JPH06749B2 - Method for producing aminomethylpyridine - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a method for producing aminomethylpyridines, more specifically, supplying a starting cyanopyridine in the presence of a hydrogenation catalyst to a reaction system, for example, an autoclave. And a catalytic reduction reaction to produce aminomethylpyridines. Aminomethylpyridines are compounds useful as intermediates for medicines.

(Prior Art) As a conventional method for producing a compound, a method in which a catalytic reduction reaction of cyanopyridines in the presence of a hydrogenation catalyst is known.
(C. A72, 66760r (1970)) According to this method, the starting material cyanopyridines and the solvents methanol, ammonia and Raney nickel are charged at the same time in a reactor, and the mixture is heated at room temperature to 80 atm.
2-aminomethylpyridine, 3-
Aminomethylpyridine and 4-aminomethylpyridine are obtained at yields of 72%, 60% and 60%, respectively. However, the above-mentioned method is not necessarily an industrially advantageous production method since it does not necessarily have a high yield and has drawbacks such as a long reaction time.

(Problems to be Solved by the Invention) The present inventors have conducted extensive studies to improve the above-mentioned disadvantages, and as a result of paying attention to the reactivity of unreacted cyanopyridines, it is inevitable that the raw material cyano is present in the presence of a hydrogenation catalyst. The inventors have found that by carrying out a catalytic reduction reaction while successively supplying pyridines into the reaction system, side reactions are suppressed and aminomethylpyridines are produced in good yield, and the present invention has been completed.

(Means for Solving Problems) The cyanopyridine used in the present invention is not particularly limited,
2-cyanopyridine, 3-cyanopyridine, from the viewpoint of producing aminomethylpyridines which are pharmaceutical intermediates
4-cyanopyridine, 2-cyano-6-methylpyridine and the like are preferably used.

In general, as such a hydrogenation reaction method, a method is known in which cyanopyridines are charged in advance in a reactor and a catalytic reduction reaction is carried out in the presence of a hydrogenation catalyst to obtain aminomethylpyridines. However, this method has a low yield and cannot be said to be an industrially advantageous method.

Therefore, as a result of intensive studies, the present inventors have surprisingly found that in the present invention, the yield is remarkably improved by performing the catalytic reduction reaction while sequentially supplying the raw material cyanopyridines into the reaction system. I found a thing.

In the conventional method, side reactions such as reactions between cyanopyridines and reactions between cyanopyridines and the formed aminomethylpyridines are likely to occur when the reaction proceeds, and a large amount of high-boiling substances are by-produced. It seems that the yield of the compounds is significantly reduced.

In carrying out the method of the present invention, in order to supply the starting cyanopyridines into the reaction system, it is necessary to charge a solvent in the reactor in advance. Examples of suitable solvents include aromatic hydrocarbons such as benzene and toluene, hydrocarbons such as hexane and cyclohexane, alcohols such as methanol and ethanol, cyclic ethers such as tetrahydrofuran and dioxane.

The amount of the solvent is not particularly limited, but when reaction efficiency is taken into consideration, it is preferably in the range of 0.5 to 5 times (weight) with respect to the cyanopyridines.

Examples of the hydrogenation catalyst used in the present invention include commonly used hydrogenation catalysts, and specific examples thereof include Raney nickel and Raney cobalt catalysts. The amount of the hydrogenation catalyst used is preferably in the range of 2 to 50% with respect to the cyanopyridines in terms of reaction efficiency, catalyst efficiency and the like.

Ammonia is not always necessary, but its presence has the effect of suppressing side reactions, and usually the same amount (weight) or less with respect to cyanopyridines is sufficient and the reaction proceeds properly.

The reaction normally proceeds at room temperature to 200 ° C., preferably 70 to 150 ° C., and the reaction pressure is atmospheric pressure or higher, preferably 5 to 50 atm.

Generally, under the above conditions, the reaction is completed in a short time of 0.5 to 5 hours and almost no unreacted cyanopyridines remain.

The aminomethylpyridines obtained by the above method can be easily isolated to a high-purity target by general isolation and purification means, for example, by removing the hydrogenation catalyst from the reaction solution by filtration and purifying the solution by distillation. it can. According to the method of the present invention, high-quality aminomethylpyridines can be obtained very easily and in good yield, and cyanopyridines can be obtained as a starting material.

