CN100343216C - Synthesis of Combretastatin A-4 supported by polymer - Google Patents
Synthesis of Combretastatin A-4 supported by polymer Download PDFInfo
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- CN100343216C CN100343216C CNB2004100425807A CN200410042580A CN100343216C CN 100343216 C CN100343216 C CN 100343216C CN B2004100425807 A CNB2004100425807 A CN B2004100425807A CN 200410042580 A CN200410042580 A CN 200410042580A CN 100343216 C CN100343216 C CN 100343216C
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Abstract
The present invention relates to a new simple preparation method for a novel anticancer drug CombretastatinA-4. The preparation method uses isovanillin and phosphonium salts (bromide 3 4 5-trimethoxy benzyl triphenylphosphine) as initial raw materials to prepare the CombretastatinA-4 by adopting a polymer support method. The new simple preparation method has the advantages of simple preparation merthod, high Z type yield, and no need of separation and purification by column chromatography, and is suitable for industrial scale preparation.
Description
Invention field
The present invention relates to the polymer supported new simple synthesis of anticarcinogen NSC 817373 (Combretastatin A-4).
Background of invention
Combretastatin A-4 is a PTS, and its chemical name is: 3,4, and 5-trimethoxy-4 '-methoxyl group-3 '-hydroxyl-cis-toluylene, molecular formula is: C
18H
20O
5
Chemical structure is shown in I:
The trees that Combretastatin A-4 is widely grown in the torrid zone and semi-tropical combretum genus are plants that a class contains cancer-resisting substance.In Africa and India, the root of this class plant, stem, leaf, bark are used as the treatment various diseases, as hepatitis, and malaria, leprosy or the like.People further investigate the combretum platymiscium, the phenanthrene of a series of antitumour activitys of purifying out, the derivative of stilbene and dibenzyl benzene.Combretastatin A-4 is that a kind of strong growth of cancer cells and tubulin gather inhibitor.G.R.Pettit in 1991 etc. have measured its chemical structure and have applied for that United States Patent (USP) (US4,996,237) pharmacological research shows that Combretastatin A-4 is that a kind of strong growth of cancer cells and tubulin gather the supression preparation.But the water-soluble development that hinders its clinical application of its extreme difference.Scientist has carried out modifying research to Combretastatin A-4 structure, and wherein successfully research is that Combretastatin A-4 phosphoric acid ester is changed into sodium salt, thereby obtains Combretastatin A-4 water-soluble prodrug molecule.Pettit had applied for United States Patent (USP) (US5,561,122) in 1996.Pettit transferred Ou Xiji company with patent subsequently, and Ou Xiji company has applied for United States Patent (USP) (USPatent in 2002
20020119951).Carried out the improvement of synthetic method.
Pharmacological research shows that Combretastatin A-4-P has very strong growth of cancer cells and suppresses the ability that tubulin gathers, and is a kind of novel cancer therapy drug.Combretastatin A-4 is the new vessel of the tumor tissues in the target growth optionally.Studies show that it is giving the vessel sealing want several minutes that tumour is correlated with, enter and flow out tumour cell that within the several hrs, new vessel is closed death thereby effectively suppress blood.But it does not influence sophisticated blood vessel, promptly normal blood vessel is not had toxic side effect.It is clinical that Combretastatin A-4 has finished the I phase in the U.S. and Britain, and effect is obvious, and prospect is exciting, and preceding to carry out the II phase clinical.
Basic raw material in the Combretastatin A-4 chemosynthesis is isovanillin and microcosmic salt (bromination 3,4,5-trimethoxy benzyl triphenyl phosphorus), and is synthetic by the wittig reaction.According to present patent and document, following several synthetic method is arranged:
First kind, use t-BuMe
2SiCl protects 3 hydroxyls of isovanillin, makes the bromine phosphonium salt of isovanillin, and with 3,4, the 5-TMB is synthetic by the wittig reaction.Main drawback is a severe reaction conditions, and Z formula productive rate is low, is not suitable for industrial-scale production.
Second kind, use t-BuMe
23 hydroxyls of SiCl protection isovanillin, with bromination 3,4,5-trimethoxy benzyl triphenyl phosphorus is synthetic by the wittig reaction.Main drawback is a severe reaction conditions, and Z formula productive rate is low, is not suitable for industrial-scale production.
The third: 3 hydroxyls of trityl chloride protection isovanillin, with 3,4, the 5-TMB is synthetic by the wittig reaction.Main drawback is a separation difficulty, the length that expends time in, and production cost increases.
