1,4-Dioxane → 1-(5-(7-Chloro-2-methyl-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(2-cyclobutylethyl)urea

HRID 715138Notes

Reaction equation

HRID 715138 reaction equation
[CH:1]1([CH2:5][CH2:6]C(O)=O)[CH2:4][CH2:3][CH2:2]1.C1C=CC(P([N:24]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.[Cl:27][C:28]1[CH:37]=[C:36]2[C:31]([CH:32]=[C:33]([C:39]3[C:40]([CH3:47])=[CH:41][C:42]([F:46])=[C:43]([CH:45]=3)[NH2:44])[C:34]([CH3:38])=[N:35]2)=[CH:30][N:29]=1.[O:48]1[CH2:53]COCC1>>[Cl:27][C:28]1[CH:37]=[C:36]2[C:31]([CH:32]=[C:33]([C:39]3[C:40]([CH3:47])=[CH:41][C:42]([F:46])=[C:43]([NH:44][C:53]([NH:24][CH2:6][CH2:5][CH:1]4[CH2:2][CH2:3][CH2:4]4)=[O:48])[CH:45]=3)[C:34]([CH3:38])=[N:35]2)=[CH:30][N:29]=1

Participants

5

Reactant 4

HCID 312751,4-DioxaneHCID 199401P,P-Diphenylphosphinic azideHCID 131550293-Cyclobutylpropanoic acidHCID 898142035-(7-Chloro-2-methyl-1,6-naphthyridin-3-yl)-2-fluoro-4-methylaniline

Product 1

HCID 898278301-(5-(7-Chloro-2-methyl-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(2-cyclobutylethyl)ureaYield 61%

Procedure

Treat a suspension of 3-cyclobutylpropanoic acid (0.204 g, 1.591 mmol) in dioxane (5 mL) with DPPA (0.438 g, 1.591 mmol), 5-(7-chloro-2-methyl-1,6-naphthyridin-3-yl)-2-fluoro-4-methylaniline (0.400 g, 1.326 mmol) and TEA (0.268 g, 2.65 mmol), stir at RT for 0.5 h then heat at 90° C. for 4 h. Concentrate the mixture to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford the title compound (348 mg, 61%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.23 (d, J=0.7 Hz, 1H), 8.30 (m, 2H), 7.98 (m, 2H), 7.22 (d, J=12.3 Hz, 1H), 6.52 (t, J=5.6 Hz, 1H), 2.95 (q, J=6.5 Hz, 2H), 2.42 (s, 3H), 2.25 (m, 1H), 1.96 (m, 2H), 1.94 (s, 3H), 1.75 (m, 2H), 1.52 (m, 4H); MS(ESI) m/z: 427.1 (M+H+).

Workup

  1. additionTreat
  2. temperaturethen heat at 90° C. for 4 h
  3. concentrationConcentrate the mixture to dryness
  4. custompurify via silica gel chromatography (EtOAc/Hex)

Sources & evidence

ORD record
ord-0b09cf37462f4edc9728376d6387248b
Source dataset
uspto-grants-2015_11
Patent number
US09187474B2

Reaction notes

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