16A was synthesized as follows:
1. 5-Bromo-2-carboxymethylbenzoic acid (4-bromophenyl)acetic acid (20 g, 93 mmol) was dissolved in thionyl chloride (40 ml) and heated at 85°C for 2 hours. Subsequently, the thionyl chloride was removed under vacuum.
2. the chloride obtained in step 1 was mixed with lead thiocyanate (Pb(SCN)2, 30 g, 93 mmol) in benzene (300 ml) and the reaction mixture was refluxed for 3 hours.
3. After the reaction mixture was cooled to room temperature, it was filtered through diatomaceous earth and the filtrate was evaporated to give an orange liquid.
4. The orange liquid was dissolved in carbon disulfide (30 ml) and added slowly and dropwise at 0 °C to a solution of carbon disulfide (60 ml) containing aluminum chloride (AlCl3, 24.7 g, 186 mmol).
5. The reaction mixture was heated to reflux and maintained for 12 hours.
6. Upon completion of the reaction, the mixture was cooled to 0°C and 1N aqueous HCl solution (200 ml) was added. The orange precipitate formed was collected, suspended in ethyl acetate and filtered to give an orange solid.
7. The orange solid was dissolved in 25% aqueous KOH solution (80 ml), heated to reflux and maintained for 15 hours.
8. After cooling to 0 °C, the pH of the reaction mixture was adjusted to 3 with 6N HCl aqueous solution.
9. The aqueous solution was extracted repeatedly using ethyl acetate, the organic layers were combined, washed with brine, dried over MgSO4 and concentrated under vacuum to give the final 5-bromo-2-(carboxymethyl)benzoic acid 16A as a yellow solid (12.22 g, 50.7% yield).
