DE644839C - Process for the preparation of pyridine-o-dicarboxylic acid amides - Google Patents

Description

It is known that N-disubstituted amides of pyridan monocarboxylic acids, especially pyridini-3-carboxylic acid, have a beneficial effect on circulation and breathing. On the other hand, it was found that pyridine-2, 5-dicarboxylic acid bis (diethylamide) as pharmacologically ineffective (Chemisches Zentralblatt 1934, II, p. 3255), and also that im Journal for Practical Chemistry, New Series, Vol. 138, p. 259 (1933), described pyridine-3, 5-dicarboxylic acid bis-diethylamide shows no pharmacological activity.

It has now been found that by converting pyridine-o-dicarboxylic acids in to the amide nitrogen by aliphatic radicals with a total of 8 to 12 carbon atoms Tetra-substituted diamides to form compounds with particularly favorable properties got.

ao For the representation of the new substituted pyridine-o-dicarboxamides one can in Usually pyridine-o-dicarboxylic acids or their derivatives, such as. B. their salts, esters, Halides and anhydrides, secondary aliphatic amines and their salts or their carbamic acid halides in the presence or absence of solvents, of condensing agents as well as acid-binding agents, such as. B. alkali, alkaline earth hydroxides and alcoholates, magnesium oxide and organic bases.

The process can also be designed in several stages by initially N-substituted Monoamides of pyridine-o-dicarboxylic acids are then produced in the above manner in N, N'-substituted diamides converted. In this way it is possible, among other things, to produce diamides, whose amide groups are variously substituted.

In the implementation of the free pyridine-o-dicarboxylic acids or corresponding monoamido carboxylic acids used with amines one advantageous condensing agents such as phosphorus halides, thionyl chloride, phosgene or phosphorus oxide. The free carboxylic acids and 'the free amines can also be replaced by their salts.

The new compounds should find therapeutic use.

example 1

19 parts of pyridine-2,3-dicarboxylic acid dichloride are reacted in benzene solution with 31 parts of diethylamine with cooling. Man

Add "strong sodium hydroxide solution, separate the benzene solution, dry it and drive off the solvent and free diethylamine. The pyridine-2,3-dicarboxylic acid bis-diethylamide obtained is recrystallized from petroleum ether. It melts at 56 to 57 ⁰ and boils at it 191 to 194 C under 7 mm pressure. The colorless crystals are easily soluble in water and in most organic solvents with the exception of petroleum ether. The same compound is obtained, for example, by the action of pyridine-2,3-dicarboxylic acid dichloride on an aqueous diethylamine solution or on diethylamine in the presence of an alkali hydroxide. Instead of alkali hydroxide, it is also possible to use alkaline earth hydroxides and alcoholates, magnesium oxide or organic bases.

In a corresponding manner, for. B. also the pyridine-2,3-dicarboxylic acid bisdiallylarnide of bp ₁ 2oo ^L C can be produced.

Example 2

6 parts of pyridine-2, 3-dicarboxylic acid dichloride are heated for 2 hours at I2O ^J C with 7 parts Diäthylaminhydrochlorid. Hydrochloric acid escapes here. According to Example 1, the pyridine-2,3-dicarboxylic acid bis-diethylamide is obtained from the reaction mass.

Example 3

167 parts of pyridine-2,3-dicarboxylic acid are added to 150 parts of diethylamine and mixed the salt formed with stirring 210 parts of phosphorus oxychloride, whereupon the Heated the reaction mixture to about 150 ° C. After completion of the implementation, one takes in Water and separates the resulting pyridine-2,3-dicarboxylic acid bis-diethylamide by alkali.

Instead of phosphorus oxychloride can, for. B. also phosphorus pentoxide, thionyl chloride or phosgene can be used.

Example 4

30 parts of pyridine-2,3-dicarboxylic anhydride are mixed with 30 parts of diethylamine. (The resulting Diätliylaminsalz the pyridine 1 2-carboxylic acid 3-carbonsäurediäthylamids is heated to 120 ⁰ C with 21 parts of phosphorus oxychloride some time. The pyridine-2, 3-dicarboxylic acid bisdiäthylamid is obtained according to the data of the foregoing examples.

