Study Of Bromine-free Synthetic Process Of Orotic Acid

Orotic acid(vitamin B13, H3dtpc),1,2,3,6-tetrahydro-2,6-dioxane-4-pyrimidinylcarboxylic acid as ketonic name and2,6-dihydroxypyrimidine-4-carboxylic acid asenol name, is an important derivative of pyrimidines for the biosynthesis ofpyrimidinyl nucleic acid and plays a unique role in the biological and pharmaceuticalchemistry. Currently, maleic anhydride and urea are used for the domestic industrialproduction of orotic acid by bromination and debromination reaction. This processroute is not satisfactory in atomic economy, safety and environmental protection, andproduct quality (containing bromine impurity). Based on previous work, wedeveloped an eco-friendly synthetic route for industrial production of orotic acid. Inthis synthetic route, dimethyl oxalate and methyl acetate were used as initial reactionraw materials to synthesize key intermediate,2-one-dimethyl succinate, throughClaisen ester condensation. The other key intermediate, methoxy carboxymethylhydantoin, was obtained by a cyclization reaction between2-one-dimethyl succinateand urea under the catalysis of an acid. The rearrangement reaction of methoxycarboxymethyl hydantoin in NaOH aqueous solution generated orotate that turnedinto orotic acid by acidification. The developed process route does not require use ofbromine or bromide, so the final product does not contain bromine element, which notonly improves the quality of the product, but also makes the process route moreeconomical, safe, and eco-friendly.By studying the temperature, catalyst, solvent, feed ratio, and dropping speedof methyl acetate in Claisen ester condensation reaction, we found that the optimalsynthetic conditions were: sodium methoxide was used as catalyst; tetrahydrofuranwas used as solvent; the molar feed ratio of dimethyl oxalate:methyl acetate:sodiummethoxide was1:1.2:1.1; reaction temperature was40℃; methyl acetate addition wasadded drop by drop within1h. The yield of2-ketone-dimethyl succinate reachedabout85%under the optimal synthetic conditions. The optimal conditions of cyclization reaction were: toluene was used as solvent; concentrated sulfuric acid wasused as catalyst. The yield of methoxy carboxymethyl hydantoin reaches about52%and the total yield was approximately30%under the optimal conditions.