4,4-dimethyl-3-oxopentanenitrile -Drug Synthesis Database

【结构式】

【分子编号】44248

【品名】4,4-dimethyl-3-oxopentanenitrile

【CA登记号】59997-51-2

【分子式】C₇H₁₁NO

【分子量】125.17048

【元素组成】C 67.17% H 8.86% N 11.19% O 12.78%

与该中间体有关的原料药合成路线共 5 条

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线1

该中间体在本合成路线中的序号：(I)

Aminopyrazole (III) was prepared by condensation of keto nitrile (I) with 3-nitrophenylhydrazine (II) in ethanolic HOAc. Subsequent reaction of (III) with 2,3-dichlorophenyl isocyanate (IV) in hot toluene produced the urea derivative (V). The nitro group of (V) was finally reduced to the title aniline by means of iron and acetic acid.

参考文献中间体

合成目标

【1】 Dumas, J.; Hatoum-Mokdad, H.; Sibley, R.; et al.; 1-Phenyl-5-pyrazolyl ureas: Potent and selective p38 kinase inhibitors. Bioorg Med Chem Lett 2000, 10, 18, 2051.
【2】 Ranges, G.E.; Bortolon, E.; Chau, T.; et al.; Pharmacological characterization of pyrazolyl urea p38 kinase inhibitors. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 149.
【3】 Dumas, J.; Bobko, M.; Bhargava, A.; et al.; Synthesis and SAR of p38 kinase inhibitors from the urea class. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 148.
【4】 Redman, A.; Smith, R.A.; Khire, U.; Wood, J.E.; Dumas, J.; Sibley, R.; Lowinger, T.B.; Scott, W.J.; Johnson, J.; Riedl, B.; Hatoum-Mokdad, H. (Bayer AG); Inhibition of p38 kinase activity using aryl and heteroaryl substd. heterocyclic ureas. WO 9932110 .

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)	44248	4,4-dimethyl-3-oxopentanenitrile	59997-51-2	C₇H₁₁NO	详情	详情
(II)	44249	1-(3-nitrophenyl)hydrazine		C₆H₇N₃O₂	详情	详情
(III)	44250	3-(tert-butyl)-1-(3-nitrophenyl)-1H-pyrazol-5-amine; 3-(tert-butyl)-1-(3-nitrophenyl)-1H-pyrazol-5-ylamine		C₁₃H₁₆N₄O₂	详情	详情
(IV)	28667	1,2-dichloro-3-isocyanatobenzene	41195-90-8	C₇H₃Cl₂NO	详情	详情
(V)	44251	N-[3-(tert-butyl)-1-(3-nitrophenyl)-1H-pyrazol-5-yl]-N'-(2,3-dichlorophenyl)urea		C₂₀H₁₉Cl₂N₅O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

The cyclization of 4-methylphenylhydrazine (I) with pivaloylacetonitrile (II) in refluxing methanol gives the aminopyrazole (III), which is treated with Troc-Cl and NaOH in water/ethyl acetate to yield the carbamate (IV). Finally, this compound is condensed with 4-[2-(4-morpholinyl)ethoxy]naphthalene-1-amine (V) by means of DIEA in hot DMSO to afford the target urea. The intermediate 4-[2-(4-morpholinyl)ethoxy]naphthalene-1-amine (V) is obtained by condensation of 2-(4-morpholinyl)ethanol (VI) with 4-nitro-1-naphthol (VII) by means of NaOH and K2CO3 in hot 1-methyl-2-pyrrolidone to yield the corresponding ether (VIII), which is finally reduced with H2 over Pd/C in methanol.

参考文献中间体

合成目标

【1】 Zhang, L.-H.; Zhu, L. (Boehringer Ingelheim Pharmaceuticals Inc.); Novel process for synthesis of heteroaryl-substd. urea cpds.. WO 0104115 .

