CN108912030B - Synthesis method of erexib - Google Patents
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- CN108912030B CN108912030B CN201810862551.7A CN201810862551A CN108912030B CN 108912030 B CN108912030 B CN 108912030B CN 201810862551 A CN201810862551 A CN 201810862551A CN 108912030 B CN108912030 B CN 108912030B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/38—2-Pyrrolones
Abstract
A synthetic method of ereoxib comprises the following steps: carrying out condensation cyclization reaction on (E) -1-p-methylsulfonylphenyl-1-nitro-2-p-tolylethylene and isocyanoacetic ester in a system of an alkali reagent and a solvent; carrying out reduction reaction on the obtained 3-p-methylphenyl-4-p-methylsulfonyl phenyl pyrrole-2-carboxylate in a system of a reducing reagent and a solvent at-78 ℃; carrying out oxidation reaction on the obtained 3-p-methylphenyl-4-p-methylsulfonyl phenyl pyrrole-2-formaldehyde in a system of hydrogen peroxide and a solvent; and carrying out substitution reaction on the obtained 3-p-methylphenyl-4-p-methylsulfonyl phenyl-3-pyrrolidine-2-ketone and 1-halopropane or hydrocarbon propyl sulfonate derivative in a system of an alkali reagent and a solvent to obtain the ereoxib. The reaction steps are simplified and optimized, the process operation is simple, and the cost is reduced; the reaction has few and controllable impurities, and is green and environment-friendly; the starting materials and the reagents used are readily available.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemical synthesis, and particularly relates to a synthetic method of erexib.
Background
A novel COX-2 selective inhibitor, namely, Iressoxib (Imrechoxib), is a class 1.1 new drug which is researched and developed by Jiangsu Hengrui company in an autonomous mode, is used for treating and relieving pain symptoms of osteoarthritis and postoperative inflammation, and is approved to be put on the market by national FDA (food and drug administration). The chemical name of the compound is N-N-propyl-3-p-methylphenyl-4-p-methylsulfonyl phenyl-3-pyrrolidine-2-ketone, and the chemical structural formula is as follows:
the first line of osteoarthritis will change in the future and specific COX-2 (a cyclooxygenase enzyme that causes joint pain and inflammation) inhibitors may replace the current acetaminophen as the first line of osteoarthritis. In the future change pattern of first-line osteoarthritis medicines, the ereoxib has good market prospect.
A plurality of patents have been reported on a preparation method of the ereoxib, and a synthetic route for preparing the ereoxib is disclosed in patents CN1134413C and US20040029951, wherein 4-methylsulfonyl styrene oxide is used as a starting material, and the ereoxib is obtained through nucleophilic ring-opening, amidation, oxidation, cyclization and other steps, and is shown as follows:
wherein, the oxidation reaction uses Jone's reagent or pyridine chromic trioxide and other oxidants, the yield of the oxidation reaction is low, the product is not easy to separate and purify, and the residue of metal chromium can influence the product quality of the raw material medicine. Patent CN107586268A modifies some compounds based on the above-mentioned route, and uses 4-methyl phenylacetic acid instead of its acyl chloride reagent in the second step, so that expensive condensing agent such as CDI is used to promote the reaction, which is not favorable for further popularization of industrial production.
