CN107417509B - Preparation method of phenylacetic acid compound - Google Patents
Preparation method of phenylacetic acid compound Download PDFInfo
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- CN107417509B CN107417509B CN201710374434.1A CN201710374434A CN107417509B CN 107417509 B CN107417509 B CN 107417509B CN 201710374434 A CN201710374434 A CN 201710374434A CN 107417509 B CN107417509 B CN 107417509B
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/093—Preparation of carboxylic acids or their salts, halides or anhydrides by hydrolysis of —CX3 groups, X being halogen
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- 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
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Abstract
The invention relates to the field of chemical synthesis, in particular to a preparation method of a phenylacetic acid compound. The invention provides a preparation method of a phenylacetic acid compound, wherein the structural formula of the phenylacetic acid compound is shown as a formula I, and the preparation method comprises the following steps: (1) diazotization addition reaction: reacting a compound of formula II in a system comprising vinylidene chloride, an acid, a diazotizing agent, a phase transfer catalyst, and a copper-based catalyst to produce a compound of formula III: (2) and (3) hydrolysis reaction: hydrolyzing the compound of formula III in the presence of an acid to produce the compound of formula I. The preparation method provided by the invention has the advantages of simple and easily obtained raw materials, simple and convenient operation, low raw material cost, mild reaction conditions, low risk, no need of expensive noble metal catalysts and complex industrial operation means, and stable product quality, thereby being suitable for realizing large-scale industrial production.
Description
Technical Field
The invention relates to the field of chemical synthesis, in particular to a preparation method of a phenylacetic acid compound.
Background
Phenylacetic acid compounds have wide applications in the fields of medicines, pesticides, electronic materials and the like. For example, p-chlorophenylacetic acid is useful as an intermediate for the production of penicillin; the o-chlorophenylacetic acid can be used as a raw material for synthesizing the high-efficiency anti-inflammatory analgesic diclofenac sodium; 2, 4-dichlorophenylacetic acid can be used as spirodiclofen serving as a synthetic acaricide; 4-bromophenylacetic acid can be used for synthesizing a medicine for treating diseases related to T-type calcium channel disorder.
The phenylacetic acid compound can be synthesized by a sodium cyanide method, a phenylacetamide method and a oxo-synthesis method. The sodium cyanide process uses methyl as raw material, and produces benzyl chloride through chlorination, and then produces benzyl cyanide through sodium cyanide benzyl chloride, and finally obtains phenylacetic acid through hydrolysis. The method has the defects that the reaction yield of benzyl chloride and sodium cyanide is low, the sodium cyanide is extremely toxic, the cyanide-containing wastewater pollutes the environment seriously, the generated phenylacetonitrile also pollutes the environment by toxic substances, and the phenylacetic acid contains extremely toxic free cyanide, so that the potential hazards are brought to the subsequent utilization. The phenylacetamide hydrolysis method is to take styrene as a raw material, react with ammonia sulfur to generate phenylacetamide, and hydrolyze to generate phenylacetic acid. The by-product 2-phenethyl mercaptan in the method has peculiar smell and pollutes the environment, the reaction needs pressurization, and the industrial operation is complicated. The oxo process is carried out by carbonylation reacting benzyl chloride in alkali and organic solvent two-phase system under carbonylation catalyst and phase transfer catalyst to obtain phenylacetate, and acidifying into phenylacetic acid. The method uses an expensive transition metal complex as a carbonylation catalyst, has high cost and great process difficulty, and is easy to inactivate or lose the catalyst, so the method is not suitable for stable industrial production.
Disclosure of Invention
In view of the above disadvantages of the prior art, the present invention aims to provide a novel preparation method for phenylacetic acid compounds, so as to solve the disadvantages of the prior art, such as complicated operation, high production cost, serious environmental pollution, potential safety hazard, etc., which are not conducive to industrial production.
In order to achieve the above objects and other related objects, the present invention provides a method for preparing phenylacetic acid compounds, which has the advantages of simple process operation, low raw material cost, high conversion rate, environmental friendliness, and is more suitable for industrial safety production, wherein the structural formula of the phenylacetic acid compounds is as shown in formula I:
wherein R is1、R2、R3、R4、R5Each independently selected from F, Cl, Br, -CH3、-C2H5、-C3H7、-CF3Or H, and is not H at the same time; when R is1、R2、R3、R4、R5When one or more of them is F, the rest are not all H;
the preparation method comprises the following steps:
(1) diazotization addition reaction: reacting a compound of formula II in a solvent system containing vinylidene chloride, acid, diazo reagent, a phase transfer catalyst and a copper catalyst to generate a compound of formula III, wherein the reaction equation is as follows:
(2) and (3) hydrolysis reaction: hydrolyzing the compound of formula III in the presence of an acid to produce a compound of formula I, wherein the reaction equation is as follows:
in some embodiments of the invention, R1～R5Any two of which are independently selected from Cl, Br, -CH3、-CF3And the others are each independently selected from H or F.
In some embodiments of the invention, the compound of formula I is selected from 3, 4-dichlorophenylacetic acid, 2, 6-dichlorophenylacetic acid, 3, 5-dimethylphenylacetic acid, 3-bromo-4-fluoro-6-methylphenylacetic acid.
In some embodiments of the invention, R1～R5Any one of them is selected from Cl, Br and-CH3、-CF3And the balance is H.
In some embodiments of the invention, the compound of formula I is selected from o-chlorophenylacetic acid, 3-chlorophenylacetic acid, 4-chlorophenylacetic acid, o-bromophenylacetic acid, 3-bromophenylacetic acid, 4-bromophenylacetic acid, 2-methylphenylacetic acid, 3-methylphenylacetic acid, 4-methylphenylacetic acid, 3-trifluoromethylphenylacetic acid, 4-trifluoromethylphenylacetic acid.
In some embodiments of the invention, R3Selected from Cl, Br, -CH3、-CF3And the balance is H.
In some embodiments of the invention, the compound of formula I is selected from 4-chlorophenylacetic acid, 4-bromophenylacetic acid, 4-methylphenylacetic acid, 4-trifluoromethylphenylacetic acid.
