methyl (E)-3-(4-formylphenyl)-2-propenoate -Drug Synthesis Database

【结构式】

【分子编号】46515

【品名】methyl (E)-3-(4-formylphenyl)-2-propenoate

【CA登记号】7560-50-1

【分子式】C₁₁H₁₀O₃

【分子量】190.1986

【元素组成】C 69.46% H 5.3% O 25.24%

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：(IV)

Reduction of 2-methylindole-3-glyoxylamide (I) with LiAlH4 affords 2-methyltryptamine (II). 4-Formylcinnamic acid (III) is esterified with methanolic HCl, and the resulting aldehyde ester (IV) is reductively aminated with 2-methyltryptamine (II) in the presence of NaBH3CN to give (V). The title hydroxamic acid is then obtained by treatment of ester (V) with aqueous hydroxylamine under basic conditions (1). Scheme 1.

参考文献中间体

合成目标

【1】 Bair, K.W., Green, M.A., Perez, L.B., Sharma, S.K., Sambucetti, L., Versace, R.W., Remiszewski, S.W. (Novartis AG; Novartis Pharma GmbH). Deacetylase inhibitors. EP 1318980, JP 2004509105, WO 0222577.

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)	65332	2-methylindole-3-glyoxylamide		C₁₀H₁₀N₂O₂	详情	详情
(II)	65333	2-Methylindole-3-ethylamine; 2-(2-Methyl-1H-indol-3-yl)-ethylamine; 3-(2-Aminoethyl)-2-methylindole	2731-06-8	C₁₁H₁₄N₂	详情	详情
(III)	55571	4-Formylcinnamic acid	23359-08-2	C₁₀H₈O₃	详情	详情
(IV)	46515	methyl (E)-3-(4-formylphenyl)-2-propenoate	7560-50-1	C₁₁H₁₀O₃	详情	详情
(V)	65334			C₂₂H₂₃N₂O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

Palladium-catalyzed coupling of 4-bromobenzaldehyde (I) with methyl acrylate (II) furnished methyl 4-formylcinnamate (III). After aldehyde protection as the ethylene acetal (IV), ester group reduction using DIBAL in cold CH2Cl2 gave rise to the cinnamyl alcohol (V). O-Alkylation of (V) with ethyl iodide in the presence of NaH produced the corresponding ethyl ether (VI). The acetal protecting group of (VI) was then hydrolyzed with HCl to yield aldehyde (VII).

参考文献中间体

合成目标

【2】 Zhang, C.; Mjalli, A.M.M. (Ontogen Corp.); Imidazole derivs. as MDR modulators. EP 0999835; US 5840721; WO 9902155 .
【1】 Dixon, R.; Zhang, C.; Sarshar, S.; Mjalli, A.M.M.; Rodarte, J.C.; Moran, E.J.; Benbatoul, K.D.; Krane, S.; 2,4,5-Trisubstituted imidazoles: Novel nontoxic modulators of P-glycoprotein mediated multidrug resistance. Part 2. Bioorg Med Chem Lett 2000, 10, 23, 2603.

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)	22231	4-Bromobenzaldehyde	1122-91-4	C₇H₅BrO	详情	详情
(II)	14156	methyl acrylate	96-33-3	C₄H₆O₂	详情	详情
(III)	46515	methyl (E)-3-(4-formylphenyl)-2-propenoate	7560-50-1	C₁₁H₁₀O₃	详情	详情
(IV)	46516	methyl (E)-3-[4-(1,3-dioxolan-2-yl)phenyl]-2-propenoate		C₁₃H₁₄O₄	详情	详情
(V)	46517	(E)-3-[4-(1,3-dioxolan-2-yl)phenyl]-2-propen-1-ol		C₁₂H₁₄O₃	详情	详情
(VI)	46518	(E)-3-[4-(1,3-dioxolan-2-yl)phenyl]-2-propenyl ethyl ether; 2-[4-[(E)-3-ethoxy-1-propenyl]phenyl]-1,3-dioxolane		C₁₄H₁₈O₃	详情	详情
(VII)	46519	4-[(E)-3-ethoxy-1-propenyl]benzaldehyde		C₁₂H₁₄O₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

The esterification of 4-formylcinnamic acid (I) with methanol and HCl gives the methyl ester (II), which can be obtained by Heck coupling of 4-bromobenzaldehyde (III) with methyl acrylate (IV). The reductocondensation of (II) with tryptamine (V) by means of NaBH(OAc)3 in dichloroethane yields the secondary amine (VI), which is alkylated with 2-(tert-butyldimethylsilyloxy)ethyl bromide (VII) by means of DIEA in DMSO to afford the tertiary amine (VIII). The reaction of the methyl ester group of (VIII) with KOH and hydroxylamine in methanol provides the silylated hydroxamic acid (IX), which is finally deprotected with TFA in water.

参考文献中间体

合成目标

【1】 Perez, L.B.; Remiszewski, S.; Sambucetti, L.; et al.; Discovery and SAR of NVP-LAQ824, a novel histone deacetylase inhibitor with in vitro and in vivo antitumor activity. Proc Am Assoc Cancer Res 2002, 43, Abst 3671.
【2】 Bair, K.W.; Versace, R.W.; Green, M.A.; Remiszewski, S.W.; Perez, L.B.; Sambucetti, L.; Sharma, S.K. (Novartis AG; Novartis-Erfindungen VmbH); Deacetylase inhibitors. WO 0222577 .

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)	55571	4-Formylcinnamic acid	23359-08-2	C₁₀H₈O₃	详情	详情
(II)	46515	methyl (E)-3-(4-formylphenyl)-2-propenoate	7560-50-1	C₁₁H₁₀O₃	详情	详情
(III)	22231	4-Bromobenzaldehyde	1122-91-4	C₇H₅BrO	详情	详情
(IV)	14156	methyl acrylate	96-33-3	C₄H₆O₂	详情	详情
(V)	40537	Tryptamine; 2-(1H-Indol-3-yl)-1-ethanamine; 2-(1H-Indol-3-yl)ethylamine	61-54-1	C₁₀H₁₂N₂	详情	详情
(VI)	55572	methyl 3-[4-({[2-(1H-indol-3-yl)ethyl]amino}methyl)phenyl]-2-propenoate		C₂₁H₂₂N₂O₂	详情	详情
(VII)	55573	2-Bromoethoxy-t-butyldimethylsilane	86864-60-0	C₈H₁₉BrOSi	详情	详情
(VIII)	55574			C₂₉H₄₀N₂O₃Si	详情	详情
(IX)	55575	3-[4-({(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)[2-(1H-indol-3-yl)ethyl]amino}methyl)phenyl]-N-hydroxy-2-propenamide		C₂₈H₃₉N₃O₃Si	详情	详情

Extended Information