阅读说明：本技术 一种非甾体抗炎药痛灭定的合成方法 (Synthetic method of non-steroidal anti-inflammatory drug tolmetin ) 是由 俞迪虎 王权 包磊 侯大鹏 于 2020-01-19 设计创作，主要内容包括：本发明公开了一种一种非甾体抗炎药痛灭定的合成方法,所述合成方法为：以柠檬酸或一水合柠檬酸为原料,依次制备含硫酸的丙酮二羧酸粗品、2-(2-乙酸基)-1-甲基-1H-吡咯-3-甲酸和2-(2-乙酸烷基酯基)-1-甲基-1H-吡咯-3-甲酸,再经脱羧、酰化、水解和酸化制得痛灭定。本发明提供的合成方法克服了目前痛灭定制备工艺依赖N-甲基吡咯的不足,是一种低成本、低污染、高收率的非甾体抗炎药痛灭定的合成方法。(The invention discloses a synthetic method of a non-steroidal anti-inflammatory drug tolmetin, which comprises the following steps: the method comprises the steps of taking citric acid or citric acid monohydrate as a raw material, sequentially preparing a sulfuric acid-containing acetone dicarboxylic acid crude product, 2- (2-acetoxyl) -1-methyl-1H-pyrrole-3-formic acid and 2- (2-acetic acid alkyl ester group) -1-methyl-1H-pyrrole-3-formic acid, and then decarboxylating, acylating, hydrolyzing and acidifying to obtain the tolmetin. The synthetic method provided by the invention overcomes the defect that the existing preparation process of the tolmetin depends on N-methyl pyrrole, and is a synthetic method of the non-steroidal anti-inflammatory drug tolmetin with low cost, low pollution and high yield.)

1. A synthetic method of a non-steroidal anti-inflammatory drug tolmetin is characterized by comprising the following steps: the method comprises the steps of taking citric acid or citric acid monohydrate as a raw material, sequentially preparing a sulfuric acid-containing acetone dicarboxylic acid crude product, 2- (2-acetoxyl) -1-methyl-1H-pyrrole-3-formic acid and 2- (2-acetic acid alkyl ester group) -1-methyl-1H-pyrrole-3-formic acid, and then decarboxylating, acylating, hydrolyzing and acidifying to obtain the tolmetin.

2. The method of synthesizing the non-steroidal anti-inflammatory drug, tolmetin, according to claim 1, characterized in that it comprises the steps of:

(1) reacting citric acid or citric acid monohydrate with concentrated sulfuric acid, crystallizing in ice water after the reaction is finished, and filtering at low temperature to prepare a sulfuric acid-containing acetone dicarboxylic acid crude product;

(2) sequentially mixing and reacting a sulfuric acid-containing acetone dicarboxylic acid crude product with a methylamine aqueous solution and a chloroacetaldehyde aqueous solution, removing unreacted methylamine and acidifying after the reaction is finished to obtain a cyclization product 2- (2-acetoxyl) -1-methyl-1H-pyrrole-3-formic acid;

(3)2- (2-acetoxy) -1-methyl-1H-pyrrole-3-formic acid and alcohol are subjected to selective esterification under the catalysis of acid, and after the reaction is finished, the temperature is reduced and crystallization is carried out to obtain a product 2- (2-alkyl acetate) -1-methyl-1H-pyrrole-3-formic acid;

(4) heating and decarboxylating 2- (2-alkyl acetate) -1-methyl-1H-pyrrole-3-formic acid to obtain a product 2- (2-alkyl acetate) -1-methyl-1H-pyrrole;

(5) 2- (2-acetic acid alkyl ester group) -1-methyl-1H-pyrrole is sequentially acylated, hydrolyzed and acidified to prepare the product of the tolmetin.

3. The method for synthesizing the non-steroidal anti-inflammatory drug vamidodine according to claim 2, wherein in the step (1), the molar ratio of the concentrated sulfuric acid to the citric acid is 5-20: 1, and the reaction temperature is 10-70 ℃.

4. The method for synthesizing the non-steroidal anti-inflammatory drug vamidodine according to claim 2, wherein in the step (2), the molar ratio of the sulfuric acid-containing acetone dicarboxylic acid crude product to methylamine to chloroacetaldehyde is 1: 1-20: 1-3, and the final pH of acidification is 0.5-2.

5. The method of claim 2, wherein in step (3) the alcohol is selected from C₄An alcohol selected from concentrated sulfuric acid, hydrochloric acid or p-toluenesulfonic acid.

6. The method for synthesizing the non-steroidal anti-inflammatory drug vamidodine according to claim 2, wherein in the step (4), the decarboxylation temperature is 130-250 ℃.

7. The method for synthesizing the non-steroidal anti-inflammatory drug vamidodine according to claim 2, wherein in step (5), the acylation method is: under the action of a catalyst, 2- (2-alkyl acetate) -1-methyl-1H-pyrrole and p-methylbenzoyl chloride are subjected to acylation reaction to generate 2- (2-alkyl acetate) -5-p-methylbenzoyl-1-methyl-1H-pyrrole, wherein alkyl is C₄The following alkyl groups.