In some embodiments of the present invention, in the step (1), the reaction is performed in the presence of a solvent, and the solvent is water and/or an organic solvent.
In some embodiments of the invention, in step (1), the solvent is a combination of water and an organic solvent, wherein the weight ratio of organic solvent to water is not greater than 2.
In some embodiments of the present invention, in the step (1), the solvent is a combination of water and an organic solvent, wherein the weight ratio of the organic solvent to the water is 0.2 to 1.5: 1.
in some embodiments of the invention, in the step (1), the mass ratio of the solvent to the compound of formula II is 1-10: 1.
In some embodiments of the invention, in the step (1), the mass ratio of the solvent to the compound of formula II is 1-5: 1.
In some embodiments of the invention, in step (1), the organic solvent is selected from the group consisting of dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, toluene, trifluorotoluene, p-chlorotrifluoromethane, acetone, and acetonitrile.
In some embodiments of the invention, in step (1), the acid is selected from HCl and/or sulfuric acid.
In some embodiments of the invention, in the step (1), the molar ratio of the acid to the compound of formula II is 1 to 3: 1.
in some embodiments of the invention, in the step (1), the molar ratio of the acid to the compound of formula II is 1.1 to 1.5: 1.
in some embodiments of the invention, in step (1), the diazotizing agent is selected from nitrite and/or nitrite ester.
In some embodiments of the invention, in step (1), the nitrite is selected from sodium nitrite.
In some embodiments of the invention, in step (1), the nitrite is selected from tert-butyl nitrite and/or isopropyl nitrite.
In some embodiments of the invention, in the step (1), the molar ratio of the diazotizing agent to the compound of formula II is 1-10: 1.
In some embodiments of the invention, in step (1), the molar ratio of the diazotizing agent to the compound of formula II is 1.1 to 1.5: 1.
In some embodiments of the present invention, in the step (1), the copper-based catalyst is selected from copper salts and/or copper oxides.
In some embodiments of the present invention, in the step (1), the copper salt is selected from one or more of cupric acetate, basic cupric carbonate, cupric chloride, cuprous chloride, cupric bromide and cuprous bromide.
In some embodiments of the invention, in the step (1), the copper oxide is selected from one or more of cupric oxide and cuprous oxide.
In some embodiments of the present invention, in the step (1), the molar ratio of the copper-based catalyst to the compound of formula II is 0.01 to 0.1: 1.
In some embodiments of the invention, in step (1), the phase transfer catalyst is selected from one or more of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetramethylammonium chloride, methyltrioctylammonium chloride, tetrabutylammonium hydroxide.
In some embodiments of the invention, in the step (1), the molar ratio of the phase transfer catalyst to the compound of formula II is 0.01-0.1: 1.
In some embodiments of the present invention, in the step (1), the molar ratio of the vinylidene chloride to the compound of formula II is 1 to 5: 1.
in some embodiments of the present invention, in the step (1), the molar ratio of the vinylidene chloride to the compound of formula II is 1-2: 1.
in some embodiments of the present invention, in the step (1), the reaction temperature is from-20 ℃ to 30 ℃.
In some embodiments of the present invention, in the step (1), the reaction temperature is from-15 ℃ to 15 ℃.
In some embodiments of the present invention, in step (1), after the reaction is completed, excess nitrous acid is extracted and killed, the organic solvent is extracted, and the organic phase is desolventized to obtain the compound of formula III.
In some embodiments of the present invention, in the step (2), the reaction is performed in the presence of a solvent selected from water and/or an organic solvent.
In some embodiments of the present invention, in the step (2), the solvent is selected from a combination of water and an organic solvent, and the weight ratio of the organic solvent to the water is not more than 2.
In some embodiments of the present invention, in the step (2), the solvent is selected from a combination of water and an organic solvent, and the weight ratio of the organic solvent to the water is 0.2 to 1.5: 1.
in some embodiments of the invention, in the step (2), the organic solvent is selected from one or more of dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, toluene, benzotrifluoride, and p-chlorotrifluoromethylene.
In some embodiments of the invention, in the step (2), the mass ratio of the solvent to the compound of formula III is 1-10: 1.
In some embodiments of the invention, in the step (2), the mass ratio of the solvent to the compound of formula III is 2-5: 1.
In some embodiments of the invention, in step (2), the acid is selected from a protic acid and/or a lewis acid.
In some embodiments of the invention, in step (2), the protic acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, oleum, nitric acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid.
In some embodiments of the invention, in step (2), the lewis acid is selected from AlCl3、FeCl3、ZnCl2、TiCl4、SnCl4、CoCl2、NiCl2、MnCl2MnO, copper acetate, copper oxide, cuprous oxide, cupric chloride, cuprous chloride, cupric bromide, cuprous bromideOne or more of the above.
In some embodiments of the invention, in the step (2), the mass ratio of the acid to the compound of formula III is 0.05-5: 1.
In some embodiments of the invention, in the step (2), the mass ratio of the acid to the compound of formula III is 0.1-2: 1.
In some embodiments of the present invention, in the step (2), the reaction temperature is 20 ℃ to 160 ℃.
In some embodiments of the present invention, in the step (2), the reaction temperature is 60 ℃ to 120 ℃.
In some embodiments of the present invention, in the step (2), the reaction is performed under a gas protection condition, and the gas used for the gas protection is selected from nitrogen and/or inert gas.
In some embodiments of the present invention, in step (2), after the reaction is completed, water is added for quenching, solid-liquid separation is performed, and a solid phase is purified to obtain the compound of formula I.
In some embodiments of the invention, in step (2), the purification is by recrystallization.
In some embodiments of the present invention, in the step (2), the solvent used for recrystallization is selected from one or more of toluene, dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, toluene, benzotrifluoride, and p-chlorotrifluorotoluene.
Detailed Description
The inventor provides a novel preparation method of phenylacetic acid compound through a large amount of exploration and research, and the preparation method has the characteristics of simple and easily obtained raw materials, simple and convenient operation, low raw material cost, mild reaction conditions, low risk, stable product quality and the like, is suitable for industrial large-scale production, and completes the invention on the basis.
