JPS5835169A - Novel synthesis of pantethine - Google Patents

Abstract

PURPOSE:To prepare pantethine which is a precursor of coenzymes, in high purity, without lowering the yield, suppressing the amount of the organic solvent to the minimal level, by using a surface active agent in the condensation of pantothenic acid with cystamine in pyridine in the presence of carbodiimide. CONSTITUTION:In the condensation of pantothenic acid or its salt with cystamine or its salt in a hydrous pyridine using carbodiimide, a surface active agent (a polyoxyethylene sorbitan fatty acid such as Tween 80 or a quaternary amine such as cetylpyridinium chloride) is added to the reaction system. By this process, pantethine can be prepared without using a hydrous solvent having low water-content. preferably, pantothenic acid salt and a cystamine salt are dissolved in water, 1pt.wt. of a surface active agent is added to the solution based on 7pts.wt. of water and suspended by stirring at room temperature, and a pyridine solution of carbodiidmide is added to the suspension under cooling (the amount of pyridine is 2pts.wt. per 7pts.wt. of water).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing pantethine, which is a precursor of coenzyme OoA useful for living organisms.

Conventionally, a method for producing pantethine by condensing nonantothenic acid and cystamine is a method of condensation using substituted hydroxyphenols, hydroxypyridines, and hydroxyquinolines as catalysts in the presence of carbodiimide (41 1987-25520). ), or N-human cII? Method using dibenztriazole and N-hydroxysuccinimide as catalysts
113821) is known.

The present inventors previously invented a method of adding inorganic salts such as ferric chloride as a catalyst when condensing pantethine with carboxyty, and succeeded in obtaining pantethine quickly and in high yield. did. This method of the invention can be said to be a considerably superior method for producing pantethine compared to conventional methods, since highly purified pantethine can be obtained quickly and in high yield. However, in order to achieve a high yield during the reaction, pyridine with a water content of 501,111 [0] is required as a solvent, which is disadvantageous in terms of solvent treatment when considering its harmful effects and toxicity when industrialized. be. The inventors of the present invention have kept this point in mind and have conducted various studies, resulting in the creation of ``Twe@
n) For polyoxyethylene sorbitan fatty acid esters such as 80ol, quaternary amine surfactants such as cetylpyridium chloride may be added to the reaction system), raw materials and carboxylic acid esters. By maintaining good contact conditions with II, we succeeded in significantly reducing the content of organic solvent in the reaction solvent without causing any decrease in yield. This allows the condensation of pantethine with carbodiimide to be carried out without using a water-containing solvent with a low water content, which is a disadvantage.

Conventionally, when condensing both raw material compounds of pantothenic acid and cystamine using carbodiimide, 30
It is known that high-temperature water-containing solvents, especially 50-hydrous pyridine, give good yields9, but even if the water content of the solvent is much hotter or lower than this, it causes an extreme decrease in yield (especially (Refer to Kaisho 5S-28118).

The present inventors have discovered that by using a surfactant, the content of pyridine, which is undesirable for industrial use, can be reduced without sacrificing the condensation yield of pantethine. That is, to a salt of pantothenic acid and a salt of cystamine dissolved in water, a polyoxyethylesin rubitan fatty acid ester-based or quaternary amine-based surfactant is added in a weight ratio of 1 to 7 parts of water. This mixture was stirred and suspended at room temperature, and then a pyridine solution of carbodiimide was added to this suspension while cooling. From then on, the same procedure as before was carried out to obtain pantethine in a yield of 76 to 84 mm. Obtained. Under these conditions, the amount of pyridine used is sufficient at 20 parts by weight to 7 parts water, and the proportion of pyridine in the solvent gold body is significantly reduced compared to the conventional method. Since the surfactant can be easily removed from the reaction system by extracting the reaction solution with a chloroform-based solvent or by applying it to an ion exchange resin, there is no problem in post-treatment after the reaction. Refined. <Ntetin has a high purity comparable to that obtained by conventional synthesis methods. From an industrial standpoint, it is extremely practical to add a surfactant during the condensation of carbodiimide with pantechi.

The surfactant used in the reaction may be any surfactant based on polyoxyethylene norbitane fatty acid ester or quaternary amine.
) 8 G[F]'' and in the latter cetylpyridium chloride gives good yields. The S charge is applied to 1 of the reaction solvent.
Approximately 0 bites is sufficient and To9, and even if more than that is added, there is no change in yield. The reaction time takes about two days at room temperature, but when the reaction temperature is set to 40°C, the reaction progresses slightly faster than at room temperature. In the case of the synthesis method of the present invention, as in the case of the conventional method, the reaction is most rapid when an inorganic salt is used as a catalyst, and it takes some time when an organic catalyst is used.

After the reaction is completed, pantethine is isolated from the reaction solution by a conventional method. For example, after one reaction, the solvent is distilled off under reduced pressure, and la? lE
Pantethine can be isolated from K by adding K water and removing insoluble materials, extracting and washing the aqueous solution with a solvent such as chloroform, and treating the aqueous layer with an ion exchange resin.

