富马酸替诺福韦酯的合成工艺改进（英文）

Improved synthesis of tenofovir disoproxil fumarate

目的合成抗病毒药物富马酸替诺福韦酯并进行工艺改进。方法以亚磷酸二乙酯和多聚甲醛为原料,经缩合、酯化反应制得对甲苯磺酰氧甲基膦酸二乙酯(4);再以(S)-缩水甘油为起始物,经氢化还原、缩合反应制得(R)-碳酸丙烯酯(7),7与腺嘌呤反应合成(R)-9-(2-羟丙基)腺嘌呤(8),8经醚化、水解反应得到替诺福韦(10),再经氯甲基碳酸异丙酯酯化、与富马酸成盐得到目标化合物。结果与结论目标化合物的结构经MS、1H-NMR谱予以确证,该合成路线的总收率提高到30.4%(文献报道的最高收率为21%)。

A practical manufacturing process of tenofovir disoproxil fumarate （TDF） was studied and optimized. Diethyl p-toluenesulfonyloxymethylphosphonate was prepared by diethyl phosphite and paraformaldehyde condensing and esterifing with p-toluenesulfonyl chloride. （S）-glycidol was hydrogenated and condensed with diethyl carbonate to afford （R）-propylene carbonate, which was coupled with adenine to give （R）-9-（2-hydroxypropyl） adenine, then etherification and hydrolysis to afford tenofovir, followed by esterification with chloromethyl isopropyl carbonate, forming fumaric acid salt to crystallize TDF. The overall yield of TDF from adenine was improved to 30. 4%. The structure of the target compound was confirmed by MS and 1H-NMR.