阅读说明：本技术 一种氰基酮洛芬合成工艺 (Synthesis process of cyano ketoprofen ) 是由 邵新华 徐保华 徐亚华 何正江 王荣洲 于 2020-06-24 设计创作，主要内容包括：一种氰基酮洛芬合成工艺,通过酰氯化、氯化工段、酯化工段、氰化、蒸馏工段、甲基化工段、水解、精制工段、酰化傅克冰析蒸馏工段、精制工段,最后得到氰基酮洛芬成品。本发明合成产品成本低、以间甲基苯甲酸为起始原料,经过酰氯化、酯化、氰化、甲基化、傅克酰基化、水解反应,合成了本发明产品,简化了工艺和操作流程,安全可靠,反应过程中产生的废水废气都通过回收再利用,釜中产生残留物做危废处理,保护了环境,促进了工业生产,提高了生产效率,本发明中合成的成品纯度达到99%以上。(A process for synthesizing cyano ketoprofen includes such steps as acylating chlorination, esterification, cyanation, distillation, methylation, hydrolysis, refining, acylating Friedel-crafts liquoring, distillation and refining. The synthetic product has low cost, the m-methyl benzoic acid is taken as the initial raw material, and the product is synthesized through the acyl chlorination, esterification, cyanidation, methylation, Friedel-crafts acylation and hydrolysis reaction, the process and the operation flow are simplified, the safety and the reliability are realized, the waste water and the waste gas generated in the reaction process are recycled, the residues generated in the kettle are treated as hazardous wastes, the environment is protected, the industrial production is promoted, the production efficiency is improved, and the purity of the synthesized finished product reaches more than 99 percent.)

1. A process for synthesizing cyano ketoprofen is characterized by comprising the following steps:

1) putting 180-200 parts of m-toluic acid and 200-240 parts of thionyl chloride into an acylation chlorination kettle, heating to reflux, keeping the temperature for 4 hours to obtain an acylate, transferring the acylate into a chlorination reaction kettle, introducing chlorine gas at 100 ℃, converting 30% of the acylate into an acyl chloride, transferring the material into a distillation kettle, carrying out reduced pressure distillation, distilling out the acyl chloride, transferring the non-chlorinated acylate into the chlorination kettle for continuous chlorination, condensing and absorbing tail gas of acyl chlorination and chlorination, and absorbing the tail end by using liquid alkali;

2) putting the acyl chloride obtained in the step 1) into an esterification reaction kettle, heating to 40 ℃, dropwise adding 30-40 parts of methanol, obtaining an esterified material for later use after dropwise adding, heating to 80 ℃, keeping the temperature for 2 hours, and recovering the methanol;

3) adding 30-35 parts of methanol and 10-14 parts of sodium cyanide into a cyanidation reaction kettle, stirring and dissolving, heating to 40 ℃, starting to dropwise add 40-50 parts of prepared esterified material, keeping the temperature at 80 ℃ for 2 hours after dropwise adding, recovering methanol for cyanidation, adding water for stirring after recovering, adding 90-100 parts of toluene and 320-350 parts of water into a washing kettle, putting the cyanided material into the washing kettle, stirring and standing, dividing water, performing cyanogen breaking treatment on a water layer, putting a benzene layer into a distillation kettle, recovering toluene, after recovering, transferring the kettle for high vacuum distillation, and collecting methyl m-cyanobenzoate;

4) putting 150-180 parts of dimethyl carbonate, 40-60 parts of methyl m-cyanomethylbenzoate and 1-2 parts of potassium carbonate into a methylation reaction kettle, heating to 172-177 ℃, keeping the pressure in the kettle to be less than 20atm, carrying out heat preservation and pressure maintaining reaction to the end point, sampling and analyzing, cooling when the residual cyanobenzyl is less than 0.80%, reducing the temperature, carrying out filter pressing after the internal temperature is reduced to be less than or equal to 55 ℃, taking out solid materials, carrying out centralized treatment to recover the potassium carbonate, compressing filtrate to a rough distillation kettle by using air pressure to recover a mixture of dimethyl carbonate and methanol, rectifying the mixture in a rectifying tower to obtain a byproduct methanol, recycling the collected dimethyl carbonate, transferring the undistilled material to the kettle, carrying out high-vacuum distillation to collect methyl m-cyanoethylbenzoate for later use, and treating residues;

5) pumping 40-45 parts of m-cyanoethyl methyl benzoate, 1-2 parts of tetrabutylammonium bromide and 180-200 parts of water into a hydrolysis kettle, cooling to 20 ℃, dropwise adding liquid alkali, keeping the temperature below 25 ℃ for 5 hours after dropwise adding, cooling to 10 ℃, dropwise adding hydrochloric acid until the pH is =3, centrifugally filtering, adding water, washing twice, and collecting wastewater;

refining the crude product in water and methanol to obtain 99.5% pure m-cyanoethyl benzoic acid, and drying the refined product for later use; the mother liquor used for refining enters a rectifying tower to recover methanol, and the methanol is refined and reused;

