2-Fluoro-2-methylpropanoic acid → 5-(1-fluoro-1-methylethyl)-3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-1,2,4-oxadiazole

HRID 639749Notes

Reaction equation

HRID 639749 reaction equation
[CH3:1][C:2]([F:7])([CH3:6])[C:3](O)=[O:4].O[N:9]=[C:10]([C:12]12[CH2:19][CH2:18][C:15]([C:20]3[N:24]([CH3:25])[C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]([F:35])([F:34])[F:33])=[N:22][N:21]=3)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)[NH2:11]>CN(C=O)C>[F:7][C:2]([C:3]1[O:4][N:11]=[C:10]([C:12]23[CH2:19][CH2:18][C:15]([C:20]4[N:24]([CH3:25])[C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:32]([F:35])([F:34])[F:33])=[N:22][N:21]=4)([CH2:16][CH2:17]2)[CH2:14][CH2:13]3)[N:9]=1)([CH3:6])[CH3:1]

Participants

4

Reactant 2

HCID 27828282-Fluoro-2-methylpropanoic acidHCID 72262919N-hydroxy-4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]octane-1-carboximidamide

Product 1

HCID 162223805-(1-fluoro-1-methylethyl)-3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-1,2,4-oxadiazole

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

A solution of 2-methyl-2-fluoropropionic acid (108 mg, 1.02 mmol) and 1′1′-carbonyldiimidazole (144 mg, 0.888 mmol) in anhydrous DMF (2.5 ml) was stirred at room temperature under nitrogen atmosphere for 30 min. To this was added N′-Hydroxy-4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]octane-1-carboximidamide (1-G) (139.5 mg, 0.355 mmol) and the solution stirred overnight under N2. The reaction was heated for 1.5 hr at 100° C. in a heat block. DMF was removed in vacuo and the solid was redissolved in CH3CN (4 ml). The product was purified by C-18 reverse phase chromatography eluting with 10-90% CH3CN (0.1% TFA)/water (0.1% TFA). The solvent was removed and the residue taken up in DCM and free-based from saturated aqueous sodium bicarbonate solution. The organic layers were dried over MgSO4 and filtered. The solvent was replaced with CH3CN/water and lyophilized to afford 5-(1-fluoro-1-methylethyl)-3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-1,2,4-oxadiazole (3-A) as a white solid. MS (ESI+)=464.13 (M+1). 1H NMR (500 MHz, CDCl3): δ 7.89-7.85 (m, 1H), 7.75-7.69 (m, 2H), 7.55 (t, 1H), 3.52 (s, 3H), 2.30 (dd, 6H), 2.15 (dd, 6H), 1.90 (s, 3H), 1.86 (s, 3H). Shh-Light II Assay: IC50: 4.2 μM.

Workup

  1. customDMF was removed in vacuo
  2. dissolutionthe solid was redissolved in CH3CN (4 ml)
  3. customThe product was purified by C-18 reverse phase chromatography
  4. washeluting with 10-90% CH3CN (0.1% TFA)/water (0.1% TFA)
  5. customThe solvent was removed
  6. dry with materialThe organic layers were dried over MgSO4
  7. filtrationfiltered

Sources & evidence

ORD record
ord-a876ae7441214812b1e04e90824b4409
Source dataset
uspto-grants-2010_04
Patent number
US07691887B2

Reaction notes

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