Ethyl 3-[Benzyl(Methyl)aMino]-2,2-difluoropropanoate synthesis

Yield:1346597-47-4 52%

Reaction Conditions:

Stage #1: Ethyl bromodifluoroacetatewith chloro-trimethyl-silane;zinc in tetrahydrofuran at 20; for 0.166667 h;
Stage #2: N-{[1H-benzo(d)(1,2,3)triazol-1-yl]methyl}-N-methyl-1-phenylmethanamine in tetrahydrofuran at 20; for 3 h;

Steps:

Synthesis of Intermediate I -06

To a suspension of Zn (5.85 g, 89.57 mmol) in THF (175 mL) (water bath) was added TMSCI (5.68 mL, 44.78 mmol). The mixture was stirred for 10 min and ethyl bromodifluoroacetate (6.32 mL, 49.26 mmol) was added. After stirring at rt for 10 min, a solution of Intermediate I-05 (11.30 g, 44.78 mmol) in THF (50 mL) was added. The reaction mixture was stirred at rt for 3 h. Sat NaHC0₃ was added, the mixture was stirred for 15 min, and filtered through a plug of celite washing with EtOAc. Layers were separated and the aqueous layer was extracted with EtOAc (x2). The combined organic layers were dried, filtered and evaporated. The residue was purified by column chromatography (Biotage, cHex/EtOAc 100:0 to 80:20) to obtain Intermediate I-06 (5.94 g, 52%).1H NMR (300 MHz, CDCI₃) δ 7.20 - 6.97 (m, 5H), 4.13 (q, J = 7.1 Hz, 2H), 3.46 (s, 2H), 2.91 (t, J = 13.1 Hz, 2H), 2.13 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H).

References:

WO2013/4984,2013,A1 Location in patent:Page/Page column 68