CN1300090C - Process for preparing aryl acetic acid - Google Patents

Abstract

The present invention relates to the preparation method of important fine chemical intermediate aryl acetic acid such as medicine, pesticide, spices; Imine is obtained by nucleophilic addition reaction of trimethylsilyl cyanide in tetrahydrofuran or acetonitrile or chlorinated hydrocarbons containing 1 to 3 carbon atoms or alcohols containing 3 to 4 carbon atoms under the catalysis of transition metal Lewis acid Formula III N-(2,3,4,6-tetrapivaloyl glucosyl)-α-aminoaryl acetonitrile, N-(2,3,4,6-tetrapivaloyl glucosyl)-α-aminoaryl The aryl acetic acid described in formula IV is obtained by hydrolysis of diacetonitrile in hydrogen halide acetic acid solution; the method raw material of the present invention is cheap and easy to get, and cost is low; Avoid using raw material sodium cyanide or hydrocyanic acid, the operation is simple and safe, The reaction yield is high; the by-products can be effectively recycled, and have great implementation value and social and economic benefits. The reaction formula is as follows: in formula II and III, Piv=(CH ₃ ) ₃ CCO; in formula IV, Ar is an aryl group.

Description

A kind of preparation method of aryl acetic acid

(1) Technical field

The invention relates to a preparation method of aryl acetic acid, an important intermediate of fine chemicals such as medicine, pesticide and spices.

(2) Background technology

In the prior art, the chemical synthesis methods related to phenylacetic acid are:

1. Preparation of target compound by nitrile hydrolysis method:

There are two kinds of phenylacetonitrile hydrolysis methods, alkaline and acidic hydrolysis methods, and phenylacetonitrile is obtained by condensation of benzyl chloride and sodium cyanide under a certain medium and a catalyst. The hydrolysis of phenylacetonitrile generally adopts an alkaline hydrolysis process, and the reaction is as follows:

              

              

              

The deficiencies of the above process are: the raw material NaCN and the intermediate product phenylacetonitrile are highly toxic, especially the highly toxic and foul-smelling substance isocyanide in the synthesis process of phenylacetonitrile. These substances are highly volatile and cause serious damage to the operating environment. Pollution, heavy waste water pollution, high treatment costs, low benzyl nitrile yield, high production costs. From the perspective of long-term development trend, this law will be gradually eliminated.

Two, benzene, formaldehyde and carbon monoxide react to prepare the target compound:

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

Three, phenylacetamide hydrolysis method (Vilgerode method) prepares target compound:

The first step of the above process needs to be pressurized and a by-product, benzene ethyl mercaptan, is produced. The by-product has a bad smell and serious pollution.

Four, benzyl alcohol method preparation target compound:

React at 150°C under high pressure for 4 to 5 hours to obtain phenylacetic acid:

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

5. Preparation of target compound by benzyl chlorocarbonylation method:

The reaction is under the action of catalysts (organic palladium complexes, rhodium complexes, carbonyl iron, iron-manganese alloys, cobalt salts and carbonyl cobalt complexes, etc.), and an appropriate organic solvent is added to make benzyl chloride proceed in a two-phase system. Carbonylation, the acidification of sodium phenylacetate to phenylacetic acid under acidic conditions:

             

             

The technical requirements in this process are high, expensive catalysts need to be used, and the catalyst particles are very small, which requires careful operation to prevent catalyst deactivation or loss, difficult catalyst separation, immature recovery methods, and difficult production.

6. Preparation of target compound by benzyl chloride-carbon dioxide electrolysis:

The process of electrolytic preparation of phenylacetic acid is to use the sacrificial anode method to realize electrocarboxylation, and to synthesize phenylacetic acid through electrocarbonylation of benzyl chloride. For example, taking Mg as an anode, the reaction is as follows:

           

           

Overall response:

In this method, the electrode material and the electrolyte are relatively expensive, the power consumption is large, the separation and recycling of the solvent, the supporting electrolyte and the by-products are difficult, the cost is high, and the industrialization is not easy.

(3) Contents of the invention

In order to solve the deficiencies of high preparation cost, complex process, high risk and low yield of arylacetic acid, especially phenylacetic acid, in the prior art, the present invention provides a method with low cost, reasonable process, safe and reliable production, and high reaction yield. Process for the preparation of high aryl acetic acids.

