Water → 2-[2-Fluoro-4-(methylthio)phenyl]-5-[(1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]pyrazine

HRID 423654Notes

Reaction equation

HRID 423654 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[CH:12][C:13]([OH:16])=[N:14][CH:15]=1.CS(O[C@@H:22]([CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[O:34][N:33]=[C:32]([CH:35]([CH3:37])[CH3:36])[N:31]=2)[CH2:26][CH2:25]1)[CH3:23])(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[N:14][C:13]([O:16][CH:22]([CH:24]2[CH2:25][CH2:26][N:27]([C:30]3[O:34][N:33]=[C:32]([CH:35]([CH3:36])[CH3:37])[N:31]=3)[CH2:28][CH2:29]2)[CH3:23])=[CH:12][N:11]=1

Participants

6

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 86638749(1R)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl methanesulfonateHCID 178503116HCID 178503116, compound

Product 1

HCID 666731972-[2-Fluoro-4-(methylthio)phenyl]-5-[(1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]pyrazineYield 43%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 5-[2-fluoro-4-(methylthio)phenyl]-2-pyrazinol (and tautomers thereof) (prepared as in Example 161, Alternative synthesis, Step 4, 0.40 g, 1.69 mmol), crude (1R)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl methanesulfonate (0.75 g, 2.29 mmol) and K2CO3 (0.48 g, 3.39 mmol) in DMF (16 mL) was stirred at 100° C. in a preheated oil bath overnight. The mixture was cooled to ambient temperature, treated with water, and the mixture was extracted with EtOAc (60 mL×2). The combined organic extract was washed with water, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to a brown oil, which was purified by chromatography on an ISCO silica gel column using 0 to 30% EtOAc/hexanes to give 0.335 g (43%) of 2-[2-fluoro-4-(methylthio)phenyl]-5-[(1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]pyrazine as a yellow viscous oil. 1H NMR (400 MHz, CDCl3): δ 8.52 (s, 1H), 8.23 (d, 1H, J=1.0 Hz), 7.85 (t, 1H, J=8.2 Hz), 7.10 (dd, 1H, Ja=8.3 Hz, Jb=1.7 Hz), 7.00 (dd, 1H, Ja=12.1 Hz, Jb=1.6 Hz), 5.20-5.05 (m, 1H), 4.25-4.15 (m, 2H), 3.10-2.95 (m, 2H), 2.87 (septet, 1H, J=6.9 Hz), 2.50 (s, 3H), 2.00-1.75 (m, 3H), 1.55-1.40 (m, 2H), 1.33 (d, 3H, J=6.4 Hz), 1.26 (d, 6H, J=6.9 Hz); LRMS (ESI), m/z 458 (M+H).

Workup

  1. temperatureThe mixture was cooled to ambient temperature
  2. extractionthe mixture was extracted with EtOAc (60 mL×2)
  3. extractionThe combined organic extract
  4. washwas washed with water, brine
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationthe filtrate was concentrated to a brown oil, which
  8. customwas purified by chromatography on an ISCO silica gel column

Sources & evidence

ORD record
ord-57f1a291bddd411b9e386b1ff864ce09
Source dataset
uspto-grants-2012_01
Patent number
US08101634B2

Reaction notes

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