Study On The Synthesis Of Orotic Acid

Orotic acid is also known as vitamin B13,whose chemical name is 1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidinecarboxylic acid.It is a nutrient playing an important role in liver protection,anti-tumor,anti-virus,promote cell me Tableolism etc.It is also a precursor of a pyrimidine compounds and occupying an important position in drug synthesis.In recent years,it is found that orotic acid can resist aging and increase the me Tableolism of cells,so orotic acid is also used in the field of cosmetics and beverages.Therefore,orotic acid is a promising product,and it is of great practical significance to study its process optimization.In this paper,orotic acid was synthesized from maleic anhydride,urea and bromine by four steps of condensation,bromination/ring-closure,elimination/acidification and refining process.The sui Table process conditions for the synthesis of orotic acid were obtained through process research.In the first condensation reaction maleic urea was synthesized from maleic anhydride and urea in glacial acetic acid as solvent.By analyzing the reaction mechanism protonic acid was selected as catalyst.The optimized synthetic condition were as follows: the amount of p-toluenesulfonic acid was 0.25%(wt)of maleic anhydride,the molar ratio n(maleic anhydride):n(urea)was 1.0:1.3,reaction time was 4h,reaction temperature was45°C.The average yield of maleic urea was 95.7% and the purity was 99.8% while solvent glacial acetic acid was recycled.The consumption of acetic acid was reduced by 41.0%.In the second step,the bromide was synthesized from maleic urea and bomine via bromination/ring-closure.In this process sodium hydroxide was introduced to convert the mixture from hetero-phase to homo-phase.The optimized synthetic comditions were as follows: the molar ratio n(maleylurea):n(bromine):n(sodium hydroxide)was 1.0:1.1:1.1,47.9g(0.3mol)maleic urea,80.0g distilled water and 13.2g sodium hydroxide were charged,successively,and bromine was quickly added at 0°C,the reaction temperature was raised at a rate of 1°C/0.5h and kept at 14°C for 4h,then was raised at a rate of 1°C/0.5h and kept at18°C for 1h,the total reaction time was 14 h,under this condition,the yield of bromide was increased to 91.8%,and the purity was increased to 97.2%.In the third step,crude orotic acid was synthesized from the bromide,sodiumhydroxide and hydrochloric acid via elimination/acidification reaction.The optimized reaction conditions were as follows: the molar ratio n(the bromide):n(sodium hydroxide)was 1.0:4.6,in 16.0%(wt)sodium hydroxide(obtained by mixing 78.0g 30% sodium hydroxide and 68.3g of distilled water)was added the bromide(30.0g)in 5 batches,and the mixture was rapidly heated to 80°C,and reacted for 1.5h,then was cooled to 25°C,and98.3g of 30% hydrochloric acid was added thereto and the mixture was stirred for 1h to precipitate crude orotic acid,the yield was 88.1% and the purity was 97.6%.In this paper,the “one-pot” process combining both bromination/ring-closure and elimination/ acidification was attempted.The “one-pot” operation was as follows: 22.5g maleic urea was uesd,and the bromination/ring-closure was the same as the modified methods;in 16.8%(wt)sodium hydroxide(obtained by mixing 98.4g 30% sodium hydroxide and 20.0g of distilled water)was added the bromination batchwise at 18°C,and after stirring for 15 min,the temperature was rapidly raised to 80°C,the reaction was carried out for 1.5h,them the mixture was cooled to 25°C,and 95.8g 30% hydrochloric acid was added for acidification,and the reaction was carried out for 1 hour,and the crude orotatic acid was obtained by suction.The crude orotic acid was obtained with a yield of 93.5% and a purity of 96.9%.The yield was increased by 12.6% than that of two-step method,and the amount of wastewater was reduced by 23.4%,and there was no significant difference in purity.In the fourth step,the crude orotic acid was purified via desolving in basic media and recrystallizing in acidic media.The optimum conditions werer as follows: the molar ratio n(orotic acid):n(ammonia):n(hydrochloric acid)was 1.0:2.5:2.8,the mixture of 10.0g(0.06mol)crude orotic acid and 110.0g distilled was heated to 80 °C,then 25% aqueous ammonia and 1.5g charcoal were charged,on stirring at 100 °C for 45 min,the mixture was filtered,the the filtrate was rapidly heated to 100°C,and 30% hydrochloric acidwas added in,after slowly cooling was precipitated the crystals of orotatic acid,the desired product was gained on suction and drying.The optimized yield reached 90.1%,the purity was99.9%,and the amount of wastewater decreased by 30.3%.The overall reaction yield after optimization was increased to 69.7%.The yield of the“one-pot” process was increased to 80.6%.