119018-29-0

Basic information

• Product Name: 4-[2-[(3-Ethyl-4-methyl-2-oxo-3-pyrrolin-1-yl)carboxamido]ethyl]benzenesulfonamide
• Synonyms: n-[2-[4-(aminosulfonyl)phenyl]ethyl]-3-ethyl-2,5-dihydro-4-methyl-2-oxo-1h-pyrrole-1-carboxamide;N-[2-[4-(AMINOSULFONYL)PHENYL]ETHYL]-3-ETHYL-4-METHYL-2-OXO-1H-PYRROLE-1-CARBOXAMIDE;4-(2-(3-Ethyl-4-Methyl-2-Oxo-3-Pyrroline-1-Carboxamido)-Ethyl)-Benzenesulfonyl A;4-[2-(3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamidoethyl]benzenesulfonamide;N-[4-2-(3-Ethyl-4-Methyl-2-Oxo-3-Pyrroline-1-Carboxamido)-Ethyl]Benzensulfonamide;Glimepiride sulfonamide;4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]benezenesulfonamide;SulfonamideofGlimepiride
• CAS NO: 119018-29-0
• Molecular Formula: C₁₆H₂₁N₃O₄S
• Molecular Weight: 351.42
• EINECS: 411-850-0
• Product Categories: PHARMACEUTICAL INTERMEDIATES;Glimepiride;Aromatics Compounds;Aromatics;Heterocycles;Sulfur & Selenium Compounds
• Mol File: 119018-29-0.mol
• Article Data: 8

Chemical Properties

• Melting Point: 177-179?C
• Appearance: white solid
• Density: 1.304
• Refractive Index: 1.588
• Storage Temp.: Refrigerator
• Solubility: DMSO (Slightly), Methanol (Slightly, Sonicated)
• PKA: 10.16±0.10(Predicted)
• CAS DataBase Reference: 4-[2-[(3-Ethyl-4-methyl-2-oxo-3-pyrrolin-1-yl)carboxamido]ethyl]benzenesulfonamide(CAS DataBase Reference)
• NIST Chemistry Reference: 4-[2-[(3-Ethyl-4-methyl-2-oxo-3-pyrrolin-1-yl)carboxamido]ethyl]benzenesulfonamide(119018-29-0)
• EPA Substance Registry System: 4-[2-[(3-Ethyl-4-methyl-2-oxo-3-pyrrolin-1-yl)carboxamido]ethyl]benzenesulfonamide(119018-29-0)

Safety Data

• Statements: 52/53
• Safety Statements: 61
• Hazardous Substances Data: 119018-29-0(Hazardous Substances Data)

Usage

Description

4-[2-[(3-Ethyl-4-methyl-2-oxo-3-pyrrolin-1-yl)carboxamido]ethyl]benzenesulfonamide, also known as Glimepiride EP Impurity B, is an intermediate compound used in the synthesis of Glimepiride. It is a white solid with specific chemical properties that make it a crucial component in the pharmaceutical industry.

Uses

Used in Pharmaceutical Industry:
4-[2-[(3-Ethyl-4-methyl-2-oxo-3-pyrrolin-1-yl)carboxamido]ethyl]benzenesulfonamide is used as an intermediate for the preparation of Glimepiride, a widely prescribed antidiabetic drug. It plays a vital role in the synthesis process, contributing to the development of medications that help manage blood sugar levels in patients with type 2 diabetes.
Used in Chemical Synthesis:
As a white solid with specific chemical properties, 4-[2-[(3-Ethyl-4-methyl-2-oxo-3-pyrrolin-1-yl)carboxamido]ethyl]benzenesulfonamide can also be utilized in various chemical synthesis processes, potentially leading to the creation of new compounds with diverse applications across different industries.

