Trifluoroacetic acid → (+/-) 2-((2-Chloro-5-cyano-3-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

HRID 921698Notes

Reaction equation

HRID 921698 reaction equation
[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH:10]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])[CH2:9]2)=[CH:6][C:5]([C:26]#[N:27])=[CH:4][C:3]=1[NH:28][C:29]1[N:34]=[C:33]([N:35]([CH:43]2[CH2:45][CH2:44]2)C(=O)OC(C)(C)C)[C:32]2=[N:46][CH:47]=[C:48]([C:49]#[N:50])[N:31]2[N:30]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH:10]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])[CH2:9]2)=[CH:6][C:5]([C:26]#[N:27])=[CH:4][C:3]=1[NH:28][C:29]1[N:34]=[C:33]([NH:35][CH:43]2[CH2:44][CH2:45]2)[C:32]2=[N:46][CH:47]=[C:48]([C:49]#[N:50])[N:31]2[N:30]=1

Participants

5

Reactant 3

HCID 6422Trifluoroacetic acidHCID 7519AnisoleHCID 86708573(+/-) Tert-butyl(2-((2-chloro-5-cyano-3-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-7-cyanoimidazo[2,1-f][1,2,4]triazin-4-yl)(cyclopropyl)carbamate

Product 1

HCID 86708574(+/-) 2-((2-Chloro-5-cyano-3-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrileYield 11.3%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Conditions

Temperature
0 °C

Procedure

(+/−) Tert-butyl (2-((2-chloro-5-cyano-3-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-7-cyanoimidazo[2,1-f][1,2,4]triazin-4-yl)(cyclopropyl)carbamate (40 mg, 0.057 mmol) was taken up in DCE (275 μL) and anisole (31.0 μL, 0.284 mmol) was added. The reaction was cooled to 0° C., and TFA (92 μL, 1.193 mmol) was added. The reaction was stirred at 0° C. for 30 min, then warmed to room temperature and stirred for 1.5 h. The solvent was removed in vacuo and the material was azeotroped 2× with toluene to remove the excess TFA. The crude material was purified by preparative HPLC to provide (+/−)2-((2-chloro-5-cyano-3-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (3.9 mg).

Workup

  1. temperaturewarmed to room temperature
  2. stirringstirred for 1.5 h
  3. customThe solvent was removed in vacuo
  4. customthe material was azeotroped 2× with toluene
  5. customto remove the excess TFA
  6. customThe crude material was purified by preparative HPLC

Sources & evidence

ORD record
ord-9f7020bc6551468f9b5b36213f4144a9
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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