SU1133842A1 - Method of obtaining trans-1,4,5,6-tetrahydro-1-methyl-2(2-2-thienyl-vinyl)pyrimidine pamoat - Google Patents

Abstract

METHOD OF OBTAINING TRANS-1,4, 5,6-TETRAHYDRO-1-METHIL-2- 2-

Description

This invention relates to an improved process for the preparation of trans-1,4,5,6-tetrahydro-1-methyl-2 2- (2-thienyl) vinyl pyrimidine pamoate, a biologically active compound used in medicine as a highly effective anthelmintic drug.

A known method of obtaining similar in structure to trans-1,4, 5,6-tetrahydro-1-methyl-2- 2- (2-thienyl) vinyl pyrimidine pamoate of cyclic amidine salts, which consists in the interaction of alcoholic solutions of cyclic | amidines with organic and inorganic acids, followed by separation of the salt formed by concentrating the alcohol solution or by adding diethyl ether to the alcohol solution of the reaction product and recrystallization from methanol. Trans-1,4,5,6-tetrahydro-1-methyl-2 2- (2-thienyl) vinyl pypyrimidine pamoate was also obtained in this way.

(pyrantel pamoat).

I

In order to achieve pharmacopoeial purity, additional purification is required of cyclic amidine salts, either with repeated crystallization from methanol or by dissolving in a mixture of methanol and ethanol and subsequent concentration of the solution. The disadvantages of the known methods for the preparation and purification of pyrantel pamoate are the impossibility of obtaining the target product in fine form without using additional mechanical grinding in a special mill, high consumption of solvents used to crystallize the target product, and the difficulty of their regeneration. The aim of the invention is to obtain a fine product and to simplify its production technology. This goal is achieved by the described method of preparing trans 1, 4,5,6-tetrahydro-1-methyl-2-; 2-thienyl) vinyl-J-pyrimidine pamoate by reacting its base with pamoic acid in dimethylformamide, the resulting salt is precipitated from the solution with water, the crystalline product formed is recrystallized by dissolving in dimethylformamide. At a temperature of 20-130 ° C and a mass ratio of pamoate: dimethylformamide 1: 6.7-7.3, the solution is cooled to 20-25 ° C and introduced at a rate of 0.02-0, 03 about. HVMHH to lower alkanol cooled to O - (+ 10) C and taken in volume 3-3.5 times the volume of dimethylformamide. Distinctive features of the proposed method are the interaction of trans-1,4,5,6 tetrahydro-1-methyl-2- 2- (2-thienyl) vinylPyrimidine with pamoic acid in dimethylformamide, precipitation of the resulting salt from a solution with water, recrystallization of the formed product by dissolving in dimethylformamide at a temperature of 120-130C and a mass ratio of pamoategdimethylformamide 1: 6.7-7.3, the subsequent cooling of the solution to 20-25 ° C and introducing it at a speed O, 02-0-, 03 ob.h. min to the lower alkanol, cooled to O - (+ 10) - C and taken in volume, 3 3.5 times and exceeding the volume of dimethylformamide. The implementation of the described method allows to obtain a fine target product (2-4w) of pharmacopoeial purity and simplify the technology of its production due to the exclusion of the grinding stage. Replacement of the solvent at the stage of obtaining trans-1,4,5,6-tetrahydro-1methyl-2- 2- (2-thienyl) vinyl pyrimidine pamoate (alcohol with dimethylformamide) makes it possible to reduce the volume by 7-10 times, simplify regeneration and reduce solvent losses. Example 1. Preparation of technical trans-1,4,5,6-tetrahydro-1methyl-2- (2- (2-thienyl) vinyl pyrimidine pamoate. 121.9 g (0.52 mol) of trans-1 crude base is dissolved , 4,5,6-tetragiAro-1-methyl-2- 2- (2-thiensh1) pyrimidine vinyl (with a basic substance content of 83%) in 1300 ml of dimethylformamide at and added with stirring 194.2 g (0.5 mole) of pamoic acid. The resulting dark solution is heated to 130 ° C for 20 minutes and 1400 mp of water is added. A crystalline precipitate begins to cool down after a while. The mixture is cooled to room temperature, the cage is filtered and washed on the filter with 500 ml of aqueous dimethylformamide (2 :), then 1500 ml of water, 500 ml of alcohol and dried in vacuum at 60-30 0 for 3 hours. 245.5 g (83%, counting on pamoic acid) of yellow are obtained crystalline trans-1,4,5,6-tetrahydro-1methyl-2- 2- (2-thienyl) vinyl pyrimidine pamoate, mp. 257-262 C (decomp. when melted on a Boetius instrument, applied at 230 ° C, heating 10 minutes before and then heating at a rate of l C / min). The resulting product has a dispersion of 13-32 U, for all other indicators it meets the requirements of the American Pharmacopoeia. The content of the basic substance according to alkalimetric titration of 100.4%, base (UV) 97.5%, pamoyaric acid (UV) 66.7% (theoretical content 65.4%). Found,%: C 63.39; H 5.24; S 5.26; N 5.00. Ts4Ngo 20bZ. Calculated,%: C 63.67; H 5.03; S 5.39; N 4.71. Example 2. Preparation of fine trans-1,4,5,6-tetrahydro-1-methyl-2- 2- (2-thienyl) vinyl pyrimidine pamoate. In a three-necked flask with a capacity of 1 l, supplied with a stirrer, a thermometer and an addition funnel. 