InChI:InChI=1/C16H21N3O4S/c1-3-14-11(2)10-19(15(14)20)16(21)18-9-8-12-4-6-13(7-5-12)24(17,22)23/h4-7H,3,8-10H2,1-2H3,(H,18,21)(H2,17,22,23)

Synthetic route

4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]benzenesulfonyl chloride (119043-16-2) → N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide (119018-29-0)

Conditions	Yield
With ammonia In water at 80℃; for 1.5h;	97.8%
With ammonia In water at 60℃; for 4h;
With ammonia at 70℃; for 3 - 4h;
With ammonium hydroxide In methanol at 20 - 30℃; for 2h; Industrial scale;	8.47 kg
With ammonium hydroxide at 20℃; for 16h;

C24H30N4O6S + 4-(2-aminoethyl)benzenesulfonamide (35303-76-5) → N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide (119018-29-0)

Conditions	Yield
With propionic acid In isopropyl alcohol for 7.5h; Reagent/catalyst; Reflux;	93.6%

4-{2-[(3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carbonyl)amino]ethyl}benzene-1-sulfonic acid → N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide (119018-29-0)

Conditions	Yield
With ammonia In 1,4-dioxane at 35℃; Temperature;	90.28%
With ammonia In 1,4-dioxane at 35℃; Temperature;	90.28%

phenyl 3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate + 4-(2-aminoethyl)benzenesulfonamide (35303-76-5) → N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide (119018-29-0)

Conditions	Yield
In tetrahydrofuran at 20℃;	85%
In isopropyl alcohol for 6h; Reflux;	85.5%

3-ethyl-4-methyl-3-pyrrolin-2-one (766-36-9) → N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide (119018-29-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: 65 percent / toluene / Heating 2: ClSO3H / 10 °C 3: NH3 / H2O / 4 h / 60 °C View Scheme
Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 1.5 h 1.2: 5 h / 20 °C 2.1: tetrahydrofuran / 20 °C View Scheme
Multi-step reaction with 3 steps 1: toluene / 2 h / 120 - 130 °C / Industrial scale 2: chlorosulfonic acid / dichloromethane / -5 - 30 °C 3: ammonium hydroxide / methanol / 2 h / 20 - 30 °C / Industrial scale View Scheme
Multi-step reaction with 3 steps 1: toluene / 4 h / Molecular sieve; Reflux; Inert atmosphere 2: chlorosulfonic acid / dichloromethane / 5.5 h / 30 - 35 °C / Inert atmosphere 3: ammonium hydroxide / 16 h / 20 °C View Scheme

1-acetyl-3-ethyl-4-methyl-1,5-dihydro-pyrrol-2-one (61892-80-6) → N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide (119018-29-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: 90 percent / Na2CO3; H2O / Heating 2: 65 percent / toluene / Heating 3: ClSO3H / 10 °C 4: NH3 / H2O / 4 h / 60 °C View Scheme

ethyl-α-ethylacetoacetate cyanohydrin (247098-17-5) → N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide (119018-29-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: 15 percent / H2; Ac2O / Ra-Ni / 40 °C / 3800 Torr 2: 90 percent / Na2CO3; H2O / Heating 3: 65 percent / toluene / Heating 4: ClSO3H / 10 °C 5: NH3 / H2O / 4 h / 60 °C View Scheme

ethyl 2-ethyl-3-oxobutanoate (607-97-6) → N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide (119018-29-0)

Conditions	Yield
Multi-step reaction with 6 steps 1: 80 percent / dimethylformamide / 0 - 5 °C 2: 15 percent / H2; Ac2O / Ra-Ni / 40 °C / 3800 Torr 3: 90 percent / Na2CO3; H2O / Heating 4: 65 percent / toluene / Heating 5: ClSO3H / 10 °C 6: NH3 / H2O / 4 h / 60 °C View Scheme

3-ethyl-4-methyl-2-oxo-N-(2-phenylethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide (247098-18-6) → N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide (119018-29-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: ClSO3H / 10 °C 2: NH3 / H2O / 4 h / 60 °C View Scheme
Multi-step reaction with 2 steps 1: chlorosulfonic acid / tetrahydrofuran / 20 °C 2: ammonia / 1,4-dioxane / 35 °C View Scheme
Multi-step reaction with 2 steps 1: chlorosulfonic acid / dichloromethane / -5 - 30 °C 2: ammonium hydroxide / methanol / 2 h / 20 - 30 °C / Industrial scale View Scheme
Multi-step reaction with 2 steps 1: chlorosulfonic acid / dichloromethane / 5.5 h / 30 - 35 °C / Inert atmosphere 2: ammonium hydroxide / 16 h / 20 °C View Scheme

