反应详情

Cyanoacetamide (62 g, 1.5 eq) and powdered lithium hydroxide (18 g, 1.5 eq) were mixed in 500 ml DMF and it was stirred at room temperature for 30 min. To the mixture was added a solution of phthalimidoacetone (100 g, 0.49 mol, purchased from TCI America, Portland, Oreg., USA, or prepared according to Lei, et al, J. Am. Chem. Soc. 2004, 126, 1626) in DMF (200 ml) over 1 h at room temperature. Additional DMF (25 ml) was used as a rinse. After stirring at room temperature for 5 min, HPLC/MS showed formation of the adol compound (MS: MH+=222.1, MNa+=244.0). Methanol (50 ml) was added followed by 25% sodium methoxide solution (160 g, 1.5 eq) and methanol rinse (50 ml). This mixture was heated at 60-65° C. for 2 h to form 2-amino-4-methyl-1H-pyrrole-3-carboxamide. To this reaction mixture was added ethyl formate (100 ml, 2.5 eq) at 40-60° C. After stirring for 15 min, more methanol (50 ml) was added followed by simultaneous addition of ethyl formate (100 ml, 2.5 eq) and 25% sodium methoxide solution (266 g, 2.5 eq) over 30 min. Additional methanol (50 ml) was added as rinse. The resulting mixture was heated at 60° C. for 5 h. More 25% sodium methoxide solution (113 ml, 1 eq) was added, and heating continued for 1 h more to convert all of the pyrrole N-formyl intermediate (MS: MH+=151.1). Water (400 ml) was added and mixture was heated at 60° C. for 30 min. Solution assay indicated the final product was formed in 69% yield. The hydrolyzed reaction mixture was concentrated under vacuum and diluted with water (1000 ml). The pH was adjusted to about 7.6 with 6 N HCl at 60-65° C. The resulting slurry was heated at 60-65° C. for 15 min and cooled slowly to 10° C. The solids were filtered, washed with water, and dried at 50-60° C. under vacuum. The final product was obtained as a light purple solid (39.5 g, 54% yield, purity: 99.8% by HPLC area).

1. stirringAfter stirring at room temperature for 5 min
2. washrinse (50 ml)
3. temperatureThis mixture was heated at 60-65° C. for 2 h