Acetic Acid → 3-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-3-oxo-1-phenylpropyl acetate

HRID 1874195Notes

Reaction equation

HRID 1874195 reaction equation
[C:1]1([CH:7]2[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:10](S(C(F)(F)F)(=O)=O)[Li].[F:19][C:20]1[CH:25]=[C:24]([O:26][C:27]([F:32])([F:31])[CH:28]([F:30])[F:29])[CH:23]=[C:22]([C@@:33]([C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)([N+:41]#[C-:42])[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:21]=1.[C:50](O)(=[O:52])[CH3:51]>C1COCC1.CCOC(C)=O>[C:50]([O:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:9][C:42]([NH:41][C@@:33]([C:22]1[CH:23]=[C:24]([O:26][C:27]([F:32])([F:31])[CH:28]([F:30])[F:29])[CH:25]=[C:20]([F:19])[CH:21]=1)([C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:10])(=[O:52])[CH3:51]

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 7276Styrene OxideHCID 59458942(R)-1-fluoro-3-(1-(4-fluorophenyl)-1-isocyano-2-phenylethyl)-5-(1,1,2,2-tetrafluoroethoxy)benzeneHCID 178506959HCID 178506959, compound

Product 1

HCID 235828663-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-3-oxo-1-phenylpropyl acetateYield 62%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 2-phenyloxirane (0.009 mL, 0.08 mmol) in THF (1.5 ml) was added LiOTf (12 mg, 0.08 mmol), (R)-1-fluoro-3-(1-(4-fluorophenyl)-1-isocyano-2-phenylethyl)-5-(1,1,2,2-tetrafluoroethoxy)benzene (30 mg, 0.07 mmol) and acetic acid (0.004 mL, 0.08 mmol) in succession. The reaction mixture was heated to reflux for 3 h. The reaction was allowed to cool to rt and diluted with EtOAc (15 mL). The organic layer was washed with sat. NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude mixture was purified by preparative HPLC YMC ODS S5 30×100 mm column 30-100% MeOH (90% in water, 0.1% TFA) gradient over 10 min with flow rate 40 mL/min and UV detection at 220 nm to yield 3-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-3-oxo-1-phenylpropyl acetate (Example 265) as a white solid (26 mg, yield 62%, 1:1 RR:RS diastereomer mixture). LCMS: RT=2.19 min [M+H] 616.3 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=4.27 min, Purity 100% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm); 1H NMR (400 MHz, CDCl3) δ ppm 1.96 (d, J=4.95 Hz, 3H), 3.01 (ddd, J=14.30, 6.87, 3.02 Hz, 1H), 3.14 (td, J=8.94, 5.22 Hz, 1H), 3.523 (d, J=13.2 Hz, 0.5H), 3.62 (m, 0.5H), 3.72 (m, 0.5H), 3.82 (d, J=13.2 Hz, 0.5H), 5.30-5.34 (m, 1H), 5.74-5.97 (m, 1H), 6.46-6.53 (m, 2H), 6.60 (d, J=10.45 Hz, 1H), 6.67-6.72 (m, 1H), 6.80-7.31 (m, 13H).

Workup

  1. temperatureThe reaction mixture was heated
  2. temperatureto reflux for 3 h
  3. washThe organic layer was washed with sat. NaCl
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe resulting crude mixture was purified by preparative HPLC YMC ODS

Sources & evidence

ORD record
ord-0ca7004758064edd801e68cb920ec20e
Source dataset
uspto-grants-2012_11
Patent number
US08304403B2

Reaction notes

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