Ethyl Acetate → 4-[4-(4-fluorophenyl)-1-{1-[(1R)-1-isoxazol-3-ylethyl]piperidin-4-yl}-1H-imidazol-5-yl]pyrimidine

HRID 1896658Notes

Reaction equation

HRID 1896658 reaction equation
CS(O[CH:6]([C:8]1[CH:12]=[CH:11][O:10][N:9]=1)[CH3:7])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:27]=[CH:28][N:29]([CH:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)[C:30]=2[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][N:32]=2)=[CH:22][CH:21]=1.C(OCC)(=O)C>CN(C=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[N:27]=[CH:28][N:29]([CH:37]3[CH2:42][CH2:41][N:40]([C@@H:6]([C:8]4[CH:12]=[CH:11][O:10][N:9]=4)[CH3:7])[CH2:39][CH2:38]3)[C:30]=2[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][N:32]=2)=[CH:24][CH:25]=1

Participants

6

Reactant 4

HCID 8857Ethyl AcetateHCID 10796Cesium carbonateHCID 574617131-Isoxazol-3-ylethyl methanesulfonateHCID 574617184-[4-(4-Fluorophenyl)-1-piperidin-4-yl-1H-imidazol-5-yl]pyrimidine

Product 1

HCID 574617264-[4-(4-fluorophenyl)-1-{1-[(1R)-1-isoxazol-3-ylethyl]piperidin-4-yl}-1H-imidazol-5-yl]pyrimidine

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of 1-isoxazol-3-ylethyl methanesulfonate (C7) (1.2 g, 6.3 mmol) in DMF (40 mL) was added cesium carbonate (1.5 g, 4.6 mmol) and 4-[4-(4-fluorophenyl)-1-piperidin-4-yl-1H-imidazol-5-yl]pyrimidine (C15) (600 mg, 1.86 mmol), and the reaction was stirred at 60° C. for 18 hours. Ethyl acetate (200 mL) was added, and the mixture was washed with water (3×40 mL), washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by preparative HPLC (Column: Phenomenex Luna, 250×50 mm; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 11% to 36% B) provided a mixture of the two enantiomeric products, which were separated by chiral HPLC (Column: Chiralcel OD, 250×20 mm, 10 μm; Mobile phase A: supercritical carbon dioxide; Mobile phase B: 2-propanol containing 0.05% diethylamine; Eluant: 60:40 A: B at 70 mL/minute) to provide 4-[4-(4-fluorophenyl)-1-{1-[(1R)-1-isoxazol-3-ylethyl]piperidin-4-yl}-1H-imidazol-5-yl]pyrimidine (9; absolute configuration is tentatively assigned) as a yellow oil (Yield: 30 mg, 0.072 mmol, 4%) [LCMS m/z 419.2 (M+1); 1H NMR (400 MHz, CDCl3) δ 1.47 (d, J=6.9 Hz, 3H), 1.93-2.06 (m, 2H), 2.12-2.28 (m, 4H), 2.98-3.05 (m, 2H), 3.96 (q, J=6.9 Hz, 1H), 4.60-4.68 (m, 1H), 6.34 (d, J=1.4 Hz, 1H), 7.02 (dd, J=8.7, 8.7 Hz, 2H), 7.15 (dd, J=5.3, 1.3 Hz, 1H), 7.40 (dd, J=8.8, 5.5 Hz, 2H), 7.83 (s, 1H), 8.38 (br s, 1H), 8.55 (d, J=5.3 Hz, 1H), 9.27 (br s, 1H); Retention time 2.81 minutes using a Chiralpak OD-H column (250×4.6 mm, 5 μm; Mobile phase A: supercritical carbon dioxide; Mobile phase B: 2-propanol containing 0.05% diethylamine; Gradient: 5% to 40% B)] and 4-[4-(4-fluorophenyl)-1-{1-[(1S)-1-isoxazol-3-ylethyl]piperidin-4-yl}-1H-imidazol-5-yl]pyrimidine (113; absolute configuration is tentatively assigned) as a yellow oil (Yield: 30 mg, 0.072 mmol, 4%) [LCMS m/z 419.1 (M+1); 1H NMR (400 MHz, CDCl3) δ 1.47 (d, J=6.9 Hz, 3H), 1.93-2.06 (m, 2H), 2.11-2.27 (m, 4H), 2.98-3.06 (m, 2H), 3.96 (q, J=6.9 Hz, 1H), 4.60-4.68 (m, 1H), 6.34 (d, J=1.5 Hz, 1H), 7.02 (dd, J=8.7, 8.7 Hz, 2H), 7.14 (br d, J=5.4 Hz, 1H), 7.39 (dd, J=8.7, 5.5 Hz, 2H), 7.83 (s, 1H), 8.39 (br s, 1H), 8.55 (d, J=5.3 Hz, 1H), 9.27 (br s, 1H); Retention time: 2.65 minutes, using a system identical to the analytical HPLC detailed above for the 1R enantiomer].

Workup

  1. washthe mixture was washed with water (3×40 mL)
  2. washwashed with saturated aqueous sodium chloride solution
  3. dry with materialdried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customPurification of the residue by preparative HPLC (Column: Phenomenex Luna, 250×50 mm; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 11% to 36% B)
  7. customprovided
  8. additiona mixture of the two enantiomeric products, which
  9. customwere separated by chiral HPLC (Column

Sources & evidence

ORD record
ord-baebf17e341e42fd94e394ac84d40806
Source dataset
uspto-grants-2013_08
Patent number
US08518944B2

Reaction notes

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