General procedure for the synthesis of 5-methyl-2-pyrimidin-2`-ylbenzoic acid from methyl 5-methyl-2-(pyrimidin-2-yl)benzoate: a solution of methyl 5-methyl-2-(pyrimidin-2-yl)benzoate from the previous step was added through an in-line filter to a pre-cleaned 100 L reaction flask, concentrated and the solvent replaced with 2-methyltetrahydrofuran (~15 L). To this solution, water (20 L) and 10 N sodium hydroxide solution (2.60 L, 26.0 mol) were added sequentially. After the addition was completed, the reaction solution turned red, and the reaction temperature was set to 72°C and maintained for 1.5 h. The reaction was confirmed to be complete by HPLC analysis. After completion of the reaction, the mixture was cooled and transferred to a 50 L extractor. The reaction flask was rinsed with 4 L of water and 10 L of methyl tertiary butyl ether (MTBE) and the rinse solution was added to the mixture in the extractor. The layers were separated and the aqueous phase was washed twice with 10L MTBE. Subsequently, the aqueous layer was reintroduced through an in-line filter into a 100 L reactor for acidification. Under cooling conditions, 2.3 L of 12N hydrochloric acid was slowly added and an exothermic phenomenon was observed, with a temperature increase of 7 to 10°C, at which point a beige precipitate (pH=1) appeared. The precipitate was collected by filtration and the filter cake was washed sequentially with cold water (3 mL/g) twice, a cold 15% MTBE/heptane and 15% toluene/heptane mixture (3 mL/g), and finally with room temperature MTBE (1.5 mL/g) and heptane (3 mL/g, twice). The resulting solid was dried under a stream of nitrogen for two days to give 5-methyl-2-pyrimidin-2`-ylbenzoic acid (E-4) as a light beige powder (2.15 kg, 10.04 mol, 97% yield).HPLC analysis showed the product to be 99.2% pure. Heavy metal analysis showed 264 ppm of palladium and 19.7 ppm of iron.The NMR hydrogen spectrum (500 MHz, DMSO-d6) data of E-4 were as follows: δ 12.65 (s, 1H); 8.85-8.82 (m, 2H); 7.78 (dd, J=7.89,2.34Hz, 1H); 7.49-7.37 (m, 3H); 2.40 (m, 3H); 2.40 (m, 3H); 2.40 (m, 3H). 3H); 2.40 (s, 3H).
