A method for preparing l-seleno-methylselenocysteine by reduction with an organic phosphine

Abstract

The application discloses a method for preparing L-selenium-methyl selenocysteine by organic phosphine reduction, which is prepared by one-pot method under the reduction of organic phosphine, taking L-serine or L-serine derivative as raw material and dimethyl diselenide as selenium source. Compared with the conventional chemical synthesis method, the method for preparing L-selenium-methyl selenocysteine by organic phosphine reduction can efficiently synthesize L-selenium-methyl selenocysteine and its derivative under the reduction of organic phosphine, can obtain L-selenium-methyl selenocysteine with high yield and high purity, has the advantages of simple synthesis route, no need to use boron hydride reducing agent or Grignard reagent with explosion hazard, mild reaction condition, safe and reliable process, cheap and easily available raw material, high product yield, high purity and the like, and has important promoting effect on realizing large-scale industrial application of L-selenium-methyl selenocysteine.

Description

Technical Field

[0001] This invention belongs to the field of organic fine chemical synthesis technology, and relates to a method for preparing L-seleno-methylselenocysteine ​​by organophosphorus reduction. Background Technology

[0002] Currently, the preparation methods for L-seleno-methylselenocysteine ​​are mainly divided into biological extraction and chemical synthesis. Biological extraction relies on natural organic selenium resources, and although it can directly obtain L-seleno-methylselenocysteine ​​in its natural form, its large-scale application is limited by low selenium content, complex extraction processes, low yield, high cost, and the potential for heavy metal contamination. In contrast, chemical synthesis, due to its relatively low production cost and ease of industrialization, has become the ideal choice for large-scale production of L-seleno-methylselenocysteine. Currently, there are six main methods for the synthesis of L-seleno-methylselenocysteine:

[0003] Method 1: α-Aminoacrylate Derivative Method

[0004] Dimethyl diselenyl ether is reduced under alkaline conditions using sodium borohydride (lithium, potassium) to generate a methylselenoacrylate intermediate, which then undergoes a Michael addition reaction with aminoacrylate to produce β-selenomethyl-α-aminoacrylate. Following saponification and acidification, a carboxylic acid compound is obtained, which is then deprotected by heating with hydrolysis to remove the acetyl group of the amino group. Finally, neutralization yields DL-selenomethylselenocysteine, which requires further enzymatic resolution to obtain L-selenomethylselenocysteine. As a crucial step in the entire process, the effectiveness of enzymatic resolution is affected by various factors, resulting in low overall yield, high production costs, and unstable purity, making it difficult to meet the needs of large-scale production.

[0005] Method 2: Sodium diselenide method

[0006] Selenium powder is reduced in situ with sodium borohydride to obtain a sodium diselenide solution, which reacts with 3-chloro-L-alanine via a bimolecular nucleophilic substitution reaction to generate L-selenocysteine. Subsequently, the Se-Se bonds are cleaved under ultra-low temperature (-70°C) conditions with metallic sodium and liquid ammonia, and finally, methylation occurs with iodomethane under alkaline conditions to obtain the target product, L-seleno-methylselenocysteine. Although this method has some theoretical feasibility, it has extremely high requirements for process conditions, such as the use of hazardous chemicals like liquid ammonia and metallic sodium, the need for nitrogen protection, and stringent equipment requirements, making it difficult to meet the needs of industrial production.

[0007] Method 3: N-tert-Butoxycarbonyl-L-serine lactone method

[0008] This method uses N-tert-butoxycarbonyl-L-serine as a raw material. First, β-lactone is prepared via an intramolecular Mitsunobu reaction in the presence of azodicarbonate and triphenylphosphine. Then, dimethyl diselenyl ether is reduced in situ under alkaline conditions using sodium borohydride (lithium or potassium) to generate mesenoyl alcohol or mesenoyl alcohol salt intermediates, which then undergo a ring-opening reaction to generate L-seleno-methylselenocysteine ​​protected by an N-tert-butoxycarbonyl group. Finally, the tert-butoxycarbonyl group is removed under trifluoroacetic acid catalysis to obtain L-seleno-methylselenocysteine. However, this method has several drawbacks: first, the preparation of β-lactone requires feeding at -78 °C for a certain period before raising the temperature to room temperature, resulting in harsh process conditions; second, the use of sodium borohydride as a reducing agent leads to various side reactions of β-lactone, resulting in a low overall yield and high cost. Therefore, this method is also difficult to adapt to large-scale production.

[0009] Method 4: 2,3-Dihalopropionitrile Method

[0010] Dimethyl diselenyl ether is reduced under alkaline conditions using sodium borohydride (lithium, potassium) to generate a methylselenoolate intermediate. This intermediate is then reacted with 2,3-dihalopropionitrile via a regioselective bimolecular nucleophilic substitution reaction to yield 2-halo-3-methylselenopropionitrile. Following acidic hydrolysis, 2-halo-3-methylselenopropionic acid is obtained, which is then aminated to give DL-seleno-methylselenocysteine. Acetyl protection of the amino group yields N-acetyl-L-seleno-methylselenocysteine. Enzymatic resolution yields N-acetyl-L-seleno-methylselenocysteine, and finally, removal of the protecting group under acidic conditions yields optically pure L-seleno-methylselenocysteine. Although this method theoretically achieves the synthesis of the target product, the substitution reaction of the haloalkane has low selectivity, and the enzymatic resolution process requires acetyl protection before removal, making it cumbersome and costly, unsuitable for large-scale industrial production.

[0011] Method 5: Sodium borohydride (lithium / potassium) reduction method

[0012] This method uses dimethyl diselenyl ether as a raw material, which is reduced under alkaline conditions using sodium borohydride (lithium, potassium) to generate a methylselenoolate intermediate. This intermediate then reacts with 3-halo-L-serine or its 3-halo-L-serine ester to obtain the L-seleno-methylselenocysteine ​​precursor, which is then deprotected by hydrolysis to obtain L-seleno-methylselenocysteine. Although this method has a simple and efficient process, the reducing agent used poses an explosion risk. Furthermore, the chiral source used is expensive, resulting in high overall production costs and making it difficult to meet the requirements for large-scale production.

[0013] Method Six: Formatting Method

[0014] This method uses methylmagnesium bromide to prepare methylselenobromide in situ with selenium powder, which then reacts with N-tert-butoxycarbonyl-3-halo-L-serine ester to obtain the L-seleno-methylselenocysteine ​​precursor. The L-seleno-methylselenocysteine ​​precursor is then hydrolyzed under acidic conditions to obtain optically pure L-seleno-methylselenocysteine. Although this reaction avoids the use of sodium borohydride, which poses an explosive risk, methylmagnesium bromide is expensive, the self-preparation of Grignard reagents presents significant safety hazards, and the reaction requires anhydrous and oxygen-free conditions, making it unsuitable for industrial production.

[0015] In summary, methods one through five require the use of sodium borohydride (lithium / potassium) as a reducing agent to prepare methylselenohydride or sodium diselenoide, posing a significant explosion risk. Method six requires the use of a methyl Grignard reagent or the preparation of a methyl Grignard reagent using metallic magnesium, also presenting safety hazards. Furthermore, existing chemical synthesis methods for L-seleno-methylselenocysteine ​​all require prior halogenation of the hydroxyl group of L-serine, resulting in complex processes, demanding conditions, and high costs, thus limiting the large-scale industrial application of L-seleno-methylselenocysteine. Therefore, directly preparing L-seleno-methylselenocysteine ​​from L-serine or its derivatives would significantly promote its large-scale industrial application. Summary of the Invention

[0016] The technical problem to be solved by the present invention is to overcome the shortcomings of the prior art and provide a method for preparing L-seleno-methylselenocysteine ​​by reduction of organophosphorus, which is simple in process, convenient in operation, mild in preparation conditions, high in safety, high in yield and high in purity.

[0017] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0018] A method for preparing L-seleno-methylselenocysteine ​​by reduction using organophosphorus compounds, using L-serine or L-serine derivatives as raw materials and dimethyl diselenoether as the selenium source, prepares L-seleno-methylselenocysteine ​​in a one-pot process under the reduction of organophosphorus compounds. The chemical reaction equation is shown in equation (1) below:

[0019] (1),

[0020] In formula (1):

[0021] The R 1 It is at least one of hydrogen (H), acetyl (Ac), tert-butyloxycarbonyl (Boc), and triphenylmethyl (Tr);

[0022] The R 2 Hydrogen (H), methyl (Me), ethyl (Et), n-propyl (n Pr), isopropyl ( i Pr), n-butyl ( n Bu), isobutyl ( i Bu), tert-butyl ( t At least one of Bu);

[0023] The R 3 n-Butyl ( n Bu), tert-butyl ( t Bu), cyclohexyl (Cy), phenyl (Ph), p-tolyl ( p -Tolyl), m-Tolyl ( m -Tolyl), o-Tolyl ( o At least one of the following: -Tolyl).

[0024] The above method, further improved, refers to R 3 n-Butyl ( n Bu), cyclohexyl (Cy), phenyl (Ph), p-tolyl ( p -Tolyl), m-Tolyl ( m At least one of the following: -Tolyl).

[0025] The above method, further improved, refers to R 3 n-Butyl ( n Bu), phenyl (Ph), p-tolyl ( p At least one of the following: -Tolyl).

[0026] The above method, further improved, when R 1 and R 2 When all hydrogen atoms are present, the chemical reaction equation for preparing the L-seleno-methylselenocysteine ​​is shown in equation (2), which includes the following steps:

[0027] S1. Dimethyl diselenyl ether, L-serine and organophosphorus are dissolved in solvent A and reacted to obtain crude L-seleno-methylselenocysteine.

[0028] S2. Dissolve the crude L-seleno-methylselenocysteine ​​obtained in step S1 in solvent B, decolorize, and recrystallize to obtain L-seleno-methylselenocysteine.

[0029] (2).

[0030] In a further improvement to the above method, in step S1, the molar ratio of dimethyl diselenyl ether to L-serine is 0.5–5:1; the molar ratio of L-serine to organophosphorus is 1:1–5; the ratio of L-serine to solvent A is 0.01 mol–10 mol:1 L; solvent A is at least one of tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, methyl tert-butyl ether, N,N-dimethylformamide, acetonitrile, N-methylpyrrolidone, and toluene; the reaction temperature is 0–100 °C; and the reaction time is 2 h–24 h.

