ethyl 2-(6-chloropyridazin-3-yl)-2,2- difluoroacetate synthesis

Yield:1208249-85-7 52.5%

Reaction Conditions:

Stage #1: ethyl 2-(6-chloropyridazin-3-yl)-2-fluoroacetatewith lithium hexamethyldisilazane in tetrahydrofuran at -78; for 0.25 h;
Stage #2: with Selectfluor in tetrahydrofuran;N,N-dimethyl-formamide at -78 - 20;

Steps:

A

To a solution of ethyl 2- (6-chloropyridazin-3-yl)-2-fluoroacetate (36.6 g, 167 mmol) in anhydrous THF (500 rnL) was added lithium hexamethyldisilazide (201 ml, 201 mmol) drop-wise at -78 ⁰C. After 15 minutes, a solution of Selectfluor (71.2 g, 201 mmol) in DMF (183 mL) was added drop- wise. Upon complete addition, the reaction was allowed to warm to ambient temperature over a 30 min period. Saturated NH₄Cl (70 mL) was then added, and THF was removed via rotary evaporation. The resulting residue was diluted with water (500 mL), extracted with Et₂O (3 x 100 mL), dried with MgSO₄, filtered, and concentrated to dryness. The resulting material was purified via MPLC (Hex:EtOAc, 8:2) to provide ethyl 2-(6-chloropyridazin-3- yl)-2,2-difluoroacetate 45D (20.8 g, 88 mmol, 52.5%). ¹H NMR (400 MHz, DMSO-J₆) δ ppm 1.25 (t, J=7.07 Hz, 3 H) 4.38 (q, J=7.07 Hz, 2 H) 8.26 (d, J=9.09 Hz, 1 H) 8.33 (d, J=8.84 Hz, 1 H). ESI-MS:m/z 237.1 (M+H)⁺.

References:

WO2010/19899,2010,A1 Location in patent:Page/Page column 165; 167