To a solution of Red-Al (65% wt in toluene, 2.29 kg, 7.36 mol) in THF (2.25 L) was charged dropwise a solution of pyrrolidine (0.61 kg, 8.6 mol) in MTBE (0.70 L) at −20° C. to −5° C. under nitrogen. Off-gassing was observed during the addition. The solution was stirred at room temperature (19° C.) overnight. Potassium t-butoxide (1M in THF, 0.52 L, 0.52 mol) was added in one portion and the mixture was stirred at room temperature for 1 h to give a clear solution. This solution was added dropwise to a suspension of 3-ethyl 5-methyl 2-amino-4-(4-fluorophenyl)-6-(1-methylethyl)-3,5-pyridinedicarboxylate (0.85 kg, 2.36 mol) in MTBE (8.50 L) at −16° C. to −13° C. After stirring at −15° C. for an additional 30 min, the mixture was quenched with 1N NaOH (7.0 L) below 5° C. and then warmed to 20° C. The organic layer was separated and washed with 1N HCl (7.0 L), aqueous NaHCO3 (saturated, 7.0 L) and water (7.0 L). Concentration in vacuo to remove most of the solvents was followed by a solvent exchange with DMF (2.0 L) which gave a clear solution of ethyl 6-amino-4-(4-fluorophenyl)-5-formyl-2-isopropylnicotinate in DMF (KF <0.1%) at 40° C. In another reactor was charged potassium t-butoxide (1M in THF, 3.5 L, 3.5 mol) in DMF (7.0 L) at 10° C. under nitrogen. To this solution was added triethylphosphonacetate (0.64 kg, 2.8 mol) slowly maintaining the temperature below 20° C. The mixture was stirred at 18-20° C. for 30 min, then cooled to −5° C. to 0° C. The solution of 6-amino-4-(4-fluorophenyl)-5-formyl-2-isopropylnicotinate in DMF was added dropwise to this mixture at 0-5° C. The mixture was stirred for additional 45 min and then quenched with 6% aqueous KH2PO4 solution (8.20 L) at 0-10° C. The resulting slurry was stirred at room temperature for 2 h. The solid was collected by filtration, washed with water (10.0 L) and dried in vacuo for two days at 50-60° C. to provide methyl 6-amino-5-(3-ethoxy-3-oxopropenyl)-4-(4-fluorophenyl)-2-isopropylnicotinate (740.0 g, yield: 81.2%) as a yellow solid: mp 160.13° C. (DSC); 1H NMR (400 MHz, CDCl3) δ 1.16-1.30 (m, 9H), 2.92-3.05 (m, 1H), 3.38-3.51 (s, 3H) 4.10-4.23 (m, 2H), 4.95-5.10 (b, 2H), 6.15-6.24 (d, 1H), 7.02-7.20 (m, 4H), 7.23-7.36 (d, 2H); 13C NMR (100 MHz, CDCl3) δ 14.20, 22.09, 22.21, 33.38, 51.90, 60.61, 110.50, 115.24, 115.46, 120.66, 121.99, 130.61, 130.69, 140,32, 148.62, 156.38, 161.37, 163.52, 163.83, 166.53, 169.17. Anal. Calcd for C21H23FN2O4: C, 65.27; H, 5.99; N, 7.25; F, 4.91. Found: C, 65.11; H, 6.21; N, 7.11; F, 4.77.
