Benzeneacetonitrile, 4-bromo- → HCID 118037358, compound

HRID 1509043Notes

Reaction equation

HRID 1509043 reaction equation
[Cl:1][C:2]1[C:3]([NH2:18])=[C:4]2[CH2:17][CH2:16][CH2:15][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1.Br[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]#[N:28])=[CH:22][CH:21]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[ClH:1].[Cl:1][C:2]1[C:3]([NH:18][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]#[N:28])=[CH:22][CH:21]=2)=[C:4]2[CH2:17][CH2:16][CH2:15][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1

Participants

7

Reactant 4

HCID 27914Benzeneacetonitrile, 4-bromo-3×HCID 62657Potassium Phosphate, TribasicHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl3×HCID 90338520HCID 90338520, compound

Product 1

HCID 118037358HCID 118037358, compoundYield 48.8%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst3×HCID 1140TolueneSolvent3×

Conditions

Temperature
100 °C

Procedure

A 20-mL vial, with stirrer bar, was charged with 3-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (0.110 g, 0.39 mmol), (4-bromophenyl)acetonitrile (0.085 g, 0.43 mmol), Pd2(dba)3 (0.011 g, 12 mmol), X-Phos (0.021 g, 0.043 mmol) and potassium phosphate (0.125 g, 0.49 mmol) in toluene (4 mL) at rt. The reaction mixture was placed under argon and stirred at 100° C. for 30 h. After this time, additional (4-bromophenyl)acetonitrile (0.085 g, 0.43 mmol), Pd2(dba)3 (0.011 g, 0.012 mmol) and X-Phos (0.021 g, 43 mmol) in toluene (1 mL) were added. After a further 16 h, an additional solution of (4-bromophenyl)acetonitrile (0.085 g, 0.43 mmol), Pd2(dba)3 (0.011 g, 0.012 mmol) and X-Phos (0.021 g, 43 mmol) in toluene (1 mL) was added and the reaction stirred for 23 h. The cooled reaction was filtered through celite and concentrated under reduced pressure. The residue was purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as the eluent followed by chromatography on silica using hexanes/ethyl acetate (10:0 to 1:1) as the eluent to afford the free base of the title compound (0.041 g, 26%) as an oil. MW=394.30. ESI MS m/z 394 [M+H]+. Treatment with 1.25M HCl in methanol (0.12 mL, 0.15 mmol, 1.5 eq.) followed by recrystallization from acetonitrile/water afforded the title compound (0.016 g, 38%) as an off-white solid. MW=430.76. M.p. 206-208° C. 1H NMR (DMSO-d6, 500 MHz) δ 8.70 (br s, 1H), 7.67 (s, 1H), 7.65-7.52 (m, 3H), 7.36-7.26 (m, 2H), 7.15-7.01 (m, 2H), 4.04 (s, 2H), 2.89 (t, J=7.5 Hz, 2H), 2.34-2.25 (m, 2H), 1.96 (quin, J=7.5 Hz, 2H); ESI MS m/z 395 [M+H]+.

Workup

  1. waitAfter a further 16 h
  2. stirringthe reaction stirred for 23 h
  3. customThe cooled reaction
  4. filtrationwas filtered through celite and
  5. concentrationconcentrated under reduced pressure
  6. customThe residue was purified by chromatography on silica

Sources & evidence

ORD record
ord-0216a9a117204bd0a312e2f06f0b532a
Source dataset
uspto-grants-2015_12
Patent number
US09221843B2

Reaction notes

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