CN1683311A - A kind of preparation method of aryl acetic acid - Google Patents

Abstract

The present invention relates to the preparation process of aryl acetic acid as one important intermediate of medicine, pesticide, perfume, etc. The preparation process includes the nucleophilic addition reaction of N-(2, 3, 4, 6-tetrapivaloyl glucityl) aryl amide and trimethyl silicon cyanide under the catalysis of transition metal and Lewis acid inside tetrahydrofuran, acetonitrile, chlorohydrocarbon with 1-3 carbon atoms or alcohol with 3 or 4 carbon atoms to obtain N-(2, 3, 4, 6-tetrapivaloyl glucityl)-alpha-amino aryl acetonitrile, and the hydrolysis of N-(2, 3, 4, 6-tetrapivaloyl glucityl)-alpha-amino aryl acetonitrile in acetic acid solution of hydrogen halide to obtain the aryl acetic acid. The present invention has low cost, high safety, high yield and reuseability of side product.

Description

Preparation method of aryl acetic acid

(I) technical field

The invention relates to a preparation method of aryl acetic acid which is an important fine chemical intermediate such as medicines, pesticides, spices and the like.

(II) background of the invention

In the prior art, chemical synthesis methods of phenylacetic acid comprise the following steps:

firstly, preparing a target compound by a nitrile hydrolysis method:

the hydrolysis method of the phenylacetonitrile comprises an alkaline hydrolysis method and an acid hydrolysis method, the phenylacetonitrile is obtained by condensing benzyl chloride and sodium cyanide under a certain medium and a catalyst, the hydrolysis of the phenylacetonitrile generally adopts an alkaline hydrolysis process, and the reaction is as follows:

the process has the following defects: the toxicity of the raw material NaCN and the intermediate product benzyl cyanide is very high, particularly, a substance, namely the benzyl cyanide which is highly toxic and has malodor, is generated in the synthetic process of the benzyl cyanide, the substances have strong volatility, serious pollution is caused to the operating environment, the pollution of waste water is serious, the treatment cost is high, the yield of the benzyl cyanide is not high, and the production cost is high. In the long term, the method must be gradually eliminated.

Secondly, reacting benzene, formaldehyde and carbon monoxide to prepare a target compound:

the method is unsafe to react under high pressure, small in amount, difficult to industrialize, expensive in catalyst and difficult to recycle.

Thirdly, preparing the target compound by a phenylacetamide hydrolysis method (Virgorode method):

the first step of the process needs pressurization, and a byproduct, namely phenethyl mercaptan, is generated, has foul smell and serious pollution.

Fourthly, preparing a target compound by a benzyl alcohol method:

reacting for 4-5 hours at 150 ℃ under high pressure to obtain phenylacetic acid:

the reaction catalyst is difficult to manufacture, expensive, high in reaction pressure and dangerous.

Preparing a target compound by a benzyl chloride carbonylation method:

under the action of catalyst (organic palladium complex, rhodium complex, carbonyl iron, iron-manganese alloy, cobalt salt, carbonyl cobalt complex, etc.), adding proper organic solvent to make benzyl chloride implement carbonylation in two-phase system, under the acidic condition making sodium phenylacetate implement acidification to obtain phenylacetic acid:

the technical requirement in the process is high, expensive catalyst needs to be used, catalyst particles are very fine and need to be carefully operated to prevent the catalyst from being inactivated or lost, the catalyst is difficult to separate, a recovery method is not mature, the production difficulty is high, and the like.

Preparing a target compound by a benzyl chloride-carbon dioxide electrolysis method:

the process for preparing phenylacetic acid by an electrolytic method is to adopt a sacrificial anode method to realize electro-carboxylation and synthesize phenylacetic acid by electro-carbonylation of benzyl chloride. If Mg is taken as an anode, the reaction is as follows:

(anodic reaction)

(cathode reaction)

And (3) total reaction:

the method has the advantages of expensive electrode materials and electrolyte, high power consumption, difficult separation and recycling of the solvent, the supporting electrolyte and byproducts, high cost and difficult industrialization.

