ENMD-2076；ENMD-981693 (as free base), -Drug Synthesis Database

【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 合成路线2

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 .

参考文献中间体

【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) .

参考文献中间体

【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

Drug NewChemical Entity Original Patent(1)