3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamide → N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide (119018-29-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydroxide; copper(l) iodide / Petroleum ether / 9 h / 85 °C 2: chlorosulfonic acid / tetrahydrofuran / 20 °C 3: ammonia / 1,4-dioxane / 35 °C View Scheme
Multi-step reaction with 3 steps 1: copper(l) iodide; sodium hydroxide / Petroleum ether / 9 h / 85 °C 2: chlorosulfonic acid / tetrahydrofuran / 20 °C 3: ammonia / 1,4-dioxane / 35 °C View Scheme

2-phenylethyl chloride (622-24-2) → N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide (119018-29-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydroxide; copper(l) iodide / Petroleum ether / 9 h / 85 °C 2: chlorosulfonic acid / tetrahydrofuran / 20 °C 3: ammonia / 1,4-dioxane / 35 °C View Scheme
Multi-step reaction with 3 steps 1: copper(l) iodide; sodium hydroxide / Petroleum ether / 9 h / 85 °C 2: chlorosulfonic acid / tetrahydrofuran / 20 °C 3: ammonia / 1,4-dioxane / 35 °C View Scheme

phenethyl isocyanate (1943-82-4) → N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide (119018-29-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: toluene / 2 h / 120 - 130 °C / Industrial scale 2: chlorosulfonic acid / dichloromethane / -5 - 30 °C 3: ammonium hydroxide / methanol / 2 h / 20 - 30 °C / Industrial scale View Scheme
Multi-step reaction with 3 steps 1: toluene / 4 h / Molecular sieve; Reflux; Inert atmosphere 2: chlorosulfonic acid / dichloromethane / 5.5 h / 30 - 35 °C / Inert atmosphere 3: ammonium hydroxide / 16 h / 20 °C View Scheme

(1R,4R)-1-isocyanato-4-methylcyclohexane (32175-00-1) + N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide (119018-29-0) → glimepiride (93479-97-1)

Conditions	Yield
In tert-butyl methyl ether; cyclohexanone at 30℃; for 10h; Temperature;	94.5%
Stage #1: N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide With potassium carbonate In acetone; butanone for 0.5h; Inert atmosphere; Reflux; Stage #2: (1R,4R)-1-isocyanato-4-methylcyclohexane In acetone; butanone Inert atmosphere; Reflux;	90%
Stage #1: N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide With potassium carbonate at 55 - 60℃; for 1h; Heating / reflux; Stage #2: (1R,4R)-1-isocyanato-4-methylcyclohexane In toluene for 12h; Heating / reflux;	86.3%

trans-4-methylcyclohexylamine + 1,1'-carbonyldiimidazole (530-62-1) + N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide (119018-29-0) → glimepiride

Conditions	Yield
Stage #1: 1,1'-carbonyldiimidazole; N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide With N,N,N,N,N,N-hexamethylphosphoric triamide; 1,8-diazabicyclo[5.4.0]undec-7-ene at 80℃; for 3h; Inert atmosphere; Heating; Stage #2: trans-4-methylcyclohexylamine Concentration; Temperature; Reagent/catalyst;	85.1%

phenyl ((1r,4r)-4-methylcyclohexyl)carbamate + N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide (119018-29-0) → glimepiride (93479-97-1)

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile for 5h; Reflux;	85%

chloroformic acid ethyl ester (541-41-3) + N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide (119018-29-0) → C19H25N3O6S

Conditions	Yield
With triethylamine In dichloromethane at 5 - 30℃;	83%
With triethylamine In dichloromethane at 0 - 30℃; for 2h;	83%

1-(4-isocyanato-cyclohexylmethoxymethyl)-4-methoxy-benzene (599174-27-3) + N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide (119018-29-0) → C32H42N4O7S (599174-28-4)

Conditions	Yield
With potassium carbonate In acetone for 8h; Heating;	80%

trans-4-methyl cyclohexyl isocyanate + N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide (119018-29-0) → amaryl (93479-97-1)

Conditions	Yield
Stage #1: N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide With potassium carbonate In tetrahydrofuran at 50 - 55℃; for 6h; Heating / reflux; Stage #2: trans-4-methyl cyclohexyl isocyanate In toluene for 6h; Heating / reflux;	50%

4-isocyanato-1,2,3,5,6, 7-hexahydro-s-indacene (210827-31-9) + N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide (119018-29-0) → 3-ethyl-N-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)phenethyl)-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide

Conditions	Yield
Stage #1: N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide With sodium hydride In tetrahydrofuran; mineral oil Stage #2: 4-isocyanato-1,2,3,5,6, 7-hexahydro-s-indacene In tetrahydrofuran; mineral oil at 20℃; for 15h; Inert atmosphere;	50%

