4-Hydroxy-3-iodo-5-methoxybenzaldehyde; 5-Iodovanillin -Drug Synthesis Database

【结构式】

【分子编号】12758

【品名】4-Hydroxy-3-iodo-5-methoxybenzaldehyde; 5-Iodovanillin

【CA登记号】5438-36-8

【分子式】C₈H₇IO₃

【分子量】278.04625

【元素组成】C 34.56% H 2.54% I 45.64% O 17.26%

与该中间体有关的原料药合成路线共 5 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5

合成路线1

该中间体在本合成路线中的序号：(I)

A new synthesis for L-659989 has been reported: The alkylation of 4-hydroxy-3-iodo-5-methoxybenzaldehyde (I) with propyl bromide in hot DMF gives 3-iodo-5-methoxy-4-propoxybenzaldehyde (II), which is condensed with tert-butyl acrylate (III) by means of NaCN in DMF to yield 3-(3-iodo-5-methoxy-4-propoxybenzoyl)propionic acid tert-butyl ester (IV). The stereoselective reduction of (IV) with chlorodiisopinocampheylborane (V) in THF affords 4(S)-hydroxy-4-(3-iodo-5-methoxy-4-propoxyphenyl)butyric acid tert-butyl ester (VI), which is hydrolyzed with KOH in methanol-water to the corresponding free acid (VII). The cyclization of (VII) with pyridinium p-toluenesulfonate in toluene gives 5(S)-(3-iodo-5-methoxy-4-propoxyphenyl)tetrahydrofuran-2-one (VIII), which is treated with dimethyl disulfide and copper in refluxing pyridine to yield 5(S)-[3-methoxy-5-(methylthio)-4-propoxyphenyl]tetrahydrofuran-2-one (IX). The oxidation of (IX) with magnesium monoperoxyphthalate in acetonitrile-water affords the corresponding sulfone (X), which is reduced with diisobutylaluminum hydride in toluene giving 5(S)-[3-methoxy-5-(methylsulfonyl)-4-propoxyphenyl]tetrahydrofuran-2-ol (XI). Finally, this compound is treated first with bromotrimethylsilane and then with 3,4,5-trimethoxyphenylmagnesium bromide, yielding the final product with a trans/cis ratio of 15/1 and a yield of 55%.

参考文献中间体

合成目标

【1】 Tschaen, D.M.; Russ, W.; Thompson, A.S.; Simpson, P.; McSwine, D.; Conversion of a silylated hemiacetal into an alpha-bromoether using trimethylsilylbromide - Synthesis of platelet activating factor antagonist. Tetrahedron Lett 1990, 31, 48, 6953.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	32378	bromo(3,4,5-trimethoxyphenyl)magnesium		C₉H₁₁BrMgO₃	详情	详情
	63472	methyl 8-oxo-8-({3-[(phenylmethyl)oxy]phenyl}amino)octanoate		C₂₂H₂₇NO₄	详情	详情
(I)	12758	4-Hydroxy-3-iodo-5-methoxybenzaldehyde; 5-Iodovanillin	5438-36-8	C₈H₇IO₃	详情	详情
(II)	12759	3-Iodo-5-methoxy-4-propoxybenzaldehyde		C₁₁H₁₃IO₃	详情	详情
(III)	12760	tert-butyl acrylate	1663-39-4	C₇H₁₂O₂	详情	详情
(IV)	12761	tert-butyl 4-(3-iodo-5-methoxy-4-propoxyphenyl)-4-oxobutanoate		C₁₈H₂₅IO₅	详情	详情
(V)	12762	Chlorodiisopinocampheylborane		C₂₂H₄₀	详情	详情
(VI)	12763	tert-butyl (4S)-4-hydroxy-4-(3-iodo-5-methoxy-4-propoxyphenyl)butanoate		C₁₈H₂₇IO₅	详情	详情
(VII)	12764	(4S)-4-Hydroxy-4-(3-iodo-5-methoxy-4-propoxyphenyl)butyric acid		C₁₄H₁₉IO₅	详情	详情
(VIII)	12765	(5S)-5-(3-Iodo-5-methoxy-4-propoxyphenyl)dihydro-2(3H)-furanone		C₁₄H₁₇IO₄	详情	详情
(IX)	12766	(5S)-5-[3-Methoxy-5-(methylsulfanyl)-4-propoxyphenyl]dihydro-2(3H)-furanone		C₁₅H₂₀O₄S	详情	详情
(X)	12767	(5S)-5-[3-Methoxy-5-(methylsulfonyl)-4-propoxyphenyl]dihydro-2(3H)-furanone		C₁₅H₂₀O₆S	详情	详情
(XI)	12768	(5S)-5-[3-Methoxy-5-(methylsulfonyl)-4-propoxyphenyl]tetrahydro-2-furanol		C₁₅H₂₂O₆S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The alkylation of 4-hydroxy-3-iodo-5-methoxybenzaldehyde (I) with propyl bromide (II) by means of K2CO3 in hot DMF gives the propyl ether (III), which is condensed with 3-(dimethylamino)-1-(3,4,5-trimethoxyphenyl)-1-propanone (IV) (obtained by reaction of 3,4,5-trimethoxyacetophenone (V) with dimethylamine and formaldehyde), yielding the asymmetric butanedione (VI). The reaction of (VI) with dimethyl disulfide by means of Cu at 160 C affords the methylsulfanyl compound (VII), which is oxidized with MCPBA in dichloromethane to provide the sulfone derivative (VIII). The reduction of the butanedione (VIII) with NaBH4 in hot ethanol gives the (RS,RS)-diol (IX), which is finally cyclized by means of TFA in chloroform.

