CN108299251B - Preparation method of glimepiride impurity - Google Patents
Preparation method of glimepiride impurity Download PDFInfo
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- CN108299251B CN108299251B CN201810148131.2A CN201810148131A CN108299251B CN 108299251 B CN108299251 B CN 108299251B CN 201810148131 A CN201810148131 A CN 201810148131A CN 108299251 B CN108299251 B CN 108299251B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
- C07C303/04—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof by substitution of hydrogen atoms by sulfo or halosulfonyl groups
- C07C303/08—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof by substitution of hydrogen atoms by sulfo or halosulfonyl groups by reaction with halogenosulfonic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/38—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reaction of ammonia or amines with sulfonic acids, or with esters, anhydrides, or halides thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a preparation method of a glimepiride impurity. Dripping acetic anhydride into a solution of 2-phenylethylamine and a low-boiling-point organic solvent for reaction to generate N-acetylphenylethylamine; dripping chlorosulfonic acid into N-acetyl phenethylamine at the temperature of below 20 ℃ to carry out chlorosulfonation reaction, and hydrolyzing to remove excessive chlorosulfonic acid after the reaction is finished; filtering and washing with water to obtain impurity J benzenesulfonyl chloride; carrying out ammonolysis on impurity J benzene sulfonyl chloride to obtain impurity J benzene sulfonamide; in acetone, reacting an impurity J benzenesulfonamide with a catalyst, and then reacting with trans-p-methyl cyclohexyl isocyanate to obtain an impurity J acetyl; performing alcoholysis on the impurity J acetyl and ethanol under the condition of a catalyst to generate impurity J and ethyl acetate; refining to obtain high-purity impurity J. The glimepiride impurity J prepared by the method has high purity, the liquid phase content is more than 98.5%, the raw materials used by the method are easy to obtain, the process parameters are controllable, and the reaction is mild.
Description
Technical Field
The invention relates to a preparation method of a glimepiride impurity, belonging to the technical field of medicinal chemistry.
Background
Glimepiride is a new medicine of two types developed by my company and U.S. JC company. Glimepiride, the first developed by Hoechst Marion Roussel (HMR) in germany, was first marketed in sweden under the trade name Amaryl in 1995 for 9 months and was approved by the FDA for entry into the us market in 1996 for the treatment of type ii (non-islet-dependent) diabetes mellitus, which was uncontrolled on diet and exercise, was the first sulfonylurea drug approved by the FDA to be used with insulin.
Glimepiride is the best sulfonylurea hypoglycemic agent in clinical evaluation at present, and has good market prospect. Compared with the similar products, the method has the following advantages: (1) the action time of the glimepiride and the receptor is short, so that the insulin secretion time is shortened, the glimepiride-containing composition has a strong insulin-saving effect, and the secondary failure of islet cells can be overcome to a certain extent. (2) The glimepiride has the advantages of high efficiency, long acting and small dosage (2-4 mg/d). (3) The glimepiride has the advantages of small side effect and high safety, and can prevent and relieve cardiovascular and cerebrovascular complications while reducing blood sugar.
In order to further ensure the quality of the medicine and prevent the safety of medication, the related impurities of the glimepiride are researched. Impurity J is an impurity in glimepiride, but the amount of the impurity J is very small and cannot be separated. The preparation of impurity J was investigated in order to provide a measurable amount of impurity J.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a preparation method of Glimepiride impurity; the glimepiride impurity J prepared by the method has high liquid phase purity, controllable process parameters and mild reaction.
The preparation method of the glimepiride impurity specifically comprises the following steps:
(1) dropwise adding acetic anhydride into a solution of 2-phenylethylamine and a low-boiling-point organic solvent for reaction to generate N-acetylphenylethylamine;
(2) dripping N-acetyl phenethylamine into chlorosulfonic acid at the temperature of below 20 ℃ for chlorosulfonation reaction, and hydrolyzing to remove excessive chlorosulfonic acid after the reaction is finished; filtering and washing with water to obtain impurity J benzenesulfonyl chloride; carrying out ammonolysis on impurity J benzene sulfonyl chloride to obtain impurity J benzene sulfonamide;
(3) in acetone, reacting an impurity J benzenesulfonamide with a catalyst, and then reacting with trans-p-methyl cyclohexyl isocyanate to obtain an impurity J acetyl;
(4) performing alcoholysis on the impurity J acetyl and ethanol under the condition of a catalyst to generate impurity J and ethyl acetate; and refining to obtain high-purity glimepiride impurity J.
