Ammonium Chloride → 2'-Fluoro-5'-[7-(1-hydroxy-1-methylethyl)-[1,8]naphthyridin-4-yl]biphenyl-2-carbonitrile

HRID 1061844Notes

Reaction equation

HRID 1061844 reaction equation
[C:1]([C:4]1[N:13]=[C:12]2[C:7]([C:8]([C:14]3[CH:15]=[CH:16][C:17]([F:28])=[C:18]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:19]=3)=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:29][Mg]Br.[NH4+].[Cl-]>C1COCC1>[F:28][C:17]1[CH:16]=[CH:15][C:14]([C:8]2[C:7]3[C:12](=[N:13][C:4]([C:1]([OH:3])([CH3:29])[CH3:2])=[CH:5][CH:6]=3)[N:11]=[CH:10][CH:9]=2)=[CH:19][C:18]=1[C:20]1[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=1

Participants

5

Reactant 3

HCID 25517Ammonium ChlorideHCID 99254355'-[7-Acetyl-[1,8]naphthyridin-4-yl]-2'-fluorobiphenyl-2-carbonitrileHCID 178418573HCID 178418573, compound2×

Product 1

HCID 101104952'-Fluoro-5'-[7-(1-hydroxy-1-methylethyl)-[1,8]naphthyridin-4-yl]biphenyl-2-carbonitrileYield 69.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

To a stirred solution of 5′-[7-acetyl-[1,8]naphthyridin-4-yl]-2′-fluorobiphenyl-2-carbonitrile (from Example 58) (28.6 mg, 0.0778 mmol) in anhydrous THF (2 mL), cooled under nitrogen to −78° C., was added dropwise methylmagnesium bromide (3.0 M solution in Et2O, 26.0 μL, 0.078 mmol). The mixture was stirred at −78° C. for a total of 85 min, adding more methylmagnesium bromide (3.0 M solution in Et2O, 26.0 μL, 0.078 mmol) after 45 min and 70 min. Saturated aqueous NH4Cl (2 mL) was then added and the mixture was allowed to warm to room temperature. The mixture was partitioned between ethyl acetate (15 mL) and water (10 mL). The aqueous layer was extracted further with ethyl acetate (15 mL), and the combined organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 3% MeOH/CH2Cl2, to afford 20.6 mg (69%) of the title compound as a white solid. δH (360 MHz, CDCl3) 1.67 (6H, s), 5.32 (1H, s), 7.44 (1H, t, J 9.1), 7.51 (1H, d, J 4.6), 7.54 (1H, td, J 7.7, 1.1), 7.58-7.65 (4H, m), 7.71 (1H, td, J 7.7, 1.1), 7.84 (1H, dd, J 7.7, 1.1), 8.51 (1H, d, J 8.8), 9.15 (1H, d, J 4.2). m/z (ES+) 384 [MH]+.

Workup

  1. custom70 min
  2. temperatureto warm to room temperature
  3. customThe mixture was partitioned between ethyl acetate (15 mL) and water (10 mL)
  4. extractionThe aqueous layer was extracted further with ethyl acetate (15 mL)
  5. dry with materialthe combined organic extracts were dried (MgSO4)
  6. customevaporated in vacuo
  7. customThe residue was purified by flash chromatography on silica gel
  8. washeluting with 3% MeOH/CH2Cl2

Sources & evidence

ORD record
ord-2cf696a145784d4e82ad34fd780a1f8b
Source dataset
uspto-grants-2005_11
Patent number
US06960598B2

Reaction notes

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