A method for preparing sodium ketoisoleucine

Abstract

This invention relates to a method for preparing sodium ketone isoleucine, belonging to the field of chemical synthesis technology. The method includes the following steps: using hydantoin and butanone as starting materials, a quasi-single-atom cesium catalyst Cs / rGO as a catalyst, deionized water as a solvent, and sodium hydroxide as a base, a two-step one-pot method is employed to prepare sodium ketone isoleucine. This invention uses hydantoin and butanone as starting materials, and completes the first condensation reaction under the action of a quasi-single-atom cesium catalyst. After the first reaction is completed, no further processing is required; stoichiometric amounts of sodium hydroxide are directly added, and a hydrolysis reaction yields sodium ketone isoleucine. The intermediates of this invention do not require separation, reducing production costs while obtaining a highly selective and high-purity product, demonstrating superior economic advantages.

Description

Technical Field

[0001] This invention relates to a method for preparing sodium ketone isoleucine, and more specifically to a two-step one-pot method for preparing sodium ketone isoleucine, belonging to the field of chemical synthesis technology. Background Technology

[0002] Sodium ketoisoleucine is the sodium salt of the essential amino acid ketoisoleucine, with the chemical formula C6H2O. 12 NO2Na. It is one of the branched-chain amino acids (BCAAs) and is widely used in pharmaceuticals, food, and nutritional supplements. As the sodium salt form of ketoisoleucine, it is mainly used to improve the solubility, stability, and bioavailability of ketoisoleucine, making it more suitable for applications in pharmaceuticals, food, and nutritional supplements. Its core function is to correct amino acid imbalances. Ketoisoleucine is one of the three branched-chain amino acids and is crucial for patients with liver disease (Nutrition Reviews 2018, 76, 840-856). The reaction process suffers from drawbacks such as too many reaction steps, excessive alkali usage, large amounts of waste, excessive acid used during neutralization, low selectivity, and high cost. Therefore, there is an urgent need to find a catalytic system to reduce the amount of alkali used, simplify the reaction steps, and improve the selectivity of sodium ketoisoleucine, the calcium intermediate of racemic ketoisoleucine.

[0003] The existing methods for synthesizing sodium ketoisoleucine mainly involve reacting ketoisoleucine (in its free form) with sodium hydroxide or sodium carbonate in an aqueous solution to produce sodium ketoisoleucine. This method requires the use of ketoisoleucine from the outset, resulting in high costs and numerous subsequent processing steps, leading to low profits. Many other studies indicate that ketoisoleucine itself can be produced through microbial fermentation (e.g., *Escherichia coli*, *Corynebacterium glutamicum*), followed by extraction and salt formation steps to prepare sodium salt (Applied Microbiology and Biotechnology, 2005, 69(3), 317-324). This method is a bio-fermentation method, requiring a high-purity carbon source, thus resulting in high production costs. Furthermore, it requires strict sterilization, presents significant technical challenges, and is therefore too expensive. Summary of the Invention

[0004] The purpose of this invention is to provide a simple and low-cost method for preparing sodium ketone isoleucine.

[0005] Specifically, this application is implemented through the following scheme:

[0006] A method for preparing sodium ketone isoleucine includes the following steps: using hydantoin and butanone as starting materials, using quasi-single-atom cesium catalyst Cs / rGO as catalyst, using deionized water as solvent, and using sodium hydroxide as base, sodium ketone isoleucine is prepared by a two-step one-pot method.

[0007] The reaction equation involved in this invention is as follows:

[0008]

[0009] The reaction principle of this invention is as follows:

[0010] This invention provides a two-step, one-pot method for preparing sodium ketone isoleucine. Specifically, using hydantoin and butanone as starting materials, a first-step condensation reaction is completed under the action of a quasi-single-atom cesium catalyst. After the first-step reaction is completed, without any further processing, stoichiometric amounts of sodium hydroxide are directly added for hydrolysis to obtain sodium ketone isoleucine. This two-step, one-pot preparation process eliminates the need for intermediate separation, reducing production costs while yielding a highly selective and high-purity product, demonstrating superior economic advantages.

[0011] Further settings are as follows:

[0012] The quasi-single-atom cesium catalyst Cs / rGO is prepared as follows: graphene oxide is added to deionized water, then cesium carbonate, an amine source and hexadecyltrimethylammonium bromide are added, ultrasonically dispersed, hydrothermally treated and cooled to room temperature, filtered and washed, vacuum dried, and then calcined at high temperature under an argon gas flow to obtain the quasi-single-atom cesium catalyst Cs / rGO.

