CN1266104C - Process for preparing (z)-3'-hydroxy-3,4,4',5-tetranetgixy diphenyl ethylene - Google Patents

Process for preparing (z)-3'-hydroxy-3,4,4',5-tetranetgixy diphenyl ethylene Download PDF

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CN1266104C
CN1266104C CN 200410051498 CN200410051498A CN1266104C CN 1266104 C CN1266104 C CN 1266104C CN 200410051498 CN200410051498 CN 200410051498 CN 200410051498 A CN200410051498 A CN 200410051498A CN 1266104 C CN1266104 C CN 1266104C
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hydroxyl
acid
trimethoxyphenyl
tetramethoxy
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CN1616388A (en
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邹永
钟荣清
张学景
何树杰
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Guangzhou Institute of Chemistry of CAS
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Abstract

The present invention relates to a process for preparing (Z)-3'-hydroxy-3, 4, 4', 5-tetramethoxy diphenyl ethylene, which comprises: cheap and easily acquired p-methoxyphenylacetic acid is used as a raw material and is bromized to obtain 3-bromine-4-methoxyphenylacetic acid, the condensation of 3-bromine-4-methoxyphenylacetic acid and 3, 4, 5-trimethoxy benzaldehyde is carried out to obtain (E)-3-(3', 4', 5'-trimethoxyphenyl)-2-(3'-bromo-4'-methoxyphenyl)-acrylic acid, and phenolic hydroxy substitution and debromination are carried out to obtain (E)-3-(3', 4', 5'-trimethoxyphenyl)-2-(3'-hydroxy-4'-methoxyphenyl)-acrylic acid; finally, decarboxylation is carried out to obtain (Z)-3'-hydroxy-3, 4, 4', 5-tetramethoxy diphenyl ethylene. The present invention provides a new design idea for introducing phenolic hydroxyl into diphenyl ethylene compounds, and also provides a new method for synthesizing (Z)-3'-hydroxy-3, 4, 4', 5-tetramethoxy diphenyl ethylene. The method has the advantages of low cost, simple post-treatment operation and high total yield.