Wherein:
the reaction temperature in the step (1) is 0-50 ℃, and preferably 5-10 ℃; the low boiling point organic solvent is one of ethyl acetate or dichloromethane, preferably dichloromethane.
In the step (1), the molar ratio of the 2-phenylethylamine to the acetic anhydride is 1: 1.0-1.1.
The chlorosulfonation temperature in the step (2) is 10-50 ℃, and preferably 20-30 ℃; the ammonolysis temperature is 10-60 deg.C, preferably 20-30 deg.C.
In the step (2), the mass ratio of the N-acetyl phenethylamine to the chlorosulfonic acid to the ammonia water used for ammonolysis is 1: 2.5-3.3: 2.5-3.5.
In the step (3), the catalyst is a weakly alkaline substance, the weakly alkaline substance is one of potassium carbonate or sodium carbonate, and potassium carbonate is preferred.
In the step (3), the reaction temperature is in a reflux state.
The molar ratio of the impurity J benzenesulfonamide, the catalyst and the trans-p-methylcyclohexyl isocyanate in the step (3) is 1: 1.28-1.32: 1.25-1.30.
The reaction temperature in the step (4) is 30-80 ℃, preferably 68-72 ℃; the catalyst is strong alkaline substance, and the strong alkaline substance is one of sodium hydroxide or potassium hydroxide, preferably sodium hydroxide.
The mol ratio of the impurity J acetyl substance to the catalyst in the step (4) is 1: 4.8-5.2.
The reaction conversion rate in the step (4) is more than 80 percent.
As a preferred technical scheme, the preparation method of the glimepiride impurity specifically comprises the following steps:
(1) preparation of N-acetylphenethylamines
Acetic anhydride is added into the solution of 2-phenylethylamine and dichloromethane at 10 deg.c to react to produce N-acetyl phenylethylamine.
(2) Preparation of impurity J benzenesulfonamide (chemical name: 4- (N-acetylaminoethyl) -benzenesulfonamide)
Adding N-acetyl phenethylamine into chlorosulfonic acid at 20 deg.C below, reacting at 25-30 deg.C for 4 hr, and hydrolyzing to remove excessive chlorosulfonic acid. Filtering and washing to obtain impurity J benzene sulfonyl chloride. And carrying out ammonolysis on the impurity J benzene sulfonyl chloride at room temperature to obtain the impurity J benzene sulfonamide.
(3) Preparation of impurity J acetyl (chemical name: 4- ((((4-reverse-methylcyclohexylamino) -carbonyl) -amino) -sulfonyl) -N-acetylphenethylamine)
In acetone, under the reflux state, the impurity J benzenesulfonamide reacts with potassium carbonate firstly, and then reacts with trans-p-methylcyclohexyl isocyanate to obtain an impurity J acetyl. Wherein potassium carbonate is used as a catalyst.
(4) Preparation of impurity J (chemical name: 4- (((4-reverse-methylcyclohexylamino) -carbonyl) -amino) -sulfonyl) -phenethylamine)
And carrying out alcoholysis on the impurity J acetyl and ethanol under a strong alkaline condition to generate impurity J and ethyl acetate. Refining to obtain high-purity impurity J.
The reaction principle of the invention is as follows:
the invention has the following beneficial effects:
the invention provides an effective synthesis method, and impurity J with a research amount can be obtained; the glimepiride impurity J prepared by the method has high purity, and the liquid phase content is more than 98.5%. The method has the advantages of easily available raw materials, controllable process parameters and mild reaction.
Detailed Description
The present invention is further described below with reference to examples.
Example 1
(1) Preparation of N-acetylphenethylamines
24.2g of 2-phenethylamine and 50ml of dichloromethane are added into a four-mouth bottle, and the temperature is reduced to below 10 ℃ by stirring. Then, acetic anhydride (21.4 g) was added dropwise thereto at a temperature of 10 ℃ or lower. After the addition, the reaction was carried out for 10 minutes under heat preservation, and 200ml of purified water was added dropwise. After standing, the organic layer was separated, and the aqueous layer was extracted once more with 25ml of dichloromethane. The combined organic layers were washed 2 times with 25ml of × 2 saturated sodium bicarbonate solution and 2 times with 25ml of × 2 purified water. The organic layer was dried over anhydrous magnesium sulfate in a suitable amount, and the solvent was distilled off at 45 ℃ under reduced pressure to obtain 32.5g of a crude N-acetylphenethylamine product, which was used in the next step without purification.
