The general procedure for the synthesis of 5-bromopyridine-2,3-dicarboxylic acid from 3-bromoquinoline is as follows:
Example 12: Synthesis of 2-bromo-7-(4-fluorobenzyl)-5,9-dihydroxy-pyrrolo[3,4-g]quinoline-6,8-dione (1008) Referring to the literature method of M.-D. Le Bas et al. (Synthesis 2001, 16, p. 2495). 100 mL of carbon tetrachloride (CCl4) was mixed with 250 mL of aqueous sodium hypochlorite (NaOCl). To this mixture was added 40 mg of ruthenium dioxide (RuO2) followed by 3 g of 3-bromoquinoline dissolved in 50 mL of CCl4. The reaction was supplemented with the addition of 30 mL of sodium hypochlorite solution as the reaction progressed to 2, 4 and 6 hours, respectively. After 24 hours of reaction, the aqueous layer was separated and collected, acidified with 3N hydrochloric acid (HCl) to pH 1. Subsequently, the aqueous layer was extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate (Na2SO4), and the solvent was removed by evaporation under reduced pressure to give 1.7 g of a yellow resinous product in 48% yield. The 1H NMR and mass spectrometry (MS) data of the product were consistent with those reported in the literature.
The resulting 1 g of anhydride was converted to the corresponding cyano ester by a known multi-step reaction sequence. A Dieckmann condensation reaction between 80 mg (0.3 mmol) of the cyano ester and 80 mg (3.6 mmol) of the imide in 2 mL of anhydrous tetrahydrofuran (THF) was carried out using 900 μL of lithium bis(trimethylsilyl)amide (LiHMDS) as a base to give the crude product. After conventional post-treatment, about 60 mg (30%) of unpurified yellow solid product was obtained. Further purification by ether milling yielded 2 mg of the high-purity product 1008. The 1H NMR (300 MHz, d6-DMSO) data were: δ 9.20 (d, 1H), 9.05 (d, 1H), 4.85 (s, 2H) ppm; and the mass spectrometry (MS) data were: m/z = 416.1 (M + H).
