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With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; N,N-dimethyl acetamide; at 0 - 20℃; |
Macrocyclic acid hemihydrate 19 (10.16 g, 18.03 mmol) was dissolved in THF (50 - 90 mL). The solution was azetropically dried at a final volume of 100 mL. Sulfonamide pTSA salt 20 (7.98 g, 1.983 mmol) followed by DMAc (15 mL) was added at ambient temperature. The batch was cooled to 0-10 C and pyridine (10 mL) was added dropwise. Then, EDC HCl (4.49 g, 23.44 mmol) was added in portions or one portion at 0-10 C. The reaction mixture was aged at 0-10 C for 1 hour, then warmed to 15-20 C for 2-4 hours. MeOAc (100 mL) followed by 15wt% citirc acid in 5% NaCl in water (50 mL) was added, while the internal temperature was maintained to < 25 C with external cooling. The separated organic phase was washed with 15wt% citirc acid in 5% NaCl in water (50 mL) followed by 5% NaCl (50 mL). The organic phase wassolvent switched to acetone at a final volume of -80 mL. Water (10 mL) was added dropwise at 35-40 C. The batch was seeded with Compound A monohydrate form III (?10 mg) and aged for 0.5 -1 hour at 35-40 C. Additional water (22 mL) was added dropwise over 2-4 hours at 35-40 C. The slurry was aged at 20 C for 2-4 hours before filtration. The wet cake was displacement washed with 60% acetone in water (40 mL x 2). Suction dry at ambient temperature gave Compound A monohydrate form III as a white solid. 1H NMR (400 MHz, CDCl3) delta 9.95 (s, br, 1 H), 7.81 (d, J = 9.1 Hz, 1 H), 7.18 (dd, J = 9.1, 2.7 Hz, 1 H), 7.16 (s, br, 1 H), 7.13 (d, J - 2.7 Hz, 1 H), 5.96 (t, J = 3.8 Hz, 1 H), 5.72 (m, 1 H), 5.68 (d, J = 10.1 Hz, 1 H), 5.19 (d, J = 17.1 Hz, 1 H), 5.07 (d, J = 10.1 Hz, 1 H), 4.52 (d, J = 11.4 Hz, 1 H), 4.45 (d, J = 9.8 Hz, 1 H), 4.36 (d, J = 10.5, 6.9 Hz, 1 H), 4.05 (dd, J = 11.5, 3.9 Hz, 1 H), 3.93 (s, 3 H), 3.78 (m, 1 H), 2.90 (m, 1 H), 2.82 (tt, J = 8.0, 4.8 Hz, 1 H), 2.74 (dt, J = 13.2, 4.8 Hz, 1 H), 2.59 (dd, J = 14.0,6.7 Hz, 1 H), 2.40 (ddd, J =14.0, 10.6, 4.0 Hz, 1 H), 2.10 (dd, J = 17.7, 8.7 Hz, I H), 1.98 (2 H, mono hydrate H20), 1.88 (dd, J 8.2, 5.9 Hz, 1 HO, 1.74 (m, 3 H), 1.61 (m, 1 H), 1.50 (m, 3 H), 1.42 (dd, J = 9.6, 5.8 Hz, 1 H), 1.22 (m, 2 H), 1.07 (s, 9 H), 0.95 (m, 4 H), 0.69 (m, 1 H), 0.47 (m, 1 H). 13C NMR (100 MHz, CDCl3) delta 173.5, 172.1, 169.1, 160.4, 157.7, 154.9, 148.4, 141.0, 134.3, 132.7, 129.1, 118.8, 118.7, 106.5, 74.4, 59.6, 59.4, 55.8, 55.5, 54.9, 41.8, 35.4, 35.3, 35.2, 34.3, 31.2, 30.7, 29.5, 28.6, 28.2, 26.6, 22.6, 18.7, 11.2, 6.31, 6.17. HPLC conditions: Ascentis Express Column, 10 cm x 4.6mm x 2.7mum; Column temperature of 40 C; Flow rate of 1.8 mL/min; and Wavelength of 215 nm |
