Triethylamine → (2R,3R)-3-Amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

HRID 2260513Notes

Reaction equation

HRID 2260513 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:21])([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C@@H:10](C)[C:11](O)=O.C([N:24](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C(O)(C)(C)C>[NH2:24][C@H:10]([CH3:11])[C@:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([OH:21])[CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 199401P,P-Diphenylphosphinic azideHCID 10040259(Alphar,betar)-beta-(2,4-difluorophenyl)-beta-hydroxy-alpha-methyl-1H-1,2,4-triazole-1-butanoic acid

Product 1

HCID 10967497(2R,3R)-3-Amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-olYield 41.2%

Reagents, catalysts & solvents 1

HCID 6386tert-ButanolSolvent

Conditions

Temperature
70 °C

Procedure

A solution of (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanoic acid (50 mg, 0.17 mmol) (obtained in reference example 30) and triethylamine (0.35 mL, 0.25 mmol) in tert-butanol (3 mL) was treated with diphenylphosphoryl azide (0.44 mL, 0.20 mmol) and the reaction mixture was heated at reflux for 25 h. Removal of the volatiles under reduced pressure afforded a crude product that was partitioned between chloroform and saturated NaHCO3 aqueous solution. The organic phase was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to a brown oil that was dissolved in methanol (2 mL) and 1N aqueous KOH (1 mL) and then heated at 70° C. during 15 h. The volatiles were removed in vacuo and the aqueous residue was acidified to pH 1 by addition of 1N aqueous HCl and washed with CHCl3. The aqueous phase was basified with saturated Na2CO3, saturated with NaCl and extracted (3x) with CHCl3. The collected organic phases were dried over anhydrous Na2SO4, the drying agent was filtered and the filtrate was concentrated to afford the title product (18.8 mg) pure by TLC analysis. An analytical sample was obtained by chromatography on silica gel (CHCl3 : MeOH 5:1) as a white solid.

Workup

  1. temperaturethe reaction mixture was heated
  2. temperatureat reflux for 25 h
  3. customRemoval of the volatiles under reduced pressure
  4. customafforded a crude product that
  5. customwas partitioned between chloroform and saturated NaHCO3 aqueous solution
  6. dry with materialThe organic phase was dried over anhydrous Na2SO4
  7. filtrationfiltered
  8. concentrationthe filtrate was concentrated in vacuo to a brown oil that
  9. dissolutionwas dissolved in methanol (2 mL)
  10. customThe volatiles were removed in vacuo
  11. additionthe aqueous residue was acidified to pH 1 by addition of 1N aqueous HCl
  12. washwashed with CHCl3
  13. extractionextracted (3x) with CHCl3
  14. dry with materialThe collected organic phases were dried over anhydrous Na2SO4
  15. filtrationthe drying agent was filtered
  16. concentrationthe filtrate was concentrated

Sources & evidence

ORD record
ord-683ca2af74e94310a68de16116328cda
Source dataset
uspto-grants-1995_12
Patent number
US05478826

Reaction notes

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