Dicyclohexylcarbodiimide → Ritonavir

HRID 433800Notes

Reaction equation

HRID 433800 reaction equation
[NH2:1][C@@H:2]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]1[S:22][CH:21]=[N:20][CH:19]=1)=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1C=CC2N(O)N=NC=2C=1.[CH3:41][N:42]([C:52]([NH:54][C@H:55]([C:59](O)=[O:60])[CH:56]([CH3:58])[CH3:57])=[O:53])[CH2:43][C:44]1[N:45]=[C:46]([CH:49]([CH3:51])[CH3:50])[S:47][CH:48]=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[CH3:41][N:42]([C:52]([NH:54][C@H:55]([C:59]([NH:1][C@@H:2]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]1[S:22][CH:21]=[N:20][CH:19]=1)=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:60])[CH:56]([CH3:58])[CH3:57])=[O:53])[CH2:43][C:44]1[N:45]=[C:46]([CH:49]([CH3:51])[CH3:50])[S:47][CH:48]=1

Participants

6

Reactant 4

HCID 10868DicyclohexylcarbodiimideHCID 757711-HydroxybenzotriazoleHCID 9818282UreidovalineHCID 111019781,3-Thiazol-5-ylmethyl N-((1S,2S,4S)-4-amino-1-benzyl-2-hydroxy-5-phenylpentyl)carbamate

Product 1

HCID 392622Ritonavir

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

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%).

Workup

  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%)

Sources & evidence

ORD record
ord-aa3b3d2e28014527a3b5eb7c9a2d1a94
Source dataset
uspto-grants-2003_12
Patent number
US06667404B2

Reaction notes

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