阅读说明：本技术 一种帕瑞昔布钠杂质的合成方法 (Synthesis method of parecoxib sodium impurity ) 是由 明方永 邹海华 周先国 胡燕英 王刚 欧阳青东 于 2021-08-06 设计创作，主要内容包括：本发明公开了一种帕瑞昔布钠杂质的合成方法,帕瑞昔布钠杂质为3-(5-甲基-4-苯基异恶唑-3-基)苯磺酰胺,合成过程包括以下步骤：1)以5-甲基-3,4-二苯基异恶唑为原料,在硝化剂的作用下发生硝化反应,得中间体I；2)以中间体I在氯磺酸的作用下发生磺酰化反应,再与氨水发生酰胺化反应,得中间体II；3)以中间体II在还原剂a作用下发生硝基还原反应,得中间体III；4)以中间体III与亚硝酸钠发生重氮化反应,再加入还原剂b发生重氮还原反应,即得3-(5-甲基-4-苯基异恶唑-3-基)苯磺酰胺。本发明制备得到高纯度的帕瑞昔布钠杂质,可作为帕瑞昔布钠研究及成品检测中的对照品,为控制帕瑞昔布钠药品的质量提供有力的保障,适用于药品质量研究。(The invention discloses a synthesis method of parecoxib sodium impurity, wherein the parecoxib sodium impurity is 3- (5-methyl-4-phenylisoxazol-3-yl) benzenesulfonamide, and the synthesis process comprises the following steps: 1) taking 5-methyl-3, 4-diphenyl isoxazole as a raw material, and carrying out nitration reaction under the action of a nitrating agent to obtain an intermediate I; 2) the intermediate I is subjected to sulfonylation reaction under the action of chlorosulfonic acid and then subjected to amidation reaction with ammonia water to obtain an intermediate II; 3) carrying out nitro reduction reaction on the intermediate II under the action of a reducing agent a to obtain an intermediate III; 4) and carrying out diazotization reaction on the intermediate III and sodium nitrite, and then adding a reducing agent b to carry out diazotization reduction reaction, thus obtaining the 3- (5-methyl-4-phenylisoxazol-3-yl) benzenesulfonamide. The parecoxib sodium impurity with high purity prepared by the method can be used as a reference substance in parecoxib sodium research and finished product detection, provides powerful guarantee for controlling the quality of parecoxib sodium medicines, and is suitable for medicine quality research.)

1. A synthesis method of parecoxib sodium impurities is characterized in that the parecoxib sodium impurities are 3- (5-methyl-4-phenylisoxazol-3-yl) benzenesulfonamide, and the specific synthesis process comprises the following steps:

(1) taking 5-methyl-3, 4-diphenyl isoxazole as a raw material, and carrying out nitration reaction under the action of a nitrating agent to obtain an intermediate I;

(2) the intermediate I is subjected to sulfonylation reaction under the action of chlorosulfonic acid and then subjected to amidation reaction with ammonia water to obtain an intermediate II;

(3) carrying out nitro reduction reaction on the intermediate II under the action of a reducing agent a to obtain an intermediate III;

(4) and carrying out diazotization reaction on the intermediate III and sodium nitrite, and then adding a reducing agent b to carry out diazotization reduction reaction, thus obtaining the target product 3- (5-methyl-4-phenylisoxazol-3-yl) benzenesulfonamide.

2. The method for synthesizing parecoxib sodium impurity according to claim 1, wherein the nitrating agent in step (1) is nitric acid or a mixed acid of nitric acid and sulfuric acid; the molar ratio of the raw material 5-methyl-3, 4-diphenyl isoxazole to the nitrating agent is 1:1 to 1.5; the nitration reaction temperature is 10-50 ℃; the nitration reaction time is 1-2 h.

3. The method for synthesizing parecoxib sodium impurity according to claim 2, wherein the nitrating agent in step (1) is a mixed acid of nitric acid and sulfuric acid; the molar ratio of the raw material 5-methyl-3, 4-diphenyl isoxazole to the nitrating agent is 1: 1.01; the nitration reaction temperature is 20-30 ℃.

4. The method for synthesizing parecoxib sodium impurity according to claim 1, wherein in step (2), the weight ratio of intermediate I to chlorosulfonic acid is 1: 5-20; the solvent for the sulfonylation reaction is solvent-free or dichloromethane, the sulfonylation reaction temperature is 25-100 ℃, and the sulfonylation reaction time is 12 h.

