2-Methoxyaniline → [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(4R,5R)-5-fluoro-4-[2-fluoro-5-(2-methoxy-phenylamino)-phenyl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl}-amine

HRID 1626112Notes

Reaction equation

HRID 1626112 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.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[CH3:77][O:78][C:79]1[CH:85]=[CH:84][CH:83]=[CH:82][C:80]=1[NH2:81]>O1CCOCC1>[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]([NH:81][C:80]4[CH:82]=[CH:83][CH:84]=[CH:85][C:79]=4[O:78][CH3:77])[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

6

Reactant 4

HCID 70002-MethoxyanilineHCID 11618717Di-tert-butyl(2',4',6'-tris(propan-2-yl)-(1,1'-biphenyl)-2-yl)phosphaneHCID 23676156Sodium t-butoxideHCID 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 71008803[bis-(4-methoxy-phenyl)-phenyl-methyl]-{(4R,5R)-5-fluoro-4-[2-fluoro-5-(2-methoxy-phenylamino)-phenyl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl}-amineYield 32%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
115 °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) (150 mg, 247 μmol) in dioxane (5 ml) was added consecutively sodium tert-butoxide (26.1 mg, 272 μmol), 2-di-tert-butylphosphino-2′4′,6′-triisopropylbiphenyl (10.5 mg, 24.7 μmol), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (7.9 mg, 7.41 μmol), and 2-methoxyaniline (60.8 mg, 55.7 μl, 494 μmol). The tube was sealed and heated 115° C. under stirring during 15 hours. For the workup, the reaction mixture was evaporated at reduced pressure, and 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 [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(4R,5R)-5-fluoro-4-[2-fluoro-5-(2-methoxy-phenylamino)-phenyl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl}-amine (51 mg, 32% yield) was obtained as a pale yellow foam. MS (ISP): m/z=650.5 [M+H]+.

Workup

  1. customThe tube was sealed
  2. customFor the workup, the reaction mixture was evaporated at reduced pressure
  3. customthe residue was purified by chromatography on a silica-NH2 phase

Sources & evidence

ORD record
ord-fe1aa466974948f9a766c12e4095d6f2
Source dataset
uspto-grants-2014_07
Patent number
US08785436B2

Reaction notes

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