WO2024109438A1

WO2024109438A1 - Preparation process of high-purity low-impurity 10-methoxyiminostilbene

Info

Publication number: WO2024109438A1
Application number: PCT/CN2023/127162
Authority: WO
Inventors: 何函蒙; 何晨勇; 陈斌
Original assignee: 浙江华洋药业有限公司
Priority date: 2022-11-23
Filing date: 2023-10-27
Publication date: 2024-05-30
Also published as: CN115650918A

Abstract

The present application discloses a preparation process of high-purity low-impurity 10-methoxyiminostilbene, comprising the following steps: S1, adding 2-aminobenzyl cyanide, an acid binding agent, and 2-halogenated benzonitrile into a solvent A, and carrying out substitution reaction to prepare a compound I; S2, in a solvent B, under the action of alkali 1, carrying out intramolecular condensation reaction on the compound I, and carrying out hydrolysis reaction and hydrochloric acid acidification to obtain a compound II; S3, in a solvent C, under the action of alkali 2, carrying out methylation reaction on the compound II and a methylation reagent to obtain a compound III; and S4, in a solvent D, under the action of a hydrogenation catalyst, carrying out catalytic hydrogenolysis reaction on the compound III to obtain 10-methoxyiminostilbene. The 10-methoxyiminostilbene prepared by the preparation process of the present application has high purity and low impurity; the preparation process conditions are easy to implement, the operation is simple, convenient and safe, the reaction conditions are mild, the process flow is short, and the post-treatment is simple; the used raw materials are cheap and easily available, and the cost is low.

Description

A preparation process of high-purity and low-impurity 10-methoxyiminostilbene

Technical Field

The present application relates to the field of pharmaceutical chemistry and chemical engineering technology, and in particular to a preparation process of high-purity and low-impurity 10-methoxyiminostilbene.

Background technique

10-Methoxy-5H-dibenzo[b,f]azepine The CAS number is 4698-11-7, the molecular formula is C ₁₅ H ₁₃ NO, it is a pale yellow to off-white crystal, and it is a chemical intermediate that can be used to prepare the drug oxcarbazepine. Oxcarbazepine has gradually become a global first-line broad-spectrum anti-epileptic drug with its unique anti-epileptic mechanism and definite efficacy and safety, and has a relatively broad market.

"China Pharmaceutical Industry Journal, 2006, 37(7), 443-444" o-nitrotoluene is condensed with formate and strong base to obtain 2,2'-di(2-nitrophenyl)ethane, which is reduced and phosphorylated to obtain 2,2'-di(2-aminophenyl)ethane diphosphate, and then cyclized at 260-300°C to prepare 10,11-dihydro-5H-dibenzo[b,f]azepine, which is then chlorinated, brominated and eliminated to obtain 5-chloroformyl iminostilbene, which is then bromine added, methoxylated, formiated and hydrolyzed to prepare oxcarbazepine. This method of preparing 10-methoxyiminostilbene from o-nitrotoluene is complicated, has high cyclization reaction temperature, low yield, low product purity, complicated purification, and large amount of three wastes, and is not suitable for industrial production.

Chinese patent documents CN101386595A and CN101423496A use 5-chloroformyl-10,11-dibromoiminodibenzyl or 10,11-dibromoiminodibenzyl as raw materials, react with potassium hydroxide or potassium methoxide methanol solution to prepare 10-methoxy-5H-dibenzo[b,f]azepine crude product, and obtain 10-methoxy-5H-dibenzo[b,f]azepine fine product after refining, and then prepare oxcarbazepine through chloroformylation reaction, amidation reaction, and hydrolysis reaction. This method uses 5-chloroformyl-10,11-dibromoiminodibenzyl or 10,11-dibromoiminodibenzyl as raw materials, and has the disadvantages of high raw material prices and high costs.

Due to the improvement of the requirements for raw materials, the quality requirements for key intermediates in the preparation of drugs are also getting higher and higher. Therefore, it is necessary to design a preparation process for high-purity and low-impurity 10-methoxyiminostilbene.

Summary of the invention

In order to solve at least one of the above technical problems, a preparation method with easy operation, mild reaction conditions, high purity and low impurities is developed. The present application provides a preparation process of high-purity and low-impurity 10-methoxyiminostilbene.

