Acetic Acid → Tert-butyl 3-(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)piperazin-1-yl)azetidine-1-carboxylate

HRID 921820Notes

Reaction equation

HRID 921820 reaction equation
[Cl:1][C:2]1[C:7]([N: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.O=[C:42]1[CH2:45][N:44]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:43]1.C(O)(=O)C.C([BH3-])#N.[Na+]>C1COCC1.CO>[Cl:1][C:2]1[C:3]([NH:16][C:17]2[N:22]=[C:21]([N:23]([CH:33]3[CH2:34][CH2:35]3)[CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:20]3=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]3[N:18]=2)=[CH:4][C:5]([C:14]#[N:15])=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH:42]2[CH2:43][N:44]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:45]2)[CH2:10][CH2:9]1

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 15194043-Oxo-azetidine-1-carboxylic acid tert-butyl esterHCID 5003444Sodium cyanoborohydrideHCID 867084922-((2-Chloro-5-cyano-3-(piperazin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

Product 1

HCID 89924048Tert-butyl 3-(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)piperazin-1-yl)azetidine-1-carboxylateYield 78.1%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 2-((2-chloro-5-cyano-3-(piperazin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (500 mg, 0.901 mmol) in THF (2.5 mL) and MeOH (2.5 mL) was added tert-butyl 3-oxoazetidine-1-carboxylate (185 mg, 1.081 mmol), acetic acid (0.052 rnL, 0.901 mmol). The reaction mixture was stirred at room temperature for overnight. The reaction mixture was cooled to 0° C., added sodium cyanoborohydride (113 mg, 1.802 mmol) and the reaction mixture was allowed to come to room temperature and stirred for 5 h at the same temperature. The solvent was removed completely under vacuum, the resultant residue was dissolved in ethyl acetate (100 ml), washed it with 10% NaHCO3 solution, brine, dried over anhydrous Na2SO4 and concentrated. The crude material was purified via ISCO (12 gm silica Redisep, 0 to 10% CH3OH—CHC13 gradient elution). The fractions were concentrated to get the tert-butyl 3-(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)piperazin-1-yl)azetidine-1-carboxylate (500 mg) as a off white solid.

Workup

  1. temperatureThe reaction mixture was cooled to 0° C.
  2. customto come to room temperature
  3. stirringstirred for 5 h at the same temperature
  4. customThe solvent was removed completely under vacuum
  5. dissolutionthe resultant residue was dissolved in ethyl acetate (100 ml)
  6. washwashed it with 10% NaHCO3 solution, brine
  7. dry with materialdried over anhydrous Na2SO4
  8. concentrationconcentrated
  9. customThe crude material was purified via ISCO (12 gm silica Redisep, 0 to 10% CH3OH—CHC13 gradient elution)
  10. concentrationThe fractions were concentrated

Sources & evidence

ORD record
ord-e41cbd2d821441bc81f8742a4d5ba93d
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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