1-methyl-1H-imidazole -Drug Synthesis Database

【结构式】

【分子编号】38630

【品名】1-methyl-1H-imidazole

【CA登记号】616-47-7

【分子式】C₄H₆N₂

【分子量】82.10512

【元素组成】C 58.52% H 7.37% N 34.12%

与该中间体有关的原料药合成路线共 4 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1

该中间体在本合成路线中的序号：(VIII)

The bromination of 6-bromo-2-methylfluoren-9-one (I) with NBS and AIBN in refluxing CCl4 gives the 2-bromomethyl compound (II), which is treated with potassium acetate in DMF to afford the acetoxymethyl derivative (III). The hydrolysis of (III) with NaOMe in methanol provides the hydroxymethyl compound (IV), which is treated with hexamethyldistannane and Pd(PPh3)4 in refluxing toluene to give the trimethylstannyl derivative (V). The condensation of (V) with the carbapenem triflate (VI) by means of a Pd catalyst in THF yields the adduct (VII), which is condensed with 1-methylimidazole by means of Tf2O in dichloromethane affording the imidazolium derivative (IX). The desilylation of (IX) with TBAF in THF gives the 1-hydroxyethyl derivative (X), which is finally treated with H2 over Pd/C in THF/ethanol/water to obtain the target compound as an inner salt. The intermediate carbapenem triflate (VI) has been obtained by reaction of 2-oxocarbapenam (XI) with Tf2O, followed by silylation with Tes-OTf.

参考文献中间体

合成目标

【1】 Greenlee, M.L.; Dininno, F.P.; Cama, L.D.; Heck, J.V. (Merck & Co., Inc.); 2-(9-Fluorenonyl)-carbapenem antibacterial agents. EP 0472306; JP 1993105679; US 5034384 .
【2】 Greenlee, M.L.; Dininno, F.P.; Cama, L.D.; Heck, J.V. (Merck & Co., Inc.); 2-(9-Fluorenonyl)-carbapenem intermediates. US 5356889 .

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)	38623	6-bromo-2-methyl-9H-fluoren-9-one		C₁₄H₉BrO	详情	详情
(II)	38624	6-bromo-2-(bromomethyl)-9H-fluoren-9-one		C₁₄H₈Br₂O	详情	详情
(III)	38625	(6-bromo-9-oxo-9H-fluoren-2-yl)methyl acetate		C₁₆H₁₁BrO₃	详情	详情
(IV)	38626	6-bromo-2-(hydroxymethyl)-9H-fluoren-9-one		C₁₄H₉BrO₂	详情	详情
(V)	38627	2-(hydroxymethyl)-6-(trimethylstannyl)-9H-fluoren-9-one		C₁₇H₁₈O₂Sn	详情	详情
(VI)	38628	4-nitrobenzyl (5R,6S)-7-oxo-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-3-[[(trifluoromethyl)sulfonyl]oxy]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate		C₂₃H₂₉F₃N₂O₉SSi	详情	详情
(VII)	38629	4-nitrobenzyl (5R,6S)-3-[7-(hydroxymethyl)-9-oxo-9H-fluoren-3-yl]-7-oxo-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate		C₃₆H₃₈N₂O₈Si	详情	详情
(VIII)	38630	1-methyl-1H-imidazole	616-47-7	C₄H₆N₂	详情	详情
(IX)	38631	1-methyl-3-[[6-((5R,6S)-2-[[(4-nitrobenzyl)oxy]carbonyl]-7-oxo-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-en-3-yl)-9-oxo-9H-fluoren-2-yl]methyl]-1H-imidazol-3-ium chloride		C₄₀H₄₃ClN₄O₇Si	详情	详情
(X)	38632	3-[[6-((5R,6S)-6-[(1R)-1-hydroxyethyl]-2-[[(4-nitrobenzyl)oxy]carbonyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl)-9-oxo-9H-fluoren-2-yl]methyl]-1-methyl-1H-imidazol-3-ium chloride		C₃₄H₂₉ClN₄O₇	详情	详情
(XI)	22686	4-nitrobenzyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate		C₁₆H₁₆N₂O₇	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

Cyclization of 3-(3-chlorophenyl)-N-phenyl-2-propenamide (I) by means of polyphosphoric acid (PPA) at 100 C gives 4-(3-chlorophenyl)-1,2,3,4-tetrahydroquinolin-2-one (II), which is condensed with 4-chlorobenzoic acid (III) by means of PPA at 140 C to yield 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-1,2,3,4-tetrahydroquinolin-2-one (IV). The dehydrogenation of (IV) by means of Br2 in bromobenzene at 160 C affords 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)quinolin-2(1H)-one (V), which is methylated with iodomethane and NaOH/benzyltrimethylammonium chloride in THF to provide 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-1-methylquinolin-2(1H)-one (VI). Condensation of compound (VI) with 1-methylimidazole (VII) by means of butyllithium in THF gives the triaryl carbinol (VIII), which is finally treated with ammonia in THF to afford R-115777.

参考文献中间体

合成目标

【1】 Sorbera, L.A.; Castaner, J.; Fernandez, R.; R-115777. Drugs Fut 2001, 26, 5, 453.
【2】 Venet, M.G.; Angibaud, P.R.; Muller, P.; Sanz, G.C. (Janssen Pharmaceutica NV); Farnesyl protein transferase inhibiting (imidazol-5-yl)methyl-2-quinolinone derivs.. EP 0865440; JP 1998511405; US 6037350; WO 9721701 .

