Combretastatin A-4, CA-4, -Drug Synthesis Database

【结构式】

【药物名称】Combretastatin A-4, CA-4

【化学名称】(Z)-3'-Hydroxy-3,4,4,',5-tetramethoxy stilbene
　　　　　　(Z)-1-(3,4,5-Trimethoxyphenyl)-2-(3-hydroxy-4-methoxyphenyl)ethene

【CA登记号】117048-59-6

【分子式】C₁₈H₂₀O₅

【分子量】316.3571

【开发单位】Arizona State University (Originator), OxiGene (Licensee)

【药理作用】Antineoplastic Enhancing Agents, Modulators of the Therapeutic Activity of Antineoplastic Agents, ONCOLYTIC DRUGS, Solid Tumors Therapy, Antimitotic Drugs, Microtubule-Stabilizing Agents

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

The CH2Cl2/MeOH extracts of Combretum caffrum stem wood were fractionated using a solvent partition sequence, followed by gel filtration and column chromatography to provide a mixture of three substituted stilbenes: combretastatin A-4 (I), combretastatin A-5 (II) and combretastatin A-6 (III). Further separation of these compounds was achieved via derivatization with tert-butyldimethylsilyl chloride and separation of the respective silyl ethers (IV), (V) and (VI) by preparative TLC. The least polar component (IV) was then desilylated by treatment with tetrabutylammonium fluoride to yield pure combretastatin A-4 (I)

参考文献中间体

【1】 Pettit, G.R.; Singh, S.B.; Boyd, M.R.; Hamel, E.; Pettit, R.K.; Schmidt, J.M.; Hogan, F.; Antineoplastic agents. 291. Isolation and synthesis of combretastatins A-4, A-5, and A-6. J Med Chem 1995, 38, 10, 1666.

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
(II)	60506	5-[(Z)-2-(3,4-dimethoxyphenyl)ethenyl]-2,3-dimethoxyphenol		C₁₈H₂₀O₅	详情	详情
(III)	65172	5-[(E)-2-(3,4-dimethoxyphenyl)ethenyl]-2,3-dimethoxyphenol		C₁₈H₂₀O₅	详情	详情
(IV)	26118	tert-butyl[2-methoxy-5-[(E)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenoxy]dimethylsilane; tert-butyl(dimethyl)silyl 2-methoxy-5-[(E)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl ether		C₂₄H₃₄O₅Si	详情	详情
(V)	60507	tert-butyl(dimethyl)silyl 5-[(Z)-2-(3,4-dimethoxyphenyl)ethenyl]-2,3-dimethoxyphenyl ether; tert-butyl{5-[(Z)-2-(3,4-dimethoxyphenyl)ethenyl]-2,3-dimethoxyphenoxy}dimethylsilane		C₂₄H₃₄O₅Si	详情	详情
(VI)	65173	tert-butyl{5-[(E)-2-(3,4-dimethoxyphenyl)ethenyl]-2,3-dimethoxyphenoxy}dimethylsilane; tert-butyl(dimethyl)silyl 5-[(E)-2-(3,4-dimethoxyphenyl)ethenyl]-2,3-dimethoxyphenyl ether		C₂₄H₃₄O₅Si	详情	详情

合成路线2

The O-silyl stilbene precursor (IV) was also synthesized by the Wittig reaction either between 3,4,5-trimethoxybenzaldehyde (VII) and the phosphonium salt (VIII) or between phosphonium bromide (IX) and 3-(tert-butyldimethylsilyloxy)-4-methoxybenzaldehyde (X), to furnish in both cases a mixture of the target Z-stilbene (IV) and its E-isomer (XI), which were separated by flash chromatography

