Hydrochloric Acid → N-(3-fluoro-4-(1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yloxy)phenyl)-1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide hydrochloride

HRID 1662033노트

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HRID 1662033 반응식
[F:1][C:2]1[CH:30]=[C:29]([NH:31][C:32]([C:34]2[C:35](=[O:48])[N:36]([C:41]3[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=3)[C:37]([CH3:40])=[CH:38][CH:39]=2)=[O:33])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]1[CH:15]=[N:16][N:17](C(OC(C)(C)C)=O)[CH:18]=1)[N:10]([CH3:26])[N:9]=[CH:8]2.[ClH:49]>C(Cl)Cl.CO>[F:1][C:2]1[CH:30]=[C:29]([NH:31][C:32]([C:34]2[C:35](=[O:48])[N:36]([C:41]3[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=3)[C:37]([CH3:40])=[CH:38][CH:39]=2)=[O:33])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]1[CH:15]=[N:16][NH:17][CH:18]=1)[N:10]([CH3:26])[N:9]=[CH:8]2.[ClH:49].[F:1][C:2]1[CH:30]=[C:29]([NH:31][C:32]([C:34]2[C:35](=[O:48])[N:36]([C:41]3[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=3)[C:37]([CH3:40])=[CH:38][CH:39]=2)=[O:33])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]1[CH:15]=[N:16][NH:17][CH:18]=1)[N:10]([CH3:26])[N:9]=[CH:8]2

참가 물질

6

반응물 2

HCID 313Hydrochloric Acid4회HCID 66766832HCID 66766832, 화합물

생성물 2

HCID 44603533MerestinibHCID 66767273N-(3-fluoro-4-(1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yloxy)phenyl)-1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide hydrochloride수율 92.8%

시약·촉매·용매 2

HCID 887Methanol용매6회HCID 6344Dichloromethane용매6회

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온도
30 °C

실험 절차

tert-Butyl 4-(5-(2-fluoro-4-(1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)-1-methyl-1H-indazol-6-yl)-1H-pyrazole-1-carboxylate (423.9 g, 649.50 mmol) is dissolved in DCM (4.24 L). HCl in MeOH (5.74 N, 799.99 mL, 4.59 mol) is added and the solution is heated at 30° C. for 1 hour. Then the reaction mixture is heated to 45° C. and DCM (1.5 L) is added. After two hours, the solution is heated to 50° C. and DCM (2 L) is added. After 3 hours, DCM (2 L) is added followed by HCl in MeOH (4.5 N, 721.67 mL, 3.25 mol). After another 45 min, DCM (1 L), HCl in MeOH (4.5 N, 288.67 mL, 1.30 mol), and MeOH (1.5 L) are added. The reaction solution is then heated to 60° C. After 4 hours, MeOH (2 L) is added and 10 min later DCM (1 L) is added followed by HCl in MeOH (4.5 N, 200 mL). After 5 hours, the reaction is complete. The reaction mixture is concentrated to about ⅓ volume. MeOH (2 L) is added and the solution is concentrated to a thick slurry. Again, MeOH (2 L) is added and the mixture is concentrated to a thick slurry. The slurry is cooled to about 10-15° C. and then filtered. The solids are washed with MeOH. The solids are placed in a 55° C. vacuum oven for 2 days to give the desired product N-(3-fluoro-4-(1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yloxy)phenyl)-1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide hydrochloride (377 g, 92.8%). MS (m/z): 551.0 (M−H).

후처리

  1. temperatureThen the reaction mixture is heated to 45° C.
  2. temperaturethe solution is heated to 50° C.
  3. waitAfter 3 hours
  4. waitAfter another 45 min
  5. temperatureThe reaction solution is then heated to 60° C
  6. waitAfter 4 hours
  7. additionis added
  8. waitAfter 5 hours
  9. concentrationThe reaction mixture is concentrated to about ⅓ volume
  10. additionMeOH (2 L) is added
  11. concentrationthe solution is concentrated to a thick slurry
  12. additionAgain, MeOH (2 L) is added
  13. concentrationthe mixture is concentrated to a thick slurry
  14. temperatureThe slurry is cooled to about 10-15° C.
  15. filtrationfiltered
  16. washThe solids are washed with MeOH
  17. customare placed in a 55° C.
  18. customfor 2 days

출처 및 근거

ORD 기록
ord-21a26f25857f4fa69977c8f58733eec0
출처 데이터셋
uspto-grants-2011_10
특허 번호
US08030302B2

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