Acetic Acid → 2-((2-Chloro-5-cyano-3-(4-(3-hydroxyazetidin-1-yl)butan-2-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

HRID 921856Notes

Reaction equation

HRID 921856 reaction equation
[Cl:1][C:2]1[C:7]([CH:8]([CH2:10][CH:11]=O)[CH3:9])=[CH:6][C:5]([C:13]#[N:14])=[CH:4][C:3]=1[NH:15][C:16]1[N:21]=[C:20]([N:22]([CH:32]2[CH2:34][CH2:33]2)[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:19]2=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:18]2[N:17]=1.[NH:40]1[CH2:43][CH:42]([OH:44])[CH2:41]1.CC(O)=O.C([BH3-])#N.[Na+]>C1COCC1.CO.CCOC(C)=O>[Cl:1][C:2]1[C:7]([CH:8]([CH2:10][CH2:11][N:40]2[CH2:43][CH:42]([OH:44])[CH2:41]2)[CH3:9])=[CH:6][C:5]([C:13]#[N:14])=[CH:4][C:3]=1[NH:15][C:16]1[N:21]=[C:20]([N:22]([CH:32]2[CH2:34][CH2:33]2)[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:19]2=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:18]2[N:17]=1

Participants

8

Reactant 4

HCID 176Acetic AcidHCID 15142903-HydroxyazetidineHCID 5003444Sodium cyanoborohydrideHCID 899237002-((2-Chloro-5-cyano-3-(4-oxobutan-2-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

Product 1

HCID 899233502-((2-Chloro-5-cyano-3-(4-(3-hydroxyazetidin-1-yl)butan-2-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrileYield 50.5%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

2-((2-chloro-5-cyano-3-(4-oxobutan-2-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (23 mg, 0.043 mmol) was taken up in THF (0.3 mL) and a solution of azetidin-3-ol (6.21 mg, 0.085 mmol) in MeOH (0.200 mL) was added. A drop of AcOH was added and the solution was stirred for 10 min. Next, sodium cyanoborohydride (5.34 mg, 0.085 mmol) was added and the reaction was stirred for 1 h. The reaction was diluted with EtOAc and washed with 2M K3PO4 solution. The organic layer was dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography (0-10% MeOH/DCM; 12 g column). 2-((2-chloro-5-cyano-3-(4-(3-hydroxyazetidin-1-yl)butan-2-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (13 mg) was obtained as a yellow glass.

Workup

  1. stirringthe reaction was stirred for 1 h
  2. washwashed with 2M K3PO4 solution
  3. dry with materialThe organic layer was dried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe material was purified by flash column chromatography (0-10% MeOH/DCM; 12 g column)

Sources & evidence

ORD record
ord-5ff45257f00445a9a21f4bbf8a74f8d2
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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