Diethyl Ether → 1-{1-[1(4-Chlorophenyl)ethyl]azetidin-3-ylidene}-1-(3,5difluorophenyl)-2-methylpropan-2-ol

HRID 602677Notes

Reaction equation

HRID 602677 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2C=CC=CC=2)[N:9]2[CH2:12][C:11](=[C:13]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)C(OC)=O)[CH2:10]2)=[CH:4][CH:3]=1.[CH3:32][Li].CC[O:36][CH2:37][CH3:38]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:9]2[CH2:10][C:11](=[C:13]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)[C:37]([CH3:38])([OH:36])[CH3:32])[CH2:12]2)[CH3:26])=[CH:4][CH:3]=1

Participants

4

Reactant 3

HCID 3283Diethyl EtherHCID 67065891Methyl {1-[(4-chlorophenyl)(phenyl)methyl]azetidin-3-ylidene}(3,5-difluorophenyl)acetateHCID 178418348HCID 178418348, compound2×

Product 1

HCID 114062781-{1-[1(4-Chlorophenyl)ethyl]azetidin-3-ylidene}-1-(3,5difluorophenyl)-2-methylpropan-2-ol

Conditions

Temperature
-78 °C

Procedure

A solution of 0.020 g (0.045 mmol) of methyl {1-[(4-chlorophenyl)(phenyl)methyl]azetidin-3-ylidene}(3,5-difluorophenyl)acetate in 5 mL dry ether was cooled to −78° C. under nitrogen. To this was added 0.1 mL of a 1M solution of methyllithium and the solution was stirred at −78° C. for 30 minutes. A second aliquot of 0.1 mL of a 1M solution of methyllithium was added and the solution was allowed to warm to 60° C. After 1 h, the reaction was quenched by addition of 5 mL water and the layers were separated. The aqueous layer was washed with three 10 mL portions of ethyl acetate and the organic extracts were combined, dried over Na2SO4 and concentrated. The residue was purified by reverse phase chromatography (Waters Xterra C18, 19 mm×10 mm) using a gradient of CH3CN—H2O-Et3N (20:80:0.1 to 60:40:0.1). Homogenous fractions were pooled and concentrated to afford the title compound; 1NMR (CDCl3) δ 0.8040.84 (m, 3H), 0.96-1.20 (m, 21), 1.16-1.23 (m, 2H), 1.35 (s, 3H), 1.36 (s, 3H), 1.40-1.66 (m, 21), 3.20-3.52 (m, 2H), 3.66-3.78 (m, 1H), 3.88-4.32 (m, 21), 6.64-6.80 (m, 3H), 7.20-7.32 (m, 2H); Mass Spectrum: m/e=422 (M+1 35Cl and 424 (M+1 37Cl).

Workup

  1. temperatureto warm to 60° C
  2. waitAfter 1 h
  3. customthe reaction was quenched by addition of 5 mL water
  4. customthe layers were separated
  5. washThe aqueous layer was washed with three 10 mL portions of ethyl acetate
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated
  8. customThe residue was purified by reverse phase chromatography (Waters Xterra C18, 19 mm×10 mm)
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-5da8e6d9a70240f1a08cb01032ddff1d
Source dataset
uspto-grants-2011_03
Patent number
US07906503B2

Reaction notes

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