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With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; N,N-dimethyl acetamide; at 0 - 20℃; |
Macrocyclic acid hemihydrate, the product of Example 15 (10.16 g, 18.03 mmol) was dissolved in THF (50 mL to 90 mL). The solution was azetropically dried at a final volume of 100 mL. Sulfonamide pTSA salt (7.98 g, 1.983 mmol) followed by DMAc (15 mL) was added at RT. The batch was cooled to 0C to 10C, and pyridine (10 mL) was added dropwise. Then, EDC HCl (4.49 g, 23.44 mmol) was added in portions or one portion at 0C to 10C. The reaction mixture was aged at 0C to 10C for 1 h, and then warmed to 15C to 20C for 2 h to 4 h. MeOAc (100 mL) followed by 15 wt% citric acid in 5% NaCl in water (50 mL) was added, while the internal temperature was maintained to < 25C with external cooling. The separated organic phase was washed with 15 wt% citric acid in 5% NaCl in water (50 mL) followed by 5% NaCl (50 mL). The organic phase was solvent-switched to acetone at a final volume of ~80 mL. Water (10 mL) was added dropwise at 35C to 40C. The batch was seeded with Compound A monohydrate form III (~10 mg) and aged for 0.5 h tol h at 35C to 40C. Additional water (22 mL) was added dropwise over 2 h to 4 h at 35C to 40C. The slurry was aged at 20C for 2 h to 4 h before filtration. The wet cake was displacement washed with 60% acetone in water (2x 40 mL). Suction drying at RT gave Compound A monohydrate form III as a white solid. XH NMR (400 MHz, CDC13) delta 9.95 (s, br, 1 H), 7.81 (d, J = 9.1 Hz, 1 H), 7.18 (dd, J = 9.1, 2.7 Hz, 1 H), 7.16 (s, br, 1 H), 7.13 (d, J = 2.7 Hz, 1 H), 5.96 (t, J = 3.8 Hz, 1 H), 5.72 (m, 1 H), 5.68 (d, J = 10.1 Hz, 1 H), 5.19 (d, J = 17.1 Hz, 1 H), 5.07 (d, J = 10.1 Hz, 1 H), 4.52 (d, J = 11.4 Hz, 1 H), 4.45 (d, J = 9.8 Hz, 1 H), 4.36 (d, J = 10.5, 6.9 Hz, 1 H), 4.05 (dd, J = 11.5, 3.9 Hz, 1 H), 3.93 (s, 3 H), 3.78 (m, 1 H), 2.90 (m, 1 H), 2.82 (tt, J = 8.0, 4.8 Hz, 1 H), 2.74 (dt, J = 13.2, 4.8 Hz, 1 H), 2.59 (dd, J = 14.0, 6.7 Hz, 1 H), 2.40 (ddd, J = 14.0, 10.6, 4.0 Hz, 1 H), 2.10 (dd, J = 17.7, 8.7 Hz, 1 H), 1.98 (2 H, mono hydrate H20), 1.88 (dd, J 8.2, 5.9 Hz, 1 HO, 1.74 (m, 3 H), 1.61 (m, 1 H), 1.50 (m, 3 H), 1.42 (dd, J = 9.6, 5.8 Hz, 1 H), 1.22 (m, 2 H), 1.07 (s, 9 H), 0.95 (m, 4 H), 0.69 (m, 1 H), 0.47 (m, 1 H). 1 C NMR (100 MHz, CDC13) delta 173.5, 172.1, 169.1, 160.4, 157.7, 154.9, 148.4, 141.0, 134.3, 132.7, 129.1, 118.8, 118.7, 106.5, 74.4, 59.6, 59.4, 55.8, 55.5, 54.9, 41.8, 35.4, 35.3, 35.2, 34.3,. 31.2, 30.7, 29.5, 28.6, 28.2, 26.6, 22.6, 18.7, 11.2, 6.31, 6.17. HPLC conditions: Ascentis Express Column, 10 cm x 4.6 mm, 2.7 muetaiota; Column temperature of 40C; Flow rate of 1.8 mL/min; and Wavelength of 215 nm. Gradiant: mm 0.1% PO4 0 20 80 5 55 45 15 55 45 25 95 5 27 95 5 27.1 20 80 32 20 80 Retention time: mm. Compound A 14.50 |