文睿,刘文强,杜芳瑜,周启璠,鲁萌萌,陈国良
WEN Rui,LIU Wenqiang,DU Fangyu,ZHOU Qifan,LU Mengmeng,CHEN Guoliang

• 1:沈阳药科大学基于靶点的药物设计与研究教育部重点实验室

摘要(Abstract)：

目的对Givinostat盐酸盐的合成工艺进行优化以提高其收率和降低成本,探索一条适合工业化生产的合成路线。方法以2,6-萘二甲酸为原料,经酯化、水解、氯代、缩合和还原5步得到中间体6-[(二乙基氨基)甲基]-2-萘甲醇;以对氨基苯甲酸为原料,经酯化、缩合2步得到中间体(4-甲氧基羰基)苯基异氰酸酯;两个中间体经缩合、水解、成盐酸盐3步得到目标化合物。结果通过ESI-MS、~1H-NM R和~(13)C-NM R法对所得目标化合物结构进行确证。采用HPLC法检测产品纯度99. 95%。中间体与杂质结构经ESI-M S、~1H-NM R法得到确证。结论整条路线总收率33. 7%,反应条件温和,收率较高,适合工业规模化生产。
Objective To develop a practical synthetic route to Givinostat hydrochloride with inexpensive starting material and acceptable overall yield. Methods The intermediate 6-[( diethylamino) methyl]-2-naphthalenemethanol was obtained via a 6-step synthesis starting from 2,6-naphthalic acid,including esterification,hydrolysis,chlorination,condensation,reduction. The intermediate( 4-methoxycarbonyl) phenyl isocyanate was obtained via a 2-step synthesis starting from para-aminobenzoic acid,including esterification and condensation. The target compound Givinostat hydrochloride was synthesized via 3-step synthesis using the two intermediates as starting material,including condensation,amination,and salinization. Results The structure of Givinostat hydrochloride was confirmed by ESI-M S,~1H-NM R,~(13)C-NM R and the HPLC purity of target compound was 99. 95%. Intermediates and impurities were confirmed by ESI-M S,~1H-NM R.Conclusion The total yield was 33. 7%. The operations were simple,the starting materials and reagents have a lowprice and are easy to get,and the reaction conditions were mild. The synthetic technology has a high yield and is suitable for industrial scale production.

关键词(KeyWords)： Givinostat盐酸盐;组蛋白去乙酰化酶抑制剂;优化;杂质
givinostat hydrochloride;histone deacetylase inhibitors;optimization;impurities

Abstract:

Keywords:

基金项目(Foundation): 国家基础人才培养基金资助项目(J1103606)

作者(Author): 文睿,刘文强,杜芳瑜,周启璠,鲁萌萌,陈国良
WEN Rui,LIU Wenqiang,DU Fangyu,ZHOU Qifan,LU Mengmeng,CHEN Guoliang

DOI: 10.14066/j.cnki.cn21-1349/r.2018.10.006

参考文献(References)：

• [1] BETTICA P,PETRINI S,D'ORIA V,et al. Histological effects of givinostat in boys w ith Duchenne muscular dystrophy[J]. Neuromuscular Disorders,2016,26(10):643-649.
• [2] BERTOLINI G,BIFFI M,LEONI F,et al. Compounds w ith anti-inflammatory and immunosuppressive activities:US,6034096 A[P]. 2000-03-07.
• [3] CHENG J J,QIN J H,GUO S H,et al. Design,synthesis and evaluation of novel HDAC inhibitors as potential antitumor agents[J]. Bioorganic&M edicinal Chemistry Letters,2014,24(19):4768-4772.
• [4]程建军,秦继红.异羟肟酸类化合物,制备方法和用途.中国,103012274 A[P]. 2013-04-03.
• [5] HINSBERGER S,DE C,GROH M,et al. Benzamidobenzoic acids as potent Pqs D inhibitors for the treatment of pseudomonas aeruginosa infections[J]. European Journal of M edicinal Chemistry,2014,76(76C):343-351.
• [6] MA Q S,LIU X H,WENG J Q,et al.. Synthesis and herbicidal activity of new pyrazine derivative[J]. Chinese Journal of Organic Chemistry,2013,33(8):1749-1754.
• [7] RAO P C,MANDAL S. Friedel-crafts alkylation of indoles w ith nitroalkenes through hydrogen-bonddonating metal-organic framew ork[J]. Chemcatchem,2017,9(7):2115-2121.
• [8] ZHANG Y Q,ANDERSON M,WEISMAN J L,et al.Evaluation of diarylureas for activity against plasmodium falciparum[J]. Acs M edicinal Chemistry Letters,2010,1(9):460-465.
• [9] HUISGEN R,RIETZ U. Mittlere Ringe,XIV. Darstellung und cyclisierung derω-[naphthyl-(2)]-fettsuren[J]. European Journal of Inorganic Chemistry,1957,90(12):2768-2784.
• [10]ROY H N,SARKAR M S,PAUL A M. An efficient and regiospecific biocatalytic esterification of some organic acids using beef pancreas lipase(Bpl)[J].Cheminform,2006,37(46):45-47.
• [11]SIEFKEN W. Mono-und Polyisocyanate IV. Mitteilungüber polyurethane[J]. European Journal of Organic Chemistry,1949,562(2):75-136.