1,4-dimethoxybenzene; 4-methoxyphenyl methyl ether -Drug Synthesis Database

【结构式】

【分子编号】21946

【品名】1,4-dimethoxybenzene; 4-methoxyphenyl methyl ether

【CA登记号】150-78-7

【分子式】C₈H₁₀O₂

【分子量】138.1662

【元素组成】C 69.55% H 7.3% O 23.16%

与该中间体有关的原料药合成路线共 10 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6 合成路线7 合成路线8 合成路线9 合成路线10

合成路线1

该中间体在本合成路线中的序号：(I)

The formylation of 1,4-dimethoxybenzene (I) with C6H11-Li, TMEDA and DMF gives 2,5-dimethoxybenzaldehyde (II), which is reduced with NaBH4 to the corresponding alcohol (III). The treatment of (III) with HBr affords the benzyl bromide (IV), which by reaction with PPh3 in hot toluene is converted into the phosphonium salt (V). The condensation of (V) with 5-formyl-2-hydroxybenzoic acid methyl ester (VI)(obtained by esterification of the corresponding acid (VII) with methanol and H2SO4) by means of LDA in THF affords the stilbene (VIII). Finally, this compound is reduced with H2 over Pd/C in ethyl acetate.

参考文献中间体

合成目标

【1】 Kucerovy, A.; et al.; An efficient large-scale synthesis of methyl 5-[2-82,5-dimethoxyphenyl)ethyl]-2-hydroxybenzoate. Org Process Res Dev 1997, 1, 4, 287.

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)	21946	1,4-dimethoxybenzene; 4-methoxyphenyl methyl ether	150-78-7	C₈H₁₀O₂	详情	详情
(II)	10174	2,5-Dimethoxybenzaldehyde	93-02-7	C₉H₁₀O₃	详情	详情
(III)	32353	(2,5-dimethoxyphenyl)methanol	33524-31-1	C₉H₁₂O₃	详情	详情
(IV)	32354	2-(bromomethyl)-4-methoxyphenyl methyl ether; 2-(bromomethyl)-1,4-dimethoxybenzene		C₉H₁₁BrO₂	详情	详情
(V)	32355	(2,5-dimethoxybenzyl)(triphenyl)phosphonium bromide		C₂₇H₂₆BrO₂P	详情	详情
(VI)	32356	methyl 5-formyl-2-hydroxybenzoate		C₉H₈O₄	详情	详情
(VII)	32357	5-Formylsalicylic acid; 5-formyl-2-hydroxybenzoic acid	616-76-2	C₈H₆O₄	详情	详情
(VIII)	32358	methyl 5-[(E)-2-(2,5-dimethoxyphenyl)ethenyl]-2-hydroxybenzoate		C₁₈H₁₈O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Improved large scale synthesis: The formylation of 1,4-dimethoxybenzene (I) with C6H11-Li, TMEDA and DMF gives 2,5-dimethoxybenzaldehyde (II), which is reduced with NaBH4 in toluene/methanol to the corresponding alcohol (III). The treatment of (III) with PBr3 in ethyl acetate affords the benzyl bromide (IV), which by reaction with dimethyl phosphite (IX) and NaH in toluene is converted into the phosphonate (X). The condensation of (X) with 5-formyl-2-hydroxybenzoic acid methyl ester (VI)(obtained by esterification of the corresponding acid (VII) with methanol and H2SO4) by means of LiHMDS in THF affords the stilbene (VIII). Finally, this compound is reduced with H2 over Pd/C in ethyl acetate.

参考文献中间体

合成目标

【1】 Kucerovy, A.; et al.; An efficient large-scale synthesis of methyl 5-[2-82,5-dimethoxyphenyl)ethyl]-2-hydroxybenzoate. Org Process Res Dev 1997, 1, 4, 287.

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)	21946	1,4-dimethoxybenzene; 4-methoxyphenyl methyl ether	150-78-7	C₈H₁₀O₂	详情	详情
(II)	10174	2,5-Dimethoxybenzaldehyde	93-02-7	C₉H₁₀O₃	详情	详情
(III)	32353	(2,5-dimethoxyphenyl)methanol	33524-31-1	C₉H₁₂O₃	详情	详情
(IV)	32354	2-(bromomethyl)-4-methoxyphenyl methyl ether; 2-(bromomethyl)-1,4-dimethoxybenzene		C₉H₁₁BrO₂	详情	详情
(VI)	32356	methyl 5-formyl-2-hydroxybenzoate		C₉H₈O₄	详情	详情
(VII)	32357	5-Formylsalicylic acid; 5-formyl-2-hydroxybenzoic acid	616-76-2	C₈H₆O₄	详情	详情
(VIII)	32358	methyl 5-[(E)-2-(2,5-dimethoxyphenyl)ethenyl]-2-hydroxybenzoate		C₁₈H₁₈O₅	详情	详情
(IX)	32359	dimethyl phosphonate	868-85-9	C₂H₇O₃P	详情	详情
(X)	32360	dimethyl 2,5-dimethoxybenzylphosphonate		C₁₁H₁₇O₅P	详情	详情

