Trifluoroacetic acid → HCID 16058764, compound

HRID 1943268Notes

Reaction equation

HRID 1943268 reaction equation
[CH2:1]([NH:3][C:4]([CH:6]1[CH2:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:13]([F:23])[CH:12]=2)(O)[CH2:7]1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>ClCCCl.CCO>[CH2:1]([NH:3][C:4]([CH:6]1[CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:13]([F:23])[CH:12]=2)[CH2:9]1)=[O:5])[CH3:2]

Participants

5

Reactant 2

HCID 6422Trifluoroacetic acidHCID 566482281337536-70-5

Product 1

HCID 16058764HCID 16058764, compoundYield 24.7%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 702EthanolSolvent

Conditions

Temperature
80 °C

Procedure

To Example 12, 3-(3-Fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-3-hydroxy-cyclobutanecarboxylic acid ethylamide (17 g, 53.1 mmol) in 200 mL of DCE at rt was added TFA (80.7 mL, 1.1 mol) and then the reaction was heated to 80° C. (oil bath). After 15 h the reaction was concentrated to approximately 45 g and used without further purification. The crude TFA salt from the above reaction was diluted with EtOH (500 mL), placed in a Parr bottle, purged with N2, and then 10% Pd/carbon (2.5 g, 14 wt %) was added. The resulting reaction mixture was hydrogenated with H2 (45 psi) at rt. After 1.5 h the reaction was purged with N2, then filtered through Celite™ and concentrated under reduced pressure. The resulting oil was diluted with EtOAc and then slowly quenched with a saturated solution of sodium bicarbonate. The layers were separated and the aqueous layer was back extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. Purification of this material was accomplished by re-crystallization. Crude title compound was taken up in a minimal amount of warm EtOAc and allowed to cool to approximately 0° C. (refrigerator). The solid was filtered, dried under reduced pressure to give the title compound (4 g, 24% yield) as a white solid: Rf=0.21 (10% MeOH/CH2Cl2); LRMS m/z Calcd for C18H25FN2O, 304.4, found, 305.3; 1H NMR (300 MHz, CDCl3): δ 7.30 (apt t, J=7.9 Hz, 1H), 6.98 (dd, J=7.9, 1.6 Hz, 1H), 6.92 (dd, J=12.0, 1.6 Hz, 1H), 5.36 (bs, 1H), 3.67 (s, 2H), 3.42-3.26 (m, 3H), 2.94-2.85 (m, 1H), 2.57-2.50 (m, 6H), 2.42-2.33 (m, 2H), 1.82-1.74 (m, 4H), 1.14 (t, J=7.5 Hz, 3H); structure confirmed by x-ray crystallography and was determined to be cis.

Workup

  1. concentrationAfter 15 h the reaction was concentrated to approximately 45 g
  2. customused without further purification
  3. customThe crude TFA salt from the above reaction
  4. custompurged with N2
  5. addition10% Pd/carbon (2.5 g, 14 wt %) was added
  6. customThe resulting reaction mixture
  7. customwas hydrogenated with H2 (45 psi) at rt
  8. customAfter 1.5 h the reaction was purged with N2
  9. filtrationfiltered through Celite™
  10. concentrationconcentrated under reduced pressure
  11. additionThe resulting oil was diluted with EtOAc
  12. customslowly quenched with a saturated solution of sodium bicarbonate
  13. customThe layers were separated
  14. extractionthe aqueous layer was back extracted with EtOAc
  15. dry with materialThe combined organic layers were dried over MgSO4
  16. filtrationfiltered
  17. concentrationconcentrated under reduced pressure
  18. customPurification of this material
  19. customwas accomplished by re-crystallization
  20. temperatureto cool to approximately 0° C. (refrigerator)
  21. filtrationThe solid was filtered
  22. customdried under reduced pressure

Sources & evidence

ORD record
ord-46f9d4749d05463da473b8e1d4d97440
Source dataset
uspto-grants-2013_03
Patent number
US08389743B2

Reaction notes

Loading…