加曲班水合物的制备方法 Download PDF

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CN100427480C
CN100427480C CNB2006101293325A CN200610129332A CN100427480C CN 100427480 C CN100427480 C CN 100427480C CN B2006101293325 A CNB2006101293325 A CN B2006101293325A CN 200610129332 A CN200610129332 A CN 200610129332A CN 100427480 C CN100427480 C CN 100427480C
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宋洪海
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Abstract

本发明涉及一种阿加曲班水合物的制备方法，将阿加曲班(Argatroban)与水回流0.5-1.0小时，溶解后冷却至室温，析出白色结晶，过滤，水洗两次，干燥，得到医用Argatroban一水合物。本发明首先保证R和S比例不变，同时保证所有无结晶水的Argatroban转化为一水合Argatroban，同时能较好的除去其它有机杂质，水合收率达90%-95%。与文献15%乙醇作为溶剂比较，操作条件温和、收率高、产品质量高。

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阿加曲班水合物的制备方法
技术领域
本发明涉及一种阿加曲班水合物的制备方法。
技术背景：
1978年日本Mitsubishi化学公司S.Okamoto等首次报导了阿加曲班(Argatroban)水合物抗凝血酶活性【US 4 101 653】。随后20多年期间，众多研究者对Argatroban的生物活性及作为医药的价值进行了深入研究。1981年，S.Okamoto在动物体内与肝素进行了比较【Okamoto，S.et al.，Biochem.Biophys.Res.Commun.101，440(1981)】；T.Kumoto等对其立体选择活性进行了报导【Kumada，T.et al.，Thromb.Res.24，285(1981)】；1984年，R.Kumato进行了临床血液透析评价【Kikumoto，R.et al.，Biochemistry 23，85(1984)】；1986年该作者报导了Argatroban抑制哺乳动物凝血酶活性，可作为治疗和预防血栓药剂和血小板凝聚抑制剂。Argatroban一水合物可作为选择性抗血栓剂、治疗慢性动脉堵塞和脑血栓等【JP 61-48829】。1992年和1993年，Taparelli和J.A.Jakubowski先后报导了Argatroban抗凝血酶的可逆性【Taparelli，C.，Trends Pharmacol.Sci.，1993，14，366，Jakubowski，J.A.et al，Rep.Med.Chem.，1992，27，99】；90年代L.R.Buch等多位研究者报导了相关研究【Buch，L.R.，Cadiosvasc.Drug Rev.，1991，9，247，Strupcnewski，J.D.et al.，Academic：San Diego，1991；Vol.26，p299，Brundish，D.et al.，J.Med.Chem.1999；42，4584，Shebuski，R.J.，Academic：San Diego，1999；Vol.26，p98】。1992年日本批准作为非肠道使用抗凝血酶药剂【Hijikata-Okunomiya，A.，et al，Thromb.Hemostasis，1992，18，135】。
阿加曲班的化学名称：(2R，4R)-1-[(2S)-5-[(Aminoiminomethyl)amino]-1-oxo-2-[[(1，2，3.4-tetrahydro-3-methyl-8-quinolinyl)sulfonyl]amino]pentyl]-4-methyl-2-piperidinecarboxylic acid，其化学成分是21(R)和21(S)的混合物，通常是64-65：36-35【US 6 440 417，Cossy.J.，et al，Bioorganic & Medicine Chemistry Letters，11(2001)，1989-1992，Journal ofPharmaceutical Sciences，Vol.82，No.6，672(1993)】。化学式：
Figure C20061012933200031
