The way to obtain 6-methyluracil-5-sulfochloride

 

The invention relates to the field of synthesis and technology of obtaining 6-methyluracil-5-sulfochloride promising starting material for the production of medicines and dyes. The method is carried out by sequential interaction of initial 6-methyluracil with chlorosulfonic acid at 80-90oC. Then treated with phosphorus trichloride at a temperature of 40-63oIn the presence of catalytic amounts of dimethylformamide (DMF) from of 0.081 to 0,163 mol per 1 mol of 6-methyluracil. The reaction mass is diluted 90-96 wt. % ethyl alcohol at a temperature of 0 to 10oWith and produce the target product. Effect: increase the yield of the target product, improve the technological process and the expansion of raw materials process sulfochloride. table 1.

The invention relates to the field of producing compounds of interest as source materials in the production of new domestic bifunctional drugs for the treatment of mycobacteriosis (leprosy, tuberculosis, syphilis), possessing immunomodulating effect, for example, by A. C. USSR 606242, A. C. the USSR 938442, A. C. the USSR 768186, A. C. the USSR 662098, Pat. RF 2141322 and others.

Known method polity and chloride tiomila at a temperature of 75oWith over 8 hours Target product was released by decomposition of the reaction mixture into a mixture of ice and water. Output MUSH accounted for 72% of theoretical, so pl. 235o[A. S. 226620, publ. 16.09.81].

The disadvantages of this method should be attributed to the relatively low yield of 6-methyluracil-5-sulfochloride, high consumption of chlorosulfonic acid and chloride tonila, as well as the difficulty of controlling the process due to the presence in the reaction of sulfochloride the induction period and the possibility of abrupt gas emissions, which creates the danger of the process.

To avoid these disadvantages has been proposed [RF Patent 2087471] a method of obtaining MUCH sequential processing of 6-methyluracil chlorosulfonic acid at 80-90oAnd then with a mixture of chlorosulfonic acid and tonila chloride in the presence of catalytic amounts of DMF introduced into the reaction mixture with chloride tiomila.

Output MUSH was 85-90% of theoretical, so pl. 235oC.

The disadvantages of the proposed methods is the necessity to use as one component of sulfochloride chloride tiomila to improve yield MUCH.

Currently in Russia there is practically no production of chloride Diego basis ("Diazepan", "Soliton", "Isoton" and so on), making them noncompetitive.

The disadvantages of the process include the need for pre-operation preparation of a mixture of dimethylformamide (DMF) with tiomila chloride, as if DMF is entered in chlorosulfonic acid and then titrated thionyl chloride, effect of catalysis does not occur in this case, the reaction takes place abruptly and significantly reduced output MUSH.

The aim of the present invention is the expansion of raw materials production of sulfa drugs, reducing the cost of the initial components of the process sulfochloride 6-methyluracil to MUSH and, consequently, reducing the cost of pharmaceuticals based on it.

This goal is achieved by the fact that 6-methyluracil treated consistently chlorosulfonic acid at 80-90oAnd then with a mixture of chlorosulfonic acid, phosphorus trichloride and catalytic amounts of DMF at 40-63oC. DMF is introduced directly into the reaction mass after the interaction of 6-methyluracil with chlorosulfonic acid and before the dosage of phosphorus trichloride.

Output 6-methyluracil-5-sulfochloride is 90-96% of theoretical.

Schemati what blica.

Example 1 20 g (strength of 0.159 mol) of 6-methyluracil metered portions at a temperature not exceeding 40oWith 49 g of chlorosulfonic acid (HSC). The temperature of the reaction mass under stirring raise within half an hour up to 80oWith and give a one-hour exposure at 80-85oC.

The reaction mass is then cooled to 40-45oAnd poured it with 1 ml DMF and then for 2 h metered 47 g (0.32 mol) of phosphorus trichloride at a temperature of 45-50oC. the Temperature of the reaction mass was raised to 60oWith and give a one-hour exposure at 60-63oC. the Reaction mass is then cooled to 5oWith and portions dispense 100 ml of 96% ethanol at 0-5oTo give a one-hour exposure at this temperature.

Eye-catching product is filtered off, washed twice with ethyl alcohol. The product is dried at a temperature of 35-40oWith under vacuum.

Output 6-methyluracil-5-sulfochloride is to 32.7 g (92% of theoretical), so pl. 235oC (decomp.).

Example 2 20 g (strength of 0.159 mol) of 6-methyluracil metered portions at a temperature not exceeding 40oWith 49 g of chlorosulfonic acid. The temperature of the reaction mass under stirring raise within half an hour up to 85oWith and give a one-hour exposure at 85-90oC.

