Hydrochloric Acid → 1-Cyclohexyl-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylic acid

HRID 1047130Notes

Reaction equation

HRID 1047130 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:7]=[C:6]([C:18]([O:20]CC)=[O:19])[C:5]2=[O:23].[CH2:24]([NH:26][C:27](=[O:47])[NH:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[C:31]([C:38]2[S:39][CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[N:42]=2)[CH:30]=1)[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Li+].Cl>O1CCOCC1.O.C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:12]1([N:8]2[C:9]3[C:4](=[CH:3][C:2]([C:32]4[CH:33]=[N:34][C:29]([NH:28][C:27]([NH:26][CH2:24][CH3:25])=[O:47])=[CH:30][C:31]=4[C:38]4[S:39][CH:40]=[C:41]([C:43]([F:46])([F:44])[F:45])[N:42]=4)=[N:11][CH:10]=3)[C:5](=[O:23])[C:6]([C:18]([OH:20])=[O:19])=[CH:7]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 10796Cesium carbonateHCID 594161896-(3-Ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-ylboronic acidHCID 86665038Ethyl 6-bromo-1-cyclohexyl-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylate2×

Product 1

HCID 687474001-Cyclohexyl-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylic acidYield 15.8%

Reagents, catalysts & solvents 3

HCID 178420553HCID 178420553, compoundCatalystHCID 962WaterSolvent2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of ethyl 6-bromo-1-cyclohexyl-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylate (Intermediate 47, 208 mg, 0.5 mmol, 1 equiv.) and 6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazole-2-yl)pyridine-3-ylboronic acid (180 mg, 0.5 mmol, 1 equiv., WO2009106885) in 1,4-dioxane (3 mL) was added tetrakis(triphenylphosphino)palladium(0) (58 mg, 0.05 mmol, 0.1 equiv.) followed by a solution of cesium carbonate (326 mg, 1.0 mmol, 2 equiv.) in water (1 mL). This reaction mixture was stirred at 100° C. for 2 h. 2 M lithium hydroxide (0.5 mL) was added. The reaction mixture was stirred at 100° C. for 9 h, cooled to room temperature, and diluted with water. To this was added 1 N HCl was added until pH 3-4 was reached. The precipitate was collected by filtration, washed with water and hexanes and dried under high pressure. The compound was purified (HPLC) and concentrated to provide 1-cyclohexyl-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylic acid as a solid (46.4 mg, 15%). Calcd for C27H25F3N6O4S [M+H]+: 587.09.

Workup

  1. stirringThe reaction mixture was stirred at 100° C. for 9 h
  2. temperaturecooled to room temperature
  3. additionwas added until pH 3-4
  4. filtrationThe precipitate was collected by filtration
  5. washwashed with water and hexanes
  6. customdried under high pressure
  7. customThe compound was purified (HPLC)
  8. concentrationconcentrated

Sources & evidence

ORD record
ord-5cf13b93626741e39b7db8a7a6a7d3c5
Source dataset
uspto-grants-2013_10
Patent number
US08569484B2

Reaction notes

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