CN107417509A - A kind of preparation method of phenylacetic acid compound - Google Patents
A kind of preparation method of phenylacetic acid compound Download PDFInfo
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- CN107417509A CN107417509A CN201710374434.1A CN201710374434A CN107417509A CN 107417509 A CN107417509 A CN 107417509A CN 201710374434 A CN201710374434 A CN 201710374434A CN 107417509 A CN107417509 A CN 107417509A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/093—Preparation of carboxylic acids or their salts, halides or anhydrides by hydrolysis of —CX3 groups, X being halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
- C07C17/272—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by addition reactions
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Abstract
The present invention relates to the field of chemical synthesis, more particularly to a kind of preparation method of phenylacetic acid compound.The present invention provides a kind of preparation method of phenylacetic acid compound, and shown in formula I, the preparation method comprises the following steps the structural formula of the phenylacetic acid compound：（1）Diazotising addition reaction：Formula II compound is reacted into production III compounds in the system containing vinylidene chloride, acid, diazo reagent, phase transfer catalyst and Cu-series catalyst：（2）Hydrolysis：Formula III compound is hydrolyzed to generation compound of formula I under the conditions of existing for acid.Preparation method raw material provided by the present invention is simple and easy to get, easy to operate, cost of material is low, reaction condition is gentle, danger is low, without using the high noble metal catalyst of price and complicated industrial operation means, product quality is stable, therefore is suitable for and realizes large-scale industrial production.
Description
Technical field
The present invention relates to the field of chemical synthesis, more particularly to a kind of preparation method of phenylacetic acid compound.
Background technology
Phenylacetic acid compound has been widely used in the fields such as medicine, agricultural chemicals, electronic material tool.For example, 4-Chlorophenylacetic acid
Intermediate available for production penicillin；O-chlorobenzene acetic acid can be as the raw material of synthesizing efficient analgesics anti-inflammatory diclofenac sodium；2,
4- fenacs can be used as synthetic acaricide Envidor；4- bromo-acids can be used for synthesis one kind to be related to T- type calcium for treatment
The medicine of passage disorder disease.
The synthetic method of phenylacetic acid compound has sodium cyanide method, phenyl acetamide method and oxo synthesis.Sodium cyanide method is with first
Base is raw material, and benzyl chloride is generated through chlorination, then generates benzene acetonitrile with Cymag cyaniding benzyl chloride, most obtains phenylacetic acid through hydrolysis afterwards.
Shortcoming is that benzyl chloride and Cymag reaction yield be not high, and Cymag severe toxicity, and cyanide wastewater pollution environment is serious and caused
Benzene acetonitrile is also toxic pollution environment, and the free cyanide of severe toxicity in phenylacetic acid be present, and hidden danger is brought for later use.Benzene second
Amide hydrolysis method is using styrene as raw material, through generating phenyl acetamide with ammoniacal liquor sulfur reaction, then hydrolyzes generation phenylacetic acid.The party
Accessory substance 2- benzene ethyl mercaptan taste cacosmia in method, environment is polluted, and reaction needs to pressurize, and industrial operation is cumbersome.Oxo synthesis
It is under carbonylating catalyst and phase transfer catalyst effect, is carbonylated by benzyl chloride in alkali and organic solvent two-phase system
Reaction, phenylacetate is generated, is then acidified into phenylacetic acid.This method is carbonylation catalyst using expensive transient metal complex
Agent, cost are big compared with high and technology difficulty, catalyst inactivation or loss easily occur, therefore be not suitable for stable industrialized production.
The content of the invention
In view of the above the shortcomings that prior art, present invention aims at provide a kind of new to prepare phenylacetic acid class chemical combination
The preparation method of thing, to solve, existing preparation method complex operation, production cost are high, environmental pollution is serious, potential safety hazard be present
The defects of etc. industrialized production is unfavorable for.
In order to achieve the above objects and other related objects, the present invention provides a kind of preparation method of phenylacetic acid compound, institute
State that preparation method technological operation is easy, cost of material is low, high conversion rate, environmentally friendly and be more suitable for industrializing safe life
Production, the structural formula of the phenylacetic acid compound is shown in formula I：
Wherein, R1、R2、R3、R4、R5It is each independently selected from F, Cl, Br ,-CH3、-C2H5、-C3H7、-CF3Or H, and it is different
When be H；Work as R1、R2、R3、R4、R5When middle one or more is F, remaining not all H；
The preparation method comprises the following steps：
(1) diazotising addition reaction：Formula II compound is being contained into vinylidene chloride, acid, diazo reagent, phase transfer catalysis (PTC)
Production III compounds are reacted in the dicyandiamide solution of agent and Cu-series catalyst, reaction equation is as follows：
(2) hydrolysis：Formula III compound is hydrolyzed to generation compound of formula I, reaction equation under the conditions of existing for acid
It is as follows：
In some embodiments of the invention, R1~R5Middle any two independence is selected from Cl, Br ,-CH3、-CF3, remaining
It is each independently selected from H or F.
In some embodiments of the invention, the compound of formula I is selected from 3,4- fenacs, 2,4- dichloro-benzenes second
Acid, 2,6- fenacs, 3,5- dimethyl phenyl acetic acids, the fluoro- 6- methylphenyl acetic acids of the bromo- 4- of 3-.
In some embodiments of the invention, R1~R5In any one be selected from Cl, Br ,-CH3、-CF3, remaining is H.
In some embodiments of the invention, the compound of formula I is selected from o-chlorobenzene acetic acid, 3- chlorobenzene acetic acids, 4- chlorobenzenes
Acetic acid, bromophenyl acetic acid, 3- bromo-acids, 4- bromo-acids, 2- methylphenyl acetic acids, 3- methylphenyl acetic acids, 4- methylphenyl acetic acids,
3- trifluoromethyl phenylacetic acids, 4- trifluoromethyl phenylacetic acids.
In some embodiments of the invention, R3Selected from Cl, Br ,-CH3、-CF3, remaining is H.
In some embodiments of the invention, the compound of formula I is selected from 4- chlorobenzene acetic acids, 4- bromo-acids, 4- methyl
Phenylacetic acid, 4- trifluoromethyl phenylacetic acids.
In some embodiments of the invention, in the step (1), reaction is carried out in the presence of a solvent, described
Solvent is water and/or organic solvent.
