JPH10231288A - Production of 2-chloro-4-aminomethylpyridine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound useful as an intermediate for synthesizing medicines, agrochemicals, etc., by reacting 2-chloro-4-tri, di or monochloromethylpyridine with an amine and hydrogen in the presence of a catalyst for hydrogenation. SOLUTION: This 2-chloro-4-aminomethylpyridine, expressed by formula II, useful as an intermediate for synthesizing medicines and agrochemicals, e.g. as an intermediate for synthesizing histamine-H2 receptor antagonists, is obtained in high yield and purity in an industrially advantageous way by reacting 2-chloro-4-trichloromethylpyridine, 2-chloro-4-dichloromethylpyridine or 2-chloro-4-chloromethylpyridine or a mixture of these pyridine derivatives with an amine (e.g. piperidine) expressed by formula I [R<1> and R<2> are each H, a (substituted) alkyl, an aryl, an aralkyl, or form a (substituted) 4-8 membered ring together with a nitrogen atom bound to either of these groups.] and hydrogen in the presence of a catalyst for hydrogenation (e.g. Raney nickel).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to 2-chloro-4-
The present invention relates to a method for producing aminomethylpyridine. 2-chloro-4-aminomethylpyridine produced by the present invention, as a synthetic intermediate for pharmaceuticals and agricultural chemicals, FRG-8813 such as histamine -H ₂ receptor antagonists (2-
(Furfurylsulfinyl) -N- (4- [4- (piperidinomethyl) -2-pyridyl] oxy- (Z) -2-
(Butenyl) acetamide) [European Journal of Pharmacology, 297, 8]
7 (1996)].

[0002]

2. Description of the Related Art Conventionally, as a method for producing 4-aminomethylpyridines having a halogen at the 2-position, 2-bromo-pyridine is used.
4-Methylpyridine is reacted with N-bromosuccinimide to give 2-bromo-4-bromomethylpyridine, which is then reacted with dimethylamine to form 2-bromopyridine.
A method for obtaining bromo-4-dimethylaminomethylpyridine is known (see JP-A-58-170779).

[0003]

In the above method, the yield of 2-bromo-4-dimethylaminomethylpyridine from 2-bromo-4-methylpyridine is as low as 34%, and it is used as a brominating agent. There are problems such as that N-bromosuccinimide is expensive. This method is performed using 2-chloro-
When applied to a method for producing 4-aminomethylpyridine, 2-chloro-4-methylpyridine is used as a raw material, which is chlorinated to obtain 2-chloro-4-chloromethylpyridine, and then 2-chloro-4-methylpyridine is obtained. A possible method is to obtain 2-chloro-4-aminomethylpyridine by aminating chloromethylpyridine. Here, as a method for producing 2-chloro-4-chloromethylpyridine as an intermediate, a method of chlorinating 2-chloro-4-methylpyridine with chlorine is known (JP-A-5-23002).
However, in this method, the chlorination of the methyl group at the 4-position occurs sequentially, and the yield of 2-chloro-4-chloromethylpyridine is low. Thus, it is possible to improve the selectivity of the monochloromethyl compound by controlling the conversion to about 50%, but this will reduce the productivity.
Therefore, it is difficult to obtain 2-chloro-4-chloromethylpyridine in high yield by this method.

On the other hand, there is known a method of reacting 2-chloro-5-trichloromethylpyridine with an amine and hydrogen in the presence of a hydrogenation catalyst to obtain 2-chloro-5-aminomethylpyridine ( See JP-A-6-279410). The amine specifically used in this method is 1
Grade amine or diamine, the yield of the target product is 77% when using ethylamine, 45% when using methylamine, and 10% when using ethylenediamine;
It is not industrially satisfactory. In addition, this method requires a large amount of the hydrogenation catalyst. Therefore, at present, there is a demand for a method of obtaining 2-chloro-4-aminomethylpyridine with a smaller amount of catalyst and higher yield. Thus, an object of the present invention is to provide 2-chloro-4-
It is an object of the present invention to provide a method for producing aminomethylpyridine in a high yield and a high purity in an industrially advantageous manner.

[0005]

According to the present invention, the object is to provide 2-chloro-4-trichloromethylpyridine,
2-chloro-4-dichloromethylpyridine or 2-
Chloro-4-chloromethylpyridine, or a mixture thereof, and a compound represented by the general formula (1)

[0006]

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(Wherein R ¹ and R ² each represent a hydrogen atom, an alkyl group which may have a substituent, an aryl group or an aralkyl group, or together with a nitrogen atom to which they are bonded, To form a four- to eight-membered ring which may have a substituent)
Amines (1)] and hydrogen in the presence of a hydrogenation catalyst.

