Beta-Propiolactone → 4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-N,N-dimethyl-1-(oxetan-3-yl)piperazine-2-carboxamide

HRID 921827Notes

Reaction equation

HRID 921827 reaction equation
[Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH:16]3[CH2:18][CH2:17]3)[C:12]3=[N:19][CH:20]=[C:21]([C:22]#[N:23])[N:11]3[N:10]=2)=[CH:6][C:5]([C:24]#[N:25])=[CH:4][C:3]=1[N:26]1[CH2:31][CH2:30][NH:29][CH:28]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:27]1.[O:37]1[CH2:40][C:39](=O)[CH2:38]1.C(OC)(OC)OC.C([BH3-])#N.[Na+].O1CCC1=O>CO.CC(O)=O.O.C1COCC1>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH:16]3[CH2:17][CH2:18]3)[C:12]3=[N:19][CH:20]=[C:21]([C:22]#[N:23])[N:11]3[N:10]=2)=[CH:6][C:5]([C:24]#[N:25])=[CH:4][C:3]=1[N:26]1[CH2:31][CH2:30][N:29]([CH:39]2[CH2:40][O:37][CH2:38]2)[CH:28]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:27]1

Participants

10

Reactant 5

HCID 2365Beta-Propiolactone3×HCID 9005Trimethyl orthoformateHCID 5003444Sodium cyanoborohydride3×HCID 150242543-OxetanoneHCID 89923475HCID 89923475, compound

Product 1

HCID 899232664-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-N,N-dimethyl-1-(oxetan-3-yl)piperazine-2-carboxamideYield 4.6%

Reagents, catalysts & solvents 4

HCID 176Acetic AcidCatalyst2×HCID 887MethanolSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-N,N-dimethylpiperazine-2-carboxamide (37 mg, 0.073 mmol, Example 563) was taken up in MeOH (0.2 mL) and THF (0.2 mL) and oxetan-3-one (9.38 μl, 0.146 mmol) and trimethyl orthoformate (0.081 mL, 0.731 mmol) were added. The reaction was stirred at room temperature for 3 h. Next, sodium cyanoborohydride (9.19 mg, 0.146 mmol) and one drop of AcOH were added and the reaction was stirred at room temperature overnight. Only a trace of product detected by LCMS, so an additional 2 eq. each of oxetanone and NaCNBH3 were added, and the reaction was heated at 50° C. for 8 h. The reaction was cooled to room temperature and an additional 2 eq. each of oxetanone and reducing agent were added. The reaction was stirred at room temperature over the weekend. An additional 2 eq. each of oxetanone and NaCNBH3 were added, along with 1 drop of AcOH, and the reaction was heated at 50° C. for 6 h. The reaction was cooled to room temperature and water was added; a yellow solid crashed out. The solid was collected by filtration and purified by preparative HPLC to provide 4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-N,N-dimethyl-1-(oxetan-3-yl)piperazine-2-carboxamide (1.9 mg).

Workup

  1. stirringthe reaction was stirred at room temperature overnight
  2. temperaturethe reaction was heated at 50° C. for 8 h
  3. temperatureThe reaction was cooled to room temperature
  4. additionwere added
  5. stirringThe reaction was stirred at room temperature over the weekend
  6. temperaturethe reaction was heated at 50° C. for 6 h
  7. temperatureThe reaction was cooled to room temperature
  8. filtrationThe solid was collected by filtration
  9. custompurified by preparative HPLC

Sources & evidence

ORD record
ord-8cf8f8d796e3456ebe95bd74b53773a1
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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