Hydrochloric Acid → HCID 131730928, compound

HRID 1047132Notes

Reaction equation

HRID 1047132 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]([C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:13]1)[CH:7]=[C:6]([C:25]([O:27]CC)=[O:26])[C:5]2=[O:30].[CH2:31]([NH:33][C:34](=[O:54])[NH:35][C:36]1[N:41]=[CH:40][C:39](B(O)O)=[C:38]([C:45]2[S:46][CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[N:49]=2)[CH:37]=1)[CH3:32].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>[CH2:21]([N:20]([CH2:23][CH3:24])[CH2:19][CH2:18][N:14]1[CH2:15][CH2:16][CH2:17][C@H:12]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([C:39]4[CH:40]=[N:41][C:36]([NH:35][C:34]([NH:33][CH2:31][CH3:32])=[O:54])=[CH:37][C:38]=4[C:45]4[S:46][CH:47]=[C:48]([C:50]([F:53])([F:51])[F:52])[N:49]=4)=[N:11][CH:10]=3)[C:5](=[O:30])[C:6]([C:25]([OH:27])=[O:26])=[CH:7]2)[CH2:13]1)[CH3:22]

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 10796Cesium carbonateHCID 594161896-(3-Ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-ylboronic acidHCID 86665053HCID 86665053, compound2×

Product 1

HCID 131730928HCID 131730928, compoundYield 30%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
100 °C

Procedure

To a solution of (S)-ethyl 6-bromo-1-(1-(2-(diethylamino)ethyl)piperidin-3-yl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylate (Intermediate 63, 461 mg, 0.96 mmol, 1 equiv.) and 6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazole-2-yl)pyridine-3-ylboronic acid (WO2009106885, 519 mg, 1.44 mmol, 1.5 equiv.) in 1,4-dioxane (4 mL) was added tetrakis(triphenylphosphino)palladium(0) (111 mg, 0.1 mmol, 0.1 equiv.) followed by a solution of cesium carbonate (627 mg, 1.92 mmol, 2.0 equiv.) in water (1.3 mL). This reaction mixture was stirred at 100° C. for 2 h. 2 M Lithium hydroxide (0.96 mL) was added. The reaction mixture was stirred at 100° C. for 9 h, 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 (C18 silica gel chromatography) and concentrated to provide (5)-1-(1-(2-(diethylamino)ethyl)piperidin-3-yl)-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 (193 mg, 30%). Calcd for C32H37F3N8O4S [M+H]+: 687.23.

Workup

  1. stirringThe reaction mixture was stirred at 100° C. for 9 h
  2. temperaturecooled to room temperature
  3. washThe precipitate was washed with water and hexanes
  4. customdried
  5. customThe compound was purified (C18 silica gel chromatography) and
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-8605cf92803c4125b82febc5cc123551
Source dataset
uspto-grants-2013_10
Patent number
US08569484B2

Reaction notes

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