Nitrogen → US10023592, Example 247

HRID 575722Notes

Reaction equation

HRID 575722 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH3:13])[C:5](=[O:12])[N:6]([CH2:8][CH:9]2[CH2:11][CH2:10]2)[CH:7]=1.[F:14][C:15]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])=[CH:20][C:19]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N#N>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH:9]1([CH2:8][N:6]2[C:5](=[O:12])[C:4]([CH3:13])=[CH:3][C:2]([C:23]3[CH:22]=[C:21]([NH:24][S:25]([CH2:28][CH3:29])(=[O:26])=[O:27])[CH:20]=[CH:19][C:18]=3[O:17][C:16]3[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:15]=3[F:14])=[CH:7]2)[CH2:11][CH2:10]1

Participants

8

Reactant 4

HCID 947NitrogenHCID 62657Potassium Phosphate, TribasicHCID 814220925-Bromo-1-(cyclopropylmethyl)-3-methylpyridin-2-oneHCID 131732853[2-(2,4-Difluorophenoxy)-5-(ethylsulfonylamino)phenyl]boronic acid

Product 1

HCID 118021865US10023592, Example 247Yield 28.8%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
75 °C

Procedure

5-bromo-3-methyl-1H-pyridin-2-one was N-alkylated with bromomethylcyclopropane to give 5-bromo-1-(cyclopropylmethyl)-3-methylpyridin-2-one. 5-bromo-1-(cyclopropylmethyl)-3-methylpyridin-2-one (100 mg, 0.41 mmol), [2-(2,4-difluorophenoxy)-5-(ethylsulfonylamino)phenyl]boronic acid (217 mg, 0.5 mol), K3PO4 (263 mg, 1.24 mmol) and Pd(dppf)Cl2 (30 mg, 41.3 umol) in dioxane (8 mL)/water (1 mL) were purged with N2 and heated at 70-80° C. for 12 h. Preparative HPLC gave the title compound (56.0 mg, 28.6% yield) as dull-red semisolid. 1H NMR (CDCl3, 400 MHz): δ 7.74 (s, 1H), 7.61 (s, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.10-7.15 (m, 1H), 6.92-7.00 (m, 2H), 6.82-6.89 (m, 1H), 6.80 (d, J=8.8 Hz, 1H), 6.71 (br. s., 1H), 3.93 (d, J=7.2 Hz, 3H), 3.12-3.21 (m, 2H), 2.24 (s, 3H), 1.42 (t, J=7.2 Hz, 3H), 1.22-1.33 (m, 1H), 0.57-0.67 (m, 2H), 0.36-0.43 (m, 2H). LCMS: 475.1 (M+1)+

Sources & evidence

ORD record
ord-e30c018af7a94f209439b705027554d1
Source dataset
uspto-grants-2015_05
Patent number
US09034900B2

Reaction notes

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