CN104817451A - Preparation method for 4-methoxyphenylacetic acid - Google Patents
Preparation method for 4-methoxyphenylacetic acid Download PDFInfo
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- CN104817451A CN104817451A CN201510111704.0A CN201510111704A CN104817451A CN 104817451 A CN104817451 A CN 104817451A CN 201510111704 A CN201510111704 A CN 201510111704A CN 104817451 A CN104817451 A CN 104817451A
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- ITECRQOOEQWFPE-UHFFFAOYSA-N COc1ccc(C(C(O)=O)O)cc1 Chemical compound COc1ccc(C(C(O)=O)O)cc1 ITECRQOOEQWFPE-UHFFFAOYSA-N 0.000 description 1
- NRPFNQUDKRYCNX-UHFFFAOYSA-N COc1ccc(CC(O)=O)cc1 Chemical compound COc1ccc(CC(O)=O)cc1 NRPFNQUDKRYCNX-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
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Abstract
The invention relates to a method for preparation of 4-methoxyphenylacetic acid through hydrogenation reduction reaction on p-methoxymandelic acid. The reaction system includes: a solvent, which is selected from water, monoalkyl acid with a carbon number of 1-6 and a mixture of them; p-methoxymandelic acid; a hydrogen source; a hydrogenation reduction catalyst; and inorganic acid. The 4-methoxyphenylacetic acid finished product prepared by the invention has purity up to 99.8% and yield up to 99.1%. The method provided by the invention has the advantages of high reaction rate, short reaction time, high yield, few by-product, and little environmental pollution, and is suitable for industrial mass production.
Description
Technical field
The present invention relates to a kind of synthetic method of homoanisic acid, particularly by the method being prepared by methoxv mandelic acid hydrogenolysis to homoanisic acid.
Background technology
Homoanisic acid (4-methoxyphenylacetic acid), molecular formula is C
9h
10o
3, molecular weight is 166.17, is generally white plates crystal, and fusing point is 84-86 DEG C, is soluble in hot water, ethyl acetate, ethanol, ether etc., dissolves in cold water.Homoanisic acid is a kind of important medicine intermediate, is widely used in the aspect such as medicine, dyestuff.Such as homoanisic acid is the important source material of synthesis dextromethorphan intermediate 1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline 99.9; Also be the important source material of synthesizing antidepressant drug Wen Lafaxin of new generation; Also be simultaneously the important intermediate α of synthesizing antitumor, antimycotic and anti-bacterial drug phenanthro-connection pyridine Alkaloid, the important source material of beta-diaryl substitutional crylic acid; In addition, homoanisic acid is also the key intermediates of multiple cardiovascular agent such as synthesis puerarin, osajin etc.
The preparation of homoanisic acid, conventional having is following several: 1, benzyl cyanogen hydrolysis method, be traditional method preparing toluylic acid, adopt p-methoxybenzyl chloride and sodium cyanide effect, generate PARA METHOXY PHENYL ACETONITRILE, hydrolysis afterwards generates homoanisic acid, the method synthesis path is simple, and reaction substrate is easy to get, low price, but reaction yield is lower, and use hypertoxic sodium cyanide, and very big to operator and environmental injury, be unfavorable for industrial production; 2, Willgerodt-Kindler rearrangement method, this method take p-methoxy-acetophenone as raw material, first sulphur and Uricida reflux in alcohol solvent obtains sulfuration piperazine, then, after resetting at 135-140 DEG C with p-methoxy-acetophenone, hydrolysis obtains homoanisic acid, the by product hydrogen sulfide that the method generates, stench severe toxicity is large to environmental hazard; 3, oxo synthesis, the method take p-methoxybenzyl chloride as raw material, under carbonylating catalyst effect, in organic solvent and sodium hydroxide system, pass into carbon monoxide carry out carbonylation reaction, generate homoanisic acid sodium, acidifying afterwards obtains homoanisic acid.The method synthesis path is shorter, and productive rate is also higher, but used catalyst costly, easily poisoning and not easily prepare and reclaim, and makes products production high cost, and carbon monoxide hazardness is also comparatively large, not easy to operate in addition.Several route is due to its respective drawback above, loses the market competitiveness gradually.At present, what mainly adopt is that aubepine is produced methoxv mandelic acid through carbene reaction, and restore the operational path that dehydroxylation generates homoanisic acid, chemical equation is as follows:
Chinese patent CN 101298416A (2008/11/05) has carried out detailed elaboration to it, wherein be reduced in the process of homoanisic acid by methoxv mandelic acid, reductive agent used is anhydrous stannous chloride, two hydrated stannous chlorides, Sodium Pyrosulfite or phosphorous acid, its two hydrated stannous chlorides yied of redution is up to 81.3-83.7%, other reductive agent reduction effect is poor, two hydrated stannous chloride prices are more expensive, and not easily reclaim, industrialization cost is higher, Sodium Pyrosulfite or phosphorous acid environmental pollution are comparatively large, and productive rate is lower.
