Preparation method of creatine ethyl ester hydrochloride

Abstract

The invention provides a preparation method of creatine ethyl ester hydrochloride, and belongs to the technical field of organic synthesis. The method comprises the following steps: dissolving creatine in absolute ethyl alcohol, adding hydrochloric acid to adjust the pH value to 2.5-3.5, then adding a copper-based complex catalyst at 60-80 DEG C, reacting for 0.5-2 hours, and after the reaction is completed, performing post-treatment to obtain a product. The copper-based complex catalyst is obtained by reacting CuSO4. 5H2O with 2, 2 '-dipyridyl in absolute ethyl alcohol to prepare a precursor, loading the precursor on a silicon dioxide carrier with a high specific surface area, and carrying out functionalization treatment through 3-aminopropyltriethoxysilane. The structure of the catalyst is optimized, the selectivity and purity of the product are remarkably improved, and high-purity and high-yield creatine ethyl ester hydrochloride is prepared. In addition, the catalyst is easy to recover and reuse, the production cost is reduced, and the method is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing creatine ethyl ester hydrochloride. Background Art

[0002] Creatine is an important physiologically active substance that is widely present in vertebrates. It is synthesized in the body by methylation of three amino acids: glycine, arginine, and methionine, and is mainly formed in the liver, kidney, and pancreas. Creatine exists in cells mainly as creatine phosphate, a temporary storage form of energy that can be quickly converted into ATP when needed to provide energy for muscle contraction and other cell activities. Therefore, creatine shows great potential in improving athletic performance, promoting muscle growth, and improving nerve function.

[0003] In recent years, as the research on creatine and its derivatives continues to deepen, people have found that creatine ethyl ester hydrochloride has significant advantages in human absorption. Compared with traditional creatine powder, creatine ethyl ester hydrochloride has higher bioavailability and can more effectively increase the concentration of creatine in the blood, thereby achieving the effect of enhancing physical strength. In addition, creatine ethyl ester hydrochloride can also reduce the occurrence of gastrointestinal discomfort, which is a great advantage for people who take creatine supplements for a long time.

[0004] At present, there are many kinds of creatine products sold on the market, from the initial creatine monohydrate to the later creatine HCl, creatine citrate, creatine malate, etc., each creatine supplement has its own characteristics. However, among the many creatine derivatives, creatine ethyl ester hydrochloride has excellent absorption efficiency due to its unique structure. However, for the synthesis method of creatine ethyl ester hydrochloride, there is currently a lack of an efficient, environmentally friendly and industrially suitable process route.

[0005] There are two main ways to prepare creatine ethyl ester hydrochloride: one is to react creatine with ethanol under certain conditions to generate creatine ethyl ester by direct esterification, and then obtain the target product by hydrochloric acid treatment; the second is the indirect conversion method, which first converts creatine into other forms of creatine ester compounds, such as creatine methyl ester or creatine isopropyl ester, and then further converts it into creatine ethyl ester hydrochloride. Although both methods can prepare creatine ethyl ester hydrochloride, there are many defects in the actual operation process. For example, the direct esterification method often requires higher temperature and longer reaction time, which not only increases energy consumption, but also may lead to the generation of by-products; and the indirect conversion method has more intermediate steps, resulting in a low overall yield and increased process complexity.

[0006] In view of the above-mentioned deficiencies in the prior art, there is an urgent need to develop a new method for preparing creatine ethyl ester hydrochloride, which should be able to overcome the problems existing in the prior art and achieve high-efficiency, environmentally friendly and low-cost large-scale production. Summary of the invention

[0007] The invention aims to provide a method for preparing creatine ethyl ester hydrochloride, which has the advantages of mild reaction conditions, high yield, few by-products, easy industrial production and the like.

[0008] In order to achieve the above object, the present invention provides the following technical solutions:

[0009] A method for preparing creatine ethyl ester hydrochloride comprises the following steps:

[0010] (1) Dissolve creatine in anhydrous ethanol, add hydrochloric acid to adjust the pH value to 2.5-3.5, and obtain solution 1;

[0011] (2) adding a copper-based complex catalyst to solution 1 and reacting at 60 to 80° C. for 0.5 to 2 hours;

[0012] (3) After the reaction is completed, cool to room temperature, add activated carbon for decolorization, and filter to obtain a filtrate;

[0013] (4) The filtrate is concentrated under reduced pressure, and the concentrated solution is cooled to promote the crystallization of creatine ethyl hydrochloride. The crystals are filtered and dried to obtain creatine ethyl hydrochloride.

