JPS6143157A - Production of pantethine - Google Patents

Abstract

PURPOSE:To obtain a compound useful as a drug in high purity in high yield, by reacting pantothetic acid with cystamine in the presence of both carbondiimide a reaction promotor (e.g., inorganic acid or organic carboxylic acid). CONSTITUTION:Pantothenic acid or its salt is reacted with cystamine or its salt by the use of carbodiimide as a condensation agent and an inorganic acid (e.g., sulfuric acid, or hydrochloric acid) or an organic carboxylic acid (e.g., acetic acid, or saliclic acid) as a reaction promotor in a mixed solvent of pyridine and water at room temperature for 5-7hr to give the aimed compound. An amount of the reaction promoter added is 0.5-5wt% based on pantothenic acid.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to an industrially advantageous method for producing pantethine, which is useful as a pharmaceutical.

BACKGROUND OF THE INVENTION Conventionally, there are various methods for producing pantethine, but industrially, the method of condensing pantothenic acid and cystamine is the shortest and most economical method for producing pantethine.

A method using carbodiimide such as dicyclohexylcarbodiimide (hereinafter referred to as DCC) as a condensing agent is known, for example, from Japanese Patent Publication No. 41-2829, but due to the low yield of about 30%, it is not suitable for industrial use. The implementation is not always satisfactory.

Therefore, in the production method using carbodiimide as a condensing agent, methods have been proposed in which various compounds are added as reaction accelerators for the purpose of improving the yield. For example, a method in which a phosphorus-hydroxy compound such as diphenyl phosphite or diethyl phosphite, or a sulfonic acid compound such as p-toluenesulfonic acid or phenylsinosulfonic acid is used as a reaction accelerator in the presence of DCC (JP-A-56 -133257), a method using inorganic salts such as ferric chloride and aluminum chloride (JP-A-57-
93953), a method using substituted hydroxyphenols, hydroxypyrimidines, and hydroxyquinolines (Japanese Unexamined Patent Publication No. 53-25520), or a method using N-hydroxybenzotriazole, hydroxysuccinimide (Japanese Unexamined Patent Publication No. 113821-1982). Public bulletin) etc. are known.

Problems to be Solved by the Invention However, these reaction accelerators are expensive,
Alternatively, the reaction treatment may be complicated, and it may be difficult to purify the target product, so it cannot necessarily be said that it is an industrially advantageous production method.

Means for Solving the Problems In order to eliminate these drawbacks and establish an industrially advantageous method for producing pantethine, the present inventors have developed a reaction accelerator that is added to the starting materials in the presence of carbodiimide. As a result of various studies on agents, it was discovered that inorganic acids or organic carboxylic acids are specifically good accelerators.

That is, the present invention is characterized in that when condensing pantothenic acid or its salts with cystamine or its salts in the presence of carbodiimide, at least one selected from inorganic acids or organic carboxylic acids is added as a reaction accelerator. The gist is a method for producing pantethine.

Examples of inorganic acids used in the present invention include sulfuric acid,
Examples of organic carboxylic acids include hydrochloric acid, phosphoric acid, and boric acid, and examples of organic carboxylic acids include acetic acid, chloroacetic acid, glycolic acid, oxalic acid, and salicylic acid. The amount added is
Usually, it is preferable to use 0.5 to 5% by weight based on the raw material pantothenic acid salt. Note that the reaction accelerator according to the present invention and a conventional reaction accelerator can also be used in combination.

The starting materials may be commercially available materials, and those in the form of salts are particularly preferred. For example, the salt of pantothenic acid includes calcium pantothenate or sodium pantothenate, and the salt of cystamine includes cystamine hydrochloride or cystamine sulfate.

As the carbodiimide condensing agent, it is usually preferable to use CC because it is easy to produce, has excellent stability, and the by-product urea derivative can be easily separated from the target product.

As the solvent, pyridine, dimethylformamide, lower alcohol, water, etc. can be used alone or in combination, but a mixed solvent of pyridine and water is preferable.