One aspect of the present invention provides a method for preparing a phenylacetic acid compound, wherein the structural formula of the phenylacetic acid compound is represented by formula I:
wherein R is1、R2、R3、R4、R5Each independently selected from F, Cl, Br, -CH3、-C2H5、-C3H7、-CF3Or H, and is not H at the same time; when R is1、R2、R3、R4、R5When one or more of them is F, the remainder are not all H.
In the invention, in the compound of the formula I, R1～R5Any two of which are independently selected from Cl, Br and-CH3、-CF3And the others are each independently selected from H or F, and specifically for example, the compound of formula I may be 3, 4-dichlorophenylacetic acid, 2, 6-dichlorophenylacetic acid, 3, 5-dimethylphenylacetic acid, 3-bromo-4-fluoro-6-methylphenylacetic acid, or the like.
In the invention, in the compound of the formula I, R1～R5Any one of them is selected from Cl, Br and-CH3、-CF3And the remainder is H, and specific examples of the compound of the formula I include o-chlorophenylacetic acid, 3-chlorophenylacetic acid, 4-chlorophenylacetic acid, o-bromophenylacetic acid, 3-bromophenylacetic acid, 4-bromophenylacetic acid, 2-methylphenylacetic acid, 3-methylphenylacetic acid, 4-methylphenylacetic acid, 3-trifluoromethylphenylacetic acid, 4-trifluoromethylphenylacetic acid and the like.
In the invention, in the compound of the formula I, R3Can be Cl, Br, -CH3、-CF3And the balance being H, and specific examples of the compound of the formula I include 4-chlorophenylacetic acid, 4-bromophenylacetic acid, 4-methylphenylacetic acid, 4-trifluoromethylphenylacetic acid and the like.
The preparation method of the phenylacetic acid compound provided by the invention can comprise diazo addition reaction, wherein the diazo addition reaction generally refers to addition reaction of diazo reaction of aromatic primary amine to generate diazonium salt, and the generated diazonium salt is further added with olefin derivatives. The diazotization addition reaction specifically comprises the following steps: reacting a compound (fluoroaniline) of formula II in a system comprising vinylidene chloride, an acid, a diazonium reagent, a phase transfer catalyst and a copper-based catalyst to produce a compound (fluorophenyltrichloroethane) of formula III, according to the following reaction equation:
in the diazotization addition reaction, the reaction can be carried out in the presence of a solvent, and a person skilled in the art can select a proper type and a proper using amount of the solvent so as to enable the reaction raw material to have good solubility in a reaction system, for example, the solvent can be water and/or an organic solvent, and for example, the mass ratio of the solvent to the compound of the formula II can be 1-10: 1, and can also be 1-5: 1. The solvent generally comprises water, and can further comprise an organic solvent, so that the reaction solvent has better dispersing capacity and solubility relative to the reaction raw materials. The skilled person can select a suitable kind and amount of the organic solvent to make the reaction raw material have good solubility in the reaction system, for example, the organic solvent may be a combination including but not limited to one or more of dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, toluene, benzotrifluoride, p-chlorotrifluoromethane, acetone, acetonitrile, and the like, and for example, the solvent includes water and an organic solvent, the weight ratio of the organic solvent to the water is not more than 2, and the preferred weight ratio of the organic solvent to the water is 0.2 to 1.5: 1.
in the diazotization addition reaction, one skilled in the art may select the appropriate type and amount of acid to be used in conjunction with the diazotizing agent, which may be, for example, nitrite and/or nitrite ester to form nitrous acid, for example, the acid used may include, but is not limited to, HCl, sulfuric acid, and the like. The acid is generally used in an equal or excess amount relative to the compound of formula II, for example, the molar ratio of the acid to the compound of formula II may be 1 to 3: 1, may be 1.1 to 1.5: 1. when used, the acid may be added to the reaction system usually in the form of an aqueous solution thereof, for example, HCl may be in the form of hydrochloric acid, sulfuric acid may be in the form of an aqueous solution thereof, and the mass concentration may usually be 10% to 40%.
In the diazotization addition reaction, one skilled in the art can select the kind and amount of suitable diazotization reagent for the action with acid, for example, the diazotization reagent used may be nitrite and/or nitrite ester, etc., preferably may be nitrite; the nitrite can be sodium nitrite and the like, and the nitrite can be one or a combination of more of tert-butyl nitrite, isopropyl nitrite and the like; the amount of the diazotizing agent used is usually the same amount or an excess amount with respect to the compound of formula II, and for example, the molar ratio of the diazotizing agent to the compound of formula II may be 1 to 10:1, or may be 1.1 to 1.5: 1.
In the diazotization addition reaction, one skilled in the art can select the kind and amount of suitable copper-based catalyst for the diazotization addition reaction, for example, the copper-based catalyst can be selected from copper salt and/or copper oxide, the copper salt can be one or more combinations of copper acetate, basic copper carbonate, copper chloride, cuprous chloride, cupric bromide, cuprous bromide, etc., the preferred copper salt is one or more combinations of basic copper carbonate, cuprous chloride, cuprous bromide, etc., and the more preferred copper salt is basic copper carbonate; the copper oxide may be a combination including, but not limited to, one or more of cupric oxide, cuprous oxide, and the like; the amount of the copper-based catalyst used is usually a catalytic amount, and for example, the molar ratio of the copper-based catalyst to the compound of formula II may be 0.01 to 0.1: 1.
In the diazotization addition reaction, one skilled in the art can select the kind and amount of a suitable phase transfer catalyst for the diazotization addition reaction. For example, the phase transfer catalyst may be a combination including, but not limited to, one or more of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetramethylammonium chloride, methyltrioctylammonium chloride, tetrabutylammonium hydroxide, and the like, and in a preferred embodiment of the present invention, the phase transfer catalyst is preferably selected from tetramethylammonium chloride and/or methyltrioctylammonium chloride; the phase transfer catalyst is generally used in a catalytic amount, for example, the molar ratio of the phase transfer catalyst to the compound of formula II is 0.01 to 0.1: 1.