合成路线3

该中间体在本合成路线中的序号：(X)

Friedel-Crafts bis-acylation of p-dimethoxybenzene (X) with anhydride (II) in molten aluminum chloride/sodium chloride afforded the benzoisoquinoline (XI). This compound was reduced with sodium dithionite to generate an intermediate leuco form (XII). Subsequent addition of Boc-ethylenediamine (VIII) to (XII) produced, after air oxidation during the work-up, the protected tetraamino compound (IX). Alternatively, addition of ethylenediamine (VII) to the intermediate (XII) led to the free base of BBR-2778, which was converted to the maleate.

参考文献中间体

合成目标

【1】 Krapcho, A.P.; et al.; 6,9-Bis[(aminoalkyl)amino]benzo[g]isoquinoline-5, 10-diones. A novel class of chromophore-modified antitumor anthracene-9,10-diones: Synthesis and antitumor evaluations. J Med Chem 1994, 37, 6, 828.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIIII)	14754	ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine	107-15-3	C₂H₈N₂	详情	详情
(II)	52806	3,4-Pyridine dicarboxylic anhydride; Pyridine-3,4-dicarboxylic anhydride	4664-08-8	C₇H₃NO₃	详情	详情
(VII)	13241	N-Boc-ethylenediamine;tert-butyl (2-aminoethyl)carbamate；tert-butyl 2-aminoethylcarbamate; tert-Butyl n-(2-aminoethyl)carbamate	57260-73-8	C₇H₁₆N₂O₂	详情	详情
(IX)	52811	tert-butyl 2-{[6-({2-[(tert-butoxycarbonyl)amino]ethyl}amino)-5,10-dioxo-5,10-dihydrobenzo[g]isoquinolin-9-yl]amino}ethylcarbamate		C₂₇H₃₅N₅O₆	详情	详情
(X)	21946	1,4-dimethoxybenzene; 4-methoxyphenyl methyl ether	150-78-7	C₈H₁₀O₂	详情	详情
(XI)	52812	6,9-dihydroxybenzo[g]isoquinoline-5,10-dione		C₁₃H₇NO₄	详情	详情
(XII)	52813	5,10-dihydroxy-7,8-dihydrobenzo[g]isoquinoline-6,9-dione		C₁₃H₉NO₄	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

Friedel Crafts condensation of p-dimethoxybenzene (I) with dichloromaleic anhydride (II) in a molten mixture of AlCl3 and NaCl yielded a dihydroxynaphthoquinone, assumed to exist as an equilibrium mixture between posicional isomers (III) and (IV). Subsequent methylation with CH3I in the presence of Ag2O yielded a mixture of dimethoxy quinones (V) and (VI) from which the target compound (V) was isolated by column chromatography.

参考文献中间体

合成目标

【1】 Huang, L.-J.; Chang, F.C.; Lee, K.H.; Wang, J.P; Teng, C.M.; Kuo, S.C.; Synthesis and antiplatelet, antiinflammatory, and antiallergic activities of substituted 3-chloro-5,8-dimethoxy-1,4-naphthoquinone and related compounds. Bioorg Med Chem 1998, 6, 12, 2261.

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)	21946	1,4-dimethoxybenzene; 4-methoxyphenyl methyl ether	150-78-7	C₈H₁₀O₂	详情	详情
(II)	21947	3,4-dichloro-2,5-furandione	1122-17-4	C₄Cl₂O₃	详情	详情
(III)	21948	2,3-dichloro-5,8-dihydroxynaphthoquinone	14918-69-5	C₁₀H₄Cl₂O₄	详情	详情
(IV)	21949	6,7-dichloro-5,8-dihydroxynaphthoquinone		C₁₀H₄Cl₂O₄	详情	详情
(VI)	21950	6,7-dichloro-5,8-dimethoxynaphthoquinone		C₁₂H₈Cl₂O₄	详情	详情

合成路线5

该中间体在本合成路线中的序号：(I)

Friedel Crafts condensation of p-dimethoxybenzene (I) with dichloromaleic anhydride (II) in a molten mixture of AlCl3 and NaCl yielded a dihydroxynaphthoquinone, assumed to exist as an equilibrium mixture between posicional isomers (III) and (IV). Subsequent methylation with CH3I in the presence of Ag2O yielded a mixture of dimethoxy quinones (V) and (VI), which were separated by column chromatography. Treatment of isomer (V) with NaOMe in MeOH then produced the target trimethoxy quinone.