[0014] Furthermore, the mass volume ratio of creatine to anhydrous ethanol in step (1) is 1 g:8-15 mL.

[0015] Furthermore, the mass of the copper-based complex catalyst in step (2) is 0.1 to 0.5% of creatine.

[0016] Furthermore, in step (4), the concentrated solution is cooled to 0-6°C for crystallization.

[0017] Furthermore, the preparation method of the copper-based complex catalyst is as follows:

[0018] (I) dissolving CuSO4·5H2O in deionized water, dissolving 2,2'-bipyridine in anhydrous ethanol, mixing the two solutions, stirring for reaction, filtering to obtain a blue precipitate, washing with deionized water, and drying to obtain a copper-based complex precursor;

[0019] (II) dissolving a copper-based complex precursor in anhydrous ethanol to obtain a copper-based complex precursor solution, adding a silica carrier to the copper-based complex precursor solution to ensure that the carrier is completely immersed in the solution, drying the mixture at 60 to 70° C. to load the copper-based complex on the silica carrier, and calcining the loaded material at 150 to 200° C. for 2 to 3 hours to obtain a loaded copper-based complex;

[0020] (III) dissolving 3-aminopropyltriethoxysilane in an ethanol aqueous solution with a mass fraction of 90-95%, then adding the supported copper-based complex, stirring for reaction, filtering, washing with ethanol, and drying to obtain a copper-based complex catalyst.

[0021] Furthermore, the molar ratio of the CuSO4·5H2O, 2,2'-bipyridine and 3-aminopropyltriethoxysilane is 1:1-2:1-2.

[0022] Furthermore, in step (I), the mass volume ratio of CuSO4·5H2O to deionized water is 1 g: 20-30 mL, and the mass volume ratio of 2,2'-bipyridine to anhydrous ethanol is 1 g: 40-60 mL.

[0023] Furthermore, the stirring reaction time in step (I) is 2 to 4 hours.

[0024] Furthermore, in step (II), the mass volume ratio of the copper-based complex precursor to anhydrous ethanol is 1 g: 20-30 mL.

[0025] Furthermore, the silica carrier in step (II) has a specific surface area of ​​200 to 500 m 2 / g of silica, the silica carrier is calcined at 400-600°C for 1-2 hours before use.

[0026] Furthermore, in step (II), the mass volume ratio of the silica carrier to the copper-based complex precursor solution is 1 g:40-60 mL.

[0027] Furthermore, the drying time in step (II) is 12 to 20 hours.

[0028] Furthermore, the mass volume ratio of 3-aminopropyltriethoxysilane to ethanol aqueous solution in step (III) is 1 g:15-25 mL.

[0029] Furthermore, the stirring reaction time in step (III) is 3.5 to 5 hours.

[0030] The core structure of the copper-based complex catalyst prepared by the present invention is a complex formed by copper ions and 2,2'-bipyridine, and 2,2'-bipyridine is used as a bidentate ligand to form a stable five-membered ring structure with copper ions through two nitrogen atoms. The formed copper-based complex is loaded on a silica carrier with a high specific surface area, and the silica carrier can provide more active sites, so that the copper-based complex forms more active centers on the carrier surface, thereby improving the catalytic efficiency. The hydroxyl groups on the carrier surface can form a stable coordination bond with the copper-based complex, optimize the coordination environment of the copper ions, and further improve the catalytic activity. In addition, the copper-based complex loaded on silica has good stability and can be used multiple times without deactivation, thereby reducing production costs. The loaded copper-based complex is further improved by functionalization treatment with 3-aminopropyltriethoxysilane. The 3-aminopropyltriethoxysilane undergoes a hydrolysis reaction to generate a silanol group, and the silanol group can undergo a condensation reaction with the hydroxyl groups on the carrier surface to form a Si iOS i bond. The amino group in the 3-aminopropyltriethoxysilane molecule can form a coordination bond with the copper ion, thereby further enhancing the binding force of the metal ion on the carrier surface. The amino group in the 3-aminopropyltriethoxysilane molecule can guide the reactant molecules to interact with the metal ions in a specific way, thereby improving the selectivity of the product; in addition, the 3-aminopropyltriethoxysilane molecule can provide a certain spatial confinement on the carrier surface, which can further improve the selectivity of the product, thereby reducing the generation of by-products and increasing the yield of the target product.

