JPH0524897B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing N-2-imidazolinylidene-p-aminobenzoic acid represented by the following formula ().

The target substance of the present invention is a new compound, and has recently been found useful as a pharmaceutical intermediate.

The method of the present invention converts ethylene thiourea trioxide into p-
This is achieved by reacting with aminobenzoic acid. Ethylene thiourea trioxide can be obtained, for example, by oxidizing ethylene thiourea with hydrogen peroxide. Implementation of the present invention is extremely simple and easy, and the reaction formula is as follows.

If you mix an aqueous solution of ethylene thiourea trioxide and sodium para-aminobenzoate, they will react at room temperature,
Since the compound of formula () precipitates, it can be filtered as it is after adjusting the pH. The pH of the reaction is preferably 4.0 to 8.5, particularly preferably 6 to 8, and the reaction temperature is preferably 0° to 100°C, particularly preferably 20° to 40°C. If the pH is adjusted to 8 after the reaction, only the compound of formula () is sparingly soluble at room temperature and can be collected by filtration. The quality is generally extremely pure and can be used as a raw material for the next process without special purification. If an acid is added to the filtrate after filtering off compound () to adjust the pH to 3.5, unreacted p-aminobenzoic acid precipitates as a free acid. This recovered product is used as the next raw material without any particular refining. Moreover, by increasing the amount of ethylene trioxide thiourine used, unreacted p-aminobenzoic acid can be made extremely small.

The advantages of the method of the present invention are (1) The raw materials ethylene thiourea, hydrogen peroxide, p-
Aminobenzoic acid is industrially produced in large quantities and can be obtained at low cost.

(2) The reaction is carried out in water at room temperature, so there is no wasted solvent loss or energy loss.

(3) There is no need to handle or generate foul-smelling amines or sulfur compounds during the reaction, making treatment easy in terms of pollution prevention.

Due to these points, it is considered to be the most suitable method for manufacturing the target product.

The examples shown below are intended to illustrate the present invention and are not intended to limit it in any way.

Example 1 Add 350 ml of water and 48.4 g of p-aminobenzoic acid to a 500 ml reaction flask, and add 28.2 g of 50% caustic soda with stirring.
was added and completely dissolved. pH about 7.5. Next, 53 g of ethylene thiourea trioxide was added at 30°C. 30-35
After reacting at ℃ for 10 hours, 8.8 g of soda carbonate was added little by little to bring the pH to 8. After 30 minutes, the precipitated crystals were filtered off, washed with water, a small amount of acetone, and dried.
Yield: 47g. Melting point over 300℃ (decomposition). The IR was consistent with that of N-2-imidazolidinylidene-p-aminobenzoic acid obtained separately.

Further, when an acid was added to the filtrate to adjust the pH to 3 to 3.5, unreacted p-aminobenzoic acid precipitated and the amount recovered was 5 g. It showed the same Rf as the standard sample by TLC.

N-2-imidazolidinylidene- obtained above
Put 3g of p-aminobenzoic acid into a 250ml flask,
25 ml of water, 70 ml of 35% hydrochloric acid and 100 ml of acetone were added and stirred overnight at room temperature. The precipitated crystals were filtered, washed with acetone, and dried.

Yield 43g, melting point 303-305°C (decomposition). The IR was consistent with that of N-2-imidazolidinylidene-p-aminobenzoic acid monohydrochloride obtained separately.

Example 2 5.1 g of ethylene thiourea trioxide in 25 ml of water and p
- 3.4 g of aminobenzoic acid was suspended, and 10 g of 10% aqueous sodium hydroxide solution was added at 20°C. Approximately 30℃, pH approximately 7
The reaction was carried out for 3 and a half hours. During that time, the pH was adjusted to about 7 with about 15 g of a 20% aqueous sodium carbonate solution. After the reaction, the pH was set to about 8, and the precipitated crystals were collected by filtration, washed with water, washed with acetone, and dried. Yield: 3.9g. Melting point over 300℃ (decomposition). The IR was consistent with that of N-2-imidazolidinylidene-p-aminobenzoic acid obtained by another method.

Example 3 Add 270 ml of 35% hydrogen peroxide to the reaction flask from step 1.
Add 200 ml of water and add 8.7 ml of ethylene thiourea while stirring.
A paste prepared by mixing g and 60 ml of water was added at 14-16°C. It took two hours.

After addition, the mixture was kept at 18°C for 1 hour and 30 minutes. Next, in order to decompose excess water peroxide in the reaction solution, a sodium sulfite aqueous solution was added at 18°C (until the iodopotash starch paper was negative). Then, 100ml of water, p-aminobenzoic acid
Add a solution of 76.7g and 44.8g of 50% caustic soda solution,
After reacting at 30-35℃ for 10 hours, soda carbonate 29.7
After adjusting the pH to 8 by adding g little by little, wash with acetone and dry.

Yield: 73.5g. Melting point over 300℃ (decomposition). IR is N-2-imidazolidinylidene-p- obtained by another method.
It was consistent with that of aminobenzoic acid.

When the filtrate was acid-precipitated to a pH of approximately 3.5, unreacted p-aminobenzoic acid was precipitated, which was filtered and washed and then dried. Collection amount
12g.

N-2-imidazolidinylidene- obtained above
58.8 g of p-amino-benzoic acid was placed in a 250 ml flask, and 96 ml of water and 33.1 g of methanesulfonic acid were added and heated to completely dissolve. Add this to 1.2g of activated carbon.
was added, filtered hot, and cooled overnight with stirring.

Thereafter, the precipitated crystals were separated by filtration, washed with a small amount of acetone, and dried. Yield: 62.4g. Melting point 244-245°C (decomposition). The IR was consistent with that of N-2-imidazolidinylidene-p-aminobenzoic acid methanesulfonate obtained by another method.

The filtrate was concentrated to obtain 7.2 g of a second crystal equivalent to the first crystal.

Claims (1)

[Claims] 1. A method for producing N-2-imidazolidinylidene-p-aminobenzoic acid, which comprises reacting ethylene thiourea trioxide and p-aminobenzoic acid.