N-methyl-2-pyrrolidone → N-[4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide

HRID 1246286

Reaktionsgleichung

Reaktionsgleichung von HRID 1246286
CN1C(=O)CCC1.[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:28][CH2:29][CH3:30])=[C:24]([NH2:27])[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:31]#[N:32])[CH:12]=[CH:13][C:14]=1[F:15].Cl.[CH3:34][N:35]([CH3:42])[CH2:36][CH:37]=[CH:38][C:39](Cl)=[O:40].C(=O)(O)[O-].[Na+]>CC#N.O>[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:28][CH2:29][CH3:30])=[C:24]([NH:27][C:39](=[O:40])[CH:38]=[CH:37][CH2:36][N:35]([CH3:42])[CH3:34])[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:31]#[N:32])[CH:12]=[CH:13][C:14]=1[F:15]

Komponenten

7

Edukt 4

HCID 13387N-methyl-2-pyrrolidoneHCID 516892Sodium BicarbonateHCID 110356856-Amino-4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethyloxyquinolineHCID 738532534-(Dimethylamino)-2-butenoyl chloride hydrochloride

Produkt 1

HCID 216467N-[4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 962WaterLösungsmittelHCID 6342AcetonitrileLösungsmittel

Versuchsvorschrift

A 3 L multi-neck flask equipped with agitator, thermometer, dip tube, and nitrogen protection is charged N-methyl pyrrolidinone (0.77 kg, 0.75 L, d=1.033 g/mL). At ambient temperature is added 4-[3-chloro-4-fluorophenyl]amino-6-amino-3-cyano-7-ethoxy quinoline (0.0748 kg). The reaction mixture is heated to 40–45° C. and maintained for about (15 minutes). The reaction mixture is cooled to (0–10° C.) and the light suspension of 4-(dimethylamino)-2-butenoyl chloride hydrochloride in CH3CN added via dip tube and positive nitrogen pressure, over (30–45 minutes) while maintaining the temperature (0–10° C.) for at least (2 hours). Reaction completion is monitored by HPLC. The reaction is complete when there is ≦2% of the starting material (4-[3-chloro-4-fluorophenyl]amino-6-amino-3-cyano-7-ethoxy quinoline) present. To a 12 L multi-neck flask equipped with agitator, thermometer, dip tube, and nitrogen protection is charged with water (2.61 kg, 2.61 L) and sodium bicarbonate (0.209 kg) with stirring until a solution is obtained followed by cooling to (20–24° C.) to which is transferred the reaction mixture above which contains ≦2% of the starting material (4-[3-chloro-4-fluorophenyl]amino-6-amino-3-cyano-7-ethoxy quinoline), via dip tube and positive nitrogen pressure, to the 12 L flask over about (45–60 minutes) while maintaining the temperature at (20–24° C.). The temperature is maintained at (20–24° C.) for at least (1 hour). Filter the reaction mixture on a Buchner funnel, rinse with water (3×0.40 kg, 3×0.40 L), and maintain suction until dripping stops. Dry the product in a vacuum oven at about (50° C.) and about (10 mm Hg) for about (28–30 hours). The yield is 78.5 g (86%) at 79.7% strength and 12.3% total impurities.

Aufarbeitung

  1. customA 3 L multi-neck flask equipped with agitator
  2. temperatureThe reaction mixture is heated to 40–45° C.
  3. temperaturemaintained for about (15 minutes)
  4. temperatureThe reaction mixture is cooled to (0–10° C.)
  5. additionadded via dip tube
  6. temperaturepositive nitrogen pressure, over (30–45 minutes) while maintaining the temperature (0–10° C.) for at least (2 hours)
  7. customReaction completion
  8. customTo a 12 L multi-neck flask equipped with agitator
  9. customis obtained
  10. temperatureby cooling to (20–24° C.) to which
  11. temperaturevia dip tube and positive nitrogen pressure, to the 12 L flask over about (45–60 minutes) while maintaining the temperature at (20–24° C.)
  12. temperatureThe temperature is maintained at (20–24° C.) for at least (1 hour)
  13. filtrationFilter the reaction mixture on a Buchner funnel
  14. washrinse with water (3×0.40 kg, 3×0.40 L)
  15. temperaturemaintain suction
  16. customDry the product in a vacuum oven at about (50° C.)
  17. customfor about (28–30 hours)

Quellen und Nachweise

ORD-Eintrag
ord-250c84a621bb42ef997ef00601bff470
Quelldatensatz
uspto-grants-2006_10
Patentnummer
US07126025B2

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