Water → 2,2,2-Trifluoro-N-(5-fluoro-1,3-thiazol-2-yl)acetamide

Temperature

-30 °C

NEt3 (63.4 mL, 455 mmol) was added to a stirred suspension of 5-bromothiazol-2-ylamine hydrobromide (102.7 g, 379 mmol) in CH2Cl2 (1.5 L). After 1 h, TFAA (64.2 mL, 455 mmol) was added dropwise at 0° C. over 15 min. The mixture was allowed to warm to 20° C. over 1 h, before being stirred for an additional 2 h. H2O (600 mL) was added and the resulting precipitate was collected. The aqueous layer of the filtrate was separated and extracted with CHCl3 (3×300 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The collected precipitate and residual solid were combined and triturated with EtOAc-n-C6H14 to give N-(5-bromothiazol-2-yl)-2,2,2-trifluoroacetamide: δH (CDCl3): 7.45 (1H, s), 13.05 (1H, br). n-BuLi (253 mL of a 1.58M solution in hexanes, 403 mmol) was added dropwise over 50 min to a stirred solution of the above amide (50.0 g, 183 mmol) in anhydrous THF (1.3 L) at −78° C. After 1.5 h, a solution of N-fluorobenzenesulphonimide (86.0 g, 275 mmol) in anhydrous THF (250 mL) was added dropwise over 30 min. The mixture was stirred for 3 h, before being warmed up to −30° C. H2O (300 mL) was added and the mixture was filtered through a Celite pad. The solid collected and Celite were washed with Et2O (400 mL) and H2O (400 mL). The organic layer of the filtrate was separated and extracted with water (2×400 mL). The combined aqueous layers were washed with Et2O (400 mL), before being acidified to pH 6.5 with 2M HCl and extracted with EtOAc (2×400 mL). The combined organic extracts were washed with H2O (2×400 mL) and brine, before being dried (MgSO4), filtered and concentrated. Column chromatography (EtOAc-n-C6H14, 1:3 to 1:2) gave N-(5-fluorothiazol-2-yl)-2,2,2-trifluoroacetamide: δH (CDCl3): 7.13 (1H, d). AcCl (12.6 mL, 175 mmol) was added dropwise to a stirred solution of this amide (15.7 g, 73 mmol) in MeOH (300 mL) at 0° C. The mixture was stirred at 20° C. for 30 min, heated under reflux for 1 h, and finally concentrated in vacuo. The residual solid was triturated with THF to give the title compound: δH (D2O): 7.00 (1H, d).

1. filtrationthe mixture was filtered through a Celite pad
2. customThe solid collected
3. washCelite were washed with Et2O (400 mL) and H2O (400 mL)
4. customThe organic layer of the filtrate was separated
5. extractionextracted with water (2×400 mL)
6. washThe combined aqueous layers were washed with Et2O (400 mL)
7. extractionextracted with EtOAc (2×400 mL)
8. washThe combined organic extracts were washed with H2O (2×400 mL) and brine
9. dry with materialbefore being dried (MgSO4)
10. filtrationfiltered
11. concentrationconcentrated

ORD record

ord-749d96f775c34028a6025ad6ce0bab73

Source dataset

uspto-grants-2007_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07214681B2