CN102010325A - Method for synthesizing p-hydroxyphenylacetic acid - Google Patents
Method for synthesizing p-hydroxyphenylacetic acid Download PDFInfo
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- CN102010325A CN102010325A CN2010105538332A CN201010553833A CN102010325A CN 102010325 A CN102010325 A CN 102010325A CN 2010105538332 A CN2010105538332 A CN 2010105538332A CN 201010553833 A CN201010553833 A CN 201010553833A CN 102010325 A CN102010325 A CN 102010325A
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Abstract
The invention discloses a method for synthesizing p-hydroxyphenylacetic acid by reducing p-hydroxymandelic acid, which is characterized by comprising the following steps of: reducing the sodium p-hydroxymandelate by using sodium borohydride or potassium borohydride as a reducing agent at the temperature of between 60 and 120 DEG C in alkaline solution to generate p-hydroxyphenylacetate; and acidifying, cooling, crystallizing and separating to obtain the product of p-hydroxymandelic acid. The synthetic reaction is carried out at normal temperature and normal pressure, the content of the p-hydroxymandelic acid product is 98.7 percent, and the total yield is 95.7 percent. The method is high in utilization rate of raw materials and suitable for mass production.
Description
Technical field
The present invention relates to a kind of synthetic method of p-hydroxyphenylaceticacid, particularly, belong to field of medicine and chemical technology with the method for the synthetic p-hydroxyphenylaceticacid of borohydride reduction parahydroxymandelic acid.
Background technology
P-hydroxyphenylaceticacid (4-Hydroxyphenyl acetic acid), molecular formula C
8H
8O
3, molecular weight 152.2 is generally white to faint yellow needle crystal, and fusing point 151-153 ℃, can distil, be soluble in hot water, ethanol, ether and ethyl acetate equal solvent, dissolve in cold water.P-hydroxyphenylaceticacid can be used as medicine and pesticide intermediate, particularly is used for the production of antihypertensive drug atenolol USP 23 in a large number.Can produce phydroxybenzeneactamide with its ammonification, etherificate can be produced homoanisic acid, and esterification can be produced p-hydroxyphenylaceticacid first vinegar, and reduction can be produced p-hydroxyphenylethanol, and these derivatives of p-hydroxyphenylaceticacid are mainly used in field of medicaments.
Once " meticulous and specialty chemicals " 2000, the 5th phase, the 18-19 page or leaf described the p-hydroxyphenylaceticacid production method in detail to the contriver.Early stage synthetic general equal amido phenenyl acid diazotization, the hydrolysis route of adopting produced, promptly earlier equal amido phenenyl acid is dissolved in alkaline solution and makes sodium salt, add people's sulfuric acid again, drip sodium nitrite solution at low temperatures, finish afterreaction half an hour, the diazonium drop of gained be added to hydrolysis in the dilute sulphuric acid of heat, hydrolysis reaction finish liquid through decolouring, filter, extract with acetic acid ethyl ester after the cooling, reclaim solvent and get finished product, yield about 85%.The also available para hydroxybenzene second of p-hydroxyphenylaceticacid cyanogen hydrolysis preparation, be about to para hydroxybenzene second cyanogen, sulfuric acid and water and mix, the reflux hydrolysis is in the hydrolyzed solution frozen water of falling people with gained, crystallization, filtration, washing, solvent extraction, recrystallization get product, yield about 92%.Above two lines progressively lose the market competitiveness on raw material sources, cost of material, quality product and production cost.The nineties in last century, main both at home and abroad phenol and the synthetic parahydroxymandelic acid of oxoethanoic acid of adopting restores the operational path that dehydroxylation is produced p-hydroxyphenylaceticacid, and chemical equation is as follows:
English Patent GB2034308 (1979-10-29) has disclosed the parahydroxymandelic acid synthetic method in detail, and synthesis yield is more stable, and p-hydroxyphenylaceticacid synthetic key problem in technology is a parahydroxymandelic acid reduction reaction technology.Day disclosure special permission communique JP58057334 (1983-04-05) discloses and adopts catalytic hydrogenation method; U.S. Pat 4590295 (1986-05-20) discloses and adopts hydroiodic acid HI is that reductive agent carries out the reductive method; U.S. Pat 4393235 (1983-07-12) discloses and adopts tin protochloride is that reductive agent carries out the reductive method; U.S. Pat 4198526 (1980-08-15) discloses and adopts chromium chloride and zinc powder is that reductive agent carries out