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【结 构 式】

【药物名称】ENMD-2076;ENMD-981693 (as free base)

【化学名称】6-(4-Methylpiperazin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)-2-[(E)-2-phenylvinyl]pyrimidin-4-amine L-tartrate

【CA登记号】934353-76-1 (as free base)

【 分 子 式 】C25H31N7O6

【 分 子 量 】525.5569

【开发单位】EntreMed, Inc. (US)

【药理作用】Aurora Kinase A Inhibitor;Protein Kinase Inhibitor;Oncolytic

合成路线1

Oxidation of 4,6-dichloro-2-(methylsulfanyl)pyrimidine (I) with 3-chlorobenzoyl peroxide in CH2Cl2 gives the sulfonyl derivative (II), which is alkynylated with phenylacetylenyl magnesium bromide (III) in THF to provide 4,6-dichloro-2-(phenylethynyl)pyrimidine (IV). Condensation of the dichloropyrimidine derivative (IV) with 5-methyl-3-aminopyrazole (V) by means of NaI and DIEA in DMA at 90 °C affords amine (VI), which is coupled with N-methylpiperazine (VII) in the presence of DMAP and DIEA in 1,4-dioxane at 100 °C to furnish the piperazinyl derivative (VIII). Reduction of alkyne (VIII) by means of LiAlH4 in THF gives alkene (IX), which is finally treated with sodium potassium tartrate .

1 Xiao, X.-Y., Patel, D.V., Ward, J.S., Bray, M.R., Agoston, G.E., Treston, A.M.(Miikana Therapeutics, Inc.). Substituted pyrazole compounds. EP 1928456, JP 2009510107, US 2007142368, WO 2007041358.
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) 65246 4,6-Dichloro-2-(methylthio)pyrimidine;4,6-dichloro-2-(methylsulfanyl)pyrimidine 6299-25-8 C5H4Cl2N2S 详情 详情
(II) 65247 4,6-Dichloro-2-(methylsulfonyl)pyrimidine; 2-(Methylsulfonyl)-4,6-Dichloropyrimidine; NSC 45040 4489-34-3 C5H4Cl2N2O2S 详情 详情
(III) 32758 bromo(2-phenylethynyl)magnesium;phenylacetylenyl magnesium bromide;(phenylethynyl)magnesium bromide C8H5BrMg 详情 详情
(IV) 68677 4,6-dichloro-2-(phenylethynyl)pyrimidine   C12H6Cl2N2 详情 详情
(V) 68679 5-methyl-3-aminopyrazole;3-Amino-5-methylpyrazole;3-Methyl-1H-pyrazol-5-amine 31230-17-8 C4H7N3 详情 详情
(VI) 68678 6-chloro-N-(5-methyl-1H-pyrazol-3-yl)-2-(phenylethynyl)pyrimidin-4-amine   C16H12ClN5 详情 详情
(VII) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(VIII) 68680 N-(5-methyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-2-(phenylethynyl)pyrimidin-4-amine   C21H23N7 详情 详情
(IX) 68681 N-(5-methyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-2-styrylpyrimidin-4-amine;6-(4-Methyl-1-piperazinyl)-N-(5-methyl-1H-pyrazol-3-yl)-2-[(1E)-2-phenylethenyl]-4-pyrimidinamine 934353-76-1 C21H25N7 详情 详情

合成路线2

Treatment of cinnamonitrile (X) with HCl in toluene/EtOH gives the O-ethyl imidate.HCl (XI), which is aminated by means of methanolic ammonia in EtOH to provide amidine (XII). Cyclization of compound (XII) with dimethylmalonate (XIII) in the presence of NaOMe in MeOH at 90 °C affords the pyrimidindione (XIV), which is chlorinated with POCl3 to generate the dichloro derivative (XV). Coupling of dichloro compound (XV) with 5-methyl-3-aminopyrazole (V) by means of NaI and DIEA in DMA at 90 °C affords the secondary amine (XVI), which is finally condensed with Nmethylpiperazine (VII) to give the free base (IX) .

1 Xiao, X.-Y., Patel, D.V., Ward, J.S., Bray, M.R., Agoston, G.E., Treston, A.M.(Miikana Therapeutics, Inc.). Substituted pyrazole compounds. EP 1928456, JP 2009510107, US 2007142368, WO 2007041358.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 68679 5-methyl-3-aminopyrazole;3-Amino-5-methylpyrazole;3-Methyl-1H-pyrazol-5-amine 31230-17-8 C4H7N3 详情 详情
(VII) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(IX) 68681 N-(5-methyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-2-styrylpyrimidin-4-amine;6-(4-Methyl-1-piperazinyl)-N-(5-methyl-1H-pyrazol-3-yl)-2-[(1E)-2-phenylethenyl]-4-pyrimidinamine 934353-76-1 C21H25N7 详情 详情
(X) 68682 Cinnamonitrile;E-3-Phenyl-2-propenenitriletrans-Cinnamonitrile 1885-38-7 C9H7N 详情 详情
(XI) 68683 ethyl cinnamimidate hydrochloride   C11H13NO.HCl 详情 详情
(XII) 68684 cinnamimidamide   C9H10N2 详情 详情
(XIII) 19373 dimethyl malonate;Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(XIV) 68685 (E)-2-styrylpyrimidine-4,6(1H,5H)-dione   C12H10N2O2 详情 详情
(XV) 68686 (E)-4,6-dichloro-2-styrylpyrimidine   C12H8Cl2N2 详情 详情
(XVI) 68687 (E)-6-chloro-N-(5-methyl-1H-pyrazol-3-yl)-2-styrylpyrimidin-4-amine   C16H14ClN5 详情 详情
Extended Information