Potassium Phosphate, Tribasic → 2-[4-(3-methylpyrazin-2-yl)phenyl]-N-[(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl]acetamide

HRID 474148Notes

Reaction equation

HRID 474148 reaction equation
CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:18][C@@H:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:23][N:22]=3)[CH3:20])=[O:17])=[CH:11][CH:10]=2)O1.Cl[C:35]1[C:40]([CH3:41])=[N:39][CH:38]=[CH:37][N:36]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[CH3:41][C:40]1[C:35]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:18][C@@H:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([F:31])([F:32])[F:30])=[CH:23][N:22]=3)[CH3:20])=[O:17])=[CH:11][CH:10]=2)=[N:36][CH:37]=[CH:38][N:39]=1

Participants

7

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 66769Pyrazine, 2-chloro-3-methyl-HCID 684960762-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide

Product 1

HCID 426099622-[4-(3-methylpyrazin-2-yl)phenyl]-N-[(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl]acetamideYield 73.5%

Reagents, catalysts & solvents 3

HCID 75806TricyclohexylphosphineCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Procedure

To a solution of 1.00 g (2.15 mmol) 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide in 5.70 ml dioxane was added 0.31 g (2.58 mmol) 2-chloro-3-methylpyrazine, 0.014 mg (0.052 mmol) tricyclohexylphosphine, 0.020 g (0.022 mmol) Pd2dba3, and 2.88 mL (3.66 mmol) 1.7M potassium phosphate. The resulting suspension was degassed for 10mins. After 30 min in the microwave at 150° C., the reaction mixture was cooled, extracted with ethyl acetate, and washed with brine. The organic layer was dried over NaSO4, filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, linear gradient 30-100% EtOAc:hexane) followed by purification by reverse phase chromatography afforded 0.68 g (73.3%) 2-[4-(3-methylpyrazin-2-yl)phenyl]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide. 1H NMR (CDCl3, 400 MHz) 8.49 (d, 1H, J=2.20 Hz); 8.45 (d, 1H, J=2.38 Hz); 8.21 (d, 1H, J=2.39 Hz); 7.57 (d, 2H, J=8.24 Hz); 7.41 (d, 2H, J=7.83 Hz); 7.24-7.17 (m, 2H); 6.73 (br d, 1H, J=7.33 Hz); 5.13 (m, 1H); 4.38 (q, 2H, J=8.05 Hz); 3.67 (s, 2H); 2.65 (s, 3H); 1.41 (d, 3H, J=6.77). FIRMS (ES) exact mass calcd for C22H21F3N4O2: 431.1689, Found: 431.1690. FLIPR alpha1I IP=24 nM.

Workup

  1. customThe resulting suspension was degassed for 10mins
  2. temperaturethe reaction mixture was cooled
  3. extractionextracted with ethyl acetate
  4. washwashed with brine
  5. dry with materialThe organic layer was dried over NaSO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customPurification by flash chromatography (silica gel, linear gradient 30-100% EtOAc:hexane)
  9. customfollowed by purification by reverse phase chromatography

Sources & evidence

ORD record
ord-39255b7e875d42ffaaf1c0a9a35d89ba
Source dataset
uspto-grants-2014_01
Patent number
US08637513B2

Reaction notes

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