Propylene Oxide → (+/-)-2-((2-Chloro-5-cyano-3-(4-(2-hydroxypropyl)-2-oxopiperazin-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

HRID 921877Notes

Reaction equation

HRID 921877 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.[CH3:42][CH:43]1[CH2:45][O:44]1.C(O)(C(F)(F)F)=O>C(O)C.C1COCC1.ClC(Cl)C.C1(OC)C=CC=CC=1>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:42][CH:43]([OH:44])[CH3:45])[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

8

Reactant 3

HCID 6378Propylene OxideHCID 6422Trifluoroacetic acidHCID 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 89923133(+/-)-2-((2-Chloro-5-cyano-3-(4-(2-hydroxypropyl)-2-oxopiperazin-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrileYield 28.9%

Reagents, catalysts & solvents 4

HCID 7519AnisoleCatalystHCID 702EthanolSolventHCID 63651,1-DichloroethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
80 °C

Procedure

A suspension 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 (16 mg, 0.028 mmol) and 2-methyloxirane (8.17 mg, 0.141 mmol) in Ethanol (0.8 mL) and THF (0.2 mL) in a sealed 1-dram vial was heated at 80° C. for 6 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 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 (4.1 mg).

Workup

  1. concentrationAfter concentration, purification via flash chromatography (0-10% MeOH in DCM, 12 g)
  2. customgave 20 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. concentrationwas concentrated
  8. custompurification via preparative HPLC

Sources & evidence

ORD record
ord-82c25872f698422a853bc06b980255b2
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

Loading…