Description

(Z)-3 '-hydroxyl-3,4,4 ', the preparation method of 5-tetramethoxy toluylene
Technical field
The present invention relates to a kind of preparation (Z)-3 '-hydroxyl-3,4,4 ', the method for 5-tetramethoxy toluylene.
Background technology
(Z)-3 '-hydroxyl-3,4,4 ', 5-tetramethoxy toluylene (Combretastatin A-4, structure is seen formula (1)) is a kind of polyhydroxystilbene natural product.Studies confirm that this compound can selectivity suppress tubulin polymerization and antimitotic, have very strong anti-tumor activity, be described as blood-vessels target agent.Its water-soluble phosphorus acidifying prodrug enters II phase clinical study at US and European, and huge listing potentiality are arranged.Obviously, only depend on plant extract can't satisfy the demand of clinical study and listing, therefore, the research of this compound chemistry synthetic method is had important and practical meanings
Formula (1)
The people such as professor Pettit of the upright university of State of Arizona, US have serial report to the biological activity and the chemosynthesis thereof of this compound, and domestic relevant report is very few.
The preparation method of bibliographical information mainly contains the Wittig reaction method (referring to Pettit G R, Singh S B, Bovd M R.J Med Chem, 1995,38:1666.), Suzuki reaction method and modification method thereof, Perkin reaction method be (referring to Furstner A, Nikolakis K.Liebigs Ann Chem, 1996,2107; Lawrrence N J, Hepworth LA.Synthesis, 1999,9:1656; Hadfield J A, Hepworth L A, Lawrence M J.J OrgChem, 2001,66:8135.).The Wittig reaction method will be used the big and relatively more expensive triphenylphosphine of toxicity, the free hydroxyl group of raw material Isovanillin needs protection, the Wittig reaction needed is carried out under-78 ℃ low temperature and absolute exacting terms such as anhydrous, and the operation route is longer relatively, and total recovery is low; Related intermediate (the Z)-5-of Suzuki reaction method (2 '-vinyl bromide)-2-methoxyl group phenol synthetic loaded down with trivial details, desired raw material 3,4,5-trimethoxy phenylo boric acid costs an arm and a leg; The reagent that the Suzuki modification method is adopted is relatively more expensive, as triphenylphosphine, organic palladium reagent (Ph 3P) 4Pd etc., intermediate 1,1-two bromo-3 ', 4 ', 5 '-also difficulty of the preparation of trimethoxy vinylbenzene and 5-iodo-2-methoxyl group phenol; The method of Perkin reaction is as follows:
With 3,4,5-trimethoxy toluylic acid and Isovanillin (formal name used at school is 3-hydroxyl-4-methoxybenzaldehyde) are raw material, and the ratio of the amount of substance that the two feeds intake is 2: 1, under the condition of aceticanhydride and triethylamine existence, are heated to 140 ℃, react 12 hours.Reaction obtain after finishing (E)-2-(3 ', 4 ', 5 '-trimethoxyphenyl)-3-(3 '-bromo-4 '-p-methoxy-phenyl)-vinylformic acid, this compound is after acidifying, ethyl acetate extraction separate, product (yield is 60%) decarboxylation under the condition of quinoline woods and Cu existence, be heated to 230 ℃, react the product that obtains formula (1) after 2 hours, use saturated Na successively through acid elution, extracted with diethyl ether separation, organic layer again 2CO 3Aftertreatments such as solution, water, NaCl solution washing, column chromatography purification.
Above-mentioned Perkin method is with expensive 3,4, and 5-trimethoxy toluylic acid is a raw material, this raw material on market, be difficult to buy and price extremely expensive, preparation then need be used highly toxic substances such as sodium cyanide voluntarily, and another kind of raw material Isovanillin price is also expensive.
Summary of the invention
Purpose of the present invention aim to provide a kind of preparation (Z)-3 '-hydroxyl-3,4,4 ', the method for 5-tetramethoxy toluylene, this method is simple and easy, raw materials used safely, be easy to get, to solve the above-mentioned problem of prior art.
We utilize the Perkin reaction method to make up the toluylene skeleton structure, with homoanisic acid cheap and easy to get is raw material, obtain 3-bromo-4-methoxyphenylacetic acid through bromination, again with 3,4, the 5-TMB take place the Perkin condensation obtain (E)-3-(3 ', 4 ', 5 '-trimethoxyphenyl)-2-(3 '-bromo-4 '-p-methoxy-phenyl)-vinylformic acid, again through phenolic hydroxyl group replace debrominate obtain (E)-3-(3 ', 4 ', 5 '-trimethoxyphenyl)-2-(3 '-hydroxyl-4 '-p-methoxy-phenyl)-vinylformic acid, after decarboxylation obtain (Z)-3 '-hydroxyl-3,4,4 ', 5-tetramethoxy toluylene.This introducing for the diphenylethylene compounds phenolic hydroxyl group provides a kind of new design philosophy, for (Z)-3 '-hydroxyl-3,4,4 ', 5-tetramethoxy toluylene synthetic provides a kind of novel method.The use of this method has reduced the cost of reaction, has simplified post-processing operation, and total recovery is also higher, thereby has realized purpose of the present invention.
A kind of preparation of the present invention (Z)-3 '-hydroxyl-3,4,4 ', the method for 5-tetramethoxy toluylene comprises following step:
(1) homoanisic acid and the bromine reaction of following formula (2);
Figure C20041005149800051
Formula (2)
(2) the 3-bromo-4-methoxyphenylacetic acid of the following formula of gained (3) in aceticanhydride, is heated to 90～150 ℃ under triethylamine catalysis, with 3,4 of following formula (4), and 5-TMB reaction acidifying after 2～12 hours, purification process;
Figure C20041005149800052
Figure C20041005149800053
Formula (3) formula (4)
(3) (the E)-3-of the following formula of gained (5) (3 ', 4 ', 5 '-trimethoxyphenyl)-2-(3 '-bromo-4 '-p-methoxy-phenyl)-vinylformic acid is in 8%～20% NaOH solution, mantoquita exists down, 80～150 ℃ of debrominates, reaction 2～3d is again through acidifying, purification process;
Figure C20041005149800061
Formula (5)
