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Cesium carbonate → N-(3-(2-chloro-5-fluorophenyl)-1,6-naphthyridin-7-yl)cyclopropanecarboxamide

HRID 468888
Notes
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Reaction equation

HRID 468888 reaction equation
Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[Cl:19])[CH:8]=[N:9]2)=[CH:4][N:3]=1.[CH:20]1([C:23]([NH2:25])=[O:24])[CH2:22][CH2:21]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:19][C:13]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=1[C:7]1[CH:8]=[N:9][C:10]2[C:5]([CH:6]=1)=[CH:4][N:3]=[C:2]([NH:25][C:23]([CH:20]1[CH2:22][CH2:21]1)=[O:24])[CH:11]=2
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 80376CyclopropanecarboxamideHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 866749667-Bromo-3-(2-chloro-5-fluorophenyl)-1,6-naphthyridine

Product 1

HCID 67976166N-(3-(2-chloro-5-fluorophenyl)-1,6-naphthyridin-7-yl)cyclopropanecarboxamideYield 43.9%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of 7-bromo-3-(2-chloro-5-fluorophenyl)-1,6-naphthyridine (40 mg, 0.1 mmol), cyclopropanecarboxamide (30 mg, 0.35 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (14 mg, 0.024 mmol), palladium acetate (5 mg, 0.024 mmol), and cesium carbonate (77 mg, 0.24 mmol) in 1,4-dioxane (1 mL) was heated at 90° C. for 1 hour. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (100 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min) to afford the title compound as an off-white solid (15 mg, 40%). 1H NMR (400 MHz, DMSO) δ 11.17 (s, 1H), 9.29 (s, 1H), 9.11 (d, J=2.2 Hz, 1H), 8.66-8.55 (m, 2H), 7.73 (dd, J=8.9, 5.2 Hz, 1H), 7.60 (dd, J=9.1, 3.1 Hz, 1H), 7.40 (td, J=8.5, 3.1 Hz, 1H), 2.18-2.06 (m, 1H), 0.96-0.81 (m, 4H). LCMS (Method E): RT=4.646 min, M+H+=342.0.

Workup

  1. customThe cooled reaction mixture
  2. washwashed with water (100 mL)
  3. customThe organic layer was separated
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. customevaporated in vacuo
  7. customto afford a residue that
  8. customwas purified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min)

Sources & evidence

ORD record
ord-022ea03707124bc9aa203289a66eacac
Source dataset
uspto-grants-2014_01
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08623889B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes