富马酸丙酚替诺福韦有关物质的合成研究  

Study on the Synthesis of Related Substances of Tenofovir Alafenamide Fumarate

作　　者：钟仁清 欧阳汝霖 梁佳 陈宣坤 梁观明 王丹 魏勇翔 Zhong Renqing;Ouyang Rulin;Liang Jia;Chen Xuankun;Liang Guanming;Wang Dan;Wei Yongxiang(Jiangxi Qingfeng Pharmaceutical Co.,Ltd.,Ganzhou 341000;Jiangxi Shanxiang Pharmaceutical Co.,Ltd.,Ganzhou 341000;Jiangxi Kerui Pharmaceutical Co.,Ltd.,Ganzhou 341000,China)

机构地区：[1]江西青峰药业有限公司,江西赣州341000 [2]江西山香药业有限公司,江西赣州341000 [3]江西科睿药业有限公司,江西赣州341000

出　　处：《广东化工》2023年第11期9-10,46,共3页Guangdong Chemical Industry

摘　　要：目的:为了控制抗逆转录病毒药物富马酸丙酚替诺福韦(TAF)的质量标准,根据现行的合成工艺,设计并合成4个有关物质。方法:腺嘌呤(TAF-SM6)和(R)-环氧丙烷发生N烷基化反应得到有关物质A,6-氯嘌呤先和(R)-1-氨基-2-丙醇发生取代反应生成B1,B1再和R-(+)-碳酸丙烯酯(TAF-SM7)发生N烷基化反应得到有关物质B,(R)-9-(2-膦酸甲氧基丙基)腺嘌呤一水合物(TAF-SM1)先和二氯亚砜双氯代得到C1,C1再和苯酚发生双取代反应得到有关物质C,有关物质D则由C1和L-丙氨酸异丙酯盐酸盐(TAF-SM4)发生酰胺化反应得到。结果:设计并合成了上述4个有关物质,并通过MS和1HNMR对其进行结构表征,纯度经HPLC检测均在95%以上。结论:本研究合成的4个有关物质,可以作为富马酸丙酚替诺福韦质量控制的杂质对照品,为提升产品质量提供了技术支持。Objective:To control the quality standard of the antiretroviral drug tenofovir alafenamide fumarate(TAF),four related substances were designed and synthesized according to the current synthesis process.Methods:The related substance A was obtained by N-alkylation reaction of TAF-SM4 and(R)-propylene oxide.The related substance B was obtained by substitution reaction of 6-Chloropurine and(R)-1-amino-2-propanol and then N-alkylation reaction with TAF-SM7.The related substance C was obtained by dichlorination of TAF-SM1 and dichlorosulfoxide and then substitution reaction with phenol.The related substance D was obtained by amidation reaction of C1 and TAF-SM4.Results:The above four related substances were designed and synthesized,and their structures were confirmed by MS and ^(1)HNMR.The purity was over 95% by HPLC.Conclusion:The four related substances synthesized in this study can be used as the reference substances in the quality control of tenofovir alafenamide fumarate,and it provides technical support for improving product quality.

关 键 词：富马酸丙酚替诺福韦 有关物质 杂质对照品 合成 腺嘌呤 

分 类 号：TQ[化学工程]