The method of obtaining 5'-benzoyl-2,3'-angerassertive


(57) Abstract:

The invention relates to the field of organic chemistry, and in particular to methods of obtaining derivatives of nucleosides, in particular to obtain 5'-0-benzoyl-2,3'-anhidrosis-thymidine. The method includes processing thymidine organic reagent solution, blocking the 5'-hydroxyl, activating the 3'-hydroxyl by methylchloride and cyclization of salts of alkali metals when heated in an organic solution, thus blocking the 5'-hydroxyl carried out by treatment with benzoyl chloride at a temperature of 5-7 - 0oWith over 70-80 hours after which the product is administered methylsulfonate and sucrose in number, respectively (mol/mol) 0.5 to 0.8:1 and 0.6:0,7:1 in relation to the original thymidine, and the cyclization is conducted water-dioxane solution of sodium carbonate at a temperature of 80-84oC for 1.5 to 3 hours at pH 6.0 and 7.5, and at the stage cyclization ratio of dioxane:water is 3-5,1. 1 C.p. f-crystals, 3 tables.

The invention relates to the field of organic chemistry, and in particular to methods of obtaining derivatives of nucleosides, in particular obtaining 5'-o-benzoyl-2,3'-anhidrosis-thymidine (BAT).

Derivatives of thymidine at the present time are of considerable interest as the surveillance of AIDS (U.S. patent N 5064946, The Lancet I (8481), Mar. 15, 1986, p.575-580).

Derivatives of 2,3-angerassertive derived from D-xylose with its subsequent transformation into a 1-(-D-xylofuranosyl)thiamine and further deoxygenating. The disadvantage of this method is complicated separation and purification (12-15 stages), as well as getting this method a product close to, but not identical to the target.

A method of obtaining BAHT from thymidine (J. Organic Chemistry, v.38, No. 25, 1973, p.4299-4305) by treating its solution in dimethylformamide 2-chloro-1-1,2-triptoreline to block 5-hydroxyl, then activate 3-hydroxy-methylchloride, after which the obtained product is isolated and heated to a temperature of 90oWith California in a mixture of water and dimethylformamide, yielding 5'-0-trityl-2,3 anhydration with a total yield of about 30%

The disadvantage of this method is the low yield of the target product associated with large losses in the allocation of intermediates, a significant number of stages of purification (approximately 10-12), the failure to obtain by this method BAHT.

The invention was the creation of a more effective method of obtaining the BAT.

It was found that the above objective is achieved by implementing locks 5 hidroxil benzoyloxy in a molar with respect to the original thymidine ratio of 0.5 to 0.8; of 0.6-0.7:1, and at the next stage, the cyclization of lead sodium carbonate in water-dioxane solution for 1.5-3 hours at a temperature of 80-84oC and at pH 6.0 and 7.5, the optimal ratio of dioxane: water 3-5:1. In the result of the process in these conditions, succeeded in increasing the yield of the target product to simplify the process, reducing it to six stages. Finding such conditions benzoylation and mesotrione thymidine allows the process without isolating the intermediate product. In particular, among the factors which have a significant effect, is the use of sucrose at the stage of activation, the introduction which allows the formation of a complex with an excess of the Ministry of agriculture to form a protective layer, excluding the negative impact of stress in the next stage, and to ensure the optimization. In the available literature the specified combination of conditions not described. Typically, these reactions proceed in a different temperature range, ratios, and other reagents, etc.

Obtaining positive results, including in the transition to industrial conditions in the new set of parameters, demonstrates compliance invention, the criterion of "technical uroven "URAL".