In some embodiments of the invention, in the step (1), the solvent is the combination of water and organic solvent, its
The weight ratio of middle organic solvent and water is no more than 2.
In some embodiments of the invention, in the step (1), the solvent is the combination of water and organic solvent, its
The weight ratio of middle organic solvent and water is 0.2~1.5：1.
In some embodiments of the invention, in the step (1), the mass ratio of solvent and Formula II compound is 1~10:
1。
In some embodiments of the invention, in the step (1), the mass ratio of solvent and Formula II compound is 1~5:
1。
In some embodiments of the invention, in the step (1), the organic solvent is selected from dichloromethane, three chloromethanes
Alkane, 1,2- dichloroethanes, tetrahydrofuran, toluene, benzotrifluoride, p-chloro benzo trifluoride-99, the one or more in acetone and acetonitrile
Combination.
In some embodiments of the invention, in the step (1), the acid is selected from HCl and/or sulfuric acid.
In some embodiments of the invention, in the step (1), the acid is 1~3 with Formula II compound mole ratio：
1。
In some of the invention embodiments, in the step (1), the acid and Formula II compound mole ratio be 1.1~
1.5：1.
In some of the invention embodiments, in the step (1), the diazo reagent be selected from nitrite and/or
Nitrous acid ester.
In some embodiments of the invention, in the step (1), the nitrite is selected from nitrite sodium.
In some of the invention embodiments, in the step (1), the nitrous acid ester be selected from nitrite tert-butyl and/
Or Isopropyl Nitrite.
In some embodiments of the invention, in the step (1), the diazo reagent and mole of Formula II compound
Than for 1~10:1.
In some embodiments of the invention, in the step (1), the diazo reagent and mole of Formula II compound
Than for 1.1~1.5:1.
In some of the invention embodiments, in the step (1), the Cu-series catalyst is selected from mantoquita and/or copper
Oxide.
In some embodiments of the invention, in the step (1), the mantoquita is selected from copper acetate, basic copper carbonate, chlorine
Change one or more combinations in copper, stannous chloride, copper bromide, cuprous bromide.
In some embodiments of the invention, in the step (1), the oxide of the copper is selected from cupric oxide, oxidation Asia
One or more combinations in copper.
In some embodiments of the invention, in the step (1), the Cu-series catalyst and mole of Formula II compound
Than for 0.01~0.1:1.
In some embodiments of the invention, in the step (1), the phase transfer catalyst is selected from tetrabutyl chlorination
In ammonium, TBAB, tetrabutylammonium iodide, tetramethyl ammonium chloride, methyl tricapryl ammonium chloride, TBAH
One or more combinations.
In some embodiments of the invention, in the step (1), the phase transfer catalyst rubs with Formula II compound
You are than being 0.01~0.1:1.
In some embodiments of the invention, in the step (1), the vinylidene chloride and Formula II compound mole ratio
For 1~5：1.
In some embodiments of the invention, in the step (1), the vinylidene chloride and Formula II compound mole ratio
For 1~2：1.
In some embodiments of the invention, in the step (1), reaction temperature is -20 DEG C~30 DEG C.
In some embodiments of the invention, in the step (1), reaction temperature is -15 DEG C~15 DEG C.
In some embodiments of the invention, in the step (1), extract go out excessive nitrite, You Jirong after the completion of reaction
Agent extraction, organic phase precipitation produce formula III compound.
In some embodiments of the invention, in the step (2), reaction is carried out in the presence of a solvent, described
Solvent is selected from water and/or organic solvent.
In some embodiments of the invention, in the step (2), the solvent is selected from the combination of water and organic solvent,
The weight of organic solvent and water ratio is no more than 2.
In some embodiments of the invention, in the step (2), the solvent is selected from the combination of water and organic solvent,
The weight of organic solvent and water ratio is 0.2~1.5：1.
In some embodiments of the invention, in the step (2), the organic solvent is selected from dichloromethane, three chloromethanes
Alkane, 1,2- dichloroethanes, tetrahydrofuran, toluene, benzotrifluoride, one or more combinations in p-chloro benzo trifluoride-99.
In some of the invention embodiments, in the step (2), the mass ratio of solvent and formula III compound for 1~
10:1。
In some embodiments of the invention, in the step (2), the mass ratio of solvent and formula III compound is 2~5:
1。
In some embodiments of the invention, in the step (2), the acid is selected from Bronsted acid and/or lewis acid.
In some embodiments of the invention, in the step (2), the Bronsted acid is selected from hydrochloric acid, hydrobromic acid, hydrogen iodine
Acid, sulfuric acid, oleum, nitric acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-methyl benzenesulfonic acid, formic acid, acetic acid.
In some embodiments of the invention, in the step (2), the lewis acid is selected from AlCl3、FeCl3、
ZnCl2、TiCl4、SnCl4、CoCl2、NiCl2、MnCl2, MnO, copper acetate, cupric oxide, cuprous oxide, copper chloride, stannous chloride,
One or more combinations in copper bromide, cuprous bromide.
In some embodiments of the invention, in the step (2), the acid and the mass ratio of formula III compound are
0.05~5:1.
In some embodiments of the invention, in the step (2), the mass ratio of the acid and formula III compound is 0.1
~2:1.
In some embodiments of the invention, in the step (2), reaction temperature is 20 DEG C~160 DEG C.
In some embodiments of the invention, in the step (2), reaction temperature is 60 DEG C~120 DEG C.
In some embodiments of the invention, in the step (2), react and carried out under conditions of gas shield, gas
Protection uses gas to be selected from nitrogen and/or inert gas.
In some embodiments of the invention, in the step (2), after the completion of reaction plus water extraction is gone out, separation of solid and liquid, solid phase
Thing produces compound of formula I after purification.
In some embodiments of the invention, in the step (2), the mode of purifying is recrystallization.
In some embodiments of the invention, in the step (2), solvent used in recrystallization is selected from toluene, dichloro
One or more in methane, chloroform, 1,2- dichloroethanes, tetrahydrofuran, toluene, benzotrifluoride, p-chloro benzo trifluoride-99
Combination.
Embodiment
Inventor is by largely exploring and studying, there is provided a kind of preparation side of new phenylacetic acid compound
Method, the preparation method have raw material is simple and easy to get, easy to operate, cost of material is low, reaction condition is gentle, danger is low, production
The features such as quality is stable, it is adapted to industrialization large-scale production, completes the present invention on this basis.
