N-[2-[4-(Aminosulfonyl)phenyl]ethyl]-3-ethyl-2,5-dihydro-4-methyl-2-oxo-1H-pyrrole-1-carboxamide

38.0 kg of methanol was sequentially added to a 100 L reactor.Industrial ammonia water 5.1Kg; start stirring, Add the above intermediate 2 crude wet product at 20-30 ° C, And the reaction was kept for 2 hours; the sample was controlled by HPLC, and the reaction was completely filtered and washed with water.The obtained white intermediate 3 crude wet product was directly charged into another 200 L reaction kettle.Further, 110.0 kg of methanol was added, and the temperature was raised to 65-75 ° C, and the mixture was stirred for 4 hours.Cool down to 20-25 ° C, filter, Drying white solid intermediate 3 refined product 8.47kg, HPLC purity >99percent, The meta isomer impurity was 0.2 3-Ethyl-4-methyl-2-oxo-2, 5-dihydro-1H-pyrrole-1-carboxylate(1; 1.349 g, 5.5 mmol) and 4-(2-aminoethyl)benzenesulfonamide(1.001 g, 5 mmol) were dissolved in THF (40 mL), and themixture was stirred at r.t. over night. After completion of thereaction (TLC), the solvent was evaporated under reduced pressure, and the crude product was purified by crystallization(EtOAc) to give a white solid yield: 1.495 g, (85percent); mp 183–185 °C.1H NMR (400 MHz, DMSO-d6): δ = 8.37 (t, J = 5.2 Hz, 1 H), 7.45(d, J = 7.8 Hz, 2 H), 7.43 (d, J = 7.8 Hz, 2 H), 7.32 (s, 2 H), 4.17 (s, 2H), 3.49 (q, J = 6.0 Hz, 2 H), 2.88 (t, J = 6.5 Hz, 2 H), 2.18 (q, J = 7.3Hz, 2 H), 2.01 (s, 3 H), 0.97 (t, J = 7.4 Hz, 3 H). 13C NMR (100MHz, DMSO-d6): δ = 172.3, 152.5, 152.1, 143.8, 142.6, 132.3, 129.5, 126.2, 52.3, 40.6, 35.5, 16.4, 13.3, 13.2. HRMS (ESI): m/z[M + Na]+ calcd for C16H21N3NaO4S: 374.1150; found: 374.1140.120 g of chlorosulfonic acid was added to a three-necked bottle, and the compound m was added in portions. After the addition, the reaction was kept at 80 C for 0.5 hour. The reaction was completely monitored by TLC, and the temperature was lowered to 25 C. The reaction was dropped into ice water and filtered to obtain a solid. Adding solid to a solution of 200 ml of ammonia water and 100 ml of water, heating to 80 C for 1.5 hours, cooling to 30 C, adding hydrochloric acid to the reaction solution, separating the solid, filtering, washing with water, drying at 50 C, The obtained white solid was 25.2 g, and the purity by HPLC was 78.08%, the impurity V 7.24%, the impurity was 16.35%, and the yield was 97.8%.Example 2Preparation of 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl ] benzene sulfonamide (IV)3-Ethyl-4-methyl-2, 5-dihydro-lH- pyrrole-2-one (II) (1.0 Kg) and beta-phenylethyl isocyanate (1.488 Kg) were mixed in anhydrous toluene (4.0 L) and refluxed for 4 hrs. The toluene was distilled off and hexane (8.0 L) was added to the reaction mixture at 5O0C. The product precipitated is cooled to 0 to 5 C to obtain the solid compound viz. 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene (2.17 Kg). It was filtered & washed with 2.0 L of hexane.To a cooled (15 to 25 C) solution of chlorosulfonic acid (2.8 L), 4-[2-(3-Ethyl-4- methyl-2-carbonyl pyrrolidine amido) ethyl] benzene (2.0 Kg) was added in small portions over a period of 2 to 3 hrs. Further it was stirred for 30 min at this temperature and then temperature was gradually raised to 30 to 350C. The reaction mass is stirred further for 2 hrs. The reaction mixture was then quenched into ice- water and stirred for 1 hr and filtered to obtain the product 4-[2-(3-Ethyl-4-methyl-2- carbonyl pyrrolidine amido) ethyl] benzene sulfonyl chloride (2.0 kg). To a cooled (15 to 200C) solution of diluted ammonia (1.4 L) 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonyl chloride was added in small portion over 1 to 2 hrs. The reaction mixture was then heated to 7O0C for 2 hrs when ammonolysis is complete. The product converted is then stirred for 1 hr at R.T. and filtered and dried at 90. to 100 C to obtain crude 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonamide (2.2 Kg) having HPLC purity in the range of 82 to 88%. The crude compound 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonamide (2.2 Kg) is then purified from mixture of organic solvents chosen from Methanol, Acetone & toluene.38.0 kg of methanol was sequentially added to a 100 L reactor.Industrial ammonia water 5.1Kg; start stirring, Add the above intermediate 2 crude wet product at 20-30 C, And the reaction was kept for 2 hours; the sample was controlled by HPLC, and the reaction was completely filtered and washed with water.The obtained white intermediate 3 crude wet product was directly charged into another 200 L reaction kettle.Further, 110.0 kg of methanol was added, and the temperature was raised