Method for preparing L-selenium-methyl selenocysteine through reduction of organic phosphine

Abstract

The invention discloses a method for preparing L-selenium-methyl selenocysteine by reduction of organic phosphine, which comprises the following steps: by taking L-serine or an L-serine derivative as a raw material and dimethyl diselenide as a selenium source, preparing the L-selenium-methyl selenocysteine by adopting a one-pot method under the reduction action of the organic phosphine. Compared with a conventional chemical synthesis method, the method for preparing the L-selenium-methyl selenocysteine through reduction of the organic phosphine has the advantages that the L-selenium-methyl selenocysteine and the derivative thereof can be efficiently synthesized under the reduction action of the organic phosphine, and the high-yield and high-purity L-selenium-methyl selenocysteine can be obtained; the method has the advantages of simple synthesis route, no need of using a borohydride reducing agent or Grignard reagent with explosion hidden danger, mild reaction conditions, safe and reliable process, cheap and easily available raw materials, high product yield, high purity and the like, and has an important promotion effect on large-scale industrial application of the L-selenium-methyl selenocysteine.

Description

Technical Field

[0001] The invention belongs to the technical field of organic fine chemical synthesis and relates to a method for preparing L-seleno-methylselenocysteine ​​by reducing organic phosphine. Background Art

[0002] At present, the preparation methods of L-seleno-methylselenocysteine ​​are mainly divided into biological extraction and chemical synthesis. The biological extraction method relies on natural organic selenium resources. Although it can directly obtain natural L-seleno-methylselenocysteine, its large-scale application is limited by its low selenium content, complex extraction process, low yield and high cost, and the existence of excessive heavy metals. In contrast, the chemical synthesis method has become an ideal choice for large-scale production of L-seleno-methylselenocysteine ​​due to its relatively low production cost and easy industrial operation. There are currently six main methods for the synthesis of L-seleno-methylselenocysteine: Method 1: α-amino acrylate derivative method Dimethyl diselenide is reduced with sodium borohydride (lithium, potassium) under alkaline conditions to generate a methyl selenol intermediate, which then undergoes a Michael addition reaction with amino acrylate to generate β-selenomethyl-α-amino acrylate. Subsequently, it undergoes saponification and acidification to obtain a carboxylic acid compound, which is then heated and hydrolyzed to remove the acetyl protection of the amino group, and finally neutralized to obtain DL-seleno-methylselenocysteine, which then needs to be enzymatically resolved to obtain L-seleno-methylselenocysteine. As a key step in the entire process, the effect of enzymatic resolution is affected by many factors, resulting in low overall yield, high production cost, unstable purity, and difficulty in meeting the needs of large-scale production.

[0003] Method 2: Sodium diselenide method Selenium powder is reduced in situ in sodium borohydride to obtain a sodium diselenide solution, which reacts with 3-chloro-L-alanine to generate L-selenocysteine ​​through a bimolecular nucleophilic substitution reaction. Subsequently, the Se-Se bond is cleaved under ultra-low temperature (-70°C) conditions of metallic sodium and liquid ammonia, and finally a methylation reaction occurs with iodomethane under alkaline conditions to obtain the target product L-seleno-methylselenocysteine. Although this method has certain theoretical feasibility, it has extremely high requirements for process conditions, such as the use of hazardous chemicals such as liquid ammonia and metallic sodium, and requires nitrogen protection. It has strict requirements on equipment and is difficult to adapt to the needs of industrial production.

[0004] Method 3: N-tert-butyloxycarbonyl-L-serine lactone method This method uses N-tert-butyloxycarbonyl-L-serine as a raw material, firstly, β-lactone is obtained by intramolecular Mitsunobu reaction under the action of azodicarbonate and triphenylphosphine, then dimethyl diselenide is reduced in situ by sodium borohydride (lithium, potassium) under alkaline conditions to generate methylselenol or methylselenol salt intermediates and the β-lactone undergoes a ring-opening reaction to generate N-tert-butyloxycarbonyl protected L-seleno-methylselenocysteine, and finally, the tert-butyloxycarbonyl group is removed under the catalysis of trifluoroacetic acid to obtain L-seleno-methylselenocysteine. However, this method has many shortcomings: first, when preparing β-lactone, it is necessary to add materials at -78 °C for a certain period of time and then heat to room temperature for reaction, resulting in harsh process conditions; second, the use of sodium borohydride as a reducing agent will result in multiple side reactions of β-lactone, resulting in a low total yield and high cost. Therefore, this method is also difficult to adapt to large-scale production.