Disclosure of the invention

In order to solve the defects of high preparation cost, complex process, high risk and low yield of the aryl acetic acid, especially the phenylacetic acid in the prior art, the invention provides the preparation method of the aryl acetic acid, which has the advantages of low cost, reasonable process, safe and reliable production and high reaction yield.

The technical scheme adopted by the invention for achieving the aim of the invention is as follows:

a process for preparing arylacetic acids of formula IV, wherein N- (2, 3, 4, 6-tetrapivaloylglucosyl) arylimines of formula IIN are subjected to nucleophilic addition reaction with trimethylsilyanide in tetrahydrofuran or acetonitrile or chlorinated hydrocarbon containing 1-3 carbon atoms or alcohol containing 3-4 carbon atoms under the catalysis of a transition metal Lewis acid, wherein the arylacetic acids of formula IIIN- (2, 3, 4, 6-tetrapivaloylglucosyl) - α -aminoarylacetonitrile, N- (2, 3, 4, 6-tetrapivaloylglucosyl) - α -aminoarylacetonitrile are hydrolyzed in a hydrohalic acetic acid solution to obtain arylacetic acids of formula IV:

in formulas II and III, Piv ═ CH₃)₃CCO; in formula IV, Ar is aryl.

Taking phenylacetic acid as an example, the preparation method of the aryl acetic acid is as follows:

n- (2, 3, 4, 6-tetrapivalyl glucosyl) phenylimine and trimethylsilanolate are subjected to nucleophilic addition reaction in tetrahydrofuran or acetonitrile or chlorohydrocarbon containing 1-3 carbon atoms or alcohol containing 3-4 carbon atoms under the catalysis of transition metal Lewis acid to obtain N- (2, 3, 4, 6-tetrapivalyl glucosyl) - α -aminobenzeneacetonitrile, and the N- (2, 3, 4, 6-tetrapivalyl glucosyl) - α -aminobenzeneacetonitrile is hydrolyzed in a hydrogen halide acetic acid solution to obtain the phenylacetic acid.

The transition metal Lewis acid is one of the following:

①SnCl₄②ZnCl₂③TiCl₄④ZnI₂⑤CuCl ⑥CuBr

⑦CuBr.S(CH₃)₂⑧CuCl₂⑨CuBr₂。

the organic solvent is one of the following solvents:

① Dichloromethane ② chloroform ③ Isopropanol ④ tetrahydrofuran ⑤ acetonitrile.

The mass content of the hydrogen halide in the hydrogen halide acetic acid solution is 30-50%, and the hydrogen halide is hydrogen bromide or hydrogen iodide.

The preferred ratio of the amount of transition metal Lewis acid to the amount of trimethylsilcyanide material is 1: 1.

Specifically, the method comprises the following steps:

(1) at the temperature of minus 40 to minus 20 ℃, dropwise adding a dichloromethane solution containing N- (2, 3, 4, 6-tetrapivalyl glucosyl) arylimine into a dichloromethane solution dissolved with trimethylsilanoate and transition metal Lewis acid;

(2) stirring and heating to room temperature for reaction, after the reaction is finished, evaporating the solvent, dissolving the residue with dichloromethane, washing, drying, evaporating, and recrystallizing the evaporated substance in N-heptane to obtain N- (2, 3, 4, 6-tetrapivalyl glucosyl) - α -aminoaryl acetonitrile;

(3) dissolving N- (2, 3, 4, 6-tetrapivalyl glucosyl) - α -amino aryl acetonitrile in a dichloromethane solution, dropwise adding a 45% HBr/HAc solution, keeping the solution at room temperature for 1-4 hours, and filtering to obtain aryl acetic acid;

further, the method comprises the following steps:

(1) at the temperature of between 40 ℃ below zero and 20 ℃ below zero, dropwise adding a dichloromethane solution containing N- (2, 3, 4, 6-tetrapivaloyl glucosyl) aryl imine into a dichloromethane solution dissolved with a trimethylsilyanide compound, wherein the ratio of the amounts of the trimethylsilyanide, a Lewis acid catalyst and the N- (2, 3, 4, 6-tetrapivaloyl glucosyl) aryl imine substances is 1.25: 1

