D-Tryptophan methyl ester hydrochloride (50.0 kg, 196 mol) was suspended in isopropyl alcohol (500 L) and treated with piperonal (32.4 kg, 216 mol) at ambient temperature under an N2 atmosphere. The mixture was stirred between 70° C. and reflux (82° C.) for 16 to 18 hours. At this time, the reaction mixture contained less than 3% Compound IIa. The reaction mixture then was cooled to 0° C., filtered, and washed with cold isopropyl alcohol (150 L). The product was dried under vacuum at less than 60° C. to yield 69.8 kg (92%) of cis-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester (Compound II)). 1H NMR (400 MHz DMSO) δ: 10.81 (1H, s), 10.67 (1H, exch.), 10.21 (1H, exch.), 7.52 (1H, d, J=8.0 Hz), 7.27 (1H, d, J=8.0 Hz), 7.11 (1H, m), 7.05-6.95 (4H, m), 6.08 (2H, s); 5.85 (1H, m), 4.71 (1H, m), 3.82 (3H, s), 3.39-3.23 (2H, m). HPLC Details: Column: SB-Phenyl 4.6×250 mm; ACN/(H2O+0.1% TFA) gradient; Temperature: 40° C.; Flow Rate=1 mL/min; UV Det.=285 μm; Injection Volume=20 μL; Diluent=1:1 ACN/H2O; Sample concentration: about 0.1 mg/mL; and Retention time=6.0 min.
