JPH0113461B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides terephthalonitrile (also known as 1,4-
Dicyanobenzene, hereinafter abbreviated as "TPN". ) in water or a water-containing organic solvent in the presence of an alkali or alkaline earth metal hydroxide and a metal catalyst for hydrogenation, by bringing hydrogen into contact with heating,
The three reactions of selective hydrogenation of the side chain nitrile group of TPN, hydrolysis, and hydrogenation of the benzene nucleus proceed simultaneously in a well-balanced manner, allowing direct 4-aminomethylcyclohexane-1-carboxylic acid (hereinafter abbreviated as "AMCHA") to occur in a single step. ).

AMCHA obtained by the method of the present invention is a mixture of trans isomer and cis isomer, and the trans isomer separated from it is a compound useful as an excellent drug with anti-plasmin action.

Many methods have already been proposed for producing AMCHA, and among these methods, the following methods are known as industrially advantageous production methods using TPN as a raw material.

4-cyanobenzoic acid is obtained by selective hydrolysis of TPM or by heating it with an aromatic dibasic acid ester (as described in the specification of Japanese Patent Publication No. 10629/1989, hereinafter the same), and the side chain nitrile of this is obtained. AMCHA is obtained by catalytic hydrogenation of the group and the benzene nucleus, respectively. (Tokuko Show 32-9073,
4-cyanobenzylamine was obtained by selective side chain catalytic hydrogenation of TPN (Japanese Patent Publication No. 40-10133),
This is hydrolyzed by a conventional method to produce 4-aminomethylbenzoic acid, and then the benzene nucleus is catalytically hydrogenated to produce AMCHA (Special Publications No. 33-27, No. 9254, No. 40, No. 32257, etc.) AMCHA is obtained by selectively oxidizing 1,4-bis(aminomethyl)cyclohexane obtained by simultaneous catalytic hydrogenation of the side chain and benzene nucleus of TPN (JP-A-55-76846). , from TPN
Known methods for producing AMCHA include carrying out multiple reactions in various orders, including side chain catalytic hydrogenation, core catalytic hydrogenation, hydrolysis, side chain exchange reactions or selective oxidation. It is made up of doing. Each method has its advantages and disadvantages, but since they all involve reactions that require selectivity, they generally involve side reactions and have low yields (the total yield from TPN is
(only around 50%). Furthermore, by-produced impurities often impede smooth reactions in subsequent reaction steps, and it is therefore essential to add the minimum necessary purification operations to each step.

In contrast, according to the method of the present invention, AMCHA can be obtained directly from TPN in a single step, and the yield exceeds the total yield of known multiple steps, making it an extremely advantageous method industrially. be able to.

Although the reaction mechanism in the method of the present invention is not clear, in the process of individually researching several of the elementary reactions mentioned above, the present inventors have discovered that if specific conditions are adopted, the target elementary reaction can be produced mildly. We have completed the present invention by discovering that AMCHA can be obtained directly in good yield under the conditions that complement each other and proceed in a well-balanced manner.

The fact that water can be used alone as a reaction solvent in the present invention is not only unconceivable in common chemical reactions using TPN as a raw material, but also because the use of water facilitates the desired reaction. It can be said to be an industrial breakthrough in that it was found to be effective in advancing the process. As the reaction solvent in the present invention, in addition to the above-mentioned water alone, preferable results can also be obtained by using hydrophilic organic solvents containing water, such as alcohols such as ethanol and propanol, and ethers such as dioxane.

The amount of solvent to be used is not particularly limited, but it is usually appropriate to use an amount of about 2 to 10 times the amount of TPN.

The alkali or alkaline earth metal hydroxide used in the method of the present invention is presumed to function as a hydrolyzing agent for the nitrile group of TPN, but it also plays an important role in making the reaction proceed mildly. It is thought that this has been achieved. Industrially, it is appropriate to use caustic soda, caustic potash, calcium hydroxide, barium hydroxide, etc., but especially when barium hydroxide is used, the content of trans isomer, which is the active ingredient in the resulting AMCHA, is high. In addition to exhibiting these characteristics, treating the reaction solution with sulfuric acid to remove barium as sulfate has the advantage that the load on the ion exchange resin can be significantly reduced in the subsequent AMCHA purification process using the ion exchange resin.

The amount of hydroxide added is preferably 1.0 equivalent or more relative to TPN.

Further, as the metal catalyst for catalytic hydrogenation used in the method of the present invention, one type or a mixture of two or more of known platinum, rhodium, palladium, ruthenium, etc. can be used. Among these, the combination of palladium and ruthenium is considered to be industrially most suitable. If alumina is used as one carrier and activated carbon is used as the other carrier, it is possible to easily separate both catalyst mixtures separated from the reaction solution after the reaction by utilizing the difference in sedimentation rate.

EXAMPLES Hereinafter, the present invention will be specifically explained with reference to Examples, but the present invention is not limited thereto.

Example 1 In a stainless steel autoclave with a stirrer,
TPN 50g, water 400ml, barium hydroxide octahydrate 70
g, 5 g of 5% palladium-alumina and 10 g of 5% ruthenium-carbon were charged, hydrogen gas was introduced at room temperature to a pressure of 100 kg/cm ² G, and the temperature was slowly raised to 100° C. while stirring. Hydrogen absorption was observed when the internal temperature was approximately 40°C, so the internal pressure was reduced from then on.
Hydrogen gas was continuously supplied to maintain the pressure at 100Kg/cm ² G. After reacting at 100°C for 5 hours, the mixture was cooled and the catalyst was separated. Add sulfuric acid to the filtrate to adjust the pH to 3, filter out the barium sulfate and white precipitate of side reaction products, and pass the filtrate through a column packed with cation exchange resin (Amberlite 120B, 200ml).
After adsorbing AMCHA, wash with water as usual.
Aqueous ammonia elution was performed. The obtained ammonia eluate was concentrated until crystals were precipitated, acetone was added thereto to precipitate AMCHA, and the mixture was filter-dried to obtain 33 g of white crystals of AMCHA.
The proportion of trans isomer contained in the obtained AMCHA was 72%.

Example 2 In Example 1, barium hydroxide octahydrate 70
When 33 g of caustic soda was used instead of 20 g, and 800 ml was used instead of 200 ml of cation exchange resin, the yield of AMCHA was 30 g, and the proportion of trans isomer contained therein was 50%.

Example 3 In Example 1, when a mixture of 200 ml of dioxane and 200 ml of water was used instead of 400 ml of water, the amount was 36 g.
White crystals of AMCHA were obtained.

Claims (1)

[Claims] 1. 4-Aminomethylcyclohexane, which is characterized by treating terephthalonitrile with hydrogen in the presence of an alkali or alkaline earth metal hydroxide and a metal catalyst using water or a mixture of water and a hydrophilic organic solvent as a solvent. Method for producing 1-carboxylic acid.