5. The method for synthesizing parecoxib sodium impurity according to claim 5, wherein in step (2), the mass-to-volume ratio of intermediate I to ammonia water is 1: 20-40 g/ml; the temperature of the amidation reaction is 10-40 ℃; the amidation reaction time is 1-2 h.

6. The method for synthesizing parecoxib sodium impurity according to claim 4 or 5, wherein in step (2), the weight ratio of intermediate I to chlorosulfonic acid is 1: 10; the solvent of the sulfonylation reaction is solvent-free, and the temperature of the sulfonylation reaction is 90 ℃; the mass volume ratio of the intermediate I to the ammonia water is 1:30 g/ml; the temperature of the amidation reaction is 20-30 ℃.

7. The method for synthesizing parecoxib sodium impurity according to any one of claims 1-5, wherein the reducing agent a in step (3) is at least one of zinc powder, iron powder and palladium carbon; the solvent of the nitro reduction reaction is at least one of methanol, ethanol, methanol solution and ethanol solution.

8. The method for synthesizing parecoxib sodium impurity of claim 7, wherein the reducing agent a in step (3) is zinc powder; the solvent of the nitro reduction reaction is an ethanol solution, and the ethanol solution is prepared from ethanol and water according to a volume ratio of 1:1, and preparing the composition.

9. The method for synthesizing parecoxib sodium impurity according to claims 1-5, wherein in step (4), the molar ratio of intermediate III to sodium nitrite is 1:1 to 1.5; the diazotization reaction temperature is-10 ℃; the diazotization reaction time is 0.5-1 h; the reducing agent b is hypophosphorous acid; the mass-volume ratio of the intermediate III to the reducing agent b is 1: 10-50 g/mL; the diazo reduction reaction temperature is 20-30 ℃; the diazo reduction reaction time is 0.5-2 h.

10. The method for synthesizing parecoxib sodium impurity according to claim 9, wherein in step (4), the molar ratio of intermediate III to sodium nitrite is 1: 1.3; the diazotization reaction temperature is-10 ℃; the diazotization reaction time is 0.5 h; the mass volume ratio of the intermediate III to the hypophosphorous acid is 1: 50 g/mL; the diazo reduction reaction time is 0.5 h.

Technical Field

The invention relates to the technical field of compound synthesis, in particular to a method for synthesizing parecoxib sodium impurity.

Background

Parecoxib Sodium (Parecoxib Sodium) is a short-term treatment for postoperative pain developed by the combination of feverfew and famasia, and is one of basic drugs for clinical multi-mode analgesia. The parecoxib sodium has the characteristics of good analgesic effect, quick response, lasting effect, capability of effectively inhibiting hyperalgesia, high gastrointestinal safety, no influence on platelet function, no additional increase of cardiovascular risk and the like; since the market, the medicine is recommended by authority guidelines at home and abroad to be widely used for treating postoperative pain of multiple departments such as general surgery, gynecology, orthopedics, stomatology and the like. The chemical name is as follows: n- [ [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfonyl ] propanamide sodium salt, parecoxib sodium for injection in 2002 was first marketed in Europe, and at least 15 countries such as Germany, France, England, etc. are now marketed. In 5 months in 2008, parecoxib sodium for injection (trade name: super resistant) is listed in China, and in 2017, parecoxib sodium for injection is listed in the national medical insurance B variety.

Impurity of parecoxib sodium in the prior art: the synthesis method of 3- (5-methyl-4-phenylisoxazol-3-yl) benzenesulfonamide is few, and mainly comprises the following methods:

the preparation of the desired compound from 5-methyl-3, 4-diphenylisoxazole by sulfonation and aminolysis has been reported in CN108047155, the process has a competitive reaction with positional isomers during sulfonation, and requires purification by preparative liquid phase, resulting in low yield.

Liu super et al reported in Chinese patent CN108675969 that 1-phenyl-1, 2-propanedione is used as a raw material, and a target product is obtained through cyclization, sulfonation, ammonolysis, bromination and coupling.

In Chinese patent CN109134395, Lexifeng and the like report that m-nitrobenzaldehyde is used as a raw material, and a target product is obtained by oximation, chlorination, cyclization, reduction, diazotization sulfonation and ammonolysis.

Therefore, the method for synthesizing the parecoxib sodium impurity 3- (5-methyl-4-phenylisoxazol-3-yl) benzenesulfonamide has short reaction steps, high yield and safe operation, has great significance for the quality research of parecoxib sodium, and provides important guiding significance for the clinical medication safety of parecoxib sodium.

