4-methoxy-3-(phenethyloxy)benzaldehyde -Drug Synthesis Database

【结构式】

【分子编号】23679

【品名】4-methoxy-3-(phenethyloxy)benzaldehyde

【CA登记号】

【分子式】C₁₆H₁₆O₃

【分子量】256.30124

【元素组成】C 74.98% H 6.29% O 18.73%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(III)

Isovanillin (I) was alkylated with phenethyl bromide (II) in the presence of K2CO3 to afford phenethyl ether (III). The aldehyde function of (III) was then reduced with NaBH4, and the resulting alcohol (IV) was converted to chloride (V) by means of SOCl2 in THF-DMF. Subsequent displacement of the chlorine atom of (V) by KCN afforded nitrile (VI), which was hydrolyzed to acid (VII) with KOH in aqueous EtOH. Further conversion of (VII) to acid chloride (VIII), followed by condensation with dipropyl amine (IX) in toluene provided amide (X). Finally, reduction with LiAlH4 gave the corresponding amine, that was isolated as the hydrochloride salt.

参考文献中间体

合成目标

【1】 Nakazato, A.; et al.; Design, synthesis, structure-activity relationship. J Med Chem 1999, 42, 6, 1076.

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)	18455	3-hydroxy-4-methoxybenzaldehyde; Isovanillin	621-59-0	C₈H₈O₃	详情	详情
(II)	20730	1-(2-bromoethyl)benzene；1-Bromo-2-phenylethane;(2-Bromoethyl)benzene;Phenethyl bromide	103-63-9	C₈H₉Br	详情	详情
(III)	23679	4-methoxy-3-(phenethyloxy)benzaldehyde		C₁₆H₁₆O₃	详情	详情
(IV)	23680	[4-methoxy-3-(phenethyloxy)phenyl]methanol		C₁₆H₁₈O₃	详情	详情
(V)	23681	4-(chloromethyl)-1-methoxy-2-(phenethyloxy)benzene; 5-(chloromethyl)-2-methoxyphenyl phenethyl ether		C₁₆H₁₇ClO₂	详情	详情
(VI)	23682	2-[4-methoxy-3-(phenethyloxy)phenyl]acetonitrile		C₁₇H₁₇NO₂	详情	详情
(VII)	23683	2-[4-methoxy-3-(phenethyloxy)phenyl]acetic acid		C₁₇H₁₈O₄	详情	详情
(VIII)	23685	2-[4-methoxy-3-(phenethyloxy)phenyl]acetyl chloride		C₁₇H₁₇ClO₃	详情	详情
(IX)	21856	N,N-dipropylamine; N-propyl-1-propanamine	142-84-7	C₆H₁₅N	详情	详情
(X)	23686	2-[4-methoxy-3-(phenethyloxy)phenyl]-N,N-dipropylacetamide		C₂₃H₃₁NO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Wittig reaction between aldehyde (I) and bromo derivative (II) by means of triethyl phosphonoacetate and NaH in 1,2-dimethoxyethane (A) affords a mixture of isomeric acrylates (IIIa-b), which are hydrogenated over Pd/C in EtOH to yield derivative (IV). Hydrolysis of ethyl ester (IV) by means of KOH or NaOH provides carboxylic acid (V), which is then converted into N-protected derivative (VI) by first treatment with diphenylphosphoryl azide (DPPA) and Et3N in refluxing benzene, followed by reaction with refluxing t-butanol. Boc removal of (VI) with TFA in CH2Cl2 furnishes free amine (VII), which is finally alkylated with propyl bromide (VIII) by means of K2CO3 in DMF to yield the target product.

参考文献中间体

合成目标

【1】 Tomisawa, K.; Ohta, K.; Nakazato, A.; Kumagai, T.; Chaki, S.; Okuyama, S.; Synthesis and SAR of 1-alkyl-2-phenylethylamine derivatives designed from N,N-dipropyl-4-methoxy-3-(2-phenylethoxy)phenylethylamine to discover sigma1 ligands. J Med Chem 1999, 42, 19, 3965.
【2】 Nakazato, A.; Kumagai, T.; Miyazawa, T.; Ohta, K.; Kawashima, Y.; Hatayama, K. (Taisho Pharmaceutical Co., Ltd.); Optically active substd. phenylalkylamine derivs.. EP 0870758; JP 1997059230; US 5990151; WO 9700238 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	10019	Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate	867-13-0	C₈H₁₇O₅P	详情	详情
(IIIa)	46235	ethyl (Z)-2-isopentyl-3-[4-methoxy-3-(phenethyloxy)phenyl]-2-propenoate		C₂₅H₃₂O₄	详情	详情
(IIIb)	46236	ethyl (E)-2-isopentyl-3-[4-methoxy-3-(phenethyloxy)phenyl]-2-propenoate		C₂₅H₃₂O₄	详情	详情
(I)	23679	4-methoxy-3-(phenethyloxy)benzaldehyde		C₁₆H₁₆O₃	详情	详情
(II)	46234	1-bromo-3-methylbutane		C₅H₁₁Br	详情	详情
(IV)	46237	ethyl 2-[4-methoxy-3-(phenethyloxy)benzyl]-5-methylhexanoate		C₂₅H₃₄O₄	详情	详情
(V)	46238	2-[4-methoxy-3-(phenethyloxy)benzyl]-5-methylhexanoic acid		C₂₃H₃₀O₄	详情	详情
(VI)	46239	tert-butyl 1-[4-methoxy-3-(phenethyloxy)benzyl]-4-methylpentylcarbamate		C₂₇H₃₉NO₄	详情	详情
(VII)	46240	1-[4-methoxy-3-(phenethyloxy)benzyl]-4-methylpentylamine; 1-[4-methoxy-3-(phenethyloxy)phenyl]-5-methyl-2-hexanamine		C₂₂H₃₁NO₂	详情	详情
(VIII)	19502	Propyl bromide; 1-Bromopropane	106-94-5	C₃H₇Br	详情	详情

Extended Information