Diisopropylethylamine → N-(4-(3-bromopyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

HRID 1046031Notes

Reaction equation

HRID 1046031 reaction equation
[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:6](=[O:17])[C:5]=1[C:18](Cl)=[O:19])[CH3:2].[Br:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[O:28][C:29]1[C:34]([F:35])=[CH:33][C:32]([NH2:36])=[C:31]([F:37])[CH:30]=1.C(N(CC)C(C)C)(C)C>C1COCC1>[Br:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[O:28][C:29]1[C:34]([F:35])=[CH:33][C:32]([NH:36][C:18]([C:5]2[C:6](=[O:17])[N:7]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH:8]=[CH:9][C:4]=2[O:3][CH2:1][CH3:2])=[O:19])=[C:31]([F:37])[CH:30]=1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 673992554-(3-Bromopyridin-4-yloxy)-2,5-difluorobenzenamineHCID 866675054-Ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonyl chloride3×

Product 1

HCID 67467723N-(4-(3-bromopyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamideYield 44.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A suspension of 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonyl chloride (freshly prepared from Example B2 (0.207 g, 0.747 mmol) using the method of Example 4) in THF (5 ml) was added to a 0° C. solution of Example A2 (0.15 g, 0.498 mmol) and N,N-diisopropylethylamine (0.870 ml, 4.98 mmol) in THF (5 ml). The mixture was allowed to warm to room temperature and stir overnight. Additional 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonyl chloride [freshly prepared from Example B2 (0.207 g, 0.747 mmol)] was added and the mixture was stirred overnight at RT. Additional 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonyl chloride [freshly prepared from Example B2 (414 mg, 0.996 mmol)] was added to the reaction mixture. After stirring for 3 h, the mixture was partitioned between CH2Cl2 and sat. Na2CO3 (aq) and extracted with sat. Na2CO3 (aq) (2×). The organic extract was dried and evaporated. The crude product was purified by silica gel chromatography (hexanes/EtOAc) to yield N-(4-(3-bromopyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.124 g, 44.4% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.24 (s, 1H), 8.74 (s, 1H), 8.37 (m, 2H). 7.92 (d, J=7.8 Hz, 1H), 7.59 (dd. J=10.9, 7.4 Hz, 1H), 7.48 (dd, J=8.8, 4.9 Hz, 2H), 7.36 (t, J=8.7 Hz, 2H), 6.88 (d, J=5.6 Hz, 1H); 6.55 (d, J=7.9 Hz, 1H); 4.28 (q, J=7.0 Hz, 2H); 1.33 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 560.1 (M+H+).

Workup

  1. additionwas added
  2. stirringthe mixture was stirred overnight at RT
  3. additionwas added to the reaction mixture
  4. stirringAfter stirring for 3 h
  5. customthe mixture was partitioned between CH2Cl2 and sat. Na2CO3 (aq)
  6. extractionextracted with sat. Na2CO3 (aq) (2×)
  7. extractionThe organic extract
  8. customwas dried
  9. customevaporated
  10. customThe crude product was purified by silica gel chromatography (hexanes/EtOAc)

Sources & evidence

ORD record
ord-4c32a7f51bff436b88531d6733c4e934
Source dataset
uspto-grants-2013_10
Patent number
US08569319B2

Reaction notes

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