Dicyclohexylcarbodiimide → Ritonavir

HRID 1457154Notes

Reaction equation

HRID 1457154 reaction equation
[CH3:1][N:2]([C:12]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[S:7][CH:8]=1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:47][C@@H:48]([CH2:70][C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)[CH2:49][C@H:50]([OH:69])[C@@H:51]([NH:59][C:60]([O:62][CH2:63][C:64]1[S:68][CH:67]=[N:66][CH:65]=1)=[O:61])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.C1C=CC2N(O)N=NC=2C=1>C1COCC1.Cl>[CH3:1][N:2]([C:12]([NH:14][C@H:15]([C:19]([NH:47][C@@H:48]([CH2:70][C:71]1[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=1)[CH2:49][C@H:50]([OH:69])[C@@H:51]([NH:59][C:60]([O:62][CH2:63][C:64]1[S:68][CH:67]=[N:66][CH:65]=1)=[O:61])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:21])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:10])[CH3:11])[S:7][CH:8]=1

Participants

8

Reactant 5

HCID 10868DicyclohexylcarbodiimideHCID 757711-HydroxybenzotriazoleHCID 9818282UreidovalineHCID 111019781,3-Thiazol-5-ylmethyl N-((1S,2S,4S)-4-amino-1-benzyl-2-hydroxy-5-phenylpentyl)carbamateHCID 178418300HCID 178418300, compound

Product 1

HCID 392622RitonavirYield 99.5%

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine (4.13 g, 13.18 mmole) and hydroxybenztriazole (2.23 g, 16.48 mmoles) were dissolved in 70 mL THF and then dicyclohexyl-carbodiimide(2.71 g, 13.18 mmoles) was added in one portion to the stirred solution under nitrogen atmosphere. This mixture was stirred for 4 h at room temperature and then filtered to remove dicyclohexylurea precipitate. The product of Example 69B (5.1 g, 11.99 mmoles) was dissolved in 100 mL THF under nitrogen atmosphere. To this stirred solution was added the filtrate of HOBT-active ester and the resulting solution was stirred at room temperature for 4 h, and the solvent removed via rotary evaporation. The residue was dissolved in 150 mL ethyl acetate and washed with 2×100 mL 1N NaOH, 100 mL brine, 100 mL of 1% w/w aqueous KHSO4 and the solvent was removed by rotary evaporation to afford a residue. The residue was dissolved in 175 mL 1N HCl, and the solution filtered to remove the small quantity of dicyclohexylurea. The filtrate solution was added to 175 mL ethyl acetate and the two phase mixture rapidly mixed. The pH of this rapidly stirred mixture was adjusted to pH=7 by dropwise addition of cold 3N NaOH. The organic layer was isolated, washed with 100 mL brine, dried over Na2 SO4, filtered, and the solvent was removed to afford 8.6 g of a colorless foam. This material was crystallized from 42 mL EtOAc and 21 mL hexane to give 7.85 g of the desired product as a white solid. mp=122°-123° C. CIMS m/z 721 (M+H)+.

Workup

  1. filtrationfiltered
  2. customto remove dicyclohexylurea precipitate
  3. stirringthe resulting solution was stirred at room temperature for 4 h
  4. customthe solvent removed via rotary evaporation
  5. dissolutionThe residue was dissolved in 150 mL ethyl acetate
  6. washwashed with 2×100 mL 1N NaOH, 100 mL brine, 100 mL of 1% w/w aqueous KHSO4
  7. customthe solvent was removed by rotary evaporation
  8. customto afford a residue
  9. filtrationthe solution filtered
  10. customto remove the small quantity of dicyclohexylurea
  11. additionThe filtrate solution was added to 175 mL ethyl acetate
  12. additionthe two phase mixture rapidly mixed
  13. additionThe pH of this rapidly stirred mixture was adjusted to pH=7 by dropwise addition of cold 3N NaOH
  14. customThe organic layer was isolated
  15. washwashed with 100 mL brine
  16. customdried over Na2 SO4
  17. filtrationfiltered
  18. customthe solvent was removed

Sources & evidence

ORD record
ord-e879310699e04f489ce2f1af832609a1
Source dataset
uspto-grants-1998_12
Patent number
US05846987

Reaction notes

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