反应详情

温度

35 °C

Aqueous sulfuric acid (8.2 L sulfuric acid and 1.1 L water premixed and cooled to 35° C. or less) was added to the crude toluene solution of (3R)-3-(4-trifluoromethyl-phenylamino)-pentanenitrile from Example 1. The resulting bilayer was stirred well and heated to 35° C. for 17 hours. The lower aqueous layer was collected and quenched with aqueous sodium hydroxide (95 L water and 10.7 kg sodium hydroxide) and diisopropyl ether (IPE) (40 L). After extraction and removal of the aqueous layer, the organic layer was combined and extracted with saturated aqueous NaHCO3 (10 L). The organic phase from the resulting bilayer was concentrated by distillation to a volume of 19 L. The solution was then cooled to room temperature and seeded with (3R)-3-(4-trifluoromethyl-phenylamino)-pentanoic acid amide and allowed to granulate for 3 hours while stirring. To the heterogenous mixture was added cyclohexane (38 L) and the mixture was granulated for an additional 11 hours. The solids were filtered, rinsed with cyclohexane (4 L), dried under vacuum at 40° C. to afford 3021 g (75%) of the title compound.

1. customThe lower aqueous layer was collected
2. customquenched with aqueous sodium hydroxide (95 L water and 10.7 kg sodium hydroxide) and diisopropyl ether (IPE) (40 L)
3. extractionAfter extraction and removal of the aqueous layer
4. extractionextracted with saturated aqueous NaHCO3 (10 L)
5. concentrationThe organic phase from the resulting bilayer was concentrated by distillation to a volume of 19 L
6. temperatureThe solution was then cooled to room temperature
7. stirringwhile stirring
8. additionTo the heterogenous mixture was added cyclohexane (38 L)
9. waitthe mixture was granulated for an additional 11 hours
10. filtrationThe solids were filtered
11. washrinsed with cyclohexane (4 L)
12. customdried under vacuum at 40° C.