JPS59500B2 - Creatine manufacturing method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing creatine by reacting sarcosine with 0-alkylisourea.

Creatine is a type of amino acid that exists mostly as creatine phosphate in the muscle tissue of vertebrates, and plays an important role in providing energy for muscle contraction.

In muscle diseases, neuromuscular diseases, and endocrine diseases, the ability of muscles to retain creatine decreases, and a large amount of creatine is excreted in the urine. Therefore, it is an important substance for physiologists as a material for producing creatine phosphate, and is useful as a clinical reagent for muscular dystrophy and creatine metabolism disorder, and as a reagent for urine tests. In ancient times, it was used as a cardiotonic agent and a digestive tonic, and there are also reports of its use as a flavor improver for seasonings in the food industry. Recently, there has been a trend toward enzyme-related uses for culture media and other applications. Traditionally, the synthesis method for creatine is
It is known that sarcosine can be obtained by subjecting sarcosine to a guanidylation reaction with (1) S-alkylisothiourea or (2) O-alkylisourea.

H2NC(=NH)N(CH3)CH2C00H+CH
35HH2NC(=NH)N(CH3)CH2C00H
+ CH3OH 5.45y of pure creatine (83% of theory) is obtained. (In the case of odor, 4.45 f
7 sarcosine (0.05 mol) is dissolved.

If stored for two weeks without absorbing moisture, needle-like crystals will precipitate. After storing it in the refrigerator for two more days, it is separated by F, washed with alcohol, and recrystallized from water. 1.35V of creatine (20.6% of theory) is obtained.

In the case of (1) using S-alkylisothiourea,
Creatine can be obtained with a fairly good yield, but no matter how the by-product mercaptan is treated, even traces of the residue give off a strong odor, which is extremely difficult to prevent in experiments. Although the purpose is to prepare a small amount indoors, it is almost impossible to mass-produce it industrially. (2
In the guanidylation reaction using O-alkylisourea in the case of It is also extremely disadvantageous. The present invention seeks to obtain highly pure creatine in good yields, such as those obtained using S-alkylisothioureas, by guanidylation with O-alkylisourea salts in an aqueous solution of sarcosine. be.

The present invention will be explained in detail below.

In general, the isoform of urea is extremely unstable compared to thiourea, and it decomposes rapidly especially in aqueous solution.
Produces urea and alcohol.

On the other hand, the reaction rate of guanidylation is very slow and requires a considerable amount of time to complete the reaction. Therefore, in the known method, free O-alkylisourea is allowed to act on sarcosine in absolute alcohol, and the reaction is completed over a very long time, but the O-alkylisourea left in the reaction is Since only one part of the product is decomposed and the other part decomposed, only a low yield can be obtained.
The characteristics of the present invention are, firstly, that the reaction is carried out in an aqueous solution of sarcosine without using any special solvent, and secondly, that the reaction is carried out in an aqueous solution of sarcosine, and secondly, a salt of O-alkylisourea is used as a guanidylating agent to achieve as much decomposition as possible. Thirdly, the reaction rate of guanidylation is increased by always maintaining the alkalinity of PHIO to 12, and fourthly, the O-alkylisourea salt is added sequentially according to the reaction rate. Sarcosine is generally commercially available as its sodium salt as a 30-38% aqueous solution.
It can be used as is, but it may also be used after performing operations such as neutralization and dehydration.

Depending on the manufacturing method and raw materials used, 0-alkylisourea salts generally have an alkyl group such as a methyl group, ethyl group, or propyl group, and depending on the acid used, they may be in the form of salts such as hydrochloric acid, sulfuric acid, methyl sulfate, or ethyl sulfate. However, any one can be used in the same manner.

The alkali for adjusting the pH is generally sodium hydroxide or potassium hydroxide, but other alkalis may be used as long as they can adjust the pH to a predetermined value.

In the case of acidity below PHLO, the reaction rate decreases,
The reaction will take a long time, during which time the decomposition of isourea will be accelerated. On the alkaline side above PH12, the generated creatine is decomposed into urea and sarcosine again,
Both result in a decrease in yield. Sequential addition of the 0-alkylisourea salt may be done by a method in which the amount is increased at the beginning and gradually decreased toward the end, or by a method in which the 0-alkylisourea salt is added in a constant amount on average, but it is possible to add the salt over a period of about 3 to 4 hours. It is preferable to terminate.

The appropriate reaction temperature is from 5°C to room temperature.If it is lower than that, the reaction time will be longer, and if it is higher than 30°C, the yield will decrease due to hydrolysis of creatine.
℃ is not preferable because decomposition is severe.

Since the sarcosine aqueous solution is quite viscous and the 0-alkylisourea salt is also viscous, it is necessary to stir as vigorously and effectively as possible.

According to the present invention, mercaptans are not generated as in the case of the conventional method (1), and without being satisfied with a low yield as in the case of (2), high yield and high purity can be obtained. of creatine can be produced. The effect is specifically shown in the examples listed below. Note that the present invention is not limited to the following examples. Example 1 A reaction vessel equipped with a stirring device and a cooling jacket was
30 kg (100 mol) of 37% sarcosine sodium aqueous solution was charged and heated at 15 to 20°C with vigorous stirring.
Always use an alkali solution of 3 kg of caustic soda dissolved in 51 m of water to PHll. 30k9 (15
0 mol) of O-methylisourea methyl sulfate is added sequentially over about 4 hours to react.

After the addition is complete, continue stirring for an additional hour and leave overnight.
The precipitated crystals are separated, washed with 121 parts of water, then washed with 101 parts of methanol, and dried at 105°C.

10.51<g (yield 80%) of anhydrous creatine are obtained. Examples 2 to 4, Comparative Examples 1 to 4 The reaction was carried out in the same manner as in Example 1 except that the amounts of the 37% sodium sarcosine solution, caustic soda, and O-methylisourea methyl sulfate were as shown in the table below.

The yield and yield of creatine obtained are shown in the table, and it is clear that there are significant differences depending on the pH value. Note that the relationship between the PH value and the creatine yield based on the above Examples and Comparative Examples is shown in the drawing.

BRIEF DESCRIPTION OF THE DRAWINGS The drawing is a chart showing the relationship between pH value and creatine yield based on Examples of the present invention and Comparative Examples.

Claims (1)

[Claims] 1 O-alkyliso(1)CH_
3SC(=NH)NH_2+CH_3NHCH_2CO
OH(2)CH_3OC(=NH)NH_2+CH_3
As an example of the NHCH_2COOH conventional method, (1) and 2
Here are some specific data for each case. In the case of (1), 4.45 g of sarcosine (0.05 mol) is mixed with 15 cc of concentrated ammonia water (specific gravity 0.912 = 2
Add 12.0 g of S-methylisothiourea sulfate dissolved in 25 cc of concentrated aqueous ammonia. Within 1 hour, mercaptan is generated at 12° C. and crystals are precipitated. Leave overnight, filter, and wash with alcohol. A method for producing creatine, which is characterized in that creatine is recrystallized from water and then reacted by successively adding urea salts.