RU2345068C2 - Method of obtaining 4-(alkylamino)pyridine - Google Patents

Abstract

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to method of obtaining 4(alkylamino)pyridines of formula

, where R - linear or branched alkyl, cycloalkyl or arylalkyl group, containing from 6 to 10 carbon atoms, preferably 7-9, which are intermediate products for obtaining pharmaceutical products. Method lies in interaction of 4-aminopyridine and aliphatic aldehyde in organic solvent medium with further hydrating of condensation products in presence of palladium catalyst at higher temperature and pressure, which is different because as solvent aliphatic alcohol C₃-C₄ is used, 4-aminopyridine being preliminary processed with aliphatic aldehyde C₆-C₁₀ with ratio 1:1.5-1:2.0 respectively for 0.8-1.2 hour at temperature 80-90°C in medium of organic solvent, then obtained mixture is introduced into catalyst suspension in organic catalyst and carried out.

EFFECT: reduction of target product cost and toxic wastes amount.

2 cl, 6 ex

Description

The invention relates to a method for producing 4- (alkylamino) pyridines of the formula (I).

where R is a linear or branched alkyl, cycloalkyl or arylalkyl group containing from 6 to 10 carbon atoms, preferably 7-9,

which are intermediate products for the preparation of active ingredients of pharmaceutical products of the formula:

where X is the anion;

Y is a linear or branched alkylene group containing from 4 to 18 carbon atoms, preferably 9-11.

Known methods for producing a substance of formula (I) set forth in J. Med. Chem. 1984, 27, 1457-1464:

Method A is based on the interaction of hydrochloric acid salts of the components, which proceeds at a very high (up to 227 ° C) temperature. The released hydrogen chloride must be disposed of, moreover, it is a strong corrosive agent, and therefore, the hardware implementation of this method is very difficult at the indicated temperatures. In addition to the above, after the condensation is formed, the hydrochloric salt of the target product is formed and an additional operation is required to obtain the target base, which is associated with the formation of a large amount of toxic waste. The yield of 4- (alkylamino) pyridine is only 75% of theoretical. Thus, the preparation of a substance of formula (I) by Method A cannot be accepted for implementation on an industrial scale.

Method B, based on the interaction of 4-aminopyridine with an aliphatic acid chloride in dichloromethane and subsequent treatment with lithium aluminum hydride, is implemented in two stages (see diagram). In the first step, HCl is formed, which is neutralized by the addition of a large amount of Et ₃ N, and the intermediate is isolated by conventional techniques. In a second step, the intermediate is dissolved in tetrahydrofuran and treated with a solution of lithium aluminum hydride in tetrahydrofuran. The yield of the target product 78%. This option is also not acceptable for use, since a huge amount of very toxic waste is generated here, and fire and explosive tetrahydrofuran and lithium aluminum hydride are used, working with which introduces additional difficulties in carrying out this method.

Closest to the proposed method is the method described in German patent DT 2708331 A1 from 02.25.1977

where the specified target product (I) is formed by the interaction of 4-aminopyridine with octane aldehyde in a ratio of 1: 3, respectively, in absolute ethanol, in a hydrogen atmosphere at a pressure of 3.16 kg / cm ² in the presence of a Pd / C catalyst - 10% at a temperature of 70- 90 ° C. After completion of the reaction, the catalyst is filtered off from the reaction mixture, from which the solvent is distilled off under vacuum. From the oily residue obtained, when cooling for several hours, the target product is isolated, which is purified by trituration with cooled hexane, filtered and washed with cold hexane. After drying under vacuum, 4- (octylamino) pyridine is obtained with a melting point of 70-73 ° C with a yield of up to 88%.

The specified method has significantly better performance compared to the above technologies. The reaction proceeds with a noticeably higher yield (88%) of the target product. The method is simpler and environmentally friendly, however, it has significant disadvantages, which include:

1) a very large (1: 3) ratio of aminopyridine: aldehyde (theoretical 1: 1), which leads to a significant appreciation of the target product and an increase in the amount of toxic waste;

2) significant consumption of solvent - expensive absolute ethanol, which is used once;

3) the resulting N-alkylpyridine has a melting point of 70-73 ° C. This indicates that the target product is contaminated with impurities remaining after its receipt.

The task of the invention is to improve the method for producing a substance of formula (I), as claimed in the prototype.

The essence of the present invention is to improve the above method for producing 4- (alkylamino) pyridines.

