2-Bromo-5-chloropyridine → HCID 178516975, compound

HRID 707436Notes

Reaction equation

HRID 707436 reaction equation
Cl.[NH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[N:9]([CH:16]3[CH2:18][CH2:17]3)[C:8]2=[O:19])[CH2:4]1.Br[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=1.C([O-])(=O)C.[Cs+]>CS(C)=O.[Cu]>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([NH:2][C@H:3]2[CH2:6][C@H:5]([N:7]3[C:11]4=[N:12][CH:13]=[CH:14][N:15]=[C:10]4[N:9]([CH:16]4[CH2:17][CH2:18]4)[C:8]3=[O:19])[CH2:4]2)=[N:22][CH:23]=1

Participants

6

Reactant 3

HCID 8170982-Bromo-5-chloropyridineHCID 5152919Cesium acetateHCID 178479284HCID 178479284, compound2×

Product 1

HCID 178516975HCID 178516975, compoundYield 3.8%

Reagents, catalysts & solvents 2

HCID 23978CopperCatalystHCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
100 °C

Procedure

To a round bottomed flask was added 1-(trans-3-aminocyclobutyl)-3-cyclopropyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one hydrochloride (Intermediate 79, 0.1128 g, 0.400 mmol), 2-bromo-5-chloropyridine (0.092 g, 0.480 mmol, Matrix Scientific), copper (2.035 mg, 0.032 mmol, Fisher Scientific), and cesium acetate (0.476 g, 2.482 mmol, Sigma-Aldrich Chemical Company, Inc.) in DMSO (0.500 ml) to stir at 100° C. for 2 days. The crude product was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 900 over 12 min. Fractions containing product peak were concentrated in vacuo. The product was taken up in DCM and loaded onto a Silicyle Si-carbonate cartridge to remove any salts to give the title compound (5.4 mg, 0.015 mmol, 3.8% yield). LCMS showed product peak at 1.448 min (m+1=356.9). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95-1.03 (m, 2 H) 1.02-1.09 (m, 2 H) 2.26-2.36 (m, 2 H) 2.96 (tt, J=7.09, 3.77 Hz, 1 H) 3.15-3.28 (m, 2 H) 4.42 (d, J=5.67 Hz, 1 H) 5.13 (quin, J=8.26 Hz, 1 H) 6.50 (d, J=9.00 Hz, 1 H) 7.30 (d, J=6.06 Hz, 1 H) 7.47 (dd, J=9.00, 2.54 Hz, 1 H) 7.92-8.03 (m, 3 H)

Workup

  1. customThe crude product was purified by reverse-phase preparative HPLC
  2. customover 12 min
  3. additionFractions containing product peak
  4. concentrationwere concentrated in vacuo
  5. customto remove any salts

Sources & evidence

ORD record
ord-28224ae849e44219bee128c8effac4b1
Source dataset
uspto-grants-2015_11
Patent number
US09174992B2

Reaction notes

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