[0031] Compared with the prior art, the advantages and beneficial effects of the present invention are:

[0032] The present invention optimizes the structure of a catalyst for preparing creatine ethyl hydrochloride, and by loading a copper-based complex on a silicon dioxide carrier with a high specific surface area and performing a 3-aminopropyltriethoxysilane functionalization treatment, the prepared catalyst significantly improves the selectivity of the target product when catalyzing the reaction of creatine and ethanol, thereby obtaining creatine ethyl hydrochloride with high purity and high yield. In addition, the catalyst of the present invention is easy to recover and reuse, thereby reducing production costs. DETAILED DESCRIPTION

[0033] The technical scheme in the embodiment of the present invention will be clearly and completely described below. Obviously, the described embodiment is only a part of the embodiment of the present invention, rather than all the embodiments. Based on the embodiment in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work are within the scope of protection of the present invention. In addition, it is worth noting that the raw materials involved in the present invention are all common commercial products unless otherwise specified.

[0034] The following sources of raw materials are provided for illustrative purposes:

[0035] Silicon dioxide was purchased from Shanghai McLean Biochemical Technology Co., Ltd., product brand: MC-SiO2-400, specific surface area 400m 2 / g;

[0036] 3-Aminopropyltriethoxysilane was purchased from Shanghai McLean Biochemical Technology Co., Ltd., product brand: MC-APTES.

[0037] Example 1

[0038] This embodiment provides a method for preparing a copper-based complex catalyst, comprising the following steps:

[0039] (I) dissolving CuSO4·5H2O in deionized water, dissolving 2,2'-bipyridine in anhydrous ethanol, mixing the two solutions, stirring for reaction, filtering to obtain a blue precipitate, washing with deionized water, and drying to obtain a copper-based complex precursor;

[0040] The mass volume ratio of CuSO4·5H2O to deionized water was 1g:25mL, the mass volume ratio of 2,2'-bipyridine to anhydrous ethanol was 1g:50mL, and the stirring reaction time was 3 hours;

[0041] (II) dissolving a copper-based complex precursor in anhydrous ethanol to obtain a copper-based complex precursor solution, adding a silica carrier to the copper-based complex precursor solution to ensure that the carrier is completely immersed in the solution, drying the mixture at 60 to 70° C. to load the copper-based complex on the silica carrier, and calcining the loaded material at 150 to 200° C. for 2 to 3 hours to obtain a loaded copper-based complex;

[0042] The mass volume ratio of the copper-based complex precursor to anhydrous ethanol is 1 g:25 mL; the silica carrier has a specific surface area of ​​400 m 2 / g of silica, the silica carrier was calcined at 500°C for 2 hours before use; the mass volume ratio of the silica carrier to the copper-based complex precursor solution was 1g:50mL; the drying time was 18 hours;

[0043] (III) dissolving 3-aminopropyltriethoxysilane in an ethanol aqueous solution with a mass fraction of 90-95%, then adding the supported copper-based complex, stirring for reaction, filtering, washing with ethanol, and drying to obtain a copper-based complex catalyst;

[0044] The mass volume ratio of 3-aminopropyltriethoxysilane to the ethanol aqueous solution was 1 g:20 mL, and the stirring reaction time was 4 hours.

[0045] Example 2

[0046] This embodiment provides a method for preparing creatine ethyl ester hydrochloride, comprising the following steps:

[0047] (1) Dissolve creatine in anhydrous ethanol at a mass volume ratio of 1 g:10 mL, add hydrochloric acid to adjust the pH value to 3, and obtain solution 1;

[0048] (2) adding the copper-based complex catalyst prepared in Example 1 to solution 1, wherein the mass of the copper-based complex catalyst is 0.3% of creatine, and reacting at 70° C. for 1 hour;

[0049] (3) After the reaction is completed, cool to room temperature, add activated carbon for decolorization, and filter to obtain a filtrate;

[0050] (4) The filtrate was concentrated under reduced pressure, and the concentrate was cooled to 4° C. to promote the crystallization of creatine ethyl hydrochloride. The crystals were filtered and dried to obtain creatine ethyl hydrochloride with a purity of 99.6% and a yield of 94.7%.