In the diazotization addition reaction, the vinylidene chloride is generally used in an equal amount or an excessive amount relative to the compound of the formula II, for example, the molar ratio of the vinylidene chloride to the compound of the formula II can be 1-5: 1, can also be 1 ~ 2: 1.
in the diazotization addition reaction, the reaction temperature can be generally-20-30 ℃ or-15 ℃. The reaction time can be adjusted by those skilled in the art according to the reaction progress, and in some embodiments of the present invention, the reaction progress of the diazotization addition reaction can be determined by, for example, gas chromatography, liquid chromatography, and the like, and the reaction time can be 1 to 24 hours.
In the diazotization addition reaction, an acid and a compound of formula II may be added to the reaction system (for example, to a solvent), a phase transfer catalyst and a copper-based catalyst may be further added, and a diazotization reagent may be further added after vinylidene chloride is added to the reaction system to carry out the reaction. After the reaction is finished, excess nitrous acid is extracted and killed, the organic solvent is extracted, and the compound of the formula III is obtained after organic phase desolventization. One skilled in the art can select a suitable reagent for extracting excess nitrous acid, such as a combination including, but not limited to, one or more of urea, sodium bisulfite, sodium sulfite, and the like. One skilled in the art can select suitable reagents for organic solvent extraction, for example using dichloromethane, trichloromethane, 1, 2-dichloroethane, tetrahydrofuran, toluene, trifluorotoluene, p-chlorotrifluoromethane, acetone, acetonitrile, ethyl acetate, isopropyl acetate, preferred organic solvents include, but are not limited to, dichloromethane, trichloromethane, 1, 2-dichloroethane, tetrahydrofuran, toluene, trifluorotoluene, p-chlorotrifluoromethane, and the like, in combination with one or more thereof.
The preparation method of the phenylacetic acid compound provided by the invention can further comprise a hydrolysis reaction, wherein the hydrolysis reaction specifically comprises the following steps: hydrolyzing a compound of formula III in the presence of an acid to produce a compound of formula I (phenylacetic acid compound) according to the following reaction equation:
in the hydrolysis reaction, the reaction can be carried out in the presence of a solvent, and a person skilled in the art can select a suitable kind and amount of the solvent to provide good solubility of the reaction raw material in the reaction system, and provide better dispersibility and solubility of the reaction solvent relative to the reaction raw material. For example, the solvent generally comprises water, and for example, the mass ratio of water to the compound of formula III may be 0.5 to 10:1, or may be 0.5 to 5: 1. The solvent may further include an organic solvent, and those skilled in the art may select a suitable kind and amount of the organic solvent to make the reaction raw material have good solubility in the reaction system, for example, the organic solvent may be a combination including but not limited to one or more of dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, toluene, benzotrifluoride, and p-chlorotrifluoromethylene, and for example, the solvent is selected from water and an organic solvent, the weight ratio of the organic solvent to the water is not more than 2, and the preferred weight ratio of the organic solvent to the water is 0.2 to 1.5: 1.
in the hydrolysis reaction, one skilled in the art can select the type and amount of suitable acid to provide conditions for hydrolysis of the compound of formula III, typically selected from protic acids (typically based on brensted acid-base theory) which may be one or a combination of more including, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, oleum, nitric acid, oleum, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, formic acid, acetic anhydride, and the like, and/or lewis acids (typically based on lewis acid-base theory) which may be one or a combination including, but not limited to, AlCl3、FeCl3、ZnCl2、TiCl4、SnCl4、CoCl2、NiCl2、MnCl2MnO, copper acetate, copper oxide, cuprous oxide, cupric chloride, cuprous chloride, cupric bromide, cuprous bromide and the like. In a particular embodiment of the invention, the acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, oleum, nitric acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, AlCl3、FeCl3、ZnCl2One or more of the following; the acid is preferably selected from the group consisting of hydrochloric acid, sulfuric acid, oleum, nitric acid, formic acid, acetic acid, and the like, and more preferably from sulfuric acid, which is typically concentrated sulfuric acid, preferably at a concentration of 80% to 98%, and oleum preferably at a concentration of 1% to 50%. The mass ratio of the acid to the compound I in the formula II can be 0.05-5: 1, and can also be 0.1-2: 1.
In the hydrolysis reaction, the reaction temperature may be usually 20 to 160 ℃ or 60 to 120 ℃. The reaction time can be adjusted by those skilled in the art according to the reaction progress, and in some embodiments of the present invention, the reaction progress of the diazotization addition reaction can be determined by, for example, gas chromatography, liquid chromatography, and the like, and the reaction time can be 1 to 24 hours.
In the hydrolysis reaction, the reaction is usually carried out under a gas protection, and the gas used for the gas protection may be a gas which does not react with the main substance (for example, the compound of formula III, the acid, the compound of formula I, etc.) in the reaction system, and may be, for example, nitrogen and/or an inert gas, and the inert gas may be, for example, helium, neon, argon, krypton, xenon, etc.
In the hydrolysis reaction, the compound of formula III may be added (e.g., dropwise) to the aqueous acid solution in portions to carry out the reaction, and the aqueous acid solution may be a dilute solution or a concentrated solution, such as a 20-98% aqueous sulfuric acid solution, a 20-36% aqueous hydrochloric acid solution, and the like. After the reaction is finished, quenching and cooling are carried out, and after solid-liquid separation and solid-phase substance purification, the compound of the formula I is obtained. The quenching can be carried out by a suitable method selected by those skilled in the art, for example, water is added for quenching, and for example, the reaction solution can be cooled and then added into ice water, or water with the temperature of 0-10 ℃ can be added into the reaction solution after cooling. The compound of formula I can be purified by a suitable method selected by those skilled in the art, for example, recrystallization and/or pulping can be used, the solvent used in the recrystallization and/or pulping process can be one or more selected from but not limited to toluene, dichloromethane, trichloromethane, 1, 2-dichloroethane, tetrahydrofuran, ethylbenzene, chlorobenzene, p-chlorotrifluoromethane, acetonitrile, acetone, etc., the preferred recrystallization solvent is one or more selected from toluene, dichloromethane, dichloroethane, etc., and the amount of recrystallization and/or pulping solvent can be 1-10 times, preferably 1-3 times, that of the compound of formula III. The skilled person can select a suitable recrystallization and/or pulping mode, for example, adding the crude product into a solvent, heating, stirring uniformly, cooling and crystallizing.
