JPH046798B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing p-aminobenzoylglutamic acid by electrolytic reduction. BACKGROUND ART p-Aminobenzoylglutamic acid has traditionally been a useful substance as an intermediate raw material for the synthesis of pharmaceuticals such as folic acid, and is usually produced by using p-nitrobenzoylglutamic acid as a raw material and cyclizing this. Examples of such methods include, for example, a method of chemical ring formation (such as U.S. Patent No. 2,537,366) or a method of catalytic reduction (Journal, American Chemical Society Vol. 79, 4391
4394, 1947, etc.), but there has been no report on a method for producing p-amino compounds by electrolytic reduction of p-nitrobenzoylglutamic acid. Many reports have been made regarding the electrolytic reduction reactions of aromatic nitrides, and in addition to the amino form, hydroxyamino forms and rearrangement products are known as such reduction products. . In order to increase the yield of the amino compound, it is generally considered to carry out the reaction under harsh conditions such as raising the reaction temperature or using an electrode plate with a high hydrogen overvoltage. However, this actually causes decomposition of the compound and side reactions,
This results in a decrease in the yield of the desired amino compound and a decrease in current efficiency. The inventors of the present application have conducted intensive studies on the electrolytic reduction of p-nitrobenzoylglutamic acid, and have established an industrially extremely advantageous method for producing p-aminobenzoylglutamic acid. That is, the present inventors have discovered that in the electrolytic reduction of p-nitrobenzoylglutamic acid, p-amino compounds can be obtained in high yield and with high current efficiency by using palladium metal as the cathode. In addition, in the electrolytic reduction of p-nitro form, p-amino form is generated via p-hydroxyamino form, but this palladium electrode is particularly effective in the process of converting p-hydroxy form to p-amino form. found it to be effective. Furthermore, if the pH of the reaction solution is approximately 5 or higher, the amount of by-products produced increases at the end of the reaction, and the target amino compound has a minimum solubility point around pH 3. Therefore, it has been found that the electrolytic reduction reaction can be carried out efficiently and smoothly in an aqueous solution with a pH of 3 or lower. The present invention has been made based on these findings. That is, the present invention provides a method for producing p-aminobenzoylglutamic acid, which comprises electrolytically reducing p-nitrobenzoylglutamic acid and/or p-hydroxyaminobenzoylglutamic acid at a pH of 3 or lower using palladium or a palladium alloy as a cathode. be. As the cathode of the present invention, palladium metal itself or various palladium alloys can be used.
Palladium metal is actually used by plating the cathode with palladium or by plating the cathode as palladium black from the viewpoint of economical efficiency rather than using palladium metal itself as the cathode. Examples of the electrode material used as a base for plating or plating include nickel, silver, carbon, titanium, tantalum, and titanium and tantalum plated with noble metals such as rhodium and platinum. In addition, as a palladium alloy,
Examples include nickel-palladium alloy and titanium-palladium alloy. From an industrial perspective, the palladium content of these alloys is 2 to 20% by weight in the case of nickel-palladium alloys and 0.05 to 0.5% by weight in the case of titanium-palladium alloys.
Preferably. Among the cathodes that can be used in the present invention,
Particularly preferably used electrodes include palladium black plated electrodes, such as platinum-plated titanium plates plated with palladium black. Plating the electrode with palladium can be carried out by making the catholyte acidic with hydrochloric acid, adding a palladium salt such as powerium chloride to the catholyte, and then passing a current of about 0.05 to 0.2 amperes/dm ² . As the anode, an acid-resistant metal such as platinum, platinum-plated titanium, platinum-coated tantalum, etc. can be used. The electrolytic reduction of the present invention is carried out by separating the cathode side and the anode side with a diaphragm. As such a diaphragm,
For example, a cation exchange membrane (CMV; manufactured by Asahi Glass Industries, Ltd.; manufactured by Nafion DuPont) is used. Dilute hydrochloric acid or dilute sulfuric acid can be used as the catholyte and anolyte. For PH control on the cathode side, mineral acids such as hydrochloric acid and sulfuric acid are used. If necessary, salts with a high degree of dissociation such as common salt, ammonium chloride, sulfate, and ammonium sulfate may be used in combination with the catholyte as an electrolyte. The electrolytic reaction is preferably carried out in the form of an aqueous solution of the raw materials, but a suspension may also be used. In the case of p-nitrobenzoylglutamic acid, the reduction reaction is carried out while maintaining the concentration of about 0.5 to 5% by weight, and in the case of p-hydroxyaminoglutamic acid, the reduction reaction is carried out while maintaining the concentration of about 0.5 to 20% by weight. be able to. P-hydroxyaminobenzoylglutamic acid can be easily produced by using p-nitrobenzoylglutamic acid as a raw material and subjecting it to an electrolytic reduction reaction using a conventional cathode such as titanium, nickel, copper, or silver. The cathodes of the present invention can also be used. At this time, the current density may be 5 to 20 A/dm ² , preferably 8 to 15 A/dm ² . The reaction solution is kept acidic, preferably at a pH of about 3 to 7, and the reaction temperature is 0 to 30°C. The reaction solution containing p-hydroxyaminobenzoylglutamic acid obtained by such an electrolytic reaction can be used as a raw material in the present invention as it is, and the reaction solution does not contain unreacted p-nitro form. It's okay. The electrolytic reaction of the present invention is carried out while adjusting the pH of the catholyte to 3 or less, preferably 0.5 to 2. The reaction temperature is 10-70°C, preferably 30-50°C.
The current density also depends on the concentration of the raw materials,
Generally, when p-nitrobenzoylglutamic acid is used as a raw material, 3 to 10 A/ ^dm2 , preferably 5 to 7 A/ ^dm2 , and when p-hydroxyaminobenzoylglutamic acid is used as a raw material, ⁵ to 15 A/dm2, Preferably 8-12A/ ^dm2
It will be held in It is preferable to adopt a method in which the amount of current applied is lowered as the reaction progresses, as is done in conventional electrolytic reactions. To separate p-aminobenzoylglutamic acid from the reaction solution after completion of the reaction, conventional means such as concentration and pH adjustment using an alkali are used. The electrolytic reaction of the present invention can be carried out using a cell commonly used for general electrolytic reactions, such as a tank type, filter press type, or plate and frame type. Industrially, it is preferable to use a filter press type or a plate and frame type. When using these cells,
During the reaction, both the catholyte and the anolyte are circulated by a pump through a relay tank. At this time, the flow rate in the cell on the cathode side is set to 5 to prevent a decrease in current efficiency.
It is desirable to set it to cm/sec or higher. According to the method of the present invention, the yield of the desired amino compound is high, and the current efficiency is also high, so it is extremely useful as an industrial production method. In particular, when p-hydroxyaminobenzoylglutamic acid is used as a raw material, there are advantages in that the reaction can proceed at a high raw material concentration and that the palladium electrode is less consumed. When the object of the present invention is used as a raw material for producing folic acid, the electrolytic reaction solution can be used as it is. Hereinafter, the present invention will be explained in more detail with reference to Examples. Example 1 Electrolytic reduction of p-nitrobenzoylglutamic acid was carried out using a filter press type electrolytic cell. (1) The manufacturing of the cell is as follows. Cathode: Platinum-plated titanium plate plated with palladium black (Note) (Platinum-plated thickness: 2 μm,
(Titanium thickness: 2 mm) Effective area: 1 dm ² (8 cm x 12.5 cm) Anode: Platinum-plated titanium plate (Platinum-plated thickness:
2 μm, titanium thickness 2 mm) Effective area 1 dm ² (8 cm x 12.5 cm) Ion exchange membrane: Nafion -315 (manufactured by Dupont) Distance between ion exchange membrane and electrode plate: 1.5 mm (Note) Plating conditions and plating method Plating conditions Cathode solution: 250ml of 3W/V% hydrochloric acid solution Anolyte solution: 300ml of 3W/V% sulfuric acid solution Temperature of catholyte: 10±1℃ Flow rate in cell: 10cm/sec on both cathode and anode side Plating method Palladium chloride 0.5 as PdCl ₂ 5 containing g
% hydrochloric acid solution was circulated to the cathode side via a relay tank. Plating was continued for 2 hours at a current density of 0.1 A/dm ² . Plating was repeated four times in the same manner. A total of 1.2 as palladium metal on the cathode plate
This means that it has been plated. After palladium black plating, the catholyte was extracted and the electrolytic cell was washed with water. (2) Electrolytic reduction of p-nitrobenzoylglutamic acid An electrolytic reduction reaction was carried out using the cell described in (1). Catholyte at the start of the reaction: 300 ml of an aqueous solution (PH 0.7) containing 2.8 g of p-nitrobenzoylglutamic acid, 2 g of common salt, and 6 g of hydrochloric acid Raw material solution fed to the catholyte after the start of the reaction: p
- as nitrobenzoylglutamic acid
895 ml of an aqueous monosodium salt solution of p-nitrobenzoylglutamic acid containing 125.3 g and 35 g of common salt. Electrolyte solution to be fed into the catholyte after the start of the reaction:
35W/V% hydrochloric acid 150ml Anolyte: 2W/V% sulfuric acid aqueous solution 300ml Catholyte temperature during reaction: 45°±1°C Flow rate in the cell: 15cm/sec for both cathodes Amount of current applied during reaction: Stepwise as shown below It was lowered to .

