반응 #1713110

반응 방정식

6-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid

thiomorpholine-1,1-dioxide HCl

triethylamine

water

→

(1,1-dioxo-1λ6-thiomorpholin-4-yl)-{6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-methanone monohydrate

용매

THF

THF

반응 조건

후처리

1. 1
   온도The resulting mixture was heated
2. 2
   온도to reflux temperature
3. 3
   workup.STIRRINGsubsequently stirred at this temperature for 50 hours
4. 4
   온도The mixture was cooled to room temperature
5. 5
   workup.DISTILLATIONFrom the resulting suspension THF was distilled off under reduced pressure and with a jacket temperature of 60° C.
6. 6
   온도The suspension was cooled to room temperature
7. 7
   workup.STIRRINGstirred for 2 hours
8. 8
   여과The crystals were filtered off
9. 9
   세척washed with a mixture of ethanol (100 mL) and water (100 mL)
10. 10
    기타subsequently dried at 55° C./<25 mbar until constant weight
11. 11
    기타to afford 28.9 g (92%) of Form B as a colorless solid with purity of 99.7% (area)

실험 절차

6-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (23.0 g, 70.1 mmol) and 1,1-carbonyldiimidazole (15.3 g, 94.6 mol, 1.35 eq.) were dissolved in THF (120 mL) and the resulting solution was stirred for one hour at room temperature. This solution was then added to a suspension of thiomorpholine-1,1-dioxide HCl (16.9 g, 98.5 mmol), DMAP (400 mg, 3.27 mmol) and triethylamine (9.78 g, 96.7 mmol) in THF (120 mL). The resulting mixture was heated to reflux temperature and subsequently stirred at this temperature for 50 hours. The mixture was cooled to room temperature and then treated within one hour with water (300 mL). From the resulting suspension THF was distilled off under reduced pressure and with a jacket temperature of 60° C. and continuously replaced by ethanol (426 g) at constant volume. The suspension was cooled to room temperature and stirred for 2 hours. The crystals were filtered off, washed with a mixture of ethanol (100 mL) and water (100 mL) and subsequently dried at 55° C./<25 mbar until constant weight to afford 28.9 g (92%) of Form B as a colorless solid with purity of 99.7% (area) as measured by HPLC.

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