N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide (119018-29-0) → trans-hydroxyglimepiride

Conditions	Yield
Multi-step reaction with 2 steps 1: 80 percent / K2CO3 / acetone / 8 h / Heating 2: BF3*OEt2 / CH2Cl2 / 0 °C View Scheme

N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide (119018-29-0) → cis-hydroxyglimepiride

Conditions	Yield
Multi-step reaction with 2 steps 1: 80 percent / K2CO3 / acetone / 8 h / Heating 2: BF3*OEt2 / CH2Cl2 / 0 °C View Scheme

(1R,4R)-1-isocyanato-4-methylcyclohexane (32175-00-1) + N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide (119018-29-0) → glimepiride (93479-97-1)

Conditions	Yield
Stage #1: (1R,4R)-1-isocyanato-4-methylcyclohexane; N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide With potassium carbonate In acetonitrile at 50 - 60℃; for 6h; Stage #2: With water at 70 - 75℃; for 4h;

Upstream product

• 247098-17-5 ethyl-α-ethylacetoacetate cyanohydrin 
• 35303-76-5 4-(2-aminoethyl)benzenesulfonamide 
• 119043-16-2 4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]benzene-1-sulfonyl chloride 
• 1943-82-4 phenethyl isocyanate 
• 622-24-2 2-phenylethyl chloride 
• 247098-18-6 3-ethyl-4-methyl-2-oxo-N-(2-phenylethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide 
• 607-97-6 ethyl 2-ethyl-3-oxobutanoate 
• 61892-80-6 1-acetyl-3-ethyl-4-methyl-1,5-dihydro-pyrrol-2-one 
• 766-36-9 3-ethyl-4-methyl-3-pyrrolin-2-one 

Downstream Products

• 93479-97-1 glimepiride 
• 93479-97-1 glimepiride 
• 93479-97-1 amaryl 
• 599174-28-4 C₃₂H₄₂N₄O₇S 

Relevant articles and documents

An Efficient and Practical Process for the Synthesis of Glimepiride

A novel and simple approach to the synthesis of glimepiride is reported. It involves the preparation of a carbamate of 3-ethyl-4-methyl-1 H -pyrrol-2(5 H)-one, followed by its reaction with 4-(2-aminoethyl)benzenesulfonamide to produce the intermediate sulfonamide. This sulfonamide, upon reaction with phenyl (trans -4-methylcyclohexyl)carbamate, gave glimepiride. This process avoids the use of phosgene, isocyanates, or chloroformates. Furthermore, sulfonation of the aryl group was eliminated, rendering the product free of the impurities reported in earlier processes.

Preparation method of glimepiride intermediate

The invention relates to a preparation method of a glimepiride intermediate compound I, and belongs to the technical field of preparation of raw material medicines. The preparation method comprises the following steps: reacting a compound II with diphenyl carbonate under the catalysis of an alkali (referring to Synlett, 28(18), 2495-2498; 2017) to prepare a compound IX; and adding a compound IX and 4-(2-aminoethyl)benzenesulfonamide according to a ratio of 1:1, adding a weak acid, adding isopropanol, and performing heating for a refluxing reaction. The invention provides the preparation methodof the glimepiride intermediate with a high purity.

Preparation method of hypoglycemic drug-glimepiride

The invention discloses a preparation method of a hypoglycemic drug-glimepiride. The chemical name of the hypoglycemic drug-glimepiride is 1-[4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-formamido)-ethyl]-benzenesulfonyl]-3-(trans-4- methyl cyclohexyl)-urea, the chemical formula of the hypoglycemic drug-glimepiride is C24H34N4O5S, and the structural formula of the hypoglycemic drug-glimepiride is described in the description. The preparation method is simple in process, short in synthetic route and high in yield, and especially increases the yield of 2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-formamido)ethyl benzene sulfonic acid greatly; the application of chlorosulfonic acid has great influence on a sulfonation effect; compared with sulfonating agents such as concentrated sulfuric acid and fuming sulfuric acid which are used in the prior art, the chlorosulfonic acid has higher sulfonating capacity, so that the production of the glimepiride is further facilitated; the preparation method iseasy in obtaining of raw materials, economical and environment-friendly, high in product yield and product purity, and beneficial to industrialization.