(4) (the E)-3-of the following formula of gained (6) (3 ', 4 ', 5 '-trimethoxyphenyl)-2-(3 '-hydroxyl-4 '-p-methoxy-phenyl)-vinylformic acid is after decarboxylation, through (Z)-3 of separating, purification process obtains following formula (1) '-hydroxyl-3,4,4 ', 5-tetramethoxy toluylene.
Formula (6)
The reaction of homoanisic acid and bromine can be by the method for bibliographical information (referring to Durbin A K, Schofeild K.Aust J Chem, 1970 in the step (1), 23:791-800), reacted 1～5 hour down at 0～30 ℃, temperature is good with 0～20 ℃, and 1～3 hour time was good.
Temperature is good with 100～140 ℃ in the step (2), and the time was good with 2～8 hours; Described purification process can adopt usual method.
The concentration of NaOH solution has certain influence to reaction in the step (3), is good with massfraction 12%～15%; Described mantoquita is copper sulfate, cupric chloride etc., and copper sulfate is best; Described purification process can adopt usual method.
(E)-3-in the step (4) (3 ', 4 ', 5 '-trimethoxyphenyl)-2-(3 '-hydroxyl-4 '-p-methoxy-phenyl)-vinylformic acid adopts the method for document through decarboxylation, under the condition that quinoline woods and metal Cu exist,, reacted 2～5 hours at 180～220 ℃; Described separation and purification process can adopt the method for document, the most handy method provided by the invention of purifying: with volume ratio is that 1: 20～1: 10 ethyl acetate-sherwood oil backflow wash-out and recrystallization gets light yellow crystal, has good crystalline form; The volume ratio of described ethyl acetate-sherwood oil was good with 1: 15～1: 10.
The present invention has remarkable advantages than literature method:
(1) compare with the Perkin method of condensing of bibliographical information, used acid is different with aldehyde, is difficult to buy and make by oneself 3,4 of difficulty, 5-trimethoxy toluylic acid thereby avoid using;
(2) yield of this step reaction of Perkin condensation is also than the literature value height;
(3) the present invention is raw materials used cheap and easy to get, all belongs to the domestic industry raw material;
(4) aftertreatment is simple, and adopting the solvent of environmental protection to carry out recrystallization can need not product purification to make to use column chromatography, and environmental pollution is little, greatly reduces reaction cost, and cri-trans selectivity has raising slightly than the method for bibliographical information.
(5) total recovery reaches more than 24.3%, is higher than other method, and the most frequently used Wittig method total recovery has only 19% at present.
Embodiment
Following experiment and operational instances are further to explanation of the present invention, should not be used as limitation of the present invention.
Embodiment 1:
Get homoanisic acid 10.2g (0.061mol) in there-necked flask, other adds the dissolving of 20mL Glacial acetic acid, drips the bromine (11.2g of 3.6mL then, 0.068mol), 45min drips off, and stirs 1 hour under ice bath again, pour in the frozen water, separate out solid, filter, dry, make 3-bromo-4-methoxyl group-toluylic acid 14.8g, yield is 98.3%, obtains the white plates crystal with the alcohol-water recrystallization, yield 70%, fusing point are 113～114 ℃ (literature value is 114～115 ℃).
Take by weighing the 3-bromo-4-methoxyphenylacetic acid 4.92g (0.02mol) that makes, other takes by weighing 3,4, and 5-TMB 4.32g (0.022mol) adds in the reaction flask, and with the dissolving of 20mL aceticanhydride, the triethylamine of Dropwise 5 .0mL is heated to 130 ℃, reacts 5 hours.Separate out solid in the frozen water with pouring into after the concentrated hydrochloric acid acidification, gained solid NaOH solution washing, behind the acidifying water layer faint yellow solid (E)-3-(3 ', 4 ', 5 '-trimethoxyphenyl)-2-(3 '-bromo-4 '-p-methoxy-phenyl)-vinylformic acid, drying weigh 6.80g, yield is 80.3%; Get 4.42g light yellow crystal (yield is 65.0%) with ethyl alcohol recrystallization.
With (E)-3-(3 ', 4 ', 5 '-trimethoxyphenyl)-2-(3 '-bromo-4 '-p-methoxy-phenyl)-vinylformic acid 3.2g (7.56mmol), the NaOH solid of 25.0g, the CuSO of 1.0g 4Add and be equipped with in two mouthfuls of flasks of prolong, add the 200mL deionized water dissolving, stir and be heated to 130 ℃ (bathing temperature), reaction 2.5d has reacted after-filtration, with the hcl acidifying of 2mol/L, ethyl acetate extraction, anhydrous MgSO 4Drying concentrates, ethyl acetate-sherwood oil recrystallization, faint yellow solid (E)-3-(3 ', 4 ', 5 '-trimethoxyphenyl)-2-(3 '-hydroxyl-4 '-p-methoxy-phenyl)-vinylformic acid, heavy 1.70g (yield 62.5%).
With (E)-3-(3 ', 4 ', 5 '-trimethoxyphenyl)-2-(3 '-hydroxyl-4 '-p-methoxy-phenyl)-vinylformic acid 1.0g (2.78mmol), Cu powder 1.5g, quinoline 10mL was 200 ℃ of following stirring reactions 2 hours.After finishing, reaction adds 30 milliliters of ethyl acetate, filter, with the salt acid elution of 1mol/L, water layer with the amount of ethyl acetate extraction, merges organic layer again, use hydrochloric acid successively again, saturated NaCl solution, water washing, dry (from the situation of a plate, almost all generate cis), concentrate, and repeatedly reflux, till a plate has not had remaining target product with ethyl acetate-sherwood oil (1: 20), merge phegma, with ethyl acetate-sherwood oil recrystallization, light yellow crystal be (Z)-3 '-hydroxyl-3,4,4 ', 5-tetramethoxy toluylene 0.53g (yield is 60.9%).
Embodiment 2: melting point compound that embodiment 1 obtains and spectroscopic data are measured
Measurement result is as follows: 116～117 ℃ of m p (115～116 ℃ of literature values).Ms?m/z(％)：316(M +，100)，301(75)。 1H?NMR(δ，ppm，J/Hz)：6.91(d，1H，J＝2.0)；6.79(dd，1H，J＝8，2.0)；6.71(d，1H，J＝8.0)；6.51(s，2H)；6.45(d，1H，J＝12.4)；6.42(d，1H，J＝12.4)；5.49(s，1H)；3.89(s，3H)；3.84(s，3H)；3.68(s，6H)。IR(KBr)：3424，3002，2938，2836，1610，1579，1508，1459，1419，1328，1182，1025，1004，944，881，854，796，765。From last result prove this compound for (Z)-3 '-hydroxyl-3,4,4 ', 5-tetramethoxy toluylene.