[0013] In the preparation of the quasi-single-atom cesium catalyst Cs / rGO: the amine source is selected from any one of aniline, amino acid, or urea; it is calcined at high temperature under an argon gas flow, with a calcination temperature of 700-900℃ and a calcination time of 1-3 hours.

[0014] The amount of catalyst used is 1.0% to 3.0% of the mass of hydantoin.

[0015] The molar ratio of sodium hydroxide to hydantoin is 1 to 2:1.

[0016] The first step of the condensation reaction is carried out at 65°C with magnetic stirring for 8–12 h. The second step of the hydrolysis reaction is carried out under reflux conditions with magnetic stirring for 4–6 h.

[0017] After the first condensation reaction is completed, sodium hydroxide in stoichiometric ratio is directly added to carry out the next reaction.

[0018] After the second step of the reaction is completed, the quasi-single-atom cesium catalyst is recovered by filtration, washed three times with deionized water and ethanol respectively, and then recycled back into the reaction.

[0019] The beneficial effects of this invention are as follows:

[0020] (1) The present invention uses a two-step one-pot process to prepare sodium ketone isoleucine, which reduces the preparation cost while obtaining a highly selective and high-purity product, thus showing better economic advantages.

[0021] (2) The present invention prepares a catalyst with quasi-single-atom cesium as the main active component and graphene oxide as the support. The catalyst is applied in the preparation process of sodium ketone isoleucine and has good catalytic activity and mechanical strength. The catalyst is also easy to recover and regenerate.

[0022] This invention designs a catalyst (Cs / rGO) for reducing graphene oxide supported on quasi-single-atom cesium. Due to the unique properties of quasi-single-atom cesium (a single cesium atom as the catalytic center), it can provide highly efficient reactive sites. The exposure of these quasi-single-atom cesium sites enhances the rate of the catalytic reaction because they provide more reaction surface, lower the energy barrier of the reaction, and enable the condensation of hydantoin and butanone, as well as the subsequent hydrolysis of the condensation product, in a one-pot, two-step process. Furthermore, the hydrolysis process only requires stoichiometric amounts of sodium hydroxide, significantly reducing the use of alkali and the number of reaction steps.

[0023] Furthermore, this catalyst is a heterogeneous catalyst; quasi-single-atom catalysts, due to their unique properties, are generally more stable than traditional nanocatalysts. Reduced graphene oxide provides a strong supporting structure that prevents the aggregation or dissolution of cesium atoms, thereby improving the long-term stability of the catalyst. The good mechanical strength and thermal stability of reduced graphene oxide ensure that the supported quasi-single-atom cesium catalyst is not easily deactivated during use, facilitating recovery and regeneration. This helps reduce catalyst waste and improve resource utilization efficiency.

[0024] (3) The process provided by the invention is simple and the conditions are mild. The catalyst can be recycled, which reduces the preparation cost while obtaining a highly selective and high-purity product.

[0025] This invention conducts the reaction at a lower temperature, avoiding the safety hazards caused by high-temperature reactions, making the reaction easier to control. At the same time, the reaction operation and post-processing are simple, exhibiting better reaction and economic advantages, and is more suitable for industrial production. Attached Figure Description

[0026] Figure 1 XPS spectrum of the quasi-single-atom cesium catalyst Cs / rGO prepared for the example.

[0027] Figure 2 The XRD pattern of the quasi-single-atom cesium catalyst Cs / rGO prepared for the example.

[0028] Figure 3 The image shows the 1H NMR spectrum of the prepared sodium ketone isoleucine. Detailed Implementation

[0029] The following detailed description of specific embodiments of the present invention, in conjunction with the accompanying drawings, does not limit the scope of the claims. Unless otherwise specified, the raw materials and reagents used in the embodiments of the present invention are all prior art or commercially available products.

