Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2000-08-28
2001-12-04
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
Reexamination Certificate
active
06326513
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for producing creatine or creatine-monohydrate.
BACKGROUND OF THE INVENTION
Creatine is present in vertebrate muscle tissues, which has the function of promoting muscle growth and building up health. Creatine can be used as a food additive, and formulations containing creatine have become an essential everyday food additive of sportsman in many countries of the world, especially in Europe and America. It also becomes more and more popular among sports enthusiasts. The need of creatine used as food additives in China is also increasing.
Conventionally, the preparation of creatine involves extraction from biological raw materials such as muscle scraps. However, such a method is not cost effective and the use of such a source is not very sanitary. Currently, creatine is mainly prepared by chemical synthesis, i.e. through reaction of cyanamide with N-methylglycine (sarcosine). However, N-methylglycine is a very expensive raw material, moreover, a satisfactory yield can not be achieved. Chinese Patent application CN 1140707A filed by the SKW Trestberg Corporation Ltd. discloses a process for preparing creatine or creatine-monohydrate, which is aimed to achieve a commercially acceptable yield and a higher purity. In this process, cyanamide is reacted with sodium N-methylglycinate or potassium N-methylglycinate in water or in a mixture of water and an organic solvent at a temperature of 20° C. to 150° C. and pH of 7 to 14. However, the cost by using this method is very high, furthermore, harmful impurities such as cyanide and/or ammonia may be present in the product. Briefly speaking, known method for preparation of creatine is not satisfactory.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a new process for producing creatine or creatine-monohydrate with a higher purity and at a lower cost, so as to overcome the problems of the prior art.
The present invention provides a method for preparing creatine or creatine-monohydrate, comprising the step of reacting N-methylglycine, sodium N-methylglycinate and/or potassium N-methylglycinate with S-methylisothiourea and/or S-methylisothiourea sulfate in water or in a mixture of water and an alcohol solvent under the temperature from 15° C. to 140° C. and a pH of 7-13.
Preferably, the creatine or creatine-monohydrate thus produced is purified by using an alkaline complexing agent.
In the method of the present invention, the reaction of N-methylglycine, sodium N-methylglycinate and/or potassium N-methylglycinate with S-methylisothiourea and/or S-methylisothiourea sulfate is preferably proceeded at a temperature of 30° C. to 80° C.
In the method of the present invention, the reaction is preferably carried out at a pH between 9 and 11. When sodium N-methylglycinate or potassium N-methylglycinate is used as the raw material, the pH of the reaction solution is preferably adjusted by using an inorganic acid, which is preferably sulfuric acid or hydrochloric acid. Alternatively, if N-methylglycine is used as the raw material, the pH of the reaction solution is preferably adjusted by using an inorganic alkali, which is preferably sodium hydroxide or potassium hydroxide.
The molar ratio of N-methylglycine, sodium N-methylglycinate or potassium N-methylglycinate to S-methylisothiourea is preferably 1:5 to 4:1. Alternatively, the molar ratio of N-methylglycine, sodium N-methylglycinate or potassium N-methylglycinate to S-methylisothiourea sulfate is preferably from 1:2.5 to 2:1. More preferably, the number of moles of N-methylglycine, sodium N-methylglycinate or potassium N-methylglycinate approximately equals to the number of moles of S-methylisothiourea or S-methylisothiourea sulfate, such as 1:1.25.
The sodium N-methylglycinate or potassium N-methylglycinate used in the present invention may be in an unprocessed aqueous solution with a concentration of 20-40% (w/w) and a purity of 85-92% (w/w).
In the present invention, S-methylisothiourea or S-methylisothiourea sulfate is used as raw materials, which is inexpensive and no harmful impurities such as cyanide or ammonia and the like will be produced.
The reaction of the present invention can be performed in water, or in a mixture of water and ethanol or methanol, which facilitates the control of the temperature.
Preferably, A hot vapor is fed into the reaction solution to facilitate the crystallization of the product. If this process is kept for 5-10 hours, the yield and the purity of the product could be enhanced.
Upon completion of the reaction, the product can be separated by centrifugation, extraction-filtration or the like. In order to enhance the purity of the product, the separated product may be subjected to treatment with water and 95% ethanol, such as washing with distilled water and 95% ethanol, respectively.
Addition of an alkaline complexing agent such as disodium ethylene diamine tetracetate (disodium EDTA) to the solution in the crystallization process of the product may play a very important role to enhance the purity of the product.
A conventional counter-flow drier or a contact drier can be used for drying the wet product, preferably under the condition of ≦40° C. and 20 millibar pressure in a vacuum drier. Then a creatine-monohydrate can be obtained. If the product is dehydrated at 60-80° C. under normal pressure or in vacuum, creatine can be obtained. There is substantially no loss of the product during this process.
Creatine or creatine-monohydrate with a yield of 65-80% (w/w) and a purity of 99-102% (based on analysis of high performance liquid chromatography, HPLC) can be prepared according to the present invention, even though a sodium N-methylglycinate or a potassium N-methylglycinate having a purity of only 85-92% are used as the raw material. The method of the present invention is applicable in production on an industrial scale.
The properties of the creatine or creatine-monohydrate prepared according to present invention are as follows:
(1) Physical appearance: white crystalline powder, odorless;
(2) 1% water solution: colorless, transparent;
(3) Weight loss in drying process (105° C.): 10.5-11.5%;
(4) Broiling assay performed by crucible method: ≦0.1 (creatine is used as the standard);
(5) Content of sulfate: ≦0.1% (creatine is used as the standard);
(6) Content of heavy metal: ≦10 ppm (creatine is used as the standard);
(7) Content of creatine: 99-102% (creatine is used as the standard);
(8) Particle size: 40 mesh (95%) (creatine is used as the standard).
Advantages of the process of the present invention are as follows:
1. The process for producing creatine or creatine-monohydrate according to present invention does not use cyanamide as the raw material, thus does not produce harmful by-products such as cyanide and ammonia.
2. The average yield of creatine or creatine-monohydrate in the process of the present invention is 71.15%, which is higher than that of the process disclosed in CN 11407074, which is 66.65%.
3. The purity of the creatine prepared according to present invention is 99-102%.
4. The sources of N-methylglycine, sodium N-methglglycinate, potassium N-methylglycinate, methylisothiourea and methylisothiourea sulfate used as the main raw material are rich and abundant, thus the cost for producing creatine or creatine-monohydrate is very much reduced.
REFERENCES:
patent: 1967400 (1934-07-01), Fischl
patent: 5719319 (1998-02-01), Weiss et al.
Allen et al. (1970). Reaction of amino acids with guanidinating agents. Canadian Journal of Biochemistry 48 (11), pp 1189-1190.*
Derwent abstract (Acc. No. 1966-14072F) of JP 64021232B. A-amino-w-guanidino-carboxylic acid.
An Lihua
Zhang Guoji
Zheng Yuwen
Armstrong, Westarman, Hattori, McLeland & Naughton, LLP
Chaudhry Mahreen
Killos Paul J.
Tianjin Tiancheng Pharmaceutical Co., LTD
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