6) step 5) refluxing the intermediate cyanoethylbenzoic acid with thionyl chloride for 10 hours in an enamel kettle, SO₂Cryogenic separation of HCL tail gas, SO₂Neutralizing a byproduct sodium sulfite with liquid alkali, absorbing HCL with water to prepare hydrochloric acid, recovering thionyl chloride to be clean, finally, vacuumizing to obtain an acylated solution, adding pure benzene to an acylate for standby, adding pure benzene and anhydrous aluminum trichloride to an enamel Friedel-crafts reactor, dropwise adding the prepared acylate at 75-80 ℃, dropwise adding for 2-3 hours, absorbing the hydrochloric acid with water to prepare tail gas, carrying out heat preservation and reflux (80-82 ℃) for reaction for 2 hours after dropwise adding, and cooling to normal temperature for standby; adding water into the ice-out kettle,Slowly placing the Friedel-crafts liquid into an ice separation kettle at 10-15 ℃, standing, layering, dividing water, selling an aluminum trichloride water layer, washing the water layer with water, mechanically using the ice separation water for the water layer, recovering pure benzene from a benzene layer, carrying out high vacuum distillation on the residual material, collecting vacuum of 2mm/hg, and taking the main fraction of a finished product as a crude product at 200 ℃;

7) and (3) putting the crude product into a refining kettle, dissolving the crude product with methanol, filtering after the materials are completely dissolved, recrystallizing the filtrate in a crystallization kettle, centrifuging and drying to obtain a finished product of the cyano ketoprofen, and recycling the methanol for reuse.

2. The process of claim 1, wherein the acid chloride in step 1) is m-chlorobenzoyl chloride.

3. The process according to claim 1, wherein the esterification material in step 2) is methyl m-chloromethyl benzoate.

Technical Field

The invention relates to the field of synthesis processes of medical intermediates, in particular to a synthesis process of cyano ketoprofen.

Background

The cyano ketoprofen is an excellent 2-aryl propionic acid non-steroidal anti-inflammatory analgesic, is applied to clinical high-efficiency antipyretic and analgesic drugs, and has good treatment effects on diseases such as rheumatism, rheumatoid arthritis, spondylitis, gout and the like.

With the rapid development of domestic economy, ketoprofen drug production technology is continuously promoted, and a plurality of common methods for synthesizing cyano ketoprofen are provided, wherein the first synthesis method is to prepare 3-acetyl benzophenone from benzoic acid serving as a starting material through bromination, Friede-crafts reaction and Grignard reaction, and then prepare ketoprofen through Darzens reaction. The second synthesis method comprises the following steps: nitrile ethyl benzophenone is used as a raw material and is prepared by sulfuric acid hydrolysis. The third synthesis method comprises the following steps: the preparation method comprises the steps of taking p-nitroacetophenone as a raw material, performing ketal protection, condensation, deprotection, reduction, diazo deamination to obtain 3-acetyl benzophenone, and performing Darzens reaction to obtain the product. The three methods for synthesizing the cyano ketoprofen have many disadvantages, namely high synthesis cost and unavailable raw materials; secondly, the synthetic purity is low, and the product cannot be refined; thirdly, the waste water is produced in large quantity and is difficult to treat; fourth, a large amount of hazardous waste is generated.

Disclosure of Invention

The invention aims to provide a process for synthesizing cyano ketoprofen, which aims to solve the problems in the background art.

In order to achieve the purpose, the invention provides the following technical scheme: a process for synthesizing cyano ketoprofen comprises the following steps:

1) putting 180-200 parts of m-toluic acid and 200-240 parts of thionyl chloride into an acylation chlorination kettle, heating to reflux, keeping the temperature for 4 hours to obtain an acylate, transferring the acylate into a chlorination reaction kettle, introducing chlorine gas at 100 ℃, converting 30% of the acylate into an acyl chloride, transferring the material into a distillation kettle, carrying out reduced pressure distillation, distilling out the acyl chloride, transferring the non-chlorinated acylate into the chlorination kettle for continuous chlorination, condensing and absorbing tail gas of acyl chlorination and chlorination, and absorbing the tail end by using liquid alkali;

2) putting the acyl chloride obtained in the step 1) into an esterification reaction kettle, heating to 40 ℃, dropwise adding 30-40 parts of methanol, obtaining an esterified material for later use after dropwise adding, heating to 80 ℃, keeping the temperature for 2 hours, and recovering the methanol;