Along with the continuous increase of homoanisic acid domestic market demand amount, product market price keeps falling, and raw material is higher to methoxv mandelic acid production cost, and existing method production economy benefit is not high, need to take effective measures and improve reduction process yield, and then improve production economy benefit.
Summary of the invention
The object of the present invention is to provide a kind of be applicable to industrial, low cost with to the method for methoxv mandelic acid for Material synthesis homoanisic acid, solve prior art yield when industrial production low, the problem that by product is many, complicated operation, cost are high.
Provided by the invention by preparing homoanisic acid method to methoxv mandelic acid hydrogenation reduction, its reaction system comprises: solvent, the unitary alkanoic acid that it is selected from water, carbon number is 1-6 and their mixture; To methoxv mandelic acid; Hydrogen source; Hydrogenating reduction catalyzer; And mineral acid.
The present invention preferably prepares homoanisic acid method, and wherein said solvent is selected from water, propionic acid, acetic acid and formic acid; Described hydrogen source is selected from hydrogen, ammonium formiate and hydrazine hydrate; Described catalyzer is selected from Raney's nickel, palladium charcoal, platinum charcoal and platinum dioxide; And described mineral acid is selected from hydrochloric acid, perchloric acid, Hydrogen bromide, hydroiodic acid HI, phosphoric acid and sulfuric acid.
The present invention preferably prepares homoanisic acid method, and wherein said solvent is acetic acid; Described hydrogen source is hydrogen; Described catalyzer is Raney's nickel; And described mineral acid is hydrochloric acid.
The present invention preferably prepares homoanisic acid method, carries out the separation of homoanisic acid, comprising after wherein said hydrogenation reduction terminates: reacting liquid filtering, concentrated, crystallization, obtain the homoanisic acid crystal of white.
The homoanisic acid finished product that the present invention obtains, purity can up to 99.8%, and yield can up to 99.1%.Advantage of the present invention is that speed of reaction is high, and the reaction times is short, and productive rate is high, and by product is few, and environmental pollution is few, is applicable to industrial mass production.
Embodiment
In method of the present invention, raw material obtains homoanisic acid to methoxv mandelic acid hydrogenolysis under catalysts conditions, more after filtration, concentrated, washing, concentrated, crystallization, separation obtain homoanisic acid sterling.Obtained homoanisic acid finished product, purity is 99.8%, and yield is 99.1%.
Raw material is synthesized by aubepine, Tetrabutyl amonium bromide, sodium hydroxide and chloroform reference literature reaction conditions methoxv mandelic acid, reaction terminates rear system and is dissolved in water, separate unnecessary chloroform, then washed with dichloromethane aqueous phase is used, water layer adds hydrochloric acid makes its pH=7 use washed with dichloromethane again, water transfer layer pH=0.1, is extracted with ethyl acetate afterwards, reconcentration organic layer, crystallization, is separated methoxv mandelic acid white crystal.