[0031] In a further improvement to the above method, in step S2, solvent B is at least one of water, methanol, and ethanol; the decolorization involves adding activated carbon to solvent B to decolorize the crude L-seleno-methylselenocysteine ​​product; the amount of activated carbon added is 1% to 5% of the theoretical product mass; the decolorization is carried out at a temperature of 20 ℃ to 100 ℃; the decolorization time is 0.5 h to 12 h; the recrystallization is carried out at a temperature of 4 ℃ to 8 ℃; the recrystallization time is 12 h to 24 h.

[0032] In a further improvement to the above method, in step S1, the molar ratio of dimethyl diselenyl ether to L-serine is 0.5–2:1; the molar ratio of L-serine to organophosphorus is 1:1–4; the ratio of L-serine to solvent A is 0.1 mol–1 mol:1 L; solvent A is at least one of tetrahydrofuran, 2-methyl-tetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, acetonitrile, and N-methylpyrrolidone; the reaction temperature is 40 °C–100 °C; and the reaction time is 6 h–18 h.

[0033] In a further improvement to the above method, in step S2, the solvent B is at least one of water and ethanol; the amount of activated carbon added is 1% to 2% of the theoretical product mass; and the decolorization is carried out at a temperature of 40 ℃ to 100 ℃.

[0034] In a further improvement to the above method, in step S1, the molar ratio of dimethyl diselenyl ether to L-serine is 0.5 to 1:1; the molar ratio of L-serine to organophosphorus is 1:1.2 to 2; the ratio of L-serine to solvent A is 0.1 mol to 0.5 mol:1 L; solvent A is at least one of tetrahydrofuran, 2-methyl-tetrahydrofuran, and ethylene glycol dimethyl ether; the reaction temperature is 60 ℃ to 90 ℃; and the reaction time is 12 h to 16 h.

[0035] In a further improvement to the above method, in step S2, the solvent B is water and ethanol; the amount of activated carbon added is 1% of the theoretical product mass; and the decolorization is carried out at a temperature of 40 ℃ to 60 ℃.

[0036] The above method, further improved, when R 1 Not hydrogen, R 2 Not hydrogen or R 1 and R 2 When neither of the components is hydrogen, the chemical reaction equation for preparing the L-seleno-methylselenocysteine ​​is shown in equation (3), which includes the following steps:

[0037] (1) Dimethyl diselenyl ether, L-serine derivative and organophosphorus are dissolved in solvent A and reacted to obtain L-seleno-methylselenocysteine ​​derivative;

[0038] (2) The L-seleno-methylselenocysteine ​​derivative obtained in step (1) is mixed with hydrochloric acid and hydrolyzed to obtain crude L-seleno-methylselenocysteine ​​hydrochloride.

[0039] (3) Dissolve the crude L-seleno-methylselenocysteine ​​hydrochloride obtained in step (2) into solvent C, add an alkalizing agent to alkalize, and obtain crude L-seleno-methylselenocysteine.

[0040] (4) Dissolve the crude L-seleno-methylselenocysteine ​​obtained in step (3) in solvent B, decolorize, recrystallize, and obtain L-seleno-methylselenocysteine.

[0041] (3).

[0042] In a further improvement to the above method, in step (1), the molar ratio of dimethyl diselenyl ether to L-serine derivative is 0.5 to 5:1; the molar ratio of L-serine derivative to organophosphorus is 1:1 to 5; the ratio of L-serine derivative to solvent A is 0.01 mol to 10 mol:1 L; solvent A is at least one of tetrahydrofuran, 2-methyl-tetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, methyl tert-butyl ether, N,N-dimethylformamide, acetonitrile, N-methylpyrrolidone, and toluene; the reaction temperature is 0 ℃ to 100 ℃; and the reaction time is 2 h to 24 h.

[0043] In a further improvement to the above method, in step (2), the concentration of hydrochloric acid is 2 mol / L to 12 mol / L; the hydrolysis is carried out at a temperature of 40 ℃ to 100 ℃; and the hydrolysis time is 2 h to 24 h.

[0044] The above method is further improved in step (3), where the crude L-selen-methylselenocysteine ​​hydrochloride product is further treated as follows before being dissolved in solvent C: the crude L-selen-methylselenocysteine ​​hydrochloride product is dissolved in solvent D and recrystallized at -20 °C for 12 h to 48 h to obtain L-selen-methylselenocysteine ​​hydrochloride; the solvent D is at least one of dichloromethane, methanol, ethanol, ethyl acetate, acetone, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, n-hexane, petroleum ether, and diethyl ether; the solvent C is at least one of methanol and ethanol; the alkalizing agent is at least one of ammonia, triethylamine, diisopropylamine, and pyridine; the alkalization is carried out at a temperature of 0 °C to 40 °C; and the pH of the system after alkalization is 5.5 to 9.

[0045] In a further improvement to the above method, in step (4), solvent B is at least one of water, methanol, and ethanol; the decolorization is performed by adding activated carbon to solvent B to decolorize the crude L-seleno-methylselenocysteine ​​product; the amount of activated carbon added is 1% to 5% of the theoretical product mass; the decolorization is carried out at a temperature of 20 ℃ to 100 ℃; the decolorization time is 0.5 h to 12 h; the recrystallization is carried out at a temperature of 4 ℃ to 8 ℃; the recrystallization time is 12 h to 24 h.

[0046] In a further improvement to the above method, in step (1), the molar ratio of dimethyl diselenyl ether to L-serine derivative is 0.5 to 2:1; the molar ratio of L-serine derivative to organophosphorus is 1:1 to 4; the ratio of L-serine derivative to solvent A is 0.1 mol to 1 mol:1 L; solvent A is at least one of tetrahydrofuran, 2-methyl-tetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, methyl tert-butyl ether, N,N-dimethylformamide, and N-methylpyrrolidone; the reaction temperature is 40 ℃ to 100 ℃; and the reaction time is 6 h to 18 h.

[0047] In a further improvement to the above method, in step (2), the concentration of hydrochloric acid is 4 mol / L to 12 mol / L; the hydrolysis is carried out at a temperature of 60 ℃ to 90 ℃; and the hydrolysis time is 2 h to 12 h.

[0048] In a further improvement to the above method, in step (3), the solvent D is one of ethanol, a combination solvent of ethanol and n-hexane, a combination solvent of ethanol and petroleum ether, or a combination solvent of ethanol and diethyl ether; the alkalizing agent is at least one of triethylamine and pyridine; the alkalization is carried out at a temperature of 0 ℃ to 30 ℃; and the pH value of the system after the alkalization is completed is 6 to 9.

[0049] In a further improvement to the above method, in step (4), the solvent B is at least one of water and ethanol; the amount of activated carbon added is 1% to 2% of the theoretical product mass; and the decolorization is carried out at a temperature of 40 ℃ to 100 ℃.

[0050] In a further improvement to the above method, in step (1), the molar ratio of dimethyl diselenyl ether to L-serine derivative is 0.5 to 1:1; the molar ratio of L-serine derivative to organophosphorus is 1:1.2 to 2; the ratio of L-serine derivative to solvent A is 0.2 mol to 0.5 mol:1 L; solvent A is at least one of tetrahydrofuran, 2-methyl-tetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, and methyl tert-butyl ether; the reaction temperature is 60 ℃ to 90 ℃; and the reaction time is 12 h to 16 h.

[0051] In a further improvement to the above method, in step (2), the concentration of hydrochloric acid is 4 mol / L to 6 mol / L; the hydrolysis is carried out at a temperature of 80 ℃ to 90 ℃; and the hydrolysis time is 6 h to 12 h.

[0052] In a further improvement to the above method, in step (3), the solvent D is one of the following: a combination solvent of ethanol and n-hexane, a combination solvent of ethanol and petroleum ether, or a combination solvent of ethanol and diethyl ether; the alkalizing reagent is triethylamine; the alkalization is carried out at a temperature of 0 ℃ to 10 ℃; and the pH value of the system after the alkalization is completed is 8 to 9.

[0053] In a further improvement to the above method, in step (4), the solvent B is water and ethanol; the amount of activated carbon added is 1% of the theoretical product mass; and the decolorization is carried out at a temperature of 40 ℃~60 ℃.

[0054] The principle of this invention for preparing L-seleno-methylselenocysteine ​​by organophosphorus reduction is as follows:

[0055] This invention is based on the synergistic activation mechanism of organophosphorus compounds: on the one hand, the oxyphilic properties of organophosphorus compounds can effectively activate the hydroxyl groups of L-serine (or its derivatives); on the other hand, the strong electron-donating effect of organophosphorus compounds can promote the activation of the Se-Se bond in dimethyl diselenyl ether, thereby achieving one-step directional construction of carbon-selenium bonds, ultimately leading to the efficient synthesis of L-seleno-methylselenocysteine ​​and its derivatives. Furthermore, when preparing L-seleno-methylselenocysteine ​​from L-serine derivatives, the amino / carboxyl protecting groups in the L-seleno-methylselenocysteine ​​derivatives can be removed by hydrolysis under hydrochloric acid catalysis. Moreover, the recrystallization purification and neutralization process of L-seleno-methylselenocysteine ​​hydrochloride are crucial for improving the purity of the final product. In particular, during neutralization, the high solubility of the generated salt in the methanol / ethanol system and the low solubility of the target product are utilized to effectively separate lipid-soluble impurities. Subsequently, through activated carbon adsorption combined with gradient recrystallization, L-seleno-methylselenocysteine ​​with an HPLC purity >99% is finally obtained.

[0056] Compared with the prior art, the advantages of the present invention are as follows:

[0057] (1) In this invention, L-serine or L-serine derivatives are used directly as chiral sources without the need for halogenation. The single-configuration L-seleno-methylselenocysteine ​​is synthesized directly in one or two steps. The synthetic route is simple and avoids the enzyme resolution step and the waste of D-configuration products caused by it.

[0058] (2) In this invention, the carbon-selenium bond construction of L-serine or L-serine derivatives and dimethyl diselenide can be achieved by utilizing the oxyphilicity and strong reducing properties of organophosphorus compounds. There is no need to use borohydride reducing agents or Grignard reagents that pose an explosion hazard. The reaction conditions are mild, the process is safe and reliable, and the raw materials are inexpensive and readily available.

