CN105622350B - A kind of synthetic method of RV - Google Patents

A kind of synthetic method of RV Download PDF

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Publication number
CN105622350B
CN105622350B CN201610096279.7A CN201610096279A CN105622350B CN 105622350 B CN105622350 B CN 105622350B CN 201610096279 A CN201610096279 A CN 201610096279A CN 105622350 B CN105622350 B CN 105622350B
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dihydroxy
preparation
organic solvent
triphenylphosphine
reaction
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CN105622350A (en
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欧文华
张婉萍
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Shanghai Institute of Technology
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Shanghai Institute of Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/11—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms
    • C07C37/20—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms using aldehydes or ketones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/001—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by modification in a side chain
    • C07C37/002—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by modification in a side chain by transformation of a functional group, e.g. oxo, carboxyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/54—Quaternary phosphonium compounds
    • C07F9/5456—Arylalkanephosphonium compounds

Abstract

The invention provides a kind of preparation method of RV, by the dissolving of 3,5 dihydroxy-benzoic acids in a solvent, is reacted with sodium borohydride and middle lewis acid, obtains 3,5 dihydroxy-benzyl alcohols；Reacted with the hydrobromic acid of 3,5 dihydroxy-benzyl alcohols and triphenylphosphine in certain solvent, obtain corresponding phosphonium salt；With phosphonium salt obtained above, with parahydroxyben-zaldehyde under highly basic effect, product RV is directly obtained.The preparation method of the present invention, step is few, avoids the upper protection of phenolic hydroxyl group and deprotection process in technique, avoids using noble metal catalyst, cost is low, simple to operate, and reaction condition is easily achieved, and is easy to industrialized production.