One aspect of the present invention provides a kind of preparation method of phenylacetic acid compound, and the structural formula of the phenylacetic acid compound is such as
Shown in Formulas I：
Wherein, R1、R2、R3、R4、R5It is each independently selected from F, Cl, Br ,-CH3、-C2H5、-C3H7、-CF3Or H, and it is different
When be H；Work as R1、R2、R3、R4、R5When middle one or more is F, remaining not all H.
In the present invention, in the compound of formula I, R1~R5In Cl, Br ,-CH can be selected from any two independence3、-
CF3, remaining is each independently selected from H or F, specifically for example, the compound of formula I can be 3,4- fenacs, 2,4- bis-
Fluoro- 6- methylphenyl acetic acids of chlorobenzene acetic acid, 2,6- fenacs, 3,5- dimethyl phenyl acetic acids, the bromo- 4- of 3- etc..
In the present invention, in the compound of formula I, R1~R5In Cl, Br ,-CH can be selected from any one3、-CF3, remaining
For H, it is specific for example, the compound of formula I can be o-chlorobenzene acetic acid, 3- chlorobenzene acetic acids, 4- chlorobenzene acetic acids, bromophenyl acetic acid,
3- bromo-acids, 4- bromo-acids, 2- methylphenyl acetic acids, 3- methylphenyl acetic acids, 4- methylphenyl acetic acids, 3- trifluoromethylbenzene second
Acid, 4- trifluoromethyl phenylacetic acids etc..
In the present invention, in the compound of formula I, R3Can be Cl, Br ,-CH3、-CF3, remaining is H, specifically for example, described
Compound of formula I can be 4- chlorobenzene acetic acids, 4- bromo-acids, 4- methylphenyl acetic acids, 4- trifluoromethyl phenylacetic acids etc..
The preparation method of phenylacetic acid compound provided by the present invention can include diazonium addition reaction, and the diazotising adds
The diazol for be often referred to primary aromatic amine generation diazo-reaction generation diazol into reaction, being generated further derives with alkene
Thing carries out the addition reaction of addition.The diazotising addition reaction specifically includes：By Formula II compound (Fluoroaniline) containing
Vinylidene chloride, acid, diazo reagent, phase transfer catalyst and Cu-series catalyst system in react production III compound (fluorine
For phenyl trichloroethanes), reaction equation is as follows：
In the diazotising addition reaction, reaction can be carried out in the presence of a solvent, and those skilled in the art can
Species and the usage amount of suitable solvent are selected to cause reaction raw materials that there is good dissolubility in reaction system, for example,
The solvent can be water and/or organic solvent, for another example solvent and the mass ratio of Formula II compound can be 1~10:1,
Can be 1~5:1.Water is generally included in the solvent, organic solvent can also be further comprised, so that reaction dissolvent phase
There is more preferably dispersibility and dissolubility for reaction raw materials.The kind of suitable organic solvent may be selected in those skilled in the art
Class and usage amount are to cause reaction raw materials to have good dissolubility in reaction system, for example, the organic solvent can be
Including but not limited to dichloromethane, chloroform, 1,2- dichloroethanes, tetrahydrofuran, toluene, benzotrifluoride, to chlorine fluoroform
One or more combinations in benzene, acetone and acetonitrile etc., for another example the solvent includes water and organic solvent, organic solvent
Weight ratio with water is no more than 2, and the weight ratio of preferable organic solvent and water is 0.2~1.5：1.
In the diazotising addition reaction, those skilled in the art may be selected the species of suitable acid and dosage be used for again
Diazotizing reagent is had an effect, for example, can be with being that nitrite and/or nitrous acid ester are acted on so as to form nitrous acid, for example,
Used acid can be including but not limited to HCl, sulfuric acid etc..The sour usage amount relative to Formula II compound be typically etc.
Amount or excess, for example, it is described acid with Formula II compound mole ratio can be 1~3：1, or 1.1~1.5：1.Acid
When in use, can be generally added into the form of its aqueous solution in reaction system, such as HCl can be in the form of hydrochloric acid, sulphur
Acid can be in the form of its aqueous solution, mass concentration typically 10%-40%.
In the diazotising addition reaction, the species and dosage of suitable diazo reagent may be selected in those skilled in the art
For being had an effect with acid, for example, used diazo reagent can be nitrite and/or nitrous acid ester etc., preferably may be used
To be nitrite；The nitrite can be that including but not limited to nitrite sodium etc., the nitrous acid ester can be bags
Include but be not limited to nitrite tert-butyl, one or more of combinations in Isopropyl Nitrite etc.；The diazo reagent makes
Dosage is typically equivalent or excess relative to Formula II compound, for example, the diazo reagent and Formula II compound are rubbed
Your ratio can be 1~10:1, or 1.1~1.5:1.
In the diazotising addition reaction, the species and dosage of suitable Cu-series catalyst may be selected in those skilled in the art
For diazotising addition reaction, for example, the Cu-series catalyst can be selected from the oxide of mantoquita and/or copper, the mantoquita can
Be one kind including but not limited in copper acetate, basic copper carbonate, copper chloride, stannous chloride, copper bromide, cuprous bromide etc. or
A variety of combinations, preferable mantoquita are one or more combinations in basic copper carbonate, stannous chloride, cuprous bromide etc., more
Preferable mantoquita is basic copper carbonate；The oxide of the copper can be including but not limited in cupric oxide, cuprous oxide etc.
One or more combinations；The usage amount of the Cu-series catalyst is typically catalytic amount, for example, the Cu-series catalyst and formula
The mol ratio of II compounds can be 0.01~0.1:1.
In the diazotising addition reaction, the species and use of suitable phase transfer catalyst may be selected in those skilled in the art
Measure and be used for diazotising addition reaction.For example, the phase transfer catalyst can be including but not limited to tetrabutylammonium chloride, four fourths
One kind in base ammonium bromide, tetrabutylammonium iodide, tetramethyl ammonium chloride, methyl tricapryl ammonium chloride, TBAH etc.
Or a variety of combinations, in an of the invention preferred embodiment, the phase transfer catalyst be preferably selected from tetramethyl ammonium chloride and/
Or methyl tricapryl ammonium chloride；The usage amount of the phase transfer catalyst is typically catalytic amount, for example, the phase transfer catalysis (PTC)
The mol ratio of agent and Formula II compound is 0.01~0.1:1.