The present application provides a preparation process of high-purity and low-impurity 10-methoxyiminostilbene, comprising the following steps:

S1: Add 2-benzylaminophenylacetonitrile, an acid-binding agent and 2-halogenated benzonitrile to solvent A to prepare compound I, i.e., N-benzyl-N-2′-cyanophenyl-2-aminophenylacetonitrile, through substitution reaction;

S2: In solvent B, under the action of base 1, compound I undergoes intramolecular condensation reaction and then hydrolysis reaction to obtain salt Acidification with acid gives compound II, i.e. 5-benzyl-10-oxa-10,11-dihydro-5H-dibenzo[b,f]azepine;

S3: In solvent C, in the presence of base 2, compound II and a methylating agent undergo a methylation reaction to obtain compound III, i.e., 5-benzyl-10-methoxyiminostilbene;

S4: In solvent D, in the presence of a hydrogenation catalyst, compound III is debenzylated by catalytic hydrogenolysis to obtain 10-methoxyiminostilbene.

Optionally, in step S1, the solvent A is one of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, toluene or chlorobenzene; and the mass ratio of the solvent A to 2-benzylaminophenylacetonitrile is (4-16):1.

Optionally, in step S1, the acid binding agent is an inorganic base or an organic base, the inorganic base is one of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate or calcium bicarbonate, and the organic base is one of triethylamine, tripropylamine, triisopropylamine or tri-n-butylamine; the molar ratio of the acid binding agent to 2-benzylaminophenylacetonitrile is (1.0-1.5):1.

Optionally, in step S1, the 2-halogenated benzonitrile is one of 2-bromobenzonitrile and 2-chlorobenzonitrile; and the molar ratio of the 2-halogenated benzonitrile to 2-benzylaminophenylacetonitrile is (1.0-1.3):1.

Optionally, in step S1, the substitution reaction temperature is 90-110°C.

Optionally, in step S2, the solvent B is one of tetrahydrofuran, 2-methyltetrahydrofuran, methyl cyclopentyl ether, N,N-dimethylformamide or chlorobenzene; and the mass ratio of the solvent B to compound I is (4-12):1.

Optionally, in step S2, the base 1 is one of sodium methoxide, sodium ethoxide, potassium tert-butoxide or sodium hydride; and the molar ratio of the base 1 to compound I is (1.0-1.5):1.

Optionally, in step S2, the intramolecular condensation reaction temperature is 30-90°C; the hydrolysis reaction temperature is 40-80°C.

Optionally, in step S2, the hydrochloric acid acidification is performed using hydrochloric acid with a mass concentration of 30-35% until the system pH is 2-2.5.

Optionally, in step S3, the solvent C is one of tetrahydrofuran, methanol, ethanol, N,N-dimethylformamide or toluene; and the mass ratio of the solvent C to compound II is (8-20):1.

Optionally, in step S3, the base 2 is one of potassium carbonate, sodium carbonate, sodium hydroxide or potassium hydroxide; and the molar ratio of the base 2 to compound II is (1.0-1.8):1.

Optionally, in step S3, the methylating agent is one of dimethyl carbonate, dimethyl sulfate, methyl bromide or methyl iodide; the molar ratio of the methylating agent to compound II is (1.5-2.2):1; and the methylation reaction temperature is 70-100°C.

Optionally, in step S4, the solvent D is one of tetrahydrofuran, methanol, ethanol or isopropanol; and the mass ratio of the solvent D to compound III is (5-12):1.

Optionally, in step S4, the hydrogenation catalyst is one of palladium carbon or Raney nickel; the mass of the palladium carbon catalyst is 1%-6% of the mass of compound III, and the mass of the Raney nickel catalyst is 10%-18% of the mass of compound III.

Optionally, in step S4, the catalytic hydrogenolysis reaction temperature is 30-60° C., and the hydrogen pressure is 0.2-0.4 MPa.

In summary, the present invention includes at least one of the following beneficial technical effects:

1. The obtained 10-methoxyiminostilbene has high purity and low impurities;

2. The preparation process conditions are easy to achieve, the operation is simple and safe, the reaction conditions are mild, the process flow is short, and the post-processing is simple;

3. The raw materials used are cheap and easy to obtain, the cost is low, the amount of three wastes generated is small, and it is green and environmentally friendly.

