反应详情

A 2-L round-bottomed flask was charged with benzyl 3-(1-propyn-1-yl)-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinecarboxylate (21.8 g, 43.5 mmol, step 5) and TFA (130 mL). Trifluoromethanesulfonic acid (11.6 mL, 131 mmol, Acros/Fisher Scientific, Waltham, Mass.) was added slowly at rt resulting orange cloudy mixture. After stirring at rt for 10 min, the volume of the reaction mixture was reduced to half in vacuo. Solid NaHCO3 was added in potions until the mixture became sludge. Saturated aqueous NaHCO3 (800 mL) was added slowly until the pH was about 8. The aqueous phase was extracted with EtOAc (3×250 mL). The combined organic phases were washed with water (500 mL) and saturated aqueous NaCl (500 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. This material was dissolved into DCM (200 mL) and triethylamine (31.0 mL, 222 mmol) was added. Then 6-aminopyridine-3-sulfonyl chloride (9.40 g, 48.8 mmol, published PCT patent application no. WO 2009/140309) was added in potions over 10 min period. The brown mixture was stirred at room temperature for 10 min. The reaction mixture was washed with water (300 mL) and saturated aqueous NaCl (300 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (780 g of total silica, 30 to 90% EtOAc in hexanes) to afford 2-(4-(4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (19.4 g) as a mixture of two enantiomers.

1. customresulting orange cloudy mixture
2. extractionThe aqueous phase was extracted with EtOAc (3×250 mL)
3. washThe combined organic phases were washed with water (500 mL) and saturated aqueous NaCl (500 mL)
4. dry with materialThe organic phase was dried over sodium sulfate
5. filtrationfiltered
6. concentrationconcentrated in vacuo
7. additionwas added
8. additionWO 2009/140309) was added in potions over 10 min period
9. stirringThe brown mixture was stirred at room temperature for 10 min
10. washThe reaction mixture was washed with water (300 mL) and saturated aqueous NaCl (300 mL)
11. dry with materialThe organic phase was dried over sodium sulfate
12. filtrationfiltered
13. concentrationconcentrated in vacuo
14. customThe crude product was purified by column chromatography (780 g of total silica, 30 to 90% EtOAc in hexanes)