盐酸利匹韦林的合成工艺改进 |
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引用本文: | 郭建锋,陈怡,李莉娥,田峦鸢,汪淼.盐酸利匹韦林的合成工艺改进[J].中国医药工业杂志,2020(4):480-483. |
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作者姓名: | 郭建锋 陈怡 李莉娥 田峦鸢 汪淼 |
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作者单位: | 宜昌人福药业有限责任公司;人福医药集团股份公司 |
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摘 要: | 本研究改进了抗病毒药盐酸利匹韦林(1)的合成工艺。甲酰乙酸乙酯(2)和S-甲基异硫脲(3)反应得2-甲硫基-4-羟基嘧啶(4)。在甲磺酸催化下,4与4-氨基苄腈(5)在乙二醇二甲醚中反应得到4-(4-羟基嘧啶-2-基)氨基]苄腈(6),反应温度由200℃降至110~120℃。6与溴化氢/乙酸溶液反应得到4-(4-溴嘧啶-2-基)氨基]苄腈(7)。用乙酸钯和三(邻甲基苯)膦代替10%钯炭作为催化剂,4-溴-2,6-二甲基苯胺(8)与丙烯腈(9)反应得到(E)-3-(4-氨基-3,5-二甲基苯基)丙烯腈(10),其顺式异构体含量由20%降至0.60%,后处理时用重结晶代替柱色谱分离纯化,收率由48%提高至87%。7和10在缚酸剂1,1,3,3-四甲基胍(TMG)的作用下发生缩合反应,再与草酸成盐、纯化得到1,纯度99.92%,1顺式异构体的含量降至0.08%。优化后的工艺操作简便,总收率52%(以2计)。
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关 键 词: | 盐酸利匹韦林 抗病毒药 合成 工艺优化 |
Improved Synthetic Process of Rilpivirine Hydrochloride |
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Authors: | GUO Jianfeng CHEN Yi LI Li'e TIAN Luanyuan WANG Miao |
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Affiliation: | (Yichang Humanwell Pharmaceutical Co.,Ltd.,Yichang 443000;Humanwell Healthcare(Group)Co.,Ltd.,Wuhan 430075) |
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Abstract: | The synthetic process of the antiviral drug rilpivirine hydrochloride(1)was improved.Ethyl formyl acetate(2)reacted with S-methylisothioure(3)to give 2-(methylthio)-4-hydroxyl-pyrimidine(4).Compound 4 reacted with 4-aminobenzonitrile(5)in ethylene glycol dimethyl ether in the presence of methanesulfonic acid to give 4-(4-hydroxypyrimidin-2-yl)amino]benzonitrile(6),and the reaction temperature decreased from 200℃to 110-120℃.Compound 6 reacted with HBr/CH3COOH to obtain 4-(4-bromopyrimidin-2-yl)amino]benzonitrile(7).4-Bromo-2,6-dimethylaniline(8)reacted with acrylonitrile(9)in the presence of palladium acetate and tris(Omethylphenyl)phosphine instead of 10%Pd/C to give(E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile(10),by which the cis-isomer was reduced from 20%to 0.60%.Meanwhile,compound 10 was purified by recrystallization instead of column chromatography in the work-up,so that the yield of this step was increased from 48%to 87%.Compound 7 was condensed with 10 under the action of 1,1,3,3-tetramethylguanidine(TMG)as acid binding agent,and the title compound in a purity of 99.92%was obtained via a salt formation with oxalic acid,and the content of cis-isomer was reduced to 0.08%.The improved process was simple and convenient with a total yield of 52%(based on 2). |
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Keywords: | rilpivirine hydrochloride antiviral drug synthesis process improvement |
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