SU578873A3 - Method of preparing 5-fluorocitazine - Google Patents

Description

one

The invention relates to an improved process for the preparation of 5-fluorocytosine, which finds use as an antifungal agent.

A known method for producing 5-fluorocytosine, including 5 stages: the conversion of 2-ethoxy-5-fluoro-4 (3N) -. Pyrimidone to 5-ft. Ruracil, which is converted into 2,4dizslpirimidine by the action of phosphorus oxychloride The latter is treated with ammonia in a solvent, the resulting 2-chloro-4-amino-5-fluoropyrimidine is hydrolyzed with concentrated acid to the cytozine 5-4to salt followed by isolation of the target product by the action of ammonia on the indicated salt l. The yield of the target product is 65% (in terms of 5-fluorouracil)

The disadvantages of the method are the multistage method and the insufficiently high yield of the target product.

The purpose of the invention is to simplify the process and increase the yield of the target product.

This is achieved by the proposed method of obtaining 5-4grocytosine by chlorination

2 etolcy-5-fto | -4 (3N) pyrimidinone with excess chloroxy phosphorus in the presence of a tertiary base in an organic solvent in 2-ETOXI-4-chloro-5-fluoropyrimidine, by aminating the latter with ammonia in a solvent and hydrolysis of the resulting 2-ethoxy-4-amino-.5-4to1-thyrimidine with concentrated hydrochloric acid to the salt of 5-4 torocytosine, from which the target product is isolated by the action of ammonia.

The distinctive features of the process are chlorination of the starting 2-to-5-α-fluoro-4 (3N) -ryrimidinone, aminating the latter to 2-ethoxy-4-amino-5 h)) torpirimidine and hydrolysis of the latter.

The proposed method allows reducing the number of stages to three, increasing the yield of the target product up to 80%,

2-Ethoxy-4-chloro-5-fluoropyrimidine is obtained by chlorinating 2-ethoxy-4 (3N) -pyrimidinone with an excess of phosphorus oxychloride in the presence of a tertiary amine, preferably dimethylaniline, in an inert organic solvent, such as toluene, benzene, hexane, trichloroethylene, chloride Methyl A preferred 50% excess of chloroxy-phosphorus and aimethyl1 "is stoichiometric. The reaction is carried out at a temperature from room temperature up to a boiling point of the reaction mixture, preferably at 50-1OO C, with the required pressure of elevated pressure. 2-ethoxy 4-chloro-5-fluoropyrim dn trp & they are rotated in 2-ethoxy-4-amino 5 4 dopamine by the action of ammonia, both gaseous and aqueous, in the presence of solvents, such as alcohol, toluene, water, and mixtures with these solvents. Reacting can be carried out at room or over-temperature, in accordance with the case of POB, with a high pressure. The preferred temperature is 20-. and ib tovn given in 1-2 ati. The hydrolysis of 2-ethoxy-4-amino-5-torpnrimidine into the salt of 5-torcytosine is carried out in the presence of strong inorganic acids such as hydrobromic, hydrochloric, or distohydrogen, sulfuric, phosphoric, or chlorine, preferably in the presence of oxygen. trirated hydrochloric acid. Water, alcohols or their mixtures can be used as solvents at this stage, preferably in an aqueous solution. The reaction can be carried out at a temperature ranging from room temperature to TeNmepaTypbi by boiling the reaction mixture and, if appropriate, under elevated pressure. The highest temperature is close to that of concentrated aqueous hydrochloric acid, for example, 8O-11O C. The process is carried out using an excess of acid, 2.5-C-edge coding (by weight). The semi-stunted salt is transferred in a known manner to a free base, in the corresponding case with a previous ammonia release from the solution, for example. To a suction flask (1.5 L) equipped with a stirrer, Tej. using a meter, reflux condenser, a chlor-karyshev tube and placed in an oil bath with a thermostat, 18O ml of dimethylanipine and 475 ml of toluene are added to 154 g of 2 ethoxy-5-fluoro-4 (ZN) -pyrimidinone; While mixing the SRI 130: ml of phosphorus oxychloride and the contents of the flask are heated to 1 0 C (in the bath), after 15 minutes the temperature reaches 98 C and the reaction solution becomes clear. At this temperature, stir for 2 hours. After cooling to 25 ° C, the solution is added dropwise over 10 minutes while cooling cooling sieve (dry leN-acetone) with stirring at 28-35 ° C to 1100 ml of water . After this, the mixture is stirred for another 45 minutes at TOO temperature, transferred to a 3 L separating tank, the lower aqueous phase is extracted and extracted twice using O 4 OC ml of toluene. The combined organic phases are evaporated in vacuo. The balance of eperOHfflor in high vacuum (0.3-1 Torr) in the bath temperature of 80-95 C and at a vapor temperature of C. Obtain 162.7 g of 2-etoxy-4-chloro-5 torairnmidnn as a colorless displa; gkp 173 ° C; 1.498. The product obtained is dissolved in a mixture of 80 O ml of alcohol and 48 ml of water, transferred to an autoclave and pumped out under pressure up to ISO Torr. Then the autoclave is pumped out of the cylinder until the pressure is 5 MPa. The temperature first rises to C, then it is lowered by cooling to 23 C. The mixture is stirred for 15 hours at 23 ° C and 4.5 atm, then the reaction mixture is cooled and the overpressure is carefully discharged. The reaction mixture is heated to 20 ° C and evaporated in vacuo at a bath temperature of 50-60 ° C to dryness. To the residue was added 4 OC ml of water and again to dryness. The solid white residue is quenched in an MOO of water, the suspension is cooled to 20 s, filtered and washed with water. The residue on the filter is stirred with 15O m of shlol-boiling of its ether and filtered again. 136.2 g of 2-ethoxy. 4-amino-5-fluoropyrimidine are obtained (91.4%); m.p. 113 ° C. In a 1.5 L flask for sulfating, equipped with a stirrer, a thermometer, a reverse bath and an oil bath with a thermostat, ZOO ml of hydrochloric acid are added to 136.2 g of 2-ethoxy-4-amino 5-fluoroparimidine. The mixture is heated to 90-95 ° C. for 20 minutes and stirred at this temperature for 2 hours. After that, the clear, slightly yellowish solution is evaporated to dryness in vacuo. The residue is dissolved in 55 O ml of water and heated to 45 ° C. Pra 4 O-45 ° C solution of OOO ml of ammonia in 1 OO ml of water is added to pH 8.5 during 30 min. The mixture is cooled for 1 hour until o-gassing is carried out on a putsch, stirred with 10O ml of water at a temperature of 2 ° C, and again sucked off. After drying, 1O3 is obtained, 1 g of crude 5C) toraitosin (yield 92.1%). The crude product is purified as follows: 1OC, 1 g of 5-fluorocytosine is dissolved in 825 ml of water at a temperature of 9 ° -95 ° C. To this slightly dry solution, 1 g of diatomaceous earth is added, and the mixture, after mixing well, is filtered in