SU415872A3 - Method of producing 4-imino-1,4-dihydropyridines derivatives - Google Patents

Description

The invention relates to the field of the preparation of 4-imino-1,4-dihydropyridines derivatives, which can be used in the pharmaceutical industry. Using the known alkylation reaction as applied to compounds of the pyridine series, new derivatives of 4-imino-1,4-dihydropyridines are obtained with high physiological activity. A method is proposed for the preparation of 4-imino-1,4-dihydropyridine derivatives of the general formula hetero-K where R4 and Rs are each hydrogen or lower alkyl, A is Re or Re-HZ, where Re is hydrogen, lower alkyl or phenyl, HZ is the salt-forming acid, hetero group of the structure where RI, R2 and R7 have the same meanings as R4 and Rs, Rs have the same meanings as Rg. The method consists in the fact that 4-aminopyridine of the formula Ri, RS where R4, Rs and Re have the indicated meanings, is subjected to condensation when heated with a compound of the formula N. —L Ri where Rb R2, Ra and R have the indicated meanings, and X- halogen, sulfonyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkoxy, phenoxy, benzyloxy, tri-lower alkyl ammonium salt or nitro group. The reaction is preferably carried out in the presence of a polar organic solvent, for example acetonitrile, lower alkanols, for example methanol, butanol, ethanol or in the presence of dioxane, dimethylformamide and / or dimethyl sulfoxide. The reaction can be carried out without a solvent or in excess of one of the reagents. The reaction is easier when heated to about 60-200 ° C, is carried out in conventional reaction vessels or at temperatures above the boiling point of the reaction mixture, or for the purpose of shortening the reaction time in an autoclave. The reaction is completed in time from one hour to several days, depending on the reactivity of the starting materials and the temperatures and pressures used. Products crystallize from a hot reaction mixture or a crystalline product can be obtained by cooling the reaction mixture; crystallization can also be facilitated by adding ether to the cooled mixture. If the product does not crystallize upon cooling, the reaction medium is removed by evaporation or by distillation. The resulting product can be purified by recrystallization from an appropriate solvent, preferably an alcohol. If a non-halogen or tri-lower alkylammonium halide salt is used as the 2-X-substituent, then the hydrogen halide salt will form additives after treating the reaction mixture (to isolate the final product) of the corresponding acid. The product obtained as a hydrohalic salt can be converted to the free base using known neutralization methods. The free base may be salified by adding the acid alone or with a suitable solvent, for example, an alkanol. The hydrogen halide salt can be replaced by any other salt of the acid by the known use of anion exchange resins, exchange reaction, or by any other well known method. Example 1. 1- (2 - Pyrimidinyl) -4-imino1, 4-dihydropyridine hydrochloride. A mixture of 14.12 g (0.15 mol) of 4-aminopyridine, 17.18 g (0.15 mol) of 2-chloropyrimidine and 80 ml of absolute ethanol is heated to reflux with stirring for 1 hour. The mixture is then cooled to room temperature. The resulting white solid is collected and dried. As a result, 26.59 g (86%) of 1- (2-pyrimidinyl) -4-imino-1,4-dihydropyridine hydrochloride are obtained with an mp. 308-309 ° C. Crystallization from methanol yields a product in the form of white prisms with m.p. 310-312 ° C. . “Calculated,%: C 51.81; And 4.35; N 26.85. C9H9C1N4. Found,%: C, 51.70; H 4.25; N 26.97. By replacing the 2-chloropyrimidine used in the example with an equimolar amount of 2-chloro-5-methylpyrimidine or 2-chloro-4-ethylpyrimidine, 1- (5-methyl-2-pyrimidinyl) -4-imino-1,4-dihydropyridine hydrochloride and 1, respectively, are obtained. - (4-ethyl-2-pyrimidinyl) -4-imino-1,4-dihydropyridine hydrochloride. Similarly, by replacing 4-aminopyridine with an equimolar amount of 4-aniline pyridine and 2 - methyl - 4 - aminopyridine, 1- (2-pyrimpdinyl) -4 - phenylamino-1,4-dihydropyridine hydrochloride and 1- (2-pyrimidinyl) 2-methyl- 4 - imino-1,4 - dihydropyridine hydrochloride. Using 2-chloropyrimidine and 4-aminopyridine, listed in the table below, in addition, 1- (2-pyrimidinyl) -4 - imino-1,4 - dihydropyridine hydrochloride is obtained with the substituents Ri, R2, Kz, R4, R5 and Rg. Example 8. 1- (2-Pyrazinyl) -4-imino-1,4-dihydropyridine hydrochloride. A solution of 3.8 g (0.04 mol) of 4-aminopyridine and 4.6 g (0.04 mol) of 2-chloropyrazine in 20 ml of ethanol is refluxed for 65 hours. The solution is then cooled rapidly to crystallize the product. After crystallization from ethanol, 3.6 g (43%) of 1- (2-pyrazinyl) -4-imino-1,4-dihydropyridine hydrochloride are obtained, m.p. 260.5-262.5 ° C. Calculated,%: C, 51.80; H 4.35; N 26.85. S9P8Y4PS1. Paydeno,%: C 52.00; P 4.31; N 26.80. By replacing 2-chloropyrazine with an equimolar amount of 5-methyl-2-chloropyrazine, 1 - (5-methyl-2-pyrazinyl) -4-imino-1,4-dihydropyridine hydrochloride is obtained. The mixture is refluxed for 15 minutes, then distilled under vacuum. Example 9. 1- (2-Pyrimidinyl) -4-imino1, 4-dihydropyridine hydrochloride. A mixture of 17.18 g (0.15 mol) of 2-chloropyrimidine and 30 g (0.275 mol) of sulfur tetrafluoride is heated in a stainless steel vessel for 3 hours at a temperature of 50-100 ° C. The mixture is cooled, poured and washed in a polyethylene vessel with a sufficient amount of diethyl ether, filtered for 15 minutes and separated in vacuo. The mixture thus obtained is 14.71 g (0.15 mol) of 2-fluoropyrimidine, 14.12 g (0.15 mol) of 4-aminopyridine and 80 ml of absolute methanol are heated under reflux and cooled to room temperature with stirring for 6 hours. and the collected dry matter is dried. The rough torus salt is dissolved in a minimum amount of water and passed through an anion exchanger C1-form. The eluate is concentrated to dryness in an acum and the residue is crystallized from methano- to form 1- (2-pyrimidinyl) -4-imio-1, 4 - dihydropyridine hydrochloride. Example 10. 1 - (2-Pyrimidinyl) -4-imio-1,4-dihydropyridine hydrochloride. A mixture of 14.12 g (0.15 mol) of 4-aminopyridine, 4.02 g (0.15 mol) of 2-sulfopyrizin, and 00 ml of absolute ethanol is heated with delegation by stirring for one hour, then cooled to room temperature and the resulting substance filter i