Detailed ways

The present application is further described in detail below with reference to the embodiments.

Unless otherwise specified, the raw materials and equipment used in the present invention are conventional raw materials and equipment (conventional commercial products) in the art and can be purchased on the market.

The present application designs a preparation process of high-purity and low-impurity 10-methoxyiminostilbene, comprising the following steps:

S2: In solvent B, in the presence of base 1, compound I undergoes an intramolecular condensation reaction, followed by a hydrolysis reaction, and acidification with hydrochloric acid to obtain compound II, i.e., 5-benzyl-10-oxa-10,11-dihydro-5H-dibenzo[b,f]azepine;

The 10-methoxyiminostilbene prepared by the preparation process has high purity and low impurities; the preparation process conditions are easy to achieve, the operation is simple and safe, the reaction conditions are mild, the process flow is short, and the post-treatment is simple.

Example

Example 1

S1: Add 120g N,N-dimethylformamide, 30g (0.148mol) 2-benzylaminophenylacetonitrile, 35.1g (0.192mol) 2-bromobenzonitrile, 30.6g (0.222mol) potassium carbonate to a 500ml four-necked flask equipped with a stirrer, a thermometer, and a reflux condenser, and stir at 105-110°C for 5h. Cool to 20-25°C, filter, wash the filter cake with 30g N,N-dimethylformamide, combine the filtrate, and recover the solvent by vacuum distillation. Add 135g isopropyl ether to the residue for recrystallization to obtain 38.9g N-benzyl-N-2′-cyanophenyl-2-aminophenylacetonitrile, with a yield of 90.7% and a liquid phase purity of 99.2%.

S2: Add 100g 2-methyltetrahydrofuran and 10.2g (0.15mol) sodium ethoxide to a 500ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel. Add a mixture of 32.3g (0.1mol) N-benzyl-N-2′-cyanophenyl-2-aminophenylacetonitrile and 30g 2-methyltetrahydrofuran dropwise at 50-55°C. After the addition is complete, stir and react at 80-85°C for 4h. Cool to 20-25°C, add 250g of water, stir and hydrolyze at 75-80°C for 3h, separate the layers, wash the aqueous layer once with 20g of dichloromethane, acidify the aqueous phase with 35wt% hydrochloric acid to a pH value of 2.0-2.5, filter and dry to obtain 26.8g of 5-benzyl-10-oxa-10,11-dihydro-5H-dibenzo[b,f]azepine with a yield of 89.8% and a liquid purity of 99.3%.

S3: Add 100g methanol, 12.5g (0.042mol) 5-benzyl-10-oxa-10,11-dihydro-5H-dibenzo[b,f]azepine, 8.32g (0.092mol) dimethyl carbonate, and 10.3g (0.075mol) potassium carbonate to a 500ml stainless steel autoclave. Seal the autoclave, heat up, and stir at 95-100℃ for 4h. Cool to 20-25℃, filter, wash the filter cake with 20g methanol, combine the filtrate, and recover the solvent by vacuum distillation. The residue is recrystallized with 50g isopropyl ether and dried to obtain 11.96g 5-benzyl-10-methoxyiminostilbene, with a yield of 91.5% and a liquid phase purity of 99.1%.

S4: Add 50g methanol, 10g (0.032mol) 5-benzyl-10-methoxyiminostilbene, and 0.6g 5wt% palladium carbon catalyst into a 100ml stainless steel autoclave. After nitrogen replacement three times, hydrogen was introduced, and the hydrogen pressure was maintained at 0.3-0.4MPa. The reaction was carried out at 55-60℃ for 5h. Nitrogen replacement three times, palladium carbon was recovered by filtration, the filtrate was concentrated and dried to obtain 6.67g 10-methoxyiminostilbene, with a yield of 93.6% and a liquid phase purity of 99.4%.

