(3,4,5-trimethoxyphenyl)methanol -Drug Synthesis Database

【结构式】

【分子编号】23613

【品名】(3,4,5-trimethoxyphenyl)methanol

【CA登记号】3840-31-1

【分子式】C₁₀H₁₄O₄

【分子量】198.21876

【元素组成】C 60.59% H 7.12% O 32.29%

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：(II)

Reduction of 3,4,5-trimethoxybenzaldehyde (I) with NaBH4 provided benzyl alcohol (II). After conversion of (II) to the benzyl chloride (III) using SOCl2, its reaction with PPh3 (IV) in refluxing xylene afforded phosphonium salt (V). Subsequent Wittig reaction of the corresponding ylide with 4,4-(ethylenedioxy)cyclohexanone (VI) produced the benzylidene derivative (VII), which was reduced to benzyl compound (VIII) by catalytic hydrogenation over Pd/C. The ketal protecting group of (VIII) was then removed by acid hydrolysis to yield cyclohexanone (IX). Finally, the target tetrahydroquinazoline was obtained by condensation of (IX) with cyanoguanidine (X) at 180 C.

参考文献中间体

合成目标

【1】 Papoulis, A.T.; Queener, S.F.; Rosowsky, A.; Forsch, R.A.; Synthesis and antiparasitic and antitumor activity. J Med Chem 1999, 42, 6, 1007.

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)	23613	(3,4,5-trimethoxyphenyl)methanol	3840-31-1	C₁₀H₁₄O₄	详情	详情
(III)	14072	3,4,5-Trimethoxybenzyl chloride; 5-(Chloromethyl)-1,2,3-trimethoxybenzene; 4-(Chloromethyl)-2,6-dimethoxyphenyl methyl ether	3840-30-0	C₁₀H₁₃ClO₃	详情	详情
(IV)	23605	trimethylphosphine	594-09-2	C₃H₉P	详情	详情
(V)	23615	triphenyl(3,4,5-trimethoxybenzyl)phosphonium		C₂₈H₂₈O₃P	详情	详情
(VI)	11377	1,4-Dioxaspiro[4.5]decan-8-one	4746-97-8	C₈H₁₂O₃	详情	详情
(VII)	23616	4-(1,4-dioxaspiro[4.5]dec-8-ylidenemethyl)-2,6-dimethoxyphenyl methyl ether; 8-(3,4,5-trimethoxybenzylidene)-1,4-dioxaspiro[4.5]decane		C₁₈H₂₄O₅	详情	详情
(VIII)	23617	4-(1,4-dioxaspiro[4.5]dec-8-ylmethyl)-2,6-dimethoxyphenyl methyl ether; 8-(3,4,5-trimethoxybenzyl)-1,4-dioxaspiro[4.5]decane		C₁₈H₂₆O₅	详情	详情
(IX)	23618	4-(3,4,5-trimethoxybenzyl)cyclohexanone		C₁₆H₂₂O₄	详情	详情
(X)	23611	N-cyanoguanidine	461-58-5	C₂H₄N₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Iodination of 3,4,5-trimethoxybenzyl alcohol (I) with iodine in the presence of silver trifluoroacetate gave the 2-iodobenzyl alcohol (II). Subsequent palladium-catalyzed carbonylation-lactonization reaction with (II) gave rise to phthalide (III). This was brominated using NBS to afford the 3-bromophthalide (IV). Finally, condensation of (IV) with (1-naphthyl)methylphosphonic acid (V) yielded the title bisphthalidyl phosphonate.

参考文献中间体

合成目标

【1】 Dang, Q.; et al.; Synthesis of phosphonate 3-phthalidyl esters as prodrugs for potential intracellular delivery of phosphonates. Bioorg Med Chem Lett 1999, 9, 11, 1505.

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)	23613	(3,4,5-trimethoxyphenyl)methanol	3840-31-1	C₁₀H₁₄O₄	详情	详情
(II)	34420	(2-iodo-3,4,5-trimethoxyphenyl)methanol		C₁₀H₁₃IO₄	详情	详情
(III)	34421	5,6,7-trimethoxy-2-benzofuran-1(3H)-one		C₁₁H₁₂O₅	详情	详情
(IV)	34422	3-bromo-5,6,7-trimethoxy-2-benzofuran-1(3H)-one		C₁₁H₁₁BrO₅	详情	详情
(V)	34423	1-naphthylmethylphosphonic acid	4730-77-2	C₁₁H₁₁O₃P	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VI)

The parent compound combretastatin A-4 (I) can be synthesized by bromination of 3,4,5-trimethoxybenzyl alcohol (VI) with lithium bromide and chlorotrimethylsilane, followed by condensation of the obtained benzylic bromide (VII) with triphenylphosphine to provide the phosphonium salt (VIII). Wittig reaction of (VIII) with 4-methoxy-3-(thexyldimethylsilyloxy)benzaldehyde (IX) affords the silyl-protected cis-stilbene (X), which is desilylated to (I) by treatment with tetrabutylammonium fluoride in THF (3, 4, 6). Scheme 2.

参考文献中间体

合成目标

【3】 Pettit, G.R., Rhodes, M.R. Antineoplastic agents 389. New syntheses of the combretastatin A-4 prodrug. Anticancer Drug Des 1998, 13(3): 183-91.
【4】 Pettit, G.R., Rhodes, M.R. (Arizona State University). Synthesis of combretastatin A-4 prodrugs and trans-isomers thereof. CA 2314238, EP 1045853, US 7018987, WO 9935150.
【6】 Griffin, R.J., Quarterman, C.P., Rathbone, D.L., Slack, J.A. (Aston Molecules Ltd.). Substd. diphenylethylenes and analogues of derivs. thereof. WO 9216486.

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)	60505	2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenol	117048-60-9	C₁₈H₂₀O₅	详情	详情
(VI)	23613	(3,4,5-trimethoxyphenyl)methanol	3840-31-1	C₁₀H₁₄O₄	详情	详情
(VII)	48498	5-(bromomethyl)-1,2,3-trimethoxybenzene; 4-(bromomethyl)-2,6-dimethoxyphenyl methyl ether		C₁₀H₁₃BrO₃	详情	详情
(VIII)	19866	triphenyl(3,4,5-trimethoxybenzyl)phosphonium bromide		C₂₈H₂₈BrO₃P	详情	详情
(IX)	65530	4-methoxy-3-(thexyldimethylsilyloxy)benzaldehyde		C₁₆H₂₆O₃Si	详情	详情
(X)	65531			C₂₃H₃₈O₂Si	详情	详情

Extended Information