现报导的Argatroban合成路线都是以硝基-L-精氨酸为起始原料、以哌啶羧酸酯或喹啉磺酰氯缩合先后次序不同，构成两条主要路线。当首先与哌啶羧酸酯缩合时，称氨基保护法：硝基-L-精氨酸的氨基用t-Boc保护、再与哌啶羧酸酯缩合、去Boc保护基、与喹啉磺酰氯缩合、酯水解、氢化去硝基得无结晶水Argatroban。若首先与喹啉磺酰氯缩合时称非保护法：硝基精氨酸与喹啉磺酰氯缩合后再与哌啶羧酸酯缩合、酯水解、氢化去硝基，亦得无结晶水目标产物。文献报导上述产品用15％乙醇重结晶，可得医用Argatroban一水合物。具体说：
氨基保护法：
1.硝基精氨酸t-Boc保护后与(2R，4R)哌啶甲酸酯缩合【EP 8746，US 4 258 192，US 4201 863，JP 81-15,267，US 6 440 417，特许公报平2-31055】。
2.硝基精氨酸t-Boc保护后与反式哌啶羧酸酯缩合、分离、拆分，再与喹啉磺酰氯缩合【Cossy.J.，et al，Bioorganic & Medicine Chemistry Letters，11(2001)，1989-1992】。
非保护法：
当L-精氨酸直接与喹啉磺酰氯缩合时反应副产物多、不易分离，不适合于工业化生产【特许公报平1-35000】。硝基-L-精氨酸为原料时反应产品单一，操作简易，适于工业化生产【EP 823 430】。
上述文献报导的方法用15％乙醇重结晶，R、S比例变化较大，不符合医用R∶S＝63～67∶37～33的范围，而且不能很好的除去其它有机杂质，很难保证产品质量，收率较低，有时不能保证完全水合。
发明内容
本发明的目的是提供一种阿加曲班水合物的制备方法，使用不同路线可制得医用一水合Argatroban，首先保证R和S比例不变，同时保证所有无结晶水的Argatroban转化为一水合Argatroban。采用水做溶剂可获得满意的结果，一水合相当完全。R、S比例变化较小，同时能较好的除去其它有机杂质，水合收率达90％-95％。
本发明提供的阿加曲班水合物的制备方法包括的步骤：
将Argatroban，加入蒸馏水中，升温80℃-100℃至回流0.5-1.0小时，固体全部溶解后，自然冷却至室温，析出白色结晶，过滤。水洗两次，100℃以内干燥，得到Argatroban一水合物。采用卡尔费休法测定水含量，Argatroban·H2O理论含水量3.4％，实验结果分析3.3-3.8％，元素分析S、N和H结果合格。
所述的阿加曲班的水含量3.3-3.8％。
所述的阿加曲班的右旋体R与左旋体S的比值：R∶S＝63～67∶37～33。
本发明提供的阿加曲班水合物的制备方法可制得医用一水合Argatroban，首先保证R和S比例不变，同时保证所有无结晶水的Argatroban转化为一水合Argatroban。采用水做溶剂可获得满意的结果，一水合相当完全。R，S比例变化较小，同时能较好的除去其它有机杂质，水合收率达90％-95％。与文献15％乙醇作为溶剂比较，操作条件温和、收率高、产品质量高。
附图说明
图1硝基精氨酸t-Boc保护后与(2R，4R)哌啶甲酸酯缩合反应路线图示。
图2硝基精氨酸t-Boc保护后与反式哌啶羧酸酯缩合、分离、拆分，再与喹啉磺酰氯缩合反应路线图示。
图3非保护法反应路线图示。
具体实施方式
实施例1.将65g Argatroban(R∶S＝65∶35)固体，加入4200ml蒸馏水中，慢慢升温至回流，固体全部溶解后，自然冷却至室温，析出白色结晶，过滤。水洗两次，100℃以内干燥，得到Argatroban一水合物将65g Argatroban(R∶S＝65∶35)，加入4200ml蒸馏水中，慢慢升温至回流，固体全部溶解后，自然冷却至室温，析出白色结晶，过滤。水洗两次，100℃以内干燥，得到Argatroban一水合物59克。收率87.3％。21(R)∶21(S)＝64.5∶34.5(HPLC法)，水含量3.55％(卡尔费休法)。
元素分析：
实验值：             S：5.95％     N：15.05％     H：7.35％
计算值(C23H38N6O6S)：S：6.08％     N：15.96％     H：7.27％
实施例2.将50克Argatroban(R∶S＝65∶35)，加入4000ml蒸馏水，升温至90℃，搅拌反应两小时，然后自然冷却至室温，析出白色结晶，过滤。水洗两次，100℃以内干燥，得到Argatroban一水合物46.8克，收率90.4％。21(R)∶21(S)＝64.8∶35.2(HPLC法)，水含量3.34％(卡尔费休法)。
元素分析：
实验值：             S：5.87％    N：15.23％    H：7.05％
计算值(C23H38N6O6S)：S：6.08％    N：15.96％    H：7.27％
对比实例.将20g Argatroban(R∶S＝65∶35)，加入120ml 15％乙醇，加热回流1小时，自然冷却至室温，析出白色结晶，过滤。水洗两次，100℃以内干燥，得产物18.9克，收率91.3％。21(R)∶21(S)＝61.5∶38.3(HPLC法)，水含量3.66％(卡尔费休法)。
元素分析：
实验值：             S：6.00％    N：16.03％    H：7.63％
计算值(C23H38N6O6S)：S：6.08％    N：15.96％    H：7.27％。

