2,4-dichloro-5-(trifluoromethyl)pyrimidine -Drug Synthesis Database

【结构式】

【分子编号】67477

【品名】2,4-dichloro-5-(trifluoromethyl)pyrimidine

【CA登记号】3932-97-6

【分子式】C₅HCl₂F₃N₂

【分子量】216.977

【元素组成】C 27.68% H 0.46% Cl 32.68% F 26.27% N 12.91%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(I)

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.

参考文献中间体

合成目标

【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

合成路线2

该中间体在本合成路线中的序号：(V)

Condensation of 3-chloropyrazine-2-carbonitrile (I) with N-methylmethanesulfonamide (II) in the presence of Cs2CO3 in acetonitrile at 80 °C gives N-(3-cyano-2-pyrazinyl)-N-methylmethanesulfonamide (III), which by nitrile reduction using H2 over Pd/C in methanolic ammonia, followed by treatment with AcOH in EtOAc provides the primary amine (IV). Condensation of 2,4-dichloro-5-(trifluoromethyl) pyrimidine (V) with 4-amino-N-methylbenzamide (VI) by means of ZnBr2 and Et3N in DCE/t-BuOH affords diaryl amine (VII). Finally, (aminomethyl)pyrazine (IV) is coupled with chloropyrimidine (VII) in the presence of DIEA in DCE/t-BuOH at 80 °C and the resulting free base is treated with HCl in MeOH .

参考文献中间体

合成目标

【1】 Luzzio, M.J., Autry, C.L., Bhattacharya, S.K. et al. (Pfizer Products Inc. ). Sulfonyl amide derivatives for the treatment of abnormal cell growth. US 2014100368; US 8247411; EP 2146779; US 2013005964; JP 2010524914; CN 103951658; US 2011166120; US 8440822; WO 2008129380.

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)	42535	3-chloro-2-pyrazinecarbonitrile	55557-52-3	C₅H₂ClN₃	详情	详情
(II)	67859	N-methylmethanesulfonamide	1184-85-6	C₂H₇NO₂S	详情	详情
(III)	67860	N-(3-cyano-2-pyrazinyl)-N-methylmethanesulfonamide		C₇H₈N₄O₂S	详情	详情
(IV)	67861	N-(3-(aminomethyl)pyrazin-2-yl)-N-methylmethanesulfonamide acetate		C₇H₁₂N₄O₂S.C₂H₄O₂	详情	详情
(V)	67477	2,4-dichloro-5-(trifluoromethyl)pyrimidine	3932-97-6	C₅HCl₂F₃N₂	详情	详情
(VI)	67862	4-amino-N-methylbenzamide	6274-22-2	C₈H₁₀N₂O	详情	详情
(VII)	67863	4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzamide		C₁₃H₁₀ClF₃N₄O	详情	详情
(VIII)	67864	N-methyl-4-((4-(((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide		C₂₀H₂₁F₃N₈O₃S	详情	详情

Extended Information