参考文献中间体

合成目标

【1】 Ponpipom, M.M.; Hwang, S.B.; Doebber, T.W.; Acton, J.J.; Alberts, A.W.; Biftu, T.; Brooker, D.R.; Bugianesi, R.L.; Chabala, J.C.; Gamble, N.L.; et al.; (±)-trans-2-(3-Methoxy-5-methylsulfonyl-4-propoxyphenyl)-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (L-659,989), a novel, potent PAF receptor antagonist. Biochem Biophys Res Commun 1988, 150, 3, 1213.

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)	12758	4-Hydroxy-3-iodo-5-methoxybenzaldehyde; 5-Iodovanillin	5438-36-8	C₈H₇IO₃	详情	详情
(II)	19502	Propyl bromide; 1-Bromopropane	106-94-5	C₃H₇Br	详情	详情
(III)	12759	3-Iodo-5-methoxy-4-propoxybenzaldehyde		C₁₁H₁₃IO₃	详情	详情
(IV)	44362	1-(3,4,5-trimethoxyphenyl)-1-ethanone	1136-86-3	C₁₁H₁₄O₄	详情	详情
(V)	44363	3-(dimethylamino)-1-(3,4,5-trimethoxyphenyl)-1-propanone		C₁₄H₂₁NO₄	详情	详情
(VI)	44369	1-(3-iodo-5-methoxy-4-propoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,4-butanedione		C₂₃H₂₇IO₇	详情	详情
(VII)	44370	1-[3-methoxy-5-(methylsulfanyl)-4-propoxyphenyl]-4-(3,4,5-trimethoxyphenyl)-1,4-butanedione		C₂₄H₃₀O₇S	详情	详情
(VIII)	44366	1-[3-methoxy-5-(methylsulfonyl)-4-propoxyphenyl]-4-(3,4,5-trimethoxyphenyl)-1,4-butanedione		C₂₄H₃₀O₉S	详情	详情
(IX)	44368	(1R,4R)-1-[3-methoxy-5-(methylsulfonyl)-4-propoxyphenyl]-4-(3,4,5-trimethoxyphenyl)-1,4-butanediol		C₂₄H₃₄O₉S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

Alkylation of 5-iodovanillin (I) with iodoethanol gave hydroxyethyl ether (II). This was condensed with vinyl ketone (III) in the presence of the thiazolium salt (IV) to produce the 1,4-diketone (V). Subsequent reduction of (V) with NaBH4 afforded 1,4-diol (VI), which was cyclized with trifluoroacetic acid in chloroform to furnish a mixture of cis and trans diaryltetrahydrofurans. The required trans isomer (VII) was isolated by column chromatography, and then treated with methanesulfonyl chloride and triethylamine to give mesylate (VIII). Further condensation of (VIII) with 4-chlorothiophenol (IX) provided sulfide (X). Finally, displacement of the iodine atom with CuCN in boiling DMF produced the title nitrile.

