CN101830793B - Method for preparing hydroxyl-substituted phenylacetic acid compound - Google Patents
Method for preparing hydroxyl-substituted phenylacetic acid compound Download PDFInfo
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- CN101830793B CN101830793B CN201010177430.2A CN201010177430A CN101830793B CN 101830793 B CN101830793 B CN 101830793B CN 201010177430 A CN201010177430 A CN 201010177430A CN 101830793 B CN101830793 B CN 101830793B
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- acid compound
- phenylacetic acid
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Abstract
The invention discloses a method for preparing a hydroxyl-substituted phenylacetic acid compound. In the method, under normal pressure, at 80 to 120 DEG C and in a nitrogen protective atmosphere, a halogenated phenylacetic acid compound undergoes a substitution reaction in the presence of 8-oxine-copper(II) and an alkali to form the hydroxyl-substituted phenylacetic acid compound. The method has the advantages of high atomic economy, simple operation, short reaction time, mold reaction conditions, high yield, low cost, less pollution and the like and makes scale preparation realized easily.
Description
Technical field
The present invention relates to chemical field, particularly a kind of preparation method of hydroxyl-substituted phenylacetic acid compound.
Background technology
The toluylic acid compounds that hydroxyl replaces is important organic synthesis intermediate, is widely used in the industries such as medicine, agricultural chemicals and spices.For example: take 3-hydroxyl-4-methoxyphenylacetic acid as the synthetic alkaloid dihydro thebainone-A with analgesia and syngignoscism of raw material; 3,5-dihydroxyphenyl acetic acid is the synthetic important source material with the natural product resveratrol of anti-oxidant, antithrombotic, Green Tea Extract and the effect such as anticancer.
At present, the preparation method of hydroxyl-substituted phenylacetic acid compound mainly contains following several: (1) method of substitution: take halogeno-benzene acetic acid as raw material, Salzburg vitriol or copper powder are catalyzer, under high pressure, high temperature, alkaline condition, carry out substitution reaction and generate the toluylic acid that hydroxyl replaces; But this method needs High Temperature High Pressure, to the requirement of equipment very high (Speciality Petrochemicals progress, 2002,3:53-56).(2) cyanide process: the phenyl aldehyde that the hydroxyl of take replaces is raw material, obtain the derivative of sulfur-bearing with rhodanine dehydrating condensation, this derivative, through being hydrolyzed into corresponding thiocarboxylic acid, generates hydroximic acid with azanol reaction, through acidylate, hydrolysis, obtain the toluylic acid compounds that hydroxyl replaces again; But this method step is various, yield is low, environmental pollution large (Zhengzhou University's journal (medicine), 2004,39 (2): 261-263).
Summary of the invention
The object of the invention is to overcome the shortcoming existing in prior art, provide a kind of simple to operate, reaction conditions is gentle, cost is low, the preparation method of eco-friendly hydroxyl-substituted phenylacetic acid compound.
Object of the present invention is achieved through the following technical solutions:
A kind of preparation method of hydroxyl-substituted phenylacetic acid compound, comprise the steps: under nitrogen protection, the copper 8-quinolinolate (II) (structural formula is formula 3) of take is catalyzer, halogeno-benzene phenylacetic acid compound (structural formula is formula 2) and alkali generation substitution reaction; Then cooling, suction filtration, extraction, decolouring, recrystallization, obtain hydroxyl-substituted phenylacetic acid compound (structural formula is formula 1).
Wherein, m=1 or 2; R=H, OMe, Cl or Me; X=Br or Cl, any one Huo Liangge position that X can be in phenyl ring 2,3,5,6.
Described catalyzer copper 8-quinolinolate (II) is to adopt oxine and Cu (II) salt to produce in water-ethanol or Water-Methanol System, and wherein Cu (II) salt is CuSO
4.5H
2o, CuCl
2.2H
2o or Cu (NO
3)
2.3H
2o.
The mol ratio of described halogeno-benzene phenylacetic acid compound and copper 8-quinolinolate (II) is 1: (0.05～1), preferred molar ratio is 1: 0.1.
Described alkali is that mass concentration is 10%～50% KOH or the NaOH aqueous solution, and preferred mass concentration is 30%.
The mol ratio of described halogeno-benzene phenylacetic acid compound and alkali is 1: (6～20), preferred molar ratio is 1: 10.
The temperature of described substitution reaction is 80～120 ℃, is preferably 110 ℃; Because the complexity difference replacing occurs different halogeno-benzene phenylacetic acid compounds, therefore the time of required substitution reaction is also different, the preferential reaction time is 4～20 hours.