Claims (6)

  1. (Z)-3 of a preparation formula (1) '-hydroxyl-3,4,4 ', the method for 5-tetramethoxy toluylene
    Formula (1)
    Comprise following step:
    (1) homoanisic acid of formula (2):
    Formula (2)
    With bromine reaction;
    (2) 3,4 of the 3-bromo-4-methoxyphenylacetic acid of the formula of gained (3) and formula (4), the 5-TMB:
    First
    Formula (3) formula (4)
    Under triethylamine catalysis, in aceticanhydride, be heated to 90～150 ℃, react acidifying after 2～12 hours, purification process;
    (3) (the E)-3-of the formula of gained (5) (3 ', 4 ', 5 '-trimethoxyphenyl)-2 (3 '-bromo-4 '-p-methoxy-phenyl) vinylformic acid:
    Figure C2004100514980002C5
    Formula (5)
    In the NaOH of massfraction 8%～20% solution, cupric salt exists down, and 80～150 ℃ of debrominates, reaction 2～3d is again through acidifying, purification process;
    (4) (the E)-3-of the formula of gained (6) (3 ', 4 ', 5 '-trimethoxyphenyl)-2-(3 '-hydroxyl-4 '-p-methoxy-phenyl)-vinylformic acid:
    Figure C2004100514980003C1
    Formula (6)
    After the decarboxylation, through (Z)-3 of separating, purification process obtains formula (1) '-hydroxyl-3,4,4 ', 5-tetramethoxy toluylene.
  2. 2. (Z)-3 of a kind of preparation formula according to claim 1 (1) '-hydroxyl-3,4,4 ', the method for 5-tetramethoxy toluylene is characterized in that, homoanisic acid described in the step (1) and bromine be reflected at 0～20 ℃, reacted 1～3 hour.
  3. 3. (Z)-3 of a kind of preparation formula according to claim 1 (1) '-hydroxyl-3,4,4 ', the method for 5-tetramethoxy toluylene is characterized in that, is heated to 100～140 ℃ in the step (2), reacts 2～8 hours.
  4. 4. (Z)-3 of a kind of preparation formula according to claim 1 (1) '-hydroxyl-3,4,4 ', the method for 5-tetramethoxy toluylene is characterized in that, the NaOH solution content described in the step (3) is massfraction 12%～15%; Described mantoquita is a copper sulfate.
  5. 5. (Z)-3 of a kind of preparation formula according to claim 1 (1) '-hydroxyl-3,4,4 ', the method of 5-tetramethoxy toluylene is characterized in that, (the E)-3-described in the step (4) (3 ', 4 ', 5 '-trimethoxyphenyl)-2-(3 '-hydroxyl-4 '-p-methoxy-phenyl)-the vinylformic acid decarboxylation under the condition that quinoline woods and metal Cu exist, at 180～220 ℃, reacted 2～5 hours; Described purification process was with ethyl acetate-sherwood oil backflow wash-out and recrystallization of 1: 20～1: 10.
  6. 6. (Z)-3 of a kind of preparation formula according to claim 5 (1) '-hydroxyl-3,4,4 ', the method for 5-tetramethoxy toluylene is characterized in that, the volume ratio of described ethyl acetate-sherwood oil is 1: 15～1: 10.
CN 200410051498 2004-09-17 2004-09-17 Process for preparing (z)-3'-hydroxy-3,4,4',5-tetranetgixy diphenyl ethylene Expired - Fee Related CN1266104C (en)

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CN100393731C (en) * 2006-02-23 2008-06-11 中国科学院广州化学研究所 Water soluble phosphate ester salt of(Z)-3'-hydroxy-3,4',5-trimethoxydiphenyl ethylene, and its preparation method ,pharmaceutical composition and uses
CN100532353C (en) * 2006-12-06 2009-08-26 中国科学院广州化学研究所 Preparation process of (Z)-3'-amino-3,4,4', 5-tetramethoxyl stilbene
CN101353296B (en) * 2008-09-02 2011-09-21 中国科学院广州化学研究所 Method for preparing (Z)-3'-hydroxy-3,4,4',5-tetramethoxy diphenyl ethylene from regenerative natural plant resource

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