[0059] (3) In this invention, by recrystallizing L-seleno-methylselenocysteine ​​hydrochloride and taking advantage of the difference in solubility between it and L-seleno-methylselenocysteine, the product can be purified and impurities removed without the need to use ion exchange resin to remove inorganic salts, and L-seleno-methylselenocysteine ​​with HPLC purity >99% can be prepared. Attached Figure Description

[0060] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings.

[0061] Figure 1 The image shows the hydrogen nuclear magnetic resonance spectrum of L-seleno-methylselenocysteine ​​prepared in Example 1 of this invention.

[0062] Figure 2The image shows the carbon NMR spectrum of L-seleno-methylselenocysteine ​​prepared in Example 1 of this invention. Detailed Implementation

[0063] The present invention will be further described below with reference to the accompanying drawings and specific preferred embodiments, but this does not limit the scope of protection of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without inventive effort are within the scope of protection of the present invention.

[0064] The "range" disclosed in this invention can be defined in the form of a lower limit and an upper limit. A given range is defined by selecting a lower limit and an upper limit, which define the boundaries of a particular range. This type of range definition can include or exclude endpoints; any endpoint can be independently included or excluded, and they can be arbitrarily combined, meaning any lower limit can be combined with any upper limit to form a range. For example, if ranges of 60–120 and 80–110 are listed for specific parameters, it is understood that ranges of 60–110 and 80–120 are also expected. Furthermore, if minimum range values ​​of 1 and 2 are listed, and maximum range values ​​of 3, 4, and 5 are also listed, then the following ranges are all expected: 1–3, 1–4, 1–5, 2–3, 2–4, and 2–5. In this invention, unless otherwise stated, the numerical range "a–b" represents a shortened representation of any combination of real numbers between a and b, where a and b are real numbers. For example, the numerical range "0 to 5" means that all real numbers between "0 and 5" have been listed in this article; "0 to 5" is just a shortened representation of these numerical combinations.

[0065] In this invention, the terms "multiple" or "various" are used unless otherwise specified, referring to a quantity greater than or equal to 2. For example, "one or more" means one or more types.

[0066] Unless otherwise specified, all embodiments and optional embodiments of the present invention can be combined with each other to form new technical solutions. The reference to "embodiment" herein means that a specific feature, structure, or characteristic described in connection with an embodiment can be included in at least one embodiment or implementation of the present invention. The appearance of this phrase in various places in the specification does not necessarily refer to the same embodiment, nor is it an independent or alternative embodiment mutually exclusive with other embodiments. It will be explicitly and implicitly understood by those skilled in the art that the embodiments described herein can be combined with other embodiments. The term "implementation" as used herein has a similar understanding.

[0067] Those skilled in the art will understand that the order in which the steps are written in the methods of various embodiments or examples does not imply a strict execution order and does not constitute any limitation on the implementation process. The detailed execution order of each step should be determined by its function and possible internal logic. Unless otherwise specified, all steps of the present invention can be performed sequentially or randomly, preferably sequentially. For example, if the method includes steps (a) and (b), it means that the method may include steps (a) and (b) performed sequentially, or it may include steps (b) and (a) performed sequentially. For example, if the method may also include step (c), it means that step (c) can be added to the method in any order. For example, the method may include steps (a), (b), and (c), or it may include steps (a), (c), and (b), or it may include steps (c), (a), and (b), etc. In the present invention, unless otherwise specified, A (e.g., B) indicates that B is a non-limiting example of A, and it can be understood that A is not limited to B.

[0068] In this invention, "optionally," "optionally," "optionally," and "further improved" refer to options that are optional, meaning they are selected from either "with" or "without." If multiple "options" appear in a technical solution, unless otherwise specified and without contradictions or mutual constraints, each "option" is independent.

[0069] To address the shortcomings of existing methods for synthesizing L-seleno-methylselenocysteine, such as complex processes, high costs, harsh conditions, low safety, low yield, and low purity, this invention creatively proposes a method for preparing L-seleno-methylselenocysteine ​​by reduction using organophosphorus compounds. This method is based on the synergistic activation mechanism of organophosphorus compounds: on the one hand, the oxyphilic properties of organophosphorus compounds can effectively activate the hydroxyl groups of L-serine (or its derivatives); on the other hand, the strong electron-donating effect of organophosphorus compounds can promote the activation of the Se-Se bond in dimethyl diselenoether, thereby achieving one-step directional construction of the carbon-selenium bond, ultimately resulting in the efficient synthesis of L-seleno-methylselenocysteine ​​and its derivatives. In addition, when preparing L-seleno-methylselenocysteine ​​using L-serine derivatives, the amino / carboxyl protecting groups in the L-seleno-methylselenocysteine ​​derivatives can be removed by hydrolysis under hydrochloric acid catalysis. Moreover, the recrystallization purification and neutralization process of L-seleno-methylselenocysteine ​​hydrochloride are crucial to improving the purity of the final product. In particular, the difference between the high solubility of the generated salt in the methanol / ethanol system and the low solubility of the target product during neutralization can be used to effectively separate lipid-soluble impurities. Then, through activated carbon adsorption combined with gradient recrystallization process, L-seleno-methylselenocysteine ​​with HPLC purity >99% can be finally obtained.

[0070] Understandably, the method for preparing L-seleno-methylselenocysteine ​​by organophosphorus reduction in this invention uses L-serine or L-serine derivatives as raw materials and dimethyl diselenoether as a selenium source. L-seleno-methylselenocysteine ​​is prepared in a one-pot process under the reduction of organophosphorus. The chemical reaction equation is as follows:

[0071] (1),

[0072] In formula (1):

[0073] R 1 It is at least one of hydrogen (H), acetyl (Ac), tert-butyloxycarbonyl (Boc), and triphenylmethyl (Tr);

[0074] R 2 Hydrogen (H), methyl (Me), ethyl (Et), n-propyl ( n Pr), isopropyl ( i Pr), n-butyl ( n Bu), isobutyl ( i Bu), tert-butyl ( t At least one of Bu);

[0075] R 3 n-Butyl ( n Bu), tert-butyl ( t Bu), cyclohexyl (Cy), phenyl (Ph), p-tolyl ( p -Tolyl), m-Tolyl ( m -Tolyl), o-Tolyl ( o At least one of the following: -Tolyl).

[0076] In some embodiments, R is further preferred. 3 n-Butyl ( n Bu), cyclohexyl (Cy), phenyl (Ph), p-tolyl ( p -Tolyl), m-Tolyl ( m At least one of (-Tolyl). As an example, R 3 It can be n-butyl ( n Bu), cyclohexyl (Cy), phenyl (Ph), p-tolyl ( p -Tolyl), m-Tolyl ( m -Tolyl), the corresponding organophosphines are tributylphosphine, tricyclohexylphosphine, triphenylphosphine, tri(p-tolyl)phosphine, and tri(m-tolyl)phosphine, in order.

[0077] In some embodiments, more preferably, R 3 n-Butyl ( nBu), phenyl (Ph), p-tolyl ( p At least one of (-Tolyl). As an example, R 3 It can be n-butyl ( n Bu), phenyl (Ph), p-tolyl ( p -Tolyl), the corresponding organophosphines are tributylphosphine, triphenylphosphine, and tri(p-tolyl)phosphine, respectively.

[0078] In this invention, by selecting a suitable type of organophosphorus, it is more conducive to promoting the reaction of L-serine or L-serine derivatives with dimethyl diselenyl ether, and ultimately more conducive to the efficient synthesis of high-quality L-seleno-methylselenocysteine.

[0079] In some embodiments, when R 1 and R 2 When both are hydrogen, i.e., when L-serine is used as the raw material, the corresponding chemical reaction equation for the preparation of L-seleno-methylselenocysteine ​​is shown in equation (2), which includes the following steps:

[0080] S1. Dimethyl diselenyl ether, L-serine and organophosphorus are dissolved in solvent A and reacted to obtain crude L-seleno-methylselenocysteine.

[0081] S2. Dissolve the crude L-seleno-methylselenocysteine ​​obtained in step S1 in solvent B, decolorize, and recrystallize to obtain L-seleno-methylselenocysteine.

[0082] (2).

[0083] In some embodiments, more preferably, in step S1, the molar ratio of dimethyl diselenyl ether to L-serine is 0.5 to 5:1. As an example, the molar ratio of dimethyl diselenyl ether to L-serine can be 0.5:1, 0.7:1, 0.9:1, 1:1, 1.2:1, 1.5:1, 1.8:1, 2:1, 2.2:1, 2.5:1, 2.8:1, 3:1, 3.2:1, 3.5:1, 3.8:1, 4:1, 4.2:1, 4.5:1, 4.8:1, or 5:1. It can also be within the range defined by any two of the above values, such as a molar ratio of dimethyl diselenyl ether to L-serine of 0.5 to 2:1, or a molar ratio of dimethyl diselenyl ether to L-serine of 0.5 to 1:1.

[0084] In some embodiments, more preferably, in step S1, the molar ratio of L-serine to organophosphorus is 1:1 to 5. As an example, the molar ratio of L-serine to organophosphorus can be 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.2, 1:2.5, 1:2.8, 1:3, 1:3.3, 1:3.5, 1:3.8, 1:4, 1:4.3, 1:4.5, 1:4.8, or 1:5. It can also be within the range defined by any two of the above values, such as a molar ratio of L-serine to organophosphorus of 1:1 to 4, or a molar ratio of L-serine to organophosphorus of 1:1.2 to 2.