8. The method of synthesizing the non-steroidal anti-inflammatory drug, tolmetin, according to claim 7, wherein the catalyst is selected from aluminum chloride or N-methylmorpholine.

9. The method for synthesizing the non-steroidal anti-inflammatory drug, tolmetin, according to claim 2, wherein in step (5), the method for hydrolysis and acidification is: adding 2- (2-alkyl acetate) -5-p-methylbenzoyl-1-methyl-1H-pyrrole and sodium hydroxide into water for hydrolysis; and then adding hydrochloric acid or sulfuric acid for acidification, wherein the pH value of the acidification end point is 1-2.

Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to a synthetic method of a non-steroidal anti-inflammatory drug tolmetin.

Background

Tolmetin (Tolmetin), chemical name: 1-methyl-5- (p-methylbenzoyl) pyrrole-2-acetic acid, a nonsteroidal anti-inflammatory analgesic, was developed by McNeil, USA, and was approved by the FDA in 1976. The effect of the medicine is similar to that of other non-steroidal anti-inflammatory drugs such as aspirin, but the side effect is light and the medicine is easily tolerated by patients. Animal experiments prove that the anti-arthritis effect of the compound is stronger than that of aspirin, weaker than that of indometacin and phenylbutazone, the analgesic effect of the compound is equivalent to that of ibuprofen, the antipyretic effect is stronger, and the compound is fast and safe to absorb after being orally taken.

Currently, the synthetic route of tolmetin mainly comprises the following modes:

(1) japanese patent (kokai8202270) invented a method for synthesizing tolmetin by using 1-methyl-2- (2-ethyl acetate) -1H-pyrrole-3-ethyl formate as a raw material. 1-methyl-2- (2-ethyl acetate) -1H-pyrrole-3-ethyl formate and p-toluoyl chloride are sequentially subjected to acylation, hydrolysis, decarboxylation and acidification to obtain the tolmetin. The method has the advantages of easily available raw materials, high cost and only 10% of total yield.

(2) German patent (DE2339140A1) discloses a process for preparing 1-methyl-1H-pyrrole-2-ethyl acetate as starting material. Acylation of 1-methyl-1H-pyrrole-2-ethyl acetate with phosgene, reaction with p-methylphenyl magnesium bromide, and hydrolysis of the product to obtain the tolmetin. This process is too toxic using phosgene as the acylating agent.

(3) Spanish patent (ES456334A1) invented a synthetic method for preparing tolmetin by reacting 5-chloro-1-methyl-2-pyrrole methanol with dimethyl sulfate, sequentially performing iodination and cyanation on the product, and hydrolyzing with dilute sulfuric acid. The method has high cost of raw materials and large toxicity by using dimethyl sulfate as a methylating agent.

(4) Chinese patent (CN101177411A) invented a synthetic method of tolmetin, which uses N-methyl pyrrole as raw material, after benzoyl chloride acylation, the product reacts with triethyl methanetricarboxylate in the presence of manganese complex to generate intermediate 1-methyl-5- (4-methyl benzoyl) -1H-pyrrole-2-triethyl methanetricarboxylate, and the compound is saponified, acidified and decarboxylated. The method has complex process, takes N-methyl pyrrole as raw material and has high cost.

(5) Chinese patent (CN103435527B) invented a method for preparing tolmetin. N-methyl pyrrole is used as a raw material to react with oxalyl chloride monoethyl ester, and an acylation product is subjected to reduction, low-temperature condensation, acylation and hydrolysis acidification to prepare the tolmetin. The method obtains the tolmetin through five steps of reaction, and the total yield reaches 60 percent. However, the method takes N-methyl pyrrole as a raw material, so that the process cost is high.

(6) US4363918, which does not give a specific implementation, protects the preparation of 2- (2-acetoxy) -1-methyl-1H-pyrrole-3-carboxylic acid using acetonedicarboxylic acid, methylamine and chloroacetaldehyde. Moreover, the acetonedicarboxylic acid is an extremely unstable crystal, is extremely easy to decompose by heating, is not suitable for storage, is expensive and has poor commercialization degree, and industrial production of tolmetin cannot be realized by using the acetonedicarboxylic acid as a starting material.

The existing synthetic route of tolmetin mostly depends on N-methyl pyrrole, and the market price of the N-methyl pyrrole is greatly increased, so that the economic benefit of the tolmetin process is obviously reduced.

Disclosure of Invention

The invention aims to overcome the defect that the existing preparation process of the tolmetin depends on N-methyl pyrrole, and provides a synthetic method of the non-steroidal anti-inflammatory drug tolmetin with low cost, low pollution and high yield.

A synthetic method of a non-steroidal anti-inflammatory drug tolmetin comprises the following steps: the method comprises the steps of taking citric acid or citric acid monohydrate as a raw material, sequentially preparing a sulfuric acid-containing acetone dicarboxylic acid crude product, 2- (2-acetoxyl) -1-methyl-1H-pyrrole-3-formic acid and 2- (2-acetic acid alkyl ester group) -1-methyl-1H-pyrrole-3-formic acid, and then decarboxylating, acylating, hydrolyzing and acidifying to obtain the tolmetin.

