DE2032403C3 - Process for the preparation of 2-aminopyridines - Google Patents

Description

in which R is a hydrogen atom, an alkyl radical with i up to 6 carbon atoms, a phenyl radical, a cycloalkyl radical having 5 to 6 carbon atoms or a pyridyl radical, R 'either a hydrogen atom or a methyl radical and R "either a Hydrogen atom or an optionally branched one Means an alkyl radical having 1 to 6 carbon atoms, characterized in that a 2-hydroxypyridine of the general formula II

(H)

in which R 'and R "have the above meaning, with an amine of the general formula NH2R (HI), in which R has the above meaning at a temperature between 200 and 500 ° C under increased pressure implements.

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Numerous technical processes for the production of 2-aminopyridines are known most advantageous process for making 2-aminopyridine in it, pyridine with sodium amide in N, N-dimethylaniline to implement. This was first published by Tschitschibabin and Zeide [J. Soot. Phys. Chem. Soo, 46, 1216 (1914); C A. 9, 1901 (1915)] proceeds with satisfactory results Yield. Considering the need to work in an anhydrous medium and sodium amide too use, the 2-aminopyridine obtained in this way, however, has a high cost price. Besides, this is Process restricted to the preparation of 2-aminopyridines with a primary amine group. That's how it is Production of 2-aminopyridines, which have a secondary amino group, required first a Preparing 2-halopyridine (generally from pyridine itself) and then using a primary amine to implement. From J. Chem. Soc. (1948), p. 198 ff, is a Process for the preparation of 4-amino-3-methylpyridine by heating the corresponding hydroxypyridine known with an aqueous concentrated ammonia solution. Copper powder is used as a catalyst or copper sulfate is used. However, this process has the disadvantage of only low yields Deliver aminopyridines.

There was now a general process for the preparation of primary and secondary 2-aminopyridines found that gives good yields of the desired end products.

55 The invention therefore relates to a process for the production of 2-aminopyridines of the general formula

in which R is a hydrogen atom, an alkyl radical with 1 to 6 Carbon atoms, a phenyl radical, a cycloalkyl radical having 5 to 6 carbon atoms or a Pyridyl radical R 'either a hydrogen atom or a methyl radical and R ″ either a hydrogen atom or an optionally branched alkyl radical having 1 to 6 carbon atoms denotes that thereby is characterized in that one is a 2-hydroxypyridine general formula

R "

R '
OH

in which R 'and R "have the above meaning, is reacted with an amine of the general formula NH ₂ R (IH), in which R has the above meaning, at a temperature between 200 and 500 ° C. under elevated pressure

In particular, the inventive method consists in using a 2-hydroxypyridine of the general Formula II to react with ammonia or an amine of the general formula III, wherein the Reactants at a temperature between 200 and 500 ° C and preferably between 250 and 400 ° C brings. The reactants are used in such amounts that at least 1 mole of amine per mole 2-hydroxypyridine is present. A considerable excess of amine can be used without that this would be detrimental to the reaction, but in practice the molar ratio is amine / 2-hydroxypyridine advantageously between 2 and 15, in order to avoid excessive pressure development, what is particularly true in the case of amines with a low boiling point

In order to achieve a reaction rate that is not too slow, it is necessary to use the apparatus to introduce such a minimum amount of reaction components that the pressure formed is sufficiently high is. This amount of reaction components and consequently also the pressure obviously depends on the reaction components, and it is not possible to generally specify a preferred range. It can be seen that the higher the pressure at which the reaction is carried out the reaction components are more volatile. So in the case of ammonia and 2-hydroxypyridine this Pressure on the order of 20 to 400 bar and is preferably between 50 and 150 bar.

The reaction can be carried out in the presence or absence of solvents. In general Solvents are not absolutely necessary, since the reaction components are mostly in liquid form under the reaction conditions. If any of the both reaction components has an elevated melting point, it can be advantageous, however, to add a chemically inert compound which is in the liquid state under the reaction conditions

Formation of a solution with the reaction components is favored

After the reaction has ended, the 2-aminopyridines are removed from the medium by any known method separated Among these, distillation under reduced pressure has proven particularly suitablea

The 2-hydroxypyridine can for example be made from glutaric acid: In the course of a the first stage converts the glutaric acid into ό-valerolactam, for example according to that in the FR-PS ι ο 8 79 918 described procedure, and then dehydrated the ό-valerolactam in a second stage after the von Galimovsky and Späth [Ber. 69,2059 (1936)] described procedure for 2-hydroxypyridine.

As examples of the ι s which can be used according to the invention 2-Hydroxypyridines of the general formula II can be used name the following:

2-hydroxypyridine, 3-methyl-2-hydroxypyridine and 4-butyl-2-hydroxypyridine.