[0085] In some embodiments, more preferably, in step S1, the ratio of L-serine to solvent A is 0.01 mol to 10 mol: 1 L / L. As an example, the ratio of L-serine to solvent A can be 0.01 mol:1 L, 0.05 mol:1 L, 0.08 mol:1 L, 0.1 mol:1 L, 0.2 mol:1 L, 0.3 mol:1 L, 0.4 mol:1 L, 0.5 mol:1 L, 0.6 mol:1 L, 0.7 mol:1 L, 0.8 mol:1 L, 0.9 mol:1 L, 1 mol:1 L, 1.1 mol:1 L, 1.2 mol:1 L, 1.3 mol:1 L, 1.4 mol:1 L, 1.5 mol:1 L, 1.6 mol:1 L, 1.7 mol:1 L, 1.8 mol:1 L, 1.9 mol:1 L, 2 mol:1 L, 2.5 mol:1 L, 3 mol:1 L, 3.3 mol:1 L, 3.4 mol:1 L, 3.4 mol:1 L, 3.4 mol:1 L, 3.4 mol:1 L, 0.01 mol:1 L, 0.05 mol:1 L, 0.08 mol:1 L, 0.1 mol:1 L, 0.02 mol:1 L, 0.2 mol:1 L, 0.3 mol:1 L, 0.3 mol:1 L, 0.4 mol:1 L, 0.05 mol:1 L, 0.08 mol:1 L, 0.08 mol:1 L, 0.09 mol:1 L, 1 mol:1 L, 1 mol:1 L, 1.1 mol:1 L, 1.2 mol:1 L, 1.3 mol:1 L, 1.4 mol:1 L, 1.5 The ratios can be 3.8 mol:1 L, 4 mol:1 L, 4.5 mol:1 L, 5 mol:1 L, 5.2 mol:1 L, 5.8 mol:1 L, 6 mol:1 L, 6.5 mol:1 L, 7 mol:1 L, 7.7 mol:1 L, 8 mol:1 L, 8.4 mol:1 L, 9 mol:1 L, 9.6 mol:1 L, 10 mol:1 L, or any two of the above values ​​can be used as endpoints within a range. For example, the ratio of L-serine to solvent A can be 0.1 mol to 1 mol:1 L, or 0.1 mol to 0.5 mol:1 L.

[0086] In some embodiments, more preferably, in step S1, solvent A is at least one selected from tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, methyl tert-butyl ether, N,N-dimethylformamide, acetonitrile, N-methylpyrrolidone, and toluene. As an example, solvent A may be at least one selected from tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, methyl tert-butyl ether, N,N-dimethylformamide, acetonitrile, N-methylpyrrolidone, and toluene. Even more preferably, solvent A is at least one selected from tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, acetonitrile, and N-methylpyrrolidone. As an example, solvent A may be at least one selected from tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, acetonitrile, and N-methylpyrrolidone. Particularly preferred is solvent A, which is at least one of tetrahydrofuran, 2-methyl-tetrahydrofuran, and ethylene glycol dimethyl ether. As an example, solvent A may be tetrahydrofuran, 2-methyl-tetrahydrofuran, or ethylene glycol dimethyl ether.

[0087] In some embodiments, more preferably, the reaction temperature in step S1 is 0℃ to 100℃. As an example, the reaction temperature can be 0℃, 10℃, 20℃, 30℃, 40℃, 45℃, 50℃, 55℃, 58℃, 60℃, 63℃, 65℃, 68℃, 70℃, 72℃, 75℃, 77℃, 80℃, 82℃, 86℃, 88℃, 90℃, 91℃, 94℃, 95℃, 96℃, 98℃, or 100℃, or it can be within a range defined by any two of the above point values, such as a reaction temperature of 40℃ to 100℃ or a reaction temperature of 60℃ to 90℃.

[0088] In some embodiments, more preferably, the reaction time in step S1 is 2 h to 24 h. As an example, the reaction time can be 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h, 21 h, 22 h, 23 h, or 24 h, or it can be within the range formed by any two of the above point values ​​as endpoints, such as a reaction time of 6 h to 18 h, or a reaction time of 12 h to 16 h.

[0089] In some embodiments, more preferably, in step S2, solvent B is at least one of water, methanol, and ethanol. As an example, solvent B can be water, methanol, and ethanol, or it can be a combination of water and methanol, or a combination of water and ethanol, but is not limited to these.

[0090] In some embodiments, more preferably, in step S2, decolorization involves adding activated carbon to solvent B to decolorize the crude L-seleno-methylselenocysteine ​​product. In this invention, activated carbon can be used as the decolorizing agent, but it is not limited to this.

[0091] In some embodiments, more preferably, in step S2, the amount of activated carbon added is 1% to 5% of the theoretical product mass. As an example, the amount of activated carbon added can be 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.5%, 3%, 3.6%, 4%, 4.4%, 4.6%, or 5% of the theoretical product mass. It can also be within a range defined by any two of the above values, such as 1% to 2% of the theoretical product mass, or 1% of the theoretical product mass.

[0092] In some embodiments, more preferably, in step S2, decolorization is performed at a temperature of 20°C to 100°C. As an example, decolorization can be performed at temperatures of 20°C, 30°C, 40°C, 42°C, 45°C, 48°C, 50°C, 52°C, 55°C, 58°C, 60°C, 65°C, 70°C, 80°C, 90°C, and 100°C, or within a range defined by any two of the above values, such as decolorization at a temperature of 40°C to 100°C, or decolorization at a temperature of 40°C to 60°C.

[0093] In some embodiments, more preferably, in step S2, the decolorization time is 0.5 h to 12 h. More preferably, in step S2, recrystallization is carried out at a temperature of 4 ℃ to 8 ℃, and the recrystallization time is 12 h to 24 h.

[0094] In some embodiments, when R 1 Not hydrogen, R 2 Not hydrogen or R 1 and R 2 When neither of the components is hydrogen, i.e., when L-serine derivatives are used as raw materials, the corresponding chemical reaction equation for the preparation of L-seleno-methylselenocysteine ​​is shown in equation (3), which includes the following steps:

[0095] (1) Dimethyl diselenyl ether, L-serine derivative and organophosphorus are dissolved in solvent A and reacted to obtain L-seleno-methylselenocysteine ​​derivative;

[0096] (2) The L-seleno-methylselenocysteine ​​derivative obtained in step (1) is mixed with hydrochloric acid and hydrolyzed to obtain crude L-seleno-methylselenocysteine ​​hydrochloride.

[0097] (3) Dissolve the crude L-seleno-methylselenocysteine ​​hydrochloride obtained in step (2) into solvent C, add an alkalizing agent to alkalize, and obtain crude L-seleno-methylselenocysteine.

[0098] (4) Dissolve the crude L-seleno-methylselenocysteine ​​obtained in step (3) in solvent B, decolorize, recrystallize, and obtain L-seleno-methylselenocysteine.

[0099] (3).

[0100] In some embodiments, more preferably, in step (1), the molar ratio of dimethyl diselenyl ether to the L-serine derivative is 0.5 to 5:1. As an example, the molar ratio of dimethyl diselenyl ether to the L-serine derivative can be 0.5:1, 0.7:1, 0.9:1, 1:1, 1.2:1, 1.5:1, 1.8:1, 2:1, 2.2:1, 2.5:1, 2.8:1, 3:1, 3.2:1, 3.5:1, 3.8:1, 4:1, 4.2:1, 4.5:1, 4.8:1, or 5:1. It can also be within the range formed by any two of the above values ​​as endpoints, such as a molar ratio of dimethyl diselenyl ether to the L-serine derivative of 0.5 to 2:1, or a molar ratio of dimethyl diselenyl ether to the L-serine derivative of 0.5 to 1:1.

[0101] In some embodiments, more preferably, in step (1), the molar ratio of L-serine derivative to organophosphorus is 1:1 to 5. As an example, the molar ratio of L-serine derivative to organophosphorus can be 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.2, 1:2.5, 1:2.8, 1:3, 1:3.3, 1:3.5, 1:3.8, 1:4, 1:4.3, 1:4.5, 1:4.8, or 1:5. It can also be within the range formed by any two of the above values ​​as endpoints, such as a molar ratio of L-serine derivative to organophosphorus of 1:1 to 4, or a molar ratio of L-serine derivative to organophosphorus of 1:1.2 to 2.

[0102] In some embodiments, more preferably, in step (1), the ratio of L-serine derivative to solvent A is 0.01 mol to 10 mol: 1 L. As an example, the ratio of L-serine derivative to solvent A can be 0.01 mol:1 L, 0.05 mol:1 L, 0.08 mol:1 L, 0.1 mol:1 L, 0.2 mol:1 L, 0.3 mol:1 L, 0.4 mol:1 L, 0.5 mol:1 L, 0.6 mol:1 L, 0.7 mol:1 L, 0.8 mol:1 L, 0.9 mol:1 L, 1 mol:1 L, 1.1 mol:1 L, 1.2 mol:1 L, 1.3 mol:1 L, 1.4 mol:1 L, 1.5 mol:1 L, 1.6 mol:1 L, 1.7 mol:1 L, 1.8 mol:1 L, 1.9 mol:1 L, 2 mol:1 L, 2.5 mol:1 L, 3 mol:1 L, 3.3 mol:1 L, 3.4 mol:1 L, 3.4 mol:1 L, 3.4 mol:1 L, 3.4 mol:1 L, 0.01 mol:1 L, 0.05 mol:1 L, 0.08 mol:1 L, 0.1 mol:1 L, 0.02 mol:1 L, 0.2 mol:1 L, 0.3 mol:1 L, 0.3 mol:1 L, 0.4 mol:1 L, 0.05 mol:1 L, 0.08 mol:1 L, 0.08 mol:1 L, 0.01 mol:1 L, 0.08 mol:1 L, 0.09 mol:1 L, 1 mol:1 L, 1 mol:1 L, 1.1 mol:1 L, 1.2 mol:1 L, The ratios can be 3.8 mol:1 L, 4 mol:1 L, 4.5 mol:1 L, 5 mol:1 L, 5.2 mol:1 L, 5.8 mol:1 L, 6 mol:1 L, 6.5 mol:1 L, 7 mol:1 L, 7.7 mol:1 L, 8 mol:1 L, 8.4 mol:1 L, 9 mol:1 L, 9.6 mol:1 L, 10 mol:1 L, or any two of the above values ​​can be used as endpoints within a range. For example, the ratio of L-serine derivative to solvent A can be 0.1 mol to 1 mol:1 L, or the ratio of L-serine derivative to solvent A can be 0.1 mol to 0.5 mol:1 L.

