Sodium t-butoxide → 2-[3,5-bis(trifluoromethyl)phenyl]-N-{6'-[(7S,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-4-methyl-3,4'-bipyridin-3'-yl}-N,2-dimethylpropanamide

HRID 421195Notes

Reaction equation

HRID 421195 reaction equation
[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][C:29]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:36][C:37]([Si:40]([CH3:54])([CH3:53])[O:41][CH2:42][C@@H:43]1[CH2:52][N:51]2[C@H:46]([CH2:47][O:48][CH2:49][CH2:50]2)[CH2:45][NH:44]1)([CH3:39])[CH3:38].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:44]3[C@H:43]([CH2:42][O:41][Si:40]([C:37]([CH3:39])([CH3:38])[CH3:36])([CH3:53])[CH3:54])[CH2:52][N:51]4[C@H:46]([CH2:47][O:48][CH2:49][CH2:50]4)[CH2:45]3)=[CH:22][C:23]=2[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][C:29]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1

Participants

5

Reactant 3

HCID 23676156Sodium t-butoxideHCID 59215768(7S,9AS)-7-(((tert-butyldimethylsilyl)oxy)methyl)octahydropyrazino[2,1-c][1,4]oxazineHCID 592159032-[3,5-bis(trifluoromethyl)phenyl]-N-(6'-chloro-4-methyl-3,4'-bipyridin-3'-yl)-N,2-dimethylpropanamide

Product 1

HCID 592158502-[3,5-bis(trifluoromethyl)phenyl]-N-{6'-[(7S,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-4-methyl-3,4'-bipyridin-3'-yl}-N,2-dimethylpropanamideYield 74.9%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
130 °C

Procedure

The 2-[3,5-bis(trifluoromethyl)phenyl]-N-(6′-chloro-4-methyl-3,4′-bipyridin-3′-yl)-N,2-dimethylpropanamide (D52, 77 mg, 0.15 mmol), (7S,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)octahydropyrazino[2,1-c][1,4]oxazine (D51, 51.5 mg, 0.18 mmol), sodium t-Butoxide (18 mg, 0.19 mmol) were degassed together in dry toluene (1.5 mL) for 5 mins before adding Bis(dibenzyleneacetone) Palladium (9 mg, 0.015 mmol) and 2-Dicyclohexylphosphino-2′-(N′N′-dimethylamino)biphenyl (15 mg, 0.038 mmol) and heating under microwave conditions at 130° C. for 30 mins. Diluted with EtOAC, washed with sat. NaHCO3×1, brine ×1, dried (MgSO4). Filtered. Solvent evaporated. Residue purified eluting with Pent to EtOAc. No Fractions isolated clean. Mixed fractions combined, solvent evaporated and residue re-purified on a 2 g SCX column, washing with MeOH (2×10 mL) before eluting the compound off with NH3 in MeOH (3×10 mL). Solvent evaporated under reduced pressure to afford a gummy solid (86 mg).

Workup

  1. additionDiluted with EtOAC
  2. washwashed with sat. NaHCO3×1, brine ×1
  3. dry with materialdried (MgSO4)
  4. filtrationFiltered
  5. customSolvent evaporated
  6. customResidue purified
  7. washeluting with Pent to EtOAc
  8. customNo Fractions isolated clean
  9. customsolvent evaporated
  10. customresidue re-purified on a 2 g SCX column
  11. washwashing with MeOH (2×10 mL)
  12. washbefore eluting the compound off with NH3 in MeOH (3×10 mL)
  13. customSolvent evaporated under reduced pressure

Sources & evidence

ORD record
ord-2b6c248ec94048a29edcecda7ee3bacb
Source dataset
uspto-grants-2012_01
Patent number
US08097618B2

Reaction notes

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