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)	20387	1-(4-methylphenyl)hydrazine		C₇H₁₀N₂	详情	详情
(II)	44248	4,4-dimethyl-3-oxopentanenitrile	59997-51-2	C₇H₁₁NO	详情	详情
(III)	55425	3-(tert-butyl)-1-(4-methylphenyl)-1H-pyrazol-5-amine; 3-(tert-butyl)-1-(4-methylphenyl)-1H-pyrazol-5-ylamine		C₁₄H₁₉N₃	详情	详情
(IV)	55426	2,2,2-trichloroethyl 3-(tert-butyl)-1-(4-methylphenyl)-1H-pyrazol-5-ylcarbamate		C₁₇H₂₀Cl₃N₃O₂	详情	详情
(V)	55427	4-[2-(4-morpholinyl)ethoxy]-1-naphthalenamine; 4-[2-(4-morpholinyl)ethoxy]-1-naphthylamine		C₁₆H₂₀N₂O₂	详情	详情
(VI)	12856	4-(2-Hydroxyethyl)morpholine; 2-(4-Morpholinyl)-1-ethanol; N-(2-Hydroxyethyl)morpholine	622-40-2	C₆H₁₃NO₂	详情	详情
(VII)	55428	4-nitro-1-naphthol		C₁₀H₇NO₃	详情	详情
(VIII)	55429	2-(4-morpholinyl)ethyl 4-nitro-1-naphthyl ether; 4-{2-[(4-nitro-1-naphthyl)oxy]ethyl}morpholine		C₁₆H₁₈N₂O₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VIII)

The N-protection of 4-amino-1-naphthol (I) with Boc2O by means of BuLi in THF gives the carbamate (II), which is condensed with 4-(2-chloroethyl)morpholine (III) by means of K2CO3 in hot acetonitrile, yielding the corresponding aryl ether (IV). The deprotection of the amino group of (IV) with HCl in dioxane affords the naphthylamine (V), which is finally condensed with 3-(tert-butyl)-1-(4-methylphenyl)-1H-pyrazole-5-amine (VI) by means of COCl2 in toluene/dichloromethane and aq. NaHCO3 to provide the target urea. The intermediate 3-(tert-butyl)-1-(4-methylphenyl)-1H-pyrazole-5-amine (VI) is obtained by cyclization of 4-methylphenylhydrazine (VII) with 4,4-dimethyl-3-oxopentanenitrile (VIII) by means of HCl in refluxing ethanol.

参考文献中间体

合成目标

【1】 Regan, J.R.; Zhang, L.-H.; Cirillo, P.F.; Hickey, E.R.; Gilmore, T.A. (Boehringer Ingelheim Pharmaceuticals Inc.); Aromatic heterocyclic cpds. as antiinflammatory agents. EP 1147104; US 6319921; WO 0043384 .

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)	55430	4-Amino-1-naphthol		C₁₀H₉NO	详情	详情
(II)	55431	tert-butyl 4-hydroxy-1-naphthylcarbamate		C₁₅H₁₇NO₃	详情	详情
(III)	27355	4-(2-chloroethyl)morpholine	3647-69-6	C₆H₁₂ClNO	详情	详情
(IV)	55432	tert-butyl 4-[2-(4-morpholinyl)ethoxy]-1-naphthylcarbamate		C₂₁H₂₈N₂O₄	详情	详情
(V)	55427	4-[2-(4-morpholinyl)ethoxy]-1-naphthalenamine; 4-[2-(4-morpholinyl)ethoxy]-1-naphthylamine		C₁₆H₂₀N₂O₂	详情	详情
(VI)	55425	3-(tert-butyl)-1-(4-methylphenyl)-1H-pyrazol-5-amine; 3-(tert-butyl)-1-(4-methylphenyl)-1H-pyrazol-5-ylamine		C₁₄H₁₉N₃	详情	详情
(VII)	20387	1-(4-methylphenyl)hydrazine		C₇H₁₀N₂	详情	详情
(VIII)	44248	4,4-dimethyl-3-oxopentanenitrile	59997-51-2	C₇H₁₁NO	详情	详情

