Cesium carbonate → (7-((3,4-Difluorobenzyl)oxy)-1,5-naphthyridin-3-yl)methanol

HRID 513962Notes

Reaction equation

HRID 513962 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17](OCC)=[O:18])[CH:13]=[N:14]2)=[N:9][CH:8]=1.OC1C=C2C(C=C(C(OCC)=O)C=N2)=NC=1.C([O-])([O-])=O.[Cs+].[Cs+].FC1C=C(C=CC=1F)CBr>CN(C=O)C.O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:17][OH:18])[CH:13]=[N:14]2)=[N:9][CH:8]=1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 5814364-(Bromomethyl)-1,2-difluorobenzeneHCID 90417578Ethyl 7-((3,4-difluorobenzyl)oxy)-1,5-naphthyridine-3-carboxylateHCID 136227102Ethyl 7-hydroxy-1,5-naphthyridine-3-carboxylate2×

Product 1

HCID 86301659(7-((3,4-Difluorobenzyl)oxy)-1,5-naphthyridin-3-yl)methanolYield 64%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

Ethyl 7-((3,4-difluorobenzyl)oxy)-1,5-naphthyridine-3-carboxylate. To a solution of ethyl 7-hydroxy-1,5-naphthyridine-3-carboxylate (Intermediate 4, 1.0 g, 4.5 mmol) in DMF (20 mL) was added Cs2CO3 (2.2 g, 6.75 mmol), followed by 3,4-difluorobenzyl bromide (0.682 mL, 5.02 mmol). The reaction was stirred at ambient temperature for 72 h. The crude reaction mixture was poured into EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic fractions were washed with brine and concentrated under reduced pressure onto silica. Purification (FCC, SiO2, 0-60%, EtOAc/hexanes) afforded the title compound as a white solid (1.05 g, 64%) 1H NMR (400 MHz, CDCl3) δ 9.48-9.41 (m, 1H), 8.97 (s, 1H), 8.89-8.82 (m, 1H), 7.69 (s, 1H), 7.37-7.29 (m, 1H), 7.25-7.19 (m, 2H), 5.20 (s, 2H), 4.54-4.40 (m, 2H), 1.51-1.41 (m, 3H). [M+H]=345.2.

Workup

  1. customThe crude reaction mixture
  2. extractionThe aqueous layer was extracted with EtOAc
  3. washthe combined organic fractions were washed with brine
  4. concentrationconcentrated under reduced pressure onto silica
  5. customPurification (FCC, SiO2, 0-60%, EtOAc/hexanes)

Sources & evidence

ORD record
ord-70ee9d7d08f042c3a58489d859fd9edc
Source dataset
uspto-grants-2015_08
Patent number
US09102674B2

Reaction notes

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