盐酸利匹韦林的合成工艺改进

Improved Synthetic Process of Rilpivirine Hydrochloride

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)。

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).