[0103] In some embodiments, more preferably, in step (1), solvent A is at least one selected from tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, methyl tert-butyl ether, N,N-dimethylformamide, acetonitrile, N-methylpyrrolidone, and toluene. As an example, solvent A may be tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, methyl tert-butyl ether, N,N-dimethylformamide, acetonitrile, N-methylpyrrolidone, and toluene, but is not limited thereto. Even more preferably, solvent A is at least one selected from tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, methyl tert-butyl ether, N,N-dimethylformamide, and N-methylpyrrolidone. As an example, solvent A may be tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, methyl tert-butyl ether, N,N-dimethylformamide, or N-methylpyrrolidone. Particularly preferred is that solvent A is at least one selected from tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, or methyl tert-butyl ether. As an example, solvent A may be tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, or methyl tert-butyl ether.

[0104] In some embodiments, more preferably, in step (1), the reaction temperature is 0 ℃ to 100 ℃. As an example, the reaction temperature can be 0 ℃, 10 ℃, 20 ℃, 30 ℃, 40 ℃, 45 ℃, 50 ℃, 55 ℃, 58 ℃, 60 ℃, 63 ℃, 65 ℃, 68 ℃, 70 ℃, 72 ℃, 75 ℃, 77 ℃, 80 ℃, 82 ℃, 86 ℃, 88 ℃, 90 ℃, 91 ℃, 94 ℃, 95 ℃, 96 ℃, 98 ℃, or 100 ℃, or it can be within the range formed by any two of the above point values ​​as endpoints, such as a reaction temperature of 40 ℃ to 100 ℃, or a reaction temperature of 60 ℃ to 90 ℃.

[0105] In some embodiments, more preferably, the reaction time in step (1) is 2 h to 24 h. As an example, the reaction time can be 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h, 21 h, 22 h, 23 h, or 24 h, or it can be within the range formed by any two of the above point values ​​as endpoints, such as a reaction time of 6 h to 18 h, or a reaction time of 12 h to 16 h.

[0106] In some embodiments, more preferably, in step (2), the concentration of hydrochloric acid is 2 mol / L to 12 mol / L. As an example, the concentration of hydrochloric acid can be 2 mol / L, 2.5 mol / L, 3 mol / L, 3.5 mol / L, 4 mol / L, 4.2 mol / L, 4.4 mol / L, 4.5 mol / L, 4.8 mol / L, 5 mol / L, 5.4 mol / L, 5.5 mol / L, 5.7 mol / L, 5.9 mol / L, 6 mol / L, 6.5 mol / L, 6.8 mol / L, 7 mol / L, 8 mol / L, 9 mol / L, 10 mol / L, 11 mol / L, or 12 mol / L. It can also be within a range defined by any two of the above values, such as a concentration of 4 mol / L to 12 mol / L, or a concentration of 4 mol / L to 6 mol / L.

[0107] In some embodiments, more preferably, in step (2), hydrolysis is carried out at a temperature of 40 ℃ to 100 ℃. As an example, hydrolysis can be carried out at temperatures of 40 ℃, 45 ℃, 50 ℃, 55 ℃, 58 ℃, 60 ℃, 63 ℃, 65 ℃, 68 ℃, 70 ℃, 72 ℃, 75 ℃, 77 ℃, 80 ℃, 82 ℃, 86 ℃, 88 ℃, 90 ℃, 91 ℃, 94 ℃, 95 ℃, 96 ℃, 98 ℃, and 100 ℃, or within a range formed by any two of the above point values ​​as endpoints, such as hydrolysis being carried out at a temperature of 60 ℃ to 90 ℃, or hydrolysis being carried out at a temperature of 80 ℃ to 90 ℃.

[0108] In some embodiments, more preferably, the hydrolysis time in step (2) is 2 h to 24 h. As an example, the hydrolysis time can be 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h, 21 h, 22 h, 23 h, or 24 h, or it can be within the range formed by any two of the above point values ​​as endpoints, such as a hydrolysis time of 2 h to 12 h, or a hydrolysis time of 6 h to 12 h.

[0109] In some embodiments, more preferably, in step (3), before the crude product of L-seleno-methylselenocysteine ​​hydrochloride is dissolved in solvent C, the following treatment is further included: the crude product of L-seleno-methylselenocysteine ​​hydrochloride is dissolved in solvent D and recrystallized at -20 °C for 12 h to 48 h to obtain L-seleno-methylselenocysteine ​​hydrochloride.

[0110] In some embodiments, more preferably, solvent D is at least one selected from dichloromethane, methanol, ethanol, ethyl acetate, acetone, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, n-hexane, petroleum ether, and diethyl ether. As an example, solvent D may be dichloromethane, methanol, ethanol, ethyl acetate, acetone, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, n-hexane, petroleum ether, and diethyl ether, but is not limited thereto. Even more preferably, solvent D is one of ethanol, a combination solvent of ethanol and n-hexane, a combination solvent of ethanol and petroleum ether, and a combination solvent of ethanol and diethyl ether. As an example, solvent D may be ethanol, a combination solvent of ethanol and n-hexane, a combination solvent of ethanol and petroleum ether, and a combination solvent of ethanol and diethyl ether. Particularly preferably, solvent D is one of a combination solvent of ethanol and n-hexane, a combination solvent of ethanol and petroleum ether, and a combination solvent of ethanol and diethyl ether. As an example, solvent D may be ethanol, a combination solvent of ethanol and n-hexane, a combination solvent of ethanol and petroleum ether, and a combination solvent of ethanol and diethyl ether.

[0111] Unless otherwise specified, the terms "combined reagents" and "combined solvents" used in this invention refer to reagents or solvents used simultaneously.

[0112] In some embodiments, more preferably, in step (3), solvent C is at least one of methanol and ethanol. As an example, solvent C may be methanol or ethanol.

[0113] In some embodiments, more preferably, in step (3), the alkalizing agent is at least one selected from ammonia, triethylamine, diisopropylamine, and pyridine. As an example, the alkalizing agent may be ammonia, triethylamine, diisopropylamine, or pyridine. More preferably, the alkalizing agent is at least one selected from triethylamine and pyridine. Particularly preferably, the alkalizing agent is triethylamine.

[0114] In some embodiments, more preferably, in step (3), the alkalization is carried out at a temperature of 0 ℃ to 40 ℃. As an example, the alkalization can be carried out at temperatures of 0 ℃, 1 ℃, 2 ℃, 3 ℃, 4 ℃, 5 ℃, 6 ℃, 7 ℃, 8 ℃, 9 ℃, 10 ℃, 11 ℃, 12 ℃, 13 ℃, 14 ℃, 15 ℃, 16 ℃, 17 ℃, 18 ℃, 19 ℃, 20 ℃, 21 ℃, 22 ℃, 23 ℃, 24 ℃, 25 ℃, 26 ℃, 27 ℃, 28 ℃, 29 ℃, 30 ℃, 31 ℃, 32 ℃, 33 ℃, 34 ℃, 35 ℃, 36 ℃, 37 ℃, 38 ℃, 39 ℃, and 40 ℃.

[0115] In some embodiments, more preferably, in step (3), the pH value of the system after alkalization is 5.5 to 9. As an example, the pH value of the system after alkalization is 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.5, 7.0, 7.5, 8, 8.2, 8.5, 8.8, or 9. It can also be within the range formed by any two of the above points as endpoints, such as the pH value of the system after alkalization being 6 to 9, or the pH value of the system after alkalization being 8 to 9.

[0116] In some embodiments, more preferably, in step (4), solvent B is at least one of water, methanol, and ethanol. As an example, solvent B is water, methanol, and ethanol, but it can also be a combination of water and methanol, or a combination of water and ethanol, but is not limited to these.

[0117] In some embodiments, more preferably, in step (4), decolorization involves adding activated carbon to solvent B to decolorize the crude L-seleno-methylselenocysteine ​​product. In this invention, activated carbon may be used as the decolorizing agent, but it is not limited to this.

[0118] In some embodiments, more preferably, in step (4), the amount of activated carbon added is 1% to 5% of the theoretical product mass. As an example, the amount of activated carbon added can be 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.5%, 3%, 3.6%, 4%, 4.4%, 4.6%, or 5% of the theoretical product mass, or it can be within the range formed by any two of the above values ​​as endpoints, such as 1% to 2% of the theoretical product mass, or 1% of the theoretical product mass.

[0119] In some embodiments, more preferably, in step (4), decolorization is carried out at a temperature of 20 ℃ to 100 ℃. As an example, decolorization can be carried out at temperatures of 20 ℃, 30 ℃, 40 ℃, 42 ℃, 45 ℃, 48 ℃, 50 ℃, 52 ℃, 55 ℃, 58 ℃, 60 ℃, 65 ℃, 70 ℃, 80 ℃, 90 ℃, and 100 ℃, or within a range consisting of any two of the above point values ​​as endpoints, such as decolorization being carried out at a temperature of 40 ℃ to 100 ℃, or decolorization being carried out at a temperature of 40 ℃ to 60 ℃.

[0120] In some embodiments, more preferably, in step (4), the decolorization time is 0.5 h to 12 h; recrystallization is carried out at a temperature of 4 ℃ to 8 ℃; and the recrystallization time is 12 h to 24 h.

[0121] The embodiments of the present invention will be described in detail below.

[0122] Example 1:

[0123] A method for preparing L-seleno-methylselenocysteine ​​by reduction with organophosphorus compounds specifically involves: using L-serine as a raw material and dimethyl diselenoether as a selenium source, preparing L-seleno-methylselenocysteine ​​in a one-pot process under the reduction of organophosphorus compounds, including the following steps:

[0124] 112.8 g (0.6 mol, 0.6 equiv.) of dimethyl diselenoether and 105 g (1.0 mol, 1.0 equiv.) of L-serine were dissolved in 2000 mL of tetrahydrofuran (solvent A). 242.4 g (1.2 mol, 1.2 equiv.) of tributylphosphine was slowly added dropwise under vigorous stirring at room temperature. The mixture was heated to 60 °C and stirred. As the reaction proceeded, the solution color gradually changed from orange-red to colorless, and a large amount of white solid precipitated. The reaction was continued for 18 hours until the L-serine reaction was complete (monitored by TLC). The reaction system was filtered, and the residue was washed three times with 100 mL of ethanol each time, yielding 165 g of a yellowish-white powdery solid, which was the crude product of L-seleno-methylselenocysteine. A yellowish-white powdery solid was mixed with water (solvent B) to dissolve the solid. The mixture was heated to 60 °C, and 1.82 g of activated carbon (1% of the theoretical mass of the product) was added. The mixture was stirred for 1 hour to decolorize L-seleno-methylselenocysteine. The mixture was then filtered, and ethanol (solvent B) was added to the filtrate. After the system temperature dropped to room temperature, the mixture was transferred to a cool cabinet at 4 °C–8 °C for crystallization for 12 hours. After filtration, the residue was washed three times with 100 mL of ethanol each time, yielding 140.1 g of a white powdery solid, which was L-seleno-methylselenocysteine. The yield of this product was 77%, and the HPLC purity was 99%.