Claims (3)

1、一种阿加曲班水合物的制备方法，其特征在于它的步骤是：
将阿加曲班固体与水在温度80℃-100℃下回流0.5-1.0小时，固体全部溶解后，自然冷却至室温，析出白色结晶，过滤，水洗两次，100℃以内干燥，得到阿加曲班一水合物。
2、根据权利要求1所述的方法，其特征在于所述的阿加曲班的一水合物的水含量为3.3-3.8％。
3、根据权利要求1所述的方法，其特征在于所述的阿加曲班一水合物的右旋体R与左旋体S的比值：R∶S＝63～67∶37～33。
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101519429B (zh) * 2009-03-31 2012-07-25 深圳翰宇药业股份有限公司 一种固相法合成阿加曲班的方法
WO2012136504A1 (en) * 2011-04-04 2012-10-11 Lundbeck Pharmaceuticals Italy S.P.A. Method for the preparation of process intermediates for the synthesis of argatroban monohydrate

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101362746B (zh) * 2007-08-06 2011-12-28 博瑞生物医药技术(苏州)有限公司 阿加曲班单一立体异构体的分离方法及多晶型物
ITPD20080106A1 (it) * 2008-04-07 2009-10-08 Lundbeck Pharmaceuticals Italy Spa Metodo di preparazione di argatroban monoidrato
CN102408468B (zh) * 2011-09-20 2012-11-21 海南灵康制药有限公司 一种阿加曲班化合物及其制法
CN103772486B (zh) * 2014-01-06 2016-01-20 天津大学 一种阿加曲班新晶型及其制备方法

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EP0008746A1 (en) * 1978-08-31 1980-03-19 Mitsubishi Kasei Corporation Alpha-(N-arylsulfonyl-L-argininamides, processes for their preparation and pharmaceutical compositions containing these substances
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101519429B (zh) * 2009-03-31 2012-07-25 深圳翰宇药业股份有限公司 一种固相法合成阿加曲班的方法
WO2012136504A1 (en) * 2011-04-04 2012-10-11 Lundbeck Pharmaceuticals Italy S.P.A. Method for the preparation of process intermediates for the synthesis of argatroban monohydrate
US9994526B2 (en) 2011-04-04 2018-06-12 Lundbeck Pharmaceuticals Italy S.P.A. Process intermediates and methods for the preparation of process intermediates for the synthesis of argatroban monohydrate
US10385020B2 (en) 2011-04-04 2019-08-20 Lundbeck Pharmaceuticals Italy S.P.A. Process intermediates and methods for the preparation of process intermediates for the synthesis of argatroban monohydrate

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