Specifically, the synthesis method comprises the following steps:

(1) reacting citric acid or citric acid monohydrate with concentrated sulfuric acid, crystallizing in ice water after the reaction is finished, and filtering at low temperature to prepare a sulfuric acid-containing acetone dicarboxylic acid crude product;

(2) sequentially mixing and reacting a sulfuric acid-containing acetone dicarboxylic acid crude product with a methylamine aqueous solution and a chloroacetaldehyde aqueous solution, removing unreacted methylamine and acidifying after the reaction is finished to obtain a cyclization product 2- (2-acetoxyl) -1-methyl-1H-pyrrole-3-formic acid;

(3)2- (2-acetoxy) -1-methyl-1H-pyrrole-3-formic acid and alcohol are subjected to selective esterification under the catalysis of acid, and after the reaction is finished, the temperature is reduced and crystallization is carried out to obtain a product 2- (2-alkyl acetate) -1-methyl-1H-pyrrole-3-formic acid;

(4) heating and decarboxylating 2- (2-alkyl acetate) -1-methyl-1H-pyrrole-3-formic acid to obtain a product 2- (2-alkyl acetate) -1-methyl-1H-pyrrole;

(5) 2- (2-acetic acid alkyl ester group) -1-methyl-1H-pyrrole is sequentially acylated, hydrolyzed and acidified to prepare the product of the tolmetin.

The reaction route in the synthesis method provided by the invention is as follows:

wherein R is methyl, ethyl, propyl and other C₄The following alkyl groups.

In the step (1), the molar ratio of the concentrated sulfuric acid to the citric acid is 5-20: 1, and the reaction temperature is 10-70 ℃.

Preferably, in the step (1), the molar ratio of the concentrated sulfuric acid to the citric acid is 5-10: 1, and the reaction temperature is 50-70 ℃. The yield of the acetone dicarboxylic acid crude product containing sulfuric acid prepared under the process conditions is high.

The dried acetonedicarboxylic acid is decomposed during the purification and purification processes, resulting in a decrease in the yield thereof, and the yield of obtaining dry high-purity acetonedicarboxylic acid is very low. We have surprisingly found that the crude acetone dicarboxylic acid containing sulfuric acid is more stable in an acidic environment and that the presence of sulfuric acid does not adversely affect subsequent processing. The invention improves the molar ratio of concentrated sulfuric acid and higher reaction temperature in the step (1), uses citric acid or citric acid monohydrate which is easy to store as a starting material, prepares the acetone dicarboxylic acid crude product containing sulfuric acid with high yield, and improves the yield of the whole preparation process by using the acetone dicarboxylic acid crude product containing sulfuric acid with high yield.

In the step (2), the molar ratio of the sulfuric acid-containing acetone dicarboxylic acid crude product to methylamine to chloroacetaldehyde is 1: 1-20: 1-3, and the final pH of acidification is 0.5-2.

Preferably, in the step (2), the molar ratio of the sulfuric acid-containing acetone dicarboxylic acid crude product to methylamine to chloroacetaldehyde is 1: 9-20: 2-3, the final pH of acidification is 0.7-1, and the yield of the cyclization product 2- (2-acetoxy) -1-methyl-1H-pyrrole-3-carboxylic acid is higher.

In step (3), the alcohol is selected from C₄An alcohol selected from concentrated sulfuric acid, hydrochloric acid or p-toluenesulfonic acid.

Preferably, in the step (3), the temperature is reduced to 0 ℃ for crystallization; the molar ratio of the 2- (2-acetoxy) -1-methyl-1H-pyrrole-3-formic acid to the alcohol to the acid is 1: 5-50: 0.01-0.5.

Preferably, in step (3), the alcohol is methanol or ethanol.

In the step (4), the decarboxylation temperature is 130-250 ℃.

Preferably, the decarboxylation temperature is 180-190 ℃.

In step (5), the acylation method is as follows: under the action of a catalyst, 2- (2-alkyl acetate) -1-methyl-1H-pyrrole and p-methylbenzoyl chloride are subjected to acylation reaction to generate 2- (2-alkyl acetate) -5-p-methylbenzoyl-1-methyl-1H-pyrrole, wherein alkyl is C₄The following alkyl groups.

The catalyst is selected from aluminum chloride or N-methylmorpholine.

Preferably, the molar ratio of the 2- (2-alkyl acetate) -1-methyl-1H-pyrrole to the p-methyl benzoyl chloride to the catalyst is 1: 1-1.6.

In step (5), the hydrolysis and acidification method comprises the following steps: adding 2- (2-alkyl acetate) -5-p-methylbenzoyl-1-methyl-1H-pyrrole and sodium hydroxide into water for hydrolysis; and then adding hydrochloric acid or sulfuric acid for acidification, wherein the pH value of the acidification end point is 1-2.

Preferably, in the hydrolysis method, the molar ratio of the 2- (2-alkyl acetate) -5-p-methylbenzoyl-1-methyl-1H-pyrrole to NaOH is 1: 1-3.