Example 2

S1: Add 120g N,N-dimethylformamide, 15g (0.076mol) 2-benzylaminophenylacetonitrile, 16.9g (0.091mol) 2-bromobenzonitrile, 14.6g (0.106mol) potassium carbonate to a 500ml four-necked flask equipped with a stirrer, a thermometer, and a reflux condenser, and stir at 100-105°C for 5h. Cool to 20-25°C, filter, wash the filter cake with 20g N,N-dimethylformamide, combine the filtrate, and recover the solvent by vacuum distillation. Add 70g isopropyl ether to the residue for recrystallization to obtain 19.7g N-benzyl-N-2′-cyanophenyl-2-aminophenylacetonitrile, with a yield of 91.2% and a liquid phase purity of 99.3%.

S2: Add 100g 2-methyltetrahydrofuran and 6.4g (0.094mol) sodium ethoxide to a 500ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel. Add dropwise a mixture of 21.7g (0.067mol) N-benzyl-N-2′-cyanophenyl-2-aminophenylacetonitrile and 30g 2-methyltetrahydrofuran at 50-55°C. After the addition is complete, stir and react at 75-80°C for 3.5h. The mixture was cooled to 20-25°C, 200 g of water was added, and the hydrolysis reaction was stirred at 70-75°C for 3 h. The layers were separated, and the aqueous layer was washed once with 20 g of dichloromethane. The aqueous phase was acidified with 35 wt% hydrochloric acid to a pH value of 2.0-2.5, filtered, and dried to obtain 18.1 g of 5-benzyl-10-oxa-10,11-dihydro-5H-dibenzo[b,f]azepine with a yield of 90.7% and a liquid phase purity of 99.4%.

S3: Add 100g methanol, 8.3g (0.028mol) 5-benzyl-10-oxa-10,11-dihydro-5H-dibenzo[b,f]azepine, 5g (0.056mol) dimethyl carbonate, and 6.1g (0.044mol) potassium carbonate to a 500ml stainless steel autoclave. Seal the autoclave, raise the temperature, and stir at 90-95℃ for 3.5h. Cool to 20-25℃, filter, and wash the filter cake with 20g methanol. The filtrate was filtered and the solvent was recovered by vacuum distillation. The residue was recrystallized with 35 g of isopropyl ether and dried to obtain 7.94 g of 5-benzyl-10-methoxyiminostilbene with a yield of 92.3% and a liquid phase purity of 99.2%.

S4: Add 50g methanol, 7.2g (0.023mol) 5-benzyl-10-methoxyiminostilbene, and 0.36g 5wt% palladium carbon catalyst into a 100ml stainless steel autoclave. After nitrogen replacement three times, hydrogen was introduced, and the hydrogen pressure was maintained at 0.3-0.4MPa. The reaction was carried out at 50-55℃ for 5h. Nitrogen replacement three times, palladium carbon was recovered by filtration, and the filtrate was concentrated and dried to obtain 4.81g 10-methoxyiminostilbene, with a yield of 93.8% and a liquid phase purity of 99.5%.

Example 3

S1: Add 120g N,N-dimethylformamide, 12g (0.061mol) 2-benzylaminophenylacetonitrile, 13.5g (0.073mol) 2-bromobenzonitrile, 10.9g (0.079mol) potassium carbonate to a 500ml four-necked flask equipped with a stirrer, a thermometer, and a reflux condenser, and stir at 95-100℃ for 4h. Cool to 20-25℃, filter, wash the filter cake with 15g N,N-dimethylformamide, combine the filtrate, and recover the solvent by vacuum distillation. Add 55g isopropyl ether to the residue for recrystallization to obtain 16.2g N-benzyl-N-2′-cyanophenyl-2-aminophenylacetonitrile, with a yield of 91.4% and a liquid phase purity of 99.5%.

S2: Add 100g 2-methyltetrahydrofuran and 4.4g (0.065mol) sodium ethoxide to a 500ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel. Add dropwise a mixture of 16.3g (0.05mol) N-benzyl-N-2′-cyanophenyl-2-aminophenylacetonitrile and 30g 2-methyltetrahydrofuran at 50-55°C. After the addition is complete, stir and react at 70-75°C for 3.5h. The mixture was cooled to 20-25°C, 200 g of water was added, and the hydrolysis reaction was stirred at 65-70°C for 3 h. The layers were separated, and the aqueous layer was washed once with 20 g of dichloromethane. The aqueous phase was acidified with 35 wt% hydrochloric acid to a pH value of 2.0-2.5, filtered, and dried to obtain 13.8 g of 5-benzyl-10-oxa-10,11-dihydro-5H-dibenzo[b,f]azepine with a yield of 91.8% and a liquid phase purity of 99.5%.

