Perfluoro-1-butanesulfonyl fluoride → 2-(4-tert-butylphenyl)-N-{(S)-[1-(2-fluoro-1,1-dimethylethyl)-1H-1,2,3-triazol-4-yl][5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}acetamide

HRID 877362Notes

Reaction equation

HRID 877362 reaction equation
[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][C@@H:15]([C:28]2[N:29]=[N:30][N:31]([C:33]([CH3:37])([CH3:36])[CH2:34]O)[CH:32]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][N:17]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.F.F.F.C(N(CC)C(C)C)(C)C.[F:59]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F>CC#N>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][C@@H:15]([C:28]2[N:29]=[N:30][N:31]([C:33]([CH3:37])([CH3:36])[CH2:34][F:59])[CH:32]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:25])[F:26])=[CH:18][N:17]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:4])[CH3:3]

Participants

6

Reactant 4

HCID 67814Perfluoro-1-butanesulfonyl fluoride3×HCID 81531DiisopropylethylamineHCID 45108321N-Ethyl-N-(propan-2-yl)propan-2-amine--hydrogen fluoride (1/3)2×HCID 681566482-(4-tert-butylphenyl)-N-{(S)-[1-(2-hydroxy-1,1-dimethylethyl)-1H-1,2,3-triazol-4-yl][5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}acetamide

Product 1

HCID 671698542-(4-tert-butylphenyl)-N-{(S)-[1-(2-fluoro-1,1-dimethylethyl)-1H-1,2,3-triazol-4-yl][5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}acetamideYield 16%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
45 °C

Procedure

To a solution of 0.02 g (0.04 mmol) 2-(4-tert-butylphenyl)-N-{(S)-[1-(2-hydroxy-1,1-dimethylethyl)-1H-1,2,3-triazol-4-yl][5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}acetamide in 0.20 ml CH3CN at rt was added 0.02 ml (0.13 mmol) DIEA, 0.009 ml (0.05 mmol) N,N-diisopropylethylamine trihydrofluoride, and 0.007 ml (0.04 mmol) perfluoro-1-butanesulfonyl fluoride (PBSF). After 2 h at room temperature, 0.007 ml (0.04 mmol) PBSF was added to the reaction mixture and the reaction was heated to 45° C. After 18 h at 45° C., the reaction temperature was increased to 60° C. After 4 h at 60° C., add 0.009 ml (0.05 mmol) N,N,-diisopropylethylamine trihydrofluoride and 0.007 ml (0.04 mmol) PBSF and continue heating. After 24 h, the reaction is still incomplete. At this point, the reaction mixture was quenched with water, filtered through a plug of silica and concentrated in vacuo. Purification by preparative HPLC (5->95% CH3CN/H2O over 15 min, 0.05% added TFA, C18) afforded 0.003 g (16%) 2-(4-tert-butylphenyl)-N-{(S)-[1-(2-fluoro-1,1-dimethylethyl)-1H-1,2,3-triazol-4-yl][5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}acetamide. ES-MS [M+1]+=522.3. 1H NMR (CDCl3, 400 MHz) 8.24 (d, 1H, J=2.65 Hz); 7.57 (s, 1H); 7.40-7.30 (m, 3H); 7.31-7.22 (m, 3H); 4.57-4.46 (d, 1H, J=47.2 Hz); 4.41 (q, 2H, J=8.06 Hz); 3.63 (s, 2H); 1.63 (s, 6H); 1.32 (s, 9H).

Workup

  1. waitAfter 18 h at 45° C.
  2. temperaturethe reaction temperature was increased to 60° C
  3. waitAfter 4 h at 60° C.
  4. temperaturecontinue heating
  5. waitAfter 24 h
  6. customAt this point, the reaction mixture was quenched with water
  7. filtrationfiltered through a plug of silica
  8. concentrationconcentrated in vacuo
  9. customPurification
  10. additionby preparative HPLC (5->95% CH3CN/H2O over 15 min, 0.05% added TFA, C18)

Sources & evidence

ORD record
ord-a5becf45f99a49ab8e75ab608a5a72bd
Source dataset
uspto-grants-2015_03
Patent number
US08987310B2

Reaction notes

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