参考文献中间体

合成目标

【1】 Cai, X.; et al.; (+-)-trans-2-[3-Methoxy-4-(4-chlorophenylthioethoxy)-5-(N-methyl-N-hydroxyureidyl)methylphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (CMI-392), a potent dual 5-lipoxygenase inhibitor and platelet-activating factor receptor antagonist. J Med Chem 1998, 41, 11, 1970.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	38258	2-iodo-1-ethanol	624-76-0	C₂H₅IO	详情	详情
(I)	12758	4-Hydroxy-3-iodo-5-methoxybenzaldehyde; 5-Iodovanillin	5438-36-8	C₈H₇IO₃	详情	详情
(II)	27940	4-(2-hydroxyethoxy)-3-iodo-5-methoxybenzaldehyde		C₁₀H₁₁IO₄	详情	详情
(III)	27941	1-(3,4,5-trimethoxyphenyl)-2-propen-1-one		C₁₂H₁₄O₄	详情	详情
(IV)	27942	3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride	4568-71-2	C₁₃H₁₆ClNOS	详情	详情
(V)	27943	1-[4-(2-hydroxyethoxy)-3-iodo-5-methoxyphenyl]-4-(3,4,5-trimethoxyphenyl)-1,4-butanedione		C₂₂H₂₅IO₈	详情	详情
(VI)	27944	1-[4-(2-hydroxyethoxy)-3-iodo-5-methoxyphenyl]-4-(3,4,5-trimethoxyphenyl)-1,4-butanediol		C₂₂H₂₉IO₈	详情	详情
(VII)	27945	2-[2-iodo-6-methoxy-4-[(2S,5S)-5-(3,4,5-trimethoxyphenyl)tetrahydro-2-furanyl]phenoxy]-1-ethanol		C₂₂H₂₇IO₇	详情	详情
(VIII)	27946	2-[2-iodo-6-methoxy-4-[(2S,5S)-5-(3,4,5-trimethoxyphenyl)tetrahydro-2-furanyl]phenoxy]ethyl methanesulfonate		C₂₃H₂₉IO₉S	详情	详情
(IX)	27947	4-chlorobenzenethiol	106-54-7	C₆H₅ClS	详情	详情
(X)	27948	(2S,5S)-2-(4-[2-[(4-chlorophenyl)sulfanyl]ethoxy]-3-iodo-5-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran		C₂₈H₃₀ClIO₆S	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

Methylation of 5-iodovanillin (I) with dimethyl sulfate and K2CO3 afforded dimethoxy derivative (II). This was condensed with 3-anilinopropionitrile (III) in the presence of potassium tert-butoxide yielding the enamino nitrile (IV). Subsequent cyclization of (IV) with guanidine hydrochloride (V) produced diaminopyrimidine (VI).

参考文献中间体

合成目标

【1】 Guerry, P.; Locher, H.H.; Hubschwerlen, C.; Wyss, P.C.; Jolidon, S.; Hartman, P.G.; Stalder, H.; Specklin, J.L.; Anti-MRSA dihydrofolate reductase inhibitors: Synthesis and SAR. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F1800.

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)	12758	4-Hydroxy-3-iodo-5-methoxybenzaldehyde; 5-Iodovanillin	5438-36-8	C₈H₇IO₃	详情	详情
(II)	40641	3-iodo-4,5-dimethoxybenzaldehyde	32024-15-0	C₉H₉IO₃	详情	详情
(III)	27195	3-anilinopropanenitrile	1075-76-9	C₉H₁₀N₂	详情	详情
(IV)	40642	(Z)-3-anilino-2-(3-iodo-4,5-dimethoxybenzyl)-2-propenenitrile		C₁₈H₁₇IN₂O₂	详情	详情
(V)	14790	Guanidine	113-00-8	CH₅N₃	详情	详情
(VI)	40643	5-(3-iodo-4,5-dimethoxybenzyl)-2,4-pyrimidinediamine; 2-amino-5-(3-iodo-4,5-dimethoxybenzyl)-4-pyrimidinylamine		C₁₃H₁₅IN₄O₂	详情	详情

合成路线5

该中间体在本合成路线中的序号：(I)

参考文献中间体

合成目标

【1】 Guerry, P.; Locher, H.H.; Hubschwerlen, C.; Wyss, P.C.; Jolidon, S.; Hartman, P.G.; Stalder, H.; Specklin, J.L.; Anti-MRSA dihydrofolate reductase inhibitors: Synthesis and SAR. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F1800.

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)	12758	4-Hydroxy-3-iodo-5-methoxybenzaldehyde; 5-Iodovanillin	5438-36-8	C₈H₇IO₃	详情	详情
(II)	40641	3-iodo-4,5-dimethoxybenzaldehyde	32024-15-0	C₉H₉IO₃	详情	详情
(III)	27195	3-anilinopropanenitrile	1075-76-9	C₉H₁₀N₂	详情	详情
(IV)	40642	(Z)-3-anilino-2-(3-iodo-4,5-dimethoxybenzyl)-2-propenenitrile		C₁₈H₁₇IN₂O₂	详情	详情
(V)	14790	Guanidine	113-00-8	CH₅N₃	详情	详情
(VI)	40643	5-(3-iodo-4,5-dimethoxybenzyl)-2,4-pyrimidinediamine; 2-amino-5-(3-iodo-4,5-dimethoxybenzyl)-4-pyrimidinylamine		C₁₃H₁₅IN₄O₂	详情	详情
(VII)	10164	ethyl acrylate	140-88-5	C₅H₈O₂	详情	详情
(VIII)	40649	ethyl (E)-3-[5-[(2,4-diamino-5-pyrimidinyl)methyl]-2,3-dimethoxyphenyl]-2-propenoate		C₁₈H₂₂N₄O₄	详情	详情

Extended Information