반응 #166258

반응 방정식

7-(4-cyclopropyl-2-fluoro-phenylamino)-benzo[d]isothiazole-6-carboxylic acid

diisopropylethylamine

O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine

EDCI

HOBt

→

title compound

수율 59.0%

7-(4-Cyclopropyl-2-fluoro-phenylamino)-benzo[d]isothiazole-6-carboxylic acid ((R)-2,3-dihydroxy-propoxy)-amide

수율 59.0%

용매

ethyl acetate

DMF

반응 조건

후처리

1. 1
   세척washed with water
2. 2
   건조a saturated aqueous solution of sodium hydrogen carbonate, then brine before being dried (Na2SO4)
3. 3
   여과filtered
4. 4
   농축concentrated in vacuo
5. 5
   workup.ADDITIONa 4.0M solution of hydrochloric acid in dioxane (1.0 mL) was added
6. 6
   workup.STIRRINGThe reaction mixture was stirred at room temperature for 1 hour
7. 7
   workup.ADDITIONbefore being diluted with ethyl acetate
8. 8
   세척washed with a saturated aqueous solution of sodium hydrogen carbonate
9. 9
   건조brine, dried (Na2SO4)
10. 10
    여과filtered
11. 11
    기타evaporated in vacuo
12. 12
    기타was 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)

실험 절차

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).

출처