The preparation method provided by the invention has the advantages of simple and easily-obtained raw materials, simple and convenient operation, low raw material cost, mild reaction conditions, low risk, no need of expensive noble metal catalysts and complex industrial operation means, and stable product quality, thereby being suitable for realizing large-scale industrial production.
The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.
It is to be understood that the processing equipment or apparatus not specifically identified in the following examples is conventional in the art.
Furthermore, it is to be understood that one or more method steps mentioned in the present invention does not exclude that other method steps may also be present before or after the combined steps or that other method steps may also be inserted between these explicitly mentioned steps, unless otherwise indicated; it is also to be understood that a combined connection between one or more devices/apparatus as referred to in the present application does not exclude that further devices/apparatus may be present before or after the combined device/apparatus or that further devices/apparatus may be interposed between two devices/apparatus explicitly referred to, unless otherwise indicated. Moreover, unless otherwise indicated, the numbering of the various method steps is merely a convenient tool for identifying the various method steps, and is not intended to limit the order in which the method steps are arranged or the scope of the invention in which the invention may be practiced, and changes or modifications in the relative relationship may be made without substantially changing the technical content.
Example 1
Preparation of 3, 4-dimethylphenylacetic acid:
adding 900 g of 20% HCl and 250g of 3, 4-dimethylaniline into a reaction bottle, and heating to 85-95 ℃ for clearing. Cooling to-5 ℃, and adding 20g of tetrabutylammonium chloride and 20g of cuprous chloride. 250g of vinylidene chloride are added dropwise. Keeping the temperature at-5 ℃, and slowly dropwise adding an aqueous solution containing 150g of sodium nitrite. The reaction was incubated for 2 hours. After the reaction is finished, quenching excessive nitrous acid. Dichloromethane was added to the mixture for extraction, and desolventization was performed to obtain 369.2g of 1- (2,2, 2-trichloroethyl) -3, 4-dimethylbenzene.
A1L three-necked flask was charged with 300g of 30% hydrochloric acid under nitrogen protection. Heating to 80-95 ℃. 200g of intermediate 1- (2,2, 2-trichloroethyl) -3, 4-dimethylbenzene are added dropwise. After the dropwise addition, the reaction was carried out for 10 hours under heat preservation. And (5) finishing the reaction. And cooling and quenching the system. Filtered, washed with water and dried to obtain 190g of crude product. Recrystallizing with 200g toluene to obtain 101.1g of pure 3, 4-dimethylphenylacetic acid, melting point of 87-89 ℃, and HPLC purity of more than 99 wt%.
Example 2
Preparation of 2, 4-dichlorophenylacetic acid:
adding 800g of 15% HCl solution and 250g of 2, 4-dichloroaniline into a reaction bottle, and heating to 85-95 ℃ for clearing. Cooling to-5 ℃, and adding 10g of tetramethylammonium chloride and 20g of cuprous chloride. 250g of vinylidene chloride are added dropwise. Keeping the temperature at-5 ℃, and slowly dropwise adding an aqueous solution containing 150g of sodium nitrite. The reaction was incubated for 2 hours. After the reaction is finished, quenching excessive nitrous acid. Dichloromethane was added to the mixture for extraction, and the mixture was desolventized to give 320.2g of 1- (2,2, 2-trichloroethyl) -2, 4-dichlorobenzene.
A1L three-necked flask was charged with 200g of a 25% sulfuric acid solution and 200g of toluene under nitrogen protection. Heating to 80-90 ℃. 200g of 1- (2,2, 2-trichloroethyl) -2, 4-dichlorobenzene are added dropwise. After the dropwise addition, the reaction was carried out for 8 hours under heat preservation. And (5) finishing the reaction. And cooling and quenching the system. After the organic phase is washed by water, the temperature is reduced and crystallization is carried out, thus obtaining 107.1g of 2, 4-dichlorophenylacetic acid, the melting point is 129-132 ℃, and the HPLC purity is more than 95 wt%.
Example 3
Preparation of 2, 6-dichlorophenylacetic acid:
adding 800g of 30% sulfuric acid solution and 250g of 2, 6-dichloroaniline into a reaction bottle, and heating to 85-95 ℃ for clearing. And cooling to-5 ℃, and adding 20g of tetrabutylammonium bromide and 20g of cuprous bromide. 200g of vinylidene chloride are added dropwise. Keeping the temperature at-5 ℃, and slowly dropwise adding an aqueous solution containing 150g of sodium nitrite. The reaction was incubated for 2 hours. After the reaction is finished, quenching excessive nitrous acid. Dichloromethane was added to the residue, and extraction and desolventization were carried out to obtain 317.4g of 1- (2,2, 2-trichloroethyl) -2, 6-dichlorobenzene.
A1L three-necked flask was charged with 300g of 30% hydrochloric acid under nitrogen protection. Heating to 80-95 ℃. 200g of intermediate 1- (2,2, 2-trichloroethyl) -2, 6-dichlorobenzene are added dropwise. After the dropwise addition, the reaction was carried out for 10 hours under heat preservation. And (5) finishing the reaction. And cooling and quenching the system. Filtration, washing with water and drying gave 203.0g of crude product. Recrystallizing with toluene to obtain 115.3g of pure 2, 6-dichlorophenylacetic acid, the melting point of 161-.