合成路线4

该中间体在本合成路线中的序号：(IX)

The reaction of 4-amino-1-naphthol (I) with Boc2O in THF gives the carbamate (II), which is condensed with 4-(2-chloroethyl)morpholine (III) by means of K2CO3 in hot acetonitrile to yield ether (IV). The hydrolysis of the carbamate group of (IV) by means of HCl in dioxane affords the naphthylamine (V), which is finally condensed with 3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-amine (VI) and phosgene (VII) in THF to provide the target urea. The intermediates 3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-amine (VI) and phosgene (VII) are obtained by cyclization of 4-methylphenylhydrazine (VIII) with 4,4-dimethyl-3-oxopentanenitrile (IX) in refluxing toluene or by means of HCl in refluxing ethanol.

参考文献中间体

合成目标

【1】 Regan, J.; et al.; Pyrazole urea-based inhibtitors of p38 MAP kinase: From lead compound to clinical candidate. J Med Chem 2002, 45, 14, 2994.

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)	55430	4-Amino-1-naphthol		C₁₀H₉NO	详情	详情
(II)	55431	tert-butyl 4-hydroxy-1-naphthylcarbamate		C₁₅H₁₇NO₃	详情	详情
(III)	27355	4-(2-chloroethyl)morpholine	3647-69-6	C₆H₁₂ClNO	详情	详情
(IV)	55432	tert-butyl 4-[2-(4-morpholinyl)ethoxy]-1-naphthylcarbamate		C₂₁H₂₈N₂O₄	详情	详情
(V)	55427	4-[2-(4-morpholinyl)ethoxy]-1-naphthalenamine; 4-[2-(4-morpholinyl)ethoxy]-1-naphthylamine		C₁₆H₂₀N₂O₂	详情	详情
(VI)	55425	3-(tert-butyl)-1-(4-methylphenyl)-1H-pyrazol-5-amine; 3-(tert-butyl)-1-(4-methylphenyl)-1H-pyrazol-5-ylamine		C₁₄H₁₉N₃	详情	详情
(VII)	56933	carbonic dichloride		CCl₂O	详情	详情
(VIII)	20387	1-(4-methylphenyl)hydrazine		C₇H₁₀N₂	详情	详情
(IX)	44248	4,4-dimethyl-3-oxopentanenitrile	59997-51-2	C₇H₁₁NO	详情	详情

合成路线5

该中间体在本合成路线中的序号：(I)

The cyclization of 2-pivaloylacetonitrile (I) with methylhydrazine (II) in refluxing ethanol gives 5-amino-3-tert-butyl-1-methylpyrazole (III), which is finally condensed with 4-(4-pyridylmethyl)aniline (IV) and carbonyldimidazole (CDI) in dichloromethane to afford the target urea. The aniline (IV) has been obtained by reduction of the corresponding nitro derivative (V) with H2 over Pd/C in ethanol.

参考文献中间体

合成目标

【1】 Dumas, J.; et al.; Synthesis and pharmacological characterization of a potent, orally active p38 kinase inhibitor. Bioorg Med Chem Lett 2002, 12, 12, 1559.

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)	44248	4,4-dimethyl-3-oxopentanenitrile	59997-51-2	C₇H₁₁NO	详情	详情
(II)	12091	1-Methylhydrazine; Monomethyl hydrazine	60-34-4	CH₆N₂	详情	详情
(III)	51506	5-Amino-3-tert-butyl-1-methylpyrazole	118430-73-2	C₈H₁₅N₃	详情	详情
(IV)	51504	4-(4-pyridinylmethyl)aniline; 4-(4-pyridinylmethyl)phenylamine		C₁₂H₁₂N₂	详情	详情
(V)	51503	4-(4-Nitrobenzyl)pyridine; 4-(p-nitrobenzyl) pyridine	1083-48-3	C₁₂H₁₀N₂O₂	详情	详情

Extended Information