2-phenyl-1H-imidazole-4-carbaldehyde -Drug Synthesis Database

【结构式】

【分子编号】35454

【品名】2-phenyl-1H-imidazole-4-carbaldehyde

【CA登记号】

【分子式】C₁₀H₈N₂O

【分子量】172.1864

【元素组成】C 69.76% H 4.68% N 16.27% O 9.29%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(VI)

The condensation of benzaldehyde (I) with malonic ester (II) by means of piperidine and acetic acid in benzene gives the unsaturated malonate (III), which by a selective ester cleavage and a Curtius rearrangement by means of N3-PO(OPh)2 and Et3N in toluene yields the unsaturated aminoester (IV). The reduction of (IV) with a chiral rhodium catalyst affords the chiral protected aminoester (V), which is cyclized to the bridged lactone (VI) by means of BF3 ethearate in dichloromethane. Reductive cleavage of the benzyloxycarbonyl benzyl ether groups of (VI) with H2 over Pd/C affords the free aminophenol (VII). The condensation of (VII) with aldehyde (VIII) (obtained by reduction of ester (IX) with DIBAL in dichloromethane) by means of KCN and AcOH, and after allylation of the aromatic OH group with allyl bromide, the intermediate (X) is obtained. The reduction of the lactone group of (X) with DIBAL, followed by desilylation with KF and cyclization with CH3SO3H affords the polycyclic compound (XI).

参考文献中间体

合成目标

【1】 Gin, D.Y.; Corey, E.J.; Kania, R.S.; Enantioselective total synthesis of Ecteinascidin 743. J Am Chem Soc 1996, 118, 38, 9202-03.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情
(I)	36449	6-(benzyloxy)-7-methyl-1,3-benzodioxole-5-carbaldehyde		C₁₆H₁₄O₄	详情	详情
(II)	36450	1-(2,2-dimethoxyethyl) 3-isobutyl malonate		C₁₀H₁₆O₆	详情	详情
(III)	36451	1-(2,2-dimethoxyethyl) 3-isobutyl 2-[(E)-[6-(benzyloxy)-7-methyl-1,3-benzodioxol-5-yl]methylidene]malonate		C₂₆H₂₈O₉	详情	详情
(IV)	36452	2,2-dimethoxyethyl (Z)-2-[[(benzyloxy)carbonyl]amino]-3-[6-(benzyloxy)-7-methyl-1,3-benzodioxol-5-yl]-2-propenoate		C₃₀H₃₁NO₉	详情	详情
(V)	36453	2,2-dimethoxyethyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[6-(benzyloxy)-7-methyl-1,3-benzodioxol-5-yl]propanoate		C₃₀H₃₃NO₉	详情	详情
(VI)	35454	2-phenyl-1H-imidazole-4-carbaldehyde		C₁₀H₈N₂O	详情	详情
(VII)	36455	(1R,12S)-9-hydroxy-8-methyl-4,6,14-trioxa-16-azatetracyclo[10.3.1.0(2,10).0(3,7)]hexadeca-2,7,9-trien-13-one		C₁₃H₁₃NO₅	详情	详情
(VIII)	36456	allyl (1S)-1-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzyl)-2-oxoethylcarbamate		C₂₆H₄₅NO₆Si₂	详情	详情
(IX)	36457	methyl (2S)-2-[[(allyloxy)carbonyl]amino]-3-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxyphenyl)propanoate		C₂₇H₄₇NO₇Si₂	详情	详情
(X)	36458	allyl (1S,2R)-2-[(1R,12S)-9-(allyloxy)-8-methyl-13-oxo-4,6,14-trioxa-16-azatetracyclo[10.3.1.0(2,10).0(3,7)]hexadeca-2,7,9-trien-16-yl]-1-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzyl)-2-cyanoethylcarbamate		C₄₃H₆₁N₃O₁₀Si₂	详情	详情
(XI)	36459	allyl (1R,2S,13R,15R,16S)-5-(allyloxy)-15-cyano-20,22-dihydroxy-13-(hydroxymethyl)-21-methoxy-6-methyl-8,10-dioxa-14,24-diazahexacyclo[14.7.1.0(2,14).0(4,12).0(7,11).0(18,23)]tetracosa-4,6,11,18,20,22-hexaene-24-carboxylate		C₃₁H₃₃N₃O₉	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