It has been found that when acetone dicarboxylic acid is produced using inexpensive citric acid or its monohydrate, the yield of dry acetone dicarboxylic acid obtained is extremely low. Although the preparation of 2- (2-acetoxy) -1-methyl-1H-pyrrole-3-carboxylic acid using acetonedicarboxylic acid, methylamine and chloroacetaldehyde is protected by US4363918, no specific implementation is given. The acetonedicarboxylic acid is a very unstable crystal, is very easy to decompose by heating, is not suitable for storage, is expensive and has poor commercialization degree, and industrial production of tolmetin cannot be realized by using the acetonedicarboxylic acid as a starting material. We have found that acetonedicarboxylic acid is stable in an acidic environment, crude acetonedicarboxylic acid containing sulfuric acid is obtained by directly using citric acid and its monohydrate as starting materials without refining acetonedicarboxylic acid, yield reduction caused by refining and purification processes is avoided, and 2- (2-acetoxy) -1-methyl-1H-pyrrole-3-carboxylic acid is prepared in high yield.

The invention has the beneficial effects that: compared with the existing synthetic route, the invention uses cheap citric acid or citric acid monohydrate as the initial raw material to synthesize the tolmetin through six-step reaction, thereby avoiding using N-methylpyrrole as the raw material and reducing the process cost. The method has the advantages of cheap raw materials, simple process, little pollution and high yield, and is suitable for large-scale industrial production of the tolmetin.

Drawings

FIG. 1 shows the NMR spectra of tolmetin (1-methyl-5- (p-methylbenzoyl) pyrrole-2-acetic acid) prepared in the example.

Detailed Description

The invention is further described below by way of specific embodiments.

Example 1

Synthesis of acetonedicarboxylic acid

1000g of concentrated sulfuric acid and 192g of citric acid are added into a 2000ml three-neck flask, stirred and reacted for 15 hours at the temperature of 50 ℃, the reaction liquid is added into 1000ml of ice water to be cooled and crystallized, and low-temperature filtration is carried out, so that 161.2g of crude acetone dicarboxylic acid containing sulfuric acid is obtained. The crude product contained 123.5g of acetone dicarboxylic acid by liquid chromatography detection, and the yield was 84.5%.

Synthesis of 2- (2-acetoxy) -1-methyl-1H-pyrrole-3-carboxylic acid

95.4g of sulfuric acid-containing crude acetonedicarboxylic acid (containing 73.1g of acetonedicarboxylic acid), 60.0g of 26% aqueous methylamine solution and 100g of 40% aqueous chloroacetaldehyde solution were mixed and stirred in an ice-water bath for 12 hours, after the reaction, unreacted methylamine and chloroacetaldehyde were removed by distillation under reduced pressure, the solution temperature was lowered to 10 ℃, hydrochloric acid was added dropwise to adjust the solution pH to 1.6, a large amount of solid was produced during the addition, filtration was performed, washing was performed twice with 50g of water, and vacuum-drying was performed at 40 ℃ to obtain 38.5g of 2- (2-acetoxy) -1-methyl-1H-pyrrole-3-carboxylic acid in a yield of 41.9%.

Synthesis of 2- (2-carbomethoxy) -1-methyl-1H-pyrrole-3-carboxylic acid

36.6g of 2- (2-acetoxy) -1-methyl-1H-pyrrole-3-carboxylic acid, 180.0g of methanol and 0.4g of p-toluenesulfonic acid were added to a 500ml flask for reflux reaction for 1H, after the reaction was completed, the temperature was reduced to 0 ℃ to precipitate a white solid, which was filtered, washed with water, and vacuum-dried at 40 ℃ to obtain 36.8g of 2- (2-carbomethoxy) -1-methyl-1H-pyrrole-3-carboxylic acid with a yield of 93.4%.

Synthesis of 2- (2-carbomethoxy) -1-methyl-1H-pyrrole

29.6g of 2- (2-carbomethoxy) -1-methyl-1H-pyrrole-3-carboxylic acid was dissolved in 100.0ml of N, N-dimethylformamide, the reaction was stirred for 2 hours while the temperature was raised to 140 ℃, after removing N, N-dimethylformamide by rotary evaporation, 100.0ml of dichloromethane was used for dilution, and washed three times with 20.0ml of saturated sodium bicarbonate, and after drying the organic phase over anhydrous magnesium sulfate, dichloromethane was removed and dried under vacuum to obtain 14.8g of 2- (2-carbomethoxy) -1-methyl-1H-pyrrole with a yield of 64.4%.

Synthesis of 2- (2-carbomethoxy) -5-p-methylbenzoyl-1-methyl-1H-pyrrole

15.4g of 2- (2-carbomethoxy) -1-methyl-1H-pyrrole, 24.8g of p-methylbenzoyl chloride and 23.5g of anhydrous aluminum chloride were dissolved in 70ml of o-xylene, refluxed for 12 hours, concentrated, diluted to 80.0ml with methanol, refluxed for 30 minutes, cooled for crystallization, and filtered to obtain 22.9g of 2- (2-carbomethoxy) -5-p-methylbenzoyl-1-methyl-1H-pyrrole in 84.0% yield.