[0008]

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(Wherein R ¹ and R ² are as defined above) [hereinafter referred to as 2-chloro-4-aminomethylpyridine (2)] Is achieved by providing a manufacturing method of

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION In the above general formula, the alkyl group represented by R ¹ and R ² is a methyl group, an ethyl group,
Examples thereof include a propyl group, an isopropyl group, a butyl group, and a tert-butyl group. These alkyl groups may have a substituent such as an amino group, and specific examples of the aminoalkyl group include 2-aminoethyl, 2-aminopropyl, 3-aminopropyl, and 2-aminobutyl. Group, 3-aminobutyl group, 4-aminobutyl group and the like. The aryl group represented by R ¹ and R ² includes
Examples include a phenyl group, a naphthyl group, and a tolyl group, and examples of the aralkyl group include a benzyl group. Also,
When R ¹ and R ² form a 4- to 8-membered ring together with the nitrogen atom to which they are bonded, examples of the nitrogen-containing group include a pyrrolidino group and a piperidino group.

The 2-chloro-4-trichloromethylpyridine, 2-chloro-4-dichloromethylpyridine or 2-chloro-4-chloromethylpyridine used as a raw material, or a mixture thereof, is prepared in the presence of a radical initiator. It can be synthesized by reacting 2-chloro-4-methylpyridine or 2-benzenesulfonyl-4-methylpyridine with chlorine (International Patent Publication WO
96/26188).

Next, 2-chloro-4-trichloromethylpyridine, 2-chloro-4-dichloromethylpyridine or 2-chloro-4-trichloromethylpyridine, or a mixture thereof (hereinafter simply referred to as a starting compound) ) To 2-chloro-4-aminomethylpyridine (2).

Examples of the amines include ammonia; monoalkylamines such as methylamine and ethylamine; diamines such as ethylenediamine and 1,2-diaminopropane; and secondary amines such as dimethylamine, diethylamine, diisopropylamine, pyrrolidine and piperidine. No. Of these, secondary amines are preferred because the aminated product is less likely to be converted into a dimer or a trimer by a sequential reaction. The amount of the amines to be used is preferably 1 to 20 moles per mole of the raw material compound, and 2 to 20 moles.
A molar ratio of 10 to 10 times is more preferable.

As the hydrogenation catalyst, a Raney catalyst such as Raney nickel and Raney cobalt; a noble metal such as ruthenium, palladium, rhodium and platinum is converted to silica, alumina,
A catalyst supported on carbon or the like may be mentioned, but Raney nickel is preferred. The amount of the hydrogenation catalyst used is preferably 1 to 50% by weight, and more preferably 2 to 10% by weight based on the amount of the starting compound.
Is preferred.

Such a reaction can be carried out in the presence or absence of a solvent. The solvent used is not particularly limited as long as it does not adversely affect the reaction. For example, alcohols such as methanol, ethanol, and isopropanol; polar solvents such as water, acetonitrile, and dimethylformamide; hexane, heptane, benzene, toluene,
Non-polar solvents such as xylene. The amount of the solvent to be used is preferably 1 to 50 times by weight relative to the raw material compound,
It is more preferably 20 to 20 times by weight.

[0016] Hydrogen pressure is preferably normal pressure to 100 kg / cm ^2, and more preferably normal pressure to 20 kg / cm ^2. The reaction temperature is preferably in the range of 0 to 100C, more preferably in the range of 10 to 50C. The reaction time varies depending on the reaction conditions, but usually 0.5 to 5 hours is appropriate.

The thus obtained 2-chloro-4-
Isolation of aminomethylpyridine (2) from the reaction mixture
Purification can be performed according to a conventional method. For example, after cooling the reaction mixture, the hydrogenation catalyst is filtered, neutralized, the solvent and the like are distilled off, extracted with water-ethyl acetate, separated, and the ethyl acetate layer is concentrated under reduced pressure. Then, the concentrate can be easily subjected to distillation under reduced pressure, chromatography and the like.

[0018]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the present invention.