To methoxv mandelic acid, under catalysts conditions, hydrogenolysis is homoanisic acid in an acidic solution, and reduction reaction procedural representation is as follows:
To methoxv mandelic acid in an acidic solution hydrogenolysis obtain homoanisic acid, the solvent adopted is propionic acid, acetic acid, formic acid, water, preferred acetic acid.The acid added is hydrochloric acid, perchloric acid, Hydrogen bromide, hydroiodic acid HI, phosphoric acid or sulfuric acid, preferred concentrated hydrochloric acid, and charging capacity is 0.5-10 times to methoxv mandelic acid molar weight, preferred 0.5-2 times, more preferably 1 times.Used catalyst is Raney's nickel, palladium charcoal, platinum charcoal or platinum dioxide, preferred Raney's nickel, and charging capacity is the 1.0-20% to methoxv mandelic acid quality, preferred 5-15%, more preferably 10.0%.Hydrogen source is hydrogen, ammonium formiate or hydrazine hydrate, is preferably hydrogen, and when hydrogen is hydrogen source, suitably increase reaction pressure and can improve speed of reaction, Reaction time shorten, increase product yield, reaction pressure is 0.1-1MPa, is preferably 0.1-0.3MPa.Reduction reaction temperature is 25-100 DEG C, preferred 50-60 DEG C.Adopt crystallisation by cooling method to isolate homoanisic acid product, by reacting liquid filtering, concentrated, washing, concentrated after crystallisation by cooling, recrystallisation solvent is water, sherwood oil and ethyl acetate mixed solvent, Virahol and sherwood oil mixed solvent, preferably water.In crystallisation by cooling process, preferably reaction solution is cooled to 0-10 DEG C, most of crystal is separated out, adopt vacuum filtration process by crystal separation, and with cold water washing, dry must homoanisic acid.For improving reaction yield, crystalline mother solution can concentrate, recrystallize.
The present invention realizes in the following ways, describes in detail below in conjunction with embodiment:
Embodiment 1
Thermometer is being housed, in 100mL two mouthfuls of flasks of hydrogen balloon, add acetic acid 30mL, to methoxv mandelic acid 1.0g (5.5mmol), palladium carbon 0.1g, perchloric acid 1.0mL, magnetic agitation, and system is sealed, open hydrogen balloon after system being vacuumized afterwards and lead to hydrogen, stirring reaction 4.0h at 60 DEG C, raw material almost reacts completely, system is filtered, concentrating under reduced pressure, then acetic acid ethyl dissolution (namely dissolving the system after concentrating) is added, and wash twice with water, separate ethyl acetate layer concentrating under reduced pressure again, white crystal is obtained afterwards with water cooling crystallization, liquid chromatography for measuring content is 99.6%, productive rate is 68.8%.
Embodiment 2
Thermometer is being housed, in 100mL two mouthfuls of flasks of hydrogen balloon, add acetic acid 30mL, to methoxv mandelic acid 1.0g (5.5mmol), palladium carbon 0.1g, hydrochloric acid 1.0mL, magnetic agitation, and system is sealed, open hydrogen balloon after system being vacuumized afterwards and lead to hydrogen, stirring reaction 2.0h at 60 DEG C, raw material almost reacts completely, system is filtered, concentrating under reduced pressure, then acetic acid ethyl dissolution is added, and wash twice with water, separate ethyl acetate layer concentrating under reduced pressure again, white crystal is obtained afterwards with water cooling crystallization, liquid chromatography for measuring content is 99.7%, productive rate is 99.1%.
Embodiment 3
In 100mL two mouthfuls of flasks that thermometer, hydrogen balloon are housed, add acetic acid 30mL, to methoxv mandelic acid 1.0g (5.5mmol), palladium carbon 0.1g, hydrochloric acid 1.0mL, magnetic agitation, and system is sealed, open hydrogen balloon after system being vacuumized afterwards and lead to hydrogen, stirred at ambient temperature reaction 15h, system is filtered, concentrating under reduced pressure, then adds acetic acid ethyl dissolution, and washes twice with water, separate ethyl acetate layer concentrating under reduced pressure again, obtain white crystal with water cooling crystallization afterwards, liquid chromatography for measuring content is 99.7%, and productive rate is 36.1%.