For achieving the purpose of the invention, the technical scheme adopted by the present invention is:

A kind of preparation method such as the aryl acetic acid of chemical formula IV, described method is to use formula IIN-(2,3,4,6-tetrapivaloyl glucosyl) aryl imine under transition metal Lewis acid catalysis THF or acetonitrile or chlorinated hydrocarbons containing 1 to 3 carbon atoms or alcohols containing 3 to 4 carbon atoms are subjected to nucleophilic addition reaction with trimethylsilyl cyanide to obtain: formula IIIN-(2,3,4 , 6-tetrapivaloyl glucosyl)-α-aminoaryl acetonitrile, N-(2,3,4,6-tetrapivaloyl glucosyl)-α-aminoaryl acetonitrile hydrolysis in hydrogen halide acetic acid solution Obtain the aryl acetic acid described in formula IV; Reaction formula is as follows:

In formulas II and III, Piv=(CH ₃ ) ₃ CCO; in formulas II, III and IV, Ar is an aryl group.

Taking phenylacetic acid as an example, the preparation method of described arylacetic acid is as follows:

N-(2,3,4,6-tetrapivaloylglucosyl)phenylimine is catalyzed by transition metal Lewis acid in tetrahydrofuran or acetonitrile or chlorinated hydrocarbons containing 1 to 3 carbon atoms or containing 3 to 4 N-(2,3,4,6-tetrapivaloylglucosyl)-alpha-aminobenzyl acetonitrile, N-(2, 3,4,6-tetrapivaloylglucosyl)-α-aminophenylacetonitrile is hydrolyzed in hydrogen halide acetic acid solution to obtain the phenylacetic acid.

Described transition metal Lewis acid is one of following:

①SnCl ₄ ②ZnCl ₂ ③TiCl ₄ ④ZnI ₂ ⑤CuCl ⑥CuBr

⑦CuBr.S(CH ₃ ) ₂ ⑧CuCl ₂ ⑨CuBr ₂ .

Described organic solvent is one of following:

① Dichloromethane ② Chloroform ③ Isopropanol ④ Tetrahydrofuran ⑤ Acetonitrile.

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

The ratio of the amount of transition metal Lewis acid to trimethylsilyl cyanide is preferably 1:1.

Specifically, the described method is as follows:

(1) At -40～-20°C, add N-(2,3,4,6-tetrapivaloylglucosyl ) dichloromethane solution of aryl imine;

(2) Stir and heat up to room temperature for reaction. After the reaction, the solvent is evaporated, and the residue is dissolved in dichloromethane. After washing, it is dried and evaporated to dryness. The evaporated matter is recrystallized in n-heptane to obtain N-(2,3 , 4,6-tetrapivaloylglucosyl)-α-aminoaryl acetonitrile;

(3) Dissolve N-(2,3,4,6-tetrapivaloylglucosyl)-α-aminoaryl acetonitrile in dichloromethane solution, then add dropwise 45% HBr/HAc solution, at room temperature Keep it for 1-4 hours and filter to obtain the aryl acetic acid.

Further, the described method is as follows:

(1) At -40～-20°C, add N-(2,3,4,6-tetrapivaloylglucosyl ) dichloromethane solution of aryl imine, the amount of said trimethylsilyl cyanide, Lewis acid catalyst, N-(2,3,4,6-tetrapivaloylglucosyl) aryl imine The ratio is 1.25:1.25:1;

(2) Stir and heat up to room temperature for reaction. After the reaction, the solvent is evaporated, and the residue is dissolved in methylene chloride. Drying, drying and then evaporating to dryness, and recrystallizing the evaporating product in n-heptane to obtain N-(2,3,4,6-tetrapivaloylglucosyl)-α-aminoaryl acetonitrile;

(3) Dissolve N-(2,3,4,6-tetrapivaloylglucosyl)-α-aminoaryl acetonitrile in dichloromethane solution, then add dropwise 45% HBr/HAc solution, at room temperature After keeping for 1-4 hours, filter to obtain the aryl acetic acid.