Among the amines of the general formula Hi, the following can be named as examples:

Ammonia, methylamine, propylamine, cyclohexylamine, Aniline, 2-aminopyridine and 4-aminopyridine.

The 2-aminopyridines of the general formula I are of great industrial importance as starting materials, those involved in the production of therapeutically effective derivatives, in particular antihistamine agents, used on.

The following examples illustrate the invention.

example 1

2.23 g of 2-hydroxypyridine and 6 g of gaseous ammonia are placed in an autoclave with a capacity of 125 cm ^{3 and the autoclave is brought to 300 °} C. for 31/2 hours. The pressure in the autoclave is about 100 bar. After cooling, the solid reaction mass is extracted with methanol. After concentrating the extracts, a residue of 2.155 g is obtained which contains 653% 2-aminopyridine and 31.6% 2-hydroxypyridine (determined by vapor phase chromatography of a methanolic solution with a content of 50%). A fraction with a boiling point of 10 ° C., which weighs 1.1 g and corresponds to 2-aminopyridine which was identified by infrared spectroscopy and its mass spectrum, is isolated by distillation under reduced pressure.

Example 2

7.8 g of 2-hydroxypyridine and 32 g of gaseous ammonia are placed in an autoclave with a capacity of 125 cm ^3. In the course of the temperature increase up to 350 ^° C., ammonia is regularly removed in such a way that the pressure is about 150 bar. It then leaves 3 hours at 350 ° C. After cooling, extraction with methanol and concentration of the extracts to obtain 7.9 g of a solid substance, 91% of 2-aminopyridine (determined by vapor phase chromatography) containing the solid substance is in 80 cm ³ of an aqueous Potassium hydroxide solution with a content of 20 g of potassium hydroxide per 100 cm ^{3 of} solution. After extraction with ether and subsequent concentration of the extracts, 2-aminopyridine is obtained.

Example 3

The procedure is as in Example 2 for 3 hours at 250 ^° C., but ammonia is removed in such a way that the pressure in the autoclave is 50 bar. A residue of 7.5 g containing 70% of 2-aminopyridine is obtained (determined by Vapor phase chromatography).

Example 4

2.56 g of 2-hydroxy-6-methylpyridine and 6 g of gaseous ammonia are placed in a 125 cm ^{3 autoclave.}

The autoclave is heated to 300 ° C. for 3½ hours brought while the pressure adjusts to around 100 bar. After cooling, extraction with methanol and Removal of the solvent leaves a residue of 2.57 g, from which one can through Distillation under reduced pressure 0.77 g of 2-amino-6-methylpyridine isolated

Example 5

5 g of 2-hydroxypyridine and 5 g of aniline are placed in a 125 ml autoclave. The autoclave is brought to 350 ^° C. for 5 hours. After cooling, the reaction mass is extracted with methanol. Concentration of the extracts gives a residue of 9.2 g which contains 30.3% 2-phenylaminopyridine (determination by vapor phase chromatography).

Example 6

In a 125 ml autoclave using 5 g of 2-hydroxypyridine and 5 g of 2-aminopyridine brings and brings the autoclave for 5 hours at 350 ⁰ Q After cooling, extraction with methanol and concentration of the extracts gave a residue of 933 is obtained g, the Contains 41.5% dipyridylamine (determined by vapor phase chromatography). The residue, which no longer contains 2-hydroxypyridine, is ^{suspended in 200 cm 3 of} water. It is extracted four times with 50 cm ^{3 of} ether each time, the extracts are concentrated and the residue obtained is recrystallized from 50 cm ^{3 of} a mixture of water and ethanol (50 to 50 volumes). This gives 2 g of dipyridylamine with a temperature of 94 to 95 ° C.

The following experiment shows that in the process according to J. Chem. Soc, 1948, p. 198 ff, only slight Yields can be achieved:

2 g of 2 (or 4) -hydroxypyridine, 20 ml of an aqueous ammonia solution (d = 0.92) and possibly traces of copper powder or copper sulfate were placed in a 125 ml autoclave. It was heated to 200 ° C. and the autoclave was kept at this temperature for 19 hours.

After cooling, there was a large excess of potassium hydroxide added and then extracted with ether. When the ether was evaporated, it fell Aminopyridine (identified by IR spectrum).

Hydroxypyridine catalyst Yields Aminopyridine 2-hydroxy With 4% 4-hydroxy With 12% 4-hydroxy With 9% 4-hydroxy without 20% 4-hydroxy without 20%

Claims (1)

Claim: Process for the preparation of 2-aminopyridines of the general Forae! R " V-R- NHR (D