JPS5951934B2 - Method for producing 4-aminomethylcyclohexanecarboxylic acid and its mineral acid salt - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is an intermediate for producing trans-4-aminomethylcyclohexanecarboxylic acid, which is useful as a pharmaceutical having antiplasmin activity.

The present invention relates to a method for producing 4-aminomethylcyclohexanecarboxylic acid.

Conventionally, the following methods 0 and 2) have been used to obtain 4-aminomethylcyclohexanecarboxylic acid from 4-hydroxyiminomethylbenzoic acid or its derivatives.

l) Catalytic reduction of 4-hydroxyiminomethylbenzoic acid or its alkyl ester in acetic anhydride in the presence of a palladium catalyst to produce an acetylated product of 4-aminomethylcyclohexanecarboxylic acid or.

Method for producing the esterified product (JP-A-51-521
59). 2) The methyl ester of 4-hydroxyiminomethylbenzoic acid is reduced by reducing the side chain oxime in the compound using a palladium catalyst in a lower alcohol solvent (Japanese Unexamined Patent Publication No. 50-88042), and b) hydrogenating the nucleus. and c), a method produced by deacetylation (ester hydrolysis).

etc. are publicly known.

However, 1), the method uses 150°C and 10°C as reaction conditions.
It is difficult to manufacture it industrially due to economical and safety considerations, as it requires high temperatures and pressures such as 0 atmospheres, and uses organic solvents such as acetic anhydride or acetic acid as a medium. be.

Furthermore, method 2) is disadvantageous because the process is complicated. The present inventors have conducted intensive studies to find a new production route for obtaining 4-aminomethylcyclohexanecarboxylic acid (hereinafter abbreviated as 4-AMCHA) and its mineral acid salt, and as a result, they have found that they can be easily produced by eliminating the drawbacks of the above-mentioned conventional methods. 4-AMCH with initiative
The present invention has been achieved to produce A and its mineral acid salt. That is, in the present invention, 4-hydroxyiminomethylbenzoic acid (hereinafter abbreviated as 4-HBA) is treated with a catalyst composed of three types of palladium, platinum, and rhodium in an aqueous medium under mineral acid acidity. make use of.

Producing a mineral acid salt of 4-AMCHA Ozushaku, which is characterized by performing aminomethylation and reduction of benzene nuclei in one step by catalytic reduction at a relatively low temperature of room temperature to about 60°C. Regarding how to. To explain the present invention in more detail, 4-HBA, which is the raw material of the present invention, can of course be prepared as a target product, but it can also be prepared using P-formylbenzoic acid and hydrochloric acid, which are obtained as by-products during the production of terephthalic acid. It is easily produced by reaction with hydroxylamine and can be obtained at low cost as an industrial raw material. Water is used as the reaction medium in the present invention. The amount used is 10-20% of the weight of the raw material 4-HBA.
Double the amount is appropriate.

This medium contains at least an equivalent amount, preferably 1, of 4-HBA.
~3 equivalents of mineral acid are added. Further, the mineral acid concentration in water is suitably about 3 to 5% (by weight). The mineral acid used in this application is a mineral acid that forms a water-soluble salt with the product (4-AMC[-1A). Examples include hydrochloric acid, sulfuric acid and nitric acid. The effect of adding this mineral acid is that 4-aminomethylbenzoic acid, which is produced as an intermediate during the reduction reaction, forms its mineral acid salt, which is easily dissolved in water and facilitates the sixth-order nuclear hydrogenation reaction. In addition, 6 mineral acids protect the side chain aminomethyl group,
It prevents side reactions such as deamination, and produces 4-A in good yield.
A mineral salt of MCHA is obtained.

If mineral acid is not present in the reaction medium water, see Example 6. The reduction reaction product is. 4-Aminomethylbenzoic acid. 4-AMCHA cannot be obtained.

As described above, the addition of mineral acid is one of the essential requirements of the present invention. The catalyst used in the present invention is a catalyst consisting of three types: palladium, platinum, and rhodium.

The catalyst may optionally contain other metals in addition to these three metals, but no particular benefit can be expected from doing so, and it is economically disadvantageous. In addition, the above three metal elements are metal 6
The compound 6 of the metal may be in any form, such as an oxide or an alloy of two or three of these metals. The catalyst is preferably used supported on a carrier such as activated carbon, diatomaceous earth or alumina, and catalysts supported on activated carbon are particularly preferred. In the case of these supported catalysts, the amount of metal supported is 2 to 10% by weight of the entire catalyst? usually used.
The amount of catalyst used is based on the starting material 4-HBA. The content of each metal may be about 0.25% by weight or more.

The ratio between the three types of palladium, platinum and rhodium is arbitrary, but considering their activity and economic efficiency, Pb:
Pt:Rh=around 1:1:1 is preferable. in this way,
Another feature of the present invention is the use of a catalyst consisting of these three types: palladium, platinum, and rhodium.

That is, palladium. Single catalyst systems such as platinum or rhodium; palladium and platinum; palladium and ruthenium; and mixed systems of two metal catalysts, such as platinum and rhodium, produce 4-aminomethylbenzoate by reduction of the side chain oxime. However, the nuclear hydrogenation reaction does not proceed at all.

Therefore, the catalyst consisting of three metals in the present invention is one of the important requirements. The catalytic reduction reaction conditions in the present method are as follows. Relatively low reaction temperatures of about 10°C to about 60°C are used.