[0125] Figure 1 The image shows the hydrogen nuclear magnetic resonance spectrum of L-seleno-methylselenocysteine ​​prepared in Example 1 of this invention. Figure 1 In this process, the deuterated solvent is D2O.

[0126] Figure 2 The image shows the carbon NMR spectrum of L-seleno-methylselenocysteine ​​prepared in Example 1 of this invention. Figure 2 In this study, the deuterated solvent was D₂O. The results were obtained through specific rotation measurement, high-resolution mass spectrometry, and... Figures 1-2 It can be known that:

[0127] [α] D 20 =-14.1 (c = 1.0 in H2O);

[0128] ESI-HRMS: Calculated value C4H9NO2SeNa + (M + Na+ = 205.9691, measured value 205.9696;

[0129] 1 H NMR (600 M, D2O) δ 3.98 (dd, J = 7.2, 4.8 Hz, 1H), 3.10 - 3.02 (m,2H), 2.07 (s, 3H).

[0130] 13 C NMR (151 M, D2O) δ 173.04, 53.69, 24.82, 4.38.

[0131] As can be seen, the preparation method in Example 1 of the present invention can prepare L-seleno-methylselenocysteine.

[0132] Examples 2-7:

[0133] A method for preparing L-seleno-methylselenocysteine ​​by reduction using organophosphorus is as follows: using L-serine as raw material and dimethyl diselenoether as selenium source, L-seleno-methylselenocysteine ​​is prepared in a one-pot process under the reduction of organophosphorus. This method is basically the same as that in Example 1, except that the organophosphorus used is different, as shown in Table 1.

[0134]

[0135] Table 1 shows that using other organophosphorus compounds instead of tributylphosphine in Example 1 also yields high-yield and high-purity L-seleno-methylselenocysteine. Specifically, when the organophosphorus compounds are triphenylphosphine and tris(p-tolyl)phosphine, the yields of L-seleno-methylselenocysteine ​​are 75% and 76%, respectively, and the HPLC purities are 99.1% and 99%, respectively. Furthermore, when the organophosphorus compounds are tricyclohexylphosphine and tris(m-tolyl)phosphine, although the yields and purities of the products decrease, they are still relatively high. The comparison shows that using tributylphosphine, triphenylphosphine, and tris(p-tolyl)phosphine is beneficial for obtaining higher yields and higher purity of L-seleno-methylselenocysteine ​​because they have lower steric hindrance and stronger electronegativity, which is more conducive to the activation of the hydroxyl group and the reduction of dimethyl diselenoether, thus resulting in higher reaction yields and purities.

[0136] Examples 8-20:

[0137] A method for preparing L-seleno-methylselenocysteine ​​by organophosphorus reduction is as follows: using L-serine as raw material and dimethyl diselenoether as selenium source, L-seleno-methylselenocysteine ​​is prepared in a one-pot process under the reduction of organophosphorus. This method is basically the same as that in Example 1, except that the solvent A used is different, as shown in Table 2.

[0138]

[0139] As shown in Table 2, when other reaction solvents are used instead of solvent A (tetrahydrofuran) in Example 1, high yield and high purity of L-seleno-methylselenocysteine ​​can also be prepared, but the yield decreases. For example, when solvent A is 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, acetonitrile, or N-methylpyrrolidone, the yields of L-seleno-methylselenocysteine ​​are 55%, 56%, 48%, 51%, and 42%, respectively, all above 40%, and the HPLC purities are 99%, 98%, 98.6%, 98.4%, and 97.6%, respectively. This indicates that using a highly polar organic solvent as the reaction solvent can promote the reaction and is beneficial for obtaining L-seleno-methylselenocysteine ​​with higher yield and higher purity. Furthermore, when solvent A is methyl tert-butyl ether, toluene, diethyl ether, or dichloromethane, the yield and purity of L-seleno-methylselenocysteine ​​decrease significantly. This is because methyl tert-butyl ether, toluene, and diethyl ether have extremely poor solubility for L-serine, preventing the reaction from proceeding. Dichloromethane, with its low boiling point, also prevents the reaction from occurring. Additionally, when solvent A is methanol, ethanol, or water, L-seleno-methylselenocysteine ​​is essentially not formed. This is because methanol and ethanol contain active hydroxyl groups that are preferentially activated by organophosphorus compounds. While water can dissolve L-serine well, dimethyl diselenoether and organophosphorus compounds are insoluble, preventing the reaction from occurring. Therefore, solvent A being tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, acetonitrile, or N-methylpyrrolidone is advantageous for preparing L-seleno-methylselenocysteine ​​with high yield and high purity. In particular, when solvent A is tetrahydrofuran, 2-methyltetrahydrofuran, or ethylene glycol dimethyl ether, L-seleno-methylselenocysteine ​​with even higher yield and higher purity can be obtained.

[0140] Examples 21-23:

[0141] A method for preparing L-seleno-methylselenocysteine ​​by reduction with organophosphorus is as follows: using L-serine as raw material and dimethyl diselenoether as selenium source, L-seleno-methylselenocysteine ​​is prepared in a one-pot process under the reduction of organophosphorus. The method is basically the same as that in Example 1, except that the molar ratio (a:b:c) of dimethyl diselenoether, L-serine and organophosphorus is different, as shown in Table 3.

[0142]

[0143] Table 3 shows that optimizing the molar ratio of dimethyl diselenyl ether, L-serine, and organophosphorus ether facilitates the rapid conversion of more L-serine and dimethyl diselenyl ether into L-seleno-methylselenocysteine, and significantly affects the formation of impurity products. The result is that high-purity L-seleno-methylselenocysteine ​​can be obtained while simultaneously increasing the product yield. Furthermore, Table 3 also shows that when the amount of organophosphorus ether is low, both the reaction yield and purity decrease because L-serine is not completely converted, thus affecting both yield and purity. Conversely, excessive amounts of organophosphorus ether also lead to a decrease in purity. Additionally, increasing the amount of dimethyl diselenyl ether does not further improve the product yield. Therefore, by optimizing the molar ratio of dimethyl diselenyl ether to L-serine to 0.5–5:1 and the molar ratio of L-serine to organophosphorus to 1:1–5, this invention facilitates the acquisition of high-yield and high-purity L-seleno-methylselenocysteine. In particular, when the molar ratio of dimethyl diselenyl ether to L-serine is 0.5–1:1 and the molar ratio of L-serine to organophosphorus to 1:1.2–2, not only can the utilization rate of raw materials be significantly improved, but also L-seleno-methylselenocysteine ​​with higher yield and higher purity can be obtained.

[0144] Example 24:

[0145] A method for preparing L-seleno-methylselenocysteine ​​by reduction with organophosphorus compounds specifically comprises the following steps: using an L-serine derivative (N-acetyl-L-serine methyl ester) as a raw material and dimethyl diselenoether as a selenium source, L-seleno-methylselenocysteine ​​is prepared in a one-pot process under the reduction of organophosphorus compounds.

[0146] 112.8 g (0.6 mol, 0.6 equiv.) of dimethyl diselenyl ether and 161 g (1.0 mol, 1.0 equiv.) of N-acetyl-L-serine methyl ester were dissolved in 2000 mL of tetrahydrofuran (solvent A). 242.4 g (1.2 mol, 1.2 equiv.) of tributylphosphine was slowly added dropwise under vigorous stirring at room temperature. The mixture was heated to 60 °C and stirred. As the reaction proceeded, the solution color gradually changed from orange-red to colorless. The reaction was continued for 12 hours until the N-acetyl-L-serine methyl ester reaction was complete (monitored by TLC). After the reaction was complete, the liquid was concentrated by rotary evaporation to obtain a pale yellow viscous liquid, which was N-acetyl-L-seleno-methylselenocysteine ​​methyl ester.

[0147] The N-acetyl-L-seleno-methylselenocysteine ​​methyl ester obtained in the previous step was added to 1000 mL of 4 mol / L hydrochloric acid at room temperature. A reflux condenser was used, and the mixture was heated to 90 °C and reacted for 6 hours. As the reaction proceeded, the oily substance in the system gradually decreased, and the solution color changed from colorless to light red and then to light yellow, while emitting a pungent odor. After the reaction was complete, excess hydrochloric acid and solvent were evaporated under reduced pressure to obtain a yellowish-white solid, which was the crude product of L-seleno-methylselenocysteine ​​hydrochloride. This solid was dissolved in 200 mL of ethanol (solvent D) and heated to boiling. Then, 200 mL of petroleum ether (solvent D) was added, and the mixture was slowly cooled to room temperature. The solution was then transferred to -20 °C for cooling and crystallization. The solid was filtered out, yielding the pure L-seleno-methylselenocysteine ​​hydrochloride. The pure L-seleno-methylselenocysteine ​​hydrochloride was dissolved in ethanol (solvent C), and alkalized to pH 8-9 with triethylamine (alkalizing reagent) at 0 °C. The product precipitated from the ethanol. The triethylamine hydrochloride was dissolved in ethanol and removed by filtration. The filter residue was washed three times with 100 mL of ethanol each time to obtain crude L-seleno-methylselenocysteine. The product was dissolved in an appropriate amount of water (solvent B), heated to 60 °C, and 1.82 g of activated carbon (1% of the theoretical mass of the product) was added and stirred for 1 hour to decolorize the crude L-seleno-methylselenocysteine. After filtration, ethanol (solvent B) was added to the filtrate. After the system temperature was lowered to room temperature, it was transferred to a 4-8 °C cooler for crystallization for 12 hours. The filter residue was washed three times with 100 mL of ethanol each time to obtain 158.3 g of white powdery solid, which is L-seleno-methylselenocysteine. The yield of this product was 87%, and the HPLC purity was 99.4%.