Distinctive features of the method of the present invention is the condensation in the environment of an aliphatic alcohol C ₃ -C ₄ , which can be used for two or three cycles, or the process of obtaining 4- (alkylamino) pyridines at elevated (2-3 times) concentrations of the starting components. This is explained by the fact that these solvents contain a higher water content in mixtures of an azeotropic composition, which, depending on the nature of the above solvents, is 12-16%, which is noticeably higher than that of ethanol (4.5%). Water has a significant negative effect on the course of the reaction to obtain a substance of formula (I) shown in the above prototype. However, the water that makes up the azeotrope is generally more strongly bound to alcohol and almost does not impede the course of the reaction, and therefore, the use of solvents with a high water content in the azeotropic mixture is more preferable. As alcohols, propanol, isopropanol, butanol or isobutanol are used, in which to reduce the consumption of aliphatic aldehyde, a mixture of aminopyridine with aliphatic aldehyde is pretreated in a ratio of 1: 1.5-1: 2, respectively, for 0.8-1.2 hours at a temperature of 80-90 ° C then the resulting mixture was added to the warmed suspension of Pd / C 10% catalyst in these solvents and hydrogenation is carried out at hydrogen pressures of 3-6 kg / cm ² to reduce the hydrogen absorption rate is 100 times as compared with the initial rates, the Strongly. After separation from the catalyst and distillation of the solvent, the target product is purified. For this, toluene is added to the remaining oily residue, heated to complete homogenization, and cooled to 2-5 ° C. The precipitate after cooling is filtered off and washed with chilled toluene. The obtained target product has a melting point of 72-73 ° C, not hygroscopic, stable during storage. The yield of 69-88%.

The following are examples illustrating but not limiting the invention.

Example 1

A mixture of 75.2 g (0.8 mol) of 4-aminopyridine, 204.8 g (1.6 mol) of octane aldehyde and 250 ml of absolute isopropanol is heated to 80-90 ° C and kept at this temperature for 0.8 hours. The resulting mixture is poured into a suspension of 7.5 g of a 10% Pd / C catalyst in 50 ml of absolute isopropanol heated to 60 ° C, include heating the reactor jacket, purging with hydrogen and hydrogenating at a temperature of 85-90 ° C and a hydrogen pressure of 3.0 kg / cm ² to reducing the rate of absorption of hydrogen by 100 times compared with the initial rate. After that, the mixture is cooled, filtered from the catalyst, the solvent is distilled off on a rotary film evaporator in a vacuum, 170 ml of toluene are added to the obtained residue, heated to 40-50 ° C and the resulting homogeneous solution is cooled to 2-5 ° C. The precipitated white crystals are filtered off and washed with chilled toluene. Get 150 g of the target product (87.9%) with a melting point of 72-73 ° C.

Example 2

Similar to example 1, but characterized in that the exposure of the mixture of the starting reagents in isopropanol is carried out for 1.2 hours, followed by hydrogenation in the presence of 6.0 g of Pd / C 10% catalyst at a temperature of 90 ° C and a hydrogen pressure of 6 kg / cm ² .

Example 3

Similar to example 1, but differs in that the starting reagents aminopyridine and octane aldehyde are taken in a ratio of 1: 1.5, drawn out for 1.2 hours and hydrogenated in the presence of 7.5 g of 10% Pd / C catalyst at a temperature of 90 ° C and a hydrogen pressure of 6 kg / cm ² . The yield of the target product 85%; t _PL = 72-73 ° C.

Example 4

It is similar to example 1, but differs in that normal butanol is used as a solvent. Yield 86%; t _pl = 72.0-73 ° C.

Example 5

Similar to example 1, but differs in that isobutyl alcohol is used as a solvent. The yield of the target product 69%; t _PL = 69-72 ° C.

Example 6

Similar to example 1, but differs in that normal propanol is used as a solvent. The yield of the target product 88%., T _PL = 72-73 ° C.

Example 7

Similar to example 1, but differs in that isopropanol with a water content of 5% is used as a solvent. The yield of the target product is 85.5%; t _PL = 72-73 ° C.

Thus, the proposed method for producing 4- (alkylamino) pyridines, which is implemented when the ratio of the starting reagents 1: (1.5-2.0) versus 1: 3 in the prototype, which leads to a significant reduction in the cost of the target product and reduce the amount of toxic waste. The range of used solvents used to implement the process is expanded. Replaced expensive absolute ethanol, and the C ₃ -C ₄ aliphatic alcohols used instead allow the synthesis to be carried out when used repeatedly for 2-3 cycles, and the above alcohols may contain up to 5% water. Obtained using the proposed method, the target product of formula (I) is less contaminated and has a higher purity.

Claims (2)

1. The method of obtaining 4- (alkylamino) pyridines, comprising condensation of 4-aminopyridine and aliphatic aldehyde in an organic solvent, followed by hydrogenation of the condensation products in the presence of a palladium catalyst at elevated temperature and pressure of hydrogen with the release of the product by known methods and purification of the target product by recrystallization, characterized in that a C ₃ -C ₄ aliphatic alcohol is used as a solvent, while 4-aminopyridine is pretreated with an aliphatic aldehyde m C ₆ -C ₁₀ with a ratio of 1: 1.5-1: 2.0, respectively, for 0.8-1.2 hours at a temperature of 80-90 ° C in an environment of an organic solvent, then the resulting mixture is introduced into the catalyst suspension in organic solvent and hydrogenation is carried out to reduce the hydrogen absorption rate by 100 times compared to the initial rate, after filtering from the catalyst and distilling off the organic solvent, the target product is purified by recrystallization from toluene. 2. The method according to claim 1, characterized in that the C ₃ -C ₄ aliphatic alcohol is used in the process for 2-3 cycles.