Synthesis of tolmetin (1-methyl-5- (p-methylbenzoyl) pyrrole-2-acetic acid)

Adding 13.6g of 2- (2-methyl acetate) -5-p-methylbenzoyl-1-methyl-1H-pyrrole and 3.0g of sodium hydroxide into 50ml of water, stirring and reacting at 40 ℃ for 3H, dropwise adding hydrochloric acid at room temperature to adjust the pH of the solution to 1.5, separating out a solid, filtering, washing and drying to obtain 10.6g of tolmetin, wherein the yield is 82.2%.

The nuclear magnetic data (hydrogen spectrum and carbon spectrum) of the tolmetin (1-methyl-5- (p-methylbenzoyl) pyrrole-2-acetic acid) prepared in the example are as follows:¹H NMR(500MHz,Chloroform-d)δ9.55(s,1H),7.71(d,2H),7.24(d,2H),6.68(d,1H),6.13(d,1H),3.94(s,3H),3.76(s,2H),2.42(s,3H)；¹³C NMR(126MHz,CDCl3)δ186.14,174.88,142.07,137.10,133.88,131.52,129.48,128.71,122.50,109.75,77.28,77.23,77.03,76.78,33.26,32.58,21.55,0.00。

example 2

Synthesis of acetonedicarboxylic acid

2000g of concentrated sulfuric acid and 192g of citric acid are added into a 2000ml three-neck flask, stirred and reacted for 15 hours at the temperature of 10 ℃, the reaction liquid is added into 1000ml of ice water to be cooled and crystallized, and low-temperature filtration is carried out, thus obtaining 103.5g of crude acetone dicarboxylic acid containing sulfuric acid. The crude product contained 77.9g of acetone dicarboxylic acid by liquid chromatography detection, and the yield was 53.3%.

Synthesis of 2- (2-acetoxy) -1-methyl-1H-pyrrole-3-carboxylic acid

97.0g of sulfuric acid-containing crude acetonedicarboxylic acid (containing 73.0g of acetonedicarboxylic acid), 360.0g of 40% aqueous methylamine solution and 200.0g of 40% aqueous chloroacetaldehyde solution were mixed and stirred in an ice-water bath for 12 hours, after the reaction, unreacted methylamine and chloroacetaldehyde were removed by distillation under reduced pressure, the solution temperature was lowered to 10 ℃, hydrochloric acid was added dropwise to adjust the solution pH to 1.0, a large amount of solid was produced during the addition, filtered, washed twice with 100g of water, and dried under vacuum at 40 ℃ to obtain 76.4g of 2- (2-acetoxy) -1-methyl-1H-pyrrole-3-carboxylic acid in a yield of 83.5%.

Synthesis of 2- (2-carbomethoxy) -1-methyl-1H-pyrrole-3-carboxylic acid

36.7g of 2- (2-acetoxy) -1-methyl-1H-pyrrole-3-carboxylic acid, 320.0g of methanol and 3.4g of p-toluenesulfonic acid were added to a 500ml flask for reflux reaction for 1H, after the reaction was completed, the temperature was reduced to 0 ℃ to precipitate a white solid, which was filtered, washed with water, and vacuum-dried at 40 ℃ to obtain 37.3g of 2- (2-carbomethoxy) -1-methyl-1H-pyrrole-3-carboxylic acid with a yield of 94.4%.

Synthesis of 2- (2-carbomethoxy) -1-methyl-1H-pyrrole

29.8g of 2- (2-carbomethoxy) -1-methyl-1H-pyrrole-3-carboxylic acid was dissolved in 100.0ml of N, N-dimethylformamide, the reaction was stirred for 2 hours while the temperature was raised to 180 ℃, after removing N, N-dimethylformamide by rotary evaporation, 100.0ml of dichloromethane was used for dilution, and washed three times with 20.0ml of saturated sodium bicarbonate, and after drying the organic phase over anhydrous magnesium sulfate, dichloromethane was removed and dried under vacuum to obtain 19.1g of 2- (2-carbomethoxy) -1-methyl-1H-pyrrole in 82.5% yield.

Synthesis of 2- (2-carbomethoxy) -5-p-methylbenzoyl-1-methyl-1H-pyrrole

15.3g of 2- (2-carbomethoxy) -1-methyl-1H-pyrrole, 18.6g of p-methylbenzoyl chloride and 17.6g of anhydrous aluminum chloride were dissolved in 60ml of o-xylene, refluxed for 12 hours, concentrated, diluted to 80.0ml with methanol, refluxed for 30 minutes, cooled for crystallization, and filtered to obtain 22.2g of 2- (2-carbomethoxy) -5-p-methylbenzoyl-1-methyl-1H-pyrrole in a yield of 81.9%.

Synthesis of tolmetin (1-methyl-5- (p-methylbenzoyl) pyrrole-2-acetic acid)

Adding 13.8g of 2- (2-methyl acetate) -5-p-methylbenzoyl-1-methyl-1H-pyrrole and 4.5g of sodium hydroxide into 50ml of water, stirring and reacting at 60 ℃ for 2H, dropwise adding hydrochloric acid at room temperature to adjust the pH of the solution to 1.5, separating out a solid, filtering, washing and drying to obtain 10.9g of tolmetin, wherein the yield is 83.3%.

