2-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenyl → 2-[3,5-bis(trifluoromethyl)phenyl]-N-(4-(2-chloro-4-fluorophenyl)-6-[(7S,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-3-pyridinyl}-N,2-dimethylpropanamide

HRID 2074847Notes

Reaction equation

HRID 2074847 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[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[Cl:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:37][C:38]([Si:41]([CH3:55])([CH3:54])[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)([CH3:40])[CH3:39].CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>C1(C)C=CC=CC=1.CCOC(C)=O>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C:13]([CH3:33])([CH3:34])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:45]3[C@H:44]([CH2:43][O:42][Si:41]([C:38]([CH3:40])([CH3:39])[CH3:37])([CH3:54])[CH3:55])[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[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[Cl:31])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:36])[F:35])[CH:8]=1

Participants

7

Reactant 4

HCID 27342172-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenyl2×HCID 23676156Sodium t-butoxideHCID 59215768(7S,9AS)-7-(((tert-butyldimethylsilyl)oxy)methyl)octahydropyrazino[2,1-c][1,4]oxazineHCID 592158082-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(2-chloro-4-fluorophenyl)-3-pyridinyl]-N,2-dimethylpropanamide

Product 1

HCID 592158392-[3,5-bis(trifluoromethyl)phenyl]-N-(4-(2-chloro-4-fluorophenyl)-6-[(7S,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-3-pyridinyl}-N,2-dimethylpropanamideYield 25%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(2-chloro-4-fluorophenyl)-3-pyridinyl]-N,2-dimethylpropanamide (D57, 60 mg, 0.11 mmol), (7S,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)octahydropyrazino[2,1-c][1,4]oxazine (D51, 37 mg, 0.13 mmol), sodium t-Butoxide (13 mg, 00.1375 mmol) were degassed together in toluene (1.2 mL) for 10 minutes before adding bis(dibenzyleneacetone) palladium (6 mg, 0.011 mmol) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (11 mg, 0.0275 mmol) and heating at 100° C. for 30 minutes under microwave conditions. Added more bis(dibenzyleneacetone) palladium (6 mg, 0.011 mmol) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (11 mg, 0.0275 mmol) and heated for a further 30 minutes at 100° C. under microwave conditions. Diluted with EtOAc, washed with sat NaHCO3 solution ×1, brine ×1, dried (MgSO4). Filtered. Solvent evaporated under reduced pressure. Residue purified eluting with 0-100% EtOAc/Pent. Solvent evaporated to afford a brown gum of the title compound in 25% yield.

Workup

  1. temperatureheated for a further 30 minutes at 100° C. under microwave conditions
  2. washwashed
  3. dry with materialdried (MgSO4)
  4. filtrationFiltered
  5. customSolvent evaporated under reduced pressure
  6. customResidue purified
  7. washeluting with 0-100% EtOAc/Pent
  8. customSolvent evaporated

Sources & evidence

ORD record
ord-ae0fa3282cd843e0a36b6ea586539436
Source dataset
uspto-grants-2011_04
Patent number
US07919491B2

Reaction notes

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