HIV整合酶抑制剂雷特格韦的合成
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摘要
目的探究雷特格韦的合成方法。方法以2-氨基-2-甲基丙腈盐酸盐为起始原料,经过苄氧羰基保护氨基、由腈转化成肟、环合形成嘧啶、N-甲基化、酯的胺解、氢气还原脱保护、再经酰化缩合成酰胺等一系列反应制备得到雷特格韦。结果与结论目标产物雷特格韦及部分中间体的化学结构经~1H-NMR和MS确证,总收率为25.29%(以2-氨基-2-甲基丙腈盐酸盐计),高于文献收率(12.0%)。
Objective To find a route to synthesize raltegravir. Methods Using 2-amino-2-methyl acrylic nitrile hydrochlodide as starting material,raltegravir was synthesized by a series of reactions like amino group protection,converting nitrile into oxime,cyclization,N-methylation,ammonolysis,deprotection and amidation. Results and Conclusions Raltegravir and parts of intermediates were characterized by IR,MS,~1H-NMR spectra,and total yield was 25. 29%( with 2-amino-2-methylacrylic nitrile hydrochloride),which was higher than that of report in literature(12. 0%).
Objective To find a route to synthesize raltegravir. Methods Using 2-amino-2-methyl acrylic nitrile hydrochlodide as starting material,raltegravir was synthesized by a series of reactions like amino group protection,converting nitrile into oxime,cyclization,N-methylation,ammonolysis,deprotection and amidation. Results and Conclusions Raltegravir and parts of intermediates were characterized by IR,MS,~1H-NMR spectra,and total yield was 25. 29%( with 2-amino-2-methylacrylic nitrile hydrochloride),which was higher than that of report in literature(12. 0%).
引文
[1]冯婧劼,张庆文,徐云根.抗HIV-1药物及其复方制剂研究新进展[J].药学进展,2012,36(12):539-546.
[2]马帅,高文磊,赵俊,等.人类免疫缺陷病毒-1整合酶抑制剂的研究进展[J].中国药学杂志,2014,49(21):1877-1881.
[3]VINCENZO S,ALESSIA P,FABIO B,et al.Discovery of raltegravir,a potent,selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection[J].J Med Chem,2008,51(18):5843-5855.
[4]郭涤亮,刘冠男,李建,等.Raltegravir的合成工艺研究[J].中国药科大学学报,2009,40(4):297-301.
[5]GUY R H,P PHILIP J P,ZHONGY L,et al.Development of a second-generation,highly efficient manufacturing route for the HIV integrase inhibitor raltegravir potassium[J].Org Process Res Dev,2011,15(1):73-83.
[6]WANGZ W,WANGM X,YAO X,et al.Hydroxyl may not be indispensable for raltegravir:Design,synthesis and SAR Studies of raltegravir derivatives as HIV-1 inhibitors[J].Eur J Med Chem,2012,50:361-369.
[2]马帅,高文磊,赵俊,等.人类免疫缺陷病毒-1整合酶抑制剂的研究进展[J].中国药学杂志,2014,49(21):1877-1881.
[3]VINCENZO S,ALESSIA P,FABIO B,et al.Discovery of raltegravir,a potent,selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection[J].J Med Chem,2008,51(18):5843-5855.
[4]郭涤亮,刘冠男,李建,等.Raltegravir的合成工艺研究[J].中国药科大学学报,2009,40(4):297-301.
[5]GUY R H,P PHILIP J P,ZHONGY L,et al.Development of a second-generation,highly efficient manufacturing route for the HIV integrase inhibitor raltegravir potassium[J].Org Process Res Dev,2011,15(1):73-83.
[6]WANGZ W,WANGM X,YAO X,et al.Hydroxyl may not be indispensable for raltegravir:Design,synthesis and SAR Studies of raltegravir derivatives as HIV-1 inhibitors[J].Eur J Med Chem,2012,50:361-369.