Reaktion #960137

Reaktionsgleichung

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

Lösungsmittel

THF

THF

Reaktionsbedingungen

Aufarbeitung

1. 1
   TemperaturThe resulting mixture was heated
2. 2
   Temperaturto reflux temperature
3. 3
   workup.STIRRINGsubsequently stirred at this temperature for 50 hours
4. 4
   TemperaturThe 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
   TemperaturThe suspension was cooled to room temperature
7. 7
   workup.STIRRINGstirred for 2 hours
8. 8
   FiltrationThe crystals were filtered off
9. 9
   Waschenwashed with a mixture of ethanol (100 mL) and water (100 mL)
10. 10
    Sonstigesubsequently dried at 55° C./<25 mbar until constant weight
11. 11
    Sonstigeto afford 28.9 g (92%) of Form B as a colorless solid with purity of 99.7% (area)

Vorschrift

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.

Quelle