In the diazotising addition reaction, the usage amount of vinylidene chloride be commonly angled relative to Formula II compound be equivalent or
Excessive, for example, the vinylidene chloride can be 1~5 with Formula II compound mole ratio：1, or 1~2：1.
In the diazotising addition reaction, typically -20 DEG C~30 DEG C of reaction temperature, or -15 DEG C~15
℃.Those skilled in the art can adjust the reaction time according to reaction process etc., can be with some of the invention embodiments
Judging the reaction process of diazotising addition reaction for example, by gas chromatography, liquid chromatography etc., the reaction time can be 1~
24h。
In the diazotising addition reaction, acid and Formula II compound can be generally added in reaction system (for example, adding
In solvent), phase transfer catalyst and Cu-series catalyst are added, diazo reagent progress is added instead after adding vinylidene chloride
Should.Extraction is gone out after the completion of reaction, and excessive nitrite, organic solvent extract, organic phase precipitation produces formula III compound.Art technology
Personnel may be selected suitable reagent and be gone out excessive nitrite for extraction, such as can be including but not limited to urea, sodium hydrogensulfite,
One or more combinations in sodium sulfite etc..Those skilled in the art may be selected suitable reagent and extract for organic solvent
Take, for example, using dichloromethane, chloroform, 1,2- dichloroethanes, tetrahydrofuran, toluene, benzotrifluoride, to chlorine fluoroform
Benzene, acetone, acetonitrile, ethyl acetate, isopropyl acetate, preferable organic solvent include but is not limited to dichloromethane, chloroform,
One or more combinations in 1,2- dichloroethanes, tetrahydrofuran, toluene, benzotrifluoride, p-chloro benzo trifluoride-99 etc..
The preparation method of phenylacetic acid compound provided by the present invention can also include hydrolysis, the hydrolysis tool
Body includes：Formula III compound is hydrolyzed to generation compound of formula I (phenylacetic acid compound), reactional equation under the conditions of existing for acid
Formula is as follows：
In the hydrolysis, reaction can be carried out in the presence of a solvent, and those skilled in the art may be selected to close
The species and usage amount of suitable solvent make it that reaction is molten to cause reaction raw materials to have good dissolubility in reaction system
Agent has more preferably dispersibility and dissolubility relative to reaction raw materials.For example, the solvent generally comprises water, for another example water
Mass ratio with formula III compound can be 0.5~10:1, or 0.5~5:1.The solvent can also include organic
Species and the usage amount of suitable organic solvent may be selected to cause reaction raw materials in reaction system in solvent, those skilled in the art
In there is good dissolubility, for example, the organic solvent can be including but not limited to dichloromethane, chloroform, 1,2-
Dichloroethanes, tetrahydrofuran, toluene, benzotrifluoride, one or more combinations in p-chloro benzo trifluoride-99, for another example described
Solvent is selected from water and organic solvent, and the weight ratio of organic solvent and water is the weight ratio of preferable organic solvent and water no more than 2
For 0.2~1.5：1.
In the hydrolysis, the species and dosage of suitable acid may be selected in those skilled in the art, can make formula to provide
The condition that III compounds hydrolyze, as a rule, the acid are selected from Bronsted acid (being typically based on cloth Leinster acid-base theory)
And/or lewis acid (being typically based on lewis' theory of acids and bases), the Bronsted acid can be including but not limited to hydrochloric acid, hydrogen bromine
Acid, hydroiodic acid, sulfuric acid, oleum, nitric acid, fuming nitric aicd, methanesulfonic acid, trifluoromethanesulfonic acid, p-methyl benzenesulfonic acid, formic acid, acetic acid,
One or more combinations in acetic anhydride etc., the lewis acid can be including but not limited to AlCl3、FeCl3、ZnCl2、
TiCl4、SnCl4、CoCl2、NiCl2、MnCl2, MnO, copper acetate, cupric oxide, cuprous oxide, copper chloride, stannous chloride, bromination
One or more combinations in copper, cuprous bromide etc..In the embodiment of the invention, the acid is selected from hydrochloric acid, hydrogen
Bromic acid, hydroiodic acid, sulfuric acid, oleum, nitric acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-methyl benzenesulfonic acid, formic acid, acetic acid, AlCl3、
FeCl3、ZnCl2One or more combinations in；The acid be preferably selected from hydrochloric acid, sulfuric acid, oleum, nitric acid, formic acid,
One or more combinations in acetic acid etc., are more preferably selected from sulfuric acid and oleum, and the sulfuric acid is usually the concentrated sulfuric acid, sulfuric acid
Concentration be preferably 80%-98%, the concentration of the oleum is preferably 1%-50%.The acid is with Formula II compound I's
Mass ratio can be 0.05~5:1, or 0.1~2:1.
In the hydrolysis, typically 20 DEG C~160 DEG C of reaction temperature, or 60 DEG C~120 DEG C.Ability
Field technique personnel can adjust the reaction time according to reaction process etc., in some embodiments of the invention, can pass through example
Such as gas chromatography, liquid chromatography judge the reaction process of diazotising addition reaction, and the reaction time can be 1~24h.
In the hydrolysis, reaction is carried out generally under conditions of gas shield, gas used in the gas shield
Body can not generally react with main matter in reaction system (for example, formula III compound, acid, compound of formula I etc.)
Gas, such as can be nitrogen and/or inert gas etc., the inert gas more specifically can be such as helium, neon, argon
Gas, Krypton, xenon etc..
Formula III compound in the hydrolysis, can be generally added portionwise to (for example, be added dropwise) to described sour water-soluble
Being reacted in liquid, the sour aqueous solution can be weak solution or concentrated solution, such as 20-98% aqueous sulfuric acid, 20-36%'s
Aqueous hydrochloric acid solution etc..Cooling is quenched after the completion of reaction, treats separation of solid and liquid, solid formation produces compound of formula I after purification.This area skill
Art personnel may be selected appropriate method and are quenched, for example, it may be plus water extraction go out, then reaction solution can for example be cooled, cooled
Add in frozen water, add 0-10 DEG C of water in reaction solution afterwards after can also cooling.Appropriate parties may be selected in those skilled in the art
Method purifies to compound of formula I, such as can be by the way of recrystallization and/or mashing, institute in recrystallization and/or pulping process
The solvent used can be including but not limited to toluene, dichloromethane, chloroform, 1,2- dichloroethanes, tetrahydrofuran, second
One or more combinations in benzene, chlorobenzene, p-chloro benzo trifluoride-99, acetonitrile, acetone etc., preferable recrystallization solvent be toluene,
The dosage of one or more combinations in dichloromethane and dichloroethanes etc., recrystallization and/or mashing solvent can be formula III
1-10 times of compound, preferable dosage are 1-3 times.Suitable recrystallization and/or mashing mode may be selected in those skilled in the art,
Such as will be heated up after crude product addition solvent, cool crystallization after stirring.
