阿哌沙班及有关物质的合成
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摘要
目的合成凝血因子Xa抑制剂阿哌沙班及其有关物质,有关物质可作为阿哌沙班的质量控制的对照品。方法以4,5,6,7-四氢-1-(4-甲氧基苯基)-7-氧代-6-(4-硝基苯基)-1H-吡唑并[3,4-c]吡啶-3-羧酸乙酯(6)为起始原料,经还原、酰胺化、环合、氨解反应得到阿哌沙班,同时合成4个阿哌沙班有关物质。结果与结论所得阿哌沙班HPLC检测纯度为99.6%,总收率为43.8%(以化合物6计)。合成的阿哌沙班以及4个阿哌沙班有关物质,结构经MS、1H-NM R确认。
Objective To synthesize apixaban,a safe and efficacious oral factor Xa inhibitor andit w as developed by Bristol-Myers Squibb Company and Pfizer Company for the treatment of venous and arterial thrombosis. Methods It w as synthesized from 6-( 4-nitrophenyl)-1-( 4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo [3,4-c] pyridine-3-ethylcarboxylate( 6) by reduction,amidation,cyclization,elimination and ammonolysis w ith an overall yield of 43. 8%( based on compound 6) and an HPLC purity of99. 6%. Meanw hile,four related substances w ere also prepared. Result and conclusion The structures of apixaban and four related compounds w ere confirmed by ESI-MS and1 H-NMR.
Objective To synthesize apixaban,a safe and efficacious oral factor Xa inhibitor andit w as developed by Bristol-Myers Squibb Company and Pfizer Company for the treatment of venous and arterial thrombosis. Methods It w as synthesized from 6-( 4-nitrophenyl)-1-( 4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo [3,4-c] pyridine-3-ethylcarboxylate( 6) by reduction,amidation,cyclization,elimination and ammonolysis w ith an overall yield of 43. 8%( based on compound 6) and an HPLC purity of99. 6%. Meanw hile,four related substances w ere also prepared. Result and conclusion The structures of apixaban and four related compounds w ere confirmed by ESI-MS and1 H-NMR.
引文
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[10]王辉,褚倩倩,哈婧,等.阿哌沙班的合成新工艺[J].中国新药杂志,2015,24(11):1290-1294.
[11]GANT T G,SHANBAZ M.Pyrazolecarboxamide inhibitors of factorⅩa:2010030983[P].2010-03-18.
[12]何超,侯云雷,祝妍,等.阿哌沙班的合成[J].中国医药工业杂志,2014,45(10):906-910.
[2]DONALD J P,MICHAEL J O,STEPHANIE K,et al.Discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1Hpyrazolo[3,4-c]pyridine-3-carboxamide(apixaban,BM S-562247)a highly potent,selective,efficacious,and orally bioavailable inhibitor of blood coagulationfactor Xa[J].Journal of M edicinal Chemistry,2007,50(22):5339-5356.
[3]WONG P C,JIANG X.Apixaban,a direct factor Xa inhibitor,inhibits tissue-factor induced human platelet aggregation in vitro:comparison w ith direct inhibitors of factorⅦa,Ⅺa and thrombin[J].Thrombsis and Haemostasis,2010,104:302-310.
[4]EUROPEAN MEDICINES AGENCY.Eliquis(apixaban)Summary of product characteristics[EB/OL].[2013-05-27].http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002148/WC500107728.pdf.
[5]PHARMACEUTICALS AND MEDICAL DEVICES AGENCY.Summary of investigation results apixaban[EB/OL].[2015-02-17].http://www.pmda.go.jp/english/
[6]尚振华,王江霞.一种阿哌沙班的制备方法:104045637A[P].2014-09-17.
[7]陶海燕,米斌,郭国贤,等.阿哌沙班的合成工艺研究[J].中国药物化学杂志,2013,23(5):385-389.
[8]ZHOU J C,MA P,LI H Y,et al.Synthesis of 4,5-dihydropyrazolo[3,4-c]pyrid-2-ones:2003049681[P].2003-06-19.
[9]RAFAEL S,LUCIUS T R,BOGUSLAW M,et al.Process for preparing 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones:20060069258A1[P].2006-03-30.
[10]王辉,褚倩倩,哈婧,等.阿哌沙班的合成新工艺[J].中国新药杂志,2015,24(11):1290-1294.
[11]GANT T G,SHANBAZ M.Pyrazolecarboxamide inhibitors of factorⅩa:2010030983[P].2010-03-18.
[12]何超,侯云雷,祝妍,等.阿哌沙班的合成[J].中国医药工业杂志,2014,45(10):906-910.