Potassium Carbonate → HCID 68746132, compound

HRID 1047131Notes

Reaction equation

HRID 1047131 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]([CH2:12][C:13]1[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=1)[CH:7]=[C:6]([C:19]([O:21]CC)=[O:20])[C:5]2=[O:24].[CH2:25]([NH:27][C:28](=[O:48])[NH:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[C:32]([C:39]2[S:40][CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[N:43]=2)[CH:31]=1)[CH3:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[CH2:25]([NH:27][C:28](=[O:48])[NH:29][C:30]1[N:35]=[CH:34][C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][N:11]=2)[N:8]([CH2:12][C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)[CH:7]=[C:6]([C:19]([OH:21])=[O:20])[C:5]3=[O:24])=[C:32]([C:39]2[S:40][CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[N:43]=2)[CH:31]=1)[CH3:26]

Participants

8

Reactant 3

HCID 11430Potassium CarbonateHCID 594161896-(3-Ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-ylboronic acidHCID 86665039HCID 86665039, compound2×

Product 1

HCID 68746132HCID 68746132, compoundYield 15%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 12976736Bis(ditert-butyl(cyclopenta-2,4-dien-1-yl)phosphane);iron(2+)CatalystHCID 962WaterSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of palladium (II) acetate (22.95 mg, 0.10 mmol, 0.1 equiv.) and 1,1′-bis(di-t-butylphosphino)ferrocene (48.5 mg, 0.10 mmol, 0.1 equiv.) in acetonitrile (3 mL) was added ethyl 6-bromo-1-((1-methyl-1H-pyrazol-4-yl)methyl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylate (Intermediate 52, 400 mg, 1.02 mmol, 1 equiv.), followed by 6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazole-2-yl)pyridine-3-ylboronic acid (WO2009106885, 372 mg, 1.03 mmol, 1.01 equiv.) and a solution of potassium carbonate (212 mg, 1.53 mmol, 1.5 equiv.) in water (1 mL). The reaction mixture was stirred at 60° C. for 9 h. The reaction mixture was concentrated under reduced pressure and resuspended in 1,4-dioxane (3 mL). 2 M Lithium Hydroxide (1.02 mL) was added, and the reaction mixture as stirred at 100° C. for 4 h. The reaction mixture was cooled to room temperature and diluted with water. 1 N HCl was added until pH 3-4 was reached. The precipitate was washed with water and hexanes and dried. The compound was purified (silica gel chromatography) and concentrated to provide 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-((1-methyl-1H-pyrazol-4-yl)methyl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylic acid (90.7 mg, 15%). Calcd for C26H21F3N8O4S [M+H]+: 599.16. H1NMR (d6-DMSO) δ 14.42 (s, 1H), 9.54 (s, 1H), 9.52 (s, 1H), 9.25 (s, 1H), 8.55 (s, 1H), 8.54 (s, 1H), 8.25 (s, 1H), 8.13 (s, 1H), 7.82 (s, 1H), 7.58 (t, 1H), 7.53 (s, 1H), 5.75 (s, 2H), 3.76 (s, 3H), 3.26-3.17 (m, 2H), 1.11 (t, 3H).

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. addition2 M Lithium Hydroxide (1.02 mL) was added
  3. stirringthe reaction mixture as stirred at 100° C. for 4 h
  4. temperatureThe reaction mixture was cooled to room temperature
  5. additiondiluted with water
  6. addition1 N HCl was added until pH 3-4
  7. washThe precipitate was washed with water and hexanes
  8. customdried
  9. customThe compound was purified (silica gel chromatography)
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-fe59cf32a78c4c7aa5bd6fc9f20950ed
Source dataset
uspto-grants-2013_10
Patent number
US08569484B2

Reaction notes

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