Ethanamine, 2,2,2-trifluoro- → Decernotinib

HRID 1894936Notes

Reaction equation

HRID 1894936 reaction equation
[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[N:15]=[C:14]([NH:16][C@:17]([CH3:23])([CH2:21][CH3:22])[C:18](O)=[O:19])[CH:13]=[CH:12][N:11]=2)=[CH:2]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[F:42][C:43]([F:47])([F:46])[CH2:44][NH2:45].C([O-])([O-])=O.[Na+].[Na+]>CC1OCCC1>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[N:15]=[C:14]([NH:16][C@:17]([CH3:23])([CH2:21][CH3:22])[C:18]([NH:45][CH2:44][C:43]([F:47])([F:46])[F:42])=[O:19])[CH:13]=[CH:12][N:11]=2)=[CH:2]1

Participants

6

Reactant 4

HCID 9773Ethanamine, 2,2,2-trifluoro-HCID 10340Sodium CarbonateHCID 111923Propylphosphonic anhydrideHCID 71187260HCID 71187260, compound2×

Product 1

HCID 59422203Decernotinib

Reagents, catalysts & solvents 1

HCID 73012-MethyltetrahydrofuranSolvent

Conditions

Temperature
62.5 °C

Procedure

To (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoic acid (4a) (limiting reagent) charge 2-methylTHF (7.5 vol), then charge T3P® (2.0 eq, 50% w/w in 2-MeTHF). Heat the mixture to 60-65° C. and maintain this temperature for no less than 3 hrs and the solids are completely dissolved. Cool to 20-25° C. then charge 2,2,2-trifluoroethylamine (2.0 eq). Continue agitation for no less than 6 hrs at 20-25° C. and until HPLC analysis showed <1.0% of (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoic acid (4a). Slowly charge a Na2CO3 solution (15 vol, 1.165M) while maintaining a batch temperature <30° C. Stir the mixture for 30 min then separate the phases. Wash the organic phase with water (4 vol). Emulsions have been observed at this point and can be addressed through addition of NaCl solution. Charge methanol (7 vol) then distill to 4 vol. Repeat 3 times. Prior to crystallization, adjust the total volume to approximately 11 vol. Heat the mixture to 50-55° C. then add water (2.45 vol, final solvent composition 22% water in methanol) over 30 min. Seed the batch with (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide (Ia) (1 wt % seed based on the compound of Formula (4a)). Stir for 4 hrs at 50-55° C. then add water over 24 h until the mixture is approximately 58 wt % water in methanol. Cool to 20-25° C., stir 1 h, then filter. Wash the cake with water (2 vol). Dry the solids at 60-65° C. to give (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide (Ia).

Workup

  1. temperaturemaintain this temperature for no less than 3 hrs
  2. dissolutionthe solids are completely dissolved
  3. temperatureCool to 20-25° C.
  4. waitContinue agitation for no less than 6 hrs at 20-25° C.
  5. temperaturewhile maintaining a batch temperature <30° C
  6. customthen separate the phases
  7. washWash the organic phase with water (4 vol)
  8. additioncan be addressed through addition of NaCl solution
  9. distillationCharge methanol (7 vol) then distill to 4 vol. Repeat 3 times
  10. customPrior to crystallization
  11. temperatureHeat the mixture to 50-55° C.
  12. waitadd water (2.45 vol, final solvent composition 22% water in methanol) over 30 min
  13. stirringStir for 4 hrs at 50-55° C.
  14. waitadd water over 24 h until the mixture is
  15. temperatureCool to 20-25° C.
  16. stirringstir 1 h
  17. filtrationfilter
  18. washWash the cake with water (2 vol)
  19. customDry the solids at 60-65° C.

Sources & evidence

ORD record
ord-6578f6528fa548fd8d9191d305820bef
Source dataset
uspto-grants-2013_08
Patent number
US08513414B2

Reaction notes

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