Diisopropylethylamine → [4-(4-Bromo-2,5-dichloro-phenoxy)-6-methyl-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone

HRID 1025889

Reaction equation

HRID 1025889 reaction equation
[Br:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([O:6][C:7]2[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[C:9]([CH3:16])[CH:8]=2)=[C:4]([Cl:20])[CH:3]=1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH:54]1([N:57]2[C:66]3[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=3)[NH:60][CH2:59][CH2:58]2)[CH2:56][CH2:55]1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH3:16])[N:10]=[CH:11][C:12]=2[C:13]([N:60]2[C:61]3[C:66](=[CH:65][CH:64]=[CH:63][CH:62]=3)[N:57]([CH:54]3[CH2:56][CH2:55]3)[CH2:58][CH2:59]2)=[O:15])=[C:4]([Cl:20])[CH:3]=1

Participants

8

Reactant 5

HCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)2×HCID 673194804-(4-Bromo-2,5-dichloro-phenoxy)-6-methyl-nicotinic acidHCID 673207551-Cyclopropyl-1,2,3,4-tetrahydroquinoxaline

Product 1

HCID 53311447[4-(4-Bromo-2,5-dichloro-phenoxy)-6-methyl-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanoneYield 23%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 0.17 g (0.451 mmol) 4-(4-bromo-2,5-dichloro-phenoxy)-6-methyl-nicotinic acid in 3 mL dry N,N-dimethylformamide was added 0.38 mL (2.225 mmol) N-ethyldiisopropylamine and 207 mg (0.541 mmol) O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1) and 94 mg (0.541 mmol) 1-cyclopropyl-1,2,3,4-tetrahydro-quinoxaline (Example 8, intermediate a). The reaction mixture was stirred at room temperature for 18 hours and then poured on 30 mL 10% aqueous sodium bicarbonate solution and 30 mL ethyl acetate. The layers were separated. The aqueous layer was extracted with 30 mL ethyl acetate and the combined organic layers were washed with 30 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography using a MPLC system (20 g silica gel column, CombiFlash Companion, Isco Inc.) with a gradient of n-heptane:ethyl acetate (100:0 to 40:60) to give 55 mg (23%) of the title compound as a light yellow solid. MS (ESI): m/z=534.018 [M+H]+.

Workup

  1. customThe layers were separated
  2. extractionThe aqueous layer was extracted with 30 mL ethyl acetate
  3. washthe combined organic layers were washed with 30 mL brine
  4. dry with materialdried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under vacuum
  7. customThe residue was purified by silica gel chromatography

Sources & evidence

ORD record
ord-3019150e2b354be6b63d9e6154aa20f3
Source dataset
uspto-grants-2014_05
Patent number
US08729091B2

Linked notes

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