methyl 2,2,2-trifluoroethanimidate → HCID 69192996, compound

HRID 132877Notes

Reaction equation

HRID 132877 reaction equation
[F:1][C:2]([F:8])([F:7])[C:3](=[NH:6])OC.FC(F)(F)C1N=[N:13][C:14]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C:15]=2[N:16]=1>COCCO>[F:8][C:2]([F:1])([F:7])[C:3]1[N:6]=[N:16][C:15]2[CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20][C:14]=2[N:13]=1

Participants

4

Reactant 2

HCID 256220methyl 2,2,2-trifluoroethanimidateHCID 69192860HCID 69192860, compound

Product 1

HCID 69192996HCID 69192996, compound

Reagents, catalysts & solvents 1

HCID 80192-MethoxyethanolSolvent

Procedure

This material was obtained by reaction of tert-butyl 3,4-dioxopiperidine-1-carboxylate from Intermediate 35, Step C, with trifluoroacetamidrazone (2,2,2-trifluoroethanimidohydrazide), prepared from methyl 2,2,2-trifluoroethanimidoate according to the procedure of Brown and Wetzel, J. Org. Chem., 30: 3729-3733 (1965), essentially as described for Intermediate 35, Step D, except that completion of the condensation and ring closure required heating in 2-methoxyethanol at reflux for 2 d. Purification of the evaporation residue by flash chromatography (silica gel, 30% ethyl acetate/hexanes) provided the crude title compound in addition to a minor amount of the other regioisomer, tert-butyl 3-(trifluoromethyl)-7,8-dihydropyrido[3,4-e][1,2,4]triazine-6(5H)-carboxylate. Further purification of the product was achieved by preparative HPLC (YMC Pro C18 column, gradient elution, 40-70% acetonitrile/water containing 0.1% trifluoroacetic acid). To prevent decomposition during isolation, excess N,N-diisopropylethylamine was added to the pooled product fractions to neutralize the trifluoroacetic acid prior to concentration in vacuo. The residue was partitioned between ethyl acetate and 5% aqueous citric acid solution. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to give the pure title compound. The regioisomers were assigned on the basis of 1H NMR chemical shift differences reported in several papers for analogous compounds. (See, for example, Konno et al., Heterocycles, 22: 2241-2244 (1984) and Neunhoeffer and Böhnisch, Liebigs Ann. Chem., 153-162 (1976).) 1H NMR (500 MHz, CDCl3) δ 5.08 (s, 2H), 3.90 (m, 2H), 3.21 (m, 2H), 1.54 (s, 9H). LC/MS: 249 (M+1-isobutene).

Workup

  1. temperatureat reflux for 2 d
  2. customPurification of the evaporation residue by flash chromatography (silica gel, 30% ethyl acetate/hexanes)
  3. customprovided the crude title compound
  4. customFurther purification of the product
  5. washwas achieved by preparative HPLC (YMC Pro C18 column, gradient elution, 40-70% acetonitrile/water containing 0.1% trifluoroacetic acid)
  6. additionwas added to the pooled product fractions
  7. concentrationto concentration in vacuo
  8. customThe residue was partitioned between ethyl acetate and 5% aqueous citric acid solution
  9. washThe organic phase was washed with brine
  10. dry with materialdried over sodium sulfate
  11. concentrationconcentrated

Sources & evidence

ORD record
ord-1f157635b70b42cb922e59c385d4cfca
Source dataset
uspto-grants-2008_06
Patent number
US07388019B2

Reaction notes

Loading…