普拉曲沙的合成工艺优化

Improved Synthetic Process of Pralatrexate

本研究改进了普拉曲沙(1)的合成工艺。4-甲氧甲酰基苯乙酸甲酯(2)与3-溴丙炔反应得到α-丙炔基-α-(4-甲氧甲酰基苯基)乙酸甲酯(3),反应中使用六甲基二硅基氨基锂(LiHMDS)代替六甲基二硅基氨基钾(KHMDS),反应选择性提高,生成的3与杂质4-[(4-甲氧基羰基)-1,6-庚二炔-4-基]苯甲酸甲酯(8)的比例由3∶1提高至99∶1。3与6-溴甲基-2,4-二氨基蝶啶(4)发生亲电取代反应,再经水解、脱羧和缩合反应得到N-[4-[1-[(2,4-二氨基-6-蝶啶基)-甲基]-3-丁炔-1-基]苯甲酰基]-L-谷氨酸二甲酯(7),最后经酯水解、酸化反应生成目标产物1。合成1时,通过分批加氢氧化钠溶液的方式,将过度水解杂质的含量控制在0.1%以下,随后直接酸化,避免因使用醇溶剂导致消旋化的发生。该工艺所得产品1纯度99.85%,ee 99.74%,总收率由27%提高至43%。

The synthetic process of pralatrexate(1)was improved.Methyl 4-(2-methoxy-2-oxoethyl)-benzoate(2)reacted with 3-bromoprop-1-yne to giveα-propynyl-α-(4-methoxyformylphenyl)methyl acetate(3).Using lithium bis(trimethylsilyl)amide(LiHMDS)instead of potassium bis(trimethylsilyl)amide(KHMDS),the reaction selectivity increased,and the ratio of compound 3 to methyl 4-[4-(methoxycarbonyl)hepta-1,6-diyn-4-yl]benzoate(8)was increased from 3∶1 to 99∶1.Compound 3 reacted with 6-(bromomethyl)pteridine-2,4-diamine(4)by electrophilic substitution,then followed by hydrolysis,decarboxylation and condensation reaction to obtain dimethyl N-[4-[1-(2,4-diaminopteridin-6-yl)but-3-yn-1-yl]benzoyl]-L-glutamate(7),and the target compound 1 was prepared by ester hydrolysis and acidification.In this reaction,the content of excessively hydrolyzed impurity controlled was less than 0.1%by adding sodium hydroxide solution in batches,and then direct acidification could avoid racemization caused by the use of alcohol solvents.The purity of the product 1 obtained by this process was 99.85%with the ee value of 99.74%,and the total yield was increased from 27%to 43%.