Description

A kind of synthetic method of RV
Technical field
The invention belongs to chemical field, is related to a kind of RV, specifically a kind of preparation method of RV.
Background technology
RV (I) is a kind of non-flavonoids polyphenolic substance containing stilbene class formation, and it is to be not only a kind of plant Antitoxin, or it is a kind of with anticancer, anti-oxidant, regulation blood fat, influence many-sided the important of health that be beneficial to man such as life-span A kind of material of function.
Because the purposes of RV is extremely extensive, its market demand is especially big with potentiality.Although it can be from some Extracted in plant, it is this to prepare Bai Lilu with biological technique method from what the method for natural middle extraction and later people were studied The method of alcohol much can not meet the needs in market.Therefore by means of the method for chemical synthesis people must could be met to this The needs of product.At present, have that the synthetic method of the RV of document report is especially more, but following several classes nothing more than：The first Approach is to react [Moreno-Manas.M.J, Quim, Ser.1985.81.157 by Witting or Witting-Horner； The documents such as Yoshiaki T.Tetrahedron.2005.61.10285] prepare RV, it is as follows.
This kind of method, all it is to be set out respectively from 3,5- dihydroxy phenyls segment or p-hydroxybenzene segment, by protecting phenol Hydroxyl, is made corresponding phosphonium ylide salt, then with 3, the 5- 4-dihydroxy benzaldehydes of protection or having protected under highly basic effect Parahydroxyben-zaldehyde reacts, then obtains product by deprotection.This main synthetic route of method will five or six steps, this does not include also Step required for the phenolic hydroxyl group protection of another segment, so, this condition route shortcoming is obvious, and route is oversize, causes total yield Rate is low, and chemical products, and it is big that process route length also results in environmental protection pressure, and then causes product cost height.
Second, by Perkin condensation reactions [,Kromp K.Chem.Ber.1941.74.189；Guy The documents such as Solladi é, etc.Tetrahedron.2003.59.3315] prepare RV.
This kind of method is also that 3, the 5- dihydroxy-benzoic acids that can be obtained by market are raw material, first prepares phenolic hydroxyl group guarantor The aldehyde of shield, then reacted with the p-hydroxyphenylaceticacid of phenolic hydroxyl group protection, then be made through being deprotected.This kind of method, which equally be unable to do without, first protects Phenolic hydroxyl group in two segments of shield is reacted again, link that is last or passing through deprotection.Plus the phenol of two segments The protection of hydroxyl, this kind of technique at least also six to seven steps, the shortcomings that step is long, are also apparent, and this kind of method with above The Witting that mentions reacts equally unavoidable dephenolize hydroxyl protection, so not only increase the environmental protection pressure of technique, while increases Add the cost of product, be unfavorable for industrial production.
Third, pass through Heck condensation reactions [Marcella Guiso, ect.TetrahedronLett.2001.43.597； The documents such as Merritt B Andru, ect.TetrahedronLett.2003.44.4819] prepare RV.
This kind of method first has to that phenol will be become one of in 3,5- dihydroxy phenyls segment or p-hydroxybenzene segment The styrene form of hydroxyl protection, other segment will become the form of the chlorobenzoyl chloride of corresponding phenolic hydroxyl group protection, Ran Hou Heck reaction products are obtained under the catalysis of noble metal catalyst palladium, then are obtained through deprotection.The shortcomings that this kind of reaction is first First one of segment must be reacted by Witting is made corresponding styrene form, and this increases technique in itself Cost.Secondly, benzene process will use expensive heavy metal catalyst, just not saying the shortcomings that its step is more, light this point Production cost does not reach requirement certainly.
Fourth, pass through other method [Alonso.E, etc.J.Org.Chem.1997.62.417；Zhang Xue-Jing, The documents such as etc.Journal of Chinese Pharmaceutical Sciences.2004.13.10] prepare Bai Lilu Alcohol.
Because the purposes of RV is wide, chemist never stopped to its study on the synthesis, as implied above logical Carbanion and carbonyl reaction are crossed, corresponding RV can also be prepared in the presence of lithium metal.But the technique does not have still Have and overcome its route to grow, the shortcomings that using dangerous lithium metal, and phenolic hydroxyl group is protected and is deprotected.
Although also constantly there is the synthesis of document report RV now, or still route is grown, phenolic hydroxyl group needs Protection and final products will be deprotected, or expensive catalyst will be used, cause production cost height.And route It is long, also bring many environmental issues to industrial production.It is short therefore, it is possible to find a route, low being still of technique of cost Worker is pursued.
The content of the invention
It is described the invention provides a kind of preparation method of RV for above-mentioned technical problem of the prior art The preparation method of this RV to solve complex process in the method for the prior art for preparing RV, separation tired Technical problem difficult, cost is high.
The invention provides a kind of preparation method of RV, comprise the following steps：
1) 3,5- dihydroxy-benzoic acids, sodium borohydride, middle lewis acid, described 3,5- dihydroxy benzenes first are weighed respectively Acid, sodium borohydride, in lewis acidic mol ratio be 1:2~4:2.6~5.2,3,5- dihydroxies are added in a reaction vessel Yl benzoic acid and sodium borohydride and the first organic solvent, add middle lewis acid, and 4~12h, warp are reacted at 20~25 DEG C 3,5- dihydroxybenzyl alcohols are obtained after crossing processing；
2) 3,5- dihydroxybenzyl alcohols are dissolved in second of organic solvent, add the hydrobromate of triphenylphosphine, The mol ratio of the hydrobromate of 3,5- dihydroxybenzyl alcohols and triphenylphosphine is 1:1~2, it is heated to 70~90 DEG C, back flow reaction, Reaction time is 12~24h, after being down to room temperature, is stirred under being cooled down under ice-water bath, after solid separates out, filtering, and filter cake acetonitrile Washing, is then washed with absolute ether, obtains bromination 3,5- dihydroxy benzyl triphenylphosphines；