[0148] The results from specific rotation measurement, high-resolution mass spectrometry, proton nuclear magnetic resonance (HMR) spectroscopy, and carbon nuclear magnetic resonance (CMR) spectroscopy show that:

[0149] [α] D 20 =-13.8 (c = 1.0 in H2O);

[0150] ESI-HRMS: Calculated value C4H9NO2SeNa + (M + Na + = 205.9691, measured value 205.9687;

[0151] 1 H NMR (600 M, D2O) δ 3.98 (dd, J = 7.2, 4.8 Hz, 1H), 3.10- 3.02 (m,2H), 2.07 (s, 3H).

[0152] 13C NMR (151 M, D2O) δ 173.04, 53.69, 24.82, 4.38.

[0153] As can be seen, the preparation method in Example 24 of the present invention can prepare L-seleno-methylselenocysteine.

[0154] Examples 25-30:

[0155] A method for preparing L-seleno-methylselenocysteine ​​by reduction using organophosphorus is as follows: using an L-serine derivative (N-acetyl-L-serine methyl ester) as a raw material and dimethyl diselenoether as a selenium source, L-seleno-methylselenocysteine ​​is prepared in a one-pot process under the reduction of organophosphorus. This method is basically the same as that in Example 24, except that the type of organophosphorus used is different, as shown in Table 4.

[0156]

[0157] As shown in Table 4, when other organophosphorus compounds are used instead of tributylphosphine in Example 24, high-yield and high-purity L-seleno-methylselenocysteine ​​can also be prepared. Specifically, when the organophosphorus compounds are triphenylphosphine and tris(p-tolyl)phosphine, the yields of L-seleno-methylselenocysteine ​​are 87% and 86%, respectively, and the HPLC purities are 99.3% and 99.3%, respectively. In addition, when the organophosphorus compounds are tricyclohexylphosphine and tris(m-tolyl)phosphine, the yields of the products decrease, but are still relatively high, and the purities are all above 99%. Furthermore, when the organophosphorus is tri-tert-butylphosphine or tris(o-tolyl)phosphine, the product yield decreases significantly. This is because when N-acetyl-L-serine methyl ester is used as a raw material, the increased steric hindrance around its hydroxyl group makes the reaction more sensitive to the structure of the organophosphorus. In particular, tri-tert-butylphosphine and tris(o-tolyl)phosphine have greater steric hindrance, thus the product yield decreases significantly when using these two sterically hindered organophosphorus compounds. Comparison shows that using tributylphosphine, triphenylphosphine, or tris(p-tolyl)phosphine is beneficial for obtaining higher yields and higher purity L-seleno-methylselenocysteine. Additionally, the method of this invention introduces hydrochloric acid for hydrolysis, and the resulting hydrochloride salt is recrystallized and alkalized. Recrystallization and alkalization effectively remove the generated salts and other impurities, improving product purity and ultimately yielding L-seleno-methylselenocysteine ​​with higher purity.

[0158] Examples 31-43:

[0159] A method for preparing L-seleno-methylselenocysteine ​​by reduction using organophosphorus is as follows: using an L-serine derivative (N-acetyl-L-serine methyl ester) as a raw material and dimethyl diselenoether as a selenium source, L-seleno-methylselenocysteine ​​is prepared in a one-pot process under the reduction of organophosphorus. This method is basically the same as that in Example 24, except that the type of solvent A is different, as shown in Table 5.

[0160]

[0161] As shown in Table 5, when other reaction solvents are used instead of solvent A (tetrahydrofuran) in Example 24, high yield and high purity of L-seleno-methylselenocysteine ​​can also be prepared, but the yield is reduced. For example, when solvent A is 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, N,N-dimethylformamide, N-methylpyrrolidone, or methyl tert-butyl ether, the yield of L-seleno-methylselenocysteine ​​is 80%, 77%, 78%, 67%, 63%, and 81%, respectively, all above 60%, and the HPLC purity is 99%, 98%, 98.6%, 97%, 97.6%, and 96%, respectively. This indicates that using a highly polar organic solvent as the reaction solvent can promote the reaction and is beneficial for obtaining L-seleno-methylselenocysteine ​​with higher yield and higher purity. Furthermore, when solvent A is toluene, diethyl ether, or dichloromethane, the yield and purity of L-seleno-methylselenocysteine ​​decrease significantly, indicating that the reaction is almost impossible in low-boiling-point, nonpolar solvents. In addition, when solvent A is methanol, ethanol, or water, L-seleno-methylselenocysteine ​​is essentially not formed. This is because methanol and ethanol do not promote the reaction, and water is insufficient to dissolve the starting material, hindering the reaction. Therefore, solvent A consisting of tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, N,N-dimethylformamide, N-methylpyrrolidone, or methyl tert-butyl ether is advantageous for preparing high-yield, high-purity L-seleno-methylselenocysteine. In particular, solvent A consisting of tetrahydrofuran or 2-methyltetrahydrofuran yields even higher yields and higher purity of L-seleno-methylselenocysteine.

[0162] Examples 44-48:

[0163] A method for preparing L-seleno-methylselenocysteine ​​by reduction with organophosphorus is as follows: using an L-serine derivative (N-acetyl-L-serine methyl ester) as a raw material and dimethyl diselenyl ether as a selenium source, L-seleno-methylselenocysteine ​​is prepared in a one-pot process under the reduction of organophosphorus. This method is basically the same as that in Example 24, except that the reaction temperature of dimethyl diselenyl ether and N-acetyl-L-serine methyl ester is different, as shown in Table 6.

[0164]

[0165] Table 6 shows that at low reaction temperatures (e.g., 0℃), the reactivity is poor, and almost no reaction occurs. At temperatures above 20℃, the reaction is promoted. Furthermore, at temperatures above 40℃, the yield and purity of the product are significantly improved. Particularly at temperatures between 60℃ and 90℃, the yield exceeds 80%, and the purity is above 99%. Table 6 also shows that at excessively high reaction temperatures (e.g., 100℃), side reactions occur, leading to a significant decrease in yield and the introduction of new impurities, requiring new impurity removal processes. This is detrimental to reducing energy consumption, simplifying the production process, and lowering production costs. Therefore, a reaction temperature between 60℃ and 90℃ yields L-seleno-methylselenocysteine ​​with higher yield and purity.

[0166] Examples 49-60:

[0167] A method for preparing L-seleno-methylselenocysteine ​​by reduction with organophosphorus is as follows: using an L-serine derivative (N-acetyl-L-serine methyl ester) as raw material and dimethyl diselenoether as selenium source, L-seleno-methylselenocysteine ​​is prepared in a one-pot process under the reduction of organophosphorus. This method is basically the same as that in Example 24, except that the solvent D used for recrystallizing the crude L-seleno-methylselenocysteine ​​hydrochloride is different, as shown in Table 7.

[0168]

[0169] As shown in Table 7, using different solvents D instead of ethanol / petroleum ether in Example 24 also yields high-yield, high-purity L-seleno-methylselenocysteine, but the yield decreases. Specifically, when solvent D is dichloromethane, methanol, ethanol, ethyl acetate, acetone, tetrahydrofuran, dichloromethane / n-hexane, ethanol / n-hexane, or ethanol / diethyl ether, the corresponding yields of L-seleno-methylselenocysteine ​​are 70%, 78%, 81%, 75%, and 76%, respectively. The yields of L-seleno-methylselenocysteine ​​were 79%, 76%, 85%, and 86%, all above 70%, with purities of 97%, 99.3%, 99.4%, 96%, 99.2%, 93%, 97%, 99.3%, and 99.4%, all above 93%. In particular, when solvent D was methanol, ethanol, acetone, ethanol / n-hexane, or ethanol / diethyl ether, the yield was above 76%, and the purity was above 99%, resulting in higher yields and higher purity of L-seleno-methylselenocysteine. However, when solvent D was N,N-dimethylformamide or acetonitrile, even recrystallization of the hydrolyzed product did not significantly improve the yield and purity of L-seleno-methylselenocysteine. Furthermore, directly alkalizing the hydrolyzed product without recrystallization leads to a significant decrease in product purity. It is evident that when L-serine derivatives (N-acetyl-L-serine methyl ester) are used as raw materials to prepare L-seleno-methylselenocysteine, recrystallization of the crude L-seleno-methylselenocysteine ​​hydrochloride product is required. Furthermore, solvents D such as dichloromethane, methanol, ethanol, ethyl acetate, acetone, tetrahydrofuran, dichloromethane / n-hexane, ethanol / n-hexane, ethanol / diethyl ether, and ethanol / petroleum ether are advantageous for preparing L-seleno-methylselenocysteine ​​with high yield and high purity.

[0170] Examples 61-69:

[0171] A method for preparing L-seleno-methylselenocysteine ​​by reduction with organophosphorus is as follows: using an L-serine derivative (N-acetyl-L-serine methyl ester) as raw material and dimethyl diselenoether as selenium source, L-seleno-methylselenocysteine ​​is prepared in a one-pot process under the reduction of organophosphorus. This method is basically the same as that in Example 24, except that the solvent C and the alkalizing reagent used are different, as shown in Table 8.

[0172]

[0173] Table 8 shows that using methanol and ethanol as solvent C is beneficial for obtaining high yield and high purity of L-seleno-methylselenocysteine, while using water as solvent C significantly reduces both the yield and purity of L-seleno-methylselenocysteine. Table 8 also shows that using ammonia, triethylamine, diisopropylamine, and pyridine as alkalizing agents also benefits the obtaining of high yield and high purity of L-seleno-methylselenocysteine, while using NaOH, NaHCO3, and Na2CO3 reduces the yield and purity of L-seleno-methylselenocysteine. The yield and purity of L-selenocysteine ​​decreased significantly. The reasons for this may be as follows: when methanol and ethanol are used as solvents, L-seleno-methylselenocysteine ​​hydrochloride is soluble, while L-seleno-methylselenocysteine ​​has low solubility. On the other hand, the hydrochloride of organic bases is soluble in ethanol, while the hydrochloride of inorganic bases is insoluble. At the same time, if an inorganic base is used to alkalize an organic solvent, the inorganic salt and L-seleno-methylselenocysteine ​​will precipitate simultaneously, which will not achieve the purpose of purification and will lead to a decrease in product purity.

