bromo(3,4,5-trimethoxyphenyl)magnesium -Drug Synthesis Database

【结构式】

【分子编号】32378

【品名】bromo(3,4,5-trimethoxyphenyl)magnesium

【CA登记号】

【分子式】C₉H₁₁BrMgO₃

【分子量】271.39354

【元素组成】C 39.83% H 4.09% Br 29.44% Mg 8.96% O 17.69%

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：(XX)

The oxidation of the aldehyde group of (XVI) with NaClO2 in tert-butanol affords the corresponding carboxylic acid (XVII), which is condensed with 2-oxazolidinone (XVIII) by means of carbonyldiimidazole (CDI) in THF to give the acyl imidazolide (XIX). The arylation of (XIX) with 3,4,5-trimethoxyphenylmagnesium bromide (XX) in THF yields the expected addition product (XXI), which is cyclized by means of TBAF in hot THF to afford the tetracyclic intermediate (XXII). Isomerization of the cis-lactone ring of (XXII) with LDA in THF affords intermediate (XXIII) with its lactone ring with the correct trans-conformation. Finally, this compound is deprotected with ethyl mercaptane and MgBr2 in ethyl ether to provide the target compound.

参考文献中间体

合成目标

【1】 Berkowitz, D.B.; et al.; Enzyme-assisted asymmetric total synthesis of (-)-podophyllotoxin and (-)-picropodophyllin. J Org Chem 2000, 65, 3, 847.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XVI)	32375	(7R,8R)-7-[[(triisopropylsilyl)oxy]methyl]-8-[[2-(trimethylsilyl)ethoxy]methoxy]-7,8-dihydronaphtho[2,3-d][1,3]dioxole-6-carbaldehyde		C₂₈H₄₆O₆Si₂	详情	详情
(XVII)	32376	(7R,8R)-7-[[(triisopropylsilyl)oxy]methyl]-8-[[2-(trimethylsilyl)ethoxy]methoxy]-7,8-dihydronaphtho[2,3-d][1,3]dioxole-6-carboxylic acid		C₂₈H₄₆O₇Si₂	详情	详情
(XVIII)	21456	1,3-oxazolidin-2-one	497-25-6	C₃H₅NO₂	详情	详情
(XIX)	32377	3-[((7R,8R)-7-[[(triisopropylsilyl)oxy]methyl]-8-[[2-(trimethylsilyl)ethoxy]methoxy]-7,8-dihydronaphtho[2,3-d][1,3]dioxol-6-yl)carbonyl]-1,3-oxazolidin-2-one		C₃₁H₄₉NO₈Si₂	详情	详情
(XX)	32378	bromo(3,4,5-trimethoxyphenyl)magnesium		C₉H₁₁BrMgO₃	详情	详情
(XXI)	32379	3-[((5R,6S,7R,8R)-7-[[(triisopropylsilyl)oxy]methyl]-5-(3,4,5-trimethoxyphenyl)-8-[[2-(trimethylsilyl)ethoxy]methoxy]-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxol-6-yl)carbonyl]-1,3-oxazolidin-2-one		C₄₀H₆₁NO₁₁Si₂	详情	详情
(XXII)	32380	(5R,5aS,8aR,9R)-5-(3,4,5-trimethoxyphenyl)-9-[[2-(trimethylsilyl)ethoxy]methoxy]-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one		C₂₈H₃₆O₉Si	详情	详情
(XXIII)	32381	(5R,5aR,8aR,9R)-5-(3,4,5-trimethoxyphenyl)-9-[[2-(trimethylsilyl)ethoxy]methoxy]-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one		C₂₈H₃₆O₉Si	详情	详情

合成路线2

该中间体在本合成路线中的序号：

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3

该中间体在本合成路线中的序号：(II)

Treatment of 3,4,5-trimethoxybromobenzene (I) with Mg in THF produces the corresponding Grignard reagent (II), which is condensed with 4-methoxy-2-nitrobenzaldehyde (III) to furnish the benzhydrol derivative (IV). Oxidation of benzhydrol (IV) by means of pyridinium dichromate leads to benzophenone (V). The nitro group of (V) is then reduced to the corresponding amine employing iron powder in AcOH.

参考文献中间体

合成目标

【1】 Liou, J.-P.; et al.; Synthesis and structure-activity relationship of 2-aminobenzophenone derivatives as antimitotic agents. J Med Chem 2002, 45, 12, 2556.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	64554	4-bromo-2,6-dimethoxyphenyl methyl ether; 5-bromo-1,2,3-trimethoxybenzene	C₉H₁₁BrO₃	详情	详情
(II)	32378	bromo(3,4,5-trimethoxyphenyl)magnesium	C₉H₁₁BrMgO₃	详情	详情
(III)	64555	4-methoxy-2-nitrobenzaldehyde	C₈H₇NO₄	详情	详情
(IV)	64556	(4-methoxy-2-nitrophenyl)(3,4,5-trimethoxyphenyl)methanol	C₁₇H₁₉NO₇	详情	详情
(V)	64557	(4-methoxy-2-nitrophenyl)(3,4,5-trimethoxyphenyl)methanone	C₁₇H₁₇NO₇	详情	详情

Extended Information