1,8-Diazabicyclo(5.4.0)undec-7-ene → 2-((2-Chloro-5-cyano-3-(1-(3-(2-hydroxyethyl)oxetan-3-yl)piperidin-4-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

HRID 921739Notes

Reaction equation

HRID 921739 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]([N:23]([CH:33]2[CH2:35][CH2:34]2)[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:20]2=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]2[N:18]=1.N12CCCN=C1CCCCC2.[O:52]1[CH2:55][C:54](=[CH:56][CH:57]=[O:58])[CH2:53]1.[BH4-].[Na+]>C1COCC1.CCOC(C)=O.CO>[Cl:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][N:11]([C:54]3([CH2:56][CH2:57][OH:58])[CH2:55][O:52][CH2:53]3)[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]([N:23]([CH:33]2[CH2:35][CH2:34]2)[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:20]2=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]2[N:18]=1

Participants

8

Reactant 4

HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 4311764Sodium borohydrideHCID 533084702-(Oxetan-3-ylidene)acetaldehydeHCID 867085292-((2-Chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

Product 1

HCID 867086242-((2-Chloro-5-cyano-3-(1-(3-(2-hydroxyethyl)oxetan-3-yl)piperidin-4-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrileYield 49.3%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-15 °C

Procedure

To a solution of 2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (375D) (50 mg, 0.090 mmol) in dry THF (0.3 mL) was added 1,8-Diazabicyclo[5.4.0]undec-7-ene (diluted with THF, 10V %) (0.013 mL, 9.02 mol) at room temperature. The mixture was cooled in an ice/NaCl bath (−15° C.). To this was added 2-(oxetan-3-ylidene)acetaldehyde (36 mg, 0.367 mmol), and left stirring at −15° C. to 0° C. for 2.5 h, then the mixture was put in the freezer for 7 days. To the reaction mixture was added MeOH (1 mL), then sodium borohydride (10.30 mg, 0.271 mmol) at room temperature and stirred for 2 hrs. Diluted with EtOAc, washed with NaHCO3, water, brine, and dried over Na2SO4. Solvent was removed. The crude material was purified by radial chromatography, eluting with DCM containing 0 to 1% MeOH to give 2-((2-chloro-5-cyano-3-(1-(3-(2-hydroxyethyl)oxetan-3-yl)piperidin-4-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (29 mg).

Workup

  1. waitleft
  2. waitthe mixture was put in the freezer for 7 days
  3. washwashed with NaHCO3, water, brine
  4. dry with materialdried over Na2SO4
  5. customSolvent was removed
  6. customThe crude material was purified by radial chromatography
  7. washeluting with DCM containing 0 to 1% MeOH

Sources & evidence

ORD record
ord-4b3f057278234d72b2873bf13bdb8b1c
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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