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Ethanamine, 2,2,2-trifluoro- → (R)-Benzyl 4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-ylcarbamate

HRID 552567
Notes
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Reaction equation

HRID 552567 reaction equation
CO[C:3](=[O:29])[C@H:4]([NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:5][C:6]1[C:7]([CH2:16]Cl)=[C:8]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[NH:11][N:10]=[CH:9]2.[F:30][C:31]([F:35])([F:34])[CH2:32][NH2:33].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:22]([O:21][C:19](=[O:20])[NH:18][C@H:4]1[C:3](=[O:29])[N:33]([CH2:32][C:31]([F:35])([F:34])[F:30])[CH2:16][C:7]2[C:8]3[CH:9]=[N:10][NH:11][C:12]=3[C:13]([Cl:15])=[CH:14][C:6]=2[CH2:5]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 3

HCID 9773Ethanamine, 2,2,2-trifluoro-2×HCID 11430Potassium CarbonateHCID 597318592-(R)-benzyloxycarbonylamino-3-(7-chloro-4-chloromethyl-1H-indazol-5-yl)propionic acid methyl ester

Product 1

HCID 59732091(R)-Benzyl 4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-ylcarbamate

Reagents, catalysts & solvents 1

HCID 6342
Acetonitrile
Solvent

Conditions

Temperature
40 °C

Procedure

A mixture of 2-(R)-benzyloxycarbonylamino-3-(7-chloro-4-chloromethyl-1H-indazol-5-yl)propionic acid methyl ester (525 mg, 1.20 mmol) [Chaturvedula et al. WO 2006/052378], trifluoroethylamine (1.0 g, 10.2 mmol), and K2CO3 (499 mg, 3.61 mmol) in CH3CN (15 mL) was heated at 40° C. in a sealed vessel for 45 h. Additional trifluoroethylamine (1.0 g, 10.2 mmol) was added and the mixture was heated at 40° C. for a further 48 h and then allowed to cool to ambient temperature. The reaction mixture was filtered through a 0.45 μm PTFE membrane and the filtrate was concentrated in vacuo. The residue was dissolved in toluene (10 mL) and AcOH (1 mL) and the mixture was heated at reflux for 6 h, allowed to cool to ambient temperature, and partitioned between saturated aqueous NaHCO3 (30 mL) and EtOAc (60 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc-100:0 to 50:50, to provide the title compound. MS: m/z=467.

Workup

  1. temperaturethe mixture was heated at 40° C. for a further 48 h
  2. temperatureto cool to ambient temperature
  3. filtrationThe reaction mixture was filtered through a 0.45 μm PTFE membrane
  4. concentrationthe filtrate was concentrated in vacuo
  5. dissolutionThe residue was dissolved in toluene (10 mL)
  6. temperatureAcOH (1 mL) and the mixture was heated
  7. temperatureat reflux for 6 h
  8. temperatureto cool to ambient temperature
  9. custompartitioned between saturated aqueous NaHCO3 (30 mL) and EtOAc (60 mL)
  10. washThe organic layer was washed with brine
  11. dry with materialdried over Na2SO4
  12. filtrationfiltered
  13. concentrationconcentrated in vacuo
  14. customThe crude product was purified by silica gel chromatography
  15. washeluting with a gradient of CH2Cl2

Sources & evidence

ORD record
ord-1c2700b4efae4ada9b28da4d7bb93927
Source dataset
uspto-grants-2011_05
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07951795B2

Reaction notes

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