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

HRID 2402560Notes

Reaction equation

HRID 2402560 reaction equation
C(N(C(C)C)CC)(C)C.[NH:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:12]([C:19]2[N:24]=[C:23]([NH:25][C@:26]([CH3:32])([CH2:30][CH3:31])[C:27](O)=[O:28])[CH:22]=[CH:21][N:20]=2)=[CH:11]1.CCCP(=O)=O.[F:39][C:40]([F:44])([F:43])[CH2:41][NH2:42]>O.ClCCl>[NH:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:12]([C:19]2[N:24]=[C:23]([NH:25][C@:26]([CH3:32])([CH2:30][CH3:31])[C:27]([NH:42][CH2:41][C:40]([F:44])([F:43])[F:39])=[O:28])[CH:22]=[CH:21][N:20]=2)=[CH:11]1

Participants

7

Reactant 4

HCID 9773Ethanamine, 2,2,2-trifluoro-HCID 81531DiisopropylethylamineHCID 16167369Propylphosphoric anhydrideHCID 71187260HCID 71187260, compound

Product 1

HCID 59422203Decernotinib

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

Diisopropylethylamine (DIEA) (3.61 kg, 28.1 moles, 2.5 equiv.) was added to (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoic acid (4a) (3.5 kg, 11.24 moles, 1.0 equiv.) in 7 volumes (32.6 kg) of dichloromethane (CH2Cl2 or DCM) while keeping the temperature at ≦30° C. Water (0.103 kg) was added to make 5.5±0.5% total water content for the reaction system, and the mixture was stirred at ≦30° C. for at least 30 minutes. The reaction mixture was cooled to 0±5° C. Propylphosphonic anhydride solution (17.9 kg, 28.1 moles, 2.5 equiv.) was added to the mixture while maintaining the temperature below 20° C. The mixture was agitated for at least an hour keeping the temperature at 20±5° C., then 2,2,2-trifluoroethylamine (1.68 kg, 16.86 moles, 1.5 equiv.) was added while maintaining the temperature below 20° C. The reaction mixture was warmed to 25±5° C. and agitated for 5 hours while holding the temperature. A 1.0 mL aliquot was removed and the reaction was determined to be 100% complete. Water (17.5 kg, 5 volumes) was added to the reaction mixture, and the resultant mixture was agitated for at least 30 minutes while maintaining the temperature below 30° C.

Workup

  1. customat ≦30° C
  2. temperaturewhile maintaining the temperature below 20° C
  3. stirringThe mixture was agitated for at least an hour
  4. customat 20±5° C.
  5. temperaturewhile maintaining the temperature below 20° C
  6. temperatureThe reaction mixture was warmed to 25±5° C.
  7. stirringagitated for 5 hours
  8. customA 1.0 mL aliquot was removed
  9. additionWater (17.5 kg, 5 volumes) was added to the reaction mixture
  10. stirringthe resultant mixture was agitated for at least 30 minutes
  11. temperaturewhile maintaining the temperature below 30° C.

Sources & evidence

ORD record
ord-292daf299ec547d79dfe4ad323c9bf2e
Source dataset
uspto-grants-2014_08
Patent number
US08796453B2

Reaction notes

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