Example 4
Preparation of 4-chlorophenylacetic acid:
adding 900 g of 25% sulfuric acid solution and 250g of 4-chloroaniline into a reaction bottle, and heating to 85-95 ℃ for clearing. And cooling to-5 ℃, and adding 20g of methyl trioctyl ammonium chloride and 20g of basic copper carbonate. 200g of vinylidene chloride are added dropwise. Keeping the temperature at-5 ℃, and slowly dropwise adding an aqueous solution containing 150g of sodium nitrite. The reaction was incubated for 2 hours. After the reaction is finished, quenching excessive nitrous acid. Dichloroethane was added to the mixture for extraction and desolventization to obtain 366.4g of 1- (2,2, 2-trichloroethyl) -4-chlorobenzene.
A1L three-necked flask was charged with 200g of 90% sulfuric acid under nitrogen protection. Heating to 80-90 ℃. 200g of intermediate 1- (2,2, 2-trichloroethyl) -4-chlorobenzene are added dropwise. After the dropwise addition, the reaction was carried out for 8 hours under heat preservation. And (5) finishing the reaction. The system is cooled and dripped into ice water for quenching. Filtration, washing of the filter cake with water and drying gave 191.0g of crude product. Recrystallizing with 200g toluene to obtain 118.0g of pure 4-chlorophenylacetic acid with a melting point of 101-105 ℃ and an HPLC purity of more than 98 wt%.
Example 5
Preparation of 2-methyl-4-fluoro-5-bromobenzoic acid:
500g of 20% hydrochloric acid solution and 250g of 2-methyl-4-fluoro-5-bromoaniline are added into a reaction bottle, and the mixture is heated to 85-95 ℃ for dissolution. And cooling to-5 ℃, and adding 20g of tetrabutylammonium chloride and 6g of cuprous oxide. 300g of vinylidene chloride are added dropwise. Keeping the temperature at-5 ℃, and slowly dropwise adding 150g of isopropyl nitrite and 600g of acetone. The reaction was incubated for 4 hours. And (5) quenching after the reaction is finished. After separation of the organic phase, desolventization was carried out to obtain 291.1g of 1- (2,2, 2-trichloroethyl) -2-methyl-4-fluoro-5-bromobenzene.
In a three-necked flask, 200g of 90% sulfuric acid was added under nitrogen protection. Heating to 80-90 ℃. 200g of 1- (2,2, 2-trichloroethyl) -2-methyl-4-fluoro-5-bromobenzene are added dropwise. After the dropwise addition, the reaction was carried out for 10 hours under heat preservation. And (5) finishing the reaction. The system is cooled and dripped into ice water for quenching. Filtration, washing of the filter cake with water and drying gave 197.0g of crude product. Recrystallization from 200g of toluene gave 121.7g of 2-methyl-4-fluoro-5-bromobenzoic acid, mp 99-104 ℃ and HPLC purity greater than 98% by weight.
Example 6
Preparation of 3-chlorophenylacetic acid:
350 g of 32% hydrochloric acid solution and 250g of 3-chloroaniline are added into a reaction bottle, and the mixture is heated to 85-95 ℃ for dissolution and cleaning. And cooling to-5 ℃, and adding 20g of methyl trioctyl ammonium chloride and 20g of cuprous oxide. 300g of vinylidene chloride are added dropwise. Keeping the temperature at-5 ℃, and slowly dropwise adding a solution containing 200g of isopropyl nitrite and 800g of dichloromethane. The reaction was incubated for 5 hours. After the reaction, the mixture was quenched, extracted and desolventized to obtain 356g of 1- (2,2, 2-trichloroethyl) -3-chlorobenzene.
A1L three-necked flask was charged with 300g of water, 100g of dichloroethane and 100g of p-toluenesulfonic acid under nitrogen protection. Stirring, heating and refluxing. 200g of intermediate 1- (2,2, 2-trichloroethyl) -3-chlorobenzene are added dropwise. After the dropwise addition, the reaction was carried out for 15 hours while maintaining the temperature. And (5) finishing the reaction. Cooling the system to 10 ℃, filtering, washing filter cakes with water, recrystallizing with 200g of dichloroethane to obtain 103.1g of pure 3-chlorophenylacetic acid, wherein the melting point is 74-78 ℃, and the HPLC purity is more than 95 wt%.
Example 7
Preparation of 3-bromophenylacetic acid:
600g of 20% hydrochloric acid solution and 250g of 3-bromoaniline are added into a reaction bottle, and the mixture is heated to 85-95 ℃ for clearing. And cooling to-5 ℃, and adding 20g of tetrabutylammonium bromide and 20g of cuprous bromide. 250g of vinylidene chloride are added dropwise. Keeping the temperature at-5 ℃, and slowly dropwise adding an aqueous solution containing 150g of sodium nitrite. The reaction was incubated for 2 hours. After the reaction, the reaction mixture was quenched, extracted and desolventized to obtain 296.3g of 1- (2,2, 2-trichloroethyl) -3-bromobenzene.
A1L three-necked flask was charged with 300g of water, 100g of dichloroethane and 50g of ferric chloride under nitrogen protection. Stirring, heating and refluxing. 200g of intermediate 1- (2,2, 2-trichloroethyl) -3-bromobenzene are added dropwise. After the dropwise addition, the reaction was carried out for 12 hours under heat preservation. And (5) finishing the reaction. The system is cooled to 10 ℃ and then filtered, filter cakes are washed by water, and the pure product of 108.7g of 3-bromobenzeneacetic acid is obtained by recrystallization with 200g of dichloroethane, the melting point is about 100 ℃ and 104 ℃, and the HPLC purity is more than 95 wt%.
Example 8
Preparation of 4-bromophenylacetic acid:
600g of 20% hydrochloric acid solution and 250g of 4-bromoaniline are added into a reaction bottle, and the mixture is heated to 80-90 ℃ for clearing. Cooling to-5 ℃, and adding 20g of tetramethylammonium bromide and 20g of basic copper carbonate. 250g of vinylidene chloride are added dropwise. Keeping the temperature at-5 ℃, and slowly dropwise adding an aqueous solution containing 150g of sodium nitrite. The reaction was incubated for 2 hours. And (5) quenching after the reaction is finished. 500g of dichloroethane was added to the mixture, and extraction and desolventization were carried out to obtain 327.9g of 1- (2,2, 2-trichloroethyl) -4-bromobenzene.
