A suspension of 40.0 g (0.173 mol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 72.1 ml (0.517 mol) of triethylamine, and 2800 ml of dichloromethane is stirred at room temperature and 67.8 ml (0.52 mol) of chlorotrimethylsilane is added. The mixture is stirred at room temperature until the solid is almost completely dissolved. A suspension of 63 g (0.362 mol) of N-acetyl-4-hydroxy-L-proline in 650 ml of dichloromethane is cooled to -10° to -15° and 41 ml (0.363 mol) of N-methylmorpholine is added followed by 28.3 ml (0.363 mol) of methyl chloroformate. The reaction is stirred at -15° to -10° for 25 minutes. The reaction temperature is then lowered below -20° and the oxonicotinic acid solution is added in aliquots keeping the temperature below -5°. When the addition is complete, the reaction is stirred in an ice bath overnight, allowing the bath to come to room temperature. The reaction is treated with 30 ml of isopropanol and 30 ml of glacial acetic acid and the resulting mixture is stirred for 10 min at room temperature. The reaction is concentrated and filtered to give 50.1 g of 6-[4-(N-acetyl-4-hydroxy-L-prolylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid [α]D23 -60.5° (cl, pH 7).