The invention provides a kind of new method for preparing phenylacetic acid compound, preparation method raw material provided by the present invention
Simple and easy to get, easy to operate, cost of material is low, reaction condition is gentle, danger is low, is urged without using the high noble metal of price
Agent and complicated industrial operation means, product quality is stable, therefore is suitable for and realizes large-scale industrial production.
Illustrate embodiments of the present invention below by way of specific instantiation, those skilled in the art can be by this specification
Disclosed content understands other advantages and effect of the present invention easily.The present invention can also pass through specific realities different in addition
The mode of applying is embodied or practiced, the various details in this specification can also be based on different viewpoints with application, without departing from
Various modifications or alterations are carried out under the spirit of the present invention.
It should be clear that in the following example not specifically dated process equipment or device using conventional equipment in the art or
Device.
In addition, it is to be understood that one or more method and steps mentioned in the present invention do not repel before and after the combination step
There can also be other method step or other method step can also be inserted between the step of these are specifically mentioned, unless separately
It is described；It should also be understood that the combination annexation between one or more equipment/devices mentioned in the present invention is not repelled
Can also have other equipment/device before and after the unit equipment/device or two equipment/devices specifically mentioning at these it
Between can also insert other equipment/device, unless otherwise indicated.Moreover, unless otherwise indicated, the numbering of various method steps is only
Differentiate the convenient tool of various method steps, rather than ordering or the enforceable model of the restriction present invention for limitation various method steps
Enclose, its relativeness is altered or modified, and in the case where changing technology contents without essence, when being also considered as, the present invention is enforceable
Category.
Embodiment 1
The preparation of 3,4- dimethyl phenyl acetic acids：
900 grams of 20%HCl and 250 gram of 3,4- dimethylanilines are added into reaction bulb, are heated to 85~95 DEG C of dissolved clarifications.Drop
Temperature arrives -5~5 DEG C, adds 20g tetrabutylammonium chlorides and 20g stannous chlorides.250g vinylidene chlorides are added dropwise.Keeping temperature -5~5
At DEG C, the aqueous solution of the natrium nitrosum containing 150g is slowly added dropwise.Insulation reaction 2 hours.Reaction finishes, and excessive nitrite is quenched.Add
Enter precipitation after dichloromethane extracts, obtain 1- (2,2,2- trichloroethyl) -3,4- dimethyl benzenes 369.2g.
1L there-necked flasks, under nitrogen protection, add 300g 30% hydrochloric acid.It is heated to 80~95 DEG C.200g intermediates are added dropwise
1- (2,2,2- trichloroethyls) -3,4- dimethyl benzenes.It is added dropwise, insulation reaction 10 hours.Reaction finishes.System cooling is quenched
Go out.Filtering, washing, is dried to obtain crude product 190g.Sterling 3 is obtained with 200g re crystallization from toluene, 4- dimethyl phenyl acetic acid 101.1g,
87-89 DEG C of fusing point, HPLC purity are more than 99wt%.
Embodiment 2
The preparation of 2,4 dichloro benzene acetic acid：
800 grams of 15%HCl solution and 250 grams of 2,4- dichloroanilines are added into reaction bulb, are heated to 85~95 DEG C of dissolved clarifications.
- 5~5 DEG C are cooled to, adds 10g tetramethyl ammonium chlorides and 20g stannous chlorides.250g vinylidene chlorides are added dropwise.Keeping temperature -5
At~5 DEG C, the aqueous solution of the natrium nitrosum containing 150g is slowly added dropwise.Insulation reaction 2 hours.Reaction finishes, and excessive nitrite is quenched.
Precipitation after dichloromethane extracts is added, obtains 1- (2,2,2- trichloroethyl) -2,4- dichloro-benzenes 320.2g.
1L there-necked flasks, under nitrogen protection, add 200g 25% sulfuric acid solution and 200g toluene.It is heated to 80~90 DEG C.
200g 1- (2,2,2- trichloroethyls) -2,4 dichloro benzene is added dropwise.It is added dropwise, insulation reaction 8 hours.Reaction finishes.By body
It is that cooling is quenched.After organic phase washing, cool crystallization, obtains 2,4- fenac 107.1g, 129-132 DEG C of fusing point, HPLC
Purity is more than 95wt%.
Embodiment 3
The preparation of 2,6- fenacs：
800 gram of 30% sulfuric acid solution and 250 grams of 2,6-DCAs are added into reaction bulb, be heated to 85~95 DEG C it is molten
Clearly.- 5~5 DEG C are cooled to, adds 20g TBABs and 20g cuprous bromides.200g vinylidene chlorides are added dropwise.Keep temperature
At -5~5 DEG C of degree, the aqueous solution of the natrium nitrosum containing 150g is slowly added dropwise.Insulation reaction 2 hours.Reaction finishes, and excessive Asia is quenched
Nitric acid.Precipitation after dichloromethane extracts is added, obtains 1- (2,2,2- trichloroethyl) -2,6- dichloro-benzenes 317.4g.
1L there-necked flasks, under nitrogen protection, add 300g 30% hydrochloric acid.It is heated to 80~95 DEG C.200g intermediates are added dropwise
1- (2,2,2- trichloroethyls) -2,6- dichloro-benzenes.It is added dropwise, insulation reaction 10 hours.Reaction finishes.System cooling is quenched
Go out.Filtering, washing, is dried to obtain crude product 203.0g.Sterling 2,6- fenac 115.3g, fusing point are obtained with re crystallization from toluene
161-163 DEG C, HPLC purity is more than 98wt%.
