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藥物詳細合成路線

Name Combretastatin A-4;CA-4
Chemical Name (Z)-3-Hydroxy-3,4,4,,5-tetramethoxy stilbene
      (Z)-1-(3,4,5-Trimethoxyphenyl)-2-(3-hydroxy-4-methoxyphenyl)ethene
CAS 117048-59-6
Related CAS
Formula C18H20O5
Structure
Formula Weight 316.3571
Stage I/II 期臨床
Company Arizona State University (Originator), OxiGene (Licensee)
Activity/Mechanism Antineoplastic Enhancing Agents, Modulators of the Therapeutic Activity of Antineoplastic Agents, ONCOLYTIC DRUGS, Solid Tumors Therapy, Antimitotic Drugs, Microtubule-Stabilizing Agents
Syn. Route 4
Route 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)
List of intermediates No.
tert-butyl (e)-3-[6-butyl-3-(3-methyl-2,3-dihydro-1,3-benzoxazol-2-yl)-2-pyridinyl]-2-propenoate (iv)
Reference 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.

Route 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
List of intermediates No.
2-(4-chlorophenyl)acetonitrile (vii)
chloromethyl (5r)-3,3-dimethyl-4,4,7-trioxo-4lambda(6)-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate (ix)
2-hydroxy-6-methylnicotinonitrile (x)
(1s,2r)-1-(methylamino)-2,3-dihydro-1h-inden-2-ol (viii)
tert-butyl (e)-3-[6-butyl-3-(3-methyl-2,3-dihydro-1,3-benzoxazol-2-yl)-2-pyridinyl]-2-propenoate (iv)
Reference 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.

Route 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
List of intermediates No.
bromo[4-(dimethoxymethyl)phenyl]magnesium (xii)
2-hydroxy-6-methylnicotinonitrile (x)
Reference 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.

Route 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
List of intermediates No.
bromo[4-(dimethoxymethyl)phenyl]magnesium (xii)
2-(acetamido)-9-[(1r,4s)-4-[(s)-nitro(phenylsulfonyl)methyl]-2-cyclopenten-1-yl]-9h-purin-6-yl diphenylcarbamate (xvii)
Reference 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.

來源:藥化網

作者:藥化小編

摘要:本文合成路線介紹的是藥物中文名(Z)-3,4,5,4',-四甲氧基-3'-羥基二苯乙烯;英文名Combretastatin A-4;CA-4;CAS[117048-59-6]

 
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