HCID 68485937, compound → 3-{[3-(Aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-methylbenzonitrile

HRID 1874898Notes

Reaction equation

HRID 1874898 reaction equation
[NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17](Br)[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[CH3:21][Zn]C>C1COCC1.C1C=CC([P]([Pd]([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)=CC=1>[NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH3:21])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1

Participants

5

Reactant 2

HCID 68485937HCID 68485937, compoundHCID 178477796HCID 178477796, compound

Product 1

HCID 684881693-{[3-(Aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-methylbenzonitrileYield 14.1%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
65 °C

Procedure

3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (0.200 g, 0.562 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.065 g, 0.056 mmol) were combined in THF (4 mL) and treated with dimethylzinc (1 M in heptane) (1.125 mL, 1.125 mmol) with stirring under an inert atmosphere. The reaction mixture was heated to 65° C. and stirred for 1 h. The reaction mixture was concentrated to dryness, partitioned between EtOAc and saturated aqueous NaHCO3, the organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in CH3OH and gravity filtered through a StratoSpheres™ PL-Thiol MP SPE+ cartridge. The filtrate was cooled in an ice bath and the resultant precipitate filtered off to give 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-methylbenzonitrile (0.023 g, 0.079 mmol, 14.07% yield) as a white solid. The mother liquor was concentrated to dryness and purified on 40 g silica gel eluted successively with EtOAc and 10% CH3OH/DCM to give a second batch of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-methylbenzonitrile (0.072 g, 0.248 mmol, 44.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.45-7.53 (m, 2H), 7.42 (s, 1H), 7.19 (s, 1H), 7.10 (s, 1H), 3.76 (s, 2H), 2.33 (s, 3H), 1.99 (br. s., 2H). LC-MS (ES−) m/z 289.99, 291.15 [M−1]. LC-MS (ES+) m/z 290.98, 293.00 [M+H].

Workup

  1. stirringstirred for 1 h
  2. concentrationThe reaction mixture was concentrated to dryness
  3. custompartitioned between EtOAc and saturated aqueous NaHCO3
  4. customthe organic phase was isolated
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated to dryness
  8. dissolutionThe residue was dissolved in CH3OH
  9. filtrationgravity filtered through a StratoSpheres™ PL-Thiol MP SPE+ cartridge
  10. temperatureThe filtrate was cooled in an ice bath
  11. filtrationthe resultant precipitate filtered off

Sources & evidence

ORD record
ord-6482f24599324b5487f1011b12e8ff66
Source dataset
uspto-grants-2012_11
Patent number
US08304419B2

Reaction notes

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