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)	46720	(E)-3-(3-chlorophenyl)-N-phenyl-2-propenamide		C₁₅H₁₂ClNO	详情	详情
(II)	46721	4-(3-chlorophenyl)-3,4-dihydro-2(1H)-quinolinone		C₁₅H₁₂ClNO	详情	详情
(III)	18359	p-chlorobenzoic acid; 4-chlorobenzoic acid	74-11-3	C₇H₅ClO₂	详情	详情
(IV)	46722	6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-3,4-dihydro-2(1H)-quinolinone		C₂₂H₁₅Cl₂NO₂	详情	详情
(V)	46723	6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-2(1H)-quinolinone		C₂₂H₁₃Cl₂NO₂	详情	详情
(VI)	46724	6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone		C₂₃H₁₅Cl₂NO₂	详情	详情
(VII)	38630	1-methyl-1H-imidazole	616-47-7	C₄H₆N₂	详情	详情
(VIII)	46725	4-(3-chlorophenyl)-6-[(4-chlorophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone		C₂₇H₂₁Cl₂N₃O₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VII)

Lithiation of 1-methylimidazole (VII), followed by quenching with triethylchlorosilane provides the 2-silyl imidazole (VIII). After metalation of (VIII) with tert-butyllithium, condensation with 4-cyanobenzaldehyde (IX) gives rise to the carbinol (X). Finally, coupling between alcohols (VI) and (X) in the presence of p-toluenesulfonic acid in refluxing toluene leads to the desired ether adduct.

参考文献中间体

合成目标

【1】 Hasvold, L.A.; et al.; Design and synthesis of pyridone farnesyltransferase inhibitors. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 126.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	60862	5-(3-chlorophenyl)-6-(hydroxymethyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitrile		C₁₃H₉ClN₂O₂	详情	详情
(VII)	38630	1-methyl-1H-imidazole	616-47-7	C₄H₆N₂	详情	详情
(VIII)	60863	1-methyl-2-(tripropylsilyl)-1H-imidazole		C₁₃H₂₆N₂Si	详情	详情
(IX)	17552	4-formylbenzonitrile; 4-Cyanobenzaldehyde	105-07-7	C₈H₅NO	详情	详情
(X)	60864	4-[hydroxy(1-methyl-1H-imidazol-2-yl)methyl]benzonitrile		C₁₂H₁₁N₃O	详情	详情

合成路线4

该中间体在本合成路线中的序号：(IX)

Decarboxylation of methyl 3-aminothiophene-2-carboxylate (I) in 2 N NaOH leads to 3-aminothiophene (II). Meldrum's acid (III) is condensed with triethyl orthoformate to produce the ethoxymethylene derivative (IV). Subsequent reaction of enol ether (IV) with 3-aminothiophene (II) gives rise to enamine (V), which is further cyclized to thienopyridinone (VI) upon heating in dowtherm A at 260 C. This is then chlorinated by means of oxalyl chloride to furnish 4-chlorothieno[3,2-b]pyridine (VII). Metalation of (VII) with butyllithium in cold THF, followed by treatment with I2 affords the aryl iodide (VIII). Palladium-catalyzed coupling of (VIII) with the lithiated derivative of 1-methylimidazole (IX) yields (X). Finally, displacement of the chloride group of (X) with 5-amino-2-methylindole (XI) provides the title compound.

参考文献中间体

合成目标

【1】 Munchhof, M.J.; Adams, M.A.; Atherton, J.A.; et al.; Development of thienopyridines as VEGFR-2 kinase inhibitors. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 129.
【2】 Sobolov-Jaynes, S.B.; Munchhof, M.J. (Pfizer Products Inc.); Thienopyrimidine and thienopyridine derivs. useful as anticancer agents. EP 1028964; JP 2001522853; WO 9924440 .

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)	27686	3-amino-2-thiophenecarboxylic acid methyl ester; methyl 3-amino-2-thiophenecarboxylate	22288-78-4	C₆H₇NO₂S	详情	详情
(II)	63448	3-thiophenylamine; 3-thiophenamine		C₄H₅NS	详情	详情
(III)	14738	Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester	2033-24-1	C₆H₈O₄	详情	详情
(IV)	63449	5-[(ethyloxy)methylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione		C₉H₁₂O₅	详情	详情
(V)	63450	2,2-dimethyl-5-[(3-thiophenylamino)methylidene]-1,3-dioxane-4,6-dione		C₁₁H₁₁NO₄S	详情	详情
(VI)	63451	thieno[3,2-b]pyridin-7(4H)-one		C₇H₅NOS	详情	详情
(VII)	63452	7-chlorothieno[3,2-b]pyridine		C₇H₄ClNS	详情	详情
(VIII)	63453	7-chloro-2-iodothieno[3,2-b]pyridine		C₇H₃ClINS	详情	详情
(IX)	38630	1-methyl-1H-imidazole	616-47-7	C₄H₆N₂	详情	详情
(X)	63454	7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine		C₁₁H₈ClN₃S	详情	详情
(XI)	63455	2-methyl-1H-indol-5-ylamine; 2-methyl-1H-indol-5-amine		C₉H₁₀N₂	详情	详情

Extended Information