Hydrochloric Acid → HCID 178499535, compound

HRID 1426364Notes

Reaction equation

HRID 1426364 reaction equation
[F:1][C:2]([F:7])([F:6])[C:3](=[NH:5])[NH2:4].[CH3:8][O:9][C:10](=[O:19])[CH2:11][C:12](=O)[CH2:13][C:14](OC)=[O:15].Cl.C(OCC)(=O)C>C[O-].[Na+].CO.C(Cl)Cl>[OH:15][C:14]1[N:4]=[C:3]([C:2]([F:7])([F:6])[F:1])[N:5]=[C:12]([CH2:11][C:10]([O:9][CH3:8])=[O:19])[CH:13]=1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 8857Ethyl AcetateHCID 74591Dimethyl 3-oxoglutarateHCID 2776882Trifluoroacetamidine

Product 1

HCID 178499535HCID 178499535, compound

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 10942334Sodium MethoxideSolvent

Procedure

2,2,2-Trifluoroethanimidamide (6.7 g, 50. mmol, Oakwood) was dissolved in 0.5 M sodium methoxide in methanol (120 mL, 60. mmol) and 3-oxo-pentanedioic acid dimethyl ester (8.4 mL, 55 mmol, Aldrich) was added. The reaction solution was stirred at room temperature for 72 hours, followed by heating to 50° C. for 42 hours. The solvent was removed in vacuo. 1N HCl (50 mL) was added, this resulted in pH 5. After stirring overnight, 4M HCl (10 mL) and ethyl acetate were added, and layers separated. The aqueous layer was extracted with ethyl acetate. The combined organic extract was washed with brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography, on 120 g silica gel cartridge, eluting with a gradient (solvent A=hexane; solvent B=3% iPrOH/EtOAc) from 0-30% solvent B in A over 40 minutes and hold at 30% for 20 minutes at a flow rate of 60 mL/min. The residue obtained on evaporation of product-containing fractions was mixed with DCM and the resulting white ppt (impurity) was removed by filtration. The filtrate was evaporated and the resulting residue was repurified (A=hexane; solvent B=iPrOH) on a 120 g silica gel cartridge, eluting with a gradient from 0-20% B in A over 25 minutes and hold at 20% B at a flow rate of 60 mL/min. Evaporated to afford an oil which crystallized on standing (5.2 g, 75% pure). A portion of the material was purified via preparative HPLC-MS (C18, eluting with a gradient of MeCN/H2O containing 0.1% TFA) to afford product used in the subsequent step. 1H NMR (300 MHz, CDCl3) δ 6.76 (s, 1H), 3.76 (s, 3H), 3.75 (s, 2H).

Workup

  1. temperatureby heating to 50° C. for 42 hours
  2. customThe solvent was removed in vacuo
  3. addition1N HCl (50 mL) was added
  4. customthis resulted in pH 5
  5. stirringAfter stirring overnight
  6. customlayers separated
  7. extractionThe aqueous layer was extracted with ethyl acetate
  8. extractionThe combined organic extract
  9. washwas washed with brine
  10. dry with materialdried over sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated
  13. washFlash chromatography, on 120 g silica gel cartridge, eluting with a gradient (solvent A=hexane; solvent B=3% iPrOH/EtOAc) from 0-30% solvent B in A over 40 minutes
  14. waithold at 30% for 20 minutes at a flow rate of 60 mL/min
  15. customThe residue obtained on evaporation of product-containing fractions
  16. customthe resulting white ppt (impurity) was removed by filtration
  17. customThe filtrate was evaporated
  18. customthe resulting residue was repurified (A=hexane
  19. washsolvent B=iPrOH) on a 120 g silica gel cartridge, eluting with a gradient from 0-20% B in A over 25 minutes
  20. customEvaporated
  21. customto afford an oil which
  22. customcrystallized
  23. customA portion of the material was purified via preparative HPLC-MS (C18
  24. washeluting with a gradient of MeCN/H2O containing 0.1% TFA)
  25. customto afford product

Sources & evidence

ORD record
ord-f363a3f056f44c03bf622d373a46d6b8
Source dataset
uspto-grants-2015_01
Patent number
US08933085B2

Reaction notes

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