反应详情

To a suspension of (viii) (2.75 g, 8.6 mmol) in DCM (30 mL) at 0° C. was added DIPEA (4.40 mL, 25.0 mmol) followed by methanesulfonyl chloride (3.30 mL, 42.0 mmol). The reaction mixture was stirred at RT for 1 h and then washed with aq. sat'd. NaHCO3 (50 mL), brine (50 mL) and dried (MgSO4). Removal of solvent in vacuo gave the crude product, which was then dissolved in EtOH (100 mL) and 1,4-dioxane (20 mL). To the resultant solution was added KOH (˜10 eq) portionwise at RT until the pH of the reaction mixture was between 8 and 9. The reaction mixture was then slowly neutralised by addition of 1M HCl (aq) and volatiles removed in vacuo. The residue was taken up in EtOAc (50 mL) and washed with water (50 mL). The organic phase was dried (MgSO4), concentrated in vacuo and the solid residue then triturated with EtOAc. The solid was separated by filtration and dried in a stream of air and purified further by automated column chromatography (Biotage SP4, 12 g Grace Resolve cartridge) eluting with EtOAc:n-heptane (gradient elution from 60% to 100%. v/v) to give Compound (1) (2.42 g, 72%). ESI-MS: calculated [M+H]+ 400.1 observed [M+H]+ 400.1. 1H NMR (400 MHz, CDCl3) δ 8.94 (brd, J=3.9 Hz, 1H), 8.38 (s, 1H), 7.99 (s, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.86-7.77 (m, 2H), 7.17 (s, 1H), 3.18 (s, 3H), 3.09 (d, J=4.7 Hz, 3H), 2.50 (s, 3H), 1.84-1.76 (m, 1H), 1.15-1.04 (m, 2H), 0.84-0.74 (m, 2H).

1. washwashed with aq. sat'd
2. dry with materialNaHCO3 (50 mL), brine (50 mL) and dried (MgSO4)
3. customRemoval of solvent in vacuo
4. customgave the crude product, which
5. customvolatiles removed in vacuo
6. washwashed with water (50 mL)
7. dry with materialThe organic phase was dried (MgSO4)
8. concentrationconcentrated in vacuo
9. customthe solid residue then triturated with EtOAc
10. customThe solid was separated by filtration
11. customdried in a stream of air
12. custompurified further by automated column chromatography (Biotage SP4, 12 g Grace Resolve cartridge)
13. washeluting with EtOAc