Particularly, when described aryl acetic acid is phenylacetic acid, the preparation method is as follows:

(1) At -40～-20°C, add N-(2,3,4,6-tetrapivaloylglucosyl)benzene dropwise to the dichloromethane solution dissolved with trimethylsilylcyanide and Lewis acid The dichloromethane solution of imine, trimethylsilyl cyanide, Lewis acid, N-(2,3,4,6-tetrapivaloylglucosyl) phenylimine molar ratio is 1.25:1.25:1;

(2) Stir and heat up to room temperature for reaction. After the reaction, the solvent is evaporated, and the residue is dissolved in CH ₂ Cl _2. The organic layer is washed with 2N hydrochloric acid, saturated aqueous sodium bicarbonate solution and water successively, and then dried with _MgSO . Evaporate to dryness after drying, and the evaporated matter is recrystallized in n-heptane;

(3) Dissolve N-(2,3,4,6-tetrapivaloylglucosyl)-α-aminophenylacetonitrile in dichloromethane solution, then add dropwise 45% HBr/HAc solution, keep at room temperature After 1 to 4 hours, filter to obtain solid phenylacetic acid.

Described formula II N-(2,3,4,6-tetrapivaloyl glucosyl) aryl imine is generally formed by formula I N-2,3,4,6-tetrapivaloyl glucosylamine The product is prepared by acid-catalyzed condensation with aldehyde, and the reaction formula is as follows:

The beneficial effect of the preparation method of aryl acetic acid of the present invention is mainly reflected in: (1) raw material is cheap and easy to get, and cost is low; (2) avoids using raw material sodium cyanide or hydrocyanic acid, simple and safe operation, reaction The yield is high; (3) the by-products can be effectively recycled, and have great implementation value and social and economic benefits.

(4) Specific implementation methods

The present invention is further described below in conjunction with specific embodiment:

Example 1: Synthesis of N-(2,3,4,6-tetrapivaloylglucosyl)-α-aminophenylacetonitrile

At -40°C to -20°C, slowly drop 1mL of dichloromethane (20mL) containing (30mmol ) Dichloromethane solution of N-(2,3,4,6-tetrapivaloylglucosyl)phenylimide, after the dropwise addition, under stirring, the solution was slowly warmed up to -20°C, and the reaction was carried out at - 20°C and monitored by TLC. After the reaction, the solvent was distilled off, and then the remaining residue was dissolved in 400mL CH ₂ Cl ₂ . The organic layer was sequentially washed with 2N HCl (100mL), saturated NaHCO ₃ (200mL×3) and water ( 200 mL), the organic layer was dried with MgSO ₄ , and the solvent was evaporated after drying to obtain 16.3 g of crude product with a yield of 86%.

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

At -20°C to 0°C, slowly add 1mL of 30mmol N-( 2,3,4,6-tetrapivaloylglucosyl) phenylimine dichloromethane solution, after the dropwise addition, under stirring, the solution is slowly warmed up to 0°C, and the reaction is carried out at 0°C and monitored by TLC , after the reaction was completed, the solvent was evaporated, and then the remaining residue was dissolved in 400mL CH ₂ Cl ₂ , the organic layer was washed with 2N HCl (100mL), saturated NaHCO ₃ (200mL×3) and water (200mL) successively, and the organic The layer was dried with MgSO ₄ , and the solvent was evaporated after drying to obtain 16.8 g of crude product with a yield of 89%.

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

At 0°C to 25°C, slowly add 1mL of 30mmol N-(2 , 3,4,6-tetrapivaloylglucosyl) dichloromethane solution of phenylimide, after the dropwise addition, under stirring, the solution is slowly warming up to 25°C, the reaction is carried out at 25°C and monitored by TLC, the reaction After the end, the solvent was evaporated, and then the remaining residue was dissolved in 400mL CH ₂ Cl ₂ , the organic layer was washed with 2N HCl (100mL), saturated NaHCO ₃ (200mL×3) and water (200mL) successively, and the organic layer was washed with MgSO ₄ was dried, the solvent was evaporated after drying, and the solvent was evaporated after drying to obtain 17.0 g of crude product with a yield of 90%.

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

Catalyst consumption is (75mmol) other with embodiment 3, obtains crude product 17.20 grams, yield is 91%.

Example 5: Synthesis of N-(2,3,4,6-tetrapivaloylglucosyl)-α-aminophenylacetonitrile

The solvent was changed to tetrahydrofuran, and the others were the same as in Example 3 to obtain 16.6 g of crude product with a yield of 88%.

Embodiment 6: The synthetic reaction solvent of N-(2,3,4,6-tetrapivaloylglucosyl)-α-aminophenylacetonitrile is changed into chloroform, and others are the same as in Example 3 to obtain 16.07 grams of crude product, The yield was 85%.

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

SnCl ₄ was used as the catalyst, and the others were the same as in Example 3 to obtain 13.4 g of crude product with a yield of 71%.

