反应详情

In a 5 L three-necked flask with overhead paddle stirrer and a nitrogen inlet. tert-butyl N-[(3S)-1-methyl-2-oxo-3-prop-2-ynyl-pyrrolidin-3-yl]carbamate (which may be prepared as described in Description 4) (104.79 g, 415.32 mmol) was suspended in tert-Butyl methyl ether (2100 mL). 2-Iodo-4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine (which may be prepared as described in Description 12) (166.34 g, 456.85 mmol) was added followed by diisopropylamine (174.63 mL, 1246 mmol) and the mixture was stirred over 20 mins. To the suspension was added copper iodide (1.58 g, 8.31 mmol) followed by bis(triphenyl-phosphine)palladium (II) dichloride (2.92 g, 4.15 mmol) and the mixture was stirred at room temperature for 3 hours. Water (1000 mL) was added and the mixture stirred for 30 mins. The phases were separated and the organic phase, washed with water (2×500 mL), dried over magnesium sulphate, filtered and evaporated to a tan foam, 230 g. The material was purified in three batches of approximately 75 g by column chromatography using an 800 g (Biotage 75L) column and eluting with a gradient of acetone in iso-hexane. This gave the title compound (D13a) (179.3 g) in good purity by NMR and consistent spectroscopically with that produced by Method 1 and the R isomer in Description 13.

1. stirringthe mixture was stirred at room temperature for 3 hours
2. stirringthe mixture stirred for 30 mins
3. customThe phases were separated
4. washthe organic phase, washed with water (2×500 mL)
5. dry with materialdried over magnesium sulphate
6. filtrationfiltered
7. customevaporated to a tan foam, 230 g
8. customThe material was purified in three batches of approximately 75 g by column chromatography
9. washeluting with a gradient of acetone in iso-hexane