S3: Add 100g methanol, 7.2g (0.024mol) 5-benzyl-10-oxa-10,11-dihydro-5H-dibenzo[b,f]azepine, 3.87g (0.043mol) dimethyl carbonate, 4.97g (0.036mol) potassium carbonate to a 500ml stainless steel autoclave. Seal the autoclave, heat up, and stir at 85-90℃ for 3.5h. Cool to 20-25℃, filter, wash the filter cake with 20g methanol, combine the filtrate, and recover the solvent by vacuum distillation. The residue is recrystallized with 30g isopropyl ether and dried to obtain 6.93g 5-benzyl-10-methoxyiminostilbene, with a yield of 93.1% and a liquid phase purity of 99.4%.

S4: Add 50g methanol, 6.26g (0.02mol) 5-benzyl-10-methoxyiminostilbene, and 0.25g 5wt% palladium carbon catalyst into a 100ml stainless steel autoclave. After nitrogen replacement three times, introduce hydrogen, maintain the hydrogen pressure at 0.2-0.3MPa, and react at 45-50℃ for 4h. Replace nitrogen three times, filter and recover palladium carbon, concentrate the filtrate, and dry to obtain 4.21g 10-methoxyiminostilbene, with a yield of 94.1% and a liquid phase purity of 99.6%.

Example 4

S1: In a 500 ml four-necked flask equipped with a stirrer, a thermometer, and a reflux condenser, add 120 g of N,N-dimethylformamide, 10 g (0.045 mol) of 2-benzylaminophenylacetonitrile, 10.0 g (0.054 mol) of 2-bromobenzonitrile, and 7.45 g (0.054 mol) of Potassium carbonate, stir and react at 95-100℃ for 5h. Cool to 20-25℃, filter, wash the filter cake with 15gN,N-dimethylformamide, combine the filtrate, and recover the solvent by vacuum distillation. Add 45g of isopropyl ether to the residue for recrystallization to obtain 13.1g of N-benzyl-N-2′-cyanophenyl-2-aminobenzeneacetonitrile, with a yield of 91.2% and a liquid phase purity of 99.4%.

S2: Add 100g 2-methyltetrahydrofuran and 3.25g (0.048mol) sodium ethoxide to a 500ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel. Add dropwise a mixture of 13g (0.04mol) N-benzyl-N-2′-cyanophenyl-2-aminophenylacetonitrile and 30g 2-methyltetrahydrofuran at 50-55°C. After the addition is complete, stir and react at 55-60°C for 4h. The mixture was cooled to 20-25°C, 200 g of water was added, and the hydrolysis reaction was stirred at 55-60°C for 3 h. The layers were separated, and the aqueous layer was washed once with 20 g of dichloromethane. The resulting aqueous phase was acidified with 35 wt% hydrochloric acid to a pH value of 2.0-2.5, filtered, and dried to obtain 10.9 g of 5-benzyl-10-oxa-10,11-dihydro-5H-dibenzo[b,f]azepine with a yield of 91.5% and a liquid phase purity of 99.5%.

S3: Add 100g methanol, 6.0g (0.02mol) 5-benzyl-10-oxa-10,11-dihydro-5H-dibenzo[b,f]azepine, 3.06g (0.034mol) dimethyl carbonate, and 3.31g (0.024mol) potassium carbonate to a 500ml stainless steel autoclave. Seal the autoclave, heat up, and stir at 80-85℃ for 4h. Cool to 20-25℃, filter, wash the filter cake with 20g methanol, combine the filtrate, and recover the solvent by vacuum distillation. The residue is recrystallized with 25g isopropyl ether and dried to obtain 5.78g 5-benzyl-10-methoxyiminostilbene, with a yield of 92.7% and a liquid phase purity of 99.6%.

S4: Add 50g methanol, 5g (0.016mol) 5-benzyl-10-methoxyiminostilbene, and 0.15g 5wt% palladium carbon catalyst into a 100ml stainless steel autoclave. After nitrogen replacement three times, hydrogen was introduced, and the hydrogen pressure was maintained at 0.2-0.3MPa. The reaction was carried out at 40-45℃ for 5h. Nitrogen replacement three times, palladium carbon was recovered by filtration, the filtrate was concentrated and dried to obtain 3.32g 10-methoxyiminostilbene, with a yield of 93.4% and a liquid phase purity of 99.5%.