Described extraction, is that filtrate is acidified to PH=2～3, is extracted with ethyl acetate, and merges organic layer, and dry, concentrating under reduced pressure obtains crude product.Described filtrate acidifying, the acid of employing is hydrochloric acid or sulfuric acid.
Described decolouring is that the crude product that extraction is obtained adopts 5% activated carbon decolorizing.Solvent for activated carbon decolorizing is ethanol or ethyl acetate, preferred alcohol; Bleaching time is 10～30min, and preferably bleaching time is 20min.
Described recrystallization, the solvent of employing is the mixture of mixture, ethyl acetate and chloroform or the mixture of ethanol and chloroform of water, ethyl acetate and sherwood oil; Preferably the solvent of recrystallization is the mixture of ethyl acetate and chloroform.
Synthetic route of the present invention is as follows:
The present invention compared with prior art tool has the following advantages and effect:
(1) consumption that the raw material that the present invention adopts and reagent are all the Chemicals that are easy to get, especially catalyzer is little and can reuse.
(2) reaction conditions of the present invention is gentle, has realized and under normal pressure, has carried out efficiently hydroxyl substitution reaction.
(3) operation of the present invention is simple, and the reaction times is short, and transformation efficiency is high, pollute little, cost is low, less demanding to equipment, is easy to realize mass-producing preparation.
Embodiment
Below in conjunction with embodiment, the present invention is done to further detailed description, but embodiments of the present invention are not limited to this.
Embodiment 1
By 3,5-dibromobenzene acetic acid (23.44g, 0.08mol), copper 8-quinolinolate (2.82g, 0.008mol) He 30% sodium hydroxide solution (175mL, 1.44mol) put in stainless steel reaction bottle, oil bath temperature rises to 120 ℃, stirring heating back flow reaction 6 hours.Stopped reaction, filters by (recovery catalyzer), uses hcl acidifying filtrate to PH=2～3, ethyl acetate extraction, merge organic layer, concentrated, obtain red viscous liquid, use suitable dissolve with ethanol, 5% decolorizing with activated carbon, ethanol-Gossypol recrystallized from chloroform, obtains white solid 3,5-dihydroxyphenyl acetic acid 12.77g, yield approximately 95%.M.p.123～124℃.
1HNMR(CD
3COCD
3，400MHz)δ8.208(s，2H，OH)，6.303～6.297(d，2H，J＝2.4Hz，2，5-ArH)，6.241～6.230(t，1H，J＝2.4Hz，4-ArH)，3.427(s，2H，CH
2).MS，m/z(％)：168(M
+).
Embodiment 2
By 3,5-dibromobenzene acetic acid (23.44g, 0.08mol), copper 8-quinolinolate (2.82g, 0.008mol) He 30% sodium hydroxide solution (75mL, 0.8mol) put in stainless steel reaction bottle, oil bath temperature rises to 110 ℃, stirring heating back flow reaction 6 hours.Stopped reaction, filters by (recovery catalyzer), uses hcl acidifying filtrate between PH=2～3, ethyl acetate extraction, merge organic layer, concentrated, obtain red viscous liquid, use suitable dissolve with ethanol, 5% decolorizing with activated carbon, ethanol-Gossypol recrystallized from chloroform, obtains white solid 3,5-dihydroxyphenyl acetic acid 13.03g, yield approximately 97%.
Embodiment 3
By 3,5-dibromobenzene acetic acid (23.44g, 0.08mol), copper 8-quinolinolate (2.82g, 0.008mol) He 30% sodium hydroxide solution (75mL, 0.8mol) put in stainless steel reaction bottle, oil bath temperature rises to 80 ℃, stirring heating back flow reaction 12 hours.Stopped reaction, filters by (recovery catalyzer), uses hcl acidifying filtrate between PH=2～3, ethyl acetate extraction, merge organic layer, concentrated, obtain red viscous liquid, use suitable acetic acid ethyl dissolution, 5% decolorizing with activated carbon, ethyl acetate-Gossypol recrystallized from chloroform, obtains white solid 3,5-dihydroxyphenyl acetic acid 11.15g, yield approximately 83.0%.
Embodiment 4
By 3,5-dibromobenzene acetic acid (23.44g, 0.08mol), copper 8-quinolinolate (1.41g, 0.004mol) He 30% sodium hydroxide solution (75mL, 0.8mol) put in stainless steel reaction bottle, oil bath temperature rises to 110 ℃, stirring heating back flow reaction 7 hours.Stopped reaction, filters by (recovery catalyzer), uses hcl acidifying filtrate between PH=2～3, ethyl acetate extraction, merge organic layer, concentrated, obtain red viscous liquid, use suitable acetic acid ethyl dissolution, 5% decolorizing with activated carbon, ethyl acetate-Gossypol recrystallized from chloroform, obtains white solid 3,5-dihydroxyphenyl acetic acid 10.94g, yield approximately 81.47%.
