JPS59108761A - Preparation of cystamine sulfate - Google Patents

Abstract

PURPOSE:To crystallize and separate the titled compound in high yield and purity, easily, in high efficiency, without producing by-products, by adding hydrogen peroxide to an aqueous solution of cysteamine, adding sulfuric acid to the mixture to obtain an aqueous solution of cystamine sulfate, and adding a specific alcohol thereto. CONSTITUTION:An aqueous solution of cysteamine (having a cysteamine concentration of 20-70wt%, preferably 30-60wt%) is oxidized with hydrogen peroxide. The obtained cystamine solution is added with sulfuric acid to obtain an aqueous solution of cystamine sulfate. Cystamine sulfate is crystallized and separated from the solution by adding a 1-4C lower aliphatic alcohol (e.g. methyl, ethyl or n-propyl alcohol) to the solution preferably in an amount to give a cystamine sulfate concentration of 20-30wt% after the addition of said alcohol. The process is economically advantageous e.g. because it requires only a moderate amount of the alcohol.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for efficiently producing high purity cystamine sulfate.

As a method for producing cystamine sulfate, for example, JP-A-55
There is a method described in the specification of No.-127360. This conventionally known method involves neutralizing an aqueous solution of cysteamine hydrochloride with an alkali (e.g., sodium hydroxide), adding hydrogen peroxide to oxidize it to obtain an aqueous cystamine solution, concentrating it, and then dissolving it in a lower aliphatic alcohol. The resulting by-product salts (eg, sodium chloride) are removed one by one, and then abrasive acid is added dropwise to the alcoholic solution of cystamine to crystallize and separate the desired cystamine sulfate. However, when mercenic acid is added to the alcoholic solution of cystamine, by-products are generated, and when cystamine sulfate is crystallized, it contains the by-products, resulting in color and low purity. .

In addition, many steps are required, such as a dehydrochlorination step for cysteamine hydrochloride, a step for concentrating an aqueous cysteamine solution, and a step for removing by-product salts (eg, sodium chloride). Furthermore, since it is difficult to completely remove by-product salts (e.g., sodium chloride) produced by dehydrochloric acid, their contamination with the product is unavoidable, which also causes a decrease in purity. ing.

The present inventors have conducted extensive research on a method to overcome the drawbacks of conventional methods and produce high-purity nstamin sulfate. As a result, a relatively high concentration cysteamine aqueous solution was oxidized with hydrogen peroxide to obtain a cystamine aqueous solution, sulfuric acid was added to it to obtain a cystamine aqueous solution, and then a lower aliphatic alcohol having 1 to 4 carbon atoms was added. The present invention was completed based on the discovery that high-purity cystamine sulfate can be produced in high yield and in a simple process by crystallizing and separating cystamine sulfate.

The production method of the present invention involves adding sulfuric acid to an aqueous cysteamine solution obtained by adding hydrogen peroxide to an aqueous cysteamine solution and causing an oxidation reaction to obtain an aqueous solution of stamine sulfate. is added to crystallize and separate cystamine sulfate.

The cysteamine aqueous solution consists of cysteamine and water, and can be easily prepared, for example, by mixing cysteamine and water. At this time, there is no particular restriction regarding the cysteamine concentration, but for example, 20 to 70% by weight,
Preferably, it can be in the range of 30-60% by weight. At relatively high concentrations, the cysteamine aqueous solution becomes a slurry, but the cysteamine aqueous solution in a slurry state can be used effectively. By increasing the concentration, the yield at the cystamine sulfate crystallization step can be increased.

Regarding the history of cysteamine (there are no restrictions), there are various methods, such as the method described in JP-A-55-111459, ``using a monohydric lower alcohol as a solvent and reducing the pressure of the reaction system to 1.5 to 9/9. Hold above α2G, -10 to +40
The reaction is carried out within the temperature IW range of ℃ while maintaining the ratio of 1.5 moles or more of hydrogen sulfide to 1 mole of ethyleneimine.
Method, JP-A-55-11506, JP-A-53-33
7-steamine prepared according to the method described in No. 65 can be effectively used.

The cystamine aqueous solution was prepared by adding hydrogen peroxide to the cysteamine aqueous solution and causing an oxidation reaction at a temperature in the range of 0 to 60°C. At this time, it is preferable to carry out the oxidation reaction in such a manner that the concentration of unreacted cysteamine is one weight molecule or less. A relatively highly concentrated cysteamine aqueous solution in a slurry state becomes a homogeneous aqueous solution as the oxidation reaction progresses. There are no particular restrictions on hydrogen peroxide, and it is convenient to use commercially available hydrogen peroxide, for example, an aqueous hydrogen peroxide solution with a concentration of 35% by weight. For example, if an aqueous cystamine solution having a concentration of about 35 Ji is prepared by adding an aqueous hydrogen peroxide solution having a concentration of 35 by weight to a cysteamine aqueous solution in a slurry state having a concentration of 50 by weight, and causing an oxidation reaction, an aqueous cystamine solution having a concentration of about 35 Ji is used. This method is suitable because cystamine sulfate can be crystallized with high yield and purity while facilitating operations in subsequent steps.

The cystamine sulfate aqueous solution is prepared by adding sulfuric acid to a relatively highly concentrated cystamine aqueous solution as described above, that is, by neutralizing cystamine with sulfuric acid in an aqueous medium. At this time, it is preferable to set the neutralization temperature to 50°C or less. As described above, since the neutralization reaction is carried out in an aqueous medium, almost no by-products are produced, even though a relatively high concentration cystamine aqueous solution is used.