[0030] In the following embodiments of the present invention, the quasi-single-atom cesium catalyst (Cs / rGO) was prepared by the following method: 0.5 g of graphene oxide (GO) was added to 100 mL of deionized water and ultrasonically dispersed for 30 min. Then, 0.01 g of cesium carbonate, 1 g of urea, and 0.075 g of CTAB were added, and ultrasonic dispersion was continued for another 30 min. After dispersion, the mixture was transferred to a hydrothermal reactor and hydrothermally heated at 180 °C for 12 h. After hydrothermal treatment, the mixture was cooled to room temperature, filtered and washed several times, and the solid was vacuum dried overnight. The dried solid was ground into a fine powder and placed in a tube furnace, calcined at 800 °C for 2 h under an argon atmosphere to obtain the quasi-single-atom cesium catalyst (Cs / rGO), labeled as catalyst A.

[0031] Catalyst characterization:

[0032] XPS plot of quasi-single-atom cesium catalyst (Cs / rGO) is shown below Figure 1 As shown: Reduced graphene oxide (rGO) is a carbon material rich in defects and functional groups, with the most abundant being CC / CC=C carbon, or sp2. 2 The carbon originates from the intact, unoxidized graphene domains within the reduced graphene oxide (rGO) framework. Its conjugated π-electron system can act as an electron donor or acceptor, regulating the electron density of Cs anchored thereto, thus affecting the catalytic activity of Cs. This electronic effect may be crucial for the synthesis of sodium isoleucine ketone. Secondly, CO / CN carbon provides hydrophilicity and auxiliary catalytic sites, and is also the main anchoring site for cesium. The remaining two C bonds are carbon-oxygen double bonds and graphitic carbon, primarily responsible for regulating the electronic structure and potentially participating in the reaction. Graphitic carbon's main role is to promote the forward reaction. The spectrum shows the highest peak for pyrrole nitrogen, followed slightly by pyridine nitrogen. The core role of pyridine nitrogen is that its lone pair electrons have a strong coordinating ability, allowing it to interact with Cs. +The ions form strong coordination bonds (CN-Cs), thus stably anchoring Cs atoms in a quasi-monoatomic form on the rGO framework. This is a classic strategy for constructing single-atom catalysts (SACs). Furthermore, it provides Lewis base sites and adsorbs reactants. The minimal graphene nitrogen also plays its role, for example, bonding with three carbon atoms and fully integrating into the graphene lattice. It also bonds with Cs, anchoring Cs sites and promoting the forward reaction. The Cs plot shows no peaks with binding energies below 724 eV, indicating that the catalyst did not form clusters, suggesting that Cs did not aggregate and the catalyst structure has a very good atomic dispersion. The main peaks appear in the binding energy range of 724–734 eV, directly proving that Cs is stably anchored on the support in an atomically dispersed ionic form, rather than forming cesium clusters or compounds. Coordinated Cs + They serve as catalytic active centers, strongly coordinating with the O / N functional groups of rGO to polarize reactant molecules, which is the basis for efficient catalysis.

[0033] The XRD pattern of the quasi-single-atom cesium catalyst (Cs / rGO) is shown below. Figure 2 As shown: Comparison of XRD patterns of graphene oxide (GO), reduced graphene oxide (rGO), and Cs / rGO without the template agent CTAB reveals that the graphene oxide peak around 10° of Cs / rGO disappears, indicating that graphene oxide has been reduced to reduced graphene oxide. We found that rGO and Cs / rGO without CTAB only have a broad diffraction peak around 25°, which is the amorphous carbon structure of reduced graphene oxide. However, the diffraction peak of Cs / rGO is significantly sharper, possibly because the addition of CTAB induces GO to stack into a certain ordered structure during the thermal reduction process, enabling it to better adsorb and catalyze the reaction.

[0034] Example 1

[0035] In a 100 ml three-necked flask, 0.1 g of the previously prepared catalyst A was added, followed by 50 ml of deionized water, and then 5.7 g (0.05 mol) of hydantoin was added sequentially. The mixture was heated to 65 °C with magnetic stirring, and 3.6 g (0.05 mol) of butanone was added dropwise. The reaction was allowed to proceed for 10 h. After the first step of the reaction was completed, the mixture was cooled to room temperature, and 4 g (0.10 mol) of sodium hydroxide was added. The mixture was then heated to reflux and reacted for 6 h. After the second step of the reaction was completed, the mixture was filtered through a Buchner funnel to obtain a quasi-single-atom cesium catalyst. The obtained catalyst was washed three times with deionized water and ethanol, respectively, for reuse. The filtrate was extracted with ethyl acetate / water, the organic phases were combined, concentrated, and dried to obtain a white solid product, sodium ketone isoleucine, with a yield of 98% and a selectivity of 92.4%.