[0174] Examples 70-77:

[0175] A method for preparing L-seleno-methylselenocysteine ​​by organophosphorus reduction is as follows: using an L-serine derivative (N-acetyl-L-serine methyl ester) as raw material and dimethyl diselenoether as selenium source, L-seleno-methylselenocysteine ​​is prepared in a one-pot process under the reduction of organophosphorus. This method is basically the same as that in Example 24, except that the amount of activated carbon and the decolorization conditions are different, as shown in Table 9.

[0176]

[0177] Table 9 shows that without decolorization, the purity of L-seleno-methylselenocysteine ​​is low. Furthermore, the product yield decreases with increasing activated carbon dosage, possibly because excessive activated carbon adsorbs more product, leading to a lower yield. However, the product yield remains above 76%, and the purity is above 99%. Considering raw material costs, the maximum economic benefit is achieved when the activated carbon dosage is 1%–5% of the theoretical product mass. Table 9 also shows that a decolorization temperature of 40℃–60℃ and a decolorization time of 1–2 h are more conducive to obtaining high yield and high purity L-seleno-methylselenocysteine. This is because: too low a decolorization temperature leads to incomplete adsorption, while too high an adsorption temperature leads to product oxidation and reduced purity; additionally, too short a decolorization time results in poor adsorption, thus reducing purity, while extending the adsorption time does not further improve purity.

[0178] Example 78:

[0179] A method for preparing L-seleno-methylselenocysteine ​​by reduction with organophosphorus compounds specifically involves: using a serine derivative (N-tert-butoxycarbonyl-L-serine methyl ester) as a raw material and dimethyl diselenoether as a selenium source, L-seleno-methylselenocysteine ​​is prepared in a one-pot process under the reduction of organophosphorus compounds, including the following steps:

[0180] 112.8 g (0.6 mol, 0.6 equiv.) of dimethyl diselenyl ether and 219 g (1.0 mol, 1.0 equiv.) of N-tert-butoxycarbonyl-L-serine methyl ester were dissolved in 2000 mL of tetrahydrofuran (solvent A). 314.4 g (1.2 mol, 1.2 equiv.) of triphenylphosphine was slowly added under vigorous stirring at room temperature. The mixture was heated to 60 °C and stirred. As the reaction proceeded, the solution color gradually changed from orange-red to colorless. The reaction was continued for 12 hours until the N-tert-butoxycarbonyl-L-serine methyl ester reaction was complete (TLC monitoring). After the reaction was complete, 400 g of calcium bromide was added, and the mixture was stirred at room temperature for 3 hours. The triphenylphosphine / calcium bromide complex precipitate was removed by filtration. The filtrate was concentrated by rotary evaporation to obtain a pale yellow viscous liquid, which was the crude product of N-tert-butoxycarbonyl-L-seleno-methylselenocysteine ​​methyl ester.

[0181] The crude N-tert-butoxycarbonyl-L-seleno-methylselenocysteine ​​methyl ester obtained in the previous step was added to 1000 mL of 4 mol / L hydrochloric acid at room temperature. The mixture was stirred at room temperature until no bubbles were generated, and a reflux condenser was used to heat the mixture to 90 °C for 6 hours. As the reaction proceeded, the oily substance in the system gradually decreased, and the solution color changed from colorless to light red and then to light yellow, while emitting a pungent odor. After the reaction was completed, excess hydrochloric acid and solvent were evaporated under reduced pressure to obtain a yellowish-white solid. 200 mL of ethanol (solvent D) was added to dissolve the solid, and the mixture was heated to boiling. Then, 200 mL of diethyl ether (solvent D) was added, and the mixture was slowly cooled to room temperature. The solution was then transferred to -20 °C for cooling and crystallization for 24 hours. The solid was filtered out, which is the pure L-seleno-methylselenocysteine ​​hydrochloride. The hydrochloride salt was dissolved in ethanol (solvent C), and triethylamine (alkalizing agent) was added at 0 °C to alkalize to pH 8-9. The product precipitated from the ethanol. The triethylamine hydrochloride was dissolved in ethanol and removed by filtration. The filter residue was washed three times with 100 mL of ethanol each time. The product was dissolved in an appropriate amount of water (solvent B), heated to 60 °C, and 1.82 g of activated carbon was added and stirred for 1 hour for decolorization. After filtration, ethanol (solvent B) was added to the filtrate. After the system temperature was cooled to room temperature, it was transferred to a 4-8 °C cool cabinet for crystallization for 12 hours. The filter residue was washed three times with 100 mL of ethanol each time to obtain 156.5 g of white powdery solid, which is L-seleno-methylselenocysteine. The yield of this product was 86.0%, and the HPLC purity was 99.4%.

[0182] The results from specific rotation measurement, high-resolution mass spectrometry, proton nuclear magnetic resonance (HMR) spectroscopy, and carbon nuclear magnetic resonance (CMR) spectroscopy show that:

[0183] [α] D 20 =-13.9 (c = 1.0 in H2O);

[0184] ESI-HRMS: Calculated value C4H9NO2SeNa + (M + Na + = 205.9691, measured value 205.9690;

[0185] 1 H NMR (600 M, D2O) δ 3.98 (dd, J = 7.2, 4.8 Hz, 1H), 3.10 - 3.02 (m,2H), 2.07 (s, 3H).

[0186] 13 C NMR (151 M, D2O) δ 173.04, 53.69, 24.82, 4.38.

[0187] As can be seen, the preparation method in Example 78 of the present invention can prepare L-seleno-methylselenocysteine.

[0188] In summary, as can be clearly seen from all the above embodiments, when using the method of the present invention, that is, using a composite reaction system composed of dimethyl diselenyl ether, L-serine or L-serine derivatives and organophosphorus compounds, high-yield L-seleno-methylselenocysteine ​​can be obtained directly through one or two steps of reaction. Furthermore, the above embodiments also demonstrate that the purification scheme adopted in this invention can greatly improve the purity of L-seleno-methylselenocysteine. In addition, the preparation method of the present invention has advantages such as a simple synthetic route, no need to use explosive borohydride reducing agents or Grignard reagents, mild reaction conditions, safe and reliable process, inexpensive and readily available raw materials, high product yield, and high purity. It plays a significant role in promoting the large-scale industrial application of L-seleno-methylselenocysteine.

[0189] The above embodiments are merely preferred embodiments of the present invention, and the scope of protection of the present invention is not limited to the above embodiments. All technical solutions falling within the scope of the present invention's concept are within the scope of protection of the present invention. It should be noted that for those skilled in the art, improvements and modifications made without departing from the principles of the present invention should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing L-seleno-methylselenocysteine ​​by reduction using organophosphorus compounds, characterized in that, L-Selen-methylselenocysteine ​​was prepared in a one-pot process using L-serine derivatives as raw materials and dimethyl diselenoether as the selenium source under the reduction of organophosphorus compounds. The chemical reaction equation for L-selen-methylselenocysteine ​​is shown in equation (3), and includes the following steps: (1) Dimethyl diselenyl ether, L-serine derivative and organophosphorus are dissolved in solvent A and reacted to obtain L-seleno-methylselenocysteine ​​derivative; the molar ratio of dimethyl diselenyl ether to L-serine derivative is 0.5 to 2:1; the molar ratio of L-serine derivative to organophosphorus is 1:1.2 to 3; the ratio of L-serine derivative to solvent A is 0.2 mol to 0.5 mol:1 L; solvent A is tetrahydrofuran; the reaction temperature is 60 ℃ to 80 ℃; the reaction time is 12 h to 16 h; (2) The L-seleno-methylselenocysteine ​​derivative obtained in step (1) is mixed with hydrochloric acid and hydrolyzed to obtain crude L-seleno-methylselenocysteine ​​hydrochloride; the concentration of the hydrochloric acid is 4 mol / L to 12 mol / L; the hydrolysis is carried out at a temperature of 60 ℃ to 90 ℃; the hydrolysis time is 2 h to 12 h. (3) Dissolve the crude L-seleno-methylselenocysteine ​​hydrochloride obtained in step (2) in solvent C, add an alkalizing agent for alkalization, and obtain crude L-seleno-methylselenocysteine; the crude L-seleno-methylselenocysteine ​​hydrochloride is further treated as follows before being dissolved in solvent C: dissolve the crude L-seleno-methylselenocysteine ​​hydrochloride in solvent D, recrystallize at -20 ℃ for 12 h to 48 h, and obtain L-seleno-methylselenocysteine ​​hydrochloride; the solvent D is one of the following: a combination solvent of ethanol and n-hexane, a combination solvent of ethanol and petroleum ether, or a combination solvent of ethanol and diethyl ether; the solvent C is at least one of methanol and ethanol; the alkalizing agent is triethylamine; the alkalization is carried out at a temperature of 0 ℃ to 30 ℃; the pH of the system after alkalization is 6 to 9. (4) Dissolve the crude L-seleno-methylselenocysteine ​​obtained in step (3) in solvent B, decolorize, and recrystallize to obtain L-seleno-methylselenocysteine; the solvent B is at least one of water and ethanol; the decolorization is performed by adding activated carbon to solvent B to decolorize the crude L-seleno-methylselenocysteine; the amount of activated carbon added is 1% to 2% of the theoretical product mass; the decolorization is carried out at a temperature of 60 °C; the decolorization time is 1 h to 2 h; the recrystallization is carried out at a temperature of 4 °C to 8 °C; the recrystallization time is 12 h to 24 h; （3）； The R 1 It is at least one of acetyl or tert-butyloxycarbonyl; The R 2 It is at least one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl; The R 3 It is at least one of n-butyl, phenyl, and p-tolyl.

2. The method according to claim 1, characterized in that, In step (1), the molar ratio of dimethyl diselenyl ether to L-serine derivative is 0.5 to 1:1; the molar ratio of L-serine derivative to organophosphorus is 1:1.2 to 2. In step (2), the concentration of hydrochloric acid is 4 mol / L to 6 mol / L; the hydrolysis is carried out at a temperature of 80 ℃ to 90 ℃; and the hydrolysis time is 6 h to 12 h. In step (3), the alkalization is carried out at a temperature of 0 ℃~10 ℃; after the alkalization is completed, the pH value of the system is 8~9; In step (4), solvent B is water and ethanol; the amount of activated carbon added is 1% of the theoretical product mass.

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