Sodium Carbonate → 5-[3-((4R,5R)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-nicotinonitrile

HRID 1626115Notes

Reaction equation

HRID 1626115 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][CH2:27][C@H:28]([F:40])[C@:29]([C:32]3[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.CC1(C)C(C)(C)OB([C:49]2[CH:50]=[N:51][CH:52]=[C:53]([CH:56]=2)[C:54]#[N:55])O1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][CH2:27][C@H:28]([F:40])[C@:29]([C:32]3[CH:37]=[C:36]([C:49]4[CH:50]=[N:51][CH:52]=[C:53]([CH:56]=4)[C:54]#[N:55])[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1

Participants

7

Reactant 4

HCID 10340Sodium CarbonateHCID 11776TriphenylphosphineHCID 164142165-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrileHCID 71008920[bis-(4-methoxy-phenyl)-phenyl-methyl]-[(4R,5R)-4-(5-bromo-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine

Product 1

HCID 710088825-[3-((4R,5R)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-nicotinonitrileYield 100.1%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
105 °C

Procedure

In a dry tube under an atmosphere of argon to a solution of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(4R,5R)-4-(5-bromo-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine (intermediate C4.3) (250 mg, 412 μmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (142 mg, 617 μmol) in 1,2-dimethoxyethane (3 ml) were added consecutively an aqueous solution of sodium carbonate (2M, 0.6 ml), triphenylphosphine (22.3 mg, 82.3 μmol), and, after flushing the mixture with argon, palladium(II)acetate (9.24 mg, 41.2 μmol). The tube was sealed and heated under stirring at 105° C. for 15 hours. After evaporation at reduced pressure, the residue was purified by chromatography on a silica-NH2 phase using a gradient of heptane/ethyl acetate=100:0 to 60:30 as the eluent. The 5-[3-((4R,5R)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-nicotinonitrile (260 mg, 100% yield) as a white foam. MS (ISP): m/z=631.4 [M+H]+.

Workup

  1. customThe tube was sealed
  2. temperatureheated
  3. customAfter evaporation at reduced pressure
  4. customthe residue was purified by chromatography on a silica-NH2 phase

Sources & evidence

ORD record
ord-3bea39cf69f340d3a2ff5881ff4a22b2
Source dataset
uspto-grants-2014_07
Patent number
US08785436B2

Reaction notes

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