The reaction mass kreisliga phosphorus at a temperature of the reaction mass 45-55oC. Next, the temperature of the reaction mass was raised to 60oWith and give a one-hour exposure at 60-63oC. the Reaction mass is then cooled to 5oWith and portions dispense 100 ml of 96% ethanol at 0 to 10oTo give a one-hour exposure at this temperature.

Eye-catching product is filtered off, washed on the filter twice with ethyl alcohol. The product is dried at a temperature of 35-40oWith under vacuum.

Output 6-methyluracil-5-sulfochloride is of 33.4 g (94% of theoretical), so pl. 235oC (decomp.).

Example 3 20 g (strength of 0.159 mol) of 6-methyluracil metered portions at a temperature not exceeding 40oWith 49 g of chlorosulfonic acid. The temperature of the reaction mass under stirring raise within half an hour up to 85oWith and give a one-hour exposure at 85-90oC. the Reaction mass is then cooled to 40-45oAnd poured it with 1 ml of 0.013 mol) in DMF and then for 2 h metered portions 24 g (0.18 mol) of phosphorus trichloride at a temperature of the reaction mass 45-50oC.

Next, the temperature of the reaction mass was raised to 60oWith and give a one-hour exposure at 60-63oC. the Reaction mass is then cooled to 5oWith and portions dispense 100 ml of 90% aqueous ethanol at 0-5oTo give czasowy alcohol - 96%.

The product is dried at a temperature of 35-40oWith under vacuum.

Output 6-methyluracil-5-sulfochloride is 32,0 g (90% of theoretical), so pl. 235oC (decomp.).

Example 4 20 grams (strength of 0.159 mol) of 6-methyluracil metered portions at a temperature not exceeding 40oWith 49 g of chlorosulfonic acid.

The temperature of the reaction mass under stirring raise within half an hour up to 85oWith and give a one-hour exposure at 85-90oC. the Reaction mass is then cooled to 40-45oWith and poured a 1.5 ml (at 0.020 mol) of DMF and then within 2 h of dosing of 35.4 g (0.24 mol) of phosphorus trichloride at a temperature of the reaction mass 45-55oC.

Next, the process carried out as described in example 2.

Output 6-methyluracil-5-sulfochloride is 34,0 g (96% of theoretical), so pl. 235oC (decomp.).

Example 5 20 g (strength of 0.159 mol) of 6-methyluracil metered portions at a temperature not exceeding 40oWith 49 g of chlorosulfonic acid.

The temperature of the reaction mixture raised with stirring to 85oWith and give a one-hour exposure at 85-90oC.

The reaction mass is then cooled to 40-45oWith and poured thereto 2 ml (0,026 mol) DMF and then within 2 h of dosing of 35.4 g (0.24 mol) of phosphorus trichloride at a temperature of the reaction is lorida is of 33.4 g (94% of theoretical), so pl. 235oC (decomp.).

Found, %: C - 26,7; 26,65; N - 2,17; 2,09; N - 23,6; 12,45; Cl - Of 15.75; 15,6; S - 14,2; 13,9.

Calculated, %: C - 26,72; N - 2,22; N - 12,47; Cl - 15,82; S - 14,3.

The impact on output MUSH ratio entering the reaction of components (6-methyluracil, phosphorus trichloride, DMF) are presented in the table.

Sequential processing of 6-methyluracil chlorosulfonic acid and phosphorus trichloride in the presence of catalytic amounts of DMF allows the process evenly without abrupt gas emissions and abrupt rise in temperature. Application for sulfochloride trichloride phosphorus allows the entire process in a single reactor by sequential dosing of components, which improves the manufacturability of the process.

From the above examples that when carrying out the process in the proposed conditions achieved by increasing output 6-methyluracil-5-sulfochloride compared to the prototypes.

The use of phosphorus trichloride in the reaction of sulfochloride expanding the raw material base for the production of sulfa drugs and opens the possibility of significant cost reduction for raw materials.


Claims

The way to obtain 6-methyluracili 80-90oIn the presence of catalytic additives of dimethylformamide, characterized in that conduct sequential processing of 6-methyluracil chlorosulfonic acid and then phosphorus trichloride in the presence of 0.081. . . 0,163 mol of dimethylformamide for 1 mol of 6-methyluracil at a temperature of 40-63oC, then the reaction mass is diluted 90-96 wt. % ethyl alcohol at a temperature of 0 to 10oWith subsequent isolation of the target product known techniques.

 

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