Example 5

^ 3 parts of pyridine ^ -carboxylic acid ^ -carboxylic acid diethylamide (prepared / .. B. from its diethylamine salt and hydrochloric acid described in Example 4) are suspended in 100 parts of toluene and mixed with 15 parts of din-propylamine. Thereto is allowed with stirring 15 parts of phosphorous oxychloride added dropwise, some time heated to 120 ⁰ C and operates' on in the manner described in the previous examples manner. The pyridine-2-carboxylic acid di-n-propylamide-3-carboxylic acid diethylamide obtained in this way forms an oil with a boiling point of ₀₄ 170 to 172 ^° C.

70 Example 6

50 parts of pyridine-3,4-dicarboxylic acid are mixed with 132 parts of phosphorus pentachloride and heated to 10 ° C. for a further hour. On cooling, the pyridine-3,4-dicarboxylic acid dichloride crystallizes out, which is suctioned off and. is washed with acetone . 30 parts of pyridine-3,4-dicarboxylic acid dichloride are reacted in an ethereal solution with 55 parts of diethylamine and, after the reaction has ended, the reaction is carried out in the manner described in Example 1. The pyridine- 3,4-di- carboxylic acid bis-diethylamide obtained in this way can be recrystallized from petroleum ether. It melts at 61 to 63 ⁰ C and boils at 143 to 146 ⁰ C under 0.3 mm pressure. It is easily soluble in water and most organic solvents.

Example 7

If in Example 6 the diethylamine is replaced by the equivalent amount of di-n-propylamine, the pyridine-3,4-dicarboxylic acid bisdi-n-propylamide is obtained in a corresponding manner as an oil that boils at 180 ° C under 0.3 mm pressure.

Examples

In a mixture of 63 parts of the disodium salt of the pyridine-2,3-dicarboxylic acid and 67 parts Diäthylaminhydrochlorid are introduced 76 parts of phosphorus oxychloride and the mixture heated until the reaction ended at about 160 ⁰ C. The pyridine-2,3-dicarboxylic acid bisdiethylainide is then isolated in the manner described in Example 1.

Example 9

19 parts of pyridine-2,3-dicarboxylic acid diphenyl ester (F 115 to 116 °, prepared from pyridine-2, 3-dicarboxylic acid dichloride and phenol by heating in a benzene solution) are mixed with 26 parts of diethylamine in the tube Heated to 120 ° for hours. After the excess diethylamine has been distilled off the pyridine-2,3-dicarboxylic acid bis-diethylamide is obtained as in Example 1.

Example 10

¹

22 parts of pyridine-2,3-dicarboxylic acid diethyl ester are with 15 parts of diethylamine and

13.6 parts of sodium alcoholate in alcoholic Mixed solution. After standing for a while, the implementation will be completed on Heated to reflux. The alcohol is distilled off and the pyridine-2,3-dicarboxylic acid bis-diethylamide is obtained in the manner described in Example 1.

Example 11

35 parts of the disodium salt of pyridine-2, 3-dicarbionic acid are mixed with 51 parts of diethylcarbarnic acid chloride warmed up. At 145 ° these connections settle under stormy conditions Evolution of carbonic acid. The mixture is heated until the reaction has ended to 2oo ° and wins the pyridine-2 ,, 3-dicarboxylic acid bis-diethylamide in the manner described in Example 1.

The reaction takes place in exactly the same way if instead of the disodium salt the calcium salt of pyridine-2,3-dicarboxylic acid is used.

Claims (2)

Patent claims: 1. Process for the preparation of pyridine-o-dicarboxamides, their amide nitrogens tetrasubstituted by aliphatic radicals with a total of 8 to 12 carbon atoms are, characterized in that pyridine-o-dicarboxylic acids are used in the usual manner or their descendants, such as B. their salts, esters, halides and anhydrides, on secondary aliphatic amines and their salts or their carbamic acid halides in the presence or absence of solvents, condensing agents and of acid-binding agents, such as. B. Alkali, alkaline earth hydroxides and alcoholates, Magnesium oxide and organic bases can act. 2. The method according to claim 1, characterized in that initially N-substituted Produces monoamides of pyridine-o-dicarboxylic acids and then converts them into N, N'-substituted diamides.