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

HRID 2402561
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HRID 2402561 반응식
[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
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참가 물질

6

반응물 4

HCID 9773Ethanamine, 2,2,2-trifluoro-HCID 10340Sodium CarbonateHCID 111923Propylphosphonic anhydrideHCID 71187260HCID 71187260, 화합물2회

생성물 1

HCID 59422203Decernotinib

시약·촉매·용매 1

HCID 73012-Methyltetrahydrofuran
용매

반응 조건

온도
62.5 °C

실험 절차

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).

후처리

  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.

출처 및 근거

ORD 기록
ord-bbb7288148244385b5f479a19c414351
출처 데이터셋
uspto-grants-2014_08
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US08796453B2

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