(2) Stirring and heating to room temperature for reaction, after the reaction is finished, evaporating the solvent, dissolving the residue in dichloromethane, washing the dichloromethane solution with 2N hydrochloric acid, saturated sodium bicarbonate water solution and water in sequence, drying with magnesium sulfate, drying, evaporating to dryness, and recrystallizing the evaporated product in N-heptane to obtain N- (2, 3, 4, 6-tetra-pivaloyl glucosyl) - α -aminoarylacetonitrile;

(3) dissolving N- (2, 3, 4, 6-tetrapivalyl glucosyl) - α -amino aryl acetonitrile in a dichloromethane solution, dropwise adding a 45% HBr/HAc solution, keeping the solution at room temperature for 1-4 hours, and filtering to obtain the aryl acetic acid.

In particular, when the aryl acetic acid is phenylacetic acid, the preparation method comprises the following steps:

(1) at the temperature of minus 40 to minus 20 ℃, dropwise adding a dichloromethane solution containing N- (2, 3, 4, 6-tetrapivalyl glucosyl) phenylimine into a dichloromethane solution dissolved with trimethylsilyanide and Lewis acid, wherein the molar ratio of the trimethylsilyanide to the Lewis acid to the N- (2, 3, 4, 6-tetrapivalyl glucosyl) phenylimine is 1.25: 1;

(2) stirring and heating to room temperature for reaction, evaporating the solvent after the reaction is finished, and dissolving the residue in CH₂Cl₂In (1), the organic layer was washed with 2N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and water in this order, and then with MgSO₄Drying, evaporating to dryness, and recrystallizing the evaporated material in n-heptane;

(3) dissolving N- (2, 3, 4, 6-tetra-pivaloyl glucosyl) - α -aminobenzyl acetonitrile in a dichloromethane solution, dropwise adding a 45% HBr/HAc solution, keeping the solution at room temperature for 1-4 hours, and filtering to obtain phenylacetic acid solid.

The N- (2, 3, 4, 6-tetrapivalyl glucosyl) arylimine is generally prepared by taking IN-2, 3, 4, 6-tetrapivalyl glucosyl amine as a substrate and condensing with aldehyde through acid catalysis, andthe reaction formula is as follows:

the preparation method of the aryl acetic acid has the following beneficial effects: (1) the raw materials are cheap and easy to obtain, and the cost is low; (2) the method avoids using raw materials of sodium cyanide or hydrocyanic acid, is simple and safe to operate, and has high reaction yield; (3) the by-product can be effectively recycled, and has great implementation value and social and economic benefits.

(IV) detailed description of the preferred embodiments

The invention is further described below with reference to specific examples:

EXAMPLE 1 Synthesis of N- (2, 3, 4, 6-Tetrapivaloylglucosyl) - α -aminophenylacetonitrile

At-40 deg.C to-20 deg.C, slowly dropping 1mL of dichloromethane solution containing (30mmol) N- (2, 3, 4, 6-tetrapivaloylglucosyl) phenylimine into dichloromethane (20mL) solution containing 3.96 g trimethyl silicon azide cyanide (37.5mmol) and CuBr (37.5mmol), stirring, slowly heating the solution to-20 deg.C, reacting at-20 deg.C, monitoring by TLC, evaporating solvent, and dissolving the residual residue in 400mL CH₂Cl₂In (1), the organic layer was successively washed with 2N HCl (100mL), saturated NaHCO₃(200 mL. times.3) and water (200mL), and the organic layer was washed with MgSO₄Drying, evaporating the solvent after drying to obtain 16.3 g of crude product, the yield is 86%.