The method for preparing ereoxib disclosed in patent CN102206178B adopts a different synthetic route, but still uses an expensive condensing agent to perform condensation cyclization reaction, and the synthetic route is as follows:
a synthetic route for preparing ereoxib, disclosed in patent CN104193664B, is as follows:
in the formula R1、R2The process route needs strong base as a condensing agent for carrying out cyclization reaction, and because more impurities and byproducts are continuously generated in each step, the process route is not beneficial to post-treatment and purification and is difficult to meet the quality requirement of bulk drugs. Therefore, it is necessary to explore the process flowShort, simple operation, low cost, safety and environmental protection, thereby being suitable for industrial production.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a method for synthesizing the erexib, which adopts the following technical scheme:
synthetic route of erexib:
The method for synthesizing the ereoxib comprises the following specific steps:
A) synthesizing 3-p-methylphenyl-4-p-methylsulfonyl phenyl pyrrole-2-carboxylate: carrying out condensation cyclization reaction on (E) -1-p-methylsulfonylphenyl-1-nitro-2-p-tolylene and isocyanoacetic ester in a system of an alkali reagent and a solvent to obtain 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carboxylic ester;
B) synthesis of 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carbaldehyde: carrying out reduction reaction on the 3-p-methylphenyl-4-p-methylsulfonyl phenyl pyrrole-2-carboxylic ester obtained in the step A) in a system of a reducing reagent and a solvent at-78 ℃ to obtain 3-p-methylphenyl-4-p-methylsulfonyl phenyl pyrrole-2-formaldehyde;
C) synthesis of 3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidin-2-one: carrying out oxidation reaction on the 3-p-methylphenyl-4-p-methylsulfonyl phenyl pyrrole-2-formaldehyde obtained in the step B) in a system of hydrogen peroxide and a solvent to obtain 3-p-methylphenyl-4-p-methylsulfonyl phenyl-3-pyrrolidine-2-ketone;
D) synthesis of erexib: and C) carrying out substitution reaction on the 3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidine-2-ketone obtained in the step C) and 1-halopropane or a hydrocarbon propyl sulfonate derivative in a system of an alkali reagent and a solvent to obtain the ereoxib.
In a particular embodiment of the invention, the isocyanoacetate in step a) is methyl isocyanoacetate or ethyl isocyanoacetate; the 3-p-methylphenyl-4-p-methylsulfonyl phenyl pyrrole-2-carboxylic acid ester is 3-p-methylphenyl-4-p-methylsulfonyl phenyl pyrrole-2-carboxylic acid methyl ester or 3-p-methylphenyl-4-p-methylsulfonyl phenyl pyrrole-2-carboxylic acid ethyl ester; the alkali reagent is potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium isopropoxide, potassium tert-pentoxide or 1, 8-diazabicyclo [5.4.0] undec-7-ene; the solvent is methanol, ethanol, N-propanol, isopropanol, N-butanol, tert-amyl alcohol, tetrahydrofuran, N-dimethylformamide, 2-methyltetrahydrofuran, methyl tert-butyl ether or toluene.
In another specific embodiment of the present invention, the molar ratio of (E) -1-p-methylsulfonylphenyl-1-nitro-2-p-tolylene, isocyanoacetate, and the alkali agent in step A) is 1.0: 1.1 to 1.5: 1.5 to 2.0.
In yet another specific embodiment of the present invention, the 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carboxylic acid ester in step B) is methyl 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carboxylate or ethyl 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carboxylate; the reducing agent is diisobutyl aluminum hydride or sodium bis (2-methoxyethoxy) aluminum hydride; the solvent is dichloromethane, 1, 2-dichloroethane, chloroform, toluene or xylene.
In still another embodiment of the present invention, the molar ratio of the 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carboxylate to the reducing agent in the step B) is 1.0: 1.1-1.5.
In a further embodiment of the present invention, the solvent in step C) is methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol or tert-amyl alcohol.
In a more specific embodiment of the invention, the molar ratio of the 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carbaldehyde to the hydrogen peroxide in the step C) is 1.0: 10.0-100.0.
In yet another specific embodiment of the present invention, the 1-halopropane in step D) is 1-chloropropane, 1-bromopropane or 1-iodopropane; the hydrocarbon propyl sulfonate derivative is propyl methanesulfonate, propyl trifluoromethanesulfonate or propyl p-toluenesulfonate; the alkali reagent is sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium isopropoxide, potassium tert-pentoxide, sodium hydroxide, potassium hydroxide, cesium carbonate, potassium carbonate or sodium carbonate; the solvent is N, N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, methyl tert-butyl ether, acetonitrile or N-methylpyrrolidone.
In still a more specific embodiment of the present invention, the molar ratio of the 3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidin-2-one, the 1-halopropane or the hydrocarbon propyl sulfonate derivative and the alkali agent in step D) is 1.0: 1.1 to 1.5: 1.5 to 2.0.
In yet another specific embodiment of the present invention, the temperature of the condensation cyclization reaction in step a) is 20 to 35 ℃, and the time of the condensation cyclization reaction is 12 to 24 hours; the time of the reduction reaction in the step B) is 2-6 h; the temperature of the oxidation reaction in the step C) is 20-40 ℃, and the reaction time is 24-72 h; the temperature of the substitution reaction in the step D) is 50-100 ℃, and the reaction time is 12-24 h.