5 load 450 ml of alcohol R OH (R-CgH or CH (011) 2), cooled to 0 - (+ 10) s, and with stirring, they are applied at a rate of 0.02-0.03 ob.h. / min. a solution of 20 g of a technical pyramide of namoate in 140 ml of dimethylformamide, obtained by heating to 120–130 ° C and then cooled to room temperature. After completion of the addition, the mixture is stirred for another 30 minutes, the precipitate is filtered off, washed with 80 ml of the appropriate alcohol and dried to constant weight. Raw solvents are regenerated from the mother liquor (see example 3). Example 3. Recovery of solvents after the preparation of a fine pyrantep pamoate. In a round bottom flask with a capacity of 1 l, equipped with a reflux condenser (25 cm long), load the liquor from example 2. Na. in a boiling water bath, the corresponding alcohol is distilled off, collecting the fraction j indicated in Table 1. Heating is continued on an oil bath, the intermediate fraction is added to the subsequent fractions (up to bp. 145–150 ° C), dimethyl formamide is distilled off from the residue, and the fraction 150-153 0 is collected (Table 3). Example 4: The reaction wire is analogous to Example 2, using 130 ml of DMF to dissolve the technical pyrantep pamoate. Product loss is 16%. And p m i me r 5. The reaction is carried out analogously to example 2 with the difference that 400 ml of alcohol are used; the loss of pyrantel pamoate is 17%, the particle size of the product is 3.5-4.3 µm. EXAMPLE 6 The reaction was carried out analogously to Example 2, but the DMF-solution of pyrantel pamoate was added at a rate of 0 .05 vol. / Min. The particle size of the resulting pyrantel pamoata 3.5-6.8 microns. To confirm the high anthelmintic activity of the finely dispersed pyrantel pamoate obtained by the described method, its effectiveness was studied in comparison with the pyrantel pamoate obtained by crystallization from aqueous dimethylformamide. 2 The drug was tested for white nipostrongylosis by the known method. The drugs were administered once at a dose of 10 mg / kg of animal weight on the 10th day after infection and the animals were opened on the third day after the start of treatment. Intensity was taken into account by comparing the number of nematodes in the test and control tpynps. In the experiment used on 15 20 animals. The comparative effectiveness of pyrantel pamoate, which is prepared by crystallization from aqueous dimethylformamide (particle size 18-32 M) and fine pyran-. the body of the pamoat obtained by the proposed method, with nipostrongylosis of white mice is presented in table 2. From table 2 it is seen that the effectiveness of the fine preparation obtained by the described method is 2 times higher than the efficiency of the preparation prepared by crystallization from aqueous dimethylformamide. The study of the toxic properties of the drug Yokazapo, that the drug is low toxic and corresponds, according to this indicator, a standard sample (see Table 3). The advantage of the described method in comparison with the known method is that the method poses the exclusion of one stage — the stage of grinding the target output and thus the stage associated with the explosive air suspension of the fine powder is excluded from the pyrantel pamoat production process. In addition, the described method allows the regeneration of the used organic solvents (dimethylformamide and alkanols), since they have significant differences in boiling points, thereby allowing them to be separated and regenerated in high yield (82-91%). The described method makes it possible to drastically reduce the volume of solvents used and thereby significantly increase the removal of the target product per unit volume of the apparatus.

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Claims (1)

METHOD FOR PRODUCING TRANS-1,4, 5,6-TETRAHYDRO-1-METHYL-2- [2- (2-THIENYL) VINYL] PYRIMIDINE PAMOATE, by reacting its base with pamoic acid in the presence of an organic solvent followed by precipitation of the product and its purification by recrystallization, characterized in that, in order to obtain a finely divided target product and to simplify the technology, dimethylformamide is used as a solvent, the salt obtained from the solution is precipitated with water, the resulting crystalline product is recrystallized by dissolving in dime formamide at a temperature of 120-130 ° C and a weight ratio pamoate dimethylformamide 1: 6.7-7.3, rast- _Ω thief cooled to 20-25 ° C and injected at a rate ® 0.02-0.03 ob.ch ./min to the lower alkanol Cg-C ^, cooled to 0 - (+10) ° С and taken in a volume 3-3.5 times the volume of dimethylformamide.