Chloride → 2-[3,5-Bis(trifluoromethyl)phenyl]-n{6-fluoro-6'-[(7s,9as)-7-(hydroxymethyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1h)-yl]-2-methyl-3,4'-bipyridin-3'-yl}-n,2-dimethylpropanamide

HRID 421268Notes

Reaction equation

HRID 421268 reaction equation
[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[C:25]([CH3:31])=[N:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CC([Si](C)(C)[O:42][CH2:43][C@@H:44]1[CH2:53][N:52]2[C@H:47]([CH2:48][O:49][CH2:50][CH2:51]2)[CH2:46][NH:45]1)(C)C.[Cl-].[OH-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:45]3[C@H:44]([CH2:43][OH:42])[CH2:53][N:52]4[C@H:47]([CH2:48][O:49][CH2:50][CH2:51]4)[CH2:46]3)=[CH:22][C:23]=2[C:24]2[C:25]([CH3:31])=[N:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1

Participants

6

Reactant 4

HCID 312ChlorideHCID 14798Sodium HydroxideHCID 59215768(7S,9AS)-7-(((tert-butyldimethylsilyl)oxy)methyl)octahydropyrazino[2,1-c][1,4]oxazineHCID 592158222-[3,5-bis(trifluoromethyl)phenyl]-N-(6'-chloro-6-fluoro-2-methyl-3,4'-bipyridin-3'-yl)-N,2-dimethylpropanamide

Product 1

HCID 160639112-[3,5-Bis(trifluoromethyl)phenyl]-n{6-fluoro-6'-[(7s,9as)-7-(hydroxymethyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1h)-yl]-2-methyl-3,4'-bipyridin-3'-yl}-n,2-dimethylpropanamideYield 16.4%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
90 °C

Procedure

2-[3,5-bis(trifluoromethyl)phenyl]-N-(6′-chloro-6-fluoro-2-methyl-3,4′-bipyridin-3′-yl)-N,2-dimethylpropanamide (D54, 53.5 mg, 0.1 mmol), (7S,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)octahydropyrazino[2,1-c][1,4]oxazine (D51, 37 mg, 0.13 mmol) were dissolved in toluene (1.5 mL). Bis tritertbutylphosphine palladium (13 mg, 0.026 mmol), followed by hexadecyltrimethylammoium chloride (10 μL, 25% aq sol), and finally sodium hydroxide solution (0.13 mL, 50% aq sol). The mixture was degassed for 5 minutes before heating at 90° C. for 4.5 hours. Cooled to R.T., diluted with EtOAc, washed with sat. NaHCO3 solution, dried (MgSO4). Filtered. Solvent evaporated. Residue purified by SCX column, washing with MeOH before eluting with NH3 in MeOH. Solvent evaporated. Residue purified by column chromatography eluting with Pent to EtOAc to 10% MeOH/EtOAc. Solvent evaporated under reduced pressure to afford a colourless solid of the title compound (11 mg).

Workup

  1. customThe mixture was degassed for 5 minutes
  2. temperatureCooled to R.T.
  3. additiondiluted with EtOAc
  4. washwashed with sat. NaHCO3 solution
  5. dry with materialdried (MgSO4)
  6. filtrationFiltered
  7. customSolvent evaporated
  8. customResidue purified by SCX column
  9. washwashing with MeOH
  10. washbefore eluting with NH3 in MeOH
  11. customSolvent evaporated
  12. customResidue purified by column chromatography
  13. washeluting with Pent to EtOAc to 10% MeOH/EtOAc
  14. customSolvent evaporated under reduced pressure

Sources & evidence

ORD record
ord-5df19e676fb348f290b711ea7fa56050
Source dataset
uspto-grants-2012_01
Patent number
US08097618B2

Reaction notes

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