Trifluoroacetic acid → 2-((2-chloro-5-cyano-3-(1,1-dioxidotetrahydro-2H-isothiazolo[2,3-a]pyrazin-5 (3H)-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

HRID 921953Notes

Reaction equation

HRID 921953 reaction equation
C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:14]([N:15]2[CH2:20][CH2:19][N:18]3[S:21](=[O:25])(=[O:24])[CH2:22][CH2:23][CH:17]3[CH2:16]2)=[CH:13][C:12]([C:26]#[N:27])=[CH:11][C:10]=1[NH:28][C:29]1[N:34]=[C:33]([N:35]([CH:45]2[CH2:47][CH2:46]2)CC2C=CC(OC)=CC=2)[C:32]2=[N:48][CH:49]=[C:50]([C:51]#[N:52])[N:31]2[N:30]=1.C1(OC)C=CC=CC=1>ClCCCl>[Cl:8][C:9]1[C:14]([N:15]2[CH2:20][CH2:19][N:18]3[S:21](=[O:25])(=[O:24])[CH2:22][CH2:23][CH:17]3[CH2:16]2)=[CH:13][C:12]([C:26]#[N:27])=[CH:11][C:10]=1[NH:28][C:29]1[N:34]=[C:33]([NH:35][CH:45]2[CH2:46][CH2:47]2)[C:32]2=[N:48][CH:49]=[C:50]([C:51]#[N:52])[N:31]2[N:30]=1

Participants

5

Reactant 3

HCID 6422Trifluoroacetic acidHCID 7519AnisoleHCID 1182533652-((2-chloro-5-cyano-3-(1,1-dioxidotetrahydro-2H-isothiazolo[2,3-a]pyrazin-5 (3H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

Product 1

HCID 1182534042-((2-chloro-5-cyano-3-(1,1-dioxidotetrahydro-2H-isothiazolo[2,3-a]pyrazin-5 (3H)-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrileYield 48.6%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Conditions

Temperature
60 °C

Procedure

TFA (0.107 mL, 1.390 mmol) was added to a solution of 2-((2-chloro-5-cyano-3-(1,1-dioxidotetrahydro-2H-isothiazolo[2,3-a]pyrazin-5(3H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (13 mg, 0.020 mmol) and anisole (8.80 μl, 0.081 mmol) in DCE (0.3 mL) and the reaction mixture was heated at 60° C. for 1 hours. The solvent was removed in vacuo and the material azeotroped with toluene 3× to remove the excess TFA. 2 ml of 2N NH3 in MeOH was added, and the solution was stirred for 20 min. The solvent was removed in vacuo and the material was purified by prep-HPLC to give 2-((2-chloro-5-cyano-3-(1,1-dioxidotetrahydro-2H-isothiazolo[2,3-a]pyrazin-5(3H)-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (5.1 mg)

Workup

  1. customThe solvent was removed in vacuo
  2. customthe material azeotroped with toluene 3×
  3. customto remove the excess TFA
  4. addition2 ml of 2N NH3 in MeOH was added
  5. customThe solvent was removed in vacuo
  6. customthe material was purified by prep-HPLC

Sources & evidence

ORD record
ord-def3ea8ccb01426fb619e3e58a9ff4cb
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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