Chlorotrimethylsilane → 6-[4-(N-acetyl-4-hydroxy-L-prolylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid

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A suspension of 172.5 g (0.75 mol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 312 ml (2.23 mol) of triethylamine, and 11.8 L of dichloromethane was stirred at 10° and 290 ml (2.28 mol) of chlorotrimethylsilane is slowly added. The resulting mixture was stirred overnight at room temperature. A mixture of 273 g (1.58 mol) of N-acetyl-4-hydroxy-L-proline and 3.5 L of dichloromethane was stirred at -15° and 177.5 ml (1.61 mol) of N-methylmorpholine was added during a 20 min period followed by 250 ml of dichloromethane. The mixture was stirred at -13° for 15 min and 125.5 ml (1.62 mol) of methyl chloroformate was added over a 25 min period at -14° followed by 150 ml of dichloromethane. The mixture was stirred at -15° for 40 min and the above silylated nicotinic acid was added over a period of 60 min at -17° followed by 500 ml of dichloromethane. The mixture was stirred for 1 hr and 40 min as the temperature rose to 1°. The mixture was stirred overnight with ice bath cooling as the temperature rose to 16° and 135 ml of glacial acetic acid was added followed by 135 ml of isopropanol. The reaction mixture was concentrated to 4 L under reduced pressure and the solid filtered, washed with dichloromethane and dried to give 245 g of 6-[4-(N-acetyl-4-hydroxy-L-prolylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid.

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