to 65-75 C, and the mixture was stirred for 4 hours.Cool down to 20-25 C, filter, Drying white solid intermediate 3 refined product 8.47kg, HPLC purity >99%, The meta isomer impurity was 0.2 10.0 g of the compound, 8.16 g of 4-(2-aminoethyl)benzenesulfonamide, 3.02 g of propionic acid and 50 g of isopropanol were heated under reflux for 7.5 h, cooled at 25 C, filtered and dried at 50 C to give the compound 113.52 g. , the yield was 94.4%, the purity of the HPLC method was 99.63%, the impurity was 0.06%, and the impurities V and VI were not detected.Add 67 kg of acetonitrile to the 200 L reactor.Intermediate 3 refined product 8.47kg, potassium carbonate 4.00kg, Turn on the agitation and warm to 50-60 ° C.6.01 kg of trans-4-methylcyclohexyl isocyanate was added, and the reaction was continued for 6 hours.Sampling HPLC control, the reaction is complete, filtered, washed, The obtained glimepiride metal salt crude wet product is put into the next step to remove the insoluble matter. Step 5: remove insolubles, acidify, and refine Adding the above-mentioned glimepiride metal salt crude wet product and 10 times by weight of purified water to a 500 L reaction kettle, Stir at 70-75 ° C for 4 hours, heat filter, filter residue to waste treatment station, The filtrate enters the clean room 500L reactor and is cooled to 20-25 °C.Add 15percent hydrochloric acid to adjust pH=1-2, filter, wash, The obtained glimepiride crude wet product is reflowed by refluxing with 5 times by weight of acetone of glimepiride crude wet product.It is then cooled to room temperature, filtered and dried to obtain a finished glimepiride.HPLC purity >99.5percent, The molar yield was 80percent (based on the intermediate 3 refined product).2-(3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethylbenzenesulfonic acid prepared in Example 3 (E)(3.8 g, 1.64 mol) was dissolved in a flask containing dioxane (40 ml) and ammonia gas was introduced at 35°C.After the reaction was completed, dilute with dichloromethane (60 ml).The organic phase was concentrated, washed with water, recrystallized from ethanol, and dried to give 2-(3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethylbenzenesulfonic acid (E) prepared in Example 3 (3.8 g, 1.64 mol )Dissolve in a flask containing dioxane (40ml) and introduce ammonia gas at 35°C.2-(3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethylbenzenesulfonamide (F) (3.11 g) was prepared, The yield was 90.28percent and the purity was 99.69percent.Under nitrogen protection, In the reactor, N-4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline- 1 -carboxamido) ethyl] -benzenesulfonamide (33.6 g, 0.1 mol)Hexamethylphosphoric triamide (200 mL), 1, 8-diazabicyclo [5, 4, 0] undecene-7 (15.2 g, 0.1 mol), Then N, N-carbonyldiimidazole (32.4 g, 0.2 mol), After heating to 80 ° C for 3 hours, hexamethylphosphoric triamide (20 mL) of trans 4-methylcyclohexylamine (11.3 g, 0.1 mol)The reaction was heated overnight, TLC detection and tracking reaction, After the disappearance of raw materials completely, Stop stirring, cool down, Suction filtration, Washed, Dry glimepiride 41.6gWhite solid.Melting at 207-208 ° C, The yield was 85.1percentCarboxamide 2 (1.054 g, 3 mmol) and carbamate 3 (0.770 g, 3.3mmol) were dissolved in MeCN (40 mL), and DBU (0.685 g, 4 5mmole) was added. The mixture was then refluxed for 5 h until the reaction was complete (TLC). The solvent was evaporatedunder reduced pressure, the residue was dissolved in EtOAc(100 mL), and the solution was extracted with 0.1 N aq HCl (2 ×50 mL). The organic layer was washed with brine (2 × 50 mL), dried (Na2SO4), filtered, and concentrated again under reducedpressure. The crude product was purified by crystallization(MeOH) to give a white solid; yield: 1.255 g (85percent); mp 202-204 °C.1H NMR (400 MHz, DMSO-d6): delta = 8.38 (t, J = 5.6 Hz, 1 H), 7.81(d, J = 8.2 Hz, 2 H), 7.46 (d, J = 8.2 Hz, 2 H), 6.28 (d, J = 7.6 Hz, 1H), 4.16 (s, 2 H), 3.50 (q, J = 6.4 Hz, 2 H), 3.21-3.15 (m, 1 H), 2.90(t, J = 7.1 Hz, 2 H), 2.18 (q, J = 7.5 Hz, 2 H), 2.01 (s, 3 H), 1.68 (d, J = 12.8 Hz, 2 H), 1.59 (d, J = 12.8 Hz, 2 H), 1.23-0.79 (m, 11 H).13C NMR (100 MHz, DMSO-d6): delta = 171.7, 151.9, 151.5, 150.4, 144.8, 138.1, 131.8, 129.0, 127.2, 51.8, 48.4, 39.9, 35.1, 33.2, 32.2, 31.1, 21.9, 15.9, 12.7, 12.6. HRMS (ESI): m/z [M + Na]+ calcdfor C24H34N4NaO5S:, 513.2148; found: 513.2133.

Molecular Weight:351.4
XLogP3:1.2
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:5
Exact Mass:351.12527733
Monoisotopic Mass:351.12527733
Topological Polar Surface Area:118
Heavy Atom Count:24
Complexity:628
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes