Acetic Acid → 2-((2-Chloro-5-cyano-3-(1-methylpiperidin-4-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

HRID 921663Notes

Reaction equation

HRID 921663 reaction equation
[C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:21]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:20][C:19]([C:28]#[N:29])=[CH:18][C:17]=1[NH:30][C:31]1[N:36]=[C:35]([N:37]([CH:47]2[CH2:49][CH2:48]2)CC2C=CC(OC)=CC=2)[C:34]2=[N:50][CH:51]=[C:52]([C:53]#[N:54])[N:33]2[N:32]=1.C=O.O.CC(O)=O.C([O-])(O)=O.[Na+].C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:15][C:16]1[C:21]([CH:22]2[CH2:23][CH2:24][N:25]([CH3:1])[CH2:26][CH2:27]2)=[CH:20][C:19]([C:28]#[N:29])=[CH:18][C:17]=1[NH:30][C:31]1[N:36]=[C:35]([NH:37][CH:47]2[CH2:49][CH2:48]2)[C:34]2=[N:50][CH:51]=[C:52]([C:53]#[N:54])[N:33]2[N:32]=1

Participants

10

Reactant 8

HCID 176Acetic AcidHCID 712FormaldehydeHCID 962WaterHCID 6422Trifluoroacetic acidHCID 7519AnisoleHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydrideHCID 867085292-((2-Chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

Product 1

HCID 867085282-((2-Chloro-5-cyano-3-(1-methylpiperidin-4-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrileYield 87.5%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Conditions

Temperature
50 °C

Procedure

Sodium triacetoxyborohydride (24.10 mg, 0.114 mmol) was added to a stirred suspension of 2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (30.0 mg, 0.038 mmol), formaldehyde 37% in water (8.47 μL, 0.114 mmol) and HOAc (16.27 μL, 0.190 mmol) in DCE (379 μL) at room temperature for 30 min. Sat. aq. NaHCO3 solution was slowly added (gas evolution) and the reaction was left stirring for 10 min. It was extracted with DCM. The organic phase was dried with sodium sulfate and the solvents were removed. The crude intermediate was dissolved in DCE (1 mL) and anisole (20.70 μL, 0.190 mmol), and TFA (0.5 mL) were added. The resulting mixture was heated at 50° C. for 3 h. Removal of the solvents was followed by preparative HPLC (Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 methanol: water with 20-mM ammonium acetate; Gradient: 40-80% B over 20 minutes, then a 5-minute hold at 100%. B; Flow: 20 mL/min.). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 14.9 mg of 2-((2-chloro-5-cyano-3-(1-methylpiperidin-4-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile.

Workup

  1. waitthe reaction was left
  2. extractionIt was extracted with DCM
  3. dry with materialThe organic phase was dried with sodium sulfate
  4. customthe solvents were removed
  5. dissolutionThe crude intermediate was dissolved in DCE (1 mL)
  6. customRemoval of the solvents
  7. waitGradient: 40-80% B over 20 minutes
  8. customa 5-minute hold
  9. additionFractions containing the desired product
  10. customdried via centrifugal evaporation

Sources & evidence

ORD record
ord-e8c99da390ba4adab0c4f0a87b3f38de
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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