Pantothenic acid or its salt, cystamine or its salt, and at least one of the above-mentioned inorganic acids or organic carboxylic acids as a reaction promoter are dissolved in this solvent,
Conveniently, a carbodiimide is then added to carry out the condensation.

There are no particular limitations on the reaction temperature and time, but 5 to 7 hours at room temperature is usually sufficient.

After the reaction is completed, the target product is separated from the reaction mixture according to a conventional method. For example, after the reaction is complete, the solvent is distilled off under reduced pressure,
After adding water to the residue and scraping off the precipitated insoluble matter, the furnace solution is washed several times with a solvent such as chloroform. Separation and purification can be achieved by treating this aqueous solution with an acidic ion exchange resin and a basic ion exchange resin, respectively, and concentrating it.

EXAMPLES The present invention will be explained in more detail with the following Examples, but the present invention is not limited thereto.

Example 1 11.9 g of calcium pantothenate, 5.6 g of cystamine hydrochloride and 0.15 g of sulfuric acid are added to 100y+j' of 25% hydrated pyridine and stirred at room temperature. After becoming a homogeneous solution, the solution was cooled to below 10°C, and DCC was added under stirring.
A solution of 2.4 g of I in pyridine 25me is added. After the addition, the mixture was stirred under cooling for 1 hour, then returned to room temperature and continued stirring for 5 hours.

After the reaction is completed, the mixture is concentrated under reduced pressure at a bath temperature of 50°C.

Add 15 me of water to the remaining amount, and separate the precipitated insoluble matter in a furnace.

Next, insoluble matter was washed with 25-ml water, and the washing liquid was combined with the furnace solution, and washed three times with 50-ml chloroform.The aqueous layer was passed through a column packed with 150-ml Amberlite IR-120B. , then the effluent was poured into 150 fnl of Amberlite IR.
Pass the solution through the A-410 column. The flow velocity is 5v=2 for each
Perform at ~2.5.

Each column is washed with 600 fne of water, and the washings are combined with the effluent and concentrated under reduced pressure at below 50°C. The obtained slightly yellow syrupy pantethine was placed in a desiccator.
Dry over phosphorus pentoxide under reduced pressure to obtain 11.5 g of the desired product. Yield 82.5%.

Example 2 The same procedure as in Example 1 was repeated except that 0.3 g of boric acid was used instead of sulfuric acid to obtain 11.9 g of pantethine. Yield: 85.5%.

Example 3 The same procedure as in Example 1 was repeated except that 0.4 g of hydrochloric acid was used instead of sulfuric acid to obtain 11.0 g of pantethine.

Yield 79.3%.

Example 4 The same procedure as in Example 1 was repeated except that 0.6 g of acetic acid was used instead of sulfuric acid to obtain 9.0 g of pantethine. Yield 65.1%.

Example 5 The same procedure as in Example 1 was repeated except that 0.3 g of salicylic acid was used instead of sulfuric acid to obtain 11.2 g of pantethine. Yield 80.5%.

The product thus obtained was a single spot on thin-layer chromatography, showing the same Rf value as the standard pantethine, and was identified as pure pantethine.

Effects of the Invention These reaction accelerators of the present invention are very common products and are easily available.
Sulfonic acid compounds, phosphorus-hydroxy compounds, inorganic salts, N-hydroxybenzotriazole, etc. are advantageous because they are cheaper than conventional ones, and as is clear from the above examples, sufficient effects can be achieved with the addition amount of a catalytic amount. The reaction process is easy, and the target product, pantethine, can be obtained with high purity and high yield, making it an extremely industrially advantageous manufacturing method.

Claims (1)

[Claims] A method for producing pantethine, which comprises adding at least one selected from inorganic acids or organic carboxylic acids as a reaction accelerator when condensing pantothenic acid or its salts with cystamine or its salts in the presence of carbodiimide.