Example 5

S1: Add 120g N,N-dimethylformamide, 7.5g (0.034mol) 2-benzylaminophenylacetonitrile, 6.29g (0.034mol) 2-bromobenzonitrile, 4.69g (0.034mol) potassium carbonate to a 500ml four-necked flask equipped with a stirrer, a thermometer, and a reflux condenser, and stir at 90-95℃ for 5h. Cool to 20-25℃, filter, wash the filter cake with 15g N,N-dimethylformamide, combine the filtrate, and recover the solvent by vacuum distillation. Add 35g isopropyl ether to the residue for recrystallization to obtain 10.1g N-benzyl-N-2′-cyanophenyl-2-aminophenylacetonitrile, with a yield of 91.3% and a liquid phase purity of 99.3%.

S2: Add 100g 2-methyltetrahydrofuran and 2.3g (0.034mol) sodium ethoxide to a 500ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel. Add dropwise a mixture of 10.8g (0.034mol) N-benzyl-N-2′-cyanophenyl-2-aminophenylacetonitrile and 30g 2-methyltetrahydrofuran at 40-45°C. After the addition is complete, stir and react at 40-45°C for 5h. The mixture was cooled to 20-25°C, 200 g of water was added, and the hydrolysis reaction was stirred at 45-50°C for 4 h. The layers were separated, and the aqueous layer was washed once with 20 g of dichloromethane. The aqueous phase was acidified with 35 wt% hydrochloric acid to a pH value of 2.0-2.5, filtered, and dried to obtain 8.93 g of 5-benzyl-10-oxa-10,11-dihydro-5H-dibenzo[b,f]azepine with a yield of 90.8% and a liquid purity of 99.4%.

S3: Add 100g methanol, 5.0g (0.017mol) 5-benzyl-10-oxa-10,11-dihydro-5H-dibenzo[b,f]azepine, 2.34g (0.026mol) dimethyl carbonate, and 2.35g (0.017mol) potassium carbonate to a 500ml stainless steel autoclave. Seal the autoclave, heat up, and stir at 70-75℃ for 5h. Cool to 20-25℃, filter, wash the filter cake with 20g methanol, combine the filtrate, and recover the solvent by vacuum distillation. The residue is recrystallized with 25g isopropyl ether and dried to obtain 4.76g 5-benzyl-10-methoxyiminostilbene, with a yield of 92.3% and a liquid phase purity of 99.5%.

S4: Add 50g methanol, 4.2g (0.013mol) 5-benzyl-10-methoxyiminostilbene, and 0.05g 5wt% palladium carbon catalyst into a 100ml stainless steel autoclave. After nitrogen replacement three times, hydrogen was introduced, and the hydrogen pressure was maintained at 0.2-0.3MPa. The reaction was carried out at 30-35℃ for 5h. Nitrogen replacement three times, palladium carbon was recovered by filtration, and the filtrate was concentrated and dried to obtain 2.78g 10-methoxyiminostilbene, with a yield of 93.3% and a liquid phase purity of 99.3%.

In Examples 1-5, the obtained 10-methoxyiminostilbene has a high purity, with a liquid phase purity of more than 99.3%. Through analysis, it can be found that the purity of the obtained 10-methoxyiminostilbene using the preparation process described in Example 3 is slightly higher than that of other examples.

The embodiments of the present application are simple and safe to operate, with mild reaction conditions and more selectivity. Most of the solvents and palladium-carbon catalysts can be recycled, the raw materials are cheap and easy to obtain, the cost is low, the amount of three wastes generated is small, and it is green and environmentally friendly, and suitable for industrial production.

The above are all preferred embodiments of the present application, and the protection scope of the present application is not limited thereto. Therefore, any equivalent changes made according to the structure, shape, and principle of the present application should be included in the protection scope of the present application.