Example 1. In the dry unit load 30,0 l (24,460 kg) absolutized pyridine, while stirring load 3.0 kg thymidine, heated the reaction mass to a temperature above 80oWith and dissolve thymidine at this temperature and with stirring for approximately 30 minutes After the complete dissolution of thymidine reaction mass is then cooled approximately the first 40oWith, and then to 0 -10oWith and start benzoylation of thymidine. To this end, the measuring device was added dropwise benzoyl chloride. Just benzoylation spend 1,85 l (2,242 kg) benzoyl chloride, the addition of which spend not less than 48 hours benzoylation Reaction monitored by thin layer chromatography on plates type "Silufol". At the end of the benzoylation reaction without cooling the reaction mass, hold the shutter for approximately two hours and start metilirovanie. From the measuring device with the speed of 60-110 drops per minute load without cooling, 1.3 l (1,924 kg) methanesulfonamide, hold the shutter speed not less than four hours at a temperature not higher than the 9oC. After cooling off and the reaction mass by vacuum via send in the Druk-filter. The resulting napravlennom cloth from filter paper and calico. The precipitate in the amount of approximately 3.2 kg taken from the plant. The filtrate in the amount of approximately 30,0 l return to the office, where the mixture is heated to 20-22oWith there load 2.5 kg of sucrose and lead exposure to sucrose in the mixture and the temperature of 20-22oC for at least four hours. After the reaction mass is directed to a rotary evaporator and distilled pyridine at a temperature in a water bath not exceeding 50oC and a vacuum of 15-20 mm RT.article VAT residue obtained after the distillation of chloroform, cooled to 22-25o(The temperature of the water bath). Get dense, sedentary mass amber color, which is dissolved in 12 l of dioxane. Received dioxane solution is directed into the apparatus and heated to a temperature 82-84oC. at the same time preparing an aqueous solution of sodium carbonate (4.0 l of distilled water and 0.5 kg of 100% sodium carbonate). The amount of water in the preparation of a solution of sodium carbonate depends on the moisture content in the returned remote sites and dioxane. Received soda solution for 15 min add in dioxane solution at a temperature 82-84oWith stirring. Then hold the shutter speed at a temperature of 80-84oC for 1 h 20 min the Noah chromatography on plates type "Silufol" (almost no stain, contains the original substance). After aging the reaction mass is then cooled to a temperature of 60-65oC. the resulting cyclization mixture of salts (anhydration and sodium salt of methansulfonate) filter on Druk-filter. Sediment from the remnants of dioxane press the air. Get around 3.2-3.4 kg of salts containing anhydration, which are unloaded in production capacity, fill with distilled water (1:3) and at a temperature of approximately 80oTo carry out the dissolution of the sodium salt of methansulfonate. Then, the resulting suspension anhydration in aqueous salt solution is cooled to a temperature of 30-40oWith and filtered on Druk-filter. The result is approximately 2.8 kg wet anhydration, which is dried in a vacuum drying Cabinet at a temperature of 35-40oWith a vacuum of 30-40 mm RT.article within 2-3 hours Receive approximately 2.5 kg of anhydration with a mass fraction of moisture not more than 0.3% by mass of the basic substance is not less than 97% in terms of dry substance 1,934 kg

Example 2. In the conditions of example 1 was studied the influence of parameters of benzoylation at the output of the target product. The results are shown in table.1.

Example 3. the

Example 4. In the conditions of example 1 were performed to study the conditions for the cyclization stage. The data are given in table. 3.

The invention implemented in a production setting company "URAL industrial-scale.

The results obtained for the production of BAP showed that it is possible to obtain a more simple technology product with a yield of about 70% of the high quality of the drug has enabled the manufacture of high-quality azidothymidine with a melting point not lower than 122oS, i.e. exceeding the similar characteristics of drugs firm "Wellcome Foundation, as well as drugs Zidovudine" and "Retrovir".

1. The method of obtaining 5'-benzoyl-2,3'-angerassertive, wherein the thymidine treated with benzoyl chloride at -7 0oWith over 70 to 80 hours, then enter methylsulfonate and sucrose at a molar ratio with the thymidine of 0.5 to 0.8:1 and 0.6 to 0.7:1, respectively, followed by the cyclization of water-dioxane solution of sodium carbonate at 80 - 84oC for 1.5 to 3.0 hours at pH 6.0 to 7.5.

2. The method according to p. 1, characterized in that the cyclization stage the ratio of dioxane:water 3 5:1.


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