Disclosure of Invention

The invention aims to provide a synthesis method of parecoxib sodium impurity, which has the advantages of short reaction steps, high yield and safe operation.

The invention is realized by the following technical scheme: a synthesis method of parecoxib sodium impurity is 3- (5-methyl-4-phenylisoxazol-3-yl) benzenesulfonamide, and the specific synthesis process comprises the following steps:

(1) taking 5-methyl-3, 4-diphenyl isoxazole as a raw material, and carrying out nitration reaction under the action of a nitrating agent to obtain an intermediate I;

(2) the intermediate I is subjected to sulfonylation reaction under the action of chlorosulfonic acid and then subjected to amidation reaction with ammonia water to obtain an intermediate II;

(3) carrying out nitro reduction reaction on the intermediate II under the action of a reducing agent a to obtain an intermediate III;

(4) and carrying out diazotization reaction on the intermediate III and sodium nitrite, and then adding a reducing agent b to carry out diazotization reduction reaction, thus obtaining the target product 3- (5-methyl-4-phenylisoxazol-3-yl) benzenesulfonamide.

The specific synthetic route is as follows:

in order to better realize the method of the invention, further, the nitrating agent in the step (1) is nitric acid or mixed acid of nitric acid and sulfuric acid; the molar ratio of the raw material 5-methyl-3, 4-diphenyl isoxazole to the nitrating agent is 1:1 to 1.5; the nitration reaction temperature is 10-50 ℃; the nitration reaction time is 1-2 h.

In order to better realize the method of the invention, further, the nitrating agent in the step (1) is mixed acid of nitric acid and sulfuric acid; the molar ratio of the raw material 5-methyl-3, 4-diphenyl isoxazole to the nitrating agent is 1: 1.01; the nitration reaction temperature is 20-30 ℃.

In order to better realize the method, in the step (2), the weight ratio of the intermediate I to chlorosulfonic acid is 1: 5-20; the solvent for the sulfonylation reaction is solvent-free or dichloromethane, the sulfonylation reaction temperature is 25-100 ℃, and the sulfonylation reaction time is 12 h.

In order to better realize the method, in the step (2), the mass-to-volume ratio of the intermediate I to the ammonia water is 1: 20-40 g/ml; the temperature of the amidation reaction is 10-40 ℃; the amidation reaction time is 1-2 h.

In order to better realize the method of the invention, further, in the step (2), the weight ratio of the intermediate I to the chlorosulfonic acid is 1: 10; the solvent of the sulfonylation reaction is solvent-free, and the temperature of the sulfonylation reaction is 90 ℃; the mass volume ratio of the intermediate I to the ammonia water is 1:30 g/ml; the temperature of the amidation reaction is 20-30 ℃.

In order to better realize the method of the invention, further, the reducing agent a in the step (3) is at least one of zinc powder, iron powder and palladium-carbon; the solvent of the nitro reduction reaction is at least one of methanol, ethanol, methanol solution and ethanol solution.

In order to better implement the method of the present invention, further, the reducing agent a in the step (3) is zinc powder; the solvent of the nitro reduction reaction is an ethanol solution, and the ethanol solution is prepared from ethanol and water according to a volume ratio of 1:1, and preparing the composition.

In order to better implement the method of the present invention, further, in the step (4), the molar ratio of the intermediate III to the sodium nitrite is 1:1 to 1.5; the diazotization reaction temperature is-10 ℃; the diazotization reaction time is 0.5-1 h; the reducing agent b is hypophosphorous acid; the mass-volume ratio of the intermediate III to the reducing agent b is 1: 10-50 g/mL; the diazo reduction reaction temperature is 20-30 ℃; the diazo reduction reaction time is 0.5-2 h.

In order to better implement the method of the present invention, further, in the step (4), the molar ratio of the intermediate III to the sodium nitrite is 1: 1.3; the diazotization reaction temperature is-10 ℃; the diazotization reaction time is 0.5 h; the mass volume ratio of the intermediate III to the hypophosphorous acid is 1: 50 g/mL; the diazo reduction reaction time was 0.5.

