Water → 8-[3-((R)-5-Amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenylamino]-[1,7]naphthyridine-3-carbonitrile

HRID 925461Notes

Reaction equation

HRID 925461 reaction equation
[NH2:1][C:2]1[CH2:7][O:6][CH2:5][C@:4]([C:11]2[CH:12]=[C:13]([NH:18][C:19]3[N:20]=[CH:21][CH:22]=[C:23]4[C:28]=3[N:27]=[CH:26][C:25](Br)=[CH:24]4)[CH:14]=[CH:15][C:16]=2[F:17])([CH:8]([F:10])[F:9])[N:3]=1.O.[CH3:31][N:32](C=O)C>[Zn].[C-]#N.[C-]#N.[Zn+2].[Zn](OC(C)=O)OC(C)=O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:1][C:2]1[CH2:7][O:6][CH2:5][C@:4]([C:11]2[CH:12]=[C:13]([NH:18][C:19]3[N:20]=[CH:21][CH:22]=[C:23]4[C:28]=3[N:27]=[CH:26][C:25]([C:31]#[N:32])=[CH:24]4)[CH:14]=[CH:15][C:16]=2[F:17])([CH:8]([F:10])[F:9])[N:3]=1

Participants

9

Reactant 3

HCID 962WaterHCID 6228DimethylformamideHCID 71549953[3-((R)-5-Amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-(3-bromo-[1,7]naphthyridin-8-yl)-amine

Product 1

HCID 715499528-[3-((R)-5-Amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenylamino]-[1,7]naphthyridine-3-carbonitrile

Reagents, catalysts & solvents 5

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 23994ZincCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 178476751HCID 178476751, compoundCatalyst

Procedure

[3-((R)-5-Amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-(3-bromo-[1,7]naphthyridin-8-yl)-amine (150 mg, 0.32 mmol), Zn powder (0.842 mg, 0.013 mmol), Zn(CN)2 (22.7 mg, 0.193 mmol), Zn(OAc)2 (2.36 mg 0.013 mmol), 1,1′-Bis-(diphenylphosphino)-ferrocene (0.54 mg, 0.001 mmol) and Tris(dibenzylideneacetone)-dipalladium (0) (0.29 mg 0.0003 mmol) were dissolved in DMF (4 ml) and water (0.04 ml) and heated under inert conditions to 95° C. for 2 h and then allowed to cool to rt. The reaction was quenched with water (10 ml) and NH3 (25%, 1 ml) and extracted with EtOAc (25 ml). The aq phase was extracted another 3× with EtOAc. The combined organic layer was washed with NaHCO3 solution and brine, treated with MgSO4 and filtered. The filtrated was concentrated and purified by column chromatography (silica gel; hexane/0-15% EtOAc) to give the desired product as a yellow solid.

Workup

  1. customThe reaction was quenched with water (10 ml) and NH3 (25%, 1 ml)
  2. extractionextracted with EtOAc (25 ml)
  3. extractionThe aq phase was extracted another 3× with EtOAc
  4. washThe combined organic layer was washed with NaHCO3 solution and brine
  5. additiontreated with MgSO4
  6. filtrationfiltered
  7. concentrationThe filtrated was concentrated
  8. custompurified by column chromatography (silica gel; hexane/0-15% EtOAc)

Sources & evidence

ORD record
ord-857e2bd88df5463a87355a09945f4cc2
Source dataset
uspto-grants-2016_03
Patent number
US09284284B2

Reaction notes

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