An Efficient and Practical Process for the Synthesis of Glimepiride

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.

Key words

glimepiride - medicinal chemistry - sulfonylurea - pyrroles - carbamates

• 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.