反应详情

温度

78 °C

To the 5-L RBF containing tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (STEP A) was added tert-butyl 4,6-dichloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (400.0 g, 1.246 mol, 1 eq). To this mixture was added IPA (400 mL), DMSO (400 mL) and DIPEA (282 mL, 1.3 eq). The resulting pink slurry was heated up to 78° C. and was stirred for 34 hours. The mixture was then cooled to room temperature and was stirred over the weekend. HPLC analysis indicated the presence of 1.6% of the starting material, 4.63% of the des-Boc side product, 72.38% of the desired product, and 11.23% of an isomer. 1H NMR analysis indicated a ratio of 5.49 of the IPA/DMSO. Isopropanol (200 mL) was added to the mixture to adjust the ratio to 6. The slurry was heated up to 78° C. Water (1.6 L) was added over a period of 1 hour at a rate which kept the temperature of the mixture above 64° C. The mixture was then cooled to room temperature and was stirred overnight. The slurry was filtered the next morning through a fritted glass funnel. The filter cake was washed with IPA/water/DMSO (800 mL, 6:4:1) and IPA/water (2×800 mL, 3:2) to give the title compound, which was dried under high vacuum at 40-45° C. until a constant weight was obtained (299.27 g, 48% yield with a 96.6% purity). 1H NMR (300 MHz, CDCl3) δ ppm 1.80-1.30 (m, 26H), 4.04 (m, 1H), 4.21 (m, 1H), 4.64 (d, J=0.9 Hz, 1H), 4.85 (br, 1H), 6.08 (br, 1H).

1. temperatureThe mixture was then cooled to room temperature
2. stirringwas stirred over the weekend