[Table] Under the above conditions, electrolytic reduction was performed for 17.0 hours while both the catholyte and anolyte were circulated through a relay tank. Regarding the raw material solution and electrolyte solution supplied to the cathode side during the electrolytic reduction reaction, 12 minutes after the start of the reaction.
It was distributed evenly over time. After the reaction, the catholyte was extracted from the system and subjected to high-performance liquid chromatography [Analytical column: Uniseal C _18/10 μm (manufactured by Gascro Industries Co., Ltd.,
Column length 4mmφin x 30cm) Mobile phase: Aqueous solution, ammonium phosphate (NH ₄ H ₂ PO ₄ ) 0.02 mol% concentration, PIC-B7 (Waters Associates) 0.7V/V
%, methanol 2.0V/V%, acetonitrile
1.9V/V%, PH=3.0, measurement wavelength: UV254nm]
As a result of quantitative analysis, the amount of p-aminobenzoylglutamine, the target compound, produced was 114.0 g. (Theoretical yield: 99.0%, current efficiency: 88.3%) Example 2 The electrolytic reduction of p-nitrobenzoylglutamic acid was carried out in the same electrolytic cell and under the same conditions as in Example 1, except as described below. Cathode: titanium-palladium alloy plate (palladium content: 0.15% by weight, thickness: 2 mm) Effective area: 1 dm ² Amount of current applied: Reduced in stages as shown below.

