tert-Butanol → {4-[1-(4-pentafluoroethyloxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenyl}-carbamic acid tert-butyl ester

HRID 1189523Notes

Reaction equation

HRID 1189523 reaction equation
[F:1][C:2]([F:26])([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].Cl[C:28]([O:30][C:31]1[CH:36]=CC([N+]([O-])=O)=C[CH:32]=1)=[O:29].[N+]([C:43]1C=CC(NC(=O)[O-])=CC=1)([O-])=O.CC(O)(C)C.[H-].[Na+]>C1COCC1>[C:31]([O:30][C:28](=[O:29])[NH:25][C:22]1[CH:23]=[CH:24][C:19]([C:16]2[N:17]=[CH:18][N:14]([C:11]3[CH:12]=[CH:13][C:8]([O:7][C:2]([F:1])([F:26])[C:3]([F:6])([F:5])[F:4])=[CH:9][CH:10]=3)[N:15]=2)=[CH:20][CH:21]=1)([CH3:36])([CH3:43])[CH3:32]

Participants

7

Reactant 5

HCID 6386tert-ButanolHCID 24758Sodium hydrideHCID 821294-Nitrophenyl chloroformateHCID 22371666N-(4-nitrophenyl)carbamateHCID 78210229HCID 78210229, compound

Product 1

HCID 86668344{4-[1-(4-pentafluoroethyloxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenyl}-carbamic acid tert-butyl esterYield 23.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent4×

Conditions

Temperature
60 °C

Procedure

A solution of 4-[1-(4-pentafluoroethyloxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenylamine (1.0 g, 2.7 mmol) in dry THF (8 mL) was stirred while p-nitrophenyl chloroformate (0.60 g, 3 mmol) was added in one portion and the solution was allowed to stir for 3 h. The resulting solid was filtered and air-dried. A smaller portion of the p-nitrophenylcarbamate (152 mg, 0.28 mmol) was suspended in dry THF (3 mL). To this were added 2-methyl-2-propanol (41 mg, 0.32 mmol) in dry THF (1 mL) followed by NaH (60% mineral oil dispersion; 26 mg, 0.67 mmol) in one portion. Additional dry THF (1 mL) was used to rinse joints, etc. The solution was heated to 60° C. (external) for 1.5 h, at which point TLC (3:3:3:1 EtOAc/hexanes/CH2Cl2/acetone) showed no starting material. The mixture was cooled and allowed to stir at 25° C. for 20 h. The mixture was cooled, poured on to ice-water (50 mL), and extracted with EtOAc (3×50 mL). The combined extracts were washed with satd aq NaCl (75 mL), dried (Na2SO4), filtered and concentrated. RP-HPLC (acid-free medium water-acetonitrile gradient) provided the title compound (31 mg, 23%) as an off-white solid: mp 205-209° C.; 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.12 (d, J=9.0 Hz, 2H), 7.80 (d, J=9.3 Hz, 2H), 7.48 (d, J=8.8 Hz, 2H), 7.38 (d, J=9.0 Hz, 2H), 6.58 (s, 1H), 1.54 (s, 9H); ESIMS m/z 471 (M+H), 469 (M−H). Compound 2 in Table 1 was synthesized as in Example 56.

Workup

  1. additionwas added in one portion
  2. filtrationThe resulting solid was filtered
  3. customair-dried
  4. washto rinse joints, etc. The solution
  5. temperatureThe mixture was cooled
  6. stirringto stir at 25° C. for 20 h
  7. temperatureThe mixture was cooled
  8. additionpoured on to ice-water (50 mL)
  9. extractionextracted with EtOAc (3×50 mL)
  10. washThe combined extracts were washed with satd aq NaCl (75 mL)
  11. dry with materialdried (Na2SO4)
  12. filtrationfiltered
  13. concentrationconcentrated

Sources & evidence

ORD record
ord-86856258f0d045de82efc9e4cfa57cc0
Source dataset
uspto-grants-2014_03
Patent number
US08674109B2

Reaction notes

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