Dimethylformamide → 3-{[3-(Aminomethyl)-6-chloro-2-fluorophenyl]oxy}-4-chloro-5-fluorobenzonitrile

HRID 1874916Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1874916
Br[C:2]1[CH:3]=[C:4]([F:20])[C:5]([Cl:19])=[C:6]([O:8][C:9]2[C:10]([F:18])=[C:11]([CH2:16][NH2:17])[CH:12]=[CH:13][C:14]=2[Cl:15])[CH:7]=1.[C:21]([Zn]C#N)#[N:22].CN(C=O)C>C(O)CC.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>[NH2:17][CH2:16][C:11]1[C:10]([F:18])=[C:9]([O:8][C:6]2[CH:7]=[C:2]([CH:3]=[C:4]([F:20])[C:5]=2[Cl:19])[C:21]#[N:22])[C:14]([Cl:15])=[CH:13][CH:12]=1

Komponenten

6

Edukt 3

HCID 6228DimethylformamideHCID 68480394({3-[(5-Bromo-2-chloro-3-fluorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)amineHCID 178514179HCID 178514179, Verbindung

Produkt 1

HCID 684872203-{[3-(Aminomethyl)-6-chloro-2-fluorophenyl]oxy}-4-chloro-5-fluorobenzonitrileAusbeute 89,8 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 178418397HCID 178418397, VerbindungKatalysatorHCID 10311-PropanolLösungsmittel

Reaktionsbedingungen

Temperatur
120 °C

Versuchsvorschrift

({3-[(5-bromo-2-chloro-3-fluorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)amine (3.00 g, 7.83 mmol) was combined with dicyanozinc (0.460 g, 3.92 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.453 g, 0.392 mmol) in n-propanol (15 mL) and heated at 120° C. for 25 min in a microwave reactor under an inert atmosphere. DMF (8 mL) was added and the reaction mixture was again heated at 120° C. for 90 min in a microwave reactor at which time LC-MS indicated complete conversion. The reaction mixture was concentrated to remove the n-propanol, diluted with EtOAc, washed four times with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 80 g silica gel eluted successively with EtOAc followed by 0 to 10% CH3OH/DCM to give 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-4-chloro-5-fluorobenzonitrile (1.16 g, 3.52 mmol, 45.0% yield) as a pale yellow oil which crystallized on standing. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92 (dd, J=8.65, 1.51 Hz, 1H), 7.47-7.58 (m, 2 H), 7.25 (s, 1H), 3.77 (s, 2H), 1.93 (br. s., 2H). LC-MS (ES−) m/z 326.96, 329.05 [M−1]. LC-MS (ES+) m/z 329.00, 330.96 [M+H].

Aufarbeitung

  1. temperaturethe reaction mixture was again heated at 120° C. for 90 min in a microwave reactor at which time LC-MS
  2. concentrationThe reaction mixture was concentrated
  3. customto remove the n-propanol
  4. additiondiluted with EtOAc
  5. washwashed four times with saturated aqueous NaHCO3
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated to dryness
  9. customThe residue was purified on 80 g silica gel
  10. washeluted successively with EtOAc

Quellen und Nachweise

ORD-Eintrag
ord-7350920764824a688229bb68c81f2da3
Quelldatensatz
uspto-grants-2012_11
Patentnummer
US08304419B2

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