A. Preparation of diethyl 3-methyl-1H-pyrrole-2,4-dicarboxylate (1A)
To a tetrahydrofuran (THF, 400 mL) solution of ethyl isocyanoacetate (38.1 mL, 0.34 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 50.8 mL, 0.34 mol) was added slowly and dropwise to a THF (100 mL) solution of acetaldehyde (9.5 mL, 0.17 mol) at 25 °C under nitrogen protection. mL) solution for 25 minutes. Subsequently, the reaction mixture was heated to 55 °C and stirred for 17 hours. Upon completion of the reaction, the mixture was cooled to 25 °C and acetic acid (20 mL) was slowly added to quench the reaction. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in ethyl acetate (800 mL) and washed sequentially with 1N hydrochloric acid (3 x 300 mL). The aqueous phases were combined and back-extracted with ethyl acetate (3 x 200 mL). All organic phases were combined and washed sequentially with saturated aqueous sodium bicarbonate (3 × 200 mL), water (100 mL) and saturated saline (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a dark brown oil. The oil was purified by rapid chromatography on a silica gel pad with ethyl acetate/hexane (1:1, v/v) as eluent, and the target compound 1A (16 g, 42% yield) was obtained as a yellow solid after concentration under reduced pressure.
HPLC purity: 100% (retention time: 3.536 min; column: YMC S5 ODS, 4.6×50 mm; mobile phase: 10-90% aqueous methanol (containing 0.2% phosphoric acid), gradient elution for 4 min at a flow rate of 4 mL/min, detection wavelength 220 nm).
Mass spectrum (electrospray ionization, ES): m/z 226.0 [M + H]+.