EXAMPLE 2 Synthesis of N- (2, 3, 4, 6-Tetrapivaloylglucosyl) - α -aminophenylacetonitrile

1mL of a solution containing 3.96 g of trimethylsilylazide cyanide (37.5mmol) and CuBr (37.5mmol) dissolved in methylene chloride (20mL) was slowly dropped at-20 ℃ to 0 ℃30mmol of N- (2, 3, 4, 6-Tetrapivaloylglucosyl) phenylimine in dichloromethane, slowly heating to 0 deg.C under stirring, reacting at 0 deg.C under TLC monitoring, evaporating off solvent, and dissolving the residue in 400mL of CH₂Cl₂In (1), the organic layer was successively washed with 2N HCl (100mL), saturated NaHCO₃(200 mL. times.3) and water (200mL), and the organic layer was washed with MgSO₄Drying, evaporating the solvent after drying to obtain 16.8 g of crude product, the yield is 89%.

EXAMPLE 3 Synthesis of N- (2, 3, 4, 6-Tetrapivaloylglucosyl) - α -aminophenylacetonitrile

1mL of a solution containing 30mmol of N- (2, 3, 4, 6-Tetrapivaloylglucosyl) benzimine in dichloromethane, after dropwise addition, the solution was slowly warmed to 25 ℃ with stirring, the reaction was carried out at 25 ℃ and monitored by TLC, after completion of the reaction, the solvent was evaporated off, and the remaining residue was dissolved in 400mL of CH₂Cl₂In (1), the organic layer was successively washed with 2N HCl (100mL), saturated NaHCO₃(200 mL. times.3) and water (200mL), and the organic layer was washed with MgSO₄Drying, evaporating the solvent after drying, and evaporating the solvent after drying to obtain 17.0 g of a crude product with the yield of 90 percent.

EXAMPLE 4 Synthesis of N- (2, 3, 4, 6-Tetrapivaloylglucosyl) - α -aminophenylacetonitrile

The same procedure as in example 3, except that the amount of the catalyst was changed to 75mmol, gave 17.20 g of a crude product in 91% yield.

EXAMPLE 5 Synthesis of N- (2, 3, 4, 6-Tetrapivaloylglucosyl) - α -aminophenylacetonitrile

The solvent was changed to tetrahydrofuran, and the same procedure as in example 3 was repeated to give 16.6 g of a crude product in 88% yield.

Example 6 Synthesis of N- (2, 3, 4, 6-Tetrapivaloylglucosyl) - α -aminophenylacetonitrile

The reaction solvent was changed to chloroform, and the same procedure as in example 3 was repeated, whereby 16.07 g of a crude product was obtained, showing a yield of 85%.

Example 7 Synthesis of N- (2, 3, 4, 6-Tetrapivaloylglucosyl) - α -aminophenylacetonitrile

SnCl for catalyst₄Otherwise, in the same manner as in example 3, 13.4 g of a crude product was obtained in a yield of 71%.

Example 8 Synthesis of N- (2, 3, 4, 6-Tetrapivaloylglucosyl) - α -aminophenylacetonitrile

TiCl for catalyst₄The solvent was changed to acetonitrile, and the same procedure as in example 3 was repeated, whereby 11.34 g of a crude product was obtained, showing a yield of 60%.

Example 9 Synthesis of N- (2, 3, 4, 6-Tetrapivaloylglucosyl) - α -aminophenylacetonitrile

ZnI for catalyst₂The solvent was changed to isopropanol and the same procedure as in example 3 gave 11.4 g of crude product in 45% yield.

Example 10 Synthesis of N- (2, 3, 4, 6-Tetrapivaloylglucosyl) - α -aminonaphthylacetonitrile

At room temperature, 1mL of a dichloromethane solution containing (30mmol) N- (2, 3, 4, 6-tetrapivaloylglucosylyl) naphthylimine was slowly dropped into a dichloromethane (20mL) solution containing 3.96 g of trimethylsilylazidinate (37.5mmol) and CuBr (37.5mmol), after dropping, the solution was slowly heated to 25 ℃ with stirring, the reaction was carried out at 25 ℃ and monitored by TLC, after completion of the reaction, the solvent was evaporated off, and the remaining residue was dissolved in 400mL of CH₂Cl₂In (1), the organic layer was successively washed with 2N HCl (100mL), saturated NaHCO₃(200 mL. times.3) and water (200mL), and the organic layer was washed with MgSO₄Drying, evaporating the solvent after drying to obtain 18.56 g of crude product with yieldThe content was 91%.