[0005] Method 4: 2,3-Dihalopropionitrile method Dimethyl diselenide is reduced by sodium borohydride (lithium, potassium) under alkaline conditions to generate a methyl selenol intermediate, which reacts with 2,3-dihalopropionitrile through a regioselective bimolecular nucleophilic substitution reaction to obtain 2-halo-3-methylselenopropionitrile, which is then hydrolyzed under acidic conditions to obtain 2-halo-3-methylselenopropionic acid, which is then aminated to obtain DL-seleno-methylselenocysteine, which is then protected by acetyl group to obtain N-acetyl-L-seleno-methylselenocysteine, which is then enzymatically resolved to obtain N-acetyl-L-seleno-methylselenocysteine, and finally optically pure L-seleno-methylselenocysteine ​​is obtained by removing the protecting group under acidic conditions. Although this method theoretically achieves the synthesis of the target product, the selectivity of the substitution reaction of halogenated hydrocarbons is low, and the enzymatic resolution process requires protection with acetyl groups before removal, which results in cumbersome steps and high costs, making it unsuitable for large-scale industrial production.

[0006] Method 5: Sodium borohydride (lithium / potassium) reduction method This method uses dimethyl diselenide as a raw material, and uses sodium borohydride (lithium, potassium) to reduce it under alkaline conditions to generate a methyl selenol salt intermediate, which is then reacted with 3-halo-L-serine or its 3-halo-L-serine ester to obtain an L-seleno-methylselenocysteine ​​precursor, and then the protecting group is removed by hydrolysis to obtain L-seleno-methylselenocysteine. Although the process flow of this method is simple and efficient, the reducing agent used has an explosion risk. In addition, the chiral source used is expensive, the overall production cost is high, and it is difficult to meet the requirements of large-scale production.

[0007] Method 6: Format method This method uses methylmagnesium bromide and selenium powder to prepare methylselenomagnesium bromide in situ, which then reacts with N-tert-butyloxycarbonyl-3-halo-L-serine ester to obtain L-seleno-methylselenocysteine ​​precursor, which is then hydrolyzed under acidic conditions to obtain optically pure L-seleno-methylselenocysteine. Although this reaction can avoid the use of sodium borohydride, which has an explosion risk, methylmagnesium bromide is expensive, and there are great safety risks in preparing Grignard reagents by yourself. In addition, the reaction needs to be carried out under anhydrous and oxygen-free conditions, and the reaction conditions are harsh and not suitable for industrial production.

[0008] In summary, methods one to five require the use of sodium borohydride (lithium / potassium) as a reducing agent to prepare methylselenol salt or sodium diselenide, which poses a great risk of explosion. Method six requires the use of a methyl Grignard reagent or the use of magnesium metal to prepare a methyl Grignard reagent by itself, which also poses a safety hazard. In addition, the raw materials used in the existing chemical synthesis methods of L-seleno-methylselenocysteine ​​all need to first undergo a halogenation reaction on the hydroxyl group of L-serine, which has problems such as complex processes, harsh conditions, and high costs, limiting the large-scale industrial application of L-seleno-methylselenocysteine. Therefore, if L-seleno-methylselenocysteine ​​can be directly prepared using L-serine or its derivatives, it will play an important role in promoting the large-scale industrial application of L-seleno-methylselenocysteine. Summary of the invention

[0009] The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide a method for preparing L-seleno-methylselenocysteine ​​by reduction with organic phosphine, which has the advantages of simple process, convenient operation, mild preparation conditions, high safety factor, high yield and high purity.

[0010] In order to solve the above technical problems, the present invention adopts the following technical solutions: A method for preparing L-seleno-methylselenocysteine ​​by reducing with an organic phosphine, using L-serine or an L-serine derivative as a raw material and dimethyl diselenide as a selenium source, and preparing L-seleno-methylselenocysteine ​​by a one-pot method under the reduction of an organic phosphine, wherein the chemical reaction equation is as follows: (1), In formula (1): The R 1 is at least one of hydrogen (H), acetyl (Ac), tert-butyloxycarbonyl (Boc), and trityl (Tr); The R 2 is 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); The R 3 For n-butyl ( n Bu), tert-butyl ( t Bu), cyclohexyl (Cy), phenyl (Ph), p-tolyl ( p -Tolyl), m-tolyl ( m -Tolyl), o-tolyl ( o -Tolyl