1,2-Bis(trimethylsiloxy)cyclobutene → 2-((2-Chloro-5-cyano-3-(1-(2-oxocyclobutyl)piperidin-4-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

HRID 921889Notes

Reaction equation

HRID 921889 reaction equation
[Cl:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][C:5]([C:14]#[N:15])=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[C:21]([NH:23][CH:24]2[CH2:26][CH2:25]2)[C:20]2=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:19]2[N:18]=1.C[Si](C)(C)[O:34][C:35]1[CH2:38][CH2:37][C:36]=1O[Si](C)(C)C>CO>[Cl:1][C:2]1[C:7]([CH:8]2[CH2:9][CH2:10][N:11]([CH:36]3[CH2:37][CH2:38][C:35]3=[O:34])[CH2:12][CH2:13]2)=[CH:6][C:5]([C:14]#[N:15])=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[C:21]([NH:23][CH:24]2[CH2:25][CH2:26]2)[C:20]2=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:19]2[N:18]=1

Participants

4

Reactant 2

HCID 27340341,2-Bis(trimethylsiloxy)cyclobuteneHCID 867085272-((2-Chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

Product 1

HCID 899231202-((2-Chloro-5-cyano-3-(1-(2-oxocyclobutyl)piperidin-4-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

To the stirred suspension of 2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile, (Example 208) (20 mg, 0.046 mmol) in TIIF (1 ml) was added drop wise a solution of 1,2-bis((trimethylsilyl)oxy)cyclobut-1-ene (12.75 mg, 0.055 mmol) in MeOH (0.4 ml) at 0° C. under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred for 5 days (converted to clear solution). Solvent was removed. The crude material was purified via preparative LC/MS with the following conditions: Column: 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: 30-70% B over 18 minutes, then a 7-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 2-((2-chloro-5-cyano-3-(1-(2-oxocyclobutyl)piperidin-4-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (6.6 mg).

Workup

  1. customSolvent was removed
  2. customThe crude material was purified via preparative LC/MS with the following conditions
  3. waitGradient: 30-70% B over 18 minutes
  4. customa 7-minute hold
  5. additionFractions containing the desired product
  6. customdried via centrifugal evaporation

Sources & evidence

ORD record
ord-f6ef8c53da8e4675955651d6dc7e7ae1
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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