3) bromination 3,5- dihydroxy benzyls triphenylphosphine, parahydroxyben-zaldehyde, highly basic are dissolved in the third organic solvent In, it is added in reaction vessel, bromination 3,5- dihydroxy benzyls triphenylphosphine, parahydroxyben-zaldehyde, the mol ratio of highly basic are 0.8-1.2：0.8-1.2：2.4-3.6；Directly heat to 60~100 DEG C, and at this temperature react 20~24 hours after by Processing obtains RV.
Further, the first described organic solvent is methyl tertiary butyl ether, absolute ether, glycol dimethyl ether.It is described The first organic solvent be used for dissolve 3,5- dihydroxy-benzoic acids and sodium borohydride.
Further, described middle lewis acid be the diethyl ether solution of boron trifluoride, alchlor, titanium trichloride or Zinc chloride.
Further, second described of organic solvent is DMSO, DMF or acetonitrile.
Further, described solid alkali is sodium hydride, hydrofining or potassium tert-butoxide.
Further, the third described organic solvent is anhydrous tetrahydro furan, methyltetrahydrofuran or N, N- diformazan Base formamide.
Further, during post processing, neutralized using concentrated hydrochloric acid, then purified again.
The present invention is to first pass through reduction reaction：By the dissolving of 3,5- dihydroxy-benzoic acids in a solvent, slowly it is added drop-wise to boron hydrogen In the organic solution for changing sodium, after dripping, continue stirring reaction at room temperature, lewis acid reagent in being then added dropwise, obtain 3, 5- dihydroxybenzyl alcohols.Pass through salt-forming reaction again：The hydrogen of triphenylphosphine is added into the organic solution of 3,5- dihydroxybenzyl alcohols Bromate, in a solvent back flow reaction obtain corresponding phosphonium salt.Finally by Ylide reaction：By above-mentioned phosphonium salt, to hydroxyl Benzaldehyde, highly basic and organic solvent are added together reaction, are heated to reflux certain time and obtain corresponding RV.
The present invention course of reaction equation be：
The present invention compares with prior art, and its technological progress is significant.The invention provides one kind to prepare RV Method, only with three steps (it is few to be truly realized step), abandoned conventional ylide route needs to protect phenolic hydroxyl group again this method What is be deprotected is numerous and diverse, and cost is low, simple to operate, and reaction condition is easily achieved, and reaction yield is also good, obtained product colour It is good, it is easy to industrialized production.
Embodiment
The present invention is described in further detail below by embodiment, the preparation method of RV is as follows：
Embodiment 1
This reaction should be carried out under nitrogen protection, keep reaction system anhydrous as far as possible.By 5g sodium borohydrides (132mmol) It is added to 54.5g glycol dimethyl ethers in reactor, stirring makes sodium borohydride be evenly dispersed in ethylene glycol dimethyl ether solution In.Weigh 6.8g (44mmol) 3,5- dihydroxy-benzoic acids to be dissolved in 34g ethylene glycol dimethyl ether solutions, be slowly dropped to (drip off), maintain the temperature between 25-30 DEG C within a hour in the ethylene glycol dimethyl ether solution of sodium borohydride.Drip Cheng Hou, continue stirring 1.5 hours at room temperature.Then, the diethyl ether solution 25g of boron trifluoride is slowly added dropwise toward reaction system (172mmol), also nearly a hour adds, and maintains temperature between 25-30 DEG C.After being added dropwise to complete, 6 are reacted at room temperature Hour.Then, 35 DEG C are warming up to, 44.3g n-butanols are added into reactant mixture, after stirring reaction half an hour, cooling, mistake Filter.Filtrate removal of solvent under reduced pressure under 70 degree/30mmHg, product 5.3g can be obtained, yield about 84%, the product can not Need to purify again and be directly used in next step.
Embodiment 2
Equipped with thermometer, the 1L of condenser pipe there-necked flask in sequentially add 3,5- dihydroxy-benzyl alcohols 5g obtained above (35.7mmol) and 300mL anhydrous acetonitriles, start to stir, and add the hydrobromate of 12.2g (35.7mmol) triphenylphosphine.Oil Bath is heated to flowing back, and stops heating after 12 hours, reaction system is down into room temperature.Then made with ice-water bath in reaction system Temperature is down to 0 DEG C, and continues stirring 30 minutes at this temperature, at this moment can find that substantial amounts of white solid separates out, filter, filter The acetonitrile that cake is crossed with sub-cooled once, is then washed with absolute ether, then dried, dried solid product 18.6g, is received Rate 72.3%.
1H NMR(300MHz,d6-DMSO):d:9.35ppm(2H,s),7.94-7.63ppm(15H,m),6.17- 6.16ppm (1H, d, J=2.09Hz), 5.82-5.80ppm (2H, t, J=2.24Hz), 4.92-4.87 (2H, d, J= 15.64Hz).
Embodiment 3
By the solid 9.31g (20mmol) obtained in embodiment two, parahydroxyben-zaldehyde 2.44g (20mmol), the tert-butyl alcohol Potassium 7.41g (66mmol) and 100 milliliters dried of anhydrous tetrahydro furan, are added in reactor, warming while stirring to 80 DEG C, Continue reaction at this temperature to be basically completed until reacting and (take around 20-24 hours), be cooled to room temperature, add 6g (5.2ml, 60mmol) 36.5% concentrated hydrochloric acid, and continue stirring reaction 30min at room temperature.Filtering, filter residue methyl- tert fourth After the washing of base ether, filtrate water washing, it is concentrated under reduced pressure and removes solvent, obtained crude product is recrystallized with alcohol-water, obtains Bai Lilu The white solid of alcohol, weight 3.42g, yield 75%.
1H NMR(300MHz,d6- DMSO) d 9.59 (bs, 1H), 9.23 (bs, 2H), 7.42 (d, J=8.70Hz, 2H), 6.97 (d, J=16.5Hz, 1H), 6.85 (d, J=16.5Hz, 1H), 6.78 (d, J=8.40Hz, 2H), 6.43 (d, J= 2.10Hz, 2H), 6.16 (t, J=2.10Hz, 1H)；13C NMR(75MHz,d6-DMSO)d 158.8,157.4,139.7, 128.5,128.1,125.9,115.7,104.6,102.1,99.8.
Above content is only the basic explanation under present inventive concept, is made according to technical scheme any equivalent Change, belong to protection scope of the present invention.