Embodiment 4
In 100mL two mouthfuls of flasks that thermometer, hydrogen balloon are housed, add acetic acid 30mL, to methoxv mandelic acid 1.0g (5.5mmol), Raney's nickel 0.1g, hydrochloric acid 1.0mL, magnetic agitation, and system is sealed, open hydrogen balloon after system being vacuumized afterwards and lead to hydrogen, stirring reaction 3.0h at 60 DEG C, system is filtered, concentrating under reduced pressure, then adds acetic acid ethyl dissolution, and washes twice with water, separate ethyl acetate layer concentrating under reduced pressure again, use water recrystallization white crystal afterwards, liquid chromatography for measuring content is 98.7%, and productive rate is 97.8%.
Embodiment 5
In 100mL autoclave, add acetic acid 30mL, to methoxv mandelic acid 1.0g (5.5mmol), palladium carbon 0.1g, hydrochloric acid 1.0mL, 0.2MPa, 2.0h is reacted under room temperature, raw material almost reacts completely, and system is filtered, concentrating under reduced pressure, then acetic acid ethyl dissolution is added, and wash twice with water, separate ethyl acetate layer concentrating under reduced pressure again, obtain white crystal with water cooling crystallization afterwards, liquid chromatography for measuring content is 98.9%, and productive rate is 99.0%.
Embodiment 6
In 100mL two mouthfuls of flasks that thermometer is housed, add acetic acid 30mL, to methoxv mandelic acid 1.0g (5.5mmol), palladium carbon 0.1g, perchloric acid 1.0mL, ammonium formiate 83mg (1.32mmol), 15.0h is reacted under 60 DEG C of magnetic agitation, system is filtered, concentrating under reduced pressure, then acetic acid ethyl dissolution is added, and wash twice with water, separate ethyl acetate layer concentrating under reduced pressure again, obtain white crystal with water cooling crystallization afterwards, liquid chromatography for measuring content is 90.6%, and productive rate is 10.8%.
Embodiment 7
In 100mL two mouthfuls of flasks that thermometer, hydrogen balloon are housed, add formic acid 30mL, to methoxv mandelic acid 1.0g (5.5mmol), palladium carbon 0.1g, concentrated hydrochloric acid 1.0mL, magnetic agitation, and system is sealed, open hydrogen balloon after system being vacuumized afterwards and lead to hydrogen, stirring reaction 10.0h at 60 DEG C, system is filtered, concentrating under reduced pressure, then adds acetic acid ethyl dissolution, and washes twice with water, separate ethyl acetate layer concentrating under reduced pressure again, obtain white crystal with water cooling crystallization afterwards, liquid chromatography for measuring content is 99.6%, and productive rate is 9.0%.
Embodiment 8
In 100mL two mouthfuls of flasks that thermometer, hydrogen balloon are housed, add water 30mL, to methoxv mandelic acid 1.0g (5.5mmol), palladium carbon 0.1g, perchloric acid 1.0mL, magnetic agitation, and system is sealed, open hydrogen balloon after system being vacuumized afterwards and lead to hydrogen, stirring reaction 10.0h at 60 DEG C, system is filtered, concentrating under reduced pressure, then adds acetic acid ethyl dissolution, and washes twice with water, separate ethyl acetate layer concentrating under reduced pressure again, obtain white crystal with water cooling crystallization afterwards, liquid chromatography for measuring content is 99.6%, and productive rate is 5.3%.
Embodiment 9
Thermometer is being housed, in 100mL two mouthfuls of flasks of hydrogen balloon, add acetic acid 30mL, to methoxv mandelic acid 1.0g (5.5mmol), Raney's nickel 0.1g, hydrochloric acid 1.0mL, magnetic agitation, and system is sealed, open hydrogen balloon after system being vacuumized afterwards and lead to hydrogen, stirring reaction 3.0h at 60 DEG C, system is filtered, concentrating under reduced pressure, then add acetic acid ethyl dissolution concentrate after system, and wash twice with water, separate ethyl acetate layer concentrating under reduced pressure again, use sherwood oil afterwards: ethyl acetate is that the mixed solvent crystallisation by cooling of 5:1 obtains white crystal, liquid chromatography for measuring content is 96.8%, productive rate is 96.6%.