(2) Preparation of impurity J benzenesulfonamide (chemical name: 4- (N-acetylaminoethyl) -benzenesulfonamide)
Adding 50ml of chlorosulfonic acid into a four-mouth bottle, and stirring and cooling to below 10 ℃. And (3) dropwise adding 32.5g of crude N-acetylphenethylamine at the temperature of 10-20 ℃. After the addition, the temperature is slowly raised to 25-30 ℃, the reaction is kept for 4 hours, and the mixture is slowly poured into 600ml of ice water under stirring. Filtration and washing of the filter cake with a large amount of purified water yielded 50.1g of wet 4- (N-acetylaminoethyl) -benzenesulfonyl chloride.
The wet 4- (N-acetylaminoethyl) -benzenesulfonyl chloride is added into a four-mouth bottle, 110ml of strong ammonia water is added, and the mixture is stirred at room temperature and ammonolyzed overnight. Evaporating under reduced pressure to remove most of ammonia, cooling ice water to below 10 deg.C, maintaining the temperature at 10-20 deg.C, adding dropwise acetic acid to adjust pH to neutral, filtering, and washing filter cake with purified water. The filter cake was dried under reduced pressure at 50 ℃ to obtain 38.5g of J-benzenesulfonamide as an impurity. HPLC content: 99.8 percent; MP: 169-171 ℃.
(3) Preparation of impurity J acetyl (chemical name: 4- ((((4-reverse-methylcyclohexylamino) -carbonyl) -amino) -sulfonyl) -N-acetylphenethylamine)
34.98g of benzene sulfonamide impurity J, 25.96g of anhydrous potassium carbonate and 650ml of acetone are added into a four-mouth bottle. Stirring, heating and refluxing for reaction for 6 hours. An acetone solution of trans-p-methylcyclohexyl isocyanate (25.51g/170ml) was added dropwise. After the addition, the reaction was continued under reflux for 6 hours. The temperature was reduced to room temperature, 800ml of purified water was added thereto, stirred for 5 minutes, and insoluble matter was removed by filtration. Acetic acid is added dropwise to the filtrate while stirring, the pH value is adjusted to be neutral, and a large amount of solid is separated out. Filtering, and washing the filter cake by purified water. The filter cake was dried under reduced pressure at 50 ℃ to obtain 46.50g of impurity J acetyl compound. HPLC content: 99.7 percent; MP: 182 ℃ and 184 ℃; MS: m/z 382.2[ (M + H) + ].
(4) Preparation of impurity J (chemical name: 4- (((4-reverse-methylcyclohexylamino) -carbonyl) -amino) -sulfonyl) -phenethylamine)
In a four-necked flask were added 6.51g of sodium hydroxide, 100ml of absolute ethanol, and 2.5ml of purified water. Heating to 35-40 deg.C, and stirring until the solution is clear. 12.5g of the impurity J acetyl compound is added, and the temperature is slowly raised to 70 +/-2 ℃ for reaction. Keeping the temperature for reaction until the reaction rate is more than 80%, stopping the reaction, and cooling to room temperature. Washed 2 times with 75ml × 2 ethyl acetate. 500ml of purified water was added to the water layer with stirring, and the mixture was crystallized with stirring at room temperature overnight. Filtration and washing of the filter cake with copious amounts of purified water.
The filter cake was added to a four-necked flask, 100ml of purified water was added, and acetic acid was added dropwise until most of the solid was dissolved (pH 5). Filtering to remove insoluble substances. The filtrate was added dropwise with stirring to a 30% aqueous solution of sodium hydroxide to adjust the pH to 7. Stirred for 3 hours, filtered and the filter cake washed with purified water. The filter cake was air dried at 45 ℃ to obtain impurity J5.2 g. HPLC: 98.6 percent; MP: 168-170 ℃; MS: m/z 340.2[ (M + H) + ].
