Dicyclohexylcarbodiimide → Ritonavir

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 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 extracted 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%). A second crystallization from 144 mL of 2:1 ethyl acetate/heptane (dissolved at ~70° C., then stirred at room temperature 12 hours) produced a thick slurry of fine white solid. The product was collected by filtration and washed with 15 mL 2:1 ethyl acetate/heptane, then dried in a vacuum oven at 55° C. for 2 days to give the desired product. Yield 11.9 g (77%).

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 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. extractionThe aqueous layer was extracted with another 25 mL ethyl acetate
10. washthe combined ethyl acetate extracts were washed with aqueous NaHCO3 (2×37 mL of 5% w/w NaHCO3)
11. dry with materialThe organic layer was dried with Na2SO4 (13 g)
12. filtrationfiltered
13. concentrationconcentrated under vacuum at ≤45° C
14. dissolutionThe residue was dissolved in a 1:1 ethyl acetate/heptane mixture (200 mL) at 70° C
15. temperatureto cool slowly
16. stirringstirred overnight at room temperature
17. customto provide a thick slurry
18. filtrationThe product was collected by filtration
19. washwashed with 1:1 ethyl acetate/heptane (20 mL)
20. customThe product was dried briefly at 55° C. in a vacuum oven
21. customto obtain an approximate weight
22. customto the second crystallization (12.85 g, 83%)
23. customA second crystallization from 144 mL of 2:1 ethyl acetate/heptane (
24. dissolutiondissolved at ~70° C.
25. stirringstirred at room temperature 12 hours)
26. customproduced a thick slurry of fine white solid
27. filtrationThe product was collected by filtration
28. washwashed with 15 mL 2:1 ethyl acetate/heptane
29. customdried in a vacuum oven at 55° C. for 2 days

ORD record

ord-289ee5f94b7543c5981841b0d2af27f9

Source dataset

uspto-grants-1997_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05674882