Thus, the method of the present invention, which can obtain pantethine in high purity and high yield while suppressing the amount of organic solvent such as pyridine to the minimum WrLK, is an extremely industrially effective method for producing pantethine.

Examples will be given and explained below.

Example 1 Sodium pantothenate 1.0 N, cystamine hydrochloride 147 N and 2-mercaptobenzimidazole a
Add 06F to water 14- and stir at room temperature. After adding Tween 80 and stirring to suspend the suspension, the suspension was cooled to 0 to 5°C, and 1.04 # of pyridine was added to the dicyclocarboxylate while stirring while cooling. Add 4 mg of the solution dropwise. After the addition is complete, the mixture is returned to room temperature and stirring is continued for 60 hours. The generated precipitate is separated by V, and then washed with water-containing pyridine. Solution F and washing solution are combined and concentrated under reduced pressure at 40°C. After adding 50% of water and 50% of Oaform to the remaining solution and dissolving it, the chloroform layer is removed. The aqueous layer was further extracted twice with chloroform (30% each), and the aqueous layer was passed through an ion exchange resin "Dowex 1 x 8 J (oaW) 40 cc" and then "Amberlite 200 J (Ha) A Occ". The eluate was combined. It was concentrated under reduced pressure at 40°C to obtain syrupy pantethine 1.2 S I. By densitometry, a purity value of 76 ml was obtained for this water-containing 1.2 SI. The obtained pantethine gave a Jl-spot of the same -Rf as that of the pantethine standard sample in thin T-chromatography and E-per chromatography.

Example 2 Sodium pantothenate 1. Oj, cystamine hydrochloride α471 and 2-mercapto are unduidazole a
Add 06jl to water 14-. Cetylpyridium chloride 2. (1.2 S
I got it. According to the densitometry method, the purity of this water-containing pantethine is 76°, so the yield of pantethine is 81°. The pantethine obtained here gave a single spot with the same -Rf as the pantethine standard in thin layer chromatography and Baper chromatography.

Example 3 Sodium pantothenate 1. ON, cystamine hydrochloride 047g and 2-mercaptobenzimidazole 0
．． Add 06j' to water 14- and stir at room temperature. Cetylpyridium chloride 2. After adding OI and stirring to suspend, a solution of 1.04 # of dicyclohexylcarbodiimide in pyridine (4) is added dropwise to this suspension while cooling to 0 to 5°C. After the dropwise addition was completed, the reaction solution was heated to 40°C and
Continue stirring for 8 hours. The same operation as in Example 1 was carried out to obtain 1.25jlt''N of syrupy pantethine.

The purity of this pantethine is 77-, hence the yield! X
'S-.

Example 4 Sodium pantothenate toII, cistane hydrochloride α
4711 and ferric chloride α05I are added to water 14- and stirred at room temperature. After adding 2.0-Tween 60, the same operation as in Example 3 was carried out to obtain syrupy pantethine 1.22I after 56 hours of reaction. The purity was 76 g, so the yield was 80.

Example 5 Sodium pantothenate 1.0,9, cystamine hydrochloride α47II and ferric chloride α05& are added to water 14- and stirred at room temperature. Dodecyltrimethylammonium chloride 2.0J! After adding I, the same operation as in Example 3 is carried out. 1.1 syrupy pantethine after 56 hours of reaction
I got 7jl. The purity was 75% and the yield was 7411%.

Example 6 Sodium pantothenate 1αaII, cystamine hydrochloride 4.7 jl and ferric chloride α21 are added to 100% of water and stirred at room temperature. Next, 15-Tween 80 was added and stirred and suspended, and the suspension was cooled to 0 to 5°C.
A solution of fLK dicyclohexylcarboxylic acid 1α211 in pyridine is added dropwise with stirring under cooling. After the completion of the addition, the mixture is heated to 40° C. and stirring is continued for 56 hours. The formed precipitate is separated by sieve and then washed with aqueous pyridine. Combine P solution and washing solution and add 40
Concentrate under reduced pressure at °C. After adding water S00- and chloroform 500- to the residue and dissolving it, the chloroform layer was removed. The aqueous layer was further extracted twice with 300% of chloroform,
The aqueous layer was washed with HP-200@500 (IC[2>Th).

1 water st, then water/methanol (8:2) mixed solvent 1
．． 5t to elute and remove residual raw materials and by-products. Maximum 41kK water/methanol (2:8) mixed solvent 1.5
Pantethine is eluted through A. *Combine the liquid and heat to 40℃
' Concentrate under reduced pressure to form a syrup of pantethine 12.69
Got nine. A purity value of 77- was obtained for this hydrated pantethine by densitometry. As a result, the yield of pantethine was 84-.

Furthermore, the pantethine obtained here gave a single spot with the same -Rf as the pantethine sample in thin layer chromatography and per-per-chromatography.

Patent author: Nisshin Seifun Co., Ltd. Same as Nisshin Chemical Co., Ltd.

Claims (1)

[Claims] A method for producing pantethine, which comprises condensing nozontothenic acid 1 or a salt thereof with cystamine or a salt thereof in aqueous pyridine using a carbodiimide, and allowing a surfactant to be present in the condensation system.