Embodiment 4
The preparation of 4- chlorobenzene acetic acids：
900 gram of 25% sulfuric acid solution and 250 grams of 4- chloroanilines are added into reaction bulb, are heated to 85~95 DEG C of dissolved clarifications.Drop
Temperature arrives -5~5 DEG C, adds 20g methyl tricapryl ammonium chlorides and 20g basic copper carbonates.200g vinylidene chlorides are added dropwise.Keep temperature
At -5~5 DEG C of degree, the aqueous solution of the natrium nitrosum containing 150g is slowly added dropwise.Insulation reaction 2 hours.Reaction finishes, and excessive Asia is quenched
Nitric acid.Precipitation after dichloroethanes extracts is added, obtains 1- (2,2,2- trichloroethyl) -4- chlorobenzenes 366.4g.
1L there-necked flasks, under nitrogen protection, add 200g 90% sulfuric acid.It is heated to 80~90 DEG C.200g intermediates are added dropwise
1- (2,2,2- trichloroethyls) -4- chlorobenzenes.It is added dropwise, insulation reaction 8 hours.Reaction finishes.System is added dropwise to ice
It is quenched among water.Filtering, filter cake washing, is dried to obtain crude product 191.0g.Sterling 4- chlorobenzene second is obtained with 200g re crystallization from toluene
Sour 118.0g, 101-105 DEG C of fusing point, HPLC purity are more than 98wt%.
Embodiment 5
The preparation of the fluoro- 5- bromo-acids of 2- methyl -4-：
500 gram of 20% hydrochloric acid solution and 250 grams of fluoro- 5- bromanilines of 2- methyl -4- are added into reaction bulb, it is heated to 85~
95 DEG C of dissolved clarifications.- 5~5 DEG C are cooled to, adds 20g tetrabutylammonium chlorides and 6g cuprous oxide.300g vinylidene chlorides are added dropwise.Protect
Hold at temperature -5~5 DEG C, 150g Isopropyl Nitrites and 600g acetone is slowly added dropwise.Insulation reaction 4 hours.Reaction finishes, and quenches
Go out.Precipitation after separation organic phase, obtains the fluoro- 5- bromobenzenes 291.1g of 1- (2,2,2- trichloroethyl) -2- methyl -4-.
In there-necked flask, under nitrogen protection, 200g 90% sulfuric acid is added.It is heated to 80~90 DEG C.200g 1- are added dropwise
The fluoro- 5- bromobenzenes of (2,2,2- trichloroethyls) -2- methyl -4-.It is added dropwise, insulation reaction 10 hours.Reaction finishes.System is dropped
Temperature is added dropwise among frozen water and is quenched.Filtering, filter cake washing, is dried to obtain crude product 197.0g.2- is obtained with 200g re crystallization from toluene
The fluoro- 5- bromo-acids 121.7g of methyl -4-, 99-104 DEG C of fusing point, HPLC purity are more than 98wt%.
Embodiment 6
The preparation of 3- chlorobenzene acetic acids：
350 gram of 32% hydrochloric acid solution and 250 grams of 3- chloroanilines are added into reaction bulb, are heated to 85~95 DEG C of dissolved clarifications.Drop
Temperature arrives -5~5 DEG C, adds 20g methyl tricapryl ammonium chlorides and 20g cuprous oxide.300g vinylidene chlorides are added dropwise.Keeping temperature-
At 5~5 DEG C, Isopropyl Nitrite containing 200g and 800g dichloromethane solutions is slowly added dropwise.Insulation reaction 5 hours.Reaction finishes,
Be quenched, extract after precipitation, obtain 1- (2,2,2- trichloroethyl) -3- chlorobenzenes 356g.
1L there-necked flasks, under nitrogen protection, add 300g water, 100g dichloroethanes and 100g p-methyl benzenesulfonic acid.Agitating and heating
Backflow.200g intermediates 1- (2,2,2- trichloroethyls) -3- chlorobenzenes are added dropwise.It is added dropwise, insulation reaction 15 hours.React
Finish.Filtered after system is cooled into 10 DEG C, filter cake washing, sterling 3- chlorobenzene acetic acids are recrystallized to give with 200g dichloroethanes
103.1g, 74-78 DEG C of fusing point, HPLC purity are more than 95wt%.
Embodiment 7
The preparation of 3- bromo-acids：
600 gram of 20% hydrochloric acid solution and 250 grams of 3- bromanilines are added into reaction bulb, are heated to 85~95 DEG C of dissolved clarifications.Drop
Temperature arrives -5~5 DEG C, adds 20g TBABs and 20g cuprous bromides.250g vinylidene chlorides are added dropwise.Keeping temperature -5~5
At DEG C, the aqueous solution of the natrium nitrosum containing 150g is slowly added dropwise.Insulation reaction 2 hours.Reaction finishes, be quenched, extract after precipitation, obtain
To 1- (2,2,2- trichloroethyls) -3- bromobenzenes 296.3g.
1L there-necked flasks, under nitrogen protection, add 300g water, 100g dichloroethanes and 50g ferric trichlorides.Agitating and heating is returned
Stream.200g intermediates 1- (2,2,2- trichloroethyls) -3- bromobenzenes are added dropwise.It is added dropwise, insulation reaction 12 hours.Reaction finishes.
Filtered after system is cooled into 10 DEG C, filter cake washing, sterling 3- bromo-acid 108.7g be recrystallized to give with 200g dichloroethanes,
About 100-104 DEG C of fusing point, HPLC purity are more than 95wt%.
Embodiment 8
The preparation of 4- bromo-acids：
600 gram of 20% hydrochloric acid solution and 250 grams of 4- bromanilines are added into reaction bulb, are heated to 80~90 DEG C of dissolved clarifications.Drop
Temperature arrives -5~5 DEG C, adds 20g 4 bromides and 20g basic copper carbonates.250g vinylidene chlorides are added dropwise.Keeping temperature -5
At~5 DEG C, the aqueous solution of the natrium nitrosum containing 150g is slowly added dropwise.Insulation reaction 2 hours.Reaction finishes, and is quenched.Add 500g bis-
Precipitation after chloroethanes extraction, obtains 1- (2,2,2- trichloroethyl) -4- bromobenzenes 327.9g.
1L there-necked flasks, under nitrogen protection, add 200g 90% sulfuric acid.It is heated to 80~90 DEG C.200g intermediates are added dropwise
1- (2,2,2- trichloroethyls) -4- bromobenzenes.It is added dropwise, insulation reaction 6 hours.Reaction finishes.System is added dropwise to ice
It is quenched among water.Filtering, filter cake washing, is dried.4- bromo-acid 117.4g, fusing point 113- are obtained with 200g re crystallization from toluene
117 DEG C, HPLC purity is more than 95wt%.
Embodiment 9
The preparation of 2- methylphenyl acetic acids：
800 gram of 30% sulfuric acid solution and 250 grams of 2-aminotoluenes are added into reaction bulb, are heated to 80~90 DEG C of dissolved clarifications.