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

The catalyst was TiCl ₄ , the solvent was changed to acetonitrile, and the others were the same as in Example 3 to obtain 11.34 g of crude product with a yield of 60%.

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

The catalyst was ZnI ₂ , the solvent was changed to isopropanol, and the others were the same as in Example 3 to obtain 11.4 g of crude product with a yield of 45%.

Example 10: Synthesis of N-(2,3,4,6-tetrapivaloylglucosyl)-α-aminonaphthaleneacetonitrile

At room temperature, slowly add 1 mL of (30 mmol) N-(2, 3,4,6- tetrapivaloyl glucosyl) dichloromethane solution of naphthyl imine, after the dropwise addition, under stirring, the solution is slowly warming up to 25°C, the reaction is carried out at 25°C and monitored by TLC, the reaction After the end, the solvent was evaporated, and then the remaining residue was dissolved in 400mL CH ₂ Cl ₂ , the organic layer was washed with 2N HCl (100mL), saturated NaHCO ₃ (200mL×3) and water (200mL) successively, and the organic layer was washed with MgSO ₄ was dried, and after drying, the solvent was evaporated to obtain 18.56 g of crude product with a yield of 91%.

Embodiment 11: Phenylacetic acid synthesis

At room temperature, slowly add N-(2,3,4,6-tetrapivaloylglucosyl)-α-aminophenylacetonitrile (13.25g) to a solution of dichloromethane (200mL) dissolved in Example 3 Add 5.5 mL of 45% hydrogen bromide acetic acid solution and 1 mL of water dropwise. After the dropwise addition, under stirring, a solid precipitate will form. Filter the precipitate to obtain 2.59 g of phenylacetic acid solid, with a yield of 91%.

Embodiment 12: the synthesis of naphthaleneacetic acid

At room temperature, slowly drop in a solution of N-(2,3,4,6-tetrapivaloylglucosyl)-α-naphthaleneacetonitrile (14.3g) obtained in Example 10 in dichloromethane (200mL) Add 5.5 mL of 45% hydrogen bromide acetic acid solution and 1 mL of water. After the dropwise addition, under stirring, a solid precipitate will form. Filter the precipitate to obtain 3.5 g of naphthalene acetic acid solid, with a yield of 90%.

Compared with the existing chemical synthesis method, the present invention has the advantages of cheap and easy-to-obtain raw materials, simple and safe operation, short reaction cycle, high reaction yield, good product quality and effective recycling of by-products, etc., and is more suitable for industrialization. method of production.

Claims (10)

1. a preparation method such as the aryl acetic acid of chemical formula IV, it is characterized in that described method is to use formula II N-(2,3,4,6-tetrapivaloyl glucosyl) aryl imine in transition Under the catalysis of metal Lewis acid, the nucleophilic addition reaction with trimethylsilyl cyanide in an organic solvent is obtained: Formula III N-(2,3,4,6-tetrapivaloylglucosyl)-α-aminoaryl Acetonitrile, N-(2,3,4,6-tetrapivaloyl glucosyl)-α-aminoaryl acetonitrile is hydrolyzed in hydrogen halide acetic acid solution to obtain the aryl acetic acid described in formula IV; the organic solvent is Tetrahydrofuran or acetonitrile or chlorinated hydrocarbons containing 1 to 3 carbon atoms or alcohols containing 3 to 4 carbon atoms;

