Hydrochloric Acid → 6-Amino-4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethyloxyquinoline

HRID 902447Notes

Reaction equation

HRID 902447 reaction equation
[CH3:1][CH2:2][O:3][C:4]1[CH:9]=[C:8]2[N:10]=[CH:11][C:12]([C:15]#[N:16])=[C:13](Cl)[C:7]2=[CH:6][C:5]=1[NH:17]C(C)=O.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[F:29])[NH2:25].CC(O)C.Cl>CS(O)(=O)=O.O>[NH2:17][C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][C:4]=1[O:3][CH2:2][CH3:1])[N:10]=[CH:11][C:12]([C:15]#[N:16])=[C:13]2[NH:25][C:24]1[CH:26]=[CH:27][C:28]([F:29])=[C:22]([Cl:21])[CH:23]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 3776IsopropanolHCID 97083-Chloro-4-fluoroanilineHCID 11358234N-(4-Chloro-3-cyano-7-ethoxy-6-quinolinyl)acetamide

Product 1

HCID 110356856-Amino-4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethyloxyquinolineYield 102.1%

Reagents, catalysts & solvents 2

HCID 6395Methanesulfonic AcidCatalystHCID 962WaterSolvent

Conditions

Temperature
84 °C

Procedure

A stirred mixture of N-(4-chloro-3-cyano-7-ethoxy-6N-acetylquinoline (274.5 g, 0.947 mol), 3-chloro-4-fluoroaniline (180 g, 1.24 mol), methanesulfonic acid, (5.5 g, 0.057 mol), and 2-propanol (6.7 L) was warmed to reflux (84° C.) for 6.5 hours. After stirring overnight at room temperature, the mixture was warmed to 80° C. Water (3.2 L) containing concentrated hydrochloric acid (655 mL of 38% aqueous HCl) was added. The reaction was kept at reflux for 5 hours. The reaction mixture was cooled to 0° C.-10° C. for 1 hour. The yellow solid product is collected by vacuum filtration and washed with 20% 2-propanol/water (700 mL) and water (2×700 mL). Drying the product in vacuo at 60° C. gave 344.8 g (91%, 99% by HPLC) of 6-Amino-4-(3-chloro-4-fluoro-phenylamino)-7-ethoxy-quinoline-3-carbonitrile as a hydrochloride salt. 1H NMR (DMSO-d6+D2O) δ1.42 (t, 3H), 4.25 (q, 2H), 7.05 (m, 1H), 7.1 (s, 1H), 7.35-7.50 (m, 3H), 7.65 (dd, 1H), 8.65 (s, 1H).

Workup

  1. temperaturewas warmed
  2. temperaturethe mixture was warmed to 80° C
  3. additionwas added
  4. temperatureat reflux for 5 hours
  5. temperatureThe reaction mixture was cooled to 0° C.-10° C. for 1 hour
  6. filtrationThe yellow solid product is collected by vacuum filtration
  7. washwashed with 20% 2-propanol/water (700 mL) and water (2×700 mL)
  8. customDrying the product in vacuo at 60° C.

Sources & evidence

ORD record
ord-bf8dd87c10114edc8730bef8acc9b1b9
Source dataset
uspto-grants-2008_04
Patent number
US07365203B2

Reaction notes

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