- 5~5 DEG C are cooled to, adds 20g 4 bromides and 20g cuprous bromides.200g vinylidene chlorides are added dropwise.Keeping temperature -5
At~5 DEG C, the aqueous solution of the natrium nitrosum containing 200g is slowly added dropwise.Insulation reaction 2 hours.Reaction finishes, and is quenched.Add 400g bis-
Precipitation after chloroethanes extraction, obtains 1- (2,2,2- trichloroethyl) -2- methylbenzenes 376.8g.
1L there-necked flasks, under nitrogen protection, add 200g 50% sulfuric acid.It is heated to 80~90 DEG C.200g intermediates are added dropwise
1- (2,2,2- trichloroethyls) -2- methylbenzenes.It is added dropwise, insulation reaction 8 hours.Reaction finishes.System cooling is quenched.Cross
Filter, filter cake washing, is dried.2- methyl acetic acid 96.5g, 87-92 DEG C of fusing point are obtained with re crystallization from toluene, HPLC purity is more than
95wt%.
Embodiment 10
The preparation of 4- methylphenyl acetic acids：
800 gram of 30% sulfuric acid solution and 250 grams of 4- methylanilines are added into reaction bulb, are heated to 80~90 DEG C of dissolved clarifications.
- 5~5 DEG C are cooled to, adds 20g 4 bromides and 20g basic copper carbonates.200g vinylidene chlorides are added dropwise.Keeping temperature-
At 5~5 DEG C, the aqueous solution of the natrium nitrosum containing 200g is slowly added dropwise.Insulation reaction 2 hours.Reaction finishes, and is quenched.Add 400g
Precipitation after dichloroethanes extraction, obtains 1- (2,2,2- trichloroethyl) -4- methylbenzenes 403.1g.
1L there-necked flasks, under nitrogen protection, add 200g 90% sulfuric acid.It is heated to 80~90 DEG C.200g intermediates are added dropwise
1- (2,2,2- trichloroethyls) -4- methylbenzenes.It is added dropwise, insulation reaction 8 hours.Reaction finishes.System cooling is quenched.Cross
Filter, filter cake washing, is dried.4- methyl acetic acid 107.2g are obtained with 200g re crystallization from toluene, and 90-92 DEG C of fusing point, HPLC purity is big
In 98wt%.
Embodiment 11
The preparation of 4- trifluoromethyl phenylacetic acids：
900 gram of 10% hydrochloric acid solution and 250 grams of 4- 5-trifluoromethylanilines are added into reaction bulb, be heated to 80~90 DEG C it is molten
Clearly.- 5~5 DEG C are cooled to, adds 10g tetramethyl ammonium chlorides and 20g basic copper carbonates.250g vinylidene chlorides are added dropwise.Keep temperature
At -5~5 DEG C of degree, the aqueous solution of the natrium nitrosum containing 200g is slowly added dropwise.Insulation reaction 2 hours.Reaction finishes, and is quenched.Add
Precipitation after the extraction of 400g dichloroethanes, obtains 1- (2,2,2- trichloroethyl) -4- trifluoromethylbenzenes 345.6g.
1L there-necked flasks, under nitrogen protection, add 200g 90% sulfuric acid.It is heated to 80~90 DEG C.200g intermediates are added dropwise
1- (2,2,2- trichloroethyls) -4- trifluoromethylbenzenes.It is added dropwise, insulation reaction 6 hours.Reaction finishes.System cooling is quenched
Go out.Filtering, filter cake washing, is dried.4- trifluoromethyl acetic acid is obtained with 200g toluene and dichloroethanes (1w/w) solvent recrystallization
120.4g, 80-84 DEG C of fusing point, HPLC purity are more than 98wt%.
In summary, the present invention effectively overcomes various shortcoming of the prior art and has high industrial utilization.
The above-described embodiments merely illustrate the principles and effects of the present invention, not for the limitation present invention.It is any ripe
Know the personage of this technology all can carry out modifications and changes under the spirit and scope without prejudice to the present invention to above-described embodiment.Cause
This, those of ordinary skill in the art is complete without departing from disclosed spirit and institute under technological thought such as
Into all equivalent modifications or change, should by the present invention claim be covered.
Claims (9)
1. a kind of preparation method of phenylacetic acid compound, the structural formula of the phenylacetic acid compound is shown in formula I：
Wherein, R1、R2、R3、R4、R5It is each independently selected from F, Cl, Br ,-CH3、-C2H5、-C3H7、-CF3Or H, and be asynchronously
H；Work as R1、R2、R3、R4、R5When middle one or more is F, remaining not all H；
The preparation method comprises the following steps：
(1) diazotising addition reaction：Formula II compound is being contained into vinylidene chloride, acid, diazo reagent, phase transfer catalyst
It is as follows with reaction production III compounds, reaction equation in the system of Cu-series catalyst：
(2) hydrolysis：Formula III compound is hydrolyzed to generation compound of formula I under the conditions of existing for acid, reaction equation is such as
Under：
2. preparation method as claimed in claim 1, it is characterised in that also including the one or more in following technical characteristic：
A1)R1~R5Middle any two independence is selected from Cl, Br ,-CH3、-CF3, remaining is each independently selected from H or F；
A2)R1~R5In any one be selected from Cl, Br ,-CH3、-CF3, remaining is H；
A3)R3Selected from Cl, Br ,-CH3、-CF3, remaining is H.
3. preparation method as claimed in claim 2, it is characterised in that also including the one or more in following technical characteristic：
B1) compound of formula I is selected from 3,4- fenacs, 2,4- fenacs, 2,6- fenacs, 3,5- diformazans
The fluoro- 6- methylphenyl acetic acids of the bromo- 4- of base phenylacetic acid, 3-；
B2) compound of formula I is selected from o-chlorobenzene acetic acid, 3- chlorobenzene acetic acids, 4- chlorobenzene acetic acids, bromophenyl acetic acid, 3- bromobenzene second
Acid, 4- bromo-acids, 2- methylphenyl acetic acids, 3- methylphenyl acetic acids, 4- methylphenyl acetic acids, 3- trifluoromethyl phenylacetic acids, 4- trifluoros
Methylphenyl acetic acid；
B3) compound of formula I is selected from 4- chlorobenzene acetic acids, 4- bromo-acids, 4- methylphenyl acetic acids, 4- trifluoromethyl phenylacetic acids.