If the reaction temperature is 60° C. or higher, side reactions such as deamination tend to occur, which is undesirable. The reaction hydrogen pressure need only be about 1 atm or higher, and the reaction will proceed easily even at a low pressure of about 1 to 10 atm. The reaction time is. Amount of catalyst used. The reaction continues until absorption of the hydrogen gas used for 6 reduction is completed, depending on the reaction temperature and reaction hydrogen pressure. Usually, it takes about several hours to 10 hours. After the reduction reaction is completed, the catalyst is removed from the furnace, and the F solution (after neutralization if the target is a free acid) is concentrated under reduced pressure, 6-acetone is added, and the mixture is left to cool.
4-AM was obtained by removing the precipitate, washing it six times, and then drying it.
CFIA or its mineral acid salt is produced.

As described above, the present invention has excellent utility as a method for industrially producing 4-AMCHA and its mineral salts. The present invention will now be explained in more detail with reference to Reference Example 6, Comparative Example, and Examples.

[Reference example]

Method 500TfL by reduction in mineral acid-free aqueous medium
! 16.59 (0.1M) of 4-hydroxyiminomethylbenzoic acid was placed in a pressure-resistant glass autoclave with a capacity of
Palladium-activated carbon 1.6 tbsp 5% platinum-activated carbon (P
t-C) 1.61 and 5e rhodium monoactivated carbon (Rt{
) 1.69 to give an initial pressure of 6 hydrogen 5k9/CIIL. Hydrogenation was carried out at a reaction temperature of room temperature to 50°C.

Hydrogen absorption ended after about 4 hours.

Since 1 part of crystals were precipitated in the reaction solution, 20T of concentrated hydrochloric acid was added.
After adding ILI to dissolve the crystals, the mixture was filtered with P to remove the catalyst.

The weight after drying was 5.59. After concentrating the liquid part under reduced pressure, acetone was added and the precipitated crystals were separated by filtration. As a result of drying, white powder 14.5I was obtained. This one is M
．． P. The temperature was 284-6°C (decomposition), and the infrared absorption spectrum of the standard product matched that of 4-aminomethylbenzoic acid hydrochloride (yield 77%). [Comparative example] Method using one or two metal catalyst systems 4-
Hydroximinomethylbenzoic acid 16.5I (0.I
M) in a 3.5% hydrochloric acid aqueous solution 200gV! , suspended in
Next, the following catalyst system was added to increase the initial hydrogen pressure to 5 kg/Cnl.
, Hydrogenation was carried out at a reaction temperature of room temperature to 50°C.

From the amount of hydrogen consumed ΔP, it was possible to determine the presence or absence of hydrogenation of side chain oxom as well as nuclear hydrogenation.

After reduction, filter the reaction solution. The catalyst was distributed door to door. Furnace liquid. After confirming 4-aminomethylbenzoic acid hydrochloride by ultraviolet absorption spectrum (228 mμ), the mixture was concentrated under reduced pressure, and the precipitated crystals were filtered and dried. The product was identified by infrared absorption spectrum. The results are shown in Table 1.

[Examples 1 to 3] In a 500 capacity pressure glass autoclave, 4-hydroxyiminomethylbenzoic acid 16.51 (0.I
M) was suspended in 200 g of 3.5% aqueous hydrochloric acid solution, and then... 5% Pd-C. 5% PtH'' and 5% Rh-0 were added in the predetermined amounts shown in Table 2 with different catalyst ratios.

Hydrogenation was carried out at an initial hydrogen pressure of 5k9/(17f) and a reaction temperature of room temperature to 45°C. After hydrogen absorption was completed, the reaction solution was filtered and the catalyst was separated.

By ultraviolet absorption spectrum analysis. It was confirmed that there was no characteristic absorption of 4-aminomethylbenzoic acid hydrochloride at 228 mμ in the furnace liquid.

After concentrating this filtrate under reduced pressure. Add acetone and let it cool to precipitate crystals. After filtering and drying, white powders were obtained. All of these have M.O. of 175-177°C. P.
From the comparison with the infrared absorption spectrum of the standard product.
It was consistent with 4-AMCH-A hydrochloride. These results are shown in Table-2. Results of esterifying each product using a conventional method (N-acetyl, n-butyl esterification) and determining the production ratio of cis-trans isomers by gas chromatography analysis. cis form 62-66%, trans form 34-3
[Example 4] Same as Example 1, in 6 reaction vessels. 4-Hydrooxoisinomethylbenzoic acid 16.
59 (0.1 M) was suspended in 570 sulfuric acid aqueous solution 2007n1, then 5% Pd{1.61, 5% Pt-Cl.
Add 6fl and 5%Rh{1.69, 6 hydrogen initial pressure 5k
9/D6 Reaction temperature Hydrogenation was performed at room temperature to 50°C.

Hydrogen absorption ended after about 6 hours.

After the same post-treatment as in Example 1, 6 white powder 15.51 was obtained.

M. of the powder. P. is 205-206℃, compared with the infrared absorption spectrum of the standard product. 41 AMCHA. Consistent with sulfate.

This product was esterified by a conventional method and analyzed by gas chromatography. As a result, the production ratio of cis-trans isomer was 6870:32%.

Claims (1)

[Claims] 1. Catalytic reduction of 4-hydroxyiminomethylbenzoic acid using mineral acid-containing water as a medium in the presence of a catalyst consisting of three types of palladium, platinum, and rhodium. , a method for producing 4-aminomethylcyclohexanecarboxylic acid and its mineral acid salt. 2. Process according to claim 1, characterized in that the mineral acid is selected from hydrochloric acid, sulfuric acid and nitric acid.