富马酸丙酚替诺福韦合成工艺改进

Progress Improvement of The Synthesis of Tenofovir Alafenamide Fumarate

对富马酸丙酚替诺福韦的合成工艺进行了改进,以干燥的替诺福韦为起始原料,与亚磷酸三苯酯反应得到(R)-9-(2-(苯基磷酰基甲氧基)丙基)腺嘌呤(3);3被氯化亚砜氯代得(R)-9-(2-(((苯基)(氯代)(磷酰基)甲氧基)丙基)腺嘌呤(4);4与L-丙氨酸异丙酯盐酸盐缩合得9-((R)-2-(((S)-((1-(异丙氧基羰基)乙基)氨基)苯氧基磷酰基)甲氧基)丙基)腺嘌呤(5);5经析晶纯化得9-((R)-2-(((S)-(((S)-1-(异丙氧基羰基)乙基)氨基)苯氧基磷酰基)甲氧基)丙基)腺嘌呤(丙酚替诺福韦,6);6与富马酸成盐得富马酸丙酚替诺福韦,其结构经1H NMR,13C NMR, MS(ESI),元素分析和XRD确证。按改进工艺进行公斤级规模放大,产品总收率达到32.2%,化学纯度99.92%,非对映异构体纯度99.99%。

The synthesis progress of tenofovir alafenamide fumarate has been developed. This route involves the dry tenofovir(2) as a starting material, which reaction with triphenyl phosphite to obtain(R)-9-[2-(phenylphosphonomethoxy)propyl]adenine(3). 3 is treated with thionyl chloride to achieve(R)-9-(2-(((phenyl)(chloro)phosphoryl) methoxy)-propyl) adenine(4), which is converted to 9-((R)-2-(((S)-((1-(isopropoxycarbonyl)ethyl)amino)phenoxyphosphoryl)methoxy)propyl) adenine(5) by condensation with L-alanine isopropyl ester hydrochloride. After purification, tenofovir alafenamide(6) is obtained. Finally, tenofovir alafenamide fumarate is obtained by the reaction of 6 with fumaric acid. The structure has been confirmed by 1H NMR, 13C NMR, MS(ESI), elemental analysis and XRD. Kilogram-scale production has been achieved according to the improved process with a total yield of 32.2%, chemical purity of 99.92% and diastereomer purity of 99.99%.