参考文献中间体

合成目标

【1】 Huang, L.-J.; Chang, F.C.; Lee, K.H.; Wang, J.P; Teng, C.M.; Kuo, S.C.; Synthesis and antiplatelet, antiinflammatory, and antiallergic activities of substituted 3-chloro-5,8-dimethoxy-1,4-naphthoquinone and related compounds. Bioorg Med Chem 1998, 6, 12, 2261.

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)	21946	1,4-dimethoxybenzene; 4-methoxyphenyl methyl ether	150-78-7	C₈H₁₀O₂	详情	详情
(II)	21947	3,4-dichloro-2,5-furandione	1122-17-4	C₄Cl₂O₃	详情	详情
(III)	21948	2,3-dichloro-5,8-dihydroxynaphthoquinone	14918-69-5	C₁₀H₄Cl₂O₄	详情	详情
(IV)	21949	6,7-dichloro-5,8-dihydroxynaphthoquinone		C₁₀H₄Cl₂O₄	详情	详情
(V)	21951	2,3-dichloro-5,8-dimethoxynaphthoquinone		C₁₂H₈Cl₂O₄	详情	详情
(VI)	21950	6,7-dichloro-5,8-dimethoxynaphthoquinone		C₁₂H₈Cl₂O₄	详情	详情

合成路线6

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】 Huang, L.-J.; Chang, F.C.; Lee, K.H.; Wang, J.P; Teng, C.M.; Kuo, S.C.; Synthesis and antiplatelet, antiinflammatory, and antiallergic activities of substituted 3-chloro-5,8-dimethoxy-1,4-naphthoquinone and related compounds. Bioorg Med Chem 1998, 6, 12, 2261.

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)	21946	1,4-dimethoxybenzene; 4-methoxyphenyl methyl ether	150-78-7	C₈H₁₀O₂	详情	详情
(II)	21947	3,4-dichloro-2,5-furandione	1122-17-4	C₄Cl₂O₃	详情	详情
(III)	21948	2,3-dichloro-5,8-dihydroxynaphthoquinone	14918-69-5	C₁₀H₄Cl₂O₄	详情	详情
(IV)	21949	6,7-dichloro-5,8-dihydroxynaphthoquinone		C₁₀H₄Cl₂O₄	详情	详情
(V)	21951	2,3-dichloro-5,8-dimethoxynaphthoquinone		C₁₂H₈Cl₂O₄	详情	详情

合成路线7

该中间体在本合成路线中的序号：(I)

Friedel Crafts condensation of p-dimethoxybenzene (I) with dichloromaleic anhydride (II) in a molten mixture of AlCl3 and NaCl yielded dihydroxynaphthoquinone (III). Subsequent acetylation with Ac2O and AcOH furnished the target diacetate.

参考文献中间体

合成目标

【1】 Huang, L.-J.; Chang, F.C.; Lee, K.H.; Wang, J.P; Teng, C.M.; Kuo, S.C.; Synthesis and antiplatelet, antiinflammatory, and antiallergic activities of substituted 3-chloro-5,8-dimethoxy-1,4-naphthoquinone and related compounds. Bioorg Med Chem 1998, 6, 12, 2261.

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)	21946	1,4-dimethoxybenzene; 4-methoxyphenyl methyl ether	150-78-7	C₈H₁₀O₂	详情	详情
(II)	21947	3,4-dichloro-2,5-furandione	1122-17-4	C₄Cl₂O₃	详情	详情
(III)	21948	2,3-dichloro-5,8-dihydroxynaphthoquinone	14918-69-5	C₁₀H₄Cl₂O₄	详情	详情

合成路线8

该中间体在本合成路线中的序号：(I)

Friedel Crafts condensation of p-dimethoxybenzene (I) with dichloromaleic anhydride (II) in a molten mixture of AlCl3 and NaCl yielded dichloronaphthazarin (III). Finally, treatment of (III) with resorcinol (IV) and Na2CO3 in DMSO at room temperature furnished the target compound.

参考文献中间体

合成目标

【1】 Chang, H.-X.; Chou, T.C.; Savaraj, N.; Liu, L.F.; Yu, C.; Cheng, C.C.; Design of antineoplastic agents based on the "2-phenylnaphthalene-type" structural pattern. 4. Synthesis and biological activity of 2-chloro-3-(substituted phenoxy)-1,4-naphthoquinones and related 5,8-dihydroxy-1,4-naphthoquinones. J Med Chem 1999, 42, 3, 405.