The technical scheme provided by the invention has the following beneficial effects: firstly, compared with the prior art, the method has the advantages that the reaction steps are obviously simplified and optimized, the process operation is simple, and the cost is reduced; secondly, the reaction has less and controllable impurities and no pollutant, and can embody the green and environment-friendly effect; thirdly, the initial raw materials and the used reagents are easy to obtain, can be produced in large quantities to meet the use requirements of the raw material medicines, and is suitable for industrial production.
Detailed Description
The following examples are given to further illustrate the present invention in non-limiting manner. Wherein the starting material (E) -1-p-methylsulfonylphenyl-1-nitro-2-p-tolylethylene can be prepared by a condensation reaction of 4-nitromethyl-1-methylsulfonylbenzene with p-methylbenzaldehyde, see the related preparation methods of Tetrahedron Vol.46, No.21, pp.7587-7598,1990.
The route to the synthesis of ereoxib of the following examples 1 to 3 is:
Example 1:
A) synthesis of methyl 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carboxylate:
(E) dissolving (21.0g) of-1-p-methylsulfonylphenyl-1-nitro-2-p-tolylethylene in isopropanol (300mL), adding sodium hydroxide (4.0g), stirring, cooling to 5-10 ℃ in an ice bath, dropwise adding an isopropanol (12mL) solution of methyl isocyanoacetate (7.2g), raising the temperature to 30 ℃ to react for 18h till the reaction is complete, and after post-treatment, recrystallizing the obtained crude product with ethanol to obtain 23.2g of methyl 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carboxylate as an off-white solid with the yield of 95%.
B) Synthesis of 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carbaldehyde:
3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carboxylic acid methyl ester (23.0g) is dissolved in dichloromethane (350mL), cooled to-78 ℃, dropwise added with a n-hexane solution of sodium bis (2-methoxyethoxy) aluminum hydride (13.8g), kept warm for 2 hours until the reaction is complete, dropwise added with dilute hydrochloric acid at low temperature to quench the reaction solution, heated to room temperature, subjected to post-treatment, and the obtained crude product is recrystallized by ethanol to obtain 17.5g of 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-formaldehyde, namely a white solid with the yield of 83%.
C) Synthesis of 3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidin-2-one:
dissolving 3-p-methylphenyl-4-p-methylsulfonylphenyl pyrrole-2-formaldehyde (17.0g) in methanol (300mL), dropwise adding hydrogen peroxide (0.50mol), reacting at 40 ℃ for 24h until the reaction is complete, and after post-treatment, recrystallizing the obtained crude product with ethanol to obtain 3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidine-2-one as a white solid (14.9 g) with a yield of 91%.
D) Synthesis of erexib:
3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidine-2-one (14.5g) is dissolved in methyl tert-butyl ether (250mL), potassium tert-butoxide (7.5g) is added, the mixture is refluxed for 1h, the temperature is reduced to room temperature, propyl trifluoromethanesulfonate (9.4g) is added dropwise, the temperature is raised to 50 ℃ and the reaction is completed for 24h, after the post-treatment, the obtained crude product is recrystallized by using a mixed solvent of ethanol and isopropanol to obtain the ereoxib, 14.7g of white-like solid is obtained, and the yield is 90%.
Example 2:
A) synthesis of ethyl 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carboxylate:
(E) -1-p-methylsulfonylphenyl-1-nitro-2-p-tolylethylene (12.0g) is dissolved in tetrahydrofuran (180mL), potassium carbonate (9.4g) is added, stirring and ice-bath cooling are carried out until the temperature reaches 5-10 ℃, a tetrahydrofuran (10mL) solution of ethyl isocyanoacetate (5.6g) is added dropwise, the temperature is increased to 35 ℃ for reaction for 12 hours until the reaction is complete, after post-treatment, the obtained crude product is recrystallized by ethanol to obtain 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carboxylic acid ethyl ester, the off-white solid is 13.5g, and the yield is 93%.
