1,3-Cyclopentanedione → 3-({[(1R,2R,3S,6S)-3-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-2-(4-fluorophenyl)-6-(hydroxymethyl)cyclohexyl]methyl}amino)cyclopent-2-en-1-one

HRID 2245244Notes

Reaction equation

HRID 2245244 reaction equation
C([O:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C@@H:13]([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[CH3:14])[C@@H:8]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C@@H:7]1[CH2:36][NH2:37])(=O)C.[C:38]1(=O)[CH2:42][CH2:41][C:40](=[O:43])[CH2:39]1>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[F:23][C:21]([F:24])([F:22])[C:19]1[CH:20]=[C:15]([C@H:13]([O:12][C@H:9]2[CH2:10][CH2:11][C@H:6]([CH2:5][OH:4])[C@@H:7]([CH2:36][NH:37][C:38]3[CH2:42][CH2:41][C:40](=[O:43])[CH:39]=3)[C@@H:8]2[C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[CH3:14])[CH:16]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:18]=1

Participants

5

Reactant 2

HCID 774661,3-CyclopentanedioneHCID 86628109HCID 86628109, compound

Product 1

HCID 866281103-({[(1R,2R,3S,6S)-3-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-2-(4-fluorophenyl)-6-(hydroxymethyl)cyclohexyl]methyl}amino)cyclopent-2-en-1-oneYield 32.2%

Reagents, catalysts & solvents 2

HCID 6101p-Toluenesulfonic acidCatalystHCID 1140TolueneSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of 0.35 g (0.65 mmol) of [(1S,2R,3R,4S)-2-(aminomethyl)-4-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)cyclohexyl]methyl acetate (from Step N) in 30 mL dry toluene was added cyclopentane-1,3-dione (0.064 g, 0.65 mmol) and a catalytic amount (˜0.5 mg) of PTSA. The resulting mixture was heated at reflux for 1 hr. The solvent was removed under vacuum and the residue was dissolved in 30 mL methanol. Sodium hydroxide (15 mL, 5 N) was added and the resulting mixture was stirred at 50° C. for 2 hr. The methanol and some of water were removed under vacuum. Water (20 mL) was added and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine, dried over Na2SO4 and the solvent was removed under vacuum. The residue was purified by prep. TLC (9:1 ethyl acetate:hexane) to give the title compound (0.12 g). 1H-NMR (CDCl3) δ: 7.70 (1H, s), 7.18 (2H, s), 6.98 (2H, m), 6.93 (2H, m), 5.18 (0.5H, bs), 4.67 (0.5H, bs), 4.22 (1H, m), 3.78 (1H, m), 3.47 (1H, m), 3.27 (1H, m), 3.07 (1H, m), 2.95 (1H, m), 2.30 (1H, t), 2.40-2.20 (5H, m), 1.90 (1H, m), 1.80 (1H, m), 1.70-1.20 (3H, m), 1.33 (3H, d, J=6.4 Hz). MS: (MH)+ 574.1.

Workup

  1. temperatureThe resulting mixture was heated
  2. temperatureat reflux for 1 hr
  3. customThe solvent was removed under vacuum
  4. dissolutionthe residue was dissolved in 30 mL methanol
  5. additionSodium hydroxide (15 mL, 5 N) was added
  6. customThe methanol and some of water were removed under vacuum
  7. additionWater (20 mL) was added
  8. extractionthe aqueous layer was extracted with ethyl acetate (3×20 mL)
  9. washThe combined extracts were washed with brine
  10. dry with materialdried over Na2SO4
  11. customthe solvent was removed under vacuum
  12. customThe residue was purified by prep

Sources & evidence

ORD record
ord-d59ac65d0b0f41ad9c175bd606338b48
Source dataset
uspto-grants-2010_03
Patent number
US07683068B2

Reaction notes

Loading…