Example 2
(1) Preparation of N-acetylphenethylamines
24.2g of 2-phenethylamine and 50ml of ethyl acetate are added into a four-mouth bottle, and the temperature is reduced to below 10 ℃ by stirring. Then, acetic anhydride (21.4 g) was added dropwise thereto at a temperature of 10 ℃ or lower. After the addition, the reaction was carried out for 10 minutes under heat preservation, and 200ml of purified water was added dropwise. After standing, the organic layer was separated, and the aqueous layer was extracted with 25ml of ethyl acetate once more. The combined organic layers were washed 2 times with 25ml of × 2 saturated sodium bicarbonate solution and 2 times with 25ml of × 2 purified water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure at 50 ℃ to obtain 30.7g of crude N-acetylphenethylamine. The product was used in the next step without further purification.
(2) Preparation of impurity J benzenesulfonamide (chemical name: 4- (N-acetylaminoethyl) -benzenesulfonamide)
Adding 50ml of chlorosulfonic acid into a four-mouth bottle, and stirring and cooling to below 10 ℃. 30.7g of crude N-acetylphenethylamine is added dropwise at the temperature of 10-20 ℃. After the addition, the temperature is slowly raised to 30 plus or minus 2 ℃, the reaction is kept for 4 hours, and the mixture is slowly poured into 600ml of ice water under stirring. Filtration and washing of the filter cake with a large amount of purified water yielded 48.2g of wet 4- (N-acetylaminoethyl) -benzenesulfonyl chloride.
Adding the wet 4- (N-acetylaminoethyl) -benzenesulfonyl chloride into a four-mouth bottle, adding 110ml of strong ammonia water, and stirring and ammonolyzing at the temperature of 30-40 ℃ overnight. Evaporating under reduced pressure to remove most of ammonia, cooling ice water to below 10 deg.C, maintaining the temperature at 10-20 deg.C, adding dropwise acetic acid to adjust pH to neutral, filtering, and washing filter cake with purified water. The filter cake was dried under reduced pressure at 50 ℃ to obtain 36.3g of the impurity J-benzenesulfonamide. HPLC content: 99.7 percent.
(3) Preparation of impurity J acetyl (chemical name: 4- ((((4-reverse-methylcyclohexylamino) -carbonyl) -amino) -sulfonyl) -N-acetylphenethylamine)
34.0g of benzene sulfonamide impurity J, 25.23g of anhydrous potassium carbonate and 650ml of acetone are added into a four-mouth bottle. Stirring, heating and refluxing for reaction for 6 hours. An acetone solution of trans-p-methylcyclohexyl isocyanate (24.80g/170ml) was added dropwise. After the addition, the reaction was continued under reflux for 6 hours. The temperature was reduced to room temperature, 800ml of purified water was added thereto, stirred for 5 minutes, and insoluble matter was removed by filtration. Acetic acid is added dropwise to the filtrate while stirring, the pH value is adjusted to be neutral, and a large amount of solid is separated out. Filtering, and washing the filter cake by purified water. The filter cake was dried under reduced pressure at 50 ℃ to obtain 43.10g of impurity J acetyl compound. HPLC content: 99.5 percent.
(4) Preparation of impurity J (chemical name: 4- (((4-reverse-methylcyclohexylamino) -carbonyl) -amino) -sulfonyl) -phenethylamine)
6.0g of sodium hydroxide, 100ml of absolute ethanol and 2.5ml of purified water were put into a four-necked flask. Heating to 35-40 deg.C, and stirring until the solution is clear. 11.5g of the impurity J acetyl compound is added, and the temperature is slowly raised to 70 +/-2 ℃ for reaction. Keeping the temperature for reaction until the reaction rate is more than 80%, stopping the reaction, and cooling to room temperature. Washed 2 times with 75ml × 2 ethyl acetate. 500ml of purified water was added to the water layer with stirring, and the mixture was crystallized with stirring at room temperature overnight. Filtration and washing of the filter cake with copious amounts of purified water.
The filter cake was added to a four-necked flask, 100ml of purified water was added, and acetic acid was added dropwise until most of the solid was dissolved (pH 5). Filtering to remove insoluble substances. The filtrate was added dropwise with stirring to a 30% aqueous solution of sodium hydroxide to adjust the pH to 7. Stirred for 3 hours, filtered and the filter cake washed with purified water. The filter cake was air-dried at 45 ℃ to obtain impurity J4.6 g. HPLC: 98.8 percent.
