JPS59108760A - Preparation of cystamine sulfate - Google Patents

Abstract

PURPOSE:To prepare the titled compound in high yield and purity, easily, without producing by-products, by oxidizing a reaction liquid containing cysteamine sulfate and derived from an aqueous solution of 2,2-dialkylthiazolidine, and crystallizing and separating the objective compound using a specific alcohol. CONSTITUTION:An aqueous solution of 2,2-dialkylthiazolidine of formula (R1 and R2 are 1-3C lower alkyl) (e.g. 2,2-dimethylthiazolidine) is hydrolyzed with sulfuric acid to obtain an aqueous solution of the reaction products containing cysteamine sulfate. The aqueous solution is oxidized with hydrogen peroxide to obtain cystamine sulfate solution, and the cystamine sulfate is crystallized and separated therefrom by the addition of a 1-4C lower aliphatic alcohol (e.g. methyl or ethyl alcohol, etc.). The amount of sulfuric acid is preferably 0.8- 1.1mol per 1mol of the compound of formula. The process is economically advantageous since it requires only a moderate amount of 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. Crystallized by-product salts (for example, chloride) are removed one by one, and peach acid is then added dropwise to the alcoholic cystamine solution to crystallize and separate the desired cystamine sulfate. However, when sulfuric acid is added to the alcoholic solution of cystamine, by-products are generated.
When cystamine sulfate is crystallized, it contains the by-product, which has the drawback of being colored and having a low purity. In addition, many steps are required, such as a dehydrochlorination step for cysteamine hydrochloride, a step for concentrating an aqueous sosteamine solution, and a step for removing by-product salts (for example, IJ chloride). Furthermore, since it is difficult to completely remove by-product salts (e.g., sodium chloride) generated by dehydrochlorination,
Contamination with products is unavoidable, and this also causes a decrease in purity.

The present inventors have overlooked the shortcomings of conventional methods, and as a result of intensive research into a method for producing high-purity cystamine nitrate,
An aqueous solution of 2,2-dialkylthiazolidine was hydrolyzed with a teracid acid to obtain an aqueous cysteamine sulfate solution, hydrogen peroxide was added thereto to obtain an aqueous cystamine sulfate solution, and then a lower fat having 1 to 4 carbon atoms was added. The present invention was completed by discovering that high-purity cystamine sulfate can be produced with 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 solution of 2,2-dialkylthiazolidine represented by the general formula (wherein R1 and R2 each independently represent a lower alkyl group having 1 to 13 carbon atoms) and adding hydration. Hydrogen peroxide is added to the reaction product aqueous solution containing cysteamine sulfate obtained by decomposition to cause an oxidation reaction to obtain a cystamine Vte salt aqueous solution, and then a lower aliphatic alcohol having 1 to 4 carbon atoms is added to crystallize cystamine sulfate. It is characterized by separation.

2.2-Dialkylthiazolidine aqueous solution i2.It consists of 2-dialkylthiazolidine and water, for example 2,2
- Can be easily prepared by dissolving dialkylthiazolidine in water. At this time, the 2,2-dialkylthiazolidine concentration is particularly limited to the ft1lJ limit (although it is inevitable that the salt concentration was
Preferably, the humidity is relatively high, giving a weight factor of 5 or more. By using such a moderate amount, the yield at the cystamine sulfate crystallization step can be improved.

2.2-Dialkylthiazolidine is a compound represented by the above general formula, and includes, for example, 2,2-dimethylthiazolidine; 2-methyl, 2-ethylthiazolidine; and 2-methyl, 2-propylthiazolidine. Since 2,2-dialkylthiazolidine can be obtained more easily and in higher yields than ethyleneimine, raw materials for the present invention are easily available (Ann, Chem, 566, 21
0. (1950)).

The reaction product aqueous solution containing cysteamine sulfate in the present invention is produced by adding sulfuric acid to the above-mentioned relatively high concentration 2,2-dialkylthiazolidine aqueous solution and generating it at a temperature in the range of 100 to 150°C for 3 to 10 hours. It was prepared by hydrolyzing the ketone while distilling it out of the system. The amount of sulfuric acid used is preferably in the range of 1.1 moles of sulfuric acid O,S per 1 mole of 2,2-dialkylthiasilicia. If the amount is less than 0.8 mol, the hydrolysis will be insufficient, resulting in a decrease in the yield and purity of the product, while if the amount is more than 1.1 mol, the product will be degraded. It is not economical because sulfuric acid remains in the solution and a purification step is required later. In addition, the reaction product aqueous solution contains cystamine sulfate as a by-product in addition to cysteamine sulfate, but this does not pose any problem in the present invention.