Example 3

Synthesis of acetonedicarboxylic acid

500g of concentrated sulfuric acid and 192g of citric acid are added into a 2000ml three-neck flask, the mixture is stirred and reacted for 15 hours at the temperature of 70 ℃, reaction liquid is added into 1000ml of ice water to be cooled and crystallized, and low-temperature filtration is carried out, so as to obtain 142.8g of crude acetone dicarboxylic acid containing sulfuric acid. The crude product contained 111.4g of acetone dicarboxylic acid by liquid chromatography detection, and the yield was 76.2%.

Synthesis of 2- (2-acetoxy) -1-methyl-1H-pyrrole-3-carboxylic acid

93.8g of sulfuric acid-containing crude acetonedicarboxylic acid (containing 73.2g of acetonedicarboxylic acid), 770g of a 40% aqueous methylamine solution and 295.0g of a 40% aqueous chloroacetaldehyde solution were mixed and stirred in an ice-water bath for 12 hours, after the reaction, unreacted methylamine and chloroacetaldehyde were removed by distillation under reduced pressure, the solution temperature was lowered to 10 ℃, hydrochloric acid was added dropwise to adjust the solution pH to 0.7, a large amount of solid was produced during the addition, the filtration was carried out, washing was carried out twice with 100g of water, and vacuum-drying was carried out at 40 ℃ to obtain 77.2g of 2- (2-acetoxy) -1-methyl-1H-pyrrole-3-carboxylic acid in a yield of 84.1%.

Synthesis of 2- (2-acetoxy) -1-methyl-1H-pyrrole-3-carboxylic acid

36.7g of 2- (2-acetoxy) -1-methyl-1H-pyrrole-3-carboxylic acid, 460.0g of ethanol and 0.6g of concentrated sulfuric acid are added into a 500ml flask for reflux reaction for 1H, the temperature is reduced to 0 ℃ after the reaction is finished, white solid is separated out, filtered, washed by water and dried in vacuum at 40 ℃ to obtain 39.6g of 2- (2-acetoxy) -1-methyl-1H-pyrrole-3-carboxylic acid with the yield of 93.6%.

Synthesis of 2- (2-ethyl acetate) -1-methyl-1H-pyrrole

31.8g of 2- (2-ethyl acetate) -1-methyl-1H-pyrrole-3-carboxylic acid is directly heated to 190 ℃ and stirred for reaction for 2H to obtain 19.8g of 2- (2-methyl acetate) -1-methyl-1H-pyrrole with the yield of 78.6%.

Synthesis of 2- (2-acetoxyl) -5-p-methylbenzoyl-1-methyl-1H-pyrrole

16.9g of 2- (2-acetoxyl) -1-methyl-1H-pyrrole, 15.6g of p-methylbenzoyl chloride and 10.3g N-methylmorpholine were dissolved in 60ml of o-xylene, and the mixture was refluxed for 12 hours, concentrated, diluted to 80.0ml with methanol, refluxed for 30 minutes, cooled to crystallize, and filtered to obtain 18.9g of 2- (2-acetoxyl) -5-p-methylbenzoyl-1-methyl-1H-pyrrole in a yield of 65.5%.

Synthesis of tolmetin (1-methyl-5- (p-methylbenzoyl) pyrrole-2-acetic acid)

14.5g of 2- (2-ethyl acetate) -5-p-methylbenzoyl-1-methyl-1H-pyrrole and 4.5g of sodium hydroxide are added into 50ml of water, stirred and reacted for 2 hours at 60 ℃, hydrochloric acid is dripped at room temperature to adjust the pH value of the solution to 1.5, solid is separated out, and the solution is filtered, washed and dried to obtain 10.3g of the tolmetin with the yield of 78.8%.

Example 4

Synthesis of acetonedicarboxylic acid

1000g of concentrated sulfuric acid and 192g of citric acid are added into a 2000ml three-neck flask, stirred and reacted for 15 hours at the temperature of 50 ℃, the reaction solution is added into 1000ml of ice water to be cooled and crystallized, and low-temperature filtration is carried out, thus obtaining 160.2g of crude acetone dicarboxylic acid containing sulfuric acid. The crude product contained 123.8g of acetone dicarboxylic acid by liquid chromatography detection, and the yield was 84.7%.

Synthesis of 2- (2-acetoxy) -1-methyl-1H-pyrrole-3-carboxylic acid

94.5g of sulfuric acid-containing crude acetone dicarboxylic acid (containing 73.0g of acetone dicarboxylic acid), 360.0g of 40% aqueous methylamine solution and 200.0g of 40% aqueous chloroacetaldehyde solution are mixed and stirred in an ice water bath for 12 hours, after the reaction, unreacted methylamine and chloroacetaldehyde are removed by distillation under reduced pressure, the solution temperature is reduced to 10 ℃, hydrochloric acid is added dropwise to adjust the pH of the solution to 1.0, a large amount of solid is generated in the dropwise addition process, filtration is carried out, washing is carried out twice with 100g of water, and vacuum drying is carried out at 40 ℃ to obtain 76.4g of 2- (2-acetoxy) -1-methyl-1H-pyrrole-3-carboxylic acid, and the yield is 83.5%.