B) Synthesis of 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carbaldehyde:
dissolving 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carboxylic acid ethyl ester (13.0g) in toluene (180mL), cooling to-78 ℃, dropwise adding a n-hexane solution of diisobutylaluminum hydride (6.3g), keeping the temperature for reacting for 4h until the reaction is complete, dropwise adding dilute hydrochloric acid to quench the reaction solution at low temperature, heating to room temperature, carrying out post-treatment, and recrystallizing the obtained crude product with ethanol to obtain 9.2g of 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-formaldehyde as a white solid with the yield of 80%.
C) Synthesis of 3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidin-2-one:
dissolving 3-p-methylphenyl-4-p-methylsulfonylphenyl pyrrole-2-formaldehyde (9.0g) in ethanol (150mL), dropwise adding hydrogen peroxide (1.33mol), reacting at 30 ℃ for 40h until the reaction is complete, and after post-treatment, recrystallizing the obtained crude product with ethanol to obtain 3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidine-2-one as white solid (8.5 g) with the yield of 98%.
D) Synthesis of erexib:
dissolving 3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidine-2-one (8.0g) in tetrahydrofuran (150mL), adding cesium carbonate (14.3g), refluxing the mixture for 1h, cooling to room temperature, dropwise adding 1-iodopropane (5.4g), heating to 80 ℃ to react for 16h till the reaction is complete, carrying out post-treatment, and recrystallizing the obtained crude product by using a mixed solvent of ethanol and isopropanol to obtain the ereoxib, wherein the yield is 88 percent, and the white-like solid is 7.9 g.
Example 3:
A) synthesis of methyl 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carboxylate:
(E) -1-p-methylsulfonylphenyl-1-nitro-2-p-tolylethylene (5.6g) is dissolved in methanol (100mL), 1, 8-diazabicyclo [5.4.0] undec-7-ene (5.4g) is added, stirring and ice-bath cooling are carried out until the temperature is 5-10 ℃, a methanol (6mL) solution of methyl isocyanoacetate (2.6g) is added dropwise, the temperature is increased to 20 ℃ for reaction for 24 hours until the reaction is complete, after the post-treatment, the obtained crude product is recrystallized by ethanol to obtain methyl 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carboxylate, 6.3g of white-like solid, and the yield is 96%.
B) Synthesis of 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carbaldehyde:
dissolving 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carboxylic acid methyl ester (6.2g) in chloroform (100mL), cooling to-78 ℃, dropwise adding a n-hexane solution of diisobutylaluminum hydride (3.6g), keeping the temperature for reacting for 6h until the reaction is complete, dropwise adding dilute hydrochloric acid to quench the reaction solution at low temperature, heating to room temperature, carrying out post-treatment, and recrystallizing the obtained crude product with ethanol to obtain 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-formaldehyde, wherein the yield is 78%.
C) Synthesis of 3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidin-2-one:
dissolving 3-p-methylphenyl-4-p-methylsulfonylphenyl pyrrole-2-formaldehyde (4.0g) in isopropanol (80mL), dropwise adding hydrogen peroxide (1.17mol), reacting at 20 ℃ for 72h until the reaction is complete, and after post-treatment, recrystallizing the obtained crude product with ethanol to obtain 3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidine-2-one as a white solid (3.7 g) with the yield of 97%.
D) Synthesis of erexib:
3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidine-2-ketone (3.2g) is dissolved in N, N-dimethylformamide (60mL), sodium hydroxide (0.8g) is added, the mixture is refluxed for 1h, then the temperature is reduced to room temperature, propyl methanesulfonate (2.0g) is added dropwise, the temperature is increased to 100 ℃ for reaction for 12h till the reaction is complete, after the post-treatment, the obtained crude product is recrystallized by using a mixed solvent of ethanol and isopropanol to obtain the ereoxib, 3.1g of off-white solid, and the yield is 87%.
