JPS6256145B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing pantethine useful as a pharmaceutical. Many methods for synthesizing pantethine are already known, but industrially, pantothenic acid or its salt and cystamine or its salt are combined in the presence of a carbodiimide and substituted hydroxyphenols, hydroxypyridines, or hydroxyquinolines are catalyzed. Method of condensation as
25520, or a method using N-hydroxybenztriazole and N-hydroxysuccinimide as catalysts (Japanese Patent Application Laid-open No. 113821-1989)
(Refer to Publication No. 1) is known.

The present inventors have conducted various studies on catalysts for the condensation of pantothenic acid or its salts with cystamine or its salts in the presence of carbodiimide, and have found that certain inorganic salts act as particularly good catalysts. . That is, in the present invention, when condensing pantothenic acid or a salt thereof and cystamine or a salt thereof in the presence of a carbodiimide, pantethine is dissolved in a short time by making ferric chloride or aluminum chloride exist in the condensation reaction system. This is a method that can be obtained with high yield.

In carrying out the method of the present invention, pantothenic acid or its salts, cystamine or its salts, and ferric chloride or aluminum chloride are dissolved in a suitable solvent, and then carbodiimide is added thereto to carry out the reaction. is convenient.
The amount of ferric chloride and aluminum chloride to be added may be a catalytic amount, but it is usually 0.03 per mole of raw material.
~0.1 molar amounts are used. Pyridine as a solvent,
Although a mixed solvent such as dimethylformamide and water can be used, hydrous pyridine is preferred. When pantothenic acid or cystamine, which is a starting material, is used as a salt, it is preferable to use calcium pantothenate or sodium pantothenate, which are easily available from an industrial standpoint, and cystamine hydrochloride or cystamine sulfate. As the carbodiimide, it is usually appropriate to use inexpensive dicyclohexylcarbodiimide. A sufficient amount of carbodiimide is 0.7 to 1.5 moles per mole of the raw material. The reaction temperature is not particularly limited, but the reaction is usually carried out at room temperature. The reaction time required in the conventional method is from several hours to several days, but in the method of the present invention, about 6 hours is sufficient.

After the reaction is completed, pantethine is isolated from the reaction solution as follows. For example, after the reaction, the solvent is distilled off under reduced pressure, water is added to the residue, and after removing insoluble matter, the aqueous solution is extracted and washed with a solvent such as chloroform, and the aqueous layer is treated with an ion exchange resin or a high porous polymer. Pantethine can be isolated by treatment.

The method of the present invention can obtain pantethine with high purity and high yield in a short time, and is therefore extremely industrially effective as a method for producing pantethine.

Examples will be given and explained below.

Example 1 10.0 g of sodium pantothenate, 4.7 g of cystamine hydrochloride and 0.50 g of ferric chloride are added to 80 c.c. of 30% aqueous pyridine and the mixture is stirred at room temperature. After the solution becomes homogeneous, the reaction solution is cooled to 0-5 DEG C., and 50 c.c. of a 30% aqueous pyridine solution containing 10.2 g of dicyclohexylcarbodiimide is added dropwise thereto while stirring while cooling. After the addition is complete, the mixture is returned to room temperature and stirring is continued for 6 hours. After the reaction is completed, the reaction solution is concentrated at 40°C under reduced pressure. Add water to the residue and separate the precipitate. Next, the precipitate is washed with water, the liquid and the washing liquid are combined, and extraction and washing are performed three times with the same amount of chloroform. Apply the aqueous layer to a column of HP-20500c.c. First, pass water 2, then water/
Methanol (8:2) mixed solvent 2 is passed through to elute impurities, and finally water/methanol (2:
8) Elute pantethine through mixed solvent 2. The eluate was concentrated under reduced pressure at 40°C, and the obtained syrupy pantethine was freeze-dried to obtain 11.0 g of white solid pantethine. As a result of quantitative determination, this pantethine had a purity of 97.7%. As a result, the yield of pantethine is 93%. The pantethine obtained here gave a single spot with the same R _f as the pantethine standard in thin layer chromatography and paper chromatography.

Example 2 The same operations as in Example 1 were performed except that 0.15 g was used instead of 0.50 g of ferric chloride, and pantethine with a purity of 97.8% was finally obtained in a yield of 86%.

Example 3 All the same operations as in Example 1 were performed except that 0.50 g of ferric chloride was replaced with 0.40 g of aluminum chloride, and finally pantethine with a purity of 97.7% was obtained.
Obtained with 93%.

Example 4 Sodium pantothenate in Example 1 10.0
All the same operations were performed except that g was changed to 10.0 g of calcium pantothenate, and the final purity was 97.8%.
of pantethine was obtained in a yield of 70%.

Claims (1)

[Claims] 1. A method for producing pantethine, which comprises causing ferric chloride or aluminum chloride to be present in the condensation system when pantothenic acid or a salt thereof is condensed with cystamine or a salt thereof using a carbodiimide.