张奇,郭明,赫畅,刘丹,张文宇,翟鑫
ZHANG Qi,GUO Ming,HE Chang,LIU Dan,ZHANG Wenyu,ZHAI Xin

• 1:沈阳药科大学制药工程学院
• 2:东北制药集团股份有限公司

摘要(Abstract)：

目的优化富马酸替诺福韦二吡呋酯的合成工艺。方法以腺嘌呤和(R)-碳酸丙烯酯为起始原料,经缩合反应得到(R)-9-(2-羟丙基)腺嘌呤(4)后,再经过O-烃化、氢溴酸水解反应得到替诺福韦一水合物(6),进一步与氯甲基碳酸异丙酯进行O-烃化反应,最后与富马酸成盐得到目标产物富马酸替诺福韦二吡呋酯(1),其结构经MS、IR、~1H-NMR、~(13)C-NM R和二维谱确证。结果与结论采用该路线可大规模制备质量合格的目标产物,反应总收率达28.6%(以腺嘌呤计),较文献提高了4.6%,纯度为99.45%;该工艺原料廉价易得,反应条件温和,后处理简便,产物纯度高,适于工业化生产。
Objective To investigate and optimize the synthetic process of tenofovir disoproxil fumarate( TDF). Methods Taking adenine( 2) and R-propylene carbonate( 3) as the starting material,( R)-9-( 2-hydroxypropyl) adenine( 4) was prepared by condensation,followed by O-alkylation and HBr hydrolysis to afford tenofovir monohydrate( 6). Further O-alkylation reaction with lisopropyl chloromethy carbonate and,finally,salifying with fumarate gave rise to the target compound tenofovir disoproxil fumarate( 1). The chemical structure of TDF and some key intermediates were confirmed by M S,IR,1 H-NM R,13 C-NM R and2 D spectra. Results and conclusions The optimized synthesis processes could be applied to prepare the final product of good quality in large scales. The total yield of TDF reached to 28. 6% based on adenine,which was above those of literature reported at 4. 6%,and the purity was 99. 45%. The improved process has several advantages over those reported procedures,including that the materials are cheaper and easier to afford,and the reaction conditions are mild and easy to operate with safety,and the high purity of TDF was suitable for industrial production.

关键词(KeyWords)： 富马酸替诺福韦酯;合成;工艺改进;抗人免疫缺陷病毒
tenofovir disoproxil fumarate;synthesis;process optimization;anti-HIV

Abstract:

Keywords:

基金项目(Foundation):

作者(Author): 张奇,郭明,赫畅,刘丹,张文宇,翟鑫
ZHANG Qi,GUO Ming,HE Chang,LIU Dan,ZHANG Wenyu,ZHAI Xin

DOI: 10.14066/j.cnki.cn21-1349/r.2018.07.005

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