Claims (6)

1. a kind of preparation method of RV, it is characterised in that comprise the following steps：
1）3,5- dihydroxy-benzoic acids, sodium borohydride, lewis acid, described 3,5- dihydroxy-benzoic acids, boron hydrogen are weighed respectively Change sodium, lewis acidic mol ratio is 1:2~4:2.6 ~ 5.2,3,5- dihydroxy-benzoic acids and boron are added in a reaction vessel Sodium hydride and the first organic solvent, add lewis acid, and 4~12h is reacted at 20 ~ 25 DEG C, obtains 3 after treatment, 5- dihydroxybenzyl alcohols；
2）3,5- dihydroxybenzyl alcohols are dissolved in second of organic solvent, add the hydrobromate of triphenylphosphine, 3,5- The mol ratio of the hydrobromate of dihydroxybenzyl alcohol and triphenylphosphine is 1:1 ~ 2, it is heated to 70 ~ 90 DEG C, back flow reaction, during reaction Between be 12~24h, after being down to room temperature, stirred under being cooled down under ice-water bath, after solid separates out, filtering, filter cake washs with acetonitrile, connect And washed with absolute ether, obtain bromination 3,5- dihydroxy benzyl triphenylphosphines；
3）By bromination 3,5- dihydroxy benzyls triphenylphosphine, parahydroxyben-zaldehyde, highly basic are dissolved in the third organic solvent, added Enter into reaction vessel, bromination 3,5- dihydroxy benzyls triphenylphosphine, parahydroxyben-zaldehyde, the mol ratio of highly basic are 0.8-1.2： 0.8-1.2：2.4-3.6；Directly heat to 60 ~ 100 DEG C, and obtained by processing after reacting 20 ~ 24 hours at this temperature RV.
2. the preparation method of RV according to claim 1, it is characterised in that：Described lewis acid is tri-chlorination Aluminium, zinc chloride, titanium tetrachloride, the diethyl ether solution of boron trifluoride.
3. the preparation method of RV according to claim 1, it is characterised in that：The first described organic solvent is Methyl tertiary butyl ether, absolute ether or glycol dimethyl ether.
4. the preparation method of RV according to claim 1, it is characterised in that：Second described of organic solvent be Anhydrous DMSO, DMF or acetonitrile.
5. the preparation method of RV according to claim 1, it is characterised in that：The third described organic solvent is Anhydrous tetrahydro furan, methyltetrahydrofuran or N,N-dimethylformamide.
6. the preparation method of RV according to claim 1, it is characterised in that：Described highly basic is hydrofining, hydrogen Change sodium or potassium tert-butoxide.
CN201610096279.7A 2016-02-22 2016-02-22 A kind of synthetic method of RV Expired - Fee Related CN105622350B (en)

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