Example 3
(1) Preparation of N-acetylphenethylamines
24.2g of 2-phenethylamine and 50ml of dichloromethane are added into a four-mouth bottle, and the temperature is reduced to below 15 ℃ by stirring. Then, 21.4g of acetic anhydride was added dropwise thereto at a temperature of 15 ℃ or lower. After the addition, the reaction was carried out for 10 minutes under heat preservation, and 200ml of purified water was added dropwise. After standing, the organic layer was separated, and the aqueous layer was extracted once more with 25ml of dichloromethane. The combined substrates were washed 2 times with 25ml of a × 2 saturated sodium bicarbonate solution and 2 times with 25ml of × 2 purified water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated off under reduced pressure at 45 ℃ to give 31.7g of crude N-acetylphenethylamine. The product was used in the next step without further purification.
(2) Preparation of impurity J benzenesulfonamide (chemical name: 4- (N-acetylaminoethyl) -benzenesulfonamide)
Adding 50ml of chlorosulfonic acid into a four-mouth bottle, and stirring and cooling to below 10 ℃. 31.7g of crude N-acetylphenethylamine is added dropwise at the temperature of 10-20 ℃. After the addition, the temperature is slowly raised to 30 plus or minus 2 ℃, the reaction is kept for 4 hours, and the mixture is slowly poured into 600ml of ice water under stirring. Filtration and washing of the filter cake with a large amount of purified water yielded 49.1g of wet 4- (N-acetylaminoethyl) -benzenesulfonyl chloride.
Adding the wet 4- (N-acetylaminoethyl) -benzenesulfonyl chloride into a four-mouth bottle, adding 110ml of strong ammonia water, and stirring and ammonolyzing at the temperature of 30 +/-2 ℃ overnight. Evaporating under reduced pressure to remove most of ammonia, cooling ice water to below 10 deg.C, maintaining the temperature at 10-20 deg.C, adding dropwise acetic acid to adjust pH to neutral, filtering, and washing filter cake with purified water. The filter cake was dried under reduced pressure at 50 ℃ to obtain 39.2g of the impurity J-benzenesulfonamide. HPLC content: 99.8 percent.
(3) Preparation of impurity J acetyl (chemical name: 4- ((((4-reverse-methylcyclohexylamino) -carbonyl) -amino) -sulfonyl) -N-acetylphenethylamine)
35.0g of impurity J benzenesulfonamide, 19.9g of anhydrous sodium carbonate and 650ml of acetone are added into a four-mouth bottle. Stirring, heating and refluxing for reaction for 6 hours. An acetone solution of trans-p-methylcyclohexyl isocyanate (25.5g/170ml) was added dropwise. After the addition, the reaction was continued under reflux for 6 hours. The temperature was reduced to room temperature, 800ml of purified water was added thereto, stirred for 5 minutes, and insoluble matter was removed by filtration. Acetic acid is added dropwise to the filtrate while stirring, the pH value is adjusted to be neutral, and a large amount of solid is separated out. Filtering, and washing the filter cake by purified water. The filter cake was dried under reduced pressure at 50 ℃ to obtain 44.20g of impurity J acetyl compound. HPLC content: 99.4 percent.
(4) Preparation of impurity J (chemical name: 4- (((4-reverse-methylcyclohexylamino) -carbonyl) -amino) -sulfonyl) -phenethylamine)
In a four-necked flask were added 8.4g of potassium hydroxide, 100ml of absolute ethanol, and 2.5ml of purified water. Heating to 35-40 deg.C, and stirring until the solution is clear. 11.5g of the impurity J acetyl compound is added, and the temperature is slowly raised to 70 +/-2 ℃ for reaction. Keeping the temperature for reaction until the reaction rate is more than 80%, stopping the reaction, and cooling to room temperature. Washed 2 times with 75ml × 2 ethyl acetate. 500ml of purified water was added to the water layer with stirring, and the mixture was crystallized with stirring at room temperature overnight. Filtration and washing of the filter cake with copious amounts of purified water.