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)	21946	1,4-dimethoxybenzene; 4-methoxyphenyl methyl ether	150-78-7	C₈H₁₀O₂	详情	详情
(II)	21947	3,4-dichloro-2,5-furandione	1122-17-4	C₄Cl₂O₃	详情	详情
(III)	21948	2,3-dichloro-5,8-dihydroxynaphthoquinone	14918-69-5	C₁₀H₄Cl₂O₄	详情	详情
(IV)	10361	1,3-Dihydroxybenzene; m-Dihydroxybenzene; Resorcinol; Resorcin; 1,3-Benzenediol	108-46-3	C₆H₆O₂	详情	详情

合成路线9

该中间体在本合成路线中的序号：(I)

Friedel Crafts condensation of p-dimethoxybenzene (I) with dichloromaleic anhydride (II) in a molten mixture of AlCl3 and NaCl yielded dichloronaphthazarin (III). Subsequent methylation of (III) with CH3I in the presence of Ag2O in CHCl3 gave a mixture of dimethoxy naphthoquinones (IV) and (V), from which the desired isomer (IV) was isolated by recrystallization from CHCl3-CCl4. Finally, treatment of (IV) with 3-methoxyphenol (VI) and Na2CO3 in DMSO at room temperature furnished the target compound.

参考文献中间体

合成目标

【1】 Chang, H.-X.; Chou, T.C.; Savaraj, N.; Liu, L.F.; Yu, C.; Cheng, C.C.; Design of antineoplastic agents based on the "2-phenylnaphthalene-type" structural pattern. 4. Synthesis and biological activity of 2-chloro-3-(substituted phenoxy)-1,4-naphthoquinones and related 5,8-dihydroxy-1,4-naphthoquinones. J Med Chem 1999, 42, 3, 405.

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)	21946	1,4-dimethoxybenzene; 4-methoxyphenyl methyl ether	150-78-7	C₈H₁₀O₂	详情	详情
(II)	21947	3,4-dichloro-2,5-furandione	1122-17-4	C₄Cl₂O₃	详情	详情
(III)	21948	2,3-dichloro-5,8-dihydroxynaphthoquinone	14918-69-5	C₁₀H₄Cl₂O₄	详情	详情
(IV)	21951	2,3-dichloro-5,8-dimethoxynaphthoquinone		C₁₂H₈Cl₂O₄	详情	详情
(V)	21950	6,7-dichloro-5,8-dimethoxynaphthoquinone		C₁₂H₈Cl₂O₄	详情	详情
(VI)	22389	3-Methoxyphenol	150-19-6	C₇H₈O₂	详情	详情

合成路线10

该中间体在本合成路线中的序号：(I)

Friedel Crafts condensation of p-dimethoxybenzene (I) with dichloromaleic anhydride (II) in a molten mixture of AlCl3 and NaCl yielded dichloronaphthazarin (III). Subsequent methylation of (III) with CH3I in the presence of Ag2O in CHCl3 gave a mixture of dimethoxy naphthoquinones (IV) and (V), from which the desired isomer (IV) was isolated by recrystallization from CHCl3-CCl4. Finally, treatment of (IV) with 3,5-dimethoxyphenol (VI) and Na2CO3 in DMSO at room temperature furnished the target compound.

参考文献中间体

合成目标

【1】 Chang, H.-X.; Chou, T.C.; Savaraj, N.; Liu, L.F.; Yu, C.; Cheng, C.C.; Design of antineoplastic agents based on the "2-phenylnaphthalene-type" structural pattern. 4. Synthesis and biological activity of 2-chloro-3-(substituted phenoxy)-1,4-naphthoquinones and related 5,8-dihydroxy-1,4-naphthoquinones. J Med Chem 1999, 42, 3, 405.

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)	21946	1,4-dimethoxybenzene; 4-methoxyphenyl methyl ether	150-78-7	C₈H₁₀O₂	详情	详情
(II)	21947	3,4-dichloro-2,5-furandione	1122-17-4	C₄Cl₂O₃	详情	详情
(III)	21948	2,3-dichloro-5,8-dihydroxynaphthoquinone	14918-69-5	C₁₀H₄Cl₂O₄	详情	详情
(IV)	21951	2,3-dichloro-5,8-dimethoxynaphthoquinone		C₁₂H₈Cl₂O₄	详情	详情
(V)	21950	6,7-dichloro-5,8-dimethoxynaphthoquinone		C₁₂H₈Cl₂O₄	详情	详情
(VI)	22390	3,5-dimethoxyphenol	500-99-2	C₈H₁₀O₃	详情	详情

Extended Information