[0051] Example 3

[0052] This embodiment provides a method for preparing creatine ethyl ester hydrochloride, comprising the following steps:

[0053] (1) Dissolve creatine in anhydrous ethanol at a mass volume ratio of 1 g:10 mL, add hydrochloric acid to adjust the pH value to 3, and obtain solution 1;

[0054] (2) adding the copper-based complex catalyst prepared in Example 1 to solution 1, wherein the mass of the copper-based complex catalyst is 0.5% of creatine, and reacting at 70° C. for 0.5 hour;

[0055] (3) After the reaction is completed, cool to room temperature, add activated carbon for decolorization, and filter to obtain a filtrate;

[0056] (4) The filtrate was concentrated under reduced pressure, and the concentrate was cooled to 4° C. to promote the crystallization of creatine ethyl hydrochloride. The crystals were filtered and dried to obtain creatine ethyl hydrochloride with a purity of 99.5% and a yield of 90.1%.

[0057] Example 4

[0058] This embodiment provides a method for preparing creatine ethyl ester hydrochloride, comprising the following steps:

[0059] (1) Dissolve creatine in anhydrous ethanol at a mass volume ratio of 1 g:14 mL, add hydrochloric acid to adjust the pH value to 3, and obtain solution 1;

[0060] (2) adding the copper-based complex catalyst prepared in Example 1 to solution 1, wherein the mass of the copper-based complex catalyst is 0.3% of creatine, and reacting at 70° C. for 2 hours;

[0061] (3) After the reaction is completed, cool to room temperature, add activated carbon for decolorization, and filter to obtain a filtrate;

[0062] (4) The filtrate was concentrated under reduced pressure, and the concentrate was cooled to 1° C. to promote the crystallization of creatine ethyl hydrochloride. The crystals were filtered and dried to obtain creatine ethyl hydrochloride with a purity of 99.1% and a yield of 94.9%.

[0063] Comparative Example 1

[0064] This comparative example provides a method for preparing creatine ethyl hydrochloride, which is different from Example 2 in that the catalyst uses the copper-based complex precursor prepared in step (I) of Example 1, and the remaining steps are the same as Example 2. The purity of the obtained creatine ethyl hydrochloride is 98.5%, and the yield is 81.6%.

[0065] Comparative Example 2

[0066] This comparative example provides a method for preparing creatine ethyl ester hydrochloride, which is different from Example 2 in that the catalyst is the supported copper-based complex prepared in steps (I) to (II) of Example 1, and the remaining steps are the same as those of Example 2. The purity of the obtained creatine ethyl hydrochloride is 99.0%, and the yield is 83.9%.

[0067] Comparative Example 3

[0068] This comparative example provides a method for preparing creatine ethyl ester hydrochloride, comprising the following steps:

[0069] (1) Dissolve creatine in anhydrous ethanol at a mass volume ratio of 1 g:10 mL, add hydrochloric acid to adjust the pH value to 3, and stir the reaction at 70°C for 7 hours;

[0070] (2) After the reaction is completed, the reaction solution is cooled to room temperature, the reaction solution is concentrated under reduced pressure, and the concentrated solution is cooled to 4° C. to promote the crystallization of creatine ethyl hydrochloride. The crystals are filtered and dried to obtain creatine ethyl hydrochloride with a purity of 93.5% and a yield of 68.1%.

[0071] Comparative Example 4

[0072] This comparative example provides a method for preparing creatine ethyl ester hydrochloride, comprising the following steps:

[0073] (1) Creatine was dissolved in anhydrous ethanol at a mass volume ratio of 1 g:10 mL, and concentrated sulfuric acid was slowly added dropwise as a catalyst under ice bath conditions. The mass concentration of the concentrated sulfuric acid was 98%, and the amount of concentrated sulfuric acid added was 2% of the mass of creatine. After the addition was completed, the system was heated to 70° C. and stirred for reaction for 7 hours;

[0074] (2) After the reaction is completed, the mixture is cooled, sodium hydroxide is added to adjust the pH value to 7, and the mixture is concentrated under reduced pressure to obtain a concentrated solution containing creatine ethyl ester;

[0075] (3) adding deionized water 6 times the mass of the concentrate to the concentrate, then adding hydrochloric acid to adjust the pH value to 3, and stirring the reaction for 20 minutes;

[0076] (4) After the reaction is completed, the mixture is cooled to 4° C. to promote the crystallization of creatine ethyl hydrochloride. The crystals are filtered, washed with cold deionized water, and dried to obtain creatine ethyl hydrochloride with a purity of 92.7% and a yield of 75.3%.