[Table] As a result of quantitative analysis after the reaction in the same manner as in Example 1, the amount of p-aminobenzoylglutamic acid produced was 109.8 g. (Theoretical yield: 95.4%, current efficiency: 79.4%) Example 3 Electrolytic reduction of p-hydroxyaminobenzoylglutamic acid was performed. p-hydroxyaminobenzoylglutamic acid was produced by using p-nitrobenzoylglutamic acid as a raw material and subjecting it to an electrolytic reduction reaction. These electrolytic reduction reactions were all carried out using a filter press type electrolytic cell. The procedures in Example 1 were followed except for the following. (1) Production of p-hydroxyaminobenzoylglutamic acid Cathode: Titanium plate (material JIS-TP-35-C, thickness 2mm) Effective area 1dm ² (8cm x 12.5cm) Cathode: 42.0g as p-nitrobenzoylglutamic acid and p containing 12.0 g of salt
- 300ml of monosodium nitrobenzoylglutamate aqueous solution Temperature of catholyte: 25±1°C After the start of the reaction, electricity was applied at 10A for 30 minutes, and then
The reaction was completed by applying current at 5A for 1.5 hours. As shown in Table 1, this reaction solution contains p-hydroxybenzoylglutamic acid as a main component. (2) Electrolytic reduction of P-hydroxyamine benzoylglutamic acid Cathode: The reaction solution obtained in (1) was adjusted to pH 0.7 by adding 41 ml of a 35% by weight aqueous hydrochloric acid solution. Cathode: Platinum plated titanium plate plated with palladium black* (platinum plate thickness 2.0 μm, titanium plate thickness 2.0 mm) Effective area 1 dm ² (*) Palladium black plating is as per Example 1
I did the same thing. Temperature of catholyte: 35°C±1°C Amount of current applied: Lowered stepwise as shown in the following table.

[Table] After the reaction was completed, the reaction sample was subjected to quantitative analysis, and the results shown in the following table were obtained.

