反应详情

温度

80 °C

To a mixture of (R)-6,8-difluorochroman-3-amine(2R,3R)-2,3-dihydroxysuccinate (compound JT′, 15 g, 44.7 mmol) and potassium thiocyanate (5.22 g, 53.7 mmol) in 2-propanol (150 ml) was added acetic acid (38.4 ml, 671 mmol) followed by N-benzyl-4-hydroxy-3-oxobutanamide (compound C, 11.13 g, 53.7 mmol) in 5 portions during 1 hours. The mixture was heated with stirring at 80° C. for 2 hours. More N-benzyl-4-hydroxy-3-oxobutanamide (1.854 g, 8.95 mmol) and potassium thiocyanate (0.870 g, 8.95 mmol) added, stirred for 1 hour. More N-benzyl-4-hydroxy-3-oxobutanamide (1.854 g, 8.95 mmol) and potassium thiocyanate (0.870 g, 8.95 mmol) added, stirred for 1 hour (in total N-benzyl-4-hydroxy-3-oxobutanamide (14.83 g, 71.6 mmol) and potassium thiocyanate (6.96 g, 71.6 mmol)), purified by HPLC at 210 nm (Kromasil 100 5C4 250×4.6 column, 0.1% TFA-ACN 50:50, 1 ml/min) with less than 1.5% compound JT′. Diluted with water (110 ml) at approx 50° C., cooled to 5° C. and aged for 1 hour. Precipitate was collected, washed with water. Wet filter cake was re-slurried in water (300 ml), solution of sodium bicarbonate (4.13 g, 49.2 mmol) in water (100 ml) was added in portions, the mixture was stirred for 15 min, filtered, washed with water (wet weight 21 g), dried on air to give (R)—N-benzyl-2-(3-(6,8-difluorochroman-3-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-yl)acetamide (12.2 g, 29.4 mmol, 65.6% yield).

1. temperatureThe mixture was heated
2. stirringstirred for 1 hour
3. custompurified by HPLC at 210 nm (Kromasil 100 5C4 250×4.6 column, 0.1% TFA-ACN 50:50, 1 ml/min) with less than 1.5% compound JT′
4. additionDiluted with water (110 ml) at approx 50° C.
5. temperaturecooled to 5° C. and aged for 1 hour
6. customPrecipitate was collected
7. washwashed with water
8. stirringthe mixture was stirred for 15 min
9. filtrationfiltered
10. washwashed with water (wet weight 21 g)
11. customdried on air