A1L three-necked flask was charged with 200g of 90% sulfuric acid under nitrogen protection. Heating to 80-90 ℃. 200g of intermediate 1- (2,2, 2-trichloroethyl) -4-bromobenzene are added dropwise. After the dropwise addition, the reaction was carried out for 6 hours under heat preservation. And (5) finishing the reaction. The system is cooled and dripped into ice water for quenching. Filtering, washing filter cake with water and drying. Recrystallization from 200g of toluene gave 117.4g of 4-bromobenzoic acid, melting point 113-.
Example 9
Preparation of 2-methylphenylacetic acid:
adding 800g of 30% sulfuric acid solution and 250g of 2-methylaniline into a reaction bottle, and heating to 80-90 ℃ for clearing. Cooling to-5 ℃, and adding 20g of tetramethylammonium bromide and 20g of cuprous bromide. 200g of vinylidene chloride are added dropwise. Keeping the temperature at-5 ℃, and slowly dropwise adding an aqueous solution containing 200g of sodium nitrite. The reaction was incubated for 2 hours. And (5) quenching after the reaction is finished. 400g of dichloroethane was added, and extraction and desolvation were carried out to obtain 376.8g of 1- (2,2, 2-trichloroethyl) -2-methylbenzene.
A1L three-necked flask was charged with 200g of 50% sulfuric acid under nitrogen protection. Heating to 80-90 ℃. 200g of intermediate 1- (2,2, 2-trichloroethyl) -2-methylbenzene are added dropwise. After the dropwise addition, the reaction was carried out for 8 hours under heat preservation. And (5) finishing the reaction. And cooling and quenching the system. Filtering, washing filter cake with water and drying. Recrystallization from toluene gave 96.5g of 2-methylacetic acid, m.p. 87-92 ℃ and HPLC purity greater than 95% by weight.
Example 10
Preparation of 4-methylphenylacetic acid:
adding 800g of 30% sulfuric acid solution and 250g of 4-methylaniline into a reaction bottle, and heating to 80-90 ℃ for clearing. Cooling to-5 ℃, and adding 20g of tetramethylammonium bromide and 20g of basic copper carbonate. 200g of vinylidene chloride are added dropwise. Keeping the temperature at-5 ℃, and slowly dropwise adding an aqueous solution containing 200g of sodium nitrite. The reaction was incubated for 2 hours. And (5) quenching after the reaction is finished. 400g of dichloroethane was added to the mixture, and the mixture was extracted and desolventized to obtain 403.1g of 1- (2,2, 2-trichloroethyl) -4-methylbenzene.
A1L three-necked flask was charged with 200g of 90% sulfuric acid under nitrogen protection. Heating to 80-90 ℃. 200g of intermediate 1- (2,2, 2-trichloroethyl) -4-methylbenzene are added dropwise. After the dropwise addition, the reaction was carried out for 8 hours under heat preservation. And (5) finishing the reaction. And cooling and quenching the system. Filtering, washing filter cake with water and drying. Recrystallization from 200g of toluene gave 107.2g of 4-methylacetic acid, melting point 90-92 ℃ and HPLC purity > 98 wt.%.
Example 11
Preparation of 4-trifluoromethylphenylacetic acid:
adding 900 g of 10% hydrochloric acid solution and 250g of 4-trifluoromethylaniline into a reaction bottle, and heating to 80-90 ℃ for dissolving. Cooling to-5 ℃, and adding 10g of tetramethylammonium chloride and 20g of basic copper carbonate. 250g of vinylidene chloride are added dropwise. Keeping the temperature at-5 ℃, and slowly dropwise adding an aqueous solution containing 200g of sodium nitrite. The reaction was incubated for 2 hours. And (5) quenching after the reaction is finished. 400g of dichloroethane was added, and extraction and desolvation were carried out to obtain 345.6g of 1- (2,2, 2-trichloroethyl) -4-trifluoromethylbenzene.
A1L three-necked flask was charged with 200g of 90% sulfuric acid under nitrogen protection. Heating to 80-90 ℃. 200g of intermediate 1- (2,2, 2-trichloroethyl) -4-trifluoromethylbenzene are added dropwise. After the dropwise addition, the reaction was carried out for 6 hours under heat preservation. And (5) finishing the reaction. And cooling and quenching the system. Filtering, washing filter cake with water and drying. Recrystallization from 200g of toluene and dichloroethane (1w/w) gave 120.4g of 4-trifluoromethylacetic acid, m.p. 80-84 ℃ and HPLC purity greater than 98 wt.%.
In conclusion, the present invention effectively overcomes various disadvantages of the prior art and has high industrial utilization value.
The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.
Claims (8)
1. A method for preparing a phenylacetic acid compound, wherein the structural formula of the phenylacetic acid compound is shown as a formula I:
wherein R is1～R5Any two of which are independently selected from Cl, Br, -CH3、-CF3And the others are each independently selected from H or F;
or, R1～R5Any one of them is selected from Cl, Br and-CH3、-CF3And the balance is H;
or, R3Selected from Cl, Br, -CH3、-CF3And the balance is H;
the preparation method comprises the following steps:
(1) diazotization addition reaction: reacting a compound of formula II in a system containing vinylidene chloride, an acid, a diazotizing agent, a phase transfer catalyst and a copper-based catalyst to produce a compound of formula III, wherein the reaction equation is as follows:
(2) and (3) hydrolysis reaction: hydrolyzing the compound of formula III in the presence of an acid to produce a compound of formula I, wherein the reaction equation is as follows:
in the step (1), the phase transfer catalyst is selected from one or more of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetramethylammonium chloride, methyltrioctylammonium chloride and tetrabutylammonium hydroxide;
in the step (1), the acid is selected from HCl.