[0036] Product confirmation: 1H NMR (400 MHz, Deuterium Oxide) δ 2.62 (d, J = 7.0 Hz, 2H), 2.09 (dh, J = 13.6, 6.8 Hz, 1H), 0.94 (d, J = 6.7 Hz, 6H).

[0037] The product's 1H NMR spectrum is as follows Figure 3 As shown, the number and location of hydrogen atoms emitted, as determined by the 1H NMR spectrum, are consistent with the predicted product analysis. The splitting pattern also reflects the coupling of the product well, confirming that it is the target product.

[0038] Example 2

[0039] To further explore the influence of catalyst preparation process on catalyst performance, the catalyst preparation process was adjusted and applied to the synthesis of sodium ketone isoleucine in Example 1.

[0040] Catalyst B: The preparation process is the same as that of catalyst A, except that the hydrothermal temperature is reduced from 180℃ to 160℃.

[0041] Catalyst C: The preparation process is the same as that of catalyst A, except that the hydrothermal temperature is increased from 180℃ to 200℃.

[0042] Catalyst D: The preparation process is the same as that of catalyst A, except that the amount of cesium carbonate is adjusted from 0.01g to 0.0075g.

[0043] Catalyst E: The preparation process is the same as that of catalyst A, except that the amount of cesium carbonate is adjusted from 0.01g to 0.02g.

[0044] Catalyst F: The preparation process is the same as that of catalyst A, except that the amount of cesium carbonate is adjusted from 0.01g to 0.03g.

[0045] Catalyst G: The preparation process is the same as that of catalyst A, except that the calcination temperature is reduced from 800℃ to 700℃.

[0046] Catalyst H: The preparation process is the same as that of catalyst A, except that the calcination temperature is increased from 800℃ to 900℃.

[0047] Catalyst I: The preparation process is the same as that of catalyst A, except that the calcination time is reduced from 2 hours to 1 hour.

[0048] Catalyst J: The preparation process is the same as that of catalyst A, except that the calcination time is increased from 2 hours to 3 hours.

[0049] Catalyst K: The preparation process is the same as that of catalyst A, except that cesium carbonate is replaced with nickel acetylacetonate.

[0050] Catalyst L: The preparation process is the same as that of catalyst A, except that cesium carbonate is replaced with ruthenium acetylacetonate.

[0051] Catalyst M: The preparation process is the same as that of catalyst A, except that cesium carbonate is replaced with palladium acetylacetone.

[0052] Catalyst N: The preparation process adopted the equal-volume impregnation method: 0.55 g of alumina was weighed and calcined in air at 550 °C for 2 h in a tube furnace. Then, about 5 mL of deionized water was added to a clean small beaker. 0.01 g of cesium carbonate was accurately weighed using an analytical balance and added to the beaker, and stirred until completely dissolved. 0.015 g of citric acid was weighed and added to the above cesium carbonate solution. The mixture was heated at room temperature and stirred until a clear and transparent solution was obtained. The solution was rotary evaporated to about 0.5 mL through the pores of the alumina, and 0.5 mL of the impregnation solution was very slowly added dropwise to the alumina using a microsyringe. During the dropwise addition, the powder was stirred quickly and gently with a glass rod to ensure uniform liquid distribution. After drying, the mixture was kept in a tube furnace at 450 °C for 4 h under an argon atmosphere, and the product Cs / Al2O3 catalyst was obtained, labeled as catalyst N.

[0053] Catalyst O: The preparation process is the same as that of catalyst N, except that the supporting material is changed from alumina to silica molecular sieve SBA-15.

[0054] The catalysts B to O prepared above were applied to the synthesis of sodium ketone isoleucine in Example 1, and their catalytic effects were tested, as shown in Table 1.

[0055] Table 1

[0056] .

[0057] As shown in Table 1, the type of metal supported on the catalyst, as well as the support, the amount of metal supported, and the preparation process, all have a significant impact on the performance of the catalyst. The catalyst using reduced graphene oxide supported on single-atom cesium (Cs / rGO) has relatively high product selectivity and conversion. However, when the supporting metal is replaced with nickel, ruthenium, or palladium, the product selectivity and conversion both decrease significantly. When catalysts N and O are supported by alumina and silica molecular sieve SBA-15, respectively, the product selectivity and conversion of alumina are both poor, while the conversion of silica molecular sieve SBA-15 is acceptable, although the selectivity decreases slightly.