Compared with the prior art, the invention has the following advantages and beneficial effects:

(1) according to the invention, through a novel self-designed synthetic route, the reaction steps are reduced, the use of a reagent which is difficult to obtain and expensive is avoided, the use of dangerous gas is avoided, and the process operation is safer;

(2) the synthesis method of the parecoxib sodium impurity 3- (5-methyl-4-phenylisoxazol-3-yl) benzenesulfonamide provided by the invention has the advantages of easily available raw materials, mild reaction conditions, short reaction steps, controllable product quality, high purity and safe process;

(3) the parecoxib sodium impurity with high purity prepared by the method can be used as a reference substance in parecoxib sodium research and finished product detection, provides powerful guarantee for controlling the quality of parecoxib sodium medicines, and is suitable for medicine quality research.

Drawings

Other features, objects and advantages of the invention will become more apparent upon reading of the detailed description of non-limiting embodiments with reference to the following drawings:

FIG. 1 is a hydrogen spectrum of parecoxib sodium impurity 3- (5-methyl-4-phenylisoxazol-3-yl) benzenesulfonamide in the present invention;

FIG. 2 is an LC-MS spectrum (a) of parecoxib sodium impurity 3- (5-methyl-4-phenylisoxazol-3-yl) benzenesulfonamide in the invention;

FIG. 3 is an LC-MS spectrum (b) of parecoxib sodium impurity 3- (5-methyl-4-phenylisoxazol-3-yl) benzenesulfonamide in the invention;

FIG. 4 is an HPLC chromatogram of parecoxib sodium impurity 3- (5-methyl-4-phenylisoxazol-3-yl) benzenesulfonamide in accordance with the present invention.

Detailed Description

The present invention will be described in further detail with reference to the following examples for the purpose of making clear the objects, process conditions and advantages of the present invention, but the embodiments of the present invention are not limited thereto, and various substitutions and modifications can be made according to the common technical knowledge and the conventional means in the art without departing from the technical idea of the present invention described above, and the specific examples described herein are only for explaining the present invention and are not intended to limit the present invention.

The invention provides a synthetic process of parecoxib sodium impurity 3- (5-methyl-4-phenylisoxazol-3-yl) benzenesulfonamide, which comprises the following steps:

the specific synthesis steps are as follows:

(1) taking 5-methyl-3, 4-diphenyl isoxazole as a raw material, and carrying out nitration reaction under the action of a nitrating agent to obtain an intermediate I;

(2) the intermediate I is subjected to sulfonylation reaction under the action of chlorosulfonic acid and then subjected to amidation reaction with ammonia water to obtain an intermediate II;

(3) carrying out nitro reduction reaction on the intermediate II under the action of a reducing agent a to obtain an intermediate III;

(4) and carrying out diazotization reaction on the intermediate III and sodium nitrite, and then adding a reducing agent b to carry out diazotization reduction reaction, thus obtaining the target product 3- (5-methyl-4-phenylisoxazol-3-yl) benzenesulfonamide.

The raw materials and equipment used in the embodiment of the present invention are known products, and are obtained by purchasing commercially available products.

Example 1:

this example provides a specific process for synthesizing parecoxib sodium impurity 3- (5-methyl-4-phenylisoxazol-3-yl) benzenesulfonamide, as follows:

(1) preparation of intermediate I

5g of raw material 5-methyl-3, 4-diphenyl isoxazole and 20ml of dichloromethane are added into a reaction bottle, the temperature is reduced to 0 ℃, 3g of nitric acid (1.5eq) is slowly added, and the reaction is carried out for 4 hours at room temperature after the addition is finished. After the reaction, 50g of water was added to the reaction solution, and the mixture was filtered to obtain a solid, which was recrystallized from ethanol and dried to obtain 4.2g of a solid (intermediate I) with a yield of 70.5%.

(2) Preparation of intermediate II

4.5g of intermediate I and 3g of chlorosulfonic acid 45g of 30g are added into a reaction flask, and the temperature is increased to 90 ℃ for reaction for 12 h. After the reaction, the reaction mixture was added to ice water, and extracted twice with ethyl acetate. The organic phases were combined and washed twice with water. To the organic phase was added 150ml of aqueous ammonia, and the mixture was stirred at room temperature for 1 hour. After the reaction, ethyl acetate was removed by concentration under reduced pressure, and the filtrate was filtered to obtain a solid, which was recrystallized from absolute ethanol, and dried to obtain 4.6g of a solid (intermediate II) with a yield of 79.7%.

(3) Preparation of intermediate III

4.5g of the intermediate II, 2.8g of iron powder, 5.03g of ammonium chloride, 30ml of ethanol and 30ml of water are added into a reaction bottle, and the temperature is raised to 60 ℃ to be stirred and reacted for 1.5 h. After the reaction, filtration was carried out, 10 times as much water was added to the filtrate, and the mixture was concentrated under reduced pressure to remove ethanol, and the concentrate was filtered and dried to obtain 3.16g of a solid (intermediate III) with a yield of 76.70%.

