247098-18-6

Basic information

• Product Name: 3-Ethyl-2,5-Dihydro-4-Methyl-2-Oxo-N-(2-Phenylethyl)-1h-Pyrrole-1-Carboxamide
• Synonyms: 3-Ethyl-2,5-Dihydro-4-Methyl-2-Oxo-N-(2-Phenylethyl)-1h-Pyrrole-1-Carboxamide;3-ETHYL-4-METHYL-2-OXO-PYRROLIDINE-1-[(CARBOXAMIDE)-ETHYL BENZENE)SULPHONYL]-N-ETHYL-CARBAMATE;1-PHENETHYLAMINOCARBONYL-3-ETHYL-4-METHYL-2,5-DIHYDRO-5-PYRROLONE;4-[2-[(3-Ethyl-4-methyl-2-oxo-3-pyrrolin-1-yl)carboxamido]ethyl]benzene;3-ethyl-4-Methyl-2-oxo-N-phenethyl-2,5-dihydro-1H-pyrrole-1-carboxaMide;3-Ethyl-4-Methyl-2-Oxo-N(2-Phenyl ethyl)-2,5-Dihydro-1H-
• CAS NO: 247098-18-6
• Molecular Formula: C₁₆H₂₀N₂O₂
• Molecular Weight: 272.3422
• Product Categories: Aromatics Compounds;Aromatics;Heterocycles
• Mol File: 247098-18-6.mol

Chemical Properties

• Appearance: /
• Density: 1.132g/cm³
• Refractive Index: 1.559
• Storage Temp.: Refrigerator
• Solubility: Acetonitrile (Slightly), Chloroform (Slightly), Methanol (Slightly)
• PKA: 12.32±0.60(Predicted)
• CAS DataBase Reference: 3-Ethyl-2,5-Dihydro-4-Methyl-2-Oxo-N-(2-Phenylethyl)-1h-Pyrrole-1-Carboxamide(CAS DataBase Reference)
• NIST Chemistry Reference: 3-Ethyl-2,5-Dihydro-4-Methyl-2-Oxo-N-(2-Phenylethyl)-1h-Pyrrole-1-Carboxamide(247098-18-6)
• EPA Substance Registry System: 3-Ethyl-2,5-Dihydro-4-Methyl-2-Oxo-N-(2-Phenylethyl)-1h-Pyrrole-1-Carboxamide(247098-18-6)

Safety Data

• Hazardous Substances Data: 247098-18-6(Hazardous Substances Data)

Usage

Chemical Properties

White Solid

InChI:InChI=1/C16H20N2O2/c1-3-14-12(2)11-18(15(14)19)16(20)17-10-9-13-7-5-4-6-8-13/h4-8H,3,9-11H2,1-2H3,(H,17,20)

Synthetic route

3-ethyl-4-methyl-3-pyrrolin-2-one (766-36-9) + phenethyl isocyanate (1943-82-4) → 3-ethyl-4-methyl-2-oxo-N-(2-phenylethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide (247098-18-6)

Conditions	Yield
In toluene at 120 - 130℃; for 2h; Industrial scale;	97%
In n-heptane at 70 - 100℃; for 7h; Temperature;	90%
In toluene for 4h; Molecular sieve; Reflux; Inert atmosphere;	80%
In toluene Heating;	65%
In toluene for 4h; Heating / reflux;

3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamide + 2-phenylethyl chloride (622-24-2) → 3-ethyl-4-methyl-2-oxo-N-(2-phenylethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide (247098-18-6)

Conditions	Yield
With copper(l) iodide; sodium hydroxide In Petroleum ether at 85℃; for 9h; Temperature;	85.24%
With copper(l) iodide; sodium hydroxide In Petroleum ether at 85℃; for 9h; Temperature;	85.24%

1-acetyl-3-ethyl-4-methyl-1,5-dihydro-pyrrol-2-one (61892-80-6) → 3-ethyl-4-methyl-2-oxo-N-(2-phenylethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide (247098-18-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 90 percent / Na2CO3; H2O / Heating 2: 65 percent / toluene / Heating View Scheme

ethyl-α-ethylacetoacetate cyanohydrin (247098-17-5) → 3-ethyl-4-methyl-2-oxo-N-(2-phenylethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide (247098-18-6)

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

ethyl 2-ethyl-3-oxobutanoate (607-97-6) → 3-ethyl-4-methyl-2-oxo-N-(2-phenylethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide (247098-18-6)

Conditions	Yield
Multi-step reaction with 4 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 View Scheme