参考文献中间体

【1】 Pettit, G.R.; Singh, S.B.; Boyd, M.R.; Hamel, E.; Pettit, R.K.; Schmidt, J.M.; Hogan, F.; Antineoplastic agents. 291. Isolation and synthesis of combretastatins A-4, A-5, and A-6. J Med Chem 1995, 38, 10, 1666.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	26118	tert-butyl[2-methoxy-5-[(E)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenoxy]dimethylsilane; tert-butyl(dimethyl)silyl 2-methoxy-5-[(E)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl ether		C₂₄H₃₄O₅Si	详情	详情
(VII)	11136	3,4,5-Trimethoxybenzaldehyde	86-81-7	C₁₀H₁₂O₄	详情	详情
(VIII)	26117	(3-[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzyl)(triphenyl)phosphonium bromide		C₃₂H₃₈BrO₂PSi	详情	详情
(IX)	19866	triphenyl(3,4,5-trimethoxybenzyl)phosphonium bromide		C₂₈H₂₈BrO₃P	详情	详情
(X)	26114	3-[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzaldehyde		C₁₄H₂₂O₃Si	详情	详情
(XI)	60508	tert-butyl{2-methoxy-4-[(E)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenoxy}dimethylsilane; tert-butyl(dimethyl)silyl 2-methoxy-4-[(E)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl ether		C₂₄H₃₄O₅Si	详情	详情

合成路线3

In a different synthetic strategy, the required dibromostyrene (XIV) was prepared in low yield by Wittig-like condensation of 3-hydroxy-4-methoxybenzaldehyde (XII) with carbon tetrabromide in the presence of PPh-3. In an improved process, the phenolic hydroxyl of (XII) was first protected as the silyl ether (X), which was then condensed with CBr4/PPh3 to give (XIII). Subsequent desilylation of (XIII) with tetrabutylammonium fluoride provided (XIV). Stereoselective debromination of the dibromostyrene (XIV) with tributyltin hydride and tetrakis(triphenylphosphine)palladium(0) led to the Z-bromostyrene (XV). This was finally subjected to a palladium-catalyzed Suzuki coupling with 3,4,5-trimethoxybenzeneboronic acid (XVI) to furnish the title Z-olefin as the major isomer

参考文献中间体

【1】 Gaukroger, K.; Hadfield, J.A.; Hepworth, L.A.; Lawrence, N.J.; McGrown, A.T.; Novel synthesis of cis and trans isomers of combretastatin A-4. J Org Chem 2001, 66, 24, 8135.

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
(X)	26114	3-[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzaldehyde		C₁₄H₂₂O₃Si	详情	详情
(XII)	18455	3-hydroxy-4-methoxybenzaldehyde; Isovanillin	621-59-0	C₈H₈O₃	详情	详情
(XIII)	60509	tert-butyl(dimethyl)silyl 5-(2,2-dibromovinyl)-2-methoxyphenyl ether; tert-butyl[5-(2,2-dibromovinyl)-2-methoxyphenoxy]dimethylsilane		C₁₅H₂₂Br₂O₂Si	详情	详情
(XIV)	60510	5-(2,2-dibromovinyl)-2-methoxyphenol		C₉H₈Br₂O₂	详情	详情
(XV)	60511	5-[(Z)-2-bromoethenyl]-2-methoxyphenol		C₉H₉BrO₂	详情	详情
(XVI)	60512	3,4,5-trimethoxyphenylboronic acid		C₉H₁₃BO₅	详情	详情

合成路线4

A further synthetic strategy was based on the Perkin condensation between 3,4,5-trimethoxyphenylacetic acid (XVII) and 3-hydroxy-4-methoxybenzaldehyde (XII). Decarboxylation of the resultant phenylcinnamic acid (XVIII) by heating with copper powder in quinoline furnished the desired stilbene, accompanied by only minor amounts of the corresponding E-isomer

参考文献中间体

【1】 Gaukroger, K.; Hadfield, J.A.; Hepworth, L.A.; Lawrence, N.J.; McGrown, A.T.; Novel synthesis of cis and trans isomers of combretastatin A-4. J Org Chem 2001, 66, 24, 8135.

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
(XII)	18455	3-hydroxy-4-methoxybenzaldehyde; Isovanillin	621-59-0	C₈H₈O₃	详情	详情
(XVII)	25349	2-(3,4,5-trimethoxyphenyl)acetic acid	937-52-0	C₁₁H₁₄O₅	详情	详情
(XVIII)	60513	(E)-3-(3-hydroxy-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-2-propenoic acid		C₁₉H₂₀O₇	详情	详情

Extended Information