Claims

A preparation process of high-purity and low-impurity 10-methoxyiminostilbene, characterized in that it comprises the following steps:

S1: Add 2-benzylaminophenylacetonitrile, an acid-binding agent and 2-halogenated benzonitrile to solvent A to prepare compound I, i.e., N-benzyl-N-2′-cyanophenyl-2-aminophenylacetonitrile, through substitution reaction;

S2: In solvent B, in the presence of base 1, compound I undergoes an intramolecular condensation reaction, followed by a hydrolysis reaction, and acidification with hydrochloric acid to obtain compound II, i.e., 5-benzyl-10-oxa-10,11-dihydro-5H-dibenzo[b,f]azepine;

S3: In solvent C, in the presence of base 2, compound II and a methylating agent undergo a methylation reaction to obtain compound III, i.e., 5-benzyl-10-methoxyiminostilbene;

S4: In solvent D, in the presence of a hydrogenation catalyst, compound III is debenzylated by catalytic hydrogenolysis to obtain 10-methoxyiminostilbene.
The preparation process of 10-methoxyiminostilbene according to claim 1, characterized in that, in the step S1, the solvent A is one of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, toluene or chlorobenzene; the mass ratio of the solvent A to 2-benzylaminophenylacetonitrile is (4-16): 1.
The preparation process of 10-methoxyiminostilbene according to claim 1, characterized in that, in the step S1, the acid binding agent is an inorganic base or an organic base, the inorganic base is one of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate or calcium bicarbonate, and the organic base is one of triethylamine, tripropylamine, triisopropylamine or tri-n-butylamine; the molar ratio of the acid binding agent to 2-benzylaminophenylacetonitrile is (1.0-1.5): 1.
The preparation process of 10-methoxyiminostilbene according to claim 1, characterized in that, in the step S1, the 2-halobenzonitrile is one of 2-bromobenzonitrile or 2-chlorobenzonitrile; the molar ratio of the 2-halobenzonitrile to 2-benzylaminophenylacetonitrile is (1.0-1.3):1.
The process for preparing 10-methoxyiminostilbene according to claim 1, characterized in that in the step S1, the substitution reaction temperature is 90-110 ° C.
The preparation process of 10-methoxyiminostilbene according to claim 1, characterized in that in the step S2: the solvent B is one of tetrahydrofuran, 2-methyltetrahydrofuran, methyl cyclopentyl ether, N,N-dimethylformamide or chlorobenzene; the mass ratio of the solvent B to the compound I is (4-12): 1;

The base 1 is one of sodium methoxide, sodium ethoxide, potassium tert-butoxide or sodium hydride; the molar ratio of the base 1 to compound I is (1.0-1.5):1.
The preparation process of 10-methoxyiminostilbene according to claim 1, characterized in that, in the step S2, the intramolecular condensation reaction temperature is 30-90 ° C; the hydrolysis reaction temperature is 40-80 ° C.
The preparation process of 10-methoxyiminostilbene according to claim 1, characterized in that in the step S2, the hydrochloric acid acidification is acidified using hydrochloric acid with a mass concentration of 30-35% until the system pH is 2-2.5.
The preparation process of 10-methoxyiminostilbene according to claim 1, characterized in that in the step S3: the solvent C is one of tetrahydrofuran, methanol, ethanol, N,N-dimethylformamide or toluene; the mass ratio of the solvent C to the compound II is (8-20):1;

The base 2 is one of potassium carbonate, sodium carbonate, sodium hydroxide or potassium hydroxide; the molar ratio of the base 2 to the compound II is (1.0-1.8):1;

The methylation agent is one of dimethyl carbonate, dimethyl sulfate, methyl bromide or methyl iodide; the molar ratio of the methylation agent to compound II is (1.5-2.2):1; and the methylation reaction temperature is 70-100°C.
The preparation process of 10-methoxyiminostilbene according to claim 1, characterized in that in the step S4: solvent D is one of tetrahydrofuran, methanol, ethanol or isopropanol; and the mass ratio of solvent D to compound III is (5-12):1;

The hydrogenation catalyst is one of palladium carbon or Raney nickel; the mass of the palladium carbon catalyst is 1%-6% of the mass of compound III, and the mass of the Raney nickel catalyst is 10%-18% of the mass of compound III;

The catalytic hydrogenolysis reaction temperature is 30-60°C, and the hydrogen pressure is 0.2-0.4MPa.