4-(Benzyloxy)-3-methoxybenzaldehyde; 4-Benzyloxy-3-methoxybenzaldehyde -Drug Synthesis Database

【结构式】

【分子编号】14045

【品名】4-(Benzyloxy)-3-methoxybenzaldehyde; 4-Benzyloxy-3-methoxybenzaldehyde

【CA登记号】2426-87-1

【分子式】C₁₅H₁₄O₃

【分子量】242.27436

【元素组成】C 74.36% H 5.82% O 19.81%

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：(II)

The synthesis of Ro 40-7592 is carried out as follows: Addition of 4-bromotoluene (I) to 4-(benzyloxy)-3-methoxybenzaldehyde (II) in the presence of butyllithium in THF at -78 C gives 4-(benzyloxy)-3-methoxy-4'-methylbenzhydrol (III). Oxidation of this compound with pyridinium chlorochromate in CH2Cl2 yields the corresponding 4-(benzyloxy)-3-methoxy-4'-methylbenzophenone (IV). Debenzylation of (IV) with 30% aqueous hydrobromic acid in acetic acid affords 4-hydroxy-3-methoxy-4'-methylbenzophenone (V). Regioselective nitration of (V) with 65% aqueous nitric acid in acetic acid gives 4-hydroxy-3-methoxy-4'-methyl-5-nitrobenzophenone (VI). Hydrolysis of the methoxy group in (VI) with 30% aqueous hydrobromic acid in boiling acetic acid affords 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone, Ro 40-7592.

参考文献中间体

合成目标

【1】 Bernauer, K.; Borgulya, J.; Bruderer, H.; Da Prada, M.; Zurcher, G. (F. Hoffmann-La Roche AG); 3,5-Disubstituted pyrocatechol derivs. EP 0237929; US 5389653; US 5476875 .
【2】 Scherschlicht, R.; Schlappi, B.; Borgulya, J.; Dingemanse, J.; Da Prada, M.; Zurcher, G.; Ro 40-7592. Drugs Fut 1991, 16, 8, 719.
【3】 Zurcher, G.; Da Prada, M.; Borgulya, J.; Bernauer, K.; Bruderer, H.; Catechol-O-methyltransferase-inhibiting pyrocatechol derivatives: Synthesis and structure-activity studies. Helv Chim Acta 1989, 72, 952-68.

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)	14044	4-Bromotoluene; 1-Bromo-4-methylbenzene	106-38-7	C₇H₇Br	详情	详情
(II)	14045	4-(Benzyloxy)-3-methoxybenzaldehyde; 4-Benzyloxy-3-methoxybenzaldehyde	2426-87-1	C₁₅H₁₄O₃	详情	详情
(III)	14046	[4-(Benzyloxy)-3-methoxyphenyl](4-methylphenyl)methanol		C₂₂H₂₂O₃	详情	详情
(IV)	14047	[4-(Benzyloxy)-3-methoxyphenyl](4-methylphenyl)methanone		C₂₂H₂₀O₃	详情	详情
(V)	14048	(4-Hydroxy-3-methoxyphenyl)(4-methylphenyl)methanone		C₁₅H₁₄O₃	详情	详情
(VI)	14049	(4-Hydroxy-3-methoxy-5-nitrophenyl)(4-methylphenyl)methanone		C₁₅H₁₃NO₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Protection of vanillin (I) as the benzyl ether (II), followed by reaction with benzylmagnesium bromide, furnished alcohol (III). Oxidation of alcohol (III) to the corresponding ketone (IV) was achieved by means of chromium trioxide or, in an improved procedure, by Oppenauer oxidation with cyclohexanone and sodium tert-butoxide. Benzyl group cleavage in (IV) either with HBr, or by transfer hydrogenolysis, yielded phenol (V). Regioselective nitration of (V) gave the ortho-nitrophenol (VI). The title compound was finally obtained by methyl ether cleavage in (VI) with boiling HBr or with AlCl3 in pyridine.

参考文献中间体

合成目标

【1】 Benes, J.; Vieira-Coelho, M.A.; Borges, N.; Freitas, A.P.; Soares-da-Silva, P.; Alves, P.C.; Learmonth, D.A.; Synthesis of 1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone and derivatives as potent and long-acting peripheral inhibitors of catechol-O-methyltransferase. J Med Chem 2002, 45, 3, 685.
【3】 Benes, J.; Soares da Silva, P.M.V.A.; Learmonth, D.A. (Portela & Ca., SA); Substd. 2-phenyl-1-(3,4-dihydroxy-5-nitrophenyl)-1-ethanones, their use in the treatment of some central and peripheral nervous system disorders and pharmaceutical compsns. containing them. EP 1010688; GB 2344819; WO 0037423 .
【2】 Learmonth, D.; et al.; Synthesis of 1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone and derivatives as potent and selective inhibitors of catechol-O-methyltransferase (COMT). 16th Int Symp Med Chem (Sept 18 2000, Bologna) 2000, Abst PA-34.

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)	22701	4-hydroxy-3-methoxybenzaldehyde	121-33-5	C₈H₈O₃	详情	详情
(II)	14045	4-(Benzyloxy)-3-methoxybenzaldehyde; 4-Benzyloxy-3-methoxybenzaldehyde	2426-87-1	C₁₅H₁₄O₃	详情	详情
(III)	59403	1-[4-(benzyloxy)-3-methoxyphenyl]-2-phenyl-1-ethanol		C₂₂H₂₂O₃	详情	详情
(IV)	59404	1-[4-(benzyloxy)-3-methoxyphenyl]-2-phenyl-1-ethanone		C₂₂H₂₀O₃	详情	详情
(V)	59405	1-(4-hydroxy-3-methoxyphenyl)-2-phenyl-1-ethanone		C₁₅H₁₄O₃	详情	详情
(VI)	59406	1-(4-hydroxy-3-methoxy-5-nitrophenyl)-2-phenyl-1-ethanone		C₁₅H₁₃NO₅	详情	详情

Extended Information