5-fluorocytosine is obtained by chlorination, ammoniation and hydrolysis of 5-fluorouracil.
1. Chlorination will add 5-fluorouracil and phosphorus oxychloride into the chlorination pot, stirring, control the drop of N, N-dimethylaniline below 20 ~C. After dropping, the reaction temperature rises to 110 C for 2 hours. Cool to room temperature and ice in brine. Stir for 1 hour at 15 C. 2,4-dichloro-5-fluoropyrimidine was obtained by filtration and washing. 2. Ammoniation dissolves 2,4-dichloro-5-fluoropyrimidine in ethanol, stirring and controlling the addition of ammonia water below 35 C. After dropping, the reaction temperature was lowered to 25 C for 3 hours. Ethanol was recovered to dry by decompression, and the temperature was raised to 20 C by stirring with water. Filtration, water washing, crystallization, drying, 4-amino-2-chloro-5-fluoropyrimidine.
3. Hydrolysis mixes 4-amino-2-chloro-5-fluoropyrimidine with hydrochloric acid, stirring and heating to 90-95 C. After reaction for 2 hours, the product is concentrated to dry under vacuum, dissolved and crystallized with water, and decolorized with activated carbon. Filtration, filtrate with ammonia water to adjust pH to 7-8, put overnight. Flucytomidine was obtained by filtering, washing and crystallizing with water and refining. The total yield was 50%. The starting material of this method is fluorouracil [51-21-8]. The precursor of fluorouracil, namely 2-methoxy-4-hydroxy-5-fluorouracil, can also be used to prepare fluorocytosine by chlorination, ammoniation and hydrolysis with a yield of 70%. The precursors were added to toluene, followed by dimethylaniline, heated to 50-60 C, and phosphorus oxychloride was added. Then the reaction temperature was 105-110 C for 3 h. Cooling to room temperature, the reaction liquid is added to the mixture of toluene and water, and stirred at 25-40 ~C. The toluene layer was separated and the water layer was extracted with toluene. The extracted liquid was merged with the toluene layer. Toluene was recovered under decompression and then 2-methoxy-4-chloro-5-fluoropyrimidine was obtained by collecting 86-90 ((2.66 kPa) fraction. The chlorinated products and anhydrous methanol were added into the pressure vessel, and ammonia was flowed to saturation at room temperature. The pressure reached 0.5 MPa by slowly rising temperature, and the stirring reaction lasted overnight. When discharged at room temperature, 2-methoxy-4-amino-5-fluoropyrimidine was obtained with a melting point of 189-191 C. It was reacted with 30% hydrochloric acid at 100-105 ~C for 3 hours. The hydrolysate is decompressed, dried, dissolved in water, alkalized with ammonia water to pH 8.5, cooled to below 5 C, filtered, and the crude product of fluorocytosine is obtained. 5-fluorocytosine can be obtained by recrystallization with water.