Embodiment 5
By 3,5-dibromobenzene acetic acid (23.44g, 0.08mol), copper 8-quinolinolate (2.82g, 0.008mol) He 10% sodium hydroxide solution (173mL, 0.48mol) put in stainless steel reaction bottle, oil bath temperature rises to 120 ℃, stirring heating back flow reaction 20 hours.Stopped reaction, filters by (recovery catalyzer), uses hcl acidifying filtrate between PH=2～3, ethyl acetate extraction, merge organic layer, concentrated, obtain red viscous liquid, use suitable acetic acid ethyl dissolution, 5% decolorizing with activated carbon, ethyl acetate-Gossypol recrystallized from chloroform, obtains white solid 3,5-dihydroxyphenyl acetic acid 10.08g, yield approximately 75.0%.
Embodiment 6
By the bromo-4-methoxyphenylacetic acid of 3-(24.5g, 0.1mol), copper 8-quinolinolate (3.52g, 0.01mol) and 30% sodium hydroxide solution (94mL, 1.0mol) are put in stainless steel reaction bottle, oil bath temperature rises between 110 ℃, stirring heating back flow reaction 10 hours.Stopped reaction, filter by (recovery catalyzer), with hcl acidifying filtrate, between PH=2～3, ethyl acetate extracts, merge organic layer, concentrated, obtain red viscous liquid, use suitable acetic acid ethyl dissolution, 5% decolorizing with activated carbon, with ethyl acetate-sherwood oil recrystallization, obtain white powder crystal 3-hydroxyl-4-methoxyphenylacetic acid 17.93g, yield approximately 98%.M.p.127.5-129℃.
1H?NMR(CD
3COCD
3，400MHz)δ7.54(S，1H，OH)，6.85～6.87(d，1H，J＝8.0Hz，5-ArH)，6.81(d，1H，J＝2.0Hz，2-ArH)，6.70～6.73(dd，1H，J
1＝8.0Hz，J
2＝2.0Hz，6-ArH)，3.80(s，3H，4-OCH
3)，3.55(s，2H，CH
2).MS，m/z(％)：182(M
+)，183(M
++1)，137，122，94，77.
Embodiment 7
By the bromo-4-methoxyphenylacetic acid of 3-(24.5g, 0.1mol), copper 8-quinolinolate (3.52g, 0.01mol) He 30% sodium hydroxide solution (94mL, 1.0mol) put in the middle of stainless steel reaction bottle, oil bath temperature rises between 110 ℃-120 ℃, stirring heating back flow reaction 10 hours.Stopped reaction, filter by (recovery catalyzer), with hcl acidifying filtrate between PH=2～3, crystallisation by cooling, suction filtration obtains crude product, uses suitable dissolve with ethanol, 5% decolorizing with activated carbon, water recrystallization can obtain solid 3-hydroxyl-4-methoxyphenylacetic acid 16.74g of white needles, yield approximately 92%.
Embodiment 8
By 2,4 dichloro benzene acetic acid (10.25g, 0.05mol), copper 8-quinolinolate (17.6g, 0.05mol) and 30% sodium hydroxide solution (94mL, 1.0mol) are put in stainless steel reaction bottle, oil bath temperature rises between 110 ℃-120 ℃, stirring heating back flow reaction 4 days.Stopped reaction, filters by (recovery catalyzer), uses hcl acidifying filtrate between PH=2～3, crystallisation by cooling, suction filtration obtains crude product, the decolorizing with activated carbon with 5%, product 2-hydroxyl-4-chlorobenzene acetic acid 4.0g that can be further purified through recrystallization, yield approximately 43%.
1H?NMR(CD
3COCD
3，400MHz)δ7.20～7.18(d，1H，J＝8.0Hz，6-ArH)，6.89(d，1H，J＝2.0Hz，3-ArH)，6.84～6.82(dd，1H，J
1＝8.0Hz，J
2＝2.0Hz，5-ArH)，3.60(s，2H，CH
2).MS，m/z(％)：186(M
+).
Embodiment 9
By 2,4 dichloro benzene acetic acid (10.25g, 0.05mol), copper 8-quinolinolate (17.6g, 0.05mol) and 40% sodium hydroxide solution (60mL, 1.0mol) are put in the middle of stainless steel reaction bottle, oil bath temperature rises to 120 ℃, stirring heating back flow reaction 20h.Stopped reaction, filters by (recovery catalyzer), uses hcl acidifying filtrate between PH=2～3, crystallisation by cooling, suction filtration obtains crude product, the decolorizing with activated carbon with 5%, the product 2-hydroxyl-4 chlorobenzene acetic acid 2.1g that can be further purified through recrystallization, yield approximately 22.6%.
