Diethyl Malonate → 2-(7-((3,4-Difluorobenzyl)oxy)-1,5-naphthyridin-3-yl)acetamide

HRID 1748414Notes

Reaction equation

HRID 1748414 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:17][C:18](OCC)=[O:19])[CH:13]=[N:14]2)=[N:9][CH:8]=1.BrC1C=[N:30]C2C(C=1)=NC=C(OCC1C=CC(F)=C(F)C=1)C=2.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCCOCCOCCOCCOCC1.C(OCC)(=O)CC(OCC)=O>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]>[F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:17][C:18]([NH2:30])=[O:19])[CH:13]=[N:14]2)=[N:9][CH:8]=1

Participants

8

Reactant 6

HCID 7761Diethyl MalonateHCID 2855718-Crown-6HCID 62657Potassium Phosphate, TribasicHCID 2734635Tri-tert-butylphosphine tetrafluoroborateHCID 90416945Ethyl 2-(7-((3,4-difluorobenzyl)oxy)-1,5-naphthyridin-3-yl)acetateHCID 904175933-Bromo-7-((3,4-difluorobenzyl)oxy)-1,5-naphthyridine

Product 1

HCID 862968492-(7-((3,4-Difluorobenzyl)oxy)-1,5-naphthyridin-3-yl)acetamideYield 53.8%

Reagents, catalysts & solvents 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
115 °C

Procedure

Ethyl 2-(7-((3,4-difluorobenzyl)oxy)-1,5-naphthyridin-3-yl)acetate. 3-Bromo-7-((3,4-difluorobenzyl)oxy)-1,5-naphthyridine (3.20 g, 9.11 mmol), Pd2(dba)3 (41.72 mg, 0.05 mmol), tri-tert-butylphosphonium tetrafluoroborate (290.84 mg, 1 mmol), potassium phosphate (5.42 g, 25.52 mmol), 1,4,7,10,13,16-hexaoxacyclooctadecane (1.2 g, 4.56 mmol), and diethyl malonate (9.17 mL, 60.15 mmol) were added to a microwave vial, which was capped and purged with nitrogen for several minutes then heated to 115° C. for 19 h. The reaction was cooled to ambient temperature then water and EtOAc were added. The layers were separated and the aqueous solution was extracted with EtOAc and DCM. The combined organic layers were washed with brine then dried (Na2SO4). The solvent was removed under reduced pressure. Purification (FCC, SiO2, 0-70%, EtOAc/hexanes) afforded the title compound as a pure beige solid (1.76 g, 53.8%). 1H NMR (400 MHz, CDCl3) δ 8.84 (dd, J=18.1, 2.5 Hz, 2H), 8.27 (d, J=1.4 Hz, 1H), 7.68 (d, J=2.6 Hz, 1H), 7.47-7.30 (m, 1H), 7.26-7.17 (m, 2H), 5.20 (s, 2H), 4.22 (q, J=7.2 Hz, 2H), 3.86 (s, 2H), 1.30 (t, J=7.2 Hz, 3H). [M+H]=359.2.

Workup

  1. customwas capped
  2. custompurged with nitrogen for several minutes
  3. temperatureThe reaction was cooled to ambient temperature
  4. additionwater and EtOAc were added
  5. customThe layers were separated
  6. extractionthe aqueous solution was extracted with EtOAc and DCM
  7. washThe combined organic layers were washed with brine
  8. dry with materialthen dried (Na2SO4)
  9. customThe solvent was removed under reduced pressure
  10. customPurification (FCC, SiO2, 0-70%, EtOAc/hexanes)

Sources & evidence

ORD record
ord-68ac2049d3a24f4a85db2e2e369222bd
Source dataset
uspto-grants-2015_10
Patent number
US09150572B2

Reaction notes

Loading…