The cystamine sulfate aqueous solution was prepared by adding hydrogen peroxide to the reaction product aqueous solution as described above 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 until the concentration of unreacted cysteamine sulfate becomes 1 weight range or less. As hydrogen peroxide,
It is convenient to use a commercially available solution, for example, an aqueous hydrogen peroxide solution with a concentration of 35%. The cystamine sulfate concentration in the reaction product aqueous solution is preferably relatively high in the range of 35 to 50% by weight. For example, by adding an aqueous hydrogen peroxide solution having a concentration by weight of 35 to a reaction product aqueous solution of busteamine sulfate having a concentration by weight of 50 to cause an oxidation reaction, a cystamine value e salt aqueous solution having a concentration by weight of about 40 is prepared. It is preferable to use an aqueous sulfate solution because it facilitates operations in subsequent steps and allows crystallization of cystamine sulfate with high yield and purity.

Crystallization of cystamine sulfate is carried out by adding a lower aliphatic alcohol having 1 to 4 carbon atoms to a cystamine sulfate aqueous solution having a relatively high concentration as described above, for example, at a concentration of 35% or more. It is something. At this time, the temperature of the system is preferably in the range of 0 to 60°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 furnace solution, 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 300% by weight is used, the crystallized cystamine sulfate tends to become paste-like, and if it becomes pasty, it becomes difficult to separate the mixture in a furnace, which is not preferable. Examples of the alcohol include methyl alcohol, ethyl alcohol, n-
Examples include propyl alcohol, isopropyl alcohol, and butyl alcohol.

The crystallization of cystamine sulfate is carried out using a relatively highly concentrated aqueous solution of cystamine salt in the absence of by-products and excess sulfuric acid, making it possible to efficiently obtain highly purified cystamine Wc (39 salt). Moreover, it is economical because only a moderate amount of alcohol is used.

The crystallized cystamine sulfate can be easily separated from the system by separating it from house to house. The P solution 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 white, smooth, crystalline cystamine sulfate.

Since this product has a dry wave length in the range of 6 to 7 weight range under reduced pressure, it is considered that it 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 Basic sulfuric acid (
98 weight ratio) was added to neutralize.

The neutralized aqueous solution was distilled to perform hydrolysis while distilling off the generated acetone, and further concentrated to complete the hydrolysis to obtain a reaction product aqueous solution having a cysteamine sulfate concentration of 70% by weight. Water was then added to adjust the concentration to 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 about 40°C. The oxidation reaction was carried out until the concentration of unreacted cysteamine sulfate was 0.1 or less by measuring the amount of -8H groups by iodometric titration. A reaction product aqueous solution 4852 was obtained.

When the -SS- group was analyzed by the potassium bromate method and the cystamine sulfate concentration was measured, it was 43.8 weight i%, 2,2
-The yield based on dimethylthiazolidine was 99.3% by weight.

Add methyl alcohol to the cystamine sulfate aqueous solution obtained in this way until the salt concentration becomes 25% by weight,
Cystamine sulfate was crystallized while maintaining the temperature at 20°C. The mixture was then dried separately to obtain white cystamine sulfate crystals. The yield was 95%. The purity of this crystal is
It was 99.3%.

Example 2 A cystamine sulfate aqueous solution was prepared in the same manner as in Example 1 except that 2-methyl, 2-ethylthiazolidine was used instead of 2,2-dimethylthiazolidine. The yield was 98.5%.

Cystamine sulfate crystals were then obtained by following the same procedure except that isopropyl alcohol was used instead of methyl alcohol. The yield was 97%. The purity of the crystal is
I was in charge of 99.1.

Claims (1)

[Claims] 1. Adding sulfuric acid to an aqueous solution of 2,2-dialkylthiazolidine represented by the general formula (wherein R1 and R2 each independently represent a lower alkyl group having 1 to 3 carbon atoms) Hydrogen peroxide is added to the reaction product aqueous solution containing cysteamine sulfate obtained by hydrolysis to cause an oxidation reaction to form a cystamine sulfate aqueous solution, and then a lower aliphatic alcohol having 1 to 4 carbon atoms is added to crystallize cystamine sulfate. A method for producing cystamine sulfate, the method comprising: separating the cystamine sulfate; 2. The amount of sulfuric acid used is 2,2-dialkylthiazolidine 1
2. The method according to claim 1, wherein the amount is in the range of 0.8 to 1.1 moles of sonic acid per mole.