2. The method of claim 1, further comprising one or more of the following technical features:
B1) the compound of the formula I is selected from 3, 4-dichlorophenylacetic acid, 2, 6-dichlorophenylacetic acid, 3, 5-dimethylphenylacetic acid and 3-bromo-4-fluoro-6-methylphenylacetic acid;
B2) the compound of the formula I is selected from o-chlorophenylacetic acid, 3-chlorophenylacetic acid, 4-chlorophenylacetic acid, o-bromophenylacetic acid, 3-bromophenylacetic acid, 4-bromophenylacetic acid, 2-methylphenylacetic acid, 3-methylphenylacetic acid, 4-methylphenylacetic acid, 3-trifluoromethylphenylacetic acid and 4-trifluoromethylphenylacetic acid;
B3) the compound of the formula I is selected from 4-chlorophenylacetic acid, 4-bromophenylacetic acid, 4-methylphenylacetic acid and 4-trifluoromethylphenylacetic acid.
3. The method of claim 1, further comprising one or more of the following technical features:
C1) in the step (1), the reaction is carried out in the presence of a solvent, wherein the solvent is water and/or an organic solvent;
C2) in the step (1), the acid is selected from HCl and/or sulfuric acid;
C3) in the step (1), the diazotizing agent is selected from nitrite and/or nitrite;
C4) in the step (1), the molar ratio of the diazotization reagent to the compound of the formula II is 1-10: 1;
C5) in the step (1), the copper-based catalyst is selected from copper salt and/or copper oxide;
C6) in the step (1), the molar ratio of the copper-based catalyst to the compound of the formula II is 0.01-0.1: 1;
C7) in the step (1), the molar ratio of the phase transfer catalyst to the compound of the formula II is 0.01-0.1: 1;
C8) in the step (1), the molar ratio of the vinylidene chloride to the compound of the formula II is 1-5: 1;
C9) in the step (1), the reaction temperature is-20 ℃ to 30 ℃;
C10) in the step (1), after the reaction is finished, excess nitrous acid is extracted and killed, the organic solvent is extracted, and the organic phase is desolventized to obtain the compound shown in the formula III.
4. The method of claim 3, further comprising one or more of the following technical features:
D1) in the step (1), the solvent is a combination of water and an organic solvent, wherein the weight ratio of the organic solvent to the water is not more than 2;
D2) in the step (1), the organic solvent is one or more of dichloromethane, trichloromethane, 1, 2-dichloroethane, tetrahydrofuran, toluene, benzotrifluoride, p-chlorotrifluoromethane, acetone and acetonitrile;
D3) in the step (1), the mass ratio of the solvent to the compound of the formula II is 1-10: 1;
D4) in the step (1), the molar ratio of the acid to the compound of the formula II is 1-3: 1;
D5) in the step (1), the nitrite is selected from sodium nitrite;
D6) in the step (1), the nitrite is selected from tert-butyl nitrite and/or isopropyl nitrite;
D7) in the step (1), the molar ratio of the diazotization reagent to the compound of the formula II is 1.1-1.5: 1;
D8) in the step (1), the cupric salt is selected from one or more of cupric acetate, basic cupric carbonate, cupric chloride, cuprous chloride, cupric bromide and cuprous bromide;
D9) in the step (1), the copper oxide is selected from one or more of cupric oxide and cuprous oxide;
D10) in the step (1), the molar ratio of the vinylidene chloride to the compound of the formula II is 1-2: 1;
D11) in the step (1), the reaction temperature is-15 ℃ to 15 ℃.
5. The method of claim 4, further comprising one or more of the following technical features:
E1) in the step (1), the solvent is a combination of water and an organic solvent, wherein the weight ratio of the organic solvent to the water is 0.2-1.5: 1;
E2) in the step (1), the mass ratio of the solvent to the compound of the formula II is 1-5: 1;
E3) in the step (1), the molar ratio of the acid to the compound of the formula II is 1.1-1.5: 1.
6. the method of claim 1, further comprising one or more of the following technical features:
F1) in the step (2), the reaction is carried out in the presence of a solvent, wherein the solvent is selected from water and/or an organic solvent;
F2) in the step (2), the acid is selected from protonic acid and/or Lewis acid;
F3) in the step (2), the mass ratio of the acid to the compound of the formula III is 0.05-5: 1;
F4) in the step (2), the reaction temperature is 20-160 ℃;
F5) in the step (2), the reaction is carried out under the condition of gas protection, and the gas used for gas protection is selected from nitrogen and/or inert gas;
F6) in the step (2), water is added for extraction and sterilization after the reaction is finished, solid-liquid separation is carried out, and the compound of the formula I is obtained after a solid phase substance is purified.
7. The method of claim 6, further comprising one or more of the following technical features:
G1) in the step (2), the solvent is selected from a combination of water and an organic solvent, and the weight ratio of the organic solvent to the water is not more than 2;
G2) in the step (2), the organic solvent is selected from one or more of dichloromethane, trichloromethane, 1, 2-dichloroethane, tetrahydrofuran, toluene, benzotrifluoride and p-chlorotrifluoromethylene;
G3) in the step (2), the mass ratio of the solvent to the compound shown in the formula III is 1-10: 1;
G4) in the step (2), the protonic acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, oleum, nitric acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, formic acid and acetic acid;
G5) in the step (2), the Lewis acid is selected from AlCl3、FeCl3、ZnCl2、TiCl4、SnCl4、CoCl2、NiCl2、MnCl2MnO, copper acetate, cupric oxide, cuprous oxide, cupric chloride, cuprous chloride, cupric bromide and cuprous bromide;
G6) in the step (2), the mass ratio of the acid to the compound of the formula III is 0.1-2: 1;
G7) in the step (2), the reaction temperature is 60-120 ℃;
G8) in the step (2), the purification mode is recrystallization.
8. The method of claim 7, further comprising one or more of the following technical features:
H1) in the step (2), the solvent is selected from the combination of water and an organic solvent, and the weight ratio of the organic solvent to the water is 0.2-1.5: 1;
H2) in the step (2), the mass ratio of the solvent to the compound of the formula III is 2-5: 1;
H3) in the step (2), the solvent used for recrystallization is selected from one or more of toluene, dichloromethane, trichloromethane, 1, 2-dichloroethane, tetrahydrofuran, toluene, benzotrifluoride and p-chlorotrifluoromethylene.
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