色瑞替尼的合成优化  

Improved Synthetic Process of Ceritinib

作　　者：聂鑫 蔡建光 翟宁[2] 吴泰志[2] 张福利[2] 

机构地区：[1]浙江工业大学长三角绿色制药协同创新中心,浙江杭州310014 [2]中国医药工业研究总院上海医药工业研究院创新药物与制药工艺国家重点实验室,上海201203 [3]浙江海正药业股份有限公司,浙江台州318000

出　　处：《中国医药工业杂志》2017年第12期1716-1720,共5页Chinese Journal of Pharmaceuticals

摘　　要：2-(异丙基磺酰基)苯胺(2)和2,4,5-三氯嘧啶(3)在乙酸钯催化下经偶联反应得2,5-二氯-N-[2-(异丙基磺酰基)-苯基]嘧啶-4-胺(4),此外,1-氯-5-异丙氧基-2-甲基-4-硝基苯(6)和吡啶-4-硼酸在二噁烷和水的混合溶剂中经Suzuki偶联制得4-(5-异丙氧基-2-甲基-4-硝基苯基)吡啶(7),化合物7在氧化铂催化下经氢化还原得2-异丙氧基-5-甲基-4-(哌啶-4-基)苯胺二盐酸盐(8),8与4经亲核取代后,再经氢氧化钠游离得色瑞替尼(1),总收率由文献的36.4%提高至57.2%(以6计),纯度99.94%。如以8的游离碱与4反应,则得1的位置异构体2-[4-(4-氨基-5-异丙氧基-2-甲基苯基)哌啶-1-基]-5-氯-N-[2-(异丙基磺酰基)苯基]嘧啶-4-胺,与1在HPLC良好分离。2,5-Dichloro-N-[2-（isopropylsulfonyl）phenyl]pyrimidin-4-amine （4） was prepared from 2-（isopropylsulfonyl）aniline （2） and 2,4,5-trichloropyrimidine （3） via a coupling reaction in the catalysis of palladium acetate. Meanwhile, 1-chloro-5-isopropoxy-2-methyl-4-nitrobenzene （6） reacted with pyridin-4-ylboronic acid via a Suzuki coupling in dioxane and water to give 4-（5-isopropoxy-2-methyl-4-nitrophenyl）pyridine （7） with a yield of 92.4%. Then the latter was reduced by hydrogenation with PtO2（10%, w/w） as the catalyst to afford 2-isopropoxy-5-methyl-4-（piperidin-4-yl）aniline dihydrochloride （8）. Then 4 was subjected to the nucleophilic reaction with compound 8 to give ceritinib （1） with a total yield of 57.2%（based on 6）, and a purity of 99.94%. By the way, if compound 4 reacted with the free base of 8, the regio-isomer of 1, i.e., 2-[4-（4-amino-5-isopropoxy-2-methylphenyl）piperidin-1-yl]-5-chloro-N-[2-（isopropylsulfonyl）phenyl]pyrimidin-4-amine （10） was obtained, which could be separated completely with 1 in HPLC.

关 键 词：色瑞替尼 ALK受体抑制剂 非小细胞肺癌 合成工艺 

分 类 号：R979.1[医药卫生—药品] R914.5[医药卫生—药学]