_{ArCH2CO2H (} IV) In formulas II and III, Piv=(CH ₃ ) ₃ CCO; in formulas II, III and IV, Ar is an aryl group. 2. the preparation method of aryl acetic acid as claimed in claim 1 is characterized in that described aryl acetic acid is phenylacetic acid, and described method is as follows: N-(2,3,4,6-tetrapivaloylglucosyl)phenylimine is catalyzed by transition metal Lewis acid in tetrahydrofuran or acetonitrile or chlorinated hydrocarbons containing 1 to 3 carbon atoms or containing 3 to 4 Carry out nucleophilic addition reaction in the alcohol of carbon atom to obtain N-(2,3,4,6-tetrapivaloylglucosyl)-α-aminophenylacetonitrile, N-(2,3,4,6-tetranew The hydrolysis of pentanoylglucosyl)-α-aminophenylacetonitrile in hydrogen halide acetic acid solution obtains the described phenylacetic acid. 3. the preparation method of aryl acetic acid as claimed in claim 1 or 2 is characterized in that described transition metal Lewis acid is one of following: ①SnCl ₄ ②ZnCl ₂ ③TiCl ₄ ④ZnI ₂ ⑤CuCl ⑥CuBr⑦CuBr.S(CH ₃ ) ₂ ⑧CuCl ₂ ⑨CuBr ₂ . 4. the preparation method of aryl acetic acid as claimed in claim 3 is characterized in that described organic solvent is one of following: ① Dichloromethane ② Chloroform ③ Isopropanol ④ Tetrahydrofuran ⑤ Acetonitrile. 5. the preparation method of aryl acetic acid as claimed in claim 4 is characterized in that the hydrogen halide mass content is 30～50% in the described hydrogen halide acetic acid solution, and described hydrogen halide is hydrogen bromide or hydrogen iodide . 6. The preparation method of aryl acetic acid as claimed in claim 4, characterized in that the ratio of the amount of the transition metal Lewis acid to the trimethylsilyl cyanide substance is 1:1. 7. the preparation method of aryl acetic acid as claimed in claim 1 is characterized in that described method is as follows: (1) At -40～-20°C, add N-(2,3,4,6-tetrapivaloylglucosyl ) dichloromethane solution of aryl imine; (2) Stir and heat up to room temperature for reaction. After the reaction, the solvent is evaporated, and the residue is dissolved in dichloromethane. After washing, it is dried and evaporated to dryness. The evaporated matter is recrystallized in n-heptane to obtain N-(2,3 , 4,6-tetrapivaloylglucosyl)-α-aminoaryl acetonitrile; (3) Dissolve N-(2,3,4,6-tetrapivaloylglucosyl)-α-aminoaryl acetonitrile in dichloromethane solution, then add dropwise 45% HBr/HAc solution, at room temperature Keep it for 1-4 hours and filter to obtain the aryl acetic acid. 8. the preparation method of aryl acetic acid as claimed in claim 7 is characterized in that described method is as follows: (1) At -40～-20°C, add N-(2,3,4,6-tetrapivaloylglucosyl ) dichloromethane solution of aryl imine, the amount of said trimethylsilyl cyanide, Lewis acid catalyst, N-(2,3,4,6-tetrapivaloylglucosyl) aryl imine The ratio is 1.25:1.25:1; (2) Stir and heat up to room temperature for reaction. After the reaction, the solvent is evaporated, and the residue is dissolved in methylene chloride. Drying, drying and then evaporating to dryness, and recrystallizing the evaporating product in n-heptane to obtain N-(2,3,4,6-tetrapivaloylglucosyl)-α-aminoaryl acetonitrile; (3) Dissolve N-(2,3,4,6-tetrapivaloylglucosyl)-α-aminoaryl acetonitrile in dichloromethane solution, then add dropwise 45% HBr/HAc solution, at room temperature After keeping for 1-4 hours, filter to obtain the aryl acetic acid. 9. the preparation method of aryl acetic acid as claimed in claim 2 is characterized in that described method is as follows: (1) At -40～-20°C, add N-(2,3,4,6-tetrapivaloylglucosyl)benzene dropwise to the dichloromethane solution dissolved with trimethylsilylcyanide and Lewis acid The dichloromethane solution of imine, trimethylsilyl cyanide, Lewis acid, N-(2,3,4,6-tetrapivaloylglucosyl) phenylimine molar ratio is 1.25:1.25:1; (2) Stir and heat up to room temperature for reaction. After the reaction, the solvent is evaporated, and the residue is dissolved in CH ₂ Cl _2. The organic layer is washed with 2N hydrochloric acid, saturated aqueous sodium bicarbonate solution and water successively, and then dried with _MgSO . Evaporate to dryness after drying, and the evaporated matter is recrystallized in n-heptane; (3) Dissolve N-(2,3,4,6-tetrapivaloylglucosyl)-α-aminophenylacetonitrile in dichloromethane solution, then add dropwise 45% HBr/HAc solution, keep at room temperature After 1 to 4 hours, filter to obtain solid phenylacetic acid. 10. the preparation method of described aryl acetic acid as claimed in claim 3 is characterized in that described formula II N-(2,3,4,6-tetrapivaloyl glucosyl) aryl imine consists of The formula IN-(2,3,4,6-tetrapivaloylglucosyl)amine is used as a substrate, and it is prepared by acid-catalyzed condensation with aldehyde;

In Formula I, Piv=(CH ₃ ) ₃ CCO.