反应详情

To a solution of the product of Example 70 (9.1 g, 21.4 mmol), HOBT (3.6 g, 23.5 mmol) and N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)-carbonyl)-L-valine (7.37 g, 23.5 mmol)in THF (170 mL) was added DCC (4.85 g, 23.5 mmol). The solution was stirred at ambient temperature for 16 hours (DCU precipitates). THF was removed under vacuum and the resulting paste was stirred with cold 1N HCl (106 mL at 5° C.) for 3 hours to dissolve the crude product. The DCU was removed by filtration and the filter cake was washed with 1N HCl (30 mL). KH2PO4 (3.2 g) was dissolved in the combined HCl filtrates. The solution was mixed with ethyl acetate (80 mL) and neutralized to pH 7 with aqueous NaOH (60.3 g of 10% w/w NaOH). The aqueous layer was extrated with another 25 mL ethyl acetate and the combined ethyl acetate extracts were washed with aqueous NaHCO3 (2×37 mL of 5% w/w NaHCO3). The organic layer was dried with Na2SO4 (13 g), filtered, and concentrated under vacuum at ≤45° C. The residue was dissolved in a 1:1 ethyl acetate/heptane mixture (200 mL) at 70° C. The solution was allowed to cool slowly and stirred overnight at room temperature to provide a thick slurry. The product was collected by filtration and washed with 1:1 ethyl acetate/heptane (20 mL). The product was dried briefly at 55° C. in a vacuum oven to obtain an approximate weight prior to the second crystallization (12.85 g, 83%).

1. custom(DCU precipitates)
2. customTHF was removed under vacuum
3. stirringthe resulting paste was stirred with cold 1N HCl (106 mL at 5° C.) for 3 hours
4. dissolutionto dissolve the crude product
5. customThe DCU was removed by filtration
6. washthe filter cake was washed with 1N HCl (30 mL)
7. dissolutionKH2PO4 (3.2 g) was dissolved in the combined HCl filtrates
8. additionThe solution was mixed with ethyl acetate (80 mL)
9. washthe combined ethyl acetate extracts were washed with aqueous NaHCO3 (2×37 mL of 5% w/w NaHCO3)
10. dry with materialThe organic layer was dried with Na2SO4 (13 g)
11. filtrationfiltered
12. concentrationconcentrated under vacuum at ≤45° C
13. dissolutionThe residue was dissolved in a 1:1 ethyl acetate/heptane mixture (200 mL) at 70° C
14. temperatureto cool slowly
15. stirringstirred overnight at room temperature
16. customto provide a thick slurry
17. filtrationThe product was collected by filtration
18. washwashed with 1:1 ethyl acetate/heptane (20 mL)
19. customThe product was dried briefly at 55° C. in a vacuum oven
20. customto obtain an approximate weight
21. customto the second crystallization (12.85 g, 83%)