Embodiment 10
Thermometer is being housed, in 100mL two mouthfuls of flasks of hydrogen balloon, add acetic acid 30mL, to methoxv mandelic acid 1.0g (5.5mmol), Raney's nickel 0.1g, hydrochloric acid 1.0mL, magnetic agitation, and system is sealed, open hydrogen balloon after system being vacuumized afterwards and lead to hydrogen, stirring reaction 3.0h at 60 DEG C, system is filtered, concentrating under reduced pressure, then add acetic acid ethyl dissolution concentrate after system, and wash twice with water, separate ethyl acetate layer concentrating under reduced pressure again, white crystal is obtained afterwards with the mixed solvent crystallisation by cooling that Virahol and sherwood oil are 1:6, liquid chromatography for measuring content is 95.7%, productive rate is 96.8%.
Claims (9)
1. by preparing a homoanisic acid method to methoxv mandelic acid hydrogenation reduction, it is characterized in that, reaction system comprises:
Solvent, the unitary alkanoic acid that it is selected from water, carbon number is 1-6 and their mixture;
To methoxv mandelic acid;
Hydrogen source;
Hydrogenating reduction catalyzer; And
Mineral acid.
2. prepare homoanisic acid method as claimed in claim 1, wherein
Described solvent is selected from water, propionic acid, acetic acid and formic acid;
Described hydrogen source is selected from hydrogen, ammonium formiate and hydrazine hydrate;
Described catalyzer is selected from Raney's nickel, palladium charcoal, platinum charcoal and platinum dioxide; And
Described mineral acid is selected from hydrochloric acid, perchloric acid, Hydrogen bromide, hydroiodic acid HI, phosphoric acid and sulfuric acid.
3. prepare homoanisic acid method as claimed in claim 1, wherein
Described solvent is acetic acid;
Described hydrogen source is hydrogen;
Described catalyzer is Raney's nickel; And
Described mineral acid is hydrochloric acid.
4. as described in any one of claim 1-3, prepare homoanisic acid method, wherein said catalyzer charging capacity is the 5-15% to methoxv mandelic acid quality.
5. as described in any one of claim 1-3, prepare homoanisic acid method, wherein said mineral acid charging capacity is to the 0.5-2 of methoxv mandelic acid molar weight doubly.
6. as described in any one of claim 1-3, prepare homoanisic acid method, wherein said hydrogenation reduction temperature is 40-60 DEG C.
7. as described in any one of claim 1-3, prepare homoanisic acid method, the separation of homoanisic acid is carried out after wherein said hydrogenation reduction terminates, comprise: reacting liquid filtering, concentrated, crystallization, obtain the homoanisic acid crystal of white.
8. according to claim 7ly prepare homoanisic acid method, wherein, at described concentrated rear material after acetic acid ethyl dissolution, water washing and secondary concentration, carry out described crystallization again, and described crystallization refers to utilizing water, sherwood oil and ethyl acetate mixed solvent or Virahol and sherwood oil mixed solvent to carry out crystallization.
9. according to claim 8ly prepare homoanisic acid method, wherein, described crystallization solvent is water.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5857334A (en) * | 1981-09-30 | 1983-04-05 | Nippon Synthetic Chem Ind Co Ltd:The | Production of hydroxyphenylacetic acid |
| CN101298416A (en) * | 2008-06-10 | 2008-11-05 | 中国科学院广州化学研究所 | Method for preparing p-methoxypheny-lethyl acid from natural anethole |
| CN103450009A (en) * | 2013-09-02 | 2013-12-18 | 江苏宝众宝达药业有限公司 | Preparation method of para-hydroxyl phenylacetic acid |
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2015
- 2015-03-13 CN CN201510111704.0A patent/CN104817451B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5857334A (en) * | 1981-09-30 | 1983-04-05 | Nippon Synthetic Chem Ind Co Ltd:The | Production of hydroxyphenylacetic acid |
| CN101298416A (en) * | 2008-06-10 | 2008-11-05 | 中国科学院广州化学研究所 | Method for preparing p-methoxypheny-lethyl acid from natural anethole |
| CN103450009A (en) * | 2013-09-02 | 2013-12-18 | 江苏宝众宝达药业有限公司 | Preparation method of para-hydroxyl phenylacetic acid |
Non-Patent Citations (1)
| Title |
|---|
| 丁雪艳: "值得开发的医药中间体对羟基苯乙酸", 《化工中间体》 * |
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