-and

g +

h

N K

R

Confirms the structure. The sample contained

wow. The residue containing 1- (2-pyrimidinyl) -4-imino-1,4-dihydropyridine bisulfite is dissolved in a minimum amount of water and passed through the anion exchange resin in the Cb form. The eluate is concentrated to dryness and the residue is crystallized twice from methanol as white prisms 1- (2-pyrimidinyl) -4-imino-1,4-dihydropyridine hydrochloride.

Example 11. 1- (2-Pyrimidinyl) -4-imino1, 4-dihydropyridine hydrochloride.

Equimolecular amounts of 2-methylthiopyrimidine and 4-aminopyrimidine are scrubbed with ethanol and maintained at 100 ° C for 16 hours. After cooling the reaction mixture, hydrochloric acid is added, precipitating product, which is filtered and dried.

In this process, the same product is obtained by replacing 2-methylthiopyrimidine with other 2-lower alkylthiopyrimidines.

Example 12. 1- (2-Pyrimidinyl) -4-imino1, 4-dihydropyrimidine hydrochloride.

2 - Methylthiopyrimidine is treated with 30% hydrogen peroxide in formic acid at room temperature to obtain 2 - methylsulfonylpyrimidine. This composition is mixed with 4-aminopyridine in dimethyl sulfoxide and maintained at 130 ° C for 1 hour. After cooling, the reaction mixture is treated with hydrochloric acid to precipitate the product as a white solid.

To obtain the same final product, the other 2-lower alkylthiopyrimidines can be converted and replaced by the 2-lower alkylsulfonylpyrimidines in a similar way.

Example 13. 1- (2-Pyrimidinyl) -4-imino1, 4-dihydropyridine hydrochloride.

2-methylthiopyrimidine and 30% hydrogen peroxide are mixed in acetone and incubated for 3 hours to form 2-methylsulfipylpyridine. The resulting product is separated from the reaction mixture and mixed with an equimolar amount of 4-aminopyridine and dimethylformallide and heated for 3 hours at 160 ° C. After cooling the reaction mixture and adding hydrochloric acid, the product is separated and collected as a white solid.

In a similar manner, it is possible to oxidize other 2-lower alkylthiopyrimidines to the corresponding 2-LOW1IH alkylsulfinylpyrimidines in order to replace and obtain the same final product.

Using instead of the 2-lower alkylthiopyrimtgdine examples 11-13

4-methyl-2-lower alkylthiopyrimidine,

4, b-dimethyl-2-niz1 alkylthiopyrimidine and

4-methyl-6-phenyl-2-lower alkylthiopyrimidine and applied methods. described in examples 11-13, receive, respectively

1- (4-methyl-2 - pyrimidinyl) - 4-imino-1,4-digdropyridine hydrochloride,

1- (4.6-dimethyl-2-pyrimidinyl) -4-imino1, 4-dihydropringine hydrochloride and

G- (4-methyl-6 - phenyl - 2 - nrimidinyl) -4imino-1, 4-dihydropyridine hydrochloride.

Replacing in examples 11-13 pyridine reagent with 4- (methylamino) -pyridine and 3-meisopropyl alcohol from dissolution.