Trifluoroacetic acid → 3-Fluoro-1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid

HRID 1948524Notes

Reaction equation

HRID 1948524 reaction equation
[F:1][C:2]1(C#N)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.C(O)(C(F)(F)F)=O.[C:17](=[O:20])([O-])[O-:18].[Cs+].[Cs+].[O:23]1[CH2:25][CH:24]1[C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([C:37]3[O:41][N:40]=[C:39]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:38]=3[C:48]([F:51])([F:50])[F:49])[O:34][N:33]=2)=[CH:28][CH:27]=1>CC(O)C.CS(C)=O>[F:1][C:2]1([C:17]([OH:18])=[O:20])[CH2:7][CH2:6][CH2:5][N:4]([CH2:25][CH:24]([OH:23])[C:26]2[CH:31]=[CH:30][C:29]([C:32]3[N:36]=[C:35]([C:37]4[O:41][N:40]=[C:39]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[C:38]=4[C:48]([F:51])([F:50])[F:49])[O:34][N:33]=3)=[CH:28][CH:27]=2)[CH2:3]1

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 10796Cesium carbonateHCID 58374180HCID 58374180, compoundHCID 866563983-(4-(Oxiran-2-yl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole

Product 1

HCID 583741183-Fluoro-1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 3776IsopropanolSolvent

Conditions

Temperature
80 °C

Procedure

To a mixture of 3-fluoropiperidine-3-carbonitrile, TFA (55 mg, 0.227 mmol), and cesium carbonate (122 mg, 0.376 mmol) in 2-propanol (2 mL) and DMSO (0.5 mL) was added 3-(4-(oxiran-2-yl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole, Preparation 28C (30 mg, 0.075 mmol). The reaction mixture was heated at 80° C. over a weekend. The reaction mixture was purified by HPLC. The purified product was lyophilized and then was dissolved in MeCN/6N HCl and heated at 50° C. overnight. The 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. Isolated fractions with correct mass were freeze-dried overnight to yield 6 mgs of 3-fluoro-1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid as a TFA salt. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.14 (2H, d, J=7.91 Hz), 7.56-7.62 (4H, m), 7.44-7.56 (3H, m), 5.13-5.24 (1H, m), 3.86-4.28 (1H, m), 3.47-3.81 (2H, m), 3.25-3.41 (2H, m), 2.08-2.15 (3H, m), 1.87-2.02 (2H, m). MS (m+1)=547. HPLC Peak RT=3.32 minutes (Analytical Method A). Purity=98%.

Workup

  1. additionwas added
  2. customThe reaction mixture was purified by HPLC
  3. dissolutionwas dissolved in MeCN/6N HCl
  4. temperatureheated at 50° C. overnight
  5. filtrationThe mixture was filtered
  6. custompurified by HPLC
  7. custom25 minute
  8. customIsolated fractions with correct mass were freeze-dried overnight

Sources & evidence

ORD record
ord-1e2d4e3f9a7147719bf9350c987f59ef
Source dataset
uspto-grants-2013_03
Patent number
US08399451B2

Reaction notes

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