Summary of the invention
The invention provides the polymer supported synthetic method of Combretastatin A-4; by 3 protections of polymer supported synthetic isovanillin, again with bromination 3,4; 5-trimethoxy benzyl triphenyl phosphorus is by wittig reaction synthetic compound VI, and hydrolysis generates Compound I again.The present invention synthetic method mainly comprise following three-step reaction:
The first step: isovanillin II and trityl chloride resin III generate 3 protection compound IV of polymer supported synthetic isovanillin under alkaline condition, carry out next step reaction after the washing.
Second step: in bromination 3,4, add highly basic in the THF solution of 5-trimethoxy benzyl triphenyl phosphorus, reaction conditions-30 ℃ is to-20 ℃, and churning time needs 30-60 minute.TLC follows the tracks of, and slowly adds polymer supported isovanillin subsequently, after reaction is finished, and water stopped reaction, separating compound VI washing with alcohol, drying.
The 3rd step: under well-beaten condition, slowly add dense HCl in compound VI, be heated to 40 ℃ to 50 ℃, stirred 60 minutes, and added ether, filter insolubles, tell organic phase, the saturated common salt water washing, anhydrous magnesium sulfate drying, underpressure distillation, ethyl alcohol recrystallization, recrystallization in sherwood oil-ether once more.
Three-step reaction is shown below:
Reagent in the above-mentioned reaction is respectively:
B in the formula
1The reagent of representative is triethylamine, pyridine, Anhydrous potassium carbonate.
B in the formula
2The reagent of representative is n-Butyl Lithium, lithium methide.
The reagent of A representative is HCl, H in the formula
2SO
4, H
3PO
4, HBr, HI.
Organic solvent in the above-mentioned reaction
The first step reaction solvent is an inert organic solvents: methylene dichloride, ethylene dichloride, benzene, toluene, tetrahydrofuran (THF) etc.
The second step reaction solvent is inert organic solvents tetrahydrofuran (THF), benzene etc.
The three-step reaction solvent is that inert organic solvents is benzene, toluene, tetrahydrofuran (THF) etc.
Cleaning solvent is in the above-mentioned reaction: tetrahydrofuran (THF), dioxy six alkane, ethanol, and water,
The characteristics of synthetic method of the present invention:
1. by polymer supported reaction, improve reaction yield, wherein Z formula productive rate height
2. product separates simply, and is consuming time few, helps commercial scale production
Example
Example one:
The first step: at 100ml three-necked bottle (stirring rod, thermometer, dropping funnel), add .10g isovanillin and 21g trityl chloride resin, add the dissolving of 40ml tetrahydrofuran (THF) and stir, be heated to 40 ℃-50 ℃ and slowly drip triethylamine 16ml, continue to stir 2 hours.Add 20ml water, termination reaction, suction filtration, water, washing with alcohol obtain compound i sovanillin-
28g.Productive rate 98%.
Second step: with in bromination trimethoxy benzyl triphenyl phosphine 16g dissolving and the 30ml tetrahydrofuran (THF), drip n-Butyl Lithium 16ml, stir 1 hour (temperature is controlled at-20 ℃--15 ℃).Add compound i sovanillin-
The tetrahydrofuran (THF) mixed solution of 10g stirred 2 hours, was warming up to room temperature gradually, added 20ml water termination reaction.Suction filtration goes out insolubles, water, and washing with alcohol gets Compound C ombretastatinA-4-
13.5g.Productive rate 97%.
The 3rd step: Compound C ombretastatinA-4-
In 10g dissolving and the tetrahydrofuran (THF), add 37% concentrated hydrochloric acid 10ml,, stirred 1 hour with 40 ℃-45 ℃.Add the 50ml anhydrous diethyl ether, suction filtration is told organic phase, underpressure distillation.Product is dissolved in ethanol, recrystallization.The gained coarse crystal obtains product C ombretastatin A-4 4.5g productive rate 84% with ethyl acetate-sherwood oil recrystallization.Mp：127-128℃；
1H-NMR(CDCl
3；δ)：6.53(s，2H，2，6-H)；6.47(dJ＝16Hz，1H，1a-H)；6.41(dJ＝16Hz，1H，1a’-H)；6.92(dJ＝2Hz，1H，2’-H)；
6.73 (dJ=8Hz, 1H, 5 '-H); 6.80 (ddJ=8﹠amp; 2Hz, 1H, 6 '-H); 5.06 (s, 1H, OH); 3.70 (s, 6H, 3,5-OCH
3); 3.87 (s, 3H, 4 '-OCH
3); 3.84 (s, 3H, 4 '-OCH
3); Ultimate analysis, experimental value: C 68.11; H 6.51, theoretical value: (C
18H
20O
5): C 68.35; H 6.37.
