莫洛替尼的合成新方法

A Novel Synthetic Method of Momelotinib

报道了Janus激酶1/2(JAK1/JAK2)抑制剂莫洛替尼(1)的合成新路线,仅包含3步反应。以4-乙酰基苯甲酸乙酯(2)为起始原料,与N,N-二甲基甲酰胺二甲基缩醛(DMF-DMA)、尿素缩合环化得到4-(2-氧代-1,2-二氢嘧啶-4-基)苯甲酸乙酯(3)。3与4-吗啉基苯胺(4)在六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(PyBOP)和1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)作用下胺化,得到4-[2-[(4-吗啉基苯基)氨基]嘧啶-4-基]苯甲酸乙酯(5)。5最后在氧气和叔丁醇钾存在下,与氨基乙腈经酰胺化得到目标产物1。纯度99.5%。该路线步骤少,总收率高(70%以2计)。

Momelotinib(1),a Janus kinase 1/2(JAK1/JAK2)inhibitor,was synthesized via a new synthetic route in three steps.The cyclization of ethyl 4-acetylbenzoate(2),N,N-dimethylformamide dimethyl acetal(DMF-DMA)and urea was achieved successfully to give ethyl 4-(2-oxo-1,2-dihydropyrimidin-4-yl)benzoate(3),which was subjected to the amination with 4-morpholinoaniline(4)in the presence of(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(PyBOP)and 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU)to afford ethyl 4-[2-[(4-morpholinophenyl)-amino]pyrimidin-4-yl]benzoate(5).Compound 5 was subjected to the amidation with 2-aminoacetonitrile in the presence of air and potassium tert-butoxide to deliver the target product with purity of 99.5%.This new synthetic route had fewer reaction steps and high overall yield(70%based on 2).