Hydrochloric Acid → HCID 57418753, compound

HRID 1665996Notes

Reaction equation

HRID 1665996 reaction equation
[NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[CH3:18].C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.[N:31](OCCC(C)C)=O.Cl.[OH-].[Na+]>C(Cl)(Cl)Cl.O>[NH:1]1[C:2]2[C:3](=[CH:4][C:5]([O:6][C:7]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:8]=3[C:9]#[N:10])=[CH:16][CH:17]=2)[CH:18]=[N:31]1

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 7918Acetic AnhydrideHCID 8053Isoamyl NitriteHCID 14798Sodium HydroxideHCID 517044Potassium AcetateHCID 574187552-(4-Amino-3-methylphenoxy)-5-fluorobenzonitrile

Product 1

HCID 57418753HCID 57418753, compoundYield 91.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6212ChloroformSolvent2×

Conditions

Temperature
0 °C

Procedure

In a 500 mL one-necked flask containing a large magnetic stir bar, 2-(4-amino-3-methylphenoxy)-5-fluorobenzonitrile (274.5 ml, 219.6 mmol) was taken up in chloroform (0.8 M) and treated with potassium acetate (25.86 g, 263.5 mmol) at room temperature. The reaction mixture was cooled to 0° C. and treated with acetic anhydride (62.28 mL, 658.8 mmol) via addition funnel over 5 minutes. The reaction was fitted with a reflux condenser, treated with additional 100 mL chloroform, and heated to 40° C. Isoamyl nitrite (58.74 mL, 439.2 mmol) was added dropwise via an addition funnel. The addition funnel was rinsed with 60 mL+40 mL of chloroform, removed, and replaced with a glass stopper. The reaction was heated to reflux for 20 hours, cooled to room temperature, and concentrated in vacuo to a brown solid. After being dried under high vacuum for 30 minutes, the brown solid was suspended in 1 L water, stirred vigorously for 15 minutes, and filtered. The resulting orange-brown solid (83 g) was taken up in 400 mL MeOH and treated with 1.0 M hydrochloric acid (241.6 mL, 241.6 mmol) at room temperature. The mixture was fitted with a reflux condenser and warmed to 70° C. for 20 hours. The reaction was cooled to 0° C. and 1.0 M sodium hydroxide (252.6 mL, 252.6 mmol) was added, followed by water (250 mL). The resulting yellow suspension was stirred in the ice bath for 10 minutes and then allowed to settle. The suspension was filtered, washed with water (1 L), air dried, dried with latex dam, and dried under high vacuum at 40° C. for 36 hours, to provide 50.7 g (91%) of the desired product as a free-flowing tan solid. MS (APCI+) m/z 254 (M+1) detected. 1H NMR (400 MHz, DMSO-d6) δ 13.38 (br, 1H), 8.07 (s, 1H), 7.94 (dd, 1H, J=3,1 Hz, J=8.2 Hz), 7.64 (d, 1H, J=9 Hz), 7.54 (m, 2H), 7.21 (dd, 1H, J=9 Hz), 6.96 (dd, 1H, J=4.3 Hz, J=9.3 Hz).

Workup

  1. customThe reaction was fitted with a reflux condenser
  2. temperatureheated to 40° C
  3. washThe addition funnel was rinsed with 60 mL+40 mL of chloroform
  4. customremoved
  5. temperatureThe reaction was heated
  6. temperatureto reflux for 20 hours
  7. temperaturecooled to room temperature
  8. concentrationconcentrated in vacuo to a brown solid
  9. customAfter being dried under high vacuum for 30 minutes
  10. filtrationfiltered
  11. customThe mixture was fitted with a reflux condenser
  12. temperaturewarmed to 70° C. for 20 hours
  13. temperatureThe reaction was cooled to 0° C.
  14. filtrationThe suspension was filtered
  15. washwashed with water (1 L), air
  16. customdried
  17. customdried with latex dam
  18. customdried under high vacuum at 40° C. for 36 hours

Sources & evidence

ORD record
ord-4b0fa8eaf5814cf0a71e7b61f80bbd8f
Source dataset
uspto-grants-2011_10
Patent number
US08039639B2

Reaction notes

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