The filter cake was added to a four-necked flask, 100ml of purified water was added, and acetic acid was added dropwise until most of the solid was dissolved (pH 5). Filtering to remove insoluble substances. The filtrate was added dropwise with stirring to a 30% aqueous solution of sodium hydroxide to adjust the pH to 7. Stirred for 3 hours, filtered and the filter cake washed with purified water. The filter cake was air-dried at 45 ℃ to give impurity J4.7 g. HPLC: 98.6 percent.
The present invention has been described in detail with reference to the embodiments, but the description is only for the preferred embodiments of the present invention and should not be construed as limiting the scope of the present invention. All equivalent changes and modifications made within the scope of the present invention shall still fall within the scope of the present invention.
Claims (10)
1. A preparation method of Glimepiride impurity is characterized by comprising the following steps: the method specifically comprises the following steps:
(1) dripping acetic anhydride into a solution of 2-phenylethylamine and a low-boiling-point organic solvent to react to generate N-acetylphenylethylamine;
(2) dripping N-acetyl phenethylamine into chlorosulfonic acid at the temperature of below 20 ℃ for chlorosulfonation reaction, and hydrolyzing to remove excessive chlorosulfonic acid after the reaction is finished; filtering and washing with water to obtain impurity J benzenesulfonyl chloride; carrying out ammonolysis on impurity J benzene sulfonyl chloride to obtain impurity J benzene sulfonamide;
(3) in acetone, reacting an impurity J benzenesulfonamide with a catalyst, and then reacting with trans-p-methyl cyclohexyl isocyanate to obtain an impurity J acetyl;
(4) performing alcoholysis on the impurity J acetyl and ethanol under the condition of a catalyst to generate impurity J and ethyl acetate; refining to obtain Glimepiride impurity J;
the molecular structural formulas of the impurity J benzene sulfonyl chloride, the impurity J benzene sulfonamide, the impurity J acetyl and the impurity J are respectively as follows:
the low boiling point organic solvent is one of ethyl acetate or dichloromethane.
2. The method for producing a glimepiride impurity according to claim 1, characterized in that: the reaction temperature in the step (1) is 0-50 ℃.
3. The method for producing a glimepiride impurity according to claim 1, characterized in that: in the step (1), the molar ratio of the 2-phenylethylamine to the acetic anhydride is 1: 1.0-1.1.
4. The method for producing a glimepiride impurity according to claim 1, characterized in that: the chlorosulfonation temperature in the step (2) is 10-50 ℃; the ammonolysis temperature is 10-50 ℃.
5. The method for producing a glimepiride impurity according to claim 1, characterized in that: in the step (2), the mass ratio of the N-acetyl phenethylamine to the chlorosulfonic acid to the ammonia water used for ammonolysis is 1: 2.5-3.3: 2.5-3.5.
6. The method for producing a glimepiride impurity according to claim 1, characterized in that: in the step (3), the catalyst is a weakly alkaline substance, and the weakly alkaline substance is one of anhydrous potassium carbonate or sodium carbonate.
7. The method for producing a glimepiride impurity according to claim 1, characterized in that: in the step (3), the reaction temperature is in a reflux state.
8. The method for producing a glimepiride impurity according to claim 1 or 6, characterized in that: the molar ratio of the impurity J benzenesulfonamide, the catalyst and the trans-p-methylcyclohexyl isocyanate in the step (3) is 1: 1.28-1.32: 1.25-1.30.
9. The method for producing a glimepiride impurity according to claim 1, characterized in that: the reaction temperature in the step (4) is 30-80 ℃; the catalyst is a strong alkaline substance, and the strong alkaline substance is one of sodium hydroxide or potassium hydroxide; the reaction conversion rate is more than 80%.
10. The method for producing a glimepiride impurity according to claim 1 or 9, characterized in that: the mol ratio of the impurity J acetyl substance to the catalyst in the step (4) is 1: 4.8-5.2.
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| Synthesis of Several New Lanthanide Glimepiride Complexes for Evaluation of Microbial Activity1;M. G. Abd El-Wahed et al.;《Russian Journal of General Chemistry》;20131231;第83卷(第12期);第2438–2446页 * |
| 降血糖新药-格列美脲合成工艺研究;邓勇等;《中国药物化学杂志》;20000630;第10卷(第2期);第134-137页 * |
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