Example 11: phenylacetic acid synthesis

5.5mL of 45% acetic acid hydrobromide solution and 1mL of water were slowly dropped into a dichloromethane (200mL) solution containing N- (2, 3, 4, 6-tetrapivaloylglucosyl) - α -aminophenylacetonitrile (13.25g) obtained in example 3 at room temperature, after dropping, a solid precipitated under stirring, and the precipitate was filtered to obtain 2.59 g of a phenylacetic acid solid with a yield of 91%.

Example 12: synthesis of naphthylacetic acid

5.5mL of 45% aqueous hydrogen bromide acetic acid and 1mL of water were slowly dropped into a dichloromethane (200mL) solution containing N- (2, 3, 4, 6-tetrapivaloylglucosyl) - α -naphthylacetonitrile (14.3g) obtained in example 10 at room temperature, after completion of dropping, a solid precipitated under stirring, and the precipitate was filtered to obtain 3.5g of naphthylacetic acid as a solid in a yield of 90%.

Compared with the existing chemical synthesis method, the method has the advantages of cheap and easily-obtained raw materials, simple and safe operation, short reaction period, high reaction yield, good product quality, effective recycling of byproducts and the like, and is suitable for industrial production.

Claims (10)

1. A preparation method of aryl acetic acid shown in a chemical formula IV ischaracterized in that nucleophilic addition reaction is carried out on trimethyl silicon cyanide and N- (2, 3, 4, 6-tetrapivalyl glucosyl) aryl imine shown in a formula IIN- (2, 3, 4, 6-tetrapivalyl glucosyl) - α -amino aryl acetonitrile shown in a formula IIN- (2, 3, 4, 6-tetrapivalyl glucosyl) - α -amino aryl acetonitrile in a transition metal Lewis acid catalyst in an organic solvent to obtain the aryl acetic acid shown in the formula IV, wherein the organic solvent is tetrahydrofuran or acetonitrile or chlorohydrocarbon containing 1-3 carbon atoms or alcohol containing 3-4 carbon atoms;

in formulas II and III, Piv ═ CH₃)₃CCO; in formula IV, Ar is aryl.

2. The process for preparing an arylacetic acid according to claim 1, wherein the arylacetic acid is phenylacetic acid, which comprises the following steps:

the N- (2, 3, 4, 6-tetrapivalyl glucosyl) phenylimine is subjected to nucleophilic addition reaction in tetrahydrofuran or acetonitrile or chlorohydrocarbon containing 1-3 carbon atoms or alcohol containing 3-4 carbon atoms under the catalysis of transition metal Lewis acid to obtain N- (2, 3, 4, 6-tetrapivalyl glucosyl) - α -aminophenylacetonitrile, and the N- (2, 3, 4, 6-tetrapivalyl glucosyl) - α -aminophenylacetonitrile is hydrolyzed in a hydrogen halide acetic acid solution to obtain the phenylacetic acid.

3. A process for the preparation of an arylacetic acid according to claim 1 or claim 2 wherein the transition metal lewis acid is one of:

①SnCl₄②ZnCl₂③TiCl₄④ZnI₂⑤CuCl ⑥CuBr⑦CuBr.S(CH₃)₂⑧CuCl₂⑨CuBr₂。

4. a process for the preparation of arylacetic acids according to claim 3 wherein the organic solvent is one of the following:

① Dichloromethane ② chloroform ③ Isopropanol ④ tetrahydrofuran ⑤ acetonitrile.

5. The method according to claim 4, wherein the hydrogen halide in the hydrogen halide-acetic acid solution is 30 to 50% by mass, and the hydrogen halide is hydrogen bromide or hydrogen iodide.

