Trimethylamine → 2-(2-fluoro-phenyl)-4-(5-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-pyridin-3-yl)-[1,8]naphthyridine

HRID 1914953Notes

Reaction equation

HRID 1914953 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][CH2:32][CH2:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1.CC1(C)C(C)(C)OB(C2C=NNC=2)O1.ClC1C=CC(F)=C(C2C=C(C3C=NC=C(C4C=NN(CCN5CCCC5)C=4)C=3)C3C(=NC=CC=3)N=2)C=1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C>COCCOC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([C:37]3[CH:36]=[N:35][N:34]([CH2:33][CH2:32][O:31][CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][O:25]4)[CH:38]=3)[CH:3]=2)[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1

Participants

9

Reactant 6

HCID 1146TrimethylamineHCID 27740104-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 18407952Tripotassium phosphate trihydrateHCID 53344959HCID 53344959, compoundHCID 593418191-[2-(oxan-2-yloxy)ethyl]-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 682645484-(5-Bromo-pyridin-3-yl)-2-(2-fluoro-phenyl)-[1,8]naphthyridine

Product 1

HCID 673805632-(2-fluoro-phenyl)-4-(5-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-pyridin-3-yl)-[1,8]naphthyridine

Reagents, catalysts & solvents 2

HCID 6102075Dichlorobis(triphenylphosphine)palladiumCatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
85 °C

Procedure

A slurry of 380 mg (1.00 mmol) 4-(5-bromo-pyridin-3-yl)-2-(2-fluoro-phenyl)-[1,8]naphthyridine, 354 mg (1.10 mmol) 1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (prepared from 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole and 2-(2-bromo-ethoxy)-tetrahydro-pyran (in analogy to example 10) and 425 mg (2.00 mmol) tri-potassium-phosphate-trihydrate in 3 ml 1,2-dimethoxyethane was heated to 85° C. under nitrogen. Then 35.1 mg (0.05 mmol) bis-(triphenylphosphine)-palladium(II)-chloride and 14 μl trimethylamine were added. The reaction mixture was stirred for 16 hours at 85° C. The reaction mixture was cooled to room temperature and partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column with dichloromethane/methanol as eluent yielding yielding 2-(2-fluoro-phenyl)-4-(5-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-pyridin-3-yl)-[1,8]naphthyridine as yellow solid; HPLC-MS: 2.13 min, [M+H] 496.

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. custompartitioned between water and dichloromethane
  3. dry with materialThe organic phase was dried over sodium sulfate
  4. customevaporated
  5. customThe residue was chromatographed on a silica gel column with dichloromethane/methanol as eluent
  6. customyielding

Sources & evidence

ORD record
ord-93862f2cadbd49ef9c8f1cdc0850b62f
Source dataset
uspto-grants-2013_12
Patent number
US08614226B2

Reaction notes

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