[0077] Creatine ethyl hydrochloride prepared in Example 2-4 of the present invention has a high purity and product yield. Example 2-4 uses a copper-based complex catalyst prepared by the present invention, in which copper sulfate and 2,2'-bipyridine form a complex, which is further loaded on a silica carrier. The carrier provides more active sites for the catalyst and improves the stability of the catalyst. 3-aminopropyltriethoxysilane enhances the activity and selectivity of the catalyst. These work together to make the product of Example 2-4 have a high purity and yield. Comparative Example 1 uses a copper-based complex precursor that has not been loaded and functionalized, lacks sufficient active sites and selectivity, resulting in low purity and yield of the product. Although the catalyst in Comparative Example 2 is loaded on silica, the functionalization treatment of 3-aminopropyltriethoxysilane is not performed, resulting in insufficient activity and selectivity of the catalyst, affecting the quality of the product. Comparative Example 3 directly reacts, lacks the guiding effect of the catalyst, has a slow reaction rate, and is prone to produce by-products, resulting in low purity and yield. Although concentrated sulfuric acid can catalyze the reaction in Comparative Example 4, it is easy to cause side reactions, thereby reducing the purity and yield.

[0078] The above is a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing creatine ethyl ester hydrochloride, comprising the following steps: (1) Dissolve creatine in anhydrous ethanol, add hydrochloric acid to adjust the pH value to 2.5-3.5, and obtain solution 1; (2) adding a copper-based complex catalyst to solution 1 and reacting at 60 to 80° C. for 0.5 to 2 hours; (3) After the reaction is completed, cool to room temperature, add activated carbon for decolorization, and filter to obtain a filtrate; (4) The filtrate is concentrated under reduced pressure, and the concentrated solution is cooled to promote the crystallization of creatine ethyl hydrochloride. The crystals are filtered and dried to obtain creatine ethyl hydrochloride.

2. The preparation method according to claim 1, characterized in that: The mass volume ratio of creatine to anhydrous ethanol in step (1) is 1 g:8-15 mL.

3. The preparation method according to claim 1, characterized in that: The mass of the copper-based complex catalyst in step (2) is 0.1-0.5% of creatine.

4. The preparation method according to claim 1, characterized in that: Step (4) cooling the concentrated solution to 0-6°C for crystallization.

5. The preparation method according to claim 1, characterized in that: The preparation method of the copper-based complex catalyst is as follows: (I) dissolving CuSO4·5H2O in deionized water, dissolving 2,2'-bipyridine in anhydrous ethanol, mixing the two solutions, stirring for reaction, filtering to obtain a blue precipitate, washing with deionized water, and drying to obtain a copper-based complex precursor; (II) dissolving a copper-based complex precursor in anhydrous ethanol to obtain a copper-based complex precursor solution, adding a silica carrier to the copper-based complex precursor solution to ensure that the carrier is completely immersed in the solution, drying the mixture at 60 to 70° C. to load the copper-based complex on the silica carrier, and calcining the loaded material at 150 to 200° C. for 2 to 3 hours to obtain a loaded copper-based complex; (III) dissolving 3-aminopropyltriethoxysilane in an ethanol aqueous solution with a mass fraction of 90-95%, then adding the supported copper-based complex, stirring for reaction, filtering, washing with ethanol, and drying to obtain a copper-based complex catalyst.

6. The preparation method according to claim 5, characterized in that: The molar ratio of the CuSO4·5H2O, 2,2'-bipyridine and 3-aminopropyltriethoxysilane is 1:1-2:1-2.

7. The preparation method according to claim 5, characterized in that: The mass volume ratio of CuSO4·5H2O to deionized water in step (I) is 1 g: 20-30 mL, the mass volume ratio of 2,2'-bipyridine to anhydrous ethanol is 1 g: 40-60 mL, and the stirring reaction time in step (I) is 2-4 hours.

8. The preparation method according to claim 5, characterized in that: In step (II), the mass volume ratio of the copper-based complex precursor to anhydrous ethanol is 1 g: 20-30 mL, the mass volume ratio of the silica carrier to the copper-based complex precursor solution is 1 g: 40-60 mL, and the drying time is 12-20 hours.

9. The preparation method according to claim 5, characterized in that: The silica carrier in step (II) has a specific surface area of ​​200 to 500 m 2 / g of silica, the silica carrier is calcined at 400-600°C for 1-2 hours before use.

10. The preparation method according to claim 5, characterized in that: The mass volume ratio of 3-aminopropyltriethoxysilane to ethanol aqueous solution in step (III) is 1 g:15-25 mL, and the stirring reaction time in step (III) is 3.5-5 hours.