反应详情

To a solution of 7-(4-cyclopropyl-2-fluoro-phenylamino)-benzo[d]isothiazole-6-carboxylic acid (155 mg, 0.47 mmol) and diisopropylethylamine (0.10 mL, 0.61 mmol) in DMF (5 mL) were added O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (97 mg, 0.66 mmol), EDCI (117 mg, 0.61 mmol) and HOBt (83 mg, 0.61 mmol). The reaction mixture was stirred for 2 hours at room temperature, diluted with ethyl acetate, washed with water, a saturated aqueous solution of sodium hydrogen carbonate, then brine before being dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was taken in MeOH (10 mL) and a 4.0M solution of hydrochloric acid in dioxane (1.0 mL) was added. The reaction mixture was stirred at room temperature for 1 hour before being diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate then brine, dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was subjected to reverse-phase HPLC (Gemini 5 micron C18 250×21.20 mm column, 0.1% formic acid, gradient acetonitrile/water, 15 to 95%, ramp time 20 minutes) to afford the title compound as a yellow solid (115 mg, 59%). LCMS (method A): RT=9.02 min, [M+H]+=418. 1H NMR (DMSO-d6, 400 MHz) 9.98 (1 H, s), 8.97 (1 H, s), 7.72 (1 H, s), 7.61 (1 H, d, J=8.35 Hz), 7.09-6.90 (3 H, m), 3.95 (1 H, dd, J=9.94, 3.81 Hz), 3.79 (2 H, d, J=16.92 Hz), 3.40 (2 H, d, J=5.46 Hz), 2.03-1.94 (1 H, m), 1.03-0.97 (2 H, m), 0.77-0.71 (2 H, m).

1. washwashed with water
2. dry with materiala saturated aqueous solution of sodium hydrogen carbonate, then brine before being dried (Na2SO4)
3. filtrationfiltered
4. concentrationconcentrated in vacuo
5. additiona 4.0M solution of hydrochloric acid in dioxane (1.0 mL) was added
6. stirringThe reaction mixture was stirred at room temperature for 1 hour
7. additionbefore being diluted with ethyl acetate
8. washwashed with a saturated aqueous solution of sodium hydrogen carbonate
9. dry with materialbrine, dried (Na2SO4)
10. filtrationfiltered
11. customevaporated in vacuo
12. customwas subjected to reverse-phase HPLC (Gemini 5 micron C18 250×21.20 mm column, 0.1% formic acid, gradient acetonitrile/water, 15 to 95%, ramp time 20 minutes)