p21活化激酶4抑制剂PF-3758309的合成工艺改进

Improved synthesis of p21-activated kinase 4 inhibitor of PF-3758309

目的对具有抗肿瘤活性的p21活化激酶4(PAK4)抑制剂PF-3758309的合成工艺进行优化。方法以3-氨基-2-噻吩甲酸甲酯为原料,经乙酰化、环化、氯代制得中间体4-氯-2-甲基噻吩并[3,2-d]嘧啶(13);以2-氨基异丁酸为原料,经加成、氨基保护、酯化、环合、酰化、脱Boc保护、与中间体N-[(2S)-2-异氰酸酯基-2-苯乙基]-N,N-二甲基胺(10)进行酰化反应、脱除乙氧羰基保护,以及与中间体13烷基化共10步反应制得目标产物PF-3758309。结果与结论目标化合物及各步中间体的结构均经MS、1H-NM R谱确证,目标化合物的总收率为30.2%(以2-氨基异丁酸计),HPLC法检测纯度为99.70%。优化后的工艺路线更易于大量制备PF-3758309,收率显著提高(文献收率为19.5%)。

The key intermediate 4-chloro-2-methylthieno [ 3,2-d ] pyrimidine of PF-3758309 was prepared from methyl 3-amino-2-thiophene carboxylate, through acetylation, cyclization, chlorination. The target compound PF-3758309 was synthesized by 10-step reactions including addition, aminoprotection, esterification, cyclization, acylation, Boc deprotection, acylation, deprotection, alkylation in an overall yield of 30. 2 % and 99.70% purity,using 2-aminoisobutyric acid as starting material. In this paper,the multi-step reactions were studied and optimized in detail, it＇s easier and more effective to the mass production of PF-3758309 after process improvement, and the yield has been improved significantly. It has laid the foundation for the industrialization of these drugs and the synthesis of analogues. The target compound and intermediates were confirmed by MS and ^1H-NMR.