Synthesis of 2- (2-propiophenoxy) -1-methyl-1H-pyrrole-3-carboxylic acid

36.7g of 2- (2-acetoxy) -1-methyl-1H-pyrrole-3-carboxylic acid, 600.0g of propanol and 10g of concentrated hydrochloric acid were added into a 500ml flask for reflux reaction for 1H, after the reaction was finished, the temperature was reduced to 0 ℃ to precipitate a white solid, which was filtered, washed with water and dried under vacuum at 40 ℃ to obtain 41.9g of 2- (2-propionylacetate) -1-methyl-1H-pyrrole-3-carboxylic acid with a yield of 92.9%.

Synthesis of 2- (2-propiophenoxy) -1-methyl-1H-pyrrole

34.0g of 2- (2-propyl acetate) -1-methyl-1H-pyrrole-3-formic acid is directly heated to 190 ℃ and stirred for reaction for 2H to obtain 20.5g of 2- (2-methyl acetate) -1-methyl-1H-pyrrole with the yield of 74.9%.

Synthesis of 2- (2-propylacetate) -5-p-methylbenzoyl-1-methyl-1H-pyrrole

18.3g of 2- (2-propionyloxy) -1-methyl-1H-pyrrole, 15.3g of p-methylbenzoyl chloride and 10.5g N-methylmorpholine were dissolved in 60ml of o-xylene, and the mixture was refluxed for 12 hours, concentrated, diluted to 80.0ml with methanol, refluxed for 30 minutes, cooled to crystallize, and filtered to obtain 18.3g of 2- (2-propionyloxy) -5-p-methylbenzoyl-1-methyl-1H-pyrrole in a yield of 60.5%.

Synthesis of tolmetin (1-methyl-5- (p-methylbenzoyl) pyrrole-2-acetic acid)

Adding 15.2g of 2- (2-propyl acetate) -5-p-methylbenzoyl-1-methyl-1H-pyrrole and 4.5g of sodium hydroxide into 50ml of water, stirring and reacting at 60 ℃ for 2H, dropwise adding hydrochloric acid at room temperature to adjust the pH of the solution to 1.5, separating out a solid, filtering, washing and drying to obtain 9.8g of tolmetin, wherein the yield is 75.0%.

Example 5

Synthesis of acetonedicarboxylic acid

1000g of concentrated sulfuric acid and 192g of citric acid are added into a 2000ml three-neck flask, stirred and reacted for 15 hours at the temperature of 50 ℃, the reaction liquid is added into 1000ml of ice water to be cooled and crystallized, and low-temperature filtration is carried out, thus obtaining 161.5g of crude acetone dicarboxylic acid containing sulfuric acid. The crude product contained 123.5g of acetone dicarboxylic acid by liquid chromatography detection, and the yield was 84.5%.

Synthesis of 2- (2-acetoxy) -1-methyl-1H-pyrrole-3-carboxylic acid

95.5g of sulfuric acid-containing crude acetonedicarboxylic acid (containing 73.0g of acetonedicarboxylic acid), 360.0g of 40% aqueous methylamine solution and 200.0g of 40% aqueous chloroacetaldehyde solution were mixed and stirred in an ice-water bath for 12 hours, after the reaction, unreacted methylamine and chloroacetaldehyde were removed by distillation under reduced pressure, the solution temperature was lowered to 10 ℃, hydrochloric acid was added dropwise to adjust the solution pH to 1.0, a large amount of solid was produced during the dropwise addition, filtered, washed twice with 100g of water, and dried under vacuum at 40 ℃ to obtain 76.4g of 2- (2-acetoxy) -1-methyl-1H-pyrrole-3-carboxylic acid in a yield of 83.5%.

Synthesis of 2- (2-carbomethoxy) -1-methyl-1H-pyrrole-3-carboxylic acid

36.7g of 2- (2-acetoxy) -1-methyl-1H-pyrrole-3-carboxylic acid, 320.0g of methanol and 3.4g of p-toluenesulfonic acid were added to a 500ml flask for reflux reaction for 1H, after the reaction was completed, the temperature was reduced to 0 ℃ to precipitate a white solid, which was filtered, washed with water, and vacuum-dried at 40 ℃ to obtain 37.3g of 2- (2-carbomethoxy) -1-methyl-1H-pyrrole-3-carboxylic acid with a yield of 94.4%.

Synthesis of 2- (2-carbomethoxy) -1-methyl-1H-pyrrole

29.6g of 2- (2-carbomethoxy) -1-methyl-1H-pyrrole-3-carboxylic acid was dissolved in 100.0ml of N, N-dimethylformamide, the reaction was stirred at 250 ℃ for 2 hours, after removing N, N-dimethylformamide by rotary evaporation, 100.0ml of dichloromethane was used for dilution, and washed three times with 20.0ml of saturated sodium bicarbonate, and the organic phase was dried over anhydrous magnesium sulfate, then dichloromethane was removed, and vacuum drying was carried out to obtain 15.6g of 2- (2-carbomethoxy) -1-methyl-1H-pyrrole with a yield of 67.8%.