Claims (9)
1. A synthetic method of ereoxib is characterized by comprising the following steps:
A) synthesizing 3-p-methylphenyl-4-p-methylsulfonyl phenyl pyrrole-2-carboxylate: carrying out condensation cyclization reaction on (E) -1-p-methylsulfonylphenyl-1-nitro-2-p-tolylene and isocyanoacetic ester in a system of an alkali reagent and a solvent to obtain 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carboxylic ester, the alkali reagent is potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium isopropoxide, potassium tert-pentoxide or 1, 8-diazabicyclo [5.4.0] undec-7-ene, the solvent is methanol, ethanol, N-propanol, isopropanol, N-butanol, tert-amyl alcohol, tetrahydrofuran, N-dimethylformamide, 2-methyltetrahydrofuran, methyl tert-butyl ether or toluene;
B) synthesis of 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carbaldehyde: carrying out reduction reaction on the 3-p-methylphenyl-4-p-methylsulfonyl phenyl pyrrole-2-carboxylic ester obtained in the step A) in a system of a reducing reagent and a solvent at-78 ℃ to obtain 3-p-methylphenyl-4-p-methylsulfonyl phenyl pyrrole-2-formaldehyde, wherein the reducing reagent is diisobutyl aluminum hydride or sodium bis (2-methoxyethoxy) aluminum hydride, and the solvent is dichloromethane, 1, 2-dichloroethane, chloroform, toluene or xylene;
C) synthesis of 3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidin-2-one: carrying out oxidation reaction on the 3-p-methylphenyl-4-p-methylsulfonylphenyl pyrrole-2-formaldehyde obtained in the step B) in a system of hydrogen peroxide and a solvent to obtain 3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidine-2-ketone, wherein the solvent is methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol or tert-amyl alcohol;
D) synthesis of erexib: and C) carrying out substitution reaction on the 3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidine-2-ketone obtained in the step C) and 1-halopropane or a hydrocarbon propyl sulfonate derivative in a system of an alkali reagent and a solvent to obtain the ereoxib, wherein the alkali reagent is sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium isopropoxide, potassium tert-pentoxide, sodium hydroxide, potassium hydroxide, cesium carbonate, potassium carbonate or sodium carbonate, and the solvent is N, N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, methyl tert-butyl ether, acetonitrile or N-methylpyrrolidone.
2. The method for synthesizing ereoxib according to claim 1, wherein the isocyanoacetate in step a) is methyl isocyanoacetate or ethyl isocyanoacetate; the 3-p-methylphenyl-4-p-methylsulfonyl phenyl pyrrole-2-carboxylic ester is 3-p-methylphenyl-4-p-methylsulfonyl phenyl pyrrole-2-carboxylic methyl ester or 3-p-methylphenyl-4-p-methylsulfonyl phenyl pyrrole-2-carboxylic ethyl ester.
3. The method for synthesizing ereoxib according to claim 1, wherein the molar ratio of (E) -1-p-methylsulfonylphenyl-1-nitro-2-p-tolylene, isocyanoacetate and the alkaline reagent in step A) is 1.0: 1.1-1.5: 1.5-2.0.
4. The method for synthesizing ereoxib according to claim 1, wherein the 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carboxylic acid ester in step B) is 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carboxylic acid methyl ester or 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carboxylic acid ethyl ester.
5. The method for synthesizing ereoxib according to claim 1, wherein the molar ratio of 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carboxylate to the reducing agent in step B) is 1.0: 1.1-1.5.
6. The method for synthesizing ereoxib according to claim 1, wherein the molar ratio of 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carbaldehyde to hydrogen peroxide in step C) is 1.0: 10.0-100.0.
7. The method for synthesizing ereoxib according to claim 1, wherein the 1-halopropane in step D) is 1-chloropropane, 1-bromopropane or 1-iodopropane; the hydrocarbon propyl sulfonate derivative is propyl methanesulfonate, propyl trifluoromethanesulfonate or propyl p-toluenesulfonate.
8. The method for synthesizing ereoxib according to claim 1, wherein the molar ratio of 3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidin-2-one, 1-halopropane or hydrocarbon propyl sulfonate derivative and alkali agent in step D) is 1.0: 1.1-1.5: 1.5-2.0.
9. The method for synthesizing ereoxib according to claim 1, wherein the temperature of the condensation cyclization reaction in step a) is 20-35 ℃, and the time of the condensation cyclization reaction is 12-24 h; the time of the reduction reaction in the step B) is 2-6 h; the temperature of the oxidation reaction in the step C) is 20-40 ℃, and the reaction time is 24-72 h; the temperature of the substitution reaction in the step D) is 50-100 ℃, and the reaction time is 12-24 h.
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