4-Methylmorpholine → HCID 178461816, compound

HRID 1424200Notes

Reaction equation

HRID 1424200 reaction equation
[CH2:1]([O:8][C:9](=[O:24])[CH:10]([CH3:23])[C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12](O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:56][C:57]1[CH:58]=[C:59]([C:64]2[CH:69]=[CH:68][C:67]([C:70]#[N:71])=[C:66]([F:72])[CH:65]=2)[CH:60]=[CH:61][C:62]=1[NH2:63]>CN(C=O)C.O>[C:19]([O:18][C:16]([NH:15][C@H:11]([C:12]1[NH:63][C:62]2[CH:61]=[CH:60][C:59]([C:64]3[CH:69]=[CH:68][C:67]([C:70]#[N:71])=[C:66]([F:72])[CH:65]=3)=[CH:58][C:57]=2[N:56]=1)[C@@H:10]([CH3:23])[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:24])=[O:17])([CH3:22])([CH3:21])[CH3:20]

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 86699113(2S)-4-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-3-methyl-4-oxobutanoic acidHCID 866991143',4'-Diamino-3-fluoro-[1,1'-biphenyl]-4-carbonitrile

Product 1

HCID 178461816HCID 178461816, compound

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of (2S)-4-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-3-methyl-4-oxobutanoic acid (Preparation 66, 713 mg, 2.11 mmol) in DMF (15 mL) was added NMM (267 mg, 2.64 mmol) and the mixture was cooled to 0° C. HATU (871 mg, 2.29 mmol) was added and the reaction stirred warming to room temperature for 2 hours. 3′,4′-diamino-3-fluoro-[1,1′-biphenyl]-4-carbonitrile (Preparation 81, 400 mg, 1.76 mmol) was added and the reaction stirred at room temperature for 18 hours. The reaction was diluted with water and extracted with EtOAc. The organic layer was collected, dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 20-40% EtOAc in heptanes. The residue was dissolved in AcOH (10 mL) and heated to 40° C. for 2 days. The reaction was cooled and concentrated in vacuo, azeotroping with DCM to afford a foam. The residue was purified using silica gel column chromatography eluting with DCM:EtOAc 94:6 to afford the title compound.

Workup

  1. temperaturewarming to room temperature for 2 hours
  2. stirringthe reaction stirred at room temperature for 18 hours
  3. extractionextracted with EtOAc
  4. customThe organic layer was collected
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified
  8. washeluting with 20-40% EtOAc in heptanes
  9. dissolutionThe residue was dissolved in AcOH (10 mL)
  10. temperatureheated to 40° C. for 2 days
  11. temperatureThe reaction was cooled
  12. concentrationconcentrated in vacuo
  13. customazeotroping with DCM
  14. customto afford a foam
  15. customThe residue was purified
  16. washeluting with DCM:EtOAc 94:6

Sources & evidence

ORD record
ord-08989691e2fa4b91a8e5c61d1bf91a6b
Source dataset
uspto-grants-2015_01
Patent number
US08927587B2

Reaction notes

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