Ammonium Chloride → 4-[(3-Bromo-2-chloro-pyridin-4-ylamino)-methyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

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Reaction Steps

Lithium bis(trimethylsilyl)amide (1M solution in THF, 5.1 ml) was added dropwise to a stirred solution of 3-bromo-2-chloro-4-aminopyridine (1.04 g) in tetrahydrofuran (15 ml) at −78° C. under N2. The resulting solution was then stirred at room temperature for 30 min., warmed to 0° C. then cooled again at −78° C. 4-Chloromethyl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.16 g, prepared according to WO 98/25605) dissolved in a minimum volume of THF was added dropwise then the solution was refluxed for 14 hours. The reaction mixture was cooled to room temperature, poured into diluted aqueous ammonium chloride, extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2 then CH2Cl2/EtOAc 8:2 cyclohexane:ethyl acetate 8:2) to afford 4-[(3-bromo-2-chloro-pyridin-4-ylamino)-methyl]-3,6-dihydro-2H -pyridine-1-carboxylic acid tert-butyl ester (1.42 g), which was identified by its mass and 1H NMR spectra. MS (ES+) 346/348/350 (MH+-isoprene), 402/404/406 (MH+).

Provenance & Evidence