Synthesis of 2- (2-carbomethoxy) -5-p-methylbenzoyl-1-methyl-1H-pyrrole

15.2g of 2- (2-carbomethoxy) -1-methyl-1H-pyrrole, 21.7g of p-methylbenzoyl chloride and 14.7g N-methylmorpholine were dissolved in 70ml of o-xylene, refluxed for 12 hours, concentrated and diluted to 80.0ml with methanol, refluxed for 30 minutes, cooled for crystallization, and filtered to obtain 22.7g of 2- (2-carbomethoxy) -5-p-methylbenzoyl-1-methyl-1H-pyrrole with a yield of 84.3%.

Synthesis of tolmetin (1-methyl-5- (p-methylbenzoyl) pyrrole-2-acetic acid)

Adding 13.7g of 2- (2-methyl acetate) -5-p-methylbenzoyl-1-methyl-1H-pyrrole and 1.5g of sodium hydroxide into 50ml of water, stirring and reacting at 90 ℃ for 2H, dropwise adding hydrochloric acid at room temperature to adjust the pH of the solution to 1.5, separating out a solid, filtering, washing and drying to obtain 8.4g of tolmetin, wherein the yield is 64.7%.

Example 6

Synthesis of acetonedicarboxylic acid

1000g of concentrated sulfuric acid and 192g of citric acid are added into a 2000ml three-neck flask, stirred and reacted for 15 hours at the temperature of 50 ℃, the reaction liquid is added into 1000ml of ice water to be cooled and crystallized, and low-temperature filtration is carried out, thus obtaining 161.0g of crude acetone dicarboxylic acid containing sulfuric acid. The crude product contained 123.3g of acetone dicarboxylic acid by liquid chromatography detection, and the yield was 84.4%.

Synthesis of 2- (2-acetoxy) -1-methyl-1H-pyrrole-3-carboxylic acid

95.6g of sulfuric acid-containing crude acetonedicarboxylic acid (containing 73.2g of acetonedicarboxylic acid), 900g of 40% aqueous methylamine solution and 300.0g of 40% aqueous chloroacetaldehyde solution were mixed and stirred in an ice-water bath for 12 hours, after the reaction, unreacted methylamine and chloroacetaldehyde were removed by distillation under reduced pressure, the solution temperature was lowered to 10 ℃, hydrochloric acid was added dropwise to adjust the solution pH to 0.7, a large amount of solid was produced during the addition, filtration was performed, washing was performed twice with 100g of water, and vacuum-drying was performed at 40 ℃ to obtain 77.2g of 2- (2-acetoxy) -1-methyl-1H-pyrrole-3-carboxylic acid in a yield of 84.1%.

Synthesis of 2- (2-carbomethoxy) -1-methyl-1H-pyrrole-3-carboxylic acid

36.6g of 2- (2-acetoxy) -1-methyl-1H-pyrrole-3-carboxylic acid, 180.0g of methanol and 0.4g of p-toluenesulfonic acid were added to a 500ml flask for reflux reaction for 1H, after the reaction was completed, the temperature was reduced to 0 ℃ to precipitate a white solid, which was filtered, washed with water, and vacuum-dried at 40 ℃ to obtain 36.8g of 2- (2-carbomethoxy) -1-methyl-1H-pyrrole-3-carboxylic acid with a yield of 93.4%.

Synthesis of 2- (2-carbomethoxy) -1-methyl-1H-pyrrole

29.7g of 2- (2-methyl acetate) -1-methyl-1H-pyrrole-3-formic acid is directly heated to 190 ℃ and stirred for reaction for 2H to obtain 19.6g of 2- (2-methyl acetate) -1-methyl-1H-pyrrole with the yield of 84.9%.

Synthesis of 2- (2-carbomethoxy) -5-p-methylbenzoyl-1-methyl-1H-pyrrole

15.5g of 2- (2-carbomethoxy) -1-methyl-1H-pyrrole, 15.5g of p-methylbenzoyl chloride and 10.1g N-methylmorpholine were dissolved in 60ml of o-xylene, refluxed for 12 hours, concentrated and diluted to 80.0ml with methanol, refluxed for 30min, cooled for crystallization, and filtered to obtain 19.5g of 2- (2-carbomethoxy) -5-p-methylbenzoyl-1-methyl-1H-pyrrole with a yield of 71.0%.

Synthesis of tolmetin (1-methyl-5- (p-methylbenzoyl) pyrrole-2-acetic acid)

Adding 13.8g of 2- (2-methyl acetate) -5-p-methylbenzoyl-1-methyl-1H-pyrrole and 4.5g of sodium hydroxide into 50ml of water, stirring and reacting at 60 ℃ for 2H, dropwise adding hydrochloric acid at room temperature to adjust the pH of the solution to 1.5, separating out a solid, filtering, washing and drying to obtain 10.9g of tolmetin, wherein the yield is 83.3%.

Wherein, the NMR spectra of tolmetin (1-methyl-5- (p-methylbenzoyl) pyrrole-2-acetic acid) prepared in examples 1-6 are shown in figure 1.

The above-mentioned embodiments are intended to illustrate the technical solutions and advantages of the present invention, and it should be understood that the above-mentioned embodiments are only the most preferred embodiments of the present invention, and are not intended to limit the present invention, and any modifications, additions, equivalents, etc. made within the scope of the principles of the present invention should be included in the scope of the present invention.