Leucine, N-(diphenylMethylene)-4-fluoro-, ethyl ester synthesis

Yield:848949-86-0 220 g

Reaction Conditions:

Stage #1: ethyl N-diphenylmethylene glycinewith potassium tert-butylate in N,N-dimethyl-formamide at 0; for 0.5 h;
Stage #2: (2-fluoro-2-methylpropyl) trifluoromethanesulfonate in N,N-dimethyl-formamide at 25; for 12 h;

Steps:

2B.2 Step 2: ethyl 2-((diphenylmethylene)amino)-4-fluoro-4-methylpentanoate

To a solution of KOtBu (97.0 g, 864 mmol, 1.05 eq) in DMF (1.10L) was added ethyl 2- ((diphenylmethylene)amino)acetate (220 g, 823 mmol, 1.00 eq) at 0 °C. After stirring for 0.5 hr, 2- fluoro-2-methylpropyl trifluoromethanesulfonate (214 g, 955 mmol, 1.16 eq) was added. The reaction solution was warmed to 25 °C and stirred for 12 hrs. The reaction was poured into 5% aqueous NH₄Cl (0.80 L) and extracted with EtOAc (2.00 L and 1.00 L). The combined organic layers were washed with brine, dried over Na₂SO₄and concentrated under vacuum to give the crude product. The crude product was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate = 100: 1 ~ 0 : 1) to provide ethyl 2-((diphenylmethylene)amino)-4-fluoro-4-methylpentanoate (220 g) as a light yellow oil.

References:

WO2021/76890,2021,A1 Location in patent:Page/Page column 239; 320