4. preparation method as claimed in claim 1, it is characterised in that also including the one or more in following technical characteristic：
C1) in the step (1), reaction is carried out in the presence of a solvent, and the solvent is water and/or organic solvent；
C2) in the step (1), the acid is selected from HCl and/or sulfuric acid；
C3) in the step (1), the diazo reagent is selected from nitrite and/or nitrous acid ester；
C4) in the step (1), the mol ratio of the diazo reagent and Formula II compound is 1~10:1；
C5) in the step (1), the Cu-series catalyst is selected from the oxide of mantoquita and/or copper；
C6) in the step (1), the mol ratio of the Cu-series catalyst and Formula II compound is 0.01~0.1:1；
C7) in the step (1), the phase transfer catalyst is selected from tetrabutylammonium chloride, TBAB, tetrabutyl iodate
One or more combinations in ammonium, tetramethyl ammonium chloride, methyl tricapryl ammonium chloride, TBAH；
C8) in the step (1), the mol ratio of the phase transfer catalyst and Formula II compound is 0.01~0.1:1；
C9) in the step (1), the vinylidene chloride is 1~5 with Formula II compound mole ratio：1；
C10) in the step (1), reaction temperature is -20 DEG C~30 DEG C；
C11 extraction is gone out) in the step (1), after the completion of reaction, and excessive nitrite, organic solvent extract, organic phase precipitation produces formula
III compounds.
5. preparation method as claimed in claim 4, it is characterised in that also including the one or more in following technical characteristic：
D1) in the step (1), the solvent is the combination of water and organic solvent, and the weight ratio of wherein organic solvent and water is
No more than 2；
D2) in the step (1), organic solvent is selected from dichloromethane, chloroform, 1,2- dichloroethanes, tetrahydrofuran, first
Benzene, benzotrifluoride, p-chloro benzo trifluoride-99, one or more combinations in acetone and acetonitrile；
D3) in the step (1), the mass ratio of solvent and Formula II compound is 1~10:1；
D4) in the step (1), the acid is 1~3 with Formula II compound mole ratio：1；
D5) in the step (1), the nitrite is selected from nitrite sodium；
D6) in the step (1), the nitrous acid ester is selected from nitrite tert-butyl and/or Isopropyl Nitrite；
D7) in the step (1), the mol ratio of the diazo reagent and Formula II compound is 1.1~1.5:1；
D8) in the step (1), the mantoquita is selected from copper acetate, basic copper carbonate, copper chloride, stannous chloride, copper bromide, bromine
Change it is cuprous in one or more combinations；
D9) in the step (1), the one or more combinations of the oxide of the copper in cupric oxide, cuprous oxide；
D10) in the step (1), the vinylidene chloride is 1~2 with Formula II compound mole ratio：1；
D11) in the step (1), reaction temperature is -15 DEG C~15 DEG C.
6. preparation method as claimed in claim 5, it is characterised in that also including the one or more in following technical characteristic：
E1) in the step (1), the solvent is the combination of water and organic solvent, and the weight ratio of wherein organic solvent and water is
0.2~1.5：1；
E2) in the step (1), the mass ratio of solvent and Formula II compound is 1~5:1；
E3) in the step (1), the acid is 1.1~1.5 with Formula II compound mole ratio：1.
7. preparation method as claimed in claim 1, it is characterised in that also including the one or more in following technical characteristic：
F1) in the step (2), reaction is carried out in the presence of a solvent, and the solvent is selected from water and/or organic solvent；
F2) in the step (2), the acid is selected from Bronsted acid and/or lewis acid；
F3) in the step (2), the mass ratio of the acid and formula III compound is 0.05~5:1；
F4) in the step (2), reaction temperature is 20 DEG C~160 DEG C；
F5) in the step (2), react and carried out under conditions of gas shield, gas shield use gas be selected from nitrogen and/
Or inert gas；
F6) in the step (2), after the completion of reaction plus water extraction is gone out, and separation of solid and liquid, solid formation produces compound of formula I after purification.
8. preparation method as claimed in claim 7, it is characterised in that also including the one or more in following technical characteristic：
G1) in the step (2), the solvent is selected from the combination of water and organic solvent, and the weight ratio of organic solvent and water is not
More than 2；
G2) in the step (2), the organic solvent is selected from dichloromethane, chloroform, 1,2- dichloroethanes, tetrahydrofuran,
Toluene, benzotrifluoride, one or more combinations in p-chloro benzo trifluoride-99；
G3) in the step (2), the mass ratio of solvent and formula III compound is 1~10:1；
G4) in the step (2), the Bronsted acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, oleum, nitric acid, first sulphur
Acid, trifluoromethanesulfonic acid, p-methyl benzenesulfonic acid, formic acid, acetic acid；
G5) in the step (2), the lewis acid is selected from AlCl3、FeCl3、ZnCl2、TiCl4、SnCl4、CoCl2、NiCl2、
MnCl2, MnO, copper acetate, cupric oxide, cuprous oxide, copper chloride, stannous chloride, copper bromide, one kind in cuprous bromide or more
The combination of kind；
G6) in the step (2), the mass ratio of the acid and formula III compound is 0.1~2:1；
G7) in the step (2), reaction temperature is 60 DEG C~120 DEG C；
G8) in the step (2), the mode of purifying is recrystallization.
9. preparation method as claimed in claim 8, it is characterised in that also including the one or more in following technical characteristic：
H1) in the step (2), the solvent is selected from the combination of water and organic solvent, and the weight ratio of organic solvent and water is 0.2
~1.5：1；
H2) in the step (2), the mass ratio of solvent and formula III compound is 2~5:1；
H3) in the step (2), solvent used in recrystallization is selected from toluene, dichloromethane, chloroform, the chloroethenes of 1,2- bis-
One or more combinations in alkane, tetrahydrofuran, toluene, benzotrifluoride, p-chloro benzo trifluoride-99.
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| CN110551027A (en) * | 2018-05-31 | 2019-12-10 | 南京理工大学 | Synthetic method of 3-hydroxy-2-phenylpropionic acid |
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