Step 1, take the concentrated sulfuric acid as catalyst preparation maleuride
Get 4000g toluene, 1000g maleic anhydride and 1300g urea, take 98% (mass percentage) concentrated sulfuric acid (consumption is 100g) as catalyst, under 70 ℃ of conditions, react for 1 hour, filter, wash and dry to obtain horse Lyurea, the product purity is 80%, and the yield is 85%.
According to the above-mentioned experimental method, the experimenters carried out 4-6 times of preparation of maleic acid, and the reaction time was 1-3 hours. As a result, the purity of the product was 75%-88%, and the yield was 80%-90%.
Detection method of maleyl urea:
HPLC method to detect purity:
Mobile phase: 0.02M KH2PO4 (pH2.5), plus 0.005M tetrabutylammonium bromide: acetonitrile (95:5)
Injection volume: 10ul
Column temperature: 25°C
Flow rate: 1.0ml/min
Chromatographic column: Kromasil Eternity-5-c18, 4.6×250mm
The time for the main peak of maleyl urea to emerge is about 6.6 minutes.
Step 2, prepare crude product orotic acid
Take 500g of maleyl urea, bromine (the mass ratio of maleyl urea to bromine is 1:1.5) and 3000g of water, and react at 20°C for 10h to obtain a bromide intermediate. Take 1 L of 10% sodium hydroxide solution, heat it to 60°C, then pour the bromide intermediate into the hot alkali solution, control the temperature at 60°C, and stir for 5 hours to obtain a clear solution. Then use concentrated hydrochloric acid (commercially available) to adjust the reaction solution to a pH of 1 to obtain solids, which are filtered, washed and dried to obtain crude orotic acid with a product purity of 96% and a product yield of 80%.
According to the above-mentioned experimental method, the experimenter carried out the preparation of orotic acid 4-6 times. Wherein, the mass ratio of maleyl urea to bromine is 1:1.5-3.0, the reaction temperature of maleyl urea and bromine is 5-20°C, and the reaction time is 10-25h; the usage amount of 10% sodium hydroxide solution is 1 -2L, when the bromide is poured, the temperature is maintained at 55-85°C; the stirring time is 5-10h. Results The product purity of orotic acid was 90%-96%, and the product yield was 72%-90%.
Detection method of crude orotic acid:
HPLC method to detect purity:
Mobile phase: 0.02M KH2PO4 (pH2.5), plus 0.005M tetrabutylammonium bromide: acetonitrile (95:5)
Injection volume: 10ul
Column temperature: 25°C
Flow rate: 1.0ml/min
Chromatographic column: Kromasil Eternity-5-c18, 4.6×250mm
The peak eluting time of crude product orotic acid is about 12 minutes.
In this preparation method, need not carry out any aftertreatment to the intermediate product of bromination, but directly join the reaction mixture containing this intermediate product of bromination in the hot alkaline solution, simplify operation steps (especially filter step ), which greatly reduces the health damage of bromine to the operator, and reduces the loss of brominated intermediate products, thereby effectively improving the yield of the final product.
Step 3, orotic acid crude product refining
Take 150g of crude orotic acid and deionized water (1000g), stir at 60°C, the solution system is white and milky; then add 100g of ammonia water dropwise to the system, and stir for 3h. Filtrate to obtain the filtrate, acidify with hydrochloric acid to pH 1, stir and cool to room temperature, filter, wash with water, collect the solid, and dry to obtain orotic acid monohydrate product with a purity of 96% and a yield of 70%.
According to the above experimental method, the experimenters carried out 4-6 times of orotic acid refining. Wherein, the amount of ammonia water for the first time is 100-300g, the stirring temperature is 55-85°C, the stirring time is 3-5h, the amount of ammonia water for the second time is 100-300g, and the stirring reaction is 3-5h. As a result, the orotic acid monohydrate product has a product purity of ≥96% and a yield of 65%-85%.
Detection method of orotic acid finished product:
HPLC method to detect purity:
Mobile phase: 0.02M KH2PO4 (pH2.5), plus 0.005M tetrabutylammonium bromide: acetonitrile (95:5)
Injection volume: 10ul
Column temperature: 25°C
Flow rate: 1.0ml/min
Chromatographic column: Kromasil Eternity-5-c18, 4.6×250mm
The orotic acid peak time is about 12 minutes.
The preparation method of orotic acid, its concrete steps are as follows:
(1) Synthesis of carbamoylaspartic acid: Add 39.9 g of aspartic acid in the reaction vessel, then add 21 g of sodium cyanate, then add 119.7 ml of water, react at 75 ° C for 4.5 hours, add mass after natural cooling The fraction is 38% concentrated hydrochloric acid until the pH is 2.3, and carbamoylaspartic acid is precipitated, filtered, and dried to obtain 28.5 g of the product, with a yield of 65%.
(2) Synthesis of hydantoin acetic acid: in a reaction vessel, add 28.5 g of carbamoylaspartic acid, add 85 milliliters of 20 wt% hydrochloric acid, heat and evaporate to dryness, recrystallize the residue in water, and filter to obtain The filter residue was dried to obtain 22.8 g of hydantoin acetic acid with a yield of 76%.
(3) Synthesis of carboxymethylhydantoin: In a reaction vessel, add 22.8 g of hydantoin acetic acid, then add 11.4 mL of liquid bromine, then add 45.6 mL of glacial acetic acid, and heat at 100° C. for 2 hours. Pour the suspension into 150 ml of boiling water within 15 minutes, cool and crystallize, filter to obtain a filter residue, and dry the filter residue at 100-105° C. to obtain 15.9 g of carboxymethylhydantoin with a yield of 73%.
(4) Synthetic of orotic acid: add carboxymethylhydantoin 15.9g in reaction vessel, add 20wt% sodium hydroxide 31.8 milliliters, be warming up to 65 ℃ with the range of temperature rise of 5 ℃ per minute, be incubated 15 minutes, Add 2.5 g of activated carbon for decolorization, filter, and acidify the filtrate to pH 4.5 with hydrochloric acid, stir at 30 rpm for half an hour, cool, filter, and dry to obtain 11.2 g of orotic acid with a yield of 68%.
