1-(3,4,5-trimethoxyphenyl)-2-propen-1-one -Drug Synthesis Database

【结构式】

【分子编号】27941

【品名】1-(3,4,5-trimethoxyphenyl)-2-propen-1-one

【CA登记号】

【分子式】C₁₂H₁₄O₄

【分子量】222.24076

【元素组成】C 64.85% H 6.35% O 28.8%

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：(III)

Synthesis of intermediate 1,4-bis(3,4,5-trimethoxyphenyl)butane-1,4-dione (V). This compound can be obtained by three related methods: 1. The Grignard reaction of 3,4,5-trimethoxybenzaldehyde (I) with vinylmagnesium bromide (II), followed by oxidation with MnO2, gives 1-(3,4,5-trimethoxyphenyl)-2-propen-1-one (III), which is then condensed with aldehyde (I) by means of the thiazolium salt (IV) to yield the target intermediate (V). 2. The condensation of 3,4,5-trimethoxyacetophenone (VI) with methylamine and formaldehyde gives 3-(dimethylamino)-1-(3,4,5-trimethoxyphenyl)-1-propanone (VII), which is treated with methyl iodide at 80 C to afford the previously reported propenone intermediate (III). 3.The direct dimerization of acetophenone (VI) by means of LDA and CuCl2 also gives the target intermediate (V). Synthesis of the target compound: The reduction of the butanedione intermediate (V) with LiAlH4 or NaBH4 gives (RS,RS)-1,4-bis(3,4,5-trimethoxyphenyl)butane-2,3-diol (IX), which is dehydrated to the target tetrahydrofuran by means of TFA, PdCl2/Cu(NO3)2 or MsCl/pyridine. Alternatively, the reduction of butanedione (V) can be performed stepwise, first with LiAlH(O-tBu)3 to give the intermediate hydroxyketone (VIII), which is reduced to the diol (IX). The isolation of the intermediate hydroxyketone (VIII) allows the separation of enantiomers offering the possibility of obtaining chiral forms of the target tetrahydrofuran.

参考文献中间体

合成目标

【1】 Doebber, T.W.; Beattie, T.R.; Shen, T.-Y.; Hwang, S.-B.; Biftu, T. (Merck & Co., Inc.); New 2,5-diaryl tetrahydrofurans and analogs thereof as PAF antagonists. AU 8656430; EP 0199324; ES 8801909; JP 1987000077 .
【2】 Biftu, T.; Chabala, J.C.; Acton, J.; Kuo, C.-H.; Stevenson, R.; 2,5-DIARYLTETRAHYDROFURANS: PAF ANTAGONISTS. Drugs Fut 1989, 14, 4, 359.

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)	11136	3,4,5-Trimethoxybenzaldehyde	86-81-7	C₁₀H₁₂O₄	详情	详情
(II)	16524	bromo(vinyl)magnesium	1826-67-1	C₂H₃BrMg	详情	详情
(III)	27941	1-(3,4,5-trimethoxyphenyl)-2-propen-1-one		C₁₂H₁₄O₄	详情	详情
(IV)	44365	3,4-diethyl-5-(2-hydroxyethyl)-1,3-thiazol-3-ium bromide		C₉H₁₆BrNOS	详情	详情
(V)	44387	1,4-bis(3,4,5-trimethoxyphenyl)-1,4-butanedione		C₂₂H₂₆O₈	详情	详情
(VI)	44362	1-(3,4,5-trimethoxyphenyl)-1-ethanone	1136-86-3	C₁₁H₁₄O₄	详情	详情
(VII)	44363	3-(dimethylamino)-1-(3,4,5-trimethoxyphenyl)-1-propanone		C₁₄H₂₁NO₄	详情	详情
(VIII)	44388	4-hydroxy-1,4-bis(3,4,5-trimethoxyphenyl)-1-butanone		C₂₂H₂₈O₈	详情	详情
(IX)	44389	(1R,4R)-1,4-bis(3,4,5-trimethoxyphenyl)-1,4-butanediol		C₂₂H₃₀O₈	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

The reaction of 3,4,5-trimethoxyacetophenone (I) with diethylamine and formaldehyde gives 3-(dimethylamino)-1-(3,4,5-trimethoxyphenyl)-1-propanone (II), which is treated with methyl iodide at 80 C to yield 1-(3,4,5-trimethoxyphenyl)-2-propen-1-one (III). The condensation of (III) with 3-methoxy-5-(methylsulfonyl)-4-propoxybenzaldehyde (IV) by means of TEA and the thiazolium derivative (V) affords the asymmetric butane-1,4-dione (VI), which is reduced with LiAlH4 or NaBH4 to provide the (RS,RS)-butane-1,4-diol (VIII). Finally, this compound is dehydrated to the target tetrahydrofuran by means of TFA, PdCl2/Cu(NO3)2 or MsCl/pyridine.

参考文献中间体

合成目标

【1】 Biftu, T.; Chabala, J.C.; Acton, J.; Kuo, C.-H.; Stevenson, R.; 2,5-DIARYLTETRAHYDROFURANS: PAF ANTAGONISTS. Drugs Fut 1989, 14, 4, 359.

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)	44362	1-(3,4,5-trimethoxyphenyl)-1-ethanone	1136-86-3	C₁₁H₁₄O₄	详情	详情
(II)	44363	3-(dimethylamino)-1-(3,4,5-trimethoxyphenyl)-1-propanone		C₁₄H₂₁NO₄	详情	详情
(III)	27941	1-(3,4,5-trimethoxyphenyl)-2-propen-1-one		C₁₂H₁₄O₄	详情	详情
(IV)	44364	3-methoxy-5-(methylsulfonyl)-4-propoxybenzaldehyde		C₁₂H₁₆O₅S	详情	详情
(V)	44365	3,4-diethyl-5-(2-hydroxyethyl)-1,3-thiazol-3-ium bromide		C₉H₁₆BrNOS	详情	详情
(VI)	44366	1-[3-methoxy-5-(methylsulfonyl)-4-propoxyphenyl]-4-(3,4,5-trimethoxyphenyl)-1,4-butanedione		C₂₄H₃₀O₉S	详情	详情
(VII)	44367	4-hydroxy-4-[3-methoxy-5-(methylsulfonyl)-4-propoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-1-butanone		C₂₄H₃₂O₉S	详情	详情
(VIII)	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：(III)

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

Extended Information