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 1430919Notes

Reaction equation

HRID 1430919 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 μmol) at RT. 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 RT and stirred for 2 hrs. Diluted with EtOAc, washed with NaHCO3, water, brine, and dried over Na2SO4. Removal of the solvent. 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. customRemoval of the solvent
  6. customThe crude material was purified by radial chromatography
  7. washeluting with DCM containing 0 to 1% MeOH

Sources & evidence

ORD record
ord-dd6ef608372d4ab387c931e3baa16714
Source dataset
uspto-grants-2015_01
Patent number
US08940736B2

Reaction notes

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