Acetic Acid → 2-((2-Chloro-5-cyano-3-(4-ethyl-2-oxopiperazin-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

HRID 921886Notes

Reaction equation

HRID 921886 reaction equation
[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]2=[O:14])=[CH:6][C:5]([C:15]#[N:16])=[CH:4][C:3]=1[NH:17][C:18]1[N:23]=[C:22]([N:24]([CH:34]2[CH2:36][CH2:35]2)CC2C=CC(OC)=CC=2)[C:21]2=[N:37][CH:38]=[C:39]([C:40]#[N:41])[N:20]2[N:19]=1.[CH:42](=O)[CH3:43].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(C(F)(F)F)=O>C(Cl)Cl.ClCCCl.C1(OC)C=CC=CC=1>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:42][CH3:43])[CH2:10][C:9]2=[O:14])=[CH:6][C:5]([C:15]#[N:16])=[CH:4][C:3]=1[NH:17][C:18]1[N:23]=[C:22]([NH:24][CH:34]2[CH2:36][CH2:35]2)[C:21]2=[N:37][CH:38]=[C:39]([C:40]#[N:41])[N:20]2[N:19]=1

Participants

9

Reactant 5

HCID 176Acetic AcidHCID 177AcetaldehydeHCID 6422Trifluoroacetic acidHCID 5049666Sodium triacetoxyborohydrideHCID 899226992-((2-Chloro-5-cyano-3-(2-oxopiperazin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

Product 1

HCID 899234112-((2-Chloro-5-cyano-3-(4-ethyl-2-oxopiperazin-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrileYield 69.9%

Reagents, catalysts & solvents 3

HCID 7519AnisoleCatalystHCID 111,2-DichloroethaneSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of 2-((2-chloro-5-cyano-3-(2-oxopiperazin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (17 mg, 0.030 mmol) in DCM (2 mL) was added acetaldehyde (13.16 mg, 0.299 mmol) and acetic acid (3.42 μl, 0.060 mmol). After stirring for 15 min, sodium triacetoxyborohydride (12.66 mg, 0.060 mmol) was added. After stirring at room temperature for 2 h, LC-MS indicated completion. After concentration, purification via flash chromatography (0-10% MeOH in DCM, 12 g) gave 20 mg of the PMB protected product. This was dissolved in 1 mL of DCE and then 1 drop of anisole was added followed by 0.5 mL of TFA. The solution was heated at 60° C. for 2.5 h. LC-MS indicated completion, and then it was cooled and concentrated. The crude was dissolved in methanol and neutralized with 7N ammonia in methanol. After stirring for 10 min it was concentrated, purification via preparative HPLC gave the title compound as a yellow solid (10 mg).

Workup

  1. stirringAfter stirring at room temperature for 2 h
  2. concentrationAfter concentration, purification via flash chromatography (0-10% MeOH in DCM, 12 g)
  3. customgave 20 mg of the PMB
  4. temperatureit was cooled
  5. concentrationconcentrated
  6. dissolutionThe crude was dissolved in methanol and neutralized with 7N ammonia in methanol
  7. stirringAfter stirring for 10 min it
  8. concentrationwas concentrated
  9. custompurification via preparative HPLC

Sources & evidence

ORD record
ord-1442195f389c449483750a0769ab1e5c
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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