Trifluoroacetic acid → 4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-1-(2,2-difluoroethyl)-N,N-dimethylpiperazine-2-carboxamide

HRID 921829노트

반응식

HRID 921829 반응식
[Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([N:15]([CH:25]3[CH2:27][CH2:26]3)CC3C=CC(OC)=CC=3)[C:12]3=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:11]3[N:10]=2)=[CH:6][C:5]([C:33]#[N:34])=[CH:4][C:3]=1[N:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH:42]([F:44])[F:43])[CH:37]([C:45]([N:47]([CH3:49])[CH3:48])=[O:46])[CH2:36]1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH:25]3[CH2:26][CH2:27]3)[C:12]3=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:11]3[N:10]=2)=[CH:6][C:5]([C:33]#[N:34])=[CH:4][C:3]=1[N:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH:42]([F:43])[F:44])[CH:37]([C:45]([N:47]([CH3:49])[CH3:48])=[O:46])[CH2:36]1

참가 물질

5

반응물 3

HCID 6422Trifluoroacetic acid3회HCID 7519AnisoleHCID 89923142HCID 89923142, 화합물

생성물 1

HCID 899227344-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-1-(2,2-difluoroethyl)-N,N-dimethylpiperazine-2-carboxamide수율 65.3%

시약·촉매·용매 1

HCID 111,2-Dichloroethane용매

실험 절차

4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-1-(2,2-difluoroethyl)-N,N-dimethylpiperazine-2-carboxamide (37 mg, 0.054 mmol) was taken up in DCE (0.5 mL) and anisole (0.029 mL, 0.268 mmol) was added, followed by TFA (0.124 mL, 1.608 mmol). The reaction was stirred at room temperature overnight. LCMS indicates mostly SM is present. An additional 30 eq. of TFA was added and the reaction was heated at 50° C. After 4 h, an additional 30 eq. of TFA was added, and the reaction heated for 1.5 h. The solvent was removed in vacuo and the material azeotroped 2× with toluene, then triturated with Et2O to remove anisole. The material was purified by preparative HPLC to provide 4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-1-(2,2-difluoroethyl)-N,N-dimethylpiperazine-2-carboxamide (20.1 mg) as a yellow solid.

후처리

  1. temperaturethe reaction was heated at 50° C
  2. waitAfter 4 h
  3. temperaturethe reaction heated for 1.5 h
  4. customThe solvent was removed in vacuo
  5. customthe material azeotroped 2× with toluene
  6. customtriturated with Et2O
  7. customto remove anisole
  8. customThe material was purified by preparative HPLC

출처 및 근거

ORD 기록
ord-d6b685fbb73540758ab13b1626976335
출처 데이터셋
uspto-grants-2016_03
특허 번호
US09273057B2

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