Trifluoroacetic acid → HCID 89923291, compound

HRID 921912Notes

Reaction equation

HRID 921912 reaction equation
[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]2)=[CH:6][C:5]([C:16]#[N:17])=[CH:4][C:3]=1[NH:18][C:19]1[N:24]=[C:23]([N:25]([CH:35]2[CH2:37][CH2:36]2)CC2C=CC(OC)=CC=2)[C:22]2=[N:38][CH:39]=[C:40]([C:41]#[N:42])[N:21]2[N:20]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.FC(F)(F)C([O-])=O>ClCCl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]2)=[CH:6][C:5]([C:16]#[N:17])=[CH:4][C:3]=1[NH:18][C:19]1[N:24]=[C:23]([NH:25][CH:35]2[CH2:36][CH2:37]2)[C:22]2=[N:38][CH:39]=[C:40]([C:41]#[N:42])[N:21]2[N:20]=1

Participants

6

Reactant 4

HCID 6422Trifluoroacetic acidHCID 7519AnisoleHCID 84468TrifluoroacetateHCID 89922871(+/-)-2-((2-Chloro-5-cyano-3-(2-(hydroxymethyl)morpholino)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

Product 1

HCID 89923291HCID 89923291, compoundYield 12.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a round bottom flask charged with (+/−)-2-((2-chloro-5-cyano-3-(2-(hydroxymethyl)morpholino)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (35.2 mg, 0.06 mmol) in dichloromethane (200 μl) was added anisole (32.8 μl, 0.300 mmol), followed by trifluoroacetic acid (185 μl, 2.400 mmol). The reaction mixture was stirred at room temperature ON. LCMS indicated primarily the trifluoroacetate product was present. Excess TFA was removed in vacuo. The residue was treated with toluene and concentrated in vacuo (2×). The crude solid was treated with 2 N NH3/MeOH (˜1.5 mL)—a solid immediately precipitated out. After 20 min, the solid was isolated by vacuum filtration. LCMS indicated the solid was the desired alcohol product. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 15-100% 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. (+/−)-2-((2-Chloro-5-cyano-3-(2-(hydroxymethyl)morpholino)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (3.5 mg) was isolated.

Workup

  1. customExcess TFA was removed in vacuo
  2. additionThe residue was treated with toluene
  3. concentrationconcentrated in vacuo (2×)
  4. additionThe crude solid was treated with 2 N NH3/MeOH (˜1.5 mL)
  5. customsolid immediately precipitated out
  6. customthe solid was isolated by vacuum filtration
  7. customThe crude material was purified via preparative LC/MS with the following conditions
  8. waitGradient: 15-100% B over 20 minutes
  9. customa 5-minute hold
  10. additionFractions containing the desired product
  11. customdried via centrifugal evaporation

Sources & evidence

ORD record
ord-339ec2329946462faad7dc7efe0b2958
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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