阿哌沙班的合成改进
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摘要
对硝基苯胺与?-戊内酯进行酰胺化、环化、双氯取代和消除反应得到3-(吗啉-4-基)-1-(4-硝基苯基)-5,6-二氢-1H-吡啶-2-酮,与[(4-甲氧基苯基)肼基]氯乙酸乙酯经1,3-偶极环加成反应、消除、还原、酰胺化、环化反应得到阿哌沙班,总收率为47.8%(以对硝基苯胺计),纯度为99.9%。
Apixaban was synthesized from 4-nitroaniline and 5-valerolactone by amidation,cyclization,dichlorination and elimination to give 3-(4-morpholinyl)-1-(4-nitrophenyl)-5,6-dihydropyridin-2(1H)-one,which was subjected to 1,3-dipolar cycloaddition with ethyl(2Z)-2-chloro-2-[(4-methoxyphenyl) hydrazinylidene]acetate,elimination,reduction,amidation and cyclization with an overall yield of 47.8%(based on 4-nitroaniline) and HPLC purity of 99.9%.
Apixaban was synthesized from 4-nitroaniline and 5-valerolactone by amidation,cyclization,dichlorination and elimination to give 3-(4-morpholinyl)-1-(4-nitrophenyl)-5,6-dihydropyridin-2(1H)-one,which was subjected to 1,3-dipolar cycloaddition with ethyl(2Z)-2-chloro-2-[(4-methoxyphenyl) hydrazinylidene]acetate,elimination,reduction,amidation and cyclization with an overall yield of 47.8%(based on 4-nitroaniline) and HPLC purity of 99.9%.
引文
[1]王磊,钟静芬,时惠麟.口服Ⅹa因子直接抑制剂阿哌沙班的临床研究进展[J].上海医药,2012,33(17):17—20.
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[3]王冠,郭晔堃,钟静芬,等.阿哌沙班合成路线图解[J].中国医药工业杂志,2012,43(2):157—159.
[4]付强强,韩佩,宫平.阿哌沙班合成路线图解[J].中国药物化学杂志,2012,22(2):167—169.
[5]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.
[6]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.
[7]Gant TG,Shahbaz M.Pyrazole carboxamide inhibitors of factor Xa:WO,2010030983A2[P].2010-03-18.
[8]薛吉军,李毅,王仕祥,等.一种抗血栓药物阿哌沙班的制备方法:中国,103342704A[P].2013-10-09.
[9]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.
[10]Zhou JC,Oh LM,Ma P,et al.Synthesis of 4,5-dihydropyrazolo[3,4-c]pyrid-2-ones:WO,03049681A2[P].2003-06-19.
[11]叶天健,刘涛,马苏旺.4-环内酰胺基苯胺的制备方法:中国,103709095A[P].2014-04-09.
[12]冀亚飞,江健安,刘倩,等.一种抗血栓药物阿匹沙班的制备方法:中国,101967145A[P].2011-02-09.
[13]赵纪山,徐强,徐卓业,等.一种阿哌沙班的合成方法:中国,102675314A[P].2012-09-19.
[14]Shapiro R,Rossano LT,Mudryk BM,et al.Process for preparing 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones:US,20060069258A1[P].2006-03-30.
[2]Hohnloser SH,Hijazi Z,Thomas L,et al.Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fi brillation:insights from the ARISTOTLE trial[J].Eur Heart J,2012,33(22):2821—2830.
[3]王冠,郭晔堃,钟静芬,等.阿哌沙班合成路线图解[J].中国医药工业杂志,2012,43(2):157—159.
[4]付强强,韩佩,宫平.阿哌沙班合成路线图解[J].中国药物化学杂志,2012,22(2):167—169.
[5]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.
[6]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.
[7]Gant TG,Shahbaz M.Pyrazole carboxamide inhibitors of factor Xa:WO,2010030983A2[P].2010-03-18.
[8]薛吉军,李毅,王仕祥,等.一种抗血栓药物阿哌沙班的制备方法:中国,103342704A[P].2013-10-09.
[9]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.
[10]Zhou JC,Oh LM,Ma P,et al.Synthesis of 4,5-dihydropyrazolo[3,4-c]pyrid-2-ones:WO,03049681A2[P].2003-06-19.
[11]叶天健,刘涛,马苏旺.4-环内酰胺基苯胺的制备方法:中国,103709095A[P].2014-04-09.
[12]冀亚飞,江健安,刘倩,等.一种抗血栓药物阿匹沙班的制备方法:中国,101967145A[P].2011-02-09.
[13]赵纪山,徐强,徐卓业,等.一种阿哌沙班的合成方法:中国,102675314A[P].2012-09-19.
[14]Shapiro R,Rossano LT,Mudryk BM,et al.Process for preparing 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones:US,20060069258A1[P].2006-03-30.