3-ethyl-4-methyl-2-oxo-N-(2-phenylethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide (247098-18-6) → 4-{2-[(3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carbonyl)amino]ethyl}benzene-1-sulfonic acid

Conditions	Yield
With chlorosulfonic acid In tetrahydrofuran at 20℃; Temperature;	88.15%
With chlorosulfonic acid In tetrahydrofuran at 20℃; Temperature;	88.15%

3-ethyl-4-methyl-2-oxo-N-(2-phenylethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide (247098-18-6) → 4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]benzenesulfonyl chloride (119043-16-2)

Conditions	Yield
With chlorosulfonic acid at 10℃;
With chlorosulfonic acid at 15 - 35℃; for 4.5 - 6.5h;
With chlorosulfonic acid In dichloromethane at -5 - 30℃;
With chlorosulfonic acid at 80℃; for 0.5h;
With chlorosulfonic acid In dichloromethane at 30 - 35℃; for 5.5h; Inert atmosphere;

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-N-(2-phenylethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide (247098-18-6) → trans-hydroxyglimepiride

Conditions	Yield
Multi-step reaction with 4 steps 1: ClSO3H / 10 °C 2: NH3 / H2O / 4 h / 60 °C 3: 80 percent / K2CO3 / acetone / 8 h / Heating 4: BF3*OEt2 / CH2Cl2 / 0 °C View Scheme

3-ethyl-4-methyl-2-oxo-N-(2-phenylethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide (247098-18-6) → cis-hydroxyglimepiride

Conditions	Yield
Multi-step reaction with 4 steps 1: ClSO3H / 10 °C 2: NH3 / H2O / 4 h / 60 °C 3: 80 percent / K2CO3 / acetone / 8 h / Heating 4: BF3*OEt2 / CH2Cl2 / 0 °C View Scheme

3-ethyl-4-methyl-2-oxo-N-(2-phenylethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide (247098-18-6) → C32H42N4O7S (599174-28-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: ClSO3H / 10 °C 2: NH3 / H2O / 4 h / 60 °C 3: 80 percent / K2CO3 / acetone / 8 h / Heating View Scheme

3-ethyl-4-methyl-2-oxo-N-(2-phenylethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide (247098-18-6) → glimepiride (93479-97-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: chlorosulfonic acid / tetrahydrofuran / 20 °C 2: ammonia / 1,4-dioxane / 35 °C 3: cyclohexanone; tert-butyl methyl ether / 10 h / 30 °C View Scheme
Multi-step reaction with 3 steps 1.1: chlorosulfonic acid / dichloromethane / 5.5 h / 30 - 35 °C / Inert atmosphere 2.1: ammonium hydroxide / 16 h / 20 °C 3.1: potassium carbonate / acetone; butanone / 0.5 h / Inert atmosphere; Reflux 3.2: Inert atmosphere; Reflux View Scheme

3-ethyl-4-methyl-2-oxo-N-(2-phenylethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide (247098-18-6) → glimepiride (93479-97-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: chlorosulfonic acid / dichloromethane / -5 - 30 °C 2.1: ammonium hydroxide / methanol / 2 h / 20 - 30 °C / Industrial scale 3.1: potassium carbonate / acetonitrile / 6 h / 50 - 60 °C 3.2: 4 h / 70 - 75 °C View Scheme

3-ethyl-4-methyl-2-oxo-N-(2-phenylethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide (247098-18-6) → C16H21N3O4S + C16H21N3O4S

Conditions	Yield
Stage #1: 3-ethyl-4-methyl-2-oxo-N-(2-phenylethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide With chlorosulfonic acid at 10 - 50℃; for 8h; Stage #2: With ammonium hydroxide at 20 - 40℃; for 8h;	A 2.8 g B 2.2 g

Upstream product

• 766-36-9 3-ethyl-4-methyl-3-pyrrolin-2-one 
• 1943-82-4 phenethyl isocyanate 
• 61892-80-6 1-acetyl-3-ethyl-4-methyl-1,5-dihydro-pyrrol-2-one 
• 247098-17-5 ethyl-α-ethylacetoacetate cyanohydrin 
• 607-97-6 ethyl 2-ethyl-3-oxobutanoate 
• 622-24-2 2-phenylethyl chloride 

Downstream Products

• 93479-97-1 glimepiride 
• 93479-97-1 glimepiride 
• 599174-28-4 C₃₂H₄₂N₄O₇S 
• 119018-29-0 N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide 
• 119043-16-2 4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]benzene-1-sulfonyl chloride 

