Synlett 2017; 28(18): 2495-2498
DOI: 10.1055/s-0036-1590836
letter
© Georg Thieme Verlag Stuttgart · New York

An Efficient and Practical Process for the Synthesis of Glimepiride

Dinesh Kumar Tanwar, Vaghela Ravikumar Surendrabhai, Manjinder Singh Gill*
  • Department of Pharmaceutical Technology (Process Chemistry), National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab-160062, India   Email: msingh@niper.ac.in
Further Information

Publication History

Received: 11 May 2017

Accepted after revision: 20 June 2017

Publication Date:
17 August 2017 (eFirst)

Abstract

A novel and simple approach to the synthesis of glimepiride is reported. It involves the preparation of a carbamate of 3-ethyl-4-methyl-1H-pyrrol-2(5H)-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.

Supporting Information

 
  • References and Notes

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  • 12 Phenyl 3-Ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate (1) NaH (0.960 g, 40 mmol) was added to anhyd DMF (20 mL) in a flask kept in an ice bath, and the mixture was stirred for 30 min. 3-Ethyl-4-methyl-1H-pyrrol-2(5H)-one (1.252 g, 10 mmol) in anhyd DMF (10 mL) was added dropwise to the above mixture, and the resulting mixture was stirred for 1.5 h. Diphenyl carbonate (4.284 g, 20 mmol) in anhyd DMF (10 mL) was added, and stirring was continued for another 5 h at r.t. When the reaction was complete (TLC), the solvent was removed under reduced pressure, and the residue was diluted with EtOAc (100 mL), washed with brine (2 × 50 mL), and dried (Na2SO4). The organic layer was filtered and concentrated under reduced pressure, and the crude product was purified by column chromatography (silica gel, 12% hexane–EtOAc) to give a viscous liquid; yield: 1.600 g, (65%). 1H NMR (400 MHz, DMSO-d 6): δ = 7.45 (t, J = 7.9 Hz, 2 H), 7.29 (t, J = 7.4 Hz, 1 H), 7.23 (d, J = 7.5 Hz, 2 H), 4.38 (s, 2 H), 2.22 (q, J = 7.5 Hz, 2 H), 2.05 (s, 3 H), 1.01 (t, J = 7.5 Hz, 3 H). 13C NMR (100 MHz, DMSO-d 6): δ = 169.5, 152.5, 150.5, 149.0, 132.6, 129.9, 126.4, 122.2, 53.0, 16.5, 13.4, 13.1. HRMS (ESI): m/z [M + Na]+ calcd for C14H15NNaO3: 268.0950; found: 268.0967.
  • 13 N-{2-[4-(Aminosulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide (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 the mixture was stirred at r.t. over night. After completion of the reaction (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, (85%); mp 183–185 °C. 1H NMR (400 MHz, DMSO-d 6): 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, 2 H), 3.49 (q, J = 6.0 Hz, 2 H), 2.88 (t, J = 6.5 Hz, 2 H), 2.18 (q, J = 7.3 Hz, 2 H), 2.01 (s, 3 H), 0.97 (t, J = 7.4 Hz, 3 H). 13C NMR (100 MHz, DMSO-d 6): 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.
  • 14 Phenyl (trans-4-Methylcyclohexyl)carbamate (3) Finely powdered diphenyl carbonate (3.213 g, 15 mmol) was suspended in a mixture of THF (4 mL) and H2O (36 mL), and the resulting suspension was stirred at r.t. trans-(4-Methylcyclohexyl)amine (1.698 g, 15 mmol) was added, and the reaction was kept at r.t. for 8 h until the reaction was complete (TLC). The mixture was extracted with EtOAc (150 mL), and the organic layer was washed sequentially with cold 10% aq NaOH (3 × 50 mL) and brine (2 × 50 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to give a crude product that was purified by column chromatography (silica gel, 8% hexane–EtOAc) to give a white solid; yield: 2.945 g (84%); mp 175–177 °C. 1H NMR (400 MHz, DMSO-d 6): δ = 7.68 (d, J = 7.9 Hz, 1 H), 7.36 (t, J = 8.1 Hz, 2 H), 7.18 (t, J = 7.3 Hz, 1 H), 7.08 (d, J = 7.6 Hz, 2 H), 3.34–3.18 (m, 1 H), 1.85 (d, J = 10.1 Hz, 2 H), 1.67 (d, J = 12.2 Hz, 2 H), 1.29–1.22 (m, 3 H), 1.03–0.91 (m, 2 H), 0.86 (d, J = 6.4 Hz, 3 H). 13C NMR (100 MHz, DMSO-d 6): δ = 153.9, 151.5, 129.6, 125.2, 122.2, 50.3, 33.9, 32.8, 31.8, 22.6. HRMS (ESI): m/z [M + Na]+ calcd for C14H19NNaO2: 256.1313; found: 256.1309.
  • 15 Glimepiride Carboxamide 2 (1.054 g, 3 mmol) and carbamate 3 (0.770 g, 3.3 mmol) were dissolved in MeCN (40 mL), and DBU (0.685 g, 4 5 mmole) was added. The mixture was then refluxed for 5 h until the reaction was complete (TLC). The solvent was evaporated under 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 reduced pressure. The crude product was purified by crystallization (MeOH) to give a white solid; yield: 1.255 g (85%); mp 202–204 °C. 1H NMR (400 MHz, DMSO-d 6): δ = 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, 1 H), 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-d 6): δ = 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]+ calcd for C24H34N4NaO5S:, 513.2148; found: 513.2133.