the reductive method; " Hebei industrial technology " 2005, the 5th phase, 264-266 page or leaf report adopts phosphorous acid to carry out the reductive method; " chemistry world " 2007, the 6th phase, 360-361 page or leaf report adopts Sodium Pyrosulfite to carry out the reductive method.Though report adopts these method p-hydroxyphenylaceticacid synthesis yields up to 75%-95% in the document, because these experiment conditions are not suitable for producing in enormous quantities, general hydrogenation method and the phosphorous acid reduction method of adopting in the industrial production, big and the catalyzer costliness of hydrogenation method facility investment, phosphorous acid reduction method actual recovery is 30%-50% only.
Continuous increase along with p-hydroxyphenylaceticacid domestic market demand amount, product market price keeps falling, raw material parahydroxymandelic acid production cost is than higher, and existing method production economic benefit is not high, need adopt an effective measure and improve the reduction process yield to improve the production economic benefit.
Summary of the invention
The purpose of this invention is to provide a kind of method that is fit to low-cost synthetic p-hydroxyphenylaceticacid in enormous quantities, solve prior art and when industrial application, produces the low problem with unstable product quality of yield.
Hydroborate has very strong reductibility, and along with the continuous expansion of its Application Areas, price declines to a great extent, the synthetic application that moves towards the industrialization from the laboratory.On the basis that studies for a long period of time, to have invented with the synthetic p-hydroxyphenylaceticacid method of borohydride reduction parahydroxymandelic acid sodium, the technical scheme of taking is:
Raw material parahydroxymandelic acid sodium is synthetic by oxoethanoic acid, phenol and the sodium hydroxide reference literature reaction conditions chamber of experimentizing, after finishing, reaction uses the unreacted phenol of toluene extracting and separating, the water of raffinate is through vacuum concentration, cooling, crystallization, separation, washing, drying, obtain a water parahydroxymandelic acid sodium white powder, also drying not, analyzing directly feeds intake behind the content carries out reduction reaction.
The reduction reaction of parahydroxymandelic acid sodium is carried out in basic solution, and the reductive agent of employing is lithium borohydride, sodium borohydride or POTASSIUM BOROHYDRIDE, and the reduction reaction procedural representation is as follows:
Parahydroxymandelic acid sodium is reduced and generates p-hydroxyphenylaceticacid sodium, and sodium borohydride is oxidized to sodium metaborate, and the hydrolytic side reactions releasing hydrogen gas takes place simultaneously.Reaction also can be adopted its carbonate with preferred 0.5-2.0mol/L sodium hydroxide of basic solution or potassium hydroxide solution.The mol ratio of parahydroxymandelic acid sodium and hydroborate was 1 when reaction fed intake: 0.25-0.5, because there is hydrolytic side reactions in hydroborate in basic solution, its charging capacity should be greater than theoretical charging capacity.Transition metal impurities such as iron, cobalt, nickel quicken the borohydride hydrolytic side reaction, should control this class foreign matter content in the solution.Improve temperature of reaction and can quicken the reduction reaction of parahydroxymandelic acid sodium, quickened the borohydride hydrolytic side reaction simultaneously, reduction reaction temperature is 60-120 ℃, preferably reacts under reflux temperature.Reduzate is dissolved in the alkaline solution with the p-hydroxyphenylaceticacid salt form, can select mineral acid acidifyings such as hydrochloric acid, sulfuric acid, phosphoric acid that it is dissociated out.For preventing that inorganic salts is separated out in the product separation process, preferably use the dilute hydrochloric acid acidifying, adjust reaction solution pH2-3, make p-hydroxyphenylaceticacid dissociate out fully.Adopt the crystallisation by cooling method to separate the p-hydroxyphenylaceticacid product, preferably reaction solution is cooled to 5-10 ℃, most of product crystallization is separated out.Adopt vacuum filtration or centrifugation to separate the crystallization of separating out, obtain p-hydroxyphenylaceticacid with cold water washing, drying.Because p-hydroxyphenylaceticacid dissolves in cold water,, mother liquor at 60-90 ℃ of following vacuum concentration, is cooled off crystallization, the recyclable again a part of p-hydroxyphenylaceticacid of drying for improving separation yield.
The parahydroxymandelic acid assay adopts liquid phase chromatography among the present invention, selects Tianjin, island LC-10 high performance liquid chromatograph for use.Chromatographic column: the C18 post (4.6mm * 250mm); Moving phase: methyl alcohol: water: phosphoric acid=1: 3: 0.03 (volume ratio); Flow velocity: 1.0mL/min; Detect wavelength: 230nm; Column temperature: room temperature.The p-hydroxyphenylaceticacid assay adopts liquid phase chromatography, chromatographic column: and the C18 post (4.6mm * 250mm); Moving phase: methyl alcohol: glacial acetic acid: water=2: 1: 2 (volume ratio); Flow velocity: 1.0mL/min; Detect wavelength: 254nm; Column temperature: room temperature.
Advantage of the present invention and beneficial effect are embodied in: the reaction of making the synthetic p-hydroxyphenylaceticacid of reductive agent with hydroborate is carried out at normal temperatures and pressures, and equipment is simple, and the raw material availability height is fit to produce in enormous quantities.
Embodiment
The present invention realizes in the following ways, describes in detail below in conjunction with embodiment:
Embodiment 1
In the 1000mL four-hole boiling flask that mechanical stirrer, thermometer, two dropping funnels and reflux condensing tube are housed, add deionized water 500mL and 30% liquid caustic soda 53.3g (0.4mol), in two dropping funnels, add 40% glyoxylic acid solution 74.1g (0.4mol) and 30% liquid caustic soda 53.3g (0.4mol) respectively.Under agitation in reactor, add phenol 45.1g (0.48mol) in batches, added in about 15 minutes, obtain light red sodium phenylate solution.In reactor, drip glyoxylic acid solution and liquid caustic soda simultaneously, keep temperature of reaction, added in about 3 hours, continue stirring reaction and extremely almost do not have till the remaining oxoethanoic acid in 4 hours at 40-45 ℃.Reaction finish the back with 10% hydrochloric acid acidizing reaction liquid to pH4, make unreacted phenol dissociate out, divide three extractions with 200mL toluene, distill recovery toluene and phenol and recycle.With the water vacuum concentration of raffinate to the 360mL, cooling, crystallization, separation, saturated nacl aqueous solution washing, 110 ℃ of dryings, a water parahydroxymandelic acid sodium white powder 69.3g, liquid chromatography for measuring content 96.1%.
Embodiment 2
Mechanical stirrer is being housed, add 1mol/L sodium hydroxide solution 200mL in the 500mL four-hole boiling flask reactor of thermometer and reflux condensing tube, the parahydroxymandelic acid sodium 43.2g (0.2mol) that adds the preparation of embodiment 1 method, be heated to 60 ℃ with water-bath, under agitation add sodium borohydride reagent 3.8g (0.1mol) in batches, 90 ℃ were reacted 2-3 hour down, after finishing, reduction reaction adjusts reaction solution to pH2-3 with 10% hydrochloric acid soln, be cooled to 5 ℃ with frozen water, crystallization, vacuum filtration, cold water washing, drying obtains p-hydroxyphenylaceticacid 25.7g, liquid chromatography for measuring content 99.1%.Mother liquor is through vacuum concentration, cooling, crystallization, the drying p-hydroxyphenylaceticacid 3.7g that gets back, liquid chromatography for measuring content 98.4%, total recovery 95.7%.