The bromination of 1,1,1-trifluoroacetone (I) according to McBee and Burton gives 3,3-dibromo-1,1,1-trifluoroacetone (II), which is hydrolyzed with aqueous NaOAc to the glyoxal (III). The cyclization of (III) with benzaldehyde (IV) and ammonia in methanol yields 2-phenyl-4-(trifluoromethyl)-1H-imidazole (V), which is converted into the carbonitrile (VI) by reaction with hot aqueous ammonium hydroxide. The reduction of (VI) with diisobutylaluminum hydride in THF affords the carbaldehyde (VII), which is finally condensed with N-tert-butylhydroxylamine (VIII) by means of NaHCO3 in hot ethanol.

参考文献中间体

合成目标

【1】 Dhainaut, A.; et al.; Synthesis, structure, and neuroprotective properties of novel imidazolyl nitrones. J Med Chem 2000, 43, 11, 2165.
【2】 Dhainaut, A.; Lestage, P.; Lockhart, B.; Tizot, A.; Goldstein, S. (ADIR et Cie.); Nitrone derivs., process for their preparation and pharmaceutical compsns. containing them. CA 2274621; EP 0967207; FR 2780404; JP 2000026428; US 6034250 .

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)	35449	1,1,1-trifluoroacetone	421-50-1	C₃H₃F₃O	详情	详情
(II)	35450	3,3-dibromo-1,1,1-trifluoroacetone	431-67-4	C₃HBr₂F₃O	详情	详情
(III)	35451	3,3,3-trifluoro-2-oxopropanal		C₃HF₃O₂	详情	详情
(IV)	10498	Benzaldehyde;Benzoic aldehyde;Phenylmethanal	100-52-7	C₇H₆O	详情	详情
(V)	35452	2-phenyl-4-(trifluoromethyl)-1H-imidazole		C₁₀H₇F₃N₂	详情	详情
(VI)	35435	(1R)-2-[12-[(2R)-2-(benzoyloxy)propyl]-2,4,6,7,9,11-hexamethoxy-3,10-dioxo-3,10-dihydro-1-perylenyl]-1-methylethyl benzoate		C₄₆H₄₂O₁₂	详情	详情
(VII)	35454	2-phenyl-1H-imidazole-4-carbaldehyde		C₁₀H₈N₂O	详情	详情
(VIII)	35455	N-(tert-butyl)hydroxylamine; 2-(hydroxyamino)-2-methylpropane		C₄H₁₁NO	详情	详情

合成路线3

该中间体在本合成路线中的序号：(V)

The hydrolysis of 2-phenyl-4-(trifluoromethyl)-1H-imidazole (I) with 1N NaOH gives 2-phenyl-1H-imidazole-4-carboxylic acid (II), which is condensed with N,O-dimethylhydroxylamine (III) by means of TBTU and DIEA in dichloromethane to yield the amide (IV). The reduction of (IV) with DIBAL in THF affords 2-phenyl-1H-imidazole-4-carbaldehyde (V), which is finally condensed with N-tert-butylhydroxylamine (VI) by means of NaHCO3 in hot ethanol to provide the target nitrone.

参考文献中间体

合成目标

【1】 Dhainaut, A.; et al.; Synthesis, structure, and neuroprotective properties of novel imidazolyl nitrones. J Med Chem 2000, 43, 11, 2165.

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)	35452	2-phenyl-4-(trifluoromethyl)-1H-imidazole		C₁₀H₇F₃N₂	详情	详情
(II)	51473	2-phenyl-1H-imidazole-4-carboxylic acid		C₁₀H₈N₂O₂	详情	详情
(III)	13361	(Methoxyamino)methane; N,O-Dimethylhydroxylamine	1117-97-1	C₂H₇NO	详情	详情
(IV)	51474	N-methoxy-N-methyl-2-phenyl-1H-imidazole-4-carboxamide		C₁₂H₁₃N₃O₂	详情	详情
(V)	35454	2-phenyl-1H-imidazole-4-carbaldehyde		C₁₀H₈N₂O	详情	详情
(VI)	35455	N-(tert-butyl)hydroxylamine; 2-(hydroxyamino)-2-methylpropane		C₄H₁₁NO	详情	详情

Extended Information