Isopropanol → 4-(4-amino-2-fluorophenoxy)-3-chloro-N-(diphenylmethylene)pyridin-2-amine

HRID 408045Notes

Reaction equation

HRID 408045 reaction equation
[Cl:1][C:2]1[C:3]([N:19]=[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[F:18].C(O)(C)C.[NH4+]=S>O>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:7]2[CH:6]=[CH:5][N:4]=[C:3]([N:19]=[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:2]=2[Cl:1])=[C:10]([F:18])[CH:11]=1

Participants

4

Reactant 2

HCID 3776IsopropanolHCID 581336033-chloro-N-(diphenylmethylene)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine2×

Product 1

HCID 581336014-(4-amino-2-fluorophenoxy)-3-chloro-N-(diphenylmethylene)pyridin-2-amineYield 103.2%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
20 °C

Procedure

The following materials were added to a 2-L Chem-Glass reactor: 3-chloro-N -(diphenylmethylene)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine (110.00 g, 221 mmol), isopropyl alcohol (990.00 mL), and ammonium sulfide (˜40% in water, 297.00 mL, 2324 mmol). The mixture was allowed to stir at 20° C. for 3-4 h. 3-Chloro-N -(diphenylmethylene)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine was not detected by HPLC analysis. The reaction mixture was heated to 70° C. and allowed to stir for 3-4 h. Once the reaction was complete, water (14 mL/g·LR) was added. The reaction mixture was cooled to 20° C. (reaction temp) over 1 h. Upon cooling a solid precipitated and was filtered off and washed with water (12.5 mL/g·LR), followed by heptane:MTBE (4:1; 5 mL/g·LR). After LOD (˜25%), 95.3 g of crude 4-(4-amino-2-fluorophenoxy )-3-chloro-N-(diphenylmethylene)pyridin-2-amine (90AP) was obtained. The crude 4-(4-amino-2-fluorophenoxy)-3-chloro-N-(diphenylmethylene)pyridin-2-amine was dissolved into n-BuOAc (7 mL/g·LR) by heating to approximately 85° C. At 85° C., heptane (7 mL/g·LR) was added dropwise until the solution became cloudy. The solution was then allowed to cool to 20° C. with stirring. Once at 20° C., the slurry was aged for 8 h. The solid was filtered, washed with heptane (5 mL/g·LR), and then dried overnight in a vacuum oven at 60° C. to afford 4-(4-amino-2-fluorophenoxy)-3-chloro-N-(diphenylmethylene)pyridin-2-amine (62.53 g; 67.69% yield) as a faint yellow solid. 1H NMR (CDCl3) δ 6.23 (dd, 1 H, J=1.0, 5.6 Hz), 6.43 (m, 1 H), 6.49 (dd, 1 H, J=2.5, 12.1 Hz), 6.92 (t, 1 H, J=8.6 Hz), 7.25-7.60 (m, 8 H), 7.87 (m, 2 H), 7.95 (d, 1 H, J=6.1 Hz); MS (ESI+) m/z 418.6 (M +H)+.

Workup

  1. temperatureThe reaction mixture was heated to 70° C.
  2. stirringto stir for 3-4 h
  3. temperatureThe reaction mixture was cooled to 20° C.
  4. custom(reaction temp) over 1 h
  5. temperatureUpon cooling a solid
  6. customprecipitated
  7. filtrationwas filtered off
  8. washwashed with water (12.5 mL/g·LR)

Sources & evidence

ORD record
ord-b063babd6ebe45918ff650ac392f1bba
Source dataset
uspto-grants-2014_06
Patent number
US08754230B2

Reaction notes

Loading…