Relevant articles and documents

Preparation method of high-purity glimepiride

The invention discloses a preparation method of high-purity glimepiride. The preparation method comprises the following specific steps: 1, adding 1-[4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)-ethyl]-benzenesulfonamide and potassium carbonate into a mixed solvent, and raising the temperature to dissolve the added substances; and 2, carrying out cooling crystallization on a solution obtained in step 1, and filtering the cooled solution to obtain 1-[4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)-ethyl]-benzenesulfonyl]-3-(trans-4-methylcyclohexyl)-urea. The glimepiride obtained by the preparation method has a purity of above 99.9% and a high yield, impurity research is sufficient and controllable, the crystal form is correct, and the preparation product quality is good,so the use requirements of people are met.

Process for synthesizing glimepiride raw material medicine

The invention discloses a process for synthesizing a glimepiride raw material medicine. A compound A, namely 3-ethyl-4-methyl-3-pyrroline-2-ketone and a compound B, namely 2-phenethyl isocyanate are taken as start raw materials. The process is characterized in that when an intermediate 1 is synthesized, filtrate is applied mechanically, so that the loss of the intermediate 1 can be reduced, the yield can be increased, and the production efficiency can be improved; when an intermediate 2 is synthesized, hydrochloric ether is adopted as a solvent, so that isomer impurities can be greatly reduced, the content of the isomer impurities can be reduced to 0.5% or less from 8%, and later purification procedures can be simple to operate; when a glimepiride metallic salt is synthesized, acetonitrileis adopted as a solvent, sufficient reactions can be achieved, the reaction time can be greatly shortened, the residue of an intermediate 3 is reduced to 0.2% or less from 5-10%, in addition, a highsolvent recycling rate can be achieved. The process disclosed by the invention is simple and safe, low in production cost, high in yield, stable in intermediate and finished product quality and applicable to industrial large-scale production and hypoglycemic drug, namely glimepiride, synthesis processes with relatively great social, economic and environmental-friendly benefits.

Preparation method of glimepiride intermediate as drug for promoting insulin secretion

The invention discloses a preparation method of a glimepiride intermediate as a drug for promoting insulin secretion. The chemical name of the glimepiride intermediate as the drug for promoting the insulin secretion is 2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-formamido) ethylbenzenesulfonamide; the method is used for preparing the glimepiride intermediate, the preparation process is concise, the synthetic route is short, the preparation efficiency is improved, glimepiride is conducive to being prepared in later period, the method is convenient for realizing industrialization, can be used for reducing the production cost and is suitable for large-batch production, and the new sought preparation method of the glimepiride intermediate is very meaningful for the economic technology of the glimepiride.

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.

Synthesis method of glimepiride key intermediate

The invention discloses a synthesis method of a glimepiride key intermediate. The synthesis method comprises the following steps: 1) dissolving a compound, A 3-ethyl-4-methyl-2-pyrrolinone, in an organic solvent, dropwise adding a compound B, phenethyl isocyanate, heating for reaction and cooling after the reaction; and 2) then adding another organic solvent, stirring, filtering and drying to obtain a compound C, 3-ethyl-4-methyl-2-oxo-3-pyrroline-1-(N-phenethyl)-formamide. By adopting the technical scheme, the synthesis method has the following technical effects: the problems that heat release is severe during a non-solvent reaction and thus mass production cannot be conducted can be solved, organic solvents with low flash point can be avoided, and mass production benefits of glimepiride key intermediates can be effectively increased.

A NOVEL PROCESS FOR PREPARATION OF SUBSTANTIALLY PURE GLIMEPIRIDE

The present invention discloses a novel process for purification of trans-4-methyl cyclohexylamine HC1 and 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonamide used in the synthesis of 3-Ethyl-2,5-dihydro-4-methyl-N-[2-[4-[[[[(trans-4-methyl cyclohexyl)amino]carbonyl]amino]sulfonyl]phenyl]ethyl]-2-oxo-1H-pyrrole-1-carboxamide(I), popularly known as Glimepiride. The present invention also discloses a novel purification of Glimepiride Form I (I), having the undesired cis isomer below 0.15%. Glimepiride (I) is useful in the treatment of diabetes mellitus.

Total synthesis of cis and trans-hydroxyglimepiride: Active metabolite of glimepiride

Syntheses of trans-hydroxyglimepiride 2b, a human metabolite of the blood glucose lowering agent glimepiride 1 and its corresponding cis-stereoisomer 2a, are described.