(Effect of the Invention) When the present invention and the conventional method are compared, in the synthesis of 2-aminomethylpyridine, the conventional method is used, for example, Comparative Example-1.
When 2-cyanopyridine as a raw material, a solvent, ammonia, and a catalyst are charged at once as shown in, the yield is 68%. In the present invention, as shown in Example-2, by supplying 2-cyanopyridine into the autoclave as the reaction progresses, the yield becomes extremely high at 96%. In the conventional method, since cyanopyridines and aminomethylpyridines coexist during the reaction, side reactions such as cyanopyridines, and cyanopyridines and aminomethylpyridines easily occur to easily generate high-boiling substances, Therefore, it is considered that the yield is lowered. In fact, according to the method of the comparative example, many unknown high boiling point products were produced. However, in the method of the present invention, the catalytic reduction reaction is carried out while supplying the starting cyanopyridines in accordance with the progress of the reaction, and thus the above-mentioned side reaction does not occur and aminomethylpyridines can be obtained in high yield.

Further, in the present invention, since side reactions hardly occur, the purification is very easy as compared with the conventional method, and, for example, a highly pure aminomethylpyridine can be obtained by simple distillation.

Next, the method of the present invention will be described with reference to examples, but the present invention is not limited thereto.

Example 1 Benzene 700 was placed in an electromagnetic stirring autoclave having a capacity of 3.
g, Raney nickel 140g liquid ammonia 7
0 g was charged, hydrogen was introduced into this, and the temperature was raised to 90 ° C. and 45 atm to increase the pressure. After the reactor internal temperature reached 90 ° C., 700 g of 2-cyanopyridine was fed into the autoclave by a high-pressure metering pump over 3 hours. Hydrogen was consumed as the reaction proceeded, so hydrogen was added successively to maintain the pressure.

When the supply of 2-cyanopyridine was stopped, the consumption of hydrogen also stopped and the reaction ended. The reaction solution was cooled and passed to separate the catalyst, and the solution was distilled to give 646 g of 2-aminomethylpyridine having a boiling point of 132 ° C. at 89 mmHg (GC purity: 99
%, Yield 88%) and bis-2-picolylamine 60 g (yield 9%) were obtained as a by-product.

Example 2 Benzene 700 was added to a magnetic stirring type autoclave with a capacity of 3.
g, 140 g of Raney cobalt developed, and 70 g of liquid ammonia were charged, and hydrogen was introduced into this to raise the temperature and pressure to 130 ° C. and 45 atm. Immediately after the reactor internal temperature reached 130 ° C., 700 g of 2-cyanopyridine was fed into the autoclave by a high-pressure metering pump over 3 hours. Hydrogen was consumed as the reaction proceeded, so hydrogen was added successively to maintain the pressure. When the supply of 2-cyanopyridine was stopped, the consumption of hydrogen also stopped and the reaction ended. Thereafter, the same treatment as in Example-1 was carried out to give 705 g of 2-aminomethylpyridine (GC
Purity 99%, yield 96%) and by-product bis-2-
13 g (yield 2%) of picolylamine was obtained.

Example-3 In the same manner as in Example-1, 700 g of 3-cyanopyridine was used instead of 2-cyanopyridine, and the same reaction and treatment were carried out to obtain 712 g of 3-aminomethylpyridine having a boiling point of 133 ° C at 30 mmHg (GC purity). 99%, yield 97%) was obtained.

Example-4 In the same manner as in Example-2, using 700 g of 4-cyanopyridine instead of 2-cyanopyridine, and similarly reacting,
After treatment, 690 g of 4-aminomethylpyridine (GC purity 99%, yield 94%) having a boiling point of 114 ° C. at 15 mmHg was obtained.

Example-5 As in Example-1, instead of 2-cyanopyridine, 6
Using 700 g of methyl-2-cyanopyridine, the same reaction and treatment were carried out and 651 g of 6-methyl-2-aminomethylpyridine having a boiling point of 117 ° C. at 40 mmHg (GC purity 99
%, Yield 90%) was obtained.

Comparative Example-1 A magnetic stirring type autoclave having a capacity of 3 was charged with 700 g of 2-cyanopyridine, 700 g of benzene, 140 g of Raney cobalt developed, and 70 g of liquid ammonia, and hydrogen was introduced into this to react at 90 ° C. and 45 atm. The reaction was carried out while adding hydrogen, and the reaction was completed in 3 hours. Thereafter, the same treatment as in Example-1 is carried out to prepare 2-aminomethylpyridine 49
9 g (GC purity 99%, yield 68%) and bis-2-picolylamine 80 g (yield 12%) were obtained.

Claims (1)

[Claims] 1. A cyanopyridine compound in the presence of a hydrogenation catalyst,
A method for producing aminomethyl pyridines, which comprises reacting while supplying a starting cyanopyridine in the reaction system in the presence of a catalyst to produce aminomethyl pyridines by catalytic reduction reaction.