[Table] Example 4 Tank-type electrolytic cell [The anolyte and catholyte are separated by an ion exchange membrane (CMV; manufactured by Asahi Glass Industries, Ltd.), and both electrode sides have a volume of 150 ml; the cathode side is stirred. is equipped with a machine] under the following conditions.
- Electrolytic reduction of nitrobenzoylglutamic acid was carried out. Cathode: Titanium-palladium alloy plate (palladium
0.15% by weight, thickness 2mm) Effective area: 0.15dm ² (3cm x 5cm) Anode: Platinum plated titanium plate (platinum plated, thickness 2μ)
(Titanium thickness: 2 mm) Effective area: 0.15 dm ² (3 cm x 5 cm) Cathode: 15 g of p-nitrobenzoylglutamic acid, 5 g of common salt, 12 g of acid, 12 g of aqueous solution in total (PH 0.1) Anolyte: 120 ml of 2% sulfuric acid aqueous solution Current Value: 0.75 A (current density: 5 A/dm ² ) Temperature of catholyte: 35 ± 1°C After continuing the reaction for 14 hours, the reaction solution was quantitatively analyzed by high-speed liquid chromatography, and the theoretical yield of p-aminobenzoylglutamic acid was determined. The efficiency was 96% (current efficiency 74.5%). Example 5 Palladium black 0.5g/dm ² as cathode plate
Platinum plated titanium plate plated with (platinum plated thickness
2.0 μm and an electrode plate area of 0.15 dm ² ), the other electrolytic reaction methods and conditions were the same as in Example 4, and the reaction was carried out for 13 hours. After the reaction, the reaction solution was quantitatively analyzed by high-speed liquid chromatography, and the theoretical yield of p-aminobenzoylglutamic acid was 98.5% (current efficiency 82.3%).
It was hot. Comparative Example 1 A platinum-plated titanium plate without palladium black plating (platinum plating thickness of 2 μm, effective area of 0.15 dm ² , 3 cm x 5 cm) was used as the cathode plate, and the other conditions were the same as in Example 4. Allowed time to react. After the reaction, quantitative analysis of the reaction solution using high-performance liquid chromatography revealed that the proportion of unreacted raw materials to the starting materials was 15%, and the theoretical production amount of p-aminobenzoylglutamic acid was 5%, p-hydroxy That of the amino form was 72%. Comparative Example 2 As a raw material solution to be charged to the cathode, 100 ml of an aqueous solution containing 15.0 g of p-nitrobenzoylglutamic acid and 5 g of common salt was prepared, and a 30% by weight aqueous solution of caustic soda was added to this solution to form a solution of PH 11.0 and PH 5.0. The same reduction as in Example 4 was carried out using each of these. The results of analyzing the reaction solution after 14 hours of reaction were as follows.

[Table] Theoretical yield and proportion of unreacted raw materials Example 6 Using a filter press type electrolytic cell (ion exchange membrane CMV was used as a diaphragm), p-nitrobenzoylglutamic acid was electrolytically reduced under the following conditions. Cathode: Titanium plate plated with palladium black Palladium black 0.5g/dm ² , titanium material JIS
-TP-35-C, titanium thickness 2mm effective area 1d
m ² (8cm x 12.5cm) Anode: Platinum-plated titanium plate (plating thickness 2.0μm,
Titanium thickness: 2 mm) Effective area: 1 dm ² (8 cm x 12.5 cm) Anolyte: 2% sulfuric acid aqueous solution 250 ml Cathode solution: p-nitrobenzoylglutamic acid 2.5 g Hydrochloric acid 2.6 g Salt 13.0 g Total 250 ml aqueous solution (PH 1.0) Raw material solution fed to the cathode side during reaction: 71 g of p-nitrobenzoylglutamic acid and 27 g of common salt
500ml of p-nitrobenzoylglutamic acid monosodium salt aqueous solution containing g Electrolyte solution supplied to the cathode side during reaction: 35% by weight
45ml of hydrochloric acid Flow rate in the cell: 7cm/sec for both anode and anode Catholyte temperature during reaction: 35±1℃ Current value during reaction: 4A Note that the raw material solution and electrolyte solution supplied to the cathode side during the reaction last for 8.5 hours. It was distributed evenly. The reaction was stopped after a total reaction time of 12 hours, and the reaction solution was quantitatively analyzed. As a result, the theoretical yield of p-aminobenzoylglutamic acid was 98.5% (theoretical current efficiency based on p-aminobenzoylglutamic acid).
81.9%).

Claims (1)

[Claims] 1. A method for producing p-aminobenzoylglutamic acid, which comprises electrolytically reducing p-nitrobenzoylglutamic acid and/or p-hydroxyaminobenzoylglutamic acid at a pH of 3 or less using palladium or a palladium alloy as a cathode.