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【结 构 式】 
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【药物名称】ROCILETINIB HYDROBROMIDE 【化学名称】N-(3-[[2-[[4-(4-Acetylpiperazin-1-yl)-2-methoxyphenyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl)acrylamide hydrobromide 【CA登记号】1374640-70-6 (as free base) 【 分 子 式 】C27H28F3N7O 【 分 子 量 】636.463 |
【开发单位】 【药理作用】Irreversible inhibitor of mutant EGFR, Treatment of NSCLC |
合成路线1
Rociletinib is prepared by condensation of 2,4-dichloro-5-trifluoromethylpyrimidine (I) with N-Boc-1,3-diaminobenzene (II) in the presence of DIEA in BuOH to give the secondary amine (III), which is N-deprotected using TFA in CH2Cl2 yielding the primary amine (IV).Coupling of amine (IV) with acryloyl chloride (V) in CH2Cl2 affords amide (VI), which is condensed with intermediate (VII) by means of TFA in dioxane at 50 °C to provide rociletinib trifluoroacetate (VIII) . Finally, rociletinib trifluoroacetate (VIII) is treated with Na2CO3 in CH2Cl2 , followed by treatment of the obtained free base with HBr.
| 【1】 Lee, K., Niu, D., Petter, R.C., Baevsky, M.F., Singh, J. (Celgene Avilomics Research, Inc.). Heterocyclic compounds and uses thereof. CN 103269704, KR 2013133202, US 2012149687, WO 2012061299, JP 2013541561, EP 2635284. |
| 【2】 Lai, M. (Celgene Avilomics Research, Inc.). Solid forms of an epidermal growth factor receptor kinase inhibitor. US 2013267530, WO 2013138495. |
| 【3】 Lai, M., Witowski, S.R., Tester, R.W., Lee, K. (Celgene Avilomics Research, Inc.). Salts of an epidermal growth factor receptor kinase inhibitor. KR 2014138941, US 2013267531, WO 2013138502. |
| 【4】 Lai, M., Allen, A.R. (Clovis Oncology, Inc.). Salts of an epidermal growth factor receptor kinase inhibitor. WO 2014182593. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 67477 | 2,4-dichloro-5-(trifluoromethyl)pyrimidine | 3932-97-6 | C5HCl2F3N2 | 详情 | 详情 |
| (II) | 67478 | tert-butyl (3-aminophenyl)carbamate | C11H16N2O2 | 详情 | 详情 | |
| (III) | 67479 | tert-butyl (3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)carbamate | C16H16ClF3N4O2 | 详情 | 详情 | |
| (IV) | 67480 | N1-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)benzene-1,3-diamine | C11H8ClF3N4 | 详情 | 详情 | |
| (V) | 11577 | Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride | 814-68-6 | C3H3ClO | 详情 | 详情 |
| (VI) | 67481 | N-(3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide | C14H10ClF3N4O | 详情 | 详情 | |
| (VII) | 67482 | 1-(4-(4-amino-3-methoxyphenyl)piperazin-1-yl)ethanone | C13H19N3O2 | 详情 | 详情 | |
| (VIII) | 67483 | N-(3-((2-((4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide 2,2,2-trifluoroacetate | C27H28F3N7O3.C2HF3O2 | 详情 | 详情 |