Ethanol, 1-ethoxy-2,2,2-trifluoro- → HCID 68224079, compound

HRID 1400801Notes

Reaction equation

HRID 1400801 reaction equation
[NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])C(=O)OC(C)(C)C)=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1.[CH2:38]([O:40][CH:41](O)[C:42]([F:45])([F:44])[F:43])[CH3:39]>CCO>[CH2:38]([O:40][CH:41]([NH:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([CH2:22][NH:23][CH2:31][CH2:32][O:33][CH3:34])=[CH:20][N:21]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1)[C:42]([F:45])([F:44])[F:43])[CH3:39]

Participants

4

Reactant 2

HCID 9897Ethanol, 1-ethoxy-2,2,2-trifluoro-4×HCID 579194724-[[2-[5-[[Boc(2-methoxyethyl)amino]methyl]-2-pyridyl]-7-thieno[3,2-b]pyridyl]oxy]-3-fluoroaniline

Product 1

HCID 68224079HCID 68224079, compoundYield 76.2%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

A solution of 11 (2 g, 3.62 mmol), PTSA monohydrate (0.76 g, 3.98 mmol) and trifluoroacetaldehyde ethyl hemiacetal (2.38 mL, 18.11 mmol) in EtOH (50 mL) was heated to reflux overnight. More trifluoroacetaldehyde ethyl hemiacetal (1.2 mL, 9.13 mmol) was added and the reaction mixture was heated to reflux overnight. Once again, more trifluoroacetaldehyde ethyl hemiacetal (2 mL, 15.22 mmol) were added and the reaction mixture was heated to reflux overnight. Finally, another portion of trifluoroacetaldehyde ethyl hemiacetal (2 mL, 15.22 mmol) and PTSA monohydrate (0.76 g, 3.98 mmol) were added and the reaction mixture was heated to reflux for 5 days. The reaction mixture was concentrated and partitioned between AcOEt and water. The organic layer was successively washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 100 g cartridge; MeOH/DCM: 0/100 to 10/90 over 20 CV), to afford the title compound 14 (1.519 g, 2.76 mmol, 76% yield) as a pale orange sticky solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.56 (d, J=1.4 Hz, 1H), 8.50 (d, J=5.5 Hz, 1H), 8.30 (s, 1H), 8.22 (d, J=8.0 Hz, 1H), 7.89 (dd, J=8.0, 2.2 Hz, 1H), 7.31 (t, J=9.1 Hz, 1H), 7.11-7.02 (m, 2H), 6.87 (dd, J=9.0, 1.8 Hz, 1H), 6.62 (dd, J=5.3, 0.8 Hz, 1H), 5.73-5.64 (m, 1H), 3.78 (s, 2H), 3.77-3.59 (m, 2H), 3.41 (t, J=5.7 Hz, 2H), 3.24 (s, 3H), 2.65 (t, J=5.7 Hz, 2H), 1.15 (t, J=7.0 Hz, 31-1), one NH proton is missing. MS (m/z): 551.6 (M+H).

Workup

  1. temperatureto reflux overnight
  2. temperaturethe reaction mixture was heated
  3. temperatureto reflux overnight
  4. temperaturethe reaction mixture was heated
  5. temperatureto reflux overnight
  6. temperaturethe reaction mixture was heated
  7. temperatureto reflux for 5 days
  8. concentrationThe reaction mixture was concentrated
  9. custompartitioned between AcOEt and water
  10. washThe organic layer was successively washed with a saturated aqueous solution of sodium bicarbonate and brine
  11. dry with materialdried over anhydrous magnesium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customThe residue was purified by Biotage (SNAP 100 g cartridge; MeOH/DCM: 0/100 to 10/90 over 20 CV)

Sources & evidence

ORD record
ord-f59cb5f6d4c8431abd6907fd889816bb
Source dataset
uspto-grants-2014_12
Patent number
US08906852B2

Reaction notes

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