反应详情

温度

25 °C

1-(3-Methyl-butylamino)-1H-pyrrole-2-carboxylic acid allyl ester (Example 1c, 0.112 g, 0.473 mmol) and [7-(methanesulfonyl-methyl-amino)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl]-acetic acid (Example 7e, 0.164 g, 0.473 mmol) were dissolved in a 3:1 mixture of dichloromethane and N,N-dimethylformamide (4 mL) at 25° C. A solution of N,N-dicyclohexylcarbodiimide (0.473 mL, 1.0 M in dichloromethane, 0.473 mmol) was added and the reaction mixture was stirred at 25° C. for 1 h then filtered. The filtrate was concentrated in vacuo and the residue was dissolved in ethanol (4 mL) at 25° C. A 21% solution of sodium ethoxide in ethanol (0.368 mL, 1.14 mmol) was added and the reaction mixture was heated at 80° C. for 6 h. After cooling to 25° C., the mixture was partitioned between 0.5 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Sequential purification of the residue by flash column chromatography (Merck silica gel 60, 40-63 μm, 5{tilde over (0)}→100% ethyl acetate in hexanes) and preparative HPLC [column=Luna 5μ C18(2) 100 Å Axia 50×21.2 mm Id; eluent=0→100% acetonitrile in water (both containing 0.05% trifluoroacetic acid) over 7.0 min, flow=30 mL/min] afforded the desired product, N-{3-[4-hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-7-yl}-N-methyl-methanesulfonamide (0.060 g, 0.119 mmol, 25% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.94 (6H, d, J=6.4 Hz), 1.50-1.54 (2H, m), 1.64-1.70 (1H, m), 2.99 (3H, bs), 3.28 (3H, bs), 4.29-4.32 (2H, m), 5.74 (1H, s), 6.12 (1H, bs), 6.49 (1H, bs), 6.90 (1H, bs), 7.30 (1H, bs), 7.60 (1H, bs), 7.82 (1H, bs). LC-MS (ESI) calcd for C22H26N4O6S2 506.13. found 507.25 [M+H+].

1. filtrationthen filtered
2. concentrationThe filtrate was concentrated in vacuo
3. dissolutionthe residue was dissolved in ethanol (4 mL) at 25° C
4. temperaturethe reaction mixture was heated at 80° C. for 6 h
5. temperatureAfter cooling to 25° C.
6. customthe mixture was partitioned between 0.5 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL)
7. dry with materialThe organic layers were dried over sodium sulfate
8. filtrationfiltered
9. concentrationconcentrated in vacuo
10. customSequential purification of the residue by flash column chromatography (Merck silica gel 60, 40-63 μm, 5{tilde over (0)}→100% ethyl acetate in hexanes) and preparative HPLC [column=Luna 5μ C18(2) 100 Å Axia 50×21.2 mm Id
11. waiteluent=0→100% acetonitrile in water (both containing 0.05% trifluoroacetic acid) over 7.0 min