[0058] In summary, catalysts using reduced graphene oxide supported on single-atom cesium (Cs / rGO) can all achieve good selectivity and conversion rates, with catalyst A showing the best performance.

[0059] Example 3

[0060] The preparation method is the same as in Example 1, except that the molar ratio of sodium hydroxide to hydantoin and the amount of catalyst are adjusted, and their effects on the reaction are tested respectively, as shown in Table 2.

[0061] Table 2

[0062] .

[0063] As shown in Table 2, considering both cost and selectivity, the reaction selectivity is highest at 92.4% when the amount of functionalized graphene catalyst (Cs / rGO) is 1.75% (0.1 g) of hydantoin mass and the molar ratio of sodium hydroxide to hydantoin is 2:1.

[0064] Example 4

[0065] The preparation method is the same as in Example 1, except that the reaction time of the first step and the reaction time of the second step are adjusted, and their effects on the reaction are tested respectively, as shown in Table 3.

[0066] Table 3

[0067] .

[0068] As shown in Table 3, considering both conversion rate and selectivity, the catalytic efficiency is best when the first step reaction time is 10 h and the second step reaction time is 6 h, with a conversion rate of 98% and a selectivity of 92.4%.

[0069] Example 5

[0070] The quasi-single-atom cesium catalyst recovered by filtration in Example 1 was first washed three times with 10 mL of deionized water, then washed three times with 10 mL of ethanol, air-dried, and then put back into the reaction. The effects of different number of cycles on the product conversion and selectivity were recorded, as shown in Table 4.

[0071] Table 4

[0072] .

[0073] As shown in Table 4, the quasi-single-atom cesium (Cs / rGO) catalyst of this invention still exhibits excellent catalytic performance after multiple uses. Even after the fifth cycle, the selectivity remains above 92%, demonstrating that the catalyst of this invention can be recycled at least five times and has excellent prospects for industrial application.

Claims

1. A method for preparing sodium ketoisoleucine, characterized by, Includes the following steps: Sodium ketone isoleucine was prepared by a two-step one-pot method using hydantoin and butanone as starting materials, quasi-single-atom cesium catalyst Cs / rGO as catalyst, deionized water as solvent, and sodium hydroxide as base. The two-step one-pot method uses hydantoin and butanone as starting materials. Under the action of the quasi-single-atom cesium catalyst Cs / rGO, the first step of the condensation reaction is completed. After the first step of the reaction is completed, no treatment is required. Sodium hydroxide in stoichiometric ratio is added directly, and the hydrolysis reaction yields sodium ketone isoleucine. The quasi-single-atom cesium catalyst Cs / rGO is prepared as follows: graphene oxide is added to deionized water, then cesium carbonate, an amine source and hexadecyltrimethylammonium bromide are added, ultrasonically dispersed, hydrothermally treated and cooled to room temperature, filtered and washed, vacuum dried, and then calcined at high temperature under an argon gas flow to obtain the quasi-single-atom cesium catalyst Cs / rGO.

2. The process for the preparation of sodium ketoisoleucine as claimed in claim 1, wherein: The amine source is selected from any one of aniline, amino acid, or urea.

3. The process for the preparation of sodium ketoisoleucine as claimed in claim 1, wherein: The sample is calcined at high temperature under an argon gas flow, with a calcination temperature of 700–900℃ and a calcination time of 1–3 hours.

4. The process for the preparation of sodium ketoisoleucine as claimed in claim 1, wherein: The amount of catalyst used is 1.0% to 3.0% of the mass of hydantoin.

5. The process for the preparation of sodium ketoisoleucine as claimed in claim 1, wherein: The molar ratio of sodium hydroxide to hydantoin is 1 to 2:

1.

6. The process for the preparation of sodium ketoisoleucine as claimed in claim 1, wherein: The first step of the condensation reaction is carried out under magnetic stirring at 65°C for 8–12 h.

7. The method for preparing sodium ketone isoleucine according to claim 1, characterized in that: The hydrolysis reaction is carried out under reflux conditions with magnetic stirring for 4–6 hours.

8. The process for the preparation of sodium ketoisoleucine as claimed in claim 1, wherein: After the hydrolysis reaction is completed, the quasi-single-atom cesium catalyst Cs / rGO is recovered by filtration, washed three times with deionized water and ethanol respectively, and then recycled back into the reaction.

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