3,3,3-Trifluoropropanoic anhydride synthesis

Yield:-

Reaction Conditions:

with dicyclohexyl-carbodiimide in dichloromethane at 20; for 48 h;

Steps:

61

General procedure: N,N′-Dicyclohexylcarbodiimide (330 mg, 1.60 mmol) is added to 3,3,3-trifluoro-2,2-dimethylpropionic acid (500 mg, 3.20 mmol) in DCM and stirring is continued for 2d at room temperature. Volatiles are evaporated under reduced pressure and the resulting residue, example 9a (100 mg, 0.23 mmol) and TEA (160 μl, 0.15 mmol) in ACN (2 mL) are heated under microwave irradiation (100° C.) for two 30 min cycles. Solvents are evaporated under reduced pressure and the resulting residue purified by flash cromatography (cyclohexane/EtOAc from 100:0 to 20:80) followed by preparative HPLC (stationary phase: Xterra C18 5 μm 30×100 mm Mobile phase: ACN/H₂O+NH₄COOH 5 mmol). [0678] Fractions containing the title compound are combined and freeze dried to furnish the title compound (35 mg, 27%). HPLC-MS (Method 5): R_t=9.63 min. MS (APCI): m/z=556 (M+H)⁺ The title compound is prepared as described for example 12, employing example 9a (150 mg, 98% content, 0.34 mmol) and 3,3,3-trifluoropropionic anhydride (198 mg, content 81%, 0.68 mmol) coming from a crude anhydride batch of 830 mg synthetized from 3,3,3-trifluoropropionic acid (500 μl, 5.66 mmol) in the place of 3,3,3-trifluoro-2,2-dimethylpropionic acid. Obtained: 38 mg (21%). HPLC-MS (Method 7): R_t=6.81 min MS (ESI pos): m/z=528 (M+H)⁺

References:

US2013/197011,2013,A1 Location in patent:Paragraph 0677; 0859; 0860; 0861; 0861; 0862