4-Bromo-3,5-dimethylpyridine → 8-(cyclopropylmethoxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one

HRID 2381064Notes

Reaction equation

HRID 2381064 reaction equation
Br[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[CH:4][C:3]=1[CH3:9].[CH:10]1([CH2:13][O:14][C:15]2[C:16]([O:35][CH3:36])=[CH:17][CH:18]=[C:19]3[C:24]=2[NH:23][C:22](=[O:25])[CH:21]=[C:20]3[NH:26]C2C(Cl)=CN=CC=2Cl)[CH2:12][CH2:11]1.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[CH:10]1([CH2:13][O:14][C:15]2[C:16]([O:35][CH3:36])=[CH:17][CH:18]=[C:19]3[C:24]=2[NH:23][C:22](=[O:25])[CH:21]=[C:20]3[NH:26][C:2]2[C:7]([CH3:8])=[CH:6][N:5]=[CH:4][C:3]=2[CH3:9])[CH2:11][CH2:12]1

Participants

6

Reactant 3

HCID 223232464-Bromo-3,5-dimethylpyridineHCID 23676156Sodium t-butoxideHCID 248519118-(Cyclopropylmethoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one

Product 1

HCID 236492908-(cyclopropylmethoxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

A solution of 4-bromo-3,5-dimethylpyridine (1.16 g, 6.21 mmol) and degassed toluene (5 mL) was added to a mixture of 4-amino-8-(cyclopropylmethoxy)-7-methoxyquinolin-2(1H)-one (1.94 g, 7.45 mmol, intermediate for Example 3), Pd2(dba)3, (0.28 g, 0.31 mmol), 2,2-dicyclohexylphosphorane triisopropylbiphenyl (0.59 g, 1.24 mmol), sodium tert-butoxide (1.20 g, 12.4 mmol), and degassed toluene (20 mL) under N2. The mixture was heated at 110° C. for 2 h, allowed to cool to rt, sonicated until the solids broke up, and then filtered through Celite with EtOAc (500 mL). The filtrate was concentrated, purified by silica gel chromatography (0→8% MeOH/CH2Cl2), and then repurified by reverse-phase HPLC (25→100% MeCN/H2O) to give 8-(cyclopropylmethoxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one: 1H NMR (400 MHz, DMSO-d6): δ 9.64 (s, 1H), 8.43 (s, 1H), 8.42 (s, 2H), 7.89 (d, 1H), 7.03 (d, 1H), 4.54 (s, 1H), 3.91 (s, 3H), 3.85 (d, 2H), 2.15 (s, 6H), 1.28 (m, 1H), 0.47 (m, 2H), 0.28 (m, 2H); MS (ESI): 365.8.

Workup

  1. customdegassed toluene (20 mL) under N2
  2. temperatureto cool to rt
  3. customsonicated until the solids
  4. filtrationfiltered through Celite with EtOAc (500 mL)
  5. concentrationThe filtrate was concentrated
  6. custompurified by silica gel chromatography (0→8% MeOH/CH2Cl2)
  7. customrepurified by reverse-phase HPLC (25→100% MeCN/H2O)

Sources & evidence

ORD record
ord-73c500161a4441c6bcd03e32469216f6
Source dataset
uspto-grants-2012_09
Patent number
US08258154B2

Reaction notes

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