Embodiment 3
Mechanical stirrer is being housed, add 1mol/L sodium hydroxide solution 200mL in the 500mL four-hole boiling flask reactor of thermometer and reflux condensing tube, the parahydroxymandelic acid sodium 43.2g (0.2mol) that adds the preparation of embodiment 1 method, be heated to 60 ℃ with water-bath, under agitation add POTASSIUM BOROHYDRIDE reagent 4.0g (0.075mol) in batches, back flow reaction 2-3 hour, after finishing, reaction adjusts reaction solution to pH2-3 with 10% hydrochloric acid soln, be cooled to 10 ℃ with frozen water, crystallization, vacuum filtration, cold water washing, drying obtains p-hydroxyphenylaceticacid 25.0g, liquid chromatography for measuring content 98.7%.Mother liquor is through vacuum concentration, cooling, crystallization, the drying p-hydroxyphenylaceticacid 4.5g that gets back, liquid chromatography for measuring content 98.1%, yield 95.7%.
Claims (6)
1. one kind with the synthetic p-hydroxyphenylaceticacid method of parahydroxymandelic acid reduction, it is characterized in that making reductive agent with hydroborate reduces parahydroxymandelic acid sodium and generate p-hydroxyphenylaceticacid salt in basic solution, obtain the p-hydroxyphenylaceticacid product through acidifying, cooling, crystallization, separation again.
2. according to the described method of claim 1, it is characterized in that the hydroborate that adopts is sodium borohydride or POTASSIUM BOROHYDRIDE.
3. according to the described method of claim 1, it is characterized in that basic solution is 0.5-2.0mol/L sodium hydroxide or potassium hydroxide solution.
4. according to the described method of claim 1, it is characterized in that reacting that the mol ratio of parahydroxymandelic acid sodium and hydroborate is 1 when feeding intake: 0.25-0.5.
5. according to the described method of claim 1, it is characterized in that reduction reaction temperature is 60-120 ℃.
6. according to the described method of claim 1, it is characterized in that adjusting reaction solution pH2-3 with acid solution after reaction is finished, make p-hydroxyphenylaceticacid dissociate out fully.
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| CN2010105538332A CN102010325A (en) | 2010-11-22 | 2010-11-22 | Method for synthesizing p-hydroxyphenylacetic acid |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105777569A (en) * | 2016-05-03 | 2016-07-20 | 芜湖宝瓶智能化服务外包有限公司 | Production method of p-hydroxyphenylacetamide |
| CN110483274A (en) * | 2019-08-26 | 2019-11-22 | 山东绅联生物科技有限公司 | A kind of preparation method of cyclopentolate hydrochloride intermediate |
| CN108047033B (en) * | 2017-12-20 | 2023-12-01 | 江西科苑生物药业有限公司 | Reaction device and method for preparing mandelic acid compound |
-
2010
- 2010-11-22 CN CN2010105538332A patent/CN102010325A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105777569A (en) * | 2016-05-03 | 2016-07-20 | 芜湖宝瓶智能化服务外包有限公司 | Production method of p-hydroxyphenylacetamide |
| CN108047033B (en) * | 2017-12-20 | 2023-12-01 | 江西科苑生物药业有限公司 | Reaction device and method for preparing mandelic acid compound |
| CN110483274A (en) * | 2019-08-26 | 2019-11-22 | 山东绅联生物科技有限公司 | A kind of preparation method of cyclopentolate hydrochloride intermediate |
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Application publication date: 20110413 |