3) adding 30-35 parts of methanol and 10-14 parts of sodium cyanide into a cyanidation reaction kettle, stirring and dissolving, heating to 40 ℃, starting to dropwise add 40-50 parts of prepared esterified material, keeping the temperature at 80 ℃ for 2 hours after dropwise adding, recovering methanol for cyanidation, adding water for stirring after recovering, adding 90-100 parts of toluene and 320-350 parts of water into a washing kettle, putting the cyanided material into the washing kettle, stirring and standing, dividing water, performing cyanogen breaking treatment on a water layer, putting a benzene layer into a distillation kettle, recovering toluene, recovering after recovering, transferring the kettle for high vacuum distillation, and collecting a benzyl cyanide finished product;

4) putting 150-180 parts of dimethyl carbonate, 40-60 parts of finished cyanobenzyl and 1-2 parts of potassium carbonate into a methylation reaction kettle, heating to 172-177 ℃, keeping the pressure in the kettle to be less than 20atm, carrying out heat preservation and pressure maintaining reaction to the end point, sampling and analyzing, when the residual cyanobenzyl is less than 0.80%, cooling, reducing the temperature to be less than or equal to 55 ℃, carrying out filter pressing, taking out solid materials, carrying out centralized treatment to recover the potassium carbonate, compressing the filtrate to a rough distillation kettle by using air pressure to recover a mixture of dimethyl carbonate and methanol, rectifying the mixture in a rectifying tower to obtain a byproduct methanol, recycling the collected dimethyl carbonate, transferring the undistilled material to the kettle, carrying out high-vacuum distillation to collect methyl m-cyanoethyl benzoate for later use, and treating residues in the kettle as;

5) pumping 40-45 parts of m-cyanoethyl methyl benzoate, 1-2 parts of tetrabutylammonium bromide and 180-200 parts of water into a hydrolysis kettle, cooling to 20 ℃, dropwise adding liquid alkali, keeping the temperature below 25 ℃ for 5 hours after dropwise adding liquid alkali, cooling to 10 ℃, dropwise adding hydrochloric acid until the pH is =3, centrifugally filtering, adding water, washing twice, and collecting wastewater. Refining the crude product in water and methanol to obtain 99.5% pure m-cyanoethyl benzoic acid, and drying the refined product for later use; the mother liquor used for refining enters a rectifying tower to recover methanol, and the methanol is refined and reused;

6) step 5) refluxing the intermediate cyanoethylbenzoic acid with thionyl chloride for 10 hours in an enamel kettle, SO₂Cryogenic separation of HCL tail gas, SO₂Neutralizing a byproduct sodium sulfite with liquid alkali, absorbing HCL with water to prepare hydrochloric acid, recovering thionyl chloride to be clean, finally, vacuumizing to obtain an acylated solution, adding pure benzene to an acylate for standby, adding pure benzene and anhydrous aluminum trichloride to an enamel Friedel-crafts reactor, dropwise adding the prepared acylate at 75-80 ℃, dropwise adding for 2-3 hours, absorbing the hydrochloric acid with water to prepare tail gas, carrying out heat preservation and reflux (80-82 ℃) for reaction for 2 hours after dropwise adding, and cooling to normal temperature for standby; separating ice outAdding water and hydrochloric acid into a kettle, slowly putting the Friedel-crafts liquid into an ice separation kettle at 10-15 ℃, standing, layering, dividing water, selling an aluminum trichloride water layer, washing the water layer with water for layering, mechanically using the ice separation water for water layer, recovering pure benzene from a benzene layer, carrying out high vacuum distillation on the residual material, collecting the vacuum of 2mm/hg, and taking the main fraction of a finished product as a crude product at 200 ℃;

7) and (3) putting the crude product into a refining kettle, dissolving the crude product with methanol, filtering after the materials are completely dissolved, recrystallizing the filtrate in a crystallization kettle, centrifuging and drying to obtain a finished product of the cyano ketoprofen, and recycling the methanol for reuse.

Preferably, the acyl chloride in the step 1) is m-chloromethyl benzoyl chloride.

Preferably, the esterification material in the step 2) is methyl m-chloromethyl benzoate.

The synthetic product has low cost, the m-methyl benzoic acid is taken as the initial raw material, and the product is synthesized through the acyl chlorination, esterification, cyanidation, methylation, Friedel-crafts acylation and hydrolysis reaction, the process and the operation flow are simplified, the safety and the reliability are realized, the waste water and the waste gas generated in the reaction process are recycled, the residues generated in the kettle are treated as hazardous wastes, the environment is protected, the industrial production is promoted, the production efficiency is improved, and the purity of the synthesized finished product reaches more than 99 percent.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.