Dimethyl malonate → Methyl 4-amino-2-methyl-3-[3-(methyloxy)phenyl]-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carboxylate

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Reaction Steps

To a solution of 2-amino-5-methyl-4-[3-(methyloxy)phenyl]-3-thiophene carbonitrile (Description 3) (2.80 g, 11.46 mmol) in toluene (75 mL) was added dimethyl malonate (1.31 mL, 11.46 mmol) and SnCl4 (2.68 mL, 22.92 mmol). The reaction mixture was then refluxed under nitrogen for ca. 2 h. The reaction mixture was then cooled to RT and concentrated in vacuo. The residue was partitioned between water and ethyl acetate (ca. 150 mL each) and the organic layer separated and washed with water (ca. 100 mL). The combined aqueous layer was re-extracted with ethyl acetate (ca. 100 mL). All organic layers were combined and passed through a phase separator and the mixture concentrated in vacuo. The residue was purified by normal phase chromatography, eluting with a gradient of 0-60% ethyl acetate in DCM followed by 0-20% MeOH in DCM, to afford the title compound (1.62 g). LCMS (A) m/z: 343 [M−1]−, Rt 1.18 min (acidic).

Provenance & Evidence