Crystallization of cystamine sulfate is carried out by adding a lower aliphatic alcohol having 1 to 4 carbon atoms to a relatively high concentration cystamine sulfate aqueous solution as described above, for example, to a cystamine sulfate aqueous solution having a concentration of 35 weight coefficient or more. It is something.

At this time, the temperature of the system is preferably in the range of 0 to 6.0°C. The amount of alcohol used is preferably such that the concentration of cystamine sulfate after addition of the alcohol is in the range of 20 to 30% by weight. If a large amount of the alcohol is used, such as less than 20% by weight, a large amount of cystamine sulfate will migrate into the lachrymal fluid, which is not preferable. Furthermore, the production volume is undesirably small compared to the volume of the system. On the other hand, if a small amount of the alcohol exceeding 30% by weight is used, the crystallized cystamine sulfate tends to become paste-like, and if it becomes paste-like, it becomes difficult to separate the reactor, which is not preferable. Examples of the alcohol include alcohol, ethyl alcohol,
Examples include n-flovir alcohol, inflovir alcohol, butyl alcohol, and the like.

Since the crystallization of cyscumine sulfate is carried out using an aqueous solution of ciscumine sulfate with a relatively high concentration and under conditions free of by-products and excess sulfuric acid, highly purified cystamine sulfate can be obtained efficiently. Moreover, since only a suitable amount of alcohol is used, it is economical.

The crystallized cystamine sulfate can be easily separated from the system by furnace separation. The furnace liquid can be effectively reused as alcohol in the next crystallization operation. After separation, it is dried under reduced pressure at a temperature of about 70°C to obtain cystamine sulfate in the form of white, smooth crystals.

Since the loss on drying under reduced pressure is in the range of 6 to 7 weight percent, this product is probably cystamine sulfate monohydrate. However, the present invention is not limited only to such crystal forms.

Hereinafter, the present invention will be explained in more detail with reference to Examples.

Example 1 Cysteamine 170? and water] and 70 r were mixed to obtain an aqueous cystyamine slurry solution having a concentration of 50% by weight.

An aqueous hydrogen peroxide solution having a concentration of 35% by weight was added to this aqueous solution, and an oxidation reaction was carried out while maintaining the temperature at 35° C. or lower. The oxidation reaction was carried out until the concentration of unreacted cysteamine was 0.1% by weight or less, by measuring the amount of -SH groups by iodometric titration. Cystamine aqueous solution 4642 was obtained. The cystamine concentration was measured by analyzing the -8s- group by the potassium bromate method and found to be 35.9% by weight, and the yield was 99.3%.

Concentrated sulfuric acid 932 (1.1 mol of sulfuric acid/1 mol of cystamine) was added to cystamine aqueous solution 3762 while stirring and keeping the temperature below 50° C. to obtain an aqueous cystamine sulfate solution.

The cystamine sulfate aqueous solution thus obtained was mixed with methyl alcohol 42o? was added and the system was cooled to a temperature of 24°C to crystallize cystamine sulfate.

The mixture was separated and dried under reduced pressure at a temperature of 70°C to obtain white cystamine sulfate crystals. The yield was 94.4%. The purity was 99.6.

Example 2 Cysteamine 1709 and water 35o? were mixed to obtain an aqueous cysteamine solution. A 35M concentrated hydrogen peroxide aqueous solution was added to this aqueous solution, and an oxidation reaction was carried out while maintaining the temperature at 35° C. or lower. The oxidation reaction was continued until the concentration of unreacted cysteamine was 0.1% by weight or less. 639 pieces of 7stamine aqueous solution having a weight temperature of 26.0 kg were obtained. The yield is 9
It was the 9th cycle. To this aqueous solution was added concentrated sulfuric acid (0.95 mol of sulfuric acid/1 mol of cystamine) to obtain an aqueous solution of cystamine sulfate while stirring and keeping the temperature below 50'C.

Inflovir alcohol 500? was added and the system was cooled to a temperature of 15°C to crystallize cystamine sulfate. Door to door, 70℃
The mixture was dried under reduced pressure at a temperature of 100 to obtain white cystamine sulfate crystals. The yield was 89.3%. Purity is 99.2%
Met.

Comparative Example 1 Cystamine aqueous solution was concentrated under reduced pressure at a temperature of 60'C,
An aqueous cystamine solution having a concentration of 85% by weight was obtained.

To this was added 4 times the amount of Improvil alcohol.

Next, sulfuric acid was added dropwise in an equimolar amount to cystamine while stirring and maintaining the temperature at 40° C. or lower. At the same time as the sulfuric acid was added, cystamine salt crystallized and the system became cloudy. going door to door,
It was dried under reduced pressure at a temperature of 70°C to obtain yellow cystamine sulfate crystals. The yield was low at 60 cycles, and the purity was also low at 78 cycles.

Claims (1)

[Scope of Claims] 1. Hydrogen peroxide is added to an aqueous cysteamine solution to cause an acidification reaction, and a polishing acid is added to an aqueous cystamine solution to obtain an aqueous cystamine sulfate solution. A method for producing cystamine sulfate, which comprises adding a group alcohol to crystallize and separate an aqueous cystamine salt. 2. The cysteamine aqueous solution has a cysteamine concentration of 20 to 7.
The manufacturing method according to claim 1, wherein the weight range is 0.