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目的研究阿伐那非的合成工艺。方法以乙氧亚甲基丙二酸二乙酯和甲基硫脲为起始原料,经环合、氯代得到中间体4-氯-2-甲硫基嘧啶-5-羧酸乙酯(3),然后与3-氯-4-甲氧基苄胺发生取代反应生成中间体4-[(3-氯-4-甲氧基苄基)氨基]-2-甲硫基嘧啶-5-羧酸乙酯(4),再经水解、缩合、氧化和取代反应得到目标产物阿伐那非。结果反应总收率达21.6%(以甲基硫脲计),产品纯度质量分数达99.6%,目标产物结构经MS、IR、~1H-NMR和~(13)C-NMR确证,部分中间体的化学结构经过MS和~1H-NMR确证,为中试放大奠定基础。结论此路线所用原料廉价易得,实验操作相对简单,收率较高,为中试放大奠定了基础。
Objective To study the synthesis of alvarion. Methods Diethyl ethoxymethylenemalonate and methylthiourea were used as starting materials to obtain the intermediate 4-chloro-2-methylthiopyrimidine-5-carboxylic acid ethyl ester by cyclization and chlorination 3) followed by a substitution reaction with 3-chloro-4-methoxybenzylamine to produce the intermediate 4 - [(3-chloro-4- methoxybenzyl) amino] -2-methylthiopyrimidin-5- The carboxylic acid ethyl ester (4) was hydrolyzed, condensed, oxidized and substituted to obtain the target product of alvarion. Results The total yield of the reaction was 21.6% (as methyl thiourea). The purity of the product reached 99.6%. The structure of the target product was confirmed by MS, IR, ~ 1H-NMR and ~ (13) C-NMR. The chemical structure was confirmed by MS and ~ 1H-NMR, which laid the foundation for the enlargement of pilot scale. Conclusion The raw materials used in this route are cheap and easy to obtain, the experimental operation is relatively simple and the yield is high, which lays the foundation for the enlargement of pilot scale.