p-Toluenesulfonic acid → HCID 11306618, compound

HRID 2377035Notes

Reaction equation

HRID 2377035 reaction equation
[C:1]1(=O)[CH2:5][CH2:4][C:3](=[O:6])[CH2:2]1.[F:8][C:9]([F:36])([F:35])[C:10]1[CH:11]=[C:12]([C@H:20]([O:22][C@@H:23]2[C@@H:27]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:26][NH:25][CH2:24]2)[CH3:21])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:36][C:9]([F:8])([F:35])[C:10]1[CH:11]=[C:12]([C@H:20]([O:22][C@@H:23]2[C@@H:27]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH2:26][N:25]([C:1]3[CH2:5][CH2:4][C:3](=[O:6])[CH:2]=3)[CH2:24]2)[CH3:21])[CH:13]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:15]=1

Participants

5

Reactant 3

HCID 6101p-Toluenesulfonic acidHCID 774661,3-CyclopentanedioneHCID 86610908HCID 86610908, compound

Product 1

HCID 11306618HCID 11306618, compound

Reagents, catalysts & solvents 1

HCID 241BenzeneSolvent

Procedure

In a pressure tube was placed 562 mg cyclopentane-1,3-dione (5.73 mmol) followed by a solution of 2.3 g (3R,4S)-3-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-fluorophenyl)pyrrolidine (5.46 mmol) (step E) in 12.5 mL benzene. To this solution was added 52 mg PTSA (0.027 mmol) and 4 Å bead molecular sieves (1 g). The tube was sealed and heated for 3 hr. The tube was cooled to RT and the resulting solution filtered and the solvent removed under vacuum. The resulting bright yellow oil was purified by column chromatography on silica gel eluting with EtOAc/hexanes (1/1), then EtOAc (100%), then methylene chloride/methanol (9/1). The fractions containing the desired product (as determined by TLC) were combined and the solvent removed under vacuum. The resulting yellow oil was purified by prep HPLC on Chiralcel OD eluting with heptanes/reagent alcohol (87.5/12.5) to afford the title compound as a white solid. 1H-NMR (CD3OD) rotamers: δ: 1.43 (d, 3H, 6.5 Hz), 2.46 (m, 2H), 2.7-2.85 (m, 2H), 3.40-3.65 (m, 3H), 3.78-4.20 (m, 3H), 4.76 (quin., 1H, 6.5 Hz), 4.97, 5.03 (2s 1H), 6.98 (t, 2H), 7.18 (br. s, 2H), 7.72 (s, 2H), 7.83 (s, 1H)ppm. MS: 502.2 (MH+) observed. Crystallization of 3-[(3R,4S)-3-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-fluorophenyl)pyrrolidin-1-yl]cyclopent-2-en-1-one was achieved in aq. methanol (mp 45-46° C.). Alternatively, crystalline solid was obtained by crystallization in ether/hexanes mixture (mp 44-45° C.).

Workup

  1. customIn a pressure tube was placed
  2. customThe tube was sealed
  3. temperatureheated for 3 hr
  4. filtrationthe resulting solution filtered
  5. customthe solvent removed under vacuum
  6. customThe resulting bright yellow oil was purified by column chromatography on silica gel eluting with EtOAc/hexanes (1/1)
  7. additionThe fractions containing the desired product (as determined by TLC)
  8. customthe solvent removed under vacuum
  9. customThe resulting yellow oil was purified by prep HPLC on Chiralcel OD
  10. washeluting with heptanes/reagent alcohol (87.5/12.5)

Sources & evidence

ORD record
ord-8590fdeb31f0458fae9dd64cc97ae70a
Source dataset
uspto-grants-2008_12
Patent number
US07468437B2

Reaction notes

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