反应详情

2-Methyl-1H-imidazole-4-carboxylic acid (29.0 g, 230 mmol), 335 ml of DMF and 165 ml of DCM were placed in to the reaction vessel under nitrogen. HBTU (7.27 g, 19.18 mmol), EDCI (44.1 g, 230 mmol) and 66.8 ml of DIPEA were added. (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (50 g, 192 mmol) was added and the reaction stirred overnight at RT. 600 ml of water was slowly added and water phase was washed with 335 ml and 500 ml of DCM. DCM phases were combined, washed with 3×600 ml of water and distilled to dryness. Acetonitrile (300 ml) was added and the mixture was heated up to 75° C. Water (300 ml) was added at >60° C., solution was allowed to cool to RT for precipitation and the mixture was stirred overnight at RT. Stirring was continued for additional 2 h at <10° C. The precipitate was filtered, washed with cold ACN:water and dried under vacuum to obtain 47 g of crude product. The title compound was recrystallized from EtOH with 75% yield. 1H-NMR (400 MHz, DMSO-d6): δ 1.08 (d, 3H), 2.30 (s, 3H), 4.23-4.48 (m, 3H), 6.95 (d, 1H), 7.41 (s, 1H), 7.82 (d, 1H), 7.95-8.07 (m, 3H), 8.09-8.12 (m, 1H), 12.12 (bs, 1H).

1. washwater phase was washed with 335 ml and 500 ml of DCM
2. washwashed with 3×600 ml of water
3. distillationdistilled to dryness
4. additionAcetonitrile (300 ml) was added
5. temperaturethe mixture was heated up to 75° C
6. additionWater (300 ml) was added at >60° C.
7. temperatureto cool to RT for precipitation
8. stirringthe mixture was stirred overnight at RT
9. stirringStirring
10. waitwas continued for additional 2 h at <10° C
11. filtrationThe precipitate was filtered
12. washwashed with cold ACN
13. dry with materialwater and dried under vacuum