Trifluoroacetic acid → 2-(4-(2-Chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-oxopiperazin-1-yl)acetamide

HRID 921876Notes

Reaction equation

HRID 921876 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.Br[CH2:43][C:44]([NH2:46])=[O:45].C([O-])([O-])=O.[K+].[K+].C(O)(C(F)(F)F)=O>CN(C=O)C.ClC(Cl)C.C1(OC)C=CC=CC=1>[Cl:1][C:2]1[C:3]([NH:17][C:18]2[N:23]=[C:22]([NH:24][CH:34]3[CH2:35][CH2:36]3)[C:21]3=[N:37][CH:38]=[C:39]([C:40]#[N:41])[N:20]3[N:19]=2)=[CH:4][C:5]([C:15]#[N:16])=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:43][C:44]([NH2:46])=[O:45])[CH2:10][C:9]1=[O:14]

Participants

8

Reactant 4

HCID 6422Trifluoroacetic acidHCID 11430Potassium CarbonateHCID 696322-BromoacetamideHCID 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 899229152-(4-(2-Chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-oxopiperazin-1-yl)acetamideYield 51.6%

Reagents, catalysts & solvents 3

HCID 7519AnisoleCatalystHCID 6228DimethylformamideSolventHCID 63651,1-DichloroethaneSolvent

Procedure

To 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 (Example 628)(10 mg, 0.018 mmol) in DMF (0.5 mL) was added 2-bromoacetamide (4.85 mg, 0.035 mmol) followed by K2CO3 (29.1 mg, 0.211 mmol) and it was stirred at room temperature for 1 h, LC-MS indicated completion. Purification via flash chromatography (0-10% MeOH in DCM, 12 g) gave 9 mg of the PMB protected product. This was dissolved in 1 mL of dichloroethane and then 1 drop of anisole was added followed by 0.5 mL of TFA. The solution was heated at 60° C. for 1 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 (4.7 mg).

Workup

  1. customPurification via flash chromatography (0-10% MeOH in DCM, 12 g)
  2. customgave 9 mg of the PMB
  3. temperatureThe solution was heated at 60° C. for 1 h
  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-ef714ed3951042bab4d2cc765f02a496
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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