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

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Reaction Steps

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).

Provenance & Evidence