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 1662033Notes

Reaction equation

HRID 1662033 reaction equation
[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

Participants

6

Reactant 2

HCID 313Hydrochloric Acid4×HCID 66766832HCID 66766832, compound

Product 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 hydrochlorideYield 92.8%

Reagents, catalysts & solvents 2

HCID 887MethanolSolvent6×HCID 6344DichloromethaneSolvent6×

Conditions

Temperature
30 °C

Procedure

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).

Workup

  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

Sources & evidence

ORD record
ord-21a26f25857f4fa69977c8f58733eec0
Source dataset
uspto-grants-2011_10
Patent number
US08030302B2

Reaction notes

Loading…