(4) Preparation of the desired product

Adding the intermediate III3.16g and hydrochloric acid 79g into a reaction bottle, stirring at room temperature for 20 minutes, and cooling to-10 ℃. Adding 0.87g of sodium nitrite and 158ml of water into another reaction bottle, stirring and dissolving, cooling to-10 ℃, dropwise adding the hydrochloric acid solution of the compound of the formula (IV), and stirring for 30min at-10 ℃ after dropwise adding. 158ml of hypophosphorous acid was added thereto, the temperature was raised to room temperature, and the mixture was stirred for 30 min. 158ml of water and 158ml of ethyl acetate were added thereto, and the mixture was separated. The aqueous phase was extracted twice with ethyl acetate and the organic phases were combined. The organic phase was washed twice with water, concentrated under reduced pressure and the concentrate was purified by column chromatography to give 2.35g of a solid (desired product) in 77.9% yield (92.89% purity by HPLC).

The hydrogen, LC-MS (liquid chromatography-mass spectrometry) -HPLC (high performance liquid chromatography) spectrum of the prepared target product 3- (5-methyl-4-phenylisoxazol-3-yl) benzenesulfonamide is shown in figures 1-4.

Example 2:

this example, based on the above examples, adjusted the grouping component and selection, provides a specific synthesis procedure of another parecoxib sodium impurity, 3- (5-methyl-4-phenylisoxazol-3-yl) benzenesulfonamide, as follows:

(1) preparation of intermediate I

5g of raw material 5-methyl-3, 4-diphenyl isoxazole and 15g of sulfuric acid are added into a reaction bottle, the temperature is reduced to 0 ℃, 2g (1.01eq) of nitric acid is slowly dripped, and the reaction is carried out for 1 to 2 hours at room temperature after the dripping is finished. After the reaction, the reaction mixture was quenched in 50g of water, filtered to obtain a solid, recrystallized with absolute ethanol, and dried to obtain 4.5g of a solid (intermediate I) with a yield of 75.5%.

(2) Preparation of intermediate II

4.5g of intermediate I and 3g of chlorosulfonic acid 45g of 30g are added into a reaction flask, and the temperature is increased to 90 ℃ for reaction for 12 h. After the reaction, the reaction mixture was added to ice water, and extracted twice with ethyl acetate. The organic phases were combined and washed twice with water. To the organic phase was added 150ml of aqueous ammonia, and the mixture was stirred at room temperature for 1 hour. After the reaction, ethyl acetate was removed by concentration under reduced pressure, and the filtrate was filtered to obtain a solid, which was recrystallized from absolute ethanol, and dried to obtain 4.6g of a solid (intermediate II) with a yield of 79.7%.

(3) Preparation of intermediate III

Adding 4.5g of the intermediate IIR, 3.2g of zinc powder, 5.03g of ammonium chloride, 30ml of ethanol and 30ml of water into a reaction bottle, heating to 60 ℃, and stirring for reaction for 1.5 hours. After the reaction, filtration was carried out, 10 times as much water was added to the filtrate, and the filtrate was concentrated under reduced pressure to remove ethanol, and the concentrate was filtered and dried to obtain 3.34g of a solid (intermediate III) with a yield of 81.0%.

(4) Preparation of the desired product

Adding the intermediate III3.16g and hydrochloric acid 79g into a reaction bottle, stirring at room temperature for 20 minutes, and cooling to-10 ℃. Adding 0.87g of sodium nitrite and 158ml of water into another reaction bottle, stirring and dissolving, cooling to-10 ℃, dropwise adding the hydrochloric acid solution of the compound of the formula (IV), and stirring for 30min at-10 ℃ after dropwise adding. 158ml of hypophosphorous acid was added thereto, the temperature was raised to room temperature, and the mixture was stirred for 30 min. 158ml of water and 158ml of ethyl acetate were added thereto, and the mixture was separated. The aqueous phase was extracted twice with ethyl acetate and the organic phases were combined. The organic phase was washed twice with water, concentrated under reduced pressure and the concentrate was purified by column chromatography to give 2.35g of a solid (desired product) in 77.9% yield (92.89% purity by HPLC).

While embodiments of the invention have been shown and described, it will be understood by those of ordinary skill in the art that: various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the claims and their equivalents.