JPS6287560A - Production of pantethine - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a synthetic intermediate for coenzyme A participating in energy metabolism, in high yield and purity, by condensing pantothenic acid with cystamine in the presence of a carbodiimide and a specific catalyst. CONSTITUTION:Pantothenic acid or its salt is made to react with cystamine or its salt in the presence of carbodiimide as a dehydrative condensation agent in a solvent such as pyridine adding one or more compounds selected from mineral acid (e.g. sulfuric acid, phosphoric acid, hydrochloric acid, etc.) as a reaction accelerator at room temperature for about 10hr to obtain pantethine. The reaction accelerator is effective at a small amount, i.e. <=50wt% preferably 0.1-10wt% based on pantothenic acid.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a method for producing pantethine by condensing pantothenic acid or its salts with cystamine or its salts in the presence of a dehydration condensing agent carposi-imide. By adding one or more compounds selected from mineral acids or salts thereof as a promoter, bantenane can be produced in extremely high yield and industrially with high purity. It relates to a manufacturing method.

[Prior art and its problems]

Pantethine produced according to the present invention is known as a compound useful as a precursor of coenzyme A, an important coenzyme involved in energy metabolism in vivo.

It has been known that when only carbodiimide is used as a dehydration condensation agent, the reaction is slow and the degree of completion is low. Proposed. That is, N-
Hydroquino compounds, substituted phenols, hydroquinpyridines, hydroquinoquinolines, C JP-A-52-144
(No. 518, JP-A-55-25520, JP-A-53-
No. 28119) or aromatic sulfonic acids, organic P-
Hydroxy/compounds (JP-A-56-133257) and the like.

The present inventors previously invented a method using mercaptobenzene derivatives and mercaptonaphthalene derivatives as additives (Japanese Patent Application Laid-Open No. 58-46062), which are industrially easier to obtain and easier to handle than known reaction accelerators. We succeeded in finding a reaction accelerator that is easy to use and has excellent performance.As a result of intensive research into a reaction accelerator that is industrially easy to handle, easy to handle, and excellent, we decided to add a specific reaction accelerator. As a result, we have discovered that pantethine can be produced with excellent results and have completed the present invention.

[Means to solve the problem]

That is, in the present invention, when producing pantethine by condensation reaction of pantothenic acid or its salts and cystamine or its salts in the presence of carbodiimide, mineral acids or seven The present invention provides an extremely industrially advantageous method for producing pantethine, which involves adding one or more compounds among salts.

〔composition〕

Specific examples of the reaction accelerator used in the present invention include mineral acids, such as sulfuric acid, phosphoric acid, hydrochloric acid, nitric acid,
Salts of sulfuric acid, phosphorous acid, etc. (in -, sodium of these mineral acids) and alkali metal rings such as potassium, sulfuric acid, potassium dihydrogen phosphate, etc. can be mentioned. . These compounds are industrially produced on a large scale, have the advantage of being available at very low prices, are easy to handle, and are groundbreaking in that they have excellent performance in peptide synthesis. It is. The reaction accelerator used in the present invention is effective when added in a small amount, and it is usually sufficient to use it in an amount of 50% by weight or less, preferably α1 to 101M%, based on pantothenic acid.

The solvent used in the present invention can be pyridine, dimethylformamide, dioxane, tetrahydrofuran, acetonitrile, lower alcohol, water, or a mixture thereof. Depending on the situation, it may be desirable to use a suitable mixture of two or more solvents. The reaction temperature may generally be room temperature, and the reaction time may be several hours to several tens of hours, usually about 10 hours.

It is desirable to use the raw material pantothenic acid or cystamine in its free form to facilitate the reaction, but it is preferable to use it in its salt form, for example, pantothenic acid is used in the Cal/Rum salt form, and cystamine is used in its hydrochloride or sulfide form. It's good to be loved.

As an example of the carbodiimide, the most suitable is zinclohequinlecarbodiimide, which is commonly used in peptide synthesis, etc., and the amount used may be equivalent to or slightly in excess of the raw material pantothenic acid, as in a known method.

