Trichloroacetimidic acid (S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl ester → HCID 86610904, compound

HRID 2377027Notes

Reaction equation

HRID 2377027 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:10]([OH:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]([F:42])([F:41])[C:22]1[CH:23]=[C:24]([C@@H:32](OC(=N)C(Cl)(Cl)Cl)[CH3:33])[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1>C(Cl)Cl>[F:20][C:21]([F:41])([F:42])[C:22]1[CH:23]=[C:24]([C@H:32]([O:19][C@@H:10]2[C@@H:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2)[CH3:33])[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=1

Participants

4

Reactant 2

HCID 11611082Trichloroacetimidic acid (S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl esterHCID 59856271HCID 59856271, compound

Product 1

HCID 86610904HCID 86610904, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of 1.0 g (3.8 mmol) (3R,4S) tert-butyl-3-hydroxy-4-phenylpyrrolidine-1-carboxylate (Step B) and 3 g (7.6 mmol, 2 equiv) (S)-trichloroacetimidate (step C) in 40 mL dry heptanes and 10 mL dry methylene chloride under nitrogen atmosphere at 0° C. was added dropwise 0.092 mL (0.8 mmol, 0.2 equiv) HBF4-dimethyl ether complex. The resulting reaction mixture was stirred at 0° C. for 24 hr. The volatiles were removed under vacuum and the residue dissolved in 10 mL methylene chloride and purified by column chromatography on silica gel eluting with hexanes/EtOAc (8/2) to afford a mixture of two products. This mixture was further purified by preparative HPLC on ChiralPak OD column eluting with heptanes/ethanol (98/2) to obtain the minor isomer (epimeric at the benzylic methyl position) and the title compound. 1H-NMR (CDCl3): (rotamers): δ: 1.43-45 (2d, 3H, 6.5 Hz), 1.49-1.52 (2s, 9H), 3.3-3.5 (m, 3H), 3.73-3.97 (m, 3H), 4.53 (q, 1H, 6.5 Hz), 7.06-7.09 (m, 2H), 7.20-7.25 (m, 3H), 7.55 (m, 2H), 7.74 (s, 1H), 7.75 (s, 2H)ppm. MS: 447.9 (M-t-Bu)+ observed.

Workup

  1. customThe resulting reaction mixture
  2. customThe volatiles were removed under vacuum
  3. dissolutionthe residue dissolved in 10 mL methylene chloride
  4. custompurified by column chromatography on silica gel eluting with hexanes/EtOAc (8/2)
  5. customto afford
  6. additiona mixture of two products
  7. customThis mixture was further purified by preparative HPLC on ChiralPak OD column
  8. washeluting with heptanes/ethanol (98/2)

Sources & evidence

ORD record
ord-0779cd21cd04411da66e92399ccc721a
Source dataset
uspto-grants-2008_12
Patent number
US07468437B2

Reaction notes

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