Reference Example 1 2-benzenesulfonyl-4-methylpyridine 23.5
A mixture of 5 g and 32 ml of chlorobenzene was heated to 80 ° C., and 2,2′-azobis (isobutyronitrile) 410 was heated.
After adding mg, chlorine (37 ml per minute) was blown in for 5 hours. During this time, 82 mg of 2,2′-azobis (isobutyronitrile) was added every hour. After the completion of the reaction, nitrogen was blown for 30 minutes, and then a 5% aqueous sodium carbonate solution 5
0 ml was added to make the solution alkaline, and methylene chloride 5
Extracted twice with 0 ml. The organic layer was washed with water (50 ml),
The solvent was concentrated under reduced pressure. By subjecting the concentrate to distillation under reduced pressure, 19.23 g of colorless oily 2-chloro-4-trichloromethylpyridine was obtained. Yield: 66.6% Purity: 80.0%

Example 1 A 2-ml autoclave obtained in Reference Example 1 was placed in a 300 ml autoclave.
Chloro-4-trichloromethylpyridine 10.0 g (purity 80%), piperidine 29.4 g, Raney nickel (Nikko Rika R-100) 0.5 g, methanol 62 m
was charged with hydrogen to a gauge pressure of 10 kg / cm ^2, and the temperature was raised to 40 ° C. When the reaction was carried out for 3 hours while introducing hydrogen so as to maintain the internal temperature at 40 to 45 ° C. and the gauge pressure at 10 kg / cm ² , the hydrogen absorption was completed. After confirming the completion of the reaction, the reaction solution was cooled to room temperature. After filtering the catalyst from the reaction solution, the filtrate was concentrated under reduced pressure. 10% hydrochloric acid aqueous solution 1 for the purpose of removing acidic and neutral impurities
Add 30 ml to acidify and add 2 ml with 50 ml methylene chloride.
After extracting twice and removing the organic layer, the aqueous layer was made alkaline with 40 ml of 40% aqueous sodium hydroxide solution, and methylene chloride was added.
Extracted three times with 0 ml. The organic layer was washed with water, the solvent was distilled off under reduced pressure, and the concentrate was distilled under reduced pressure to give colorless oily 2-chloro-4-piperidinomethylpyridine 6.30.
g was obtained. Yield: 85.9% Purity: 99.4% Boiling point: 84 to 86 ° C / 0.2 mmHg ¹ H-NMR spectrum (CDCl ₃ ) δ: 1.30 to
1.80 (m, 6H), 2.20 to 2.50 (br, 4
H), 3.44 (s, 2H), 7.20 (d, J = 5.
0 Hz, 1H), 7.33 (S, 1H), 8.28
(D, J = 5.0 Hz, 1H)

Example 2 A 2-ml autoclave obtained in Reference Example 1 was placed in a 100 ml autoclave.
After charging 10.0 g (purity 80%) of chloro-4-trichloromethylpyridine, 14.7 g of piperidine, 0.25 g of Raney nickel (R-100, manufactured by Nikko Rica) and 20 ml of methanol, 5 g of chloro-4-trichloromethylpyridine were prepared under the same conditions as in Example 1. Allowed to react for hours. Post-treatment and purification after the reaction were also performed in the same manner as in Example 1 to obtain 6.19 g of the intended product, 2-chloro-4-piperidinomethylpyridine. Yield: 84.4% Purity: 99.5%

Example 3 A 2-ml autoclave obtained in Reference Example 1 was placed in a 100 ml autoclave.
The same conditions as in Example 1 were prepared by charging 10.0 g of chloro-4-trichloromethylpyridine (purity 80%), 26.8 g of a 40% aqueous solution of methylamine, 0.5 g of Raney nickel (R-100 manufactured by Nikko Rica) and 20 ml of methanol. For 5 hours. Post-treatment and purification after the reaction were also performed in the same manner as in Example 1 to obtain 3.75 g of the desired product, 2-chloro-4-piperidinomethylpyridine. Yield: 68.6% Purity: 99.1%

[0023]

According to the present invention, there is provided a process for producing 2-chloro-4-aminomethylpyridine (2) with high yield and high purity in an industrially advantageous manner.

Claims (2)

[Claims] 1. 2-chloro-4-trichloromethylpyridine, 2-chloro-4-dichloromethylpyridine or 2-chloro-4-chloromethylpyridine, or a mixture thereof, and a compound represented by the general formula (1): ## STR1 ## (Wherein R ¹ and R ² each represent a hydrogen atom, an alkyl group which may have a substituent, an aryl group or an aralkyl group, or a substituent together with a nitrogen atom to which they are bonded. Which forms a 4- to 8-membered ring which may have a hydrogen atom and a hydrogen atom in the presence of a hydrogenation catalyst. (Wherein R ¹ and R ² are as defined above). 2. The method according to claim 1, wherein the amine is a secondary amine.