Trifluoroacetic acid → 2-((3-(4-(1-Acetylazetidin-3-yl)piperazin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

HRID 921823Notes

Reaction equation

HRID 921823 reaction equation
[C:1]([N:4]1[CH2:7][CH:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:15]([Cl:47])=[C:16]([NH:22][C:23]4[N:28]=[C:27]([N:29]([CH:39]5[CH2:41][CH2:40]5)CC5C=CC(OC)=CC=5)[C:26]5=[N:42][CH:43]=[C:44]([C:45]#[N:46])[N:25]5[N:24]=4)[CH:17]=[C:18]([C:20]#[N:21])[CH:19]=3)[CH2:10][CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[C:1]([N:4]1[CH2:7][CH:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:15]([Cl:47])=[C:16]([NH:22][C:23]4[N:28]=[C:27]([NH:29][CH:39]5[CH2:40][CH2:41]5)[C:26]5=[N:42][CH:43]=[C:44]([C:45]#[N:46])[N:25]5[N:24]=4)[CH:17]=[C:18]([C:20]#[N:21])[CH:19]=3)[CH2:10][CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2]

Participants

5

Reactant 3

HCID 6422Trifluoroacetic acidHCID 7519AnisoleHCID 1182533432-((3-(4-(1-Acetylazetidin-3-yl)piperazin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

Product 1

HCID 899225942-((3-(4-(1-Acetylazetidin-3-yl)piperazin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrileYield 55.6%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of 2-((3-(4-(1-acetylazetidin-3-yl)piperazin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (110 mg, 0.169 mmol) in DCE (1.1 mL) and anisole (0.108 mL, 0.985 mmol) was added TFA (0.296 mL, 3.84 mmol) slowly drop wise at room temperature and the reaction mixture was heated at 50° C. for overnight. The reaction mixture was concentrated to remove solvent completely; the resultant residue was washed with hexane to remove anisole. The residue was diluted with Ethyl acetate, washed with aq. ammonia solution, brine, dried over Na2SO4 and concentrated. The crude material was purified by reverse phase HPLC, the fractions were concentrated and the resultant solid was dissolved in HPLC grade Chloroform (20 ml), washed with 10% NaHCO3 solution, brine, dried over Na2SO4 and concentrated. The solid was dissolved in Acetonitrile/water (1:3). Froze the mixture using a dry-ice acetone bath and then dried under lyophilization for 2 days. Lyophlization afforded 2-((3-(4-(1-acetylazetidin-3-yl)piperazin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (50 mg) as a off white solid.

Workup

  1. customslowly drop wise at room temperature
  2. concentrationThe reaction mixture was concentrated
  3. customto remove solvent completely
  4. washthe resultant residue was washed with hexane
  5. customto remove anisole
  6. additionThe residue was diluted with Ethyl acetate
  7. washwashed with aq. ammonia solution, brine
  8. dry with materialdried over Na2SO4
  9. concentrationconcentrated
  10. customThe crude material was purified by reverse phase HPLC
  11. concentrationthe fractions were concentrated
  12. dissolutionthe resultant solid was dissolved in HPLC grade Chloroform (20 ml)
  13. washwashed with 10% NaHCO3 solution, brine
  14. dry with materialdried over Na2SO4
  15. concentrationconcentrated
  16. dissolutionThe solid was dissolved in Acetonitrile/water (1:3)
  17. customdried under lyophilization for 2 days

Sources & evidence

ORD record
ord-1dea1e4a0ca1472ca5249f3d1585f383
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

Loading…