As for the method for isolating pantethine from the reaction product obtained according to the method of the present invention, a known method may be adopted as is. That is, water is added to the reaction-completed solution to remove the precipitate, the solvent is distilled off from the solution, and the precipitated crystals are further removed by filtration. After washing with a solvent such as ethyl acetate, purification with an ion exchange resin is performed, and the treated solution is concentrated to dryness under reduced pressure to obtain highly pure pantethine.

〔effect〕

Pantethine requires extremely high quality purification. Therefore, in the actual production process, not only the reaction process but also the a-manufacturing process is an important process. It goes without saying that what determines the purification load of this purification step is the impurity components and amount of impurities in the reaction product. Here, the catalyst plays a very important role in the production of pantechi, and even a slight difference in reaction yield greatly affects the production capacity and cost.

Although conventionally known catalysts can produce pantethine, most of them have a major drawback in terms of the burden of the purification process. The catalyst of the present invention is very excellent in this respect, and can be said to be an extremely advantageous catalyst overall, including its ease of availability, ease of handling, and low cost.

The present invention will be explained below with reference to Examples.

Example 1゜Pantotene e21. qy, cystamine 7.5? , 9α502 sulfur was dissolved in 110 fK13 of hydrated pyridine, and 22.7 f K13 of lupodiimide was added to the synchro. The mixture was then stirred at room temperature for 10 hours. Next, water 2002 was added, and the precipitated synchrohexyl urea crystals were separated from each other. The pyridine in the F solution was distilled off by azeotropic distillation with water, and the precipitated crystals of synchhexyl urea, etc. were separated from house to house and mixed with 10 ethyl acetate.
Washed twice with 02. Ethyl acetate present in the aqueous layer is removed under reduced pressure and, if necessary, decolorized by treatment with activated carbon. The obtained liquid was treated with strong acidic ion exchange resin Amberlite IR-12.
Desalination was carried out through a mixed bed of 0B, H type 50-1, strongly basic ion exchange resin Amberlite IRA-410, and OH'' type 50-.

Next, the treated solution was concentrated to dryness under reduced pressure, and pantethine 251
2 (theoretical yield 8&8% from cystamine) was obtained. This product is a separately synthesized pantethine preparation and IR and TLC R.
The f values matched.

Examples 2 to 6 Instead of sulfuric acid in Example 1, 55 dihydrochloric acid 1,12
．． 60 nitric acid 1.0? , 80%! J&a4r, 6%
Sulfurous acid water a02, or Visulfuric acid water Sungsu) IJum 1
．． The results using 5 f are shown in Table 1.

Chapter 1 Table

Claims (1)

[Claims] 1. When producing pantethine by condensing pantothenic acid or its salts with cystamine or its salts in the presence of carbodiimide, mineral acids or its salts are added to the reaction system as a reaction accelerator. A method for producing pantethine, which comprises adding one or more compounds among salts. 2. The manufacturing method according to claim 1, characterized in that a reaction accelerator is added in an amount of 50% by weight or less based on pantothenic acid. 3. The manufacturing method according to claim 1, wherein the mineral acid is one or more selected from sulfuric acid, phosphoric acid, hydrochloric acid, nitric acid, sulfurous acid, and phosphorous acid. 4. The manufacturing method according to claim 1, wherein the salts of mineral acids are salts selected from alkali metals such as sodium and potassium, and alkaline earth metals such as calcium. 5. The manufacturing method according to claim 1, wherein the mineral acid salt is one or more selected from sodium hydrogen sulfate and potassium dihydrogen phosphate. 6. The manufacturing method according to claim 1, wherein the salt of pantothenic acid is an alkaline earth metal salt such as calcium. 7. The manufacturing method according to claim 1, wherein the cystamine salt is a hydrochloride or a sulfate. 8. The solvent used is pyridine, dimethylformamide, dioxane, tetrahydrofuran, acetonitrile,
The manufacturing method according to claim 1, characterized in that the alcohol is one or more of a lower alcohol and water.