MGCD0103的合成工艺改进  

Improved synthesis of MGCD0103

作　　者：徐明[1] 赵砚瑾[2] 钱鹏宇[1] 王永珍[3] 李艳阳[2] 谢宁[1] 李庶心[2] 

机构地区：[1]江西中医学院研究生部,江西南昌330006 [2]军事医学科学院放射与辐射医学研究所,北京100850 [3]中南大学湘雅药学院,湖南长沙410013

出　　处：《中国药物化学杂志》2013年第4期297-299,共3页Chinese Journal of Medicinal Chemistry

基　　金：国家科技重大专项(2012ZX09102101-013);国家自然科学基金项目(30772628)

摘　　要：目的改进MGCD0103的合成工艺。方法以3-乙酰吡啶为原料,与N,N-二甲基甲酰胺二甲缩醛缩合后,与4-胍基甲基-苯甲酸环合,再与邻苯二胺缩合得到MGCD0103。结果与结论目标化合物经1H-NMR和MS鉴定,改进后的工艺合成路线缩短、反应条件温和,总收率为42%(以3-乙酰吡啶计,提高了16%),生产成本显著降低,更适合工业化生产。MGCD0103 （1）is an isotype-selective small molecule histone deacetylase inhibitor （HDACi）, which is orally bioavailable and has significant antitumor activity in vivo. Phase II clinical trial has been completed in patients with refractory chronic lymphocytic leukemia. Its synthetic route was optimized and im- proved. The target compound was obtained via a four-step reaction sequence starting from commercially available 3-acetylpyridine （ 2 ） and 4- （ aminomethyl ） benzoicacid （ 4 ）. The reaction of 2 with N, N-dimethyl- formamide dimethyl acetal provided 3-dimethylamino-1-pyridin-3-ylpropenone （3）as the first synthetic inter- mediate. Treatment of 4 with S-methyl-iso-thiourea sulfate in a basic medium produced 4-（guanidinomethyl） benzoic acid （ 5 ）, then 3 was reacted with 5 to get 4- （ （ 4- （ pyridin-3-yl ） pyrimidin-2-ylamino ） methyl ） benzo- ic acid（6） ,6 underwent an amide coupling reaction with 1,2-phenylenediamine to give target compound 1. The overall yield was about 42%, which increased by 16% （based on 3-acetylpyridine）. The chemical struc- ture of MGCD0103 was characterized by MS, 1H-NMR. Compared with the original synthetic process,the new route is facile and suitable for industrialized production with lower pollution and higher yield.

关 键 词：抗肿瘤药 组蛋白去乙酰化酶抑制剂 MGCD0103 工艺改进 

分 类 号：R914[医药卫生—药物化学]