6. A process for preparing an arylacetic acid according to claim 4, wherein the transition metal Lewis acid and trimethylsilcyanide are present in a ratio of 1: 1.

7. A process for the preparation of arylacetic acids according to claim 1, characterized in that it comprises the following steps:

(1) at the temperature of minus 40 to minus 20 ℃, dropwise adding a dichloromethane solution containing N- (2, 3, 4, 6-tetrapivalyl glucosyl) arylimine into a dichloromethane solution dissolved with trimethylsilanoate and transition metal Lewis acid;

(2) stirring and heating to room temperature for reaction, after the reaction is finished, evaporating the solvent, dissolving the residue with dichloromethane, washing, drying, evaporating, and recrystallizing the evaporated substance in N-heptane to obtain N- (2, 3, 4, 6-tetrapivalyl glucosyl) - α -aminoaryl acetonitrile;

(3) dissolving N- (2, 3, 4, 6-tetrapivalyl glucosyl) - α -amino aryl acetonitrile in a dichloromethane solution, dropwise adding a 45% HBr/HAc solution, keeping the solution at room temperature for 1-4 hours, and filtering to obtain aryl acetic acid;

8. a process for the preparation of an arylacetic acid according to claim 7, characterised in that it comprises the following steps:

(1) dripping a dichloromethane solution containing N- (2, 3, 4, 6-tetrapivaloyl glucosyl) aryl imine into a dichloromethane solution dissolved with a trimethylsilylcyanide compound at the temperature of-40 to-20 ℃, wherein the amount ratio of the trimethylsilylcyanide to a Lewis acid catalyst to the N- (2, 3, 4, 6-tetrapivaloyl glucosyl) aryl imine substance is 1.25: 1;

(2) stirring and heating to room temperature for reaction, after the reaction is finished, evaporating the solvent, dissolving the residue in dichloromethane, washing the dichloromethane solution with 2N hydrochloric acid, saturated sodium bicarbonate water solution and water in sequence, drying with magnesium sulfate, drying, evaporating to dryness, and recrystallizing the evaporated product in N-heptane to obtain N- (2, 3, 4, 6-tetra-pivaloyl glucosyl) - α -aminoarylacetonitrile;

(3) dissolving N- (2, 3, 4, 6-tetrapivalyl glucosyl) - α -amino aryl acetonitrile in a dichloromethane solution, dropwise adding a 45% HBr/HAc solution, keeping the solution at room temperature for 1-4 hours, and filtering to obtain the aryl acetic acid.

9. A process for the preparation of arylacetic acids according to claim 2, characterized in that it comprises the following steps:

(1) at the temperature of minus 40 to minus 20 ℃, dropwise adding a dichloromethane solution containing N- (2, 3, 4, 6-tetrapivalyl glucosyl) phenylimine into a dichloromethane solution dissolved with trimethylsilyanide and Lewis acid, wherein the molar ratio of the trimethylsilyanide to the Lewis acid to the N- (2, 3, 4, 6-tetrapivalyl glucosyl) phenylimine is 1.25: 1;

(2) stirring and heating to room temperature for reaction, evaporating the solvent after the reaction is finished, and dissolving the residue in CH₂Cl₂In (1), the organic layer was washed with 2N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and water in this order, and then with MgSO₄Drying, evaporating to dryness, and recrystallizing the evaporated material in n-heptane;

(3) dissolving N- (2, 3, 4, 6-tetra-pivaloyl glucosyl) - α -aminobenzyl acetonitrile in a dichloromethane solution, dropwise adding a 45% HBr/HAc solution, keeping the solution at room temperature for 1-4 hours, and filtering to obtain phenylacetic acid solid.

10. The process for preparing arylacetic acids according to claim 3, wherein the arylimine of the formula IIN- (2, 3, 4, 6-tetrapivaloylglucosyl) is prepared by acid-catalyzed condensation with an aldehyde using an amine of the formula IN- (2, 3, 4, 6-tetrapivaloylglucosyl) as a substrate;

in formula I, Piv ═ CH₃)₃CCO。