反应详情

温度

50 °C

A solution of N-(2-ethyl-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-yl)-2-methyl-propane-2-sulfinamide (118 mg, 0.31 mmol) in MeOH (20 mL) was passed through the H-Cube® (full H2, 60° C., flow rate: 1 mL/min, 30 mm 20% Pd(OH)2/C cartridge). The solvent was removed under reduced pressure and the crude residue was re-dissolved in MeOH (1 mL). 5-(tert-Butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (119 mg, 0.33 mmol) was added followed by DIPEA (0.16 mL, 0.95 mmol) and the reaction mixture was heated at 50° C. for 15 min. After cooling to room temperature, propylphosphonic anhydride solution (0.17 mL, 50% wt in EtOAc, 0.34 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 16 hr. The mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (10 mL), washed with 1 M aqueous NaOH (3×10 mL), 1 M aqueous HCl (2×10 mL) and brine (10 mL). The organic layer was separated, dried over Na2SO4, concentrated under reduced pressure and purified via silica gel chromatography (0-10% 7 M ammonia in MeOH/DCM) to give an oil as a mixture of isomers. This oil was dissolved in MeOH (2 mL) and HCl in dioxane (4 M, 4.0 mmol, 1 mL) was added. The reaction mixture was stirred at room temperature for 18 hr and the solvents removed under reduced pressure. Purification via chiral preparative HPLC gave 112 as a white solid (9 mg, 5% over three steps). 1H NMR (400 MHz, CDCl3) δ 9.63 (s, 1H), 8.15 (s, 1H), 7.34 (tt, J=8.4, 6.1 Hz, 1H), 7.05-6.97 (m, 2H), 6.16 (s, 2H), 4.80 (dd, J=8.2, 3.9 Hz, 1H), 3.77 (s, 3H), 3.71-3.62 (m, 1H), 3.39-3.32 (m, 1H), 2.18-2.09 (m, 1H), 2.08-1.98 (m, 1H), 1.93-1.74 (m, 2H), 1.71-1.57 (m, 3H), 1.46-1.33 (m, 3H), 0.81 (t, J=7.4 Hz, 3H). LCMS (ES+) m/z 477 (M+1).

1. customThe solvent was removed under reduced pressure
2. dissolutionthe crude residue was re-dissolved in MeOH (1 mL)
3. temperatureAfter cooling to room temperature
4. concentrationThe mixture was concentrated under reduced pressure
5. dissolutionthe residue was dissolved in EtOAc (10 mL)
6. washwashed with 1 M aqueous NaOH (3×10 mL), 1 M aqueous HCl (2×10 mL) and brine (10 mL)
7. customThe organic layer was separated
8. dry with materialdried over Na2SO4
9. concentrationconcentrated under reduced pressure
10. custompurified via silica gel chromatography (0-10% 7 M ammonia in MeOH/DCM)
11. customto give an oil
12. additionas a mixture of isomers
13. stirringThe reaction mixture was stirred at room temperature for 18 hr
14. customthe solvents removed under reduced pressure
15. customPurification via chiral preparative HPLC