Cesium carbonate → 2-(1-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)-2-methylpropanoic acid

HRID 1948539Notes

Reaction equation

HRID 1948539 reaction equation
[O:1]1[CH2:3][C@@H:2]1[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:16]=3[C:26]([F:29])([F:28])[F:27])[O:12][N:11]=2)=[CH:6][CH:5]=1.[CH3:30][C:31]([CH:38]1[CH2:43][CH2:42][CH2:41][NH:40][CH2:39]1)([CH3:37])[C:32]([O:34]CC)=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CCO>[OH:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:16]=3[C:26]([F:28])([F:27])[F:29])[O:12][N:11]=2)=[CH:8][CH:9]=1)[CH2:3][N:40]1[CH2:41][CH2:42][CH2:43][CH:38]([C:31]([CH3:37])([CH3:30])[C:32]([OH:34])=[O:33])[CH2:39]1

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 59830632HCID 59830632, compoundHCID 87214277HCID 87214277, compound

Product 1

HCID 669556822-(1-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)-2-methylpropanoic acid

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
80 °C

Procedure

To a mixture of (S)-3-(4-(oxiran-2-yl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole, Preparation 28C-peak 1 (30 mg, 0.075 mmol) and ethyl 2-methyl-2-(piperidin-3-yl)propanoate (14.97 mg, 0.075 mmol) in EtOH (10 mL) was added cesium carbonate (147 mg, 0.451 mmol). The reaction mixture was heated at 80° C. overnight. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Fractions with correct mass were isolated and concentrated in vacuo. This residue was heated in 6N HCl/dioxane (1:1) at 60° C. for 3 days. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Fractions with correct mass were isolated and freeze-dried overnight. Obtained 6 mg of 2-(1-((S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)-2-methylpropanoic. 1H NMR (400 MHz, MeOD) δ ppm 8.14 (2H, d, J=8.36 Hz), 7.57-7.64 (4H, m), 7.44-7.55 (3H, m), 5.09-5.27 (1H, m), 3.70 (2H, d, J=10.34 Hz), 3.57 (1H, br. s.), 3.23-3.27 (2H, m), 2.79-2.97 (1H, m), 1.73-1.95 (2H, m), 1.24-1.42 (2H, m), 1.15 (3H, d, J=2.86 Hz), 1.11 (3H, s), 0.76 (1H, dd, J=11.44, 9.68 Hz). MS (m+1)=571 HPLC Peak RT=3.35 minutes (Analytical Method A). Purity=92%.

Workup

  1. filtrationThe reaction mixture was filtered
  2. custompurified by HPLC
  3. custom25 minute
  4. customFractions with correct mass were isolated
  5. concentrationconcentrated in vacuo
  6. temperatureThis residue was heated in 6N HCl/dioxane (1:1) at 60° C. for 3 days
  7. filtrationThe reaction mixture was filtered
  8. custompurified by HPLC
  9. custom25 minute
  10. customFractions with correct mass were isolated
  11. customfreeze-dried overnight
  12. customObtained 6 mg of 2-(1-((S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)-2-methylpropanoic

Sources & evidence

ORD record
ord-36708a6af7934f68963044021e027d16
Source dataset
uspto-grants-2013_03
Patent number
US08399451B2

Reaction notes

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