LCL-161

1005342-82-4

1005342-46-0

General procedure for the synthesis of (S)-N-((S)-1-cyclohexyl-2-((S)-2-(4-(4-fluorobenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide from B6 to B7 (Compound (I)) using Compound (CAS:1005342-82-4) as a raw material. To a 2L Argonaut reactor containing 120 g (20 mmol) of crude B6 was added 360.8 g (400 mL) of ethyl acetate. The solution was heated to 45±3°C and 109.1 g (120 mL) of isopropanol solution of 5-6N HCl was slowly added while maintaining the temperature at 45±3°C for 30 min. Stirring was continued at 45±3°C for 2 hours. Samples were taken for process control analysis. If the process control analysis passed, the reaction mixture was cooled to 18±3°C. The solution was slowly added to another 2L Argonaut reactor, which was pre-filled with 500g of water and 82.9g of potassium carbonate, while controlling the temperature at 5 ± 3°C. After stirring at 5±3°C for 30 minutes, 451 g (500 mL) of ethyl acetate was added. The solution was warmed to 20±3°C and kept for 1 hour. The two layers were separated and the upper organic phase was retained as B7 was present in this phase. The organic layer was washed with 286.6 g (250 mL) of brine and the lower aqueous phase was discarded. The upper organic phase was concentrated under reduced pressure to 500 mL at 30 °C. 1368 g (2 L) of heptane was slowly added while maintaining the temperature at 30 ± 3 °C. The suspension was cooled to 18 °C and the temperature was set at 30 ± 3 °C. The suspension was cooled to 18±3°C and held for 1 hr. The solids were collected by filtration and washed with 136 g (200 mL) of simvastatin-containing heptane. The solid was dried in an oven at 45°C for 16 hours to give 80 g of B7 in 80% yield.