Claims (8)
1. the preparation method of a hydroxyl-substituted phenylacetic acid compound, it is characterized in that comprising the steps: under nitrogen protection, the copper 8-quinolinolate (II) (formula 3) of take is catalyzer, halogeno-benzene phenylacetic acid compound (formula 2) and alkali generation substitution reaction, the temperature of described substitution reaction is 80～120 ℃, and the reaction times is 4～20 hours; Then cooling, suction filtration, extraction, decolouring, recrystallization, obtain hydroxyl-substituted phenylacetic acid compound (formula 1);
Wherein, m=1 or 2; R=H, OMe, Cl or Me; X=Br or Cl, any one Huo Liangge position that X can be in phenyl ring 2,3,5,6.
2. the preparation method of hydroxyl-substituted phenylacetic acid compound according to claim 1, it is characterized in that: described catalyzer copper 8-quinolinolate (II) is to adopt oxine and Cu (II) salt to produce in water-ethanol or Water-Methanol System, and wherein Cu (II) salt is CuSO
4.5H
2o, CuCl
2.2H
2o or Cu (NO
3)
23H
2o.
3. the preparation method of hydroxyl-substituted phenylacetic acid compound according to claim 1, is characterized in that: the mol ratio of described halogeno-benzene phenylacetic acid compound and copper 8-quinolinolate (II) is 1:(0.05～1).
4. the preparation method of hydroxyl-substituted phenylacetic acid compound according to claim 1, is characterized in that: described alkali is that mass concentration is 10%～50% KOH or the NaOH aqueous solution.
5. the preparation method of hydroxyl-substituted phenylacetic acid compound according to claim 1, is characterized in that: the mol ratio of described halogeno-benzene phenylacetic acid compound and alkali is 1:(6～20).
6. the preparation method of hydroxyl-substituted phenylacetic acid compound according to claim 1, is characterized in that: described extraction is that filtrate is acidified to PH=2～3, is extracted with ethyl acetate, and merges organic layer, and dry, concentrating under reduced pressure obtains crude product.
7. the preparation method of hydroxyl-substituted phenylacetic acid compound according to claim 1, is characterized in that: described decolouring is that the crude product that extraction is obtained adopts 5% activated carbon decolorizing; Solvent for activated carbon decolorizing is ethanol or ethyl acetate; Bleaching time is 10～30min.
8. the preparation method of hydroxyl-substituted phenylacetic acid compound according to claim 1, it is characterized in that: described recrystallization, the solvent of employing is the mixture of the mixture of water or ethyl acetate and sherwood oil or the mixture of ethyl acetate and chloroform or ethanol and chloroform.
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| CN104230713B (en) * | 2013-06-18 | 2018-11-27 | 凯米诺瓦有限公司 | The method for being used to prepare 2- (2- hydroxy phenyl) alkyl acetate |
| CN104230800B (en) * | 2014-08-20 | 2016-08-24 | 邯郸惠达化工有限公司 | A kind of preparation method of copper 8-quinolinolate |
| CN105152918A (en) * | 2015-09-06 | 2015-12-16 | 联化科技(盐城)有限公司 | Preparation method of methoxyphenylacetic acid and intermediate and salt thereof |
| CN105541597B (en) * | 2015-12-29 | 2018-06-01 | 中山大学 | A kind of preparation method of 2,4- dihydroxyphenyl acetic acids |
| CN107686440B (en) * | 2016-08-04 | 2022-07-08 | 辽宁天予化工有限公司 | Preparation method of m-trifluoromethylphenol |
| CN113372367A (en) * | 2021-05-28 | 2021-09-10 | 无锡颐景丰科技有限公司 | Synthesis method of high-purity 8-hydroxyquinoline copper |
Citations (1)
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|---|---|---|---|---|
| CN1733674A (en) * | 2005-08-05 | 2006-02-15 | 上海康鹏化学有限公司 | Preparation method of double(2-hydroxyl hexafluopropyl) phenol |
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| CN1733674A (en) * | 2005-08-05 | 2006-02-15 | 上海康鹏化学有限公司 | Preparation method of double(2-hydroxyl hexafluopropyl) phenol |
Non-Patent Citations (2)
| Title |
|---|
| 对羟基苯乙酸的合成研究;蒋培华 等;《精细石油化工进展》;20020731;第3卷(第7期);第53-56页 * |
| 蒋培华 等.对羟基苯乙酸的合成研究.《精细石油化工进展》.2002,第3卷(第7期),第53-56页. |
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