Example two:
The first step: at 51 three-necked bottles (stirring rod, thermometer, dropping funnel), add .500g isovanillin and 1050g trityl chloride resin, add the dissolving of 2000ml tetrahydrofuran (THF) and stir, be heated to 40 ℃-50 ℃ and slowly drip triethylamine 800ml, continue to stir 2 hours.Add 1000ml water, termination reaction, suction filtration, water, washing with alcohol obtain compound i sovanillin-
1400g.Productive rate 97.9%.
Second step: with in bromination trimethoxy benzyl triphenyl phosphine 800g dissolving and the 1500ml tetrahydrofuran (THF), drip n-Butyl Lithium 800ml, stir 1 hour (temperature is controlled at-20 ℃--15 ℃).Add compound i sovanillin-
The tetrahydrofuran (THF) mixed solution of 500g stirred 2 hours, was warming up to room temperature gradually, added 1000ml water termination reaction.Suction filtration goes out insolubles, water, and washing with alcohol gets Compound C ombretastatinA-4-
693.5g.Productive rate 99.7%.
The 3rd step: Compound C ombretastatinA-4-
In 600g dissolving and the tetrahydrofuran (THF), add 37% concentrated hydrochloric acid 750ml,, stirred 3 hours with 40 ℃-45 ℃.Add the 50ml anhydrous diethyl ether, suction filtration is told organic phase, underpressure distillation.Product is dissolved in ethanol, recrystallization.The gained coarse crystal obtains product C ombretastatinA-4 286g productive rate 88% with ethyl acetate-sherwood oil recrystallization.The fusing point of product,
1H-NMR, ultimate analysis data are with example one.
Claims (4)
1. the synthetic method of polymer supported synthetic NSC 817373; has reaction formula one; it is characterized in that: with the hydroxyl of the immobilized protection isovanillin of trityl chloride resin 3-position; and further with bromination 3; 4; the Wittig reaction takes place in 5-trimethoxy Bian base triphenyl phosphonium, sloughs the polymkeric substance protecting group then, generates NSC 817373:
Wherein,
B1 is an organic amine, and B2 is an organolithium compound, and A is the strongly-acid material.
2. the synthetic method of polymer supported synthetic NSC 817373 as claimed in claim 1 is characterized in that, described B1 is diisopropylethylamine or triethylamine or pyridine.
3. the synthetic method of polymer supported synthetic NSC 817373 as claimed in claim 1 is characterized in that, described B2 is n-Butyl Lithium or lithium methide.
4. the synthetic method of polymer supported synthetic NSC 817373 as claimed in claim 1 is characterized in that, described A is hydrochloric acid or sulfuric acid or phosphoric acid or Hydrogen bromide or hydroiodic acid HI and trifluoroacetic acid and their mixture thereof.
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2004100425807A CN100343216C (en) | 2004-05-25 | 2004-05-25 | Synthesis of Combretastatin A-4 supported by polymer |
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| CNB2004100425807A CN100343216C (en) | 2004-05-25 | 2004-05-25 | Synthesis of Combretastatin A-4 supported by polymer |
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|---|---|
| CN1704393A CN1704393A (en) | 2005-12-07 |
| CN100343216C true CN100343216C (en) | 2007-10-17 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1896042B (en) * | 2005-07-13 | 2010-12-08 | 浙江赛尔生物医学研究有限公司 | Production of hair orchid |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4996237A (en) * | 1987-01-06 | 1991-02-26 | Arizona Board Of Regents | Combretastatin A-4 |
| US5561122A (en) * | 1994-12-22 | 1996-10-01 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Combretastatin A-4 prodrug |
| US6743937B2 (en) * | 2000-07-17 | 2004-06-01 | Oxigene, Inc. | Efficient method of synthesizing combretastatin A-4 prodrugs |
-
2004
- 2004-05-25 CN CNB2004100425807A patent/CN100343216C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4996237A (en) * | 1987-01-06 | 1991-02-26 | Arizona Board Of Regents | Combretastatin A-4 |
| US5561122A (en) * | 1994-12-22 | 1996-10-01 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Combretastatin A-4 prodrug |
| US6743937B2 (en) * | 2000-07-17 | 2004-06-01 | Oxigene, Inc. | Efficient method of synthesizing combretastatin A-4 prodrugs |
Non-Patent Citations (1)
| Title |
|---|
| COMBRETASTATINA -4全合成中的光化学WITTIG反应 杜树志等，化学通报，第1期 2004 * |
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| CN1704393A (en) | 2005-12-07 |
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