Potassium Hydroxide → 6-Chloro-2-(5-fluoro-2-methylphenyl)-4-methyl-1,7-naphthyridine

HRID 1502301Notes

Reaction equation

HRID 1502301 reaction equation
[NH2:1][C:2]1[C:3]([CH:9](O)[CH3:10])=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[F:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:22])=[C:17]([C:19](=O)[CH3:20])[CH:18]=1.[OH-].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru]Cl>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][N:6]=1)[N:1]=[C:19]([C:17]1[CH:18]=[C:13]([F:12])[CH:14]=[CH:15][C:16]=1[CH3:22])[CH:20]=[C:9]2[CH3:10]

Participants

6

Reactant 4

HCID 14797Potassium HydroxideHCID 312751,4-DioxaneHCID 153354201-(5-Fluoro-2-methylphenyl)ethan-1-oneHCID 866749441-(5-Amino-2-chloropyridin-4-yl)ethanol

Product 1

HCID 866749456-Chloro-2-(5-fluoro-2-methylphenyl)-4-methyl-1,7-naphthyridineYield 36.3%

Reagents, catalysts & solvents 1

HCID 11007548Dichlorotris(triphenylphosphine)rutheniumCatalyst

Conditions

Temperature
80 °C

Procedure

A screw-top vial was charged with 1-(5-amino-2-chloropyridin-4-yl)ethanol (46.3 mg, 0.268 mmol), 5′-fluoro-2′-methylacetophenone (82.0 mg, 0.540 mmol), tris(triphenylphosphine)ruthenium(II) dichloride (13.0 mg, 0.013 mmol), potassium hydroxide (15 mg, 0.27 mmol), and 1,4-dioxane (1.5 mL, 19 mmol). The reaction vial was flushed with nitrogen gas, sealed with a teflon lined cap, and heated at 80° C. for 2 hours. The reaction mixture was then diluted in ethyl acetate, filtered through celite, washed with water and brine, dried over MgSO4, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-100% ethyl acetate in heptane) to yield 27.9 mg (36%) of 6-chloro-2-(5-fluoro-2-methylphenyl)-4-methyl-1,7-naphthyridine. LCMS (ESI): M+H=287.2; 1H NMR (400 MHz, DMSO) δ 9.27 (s, 1H), 8.20 (s, 1H), 7.91 (s, 1H), 7.41 (m, 2H), 7.26 (m, 1H), 2.75 (s, 3H), 2.37 (s, 3H).

Workup

  1. customThe reaction
  2. customvial was flushed with nitrogen gas
  3. customsealed with a teflon
  4. customlined cap
  5. additionThe reaction mixture was then diluted in ethyl acetate
  6. filtrationfiltered through celite
  7. washwashed with water and brine
  8. dry with materialdried over MgSO4
  9. customevaporated in vacuo
  10. customThe crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-100% ethyl acetate in heptane)

Sources & evidence

ORD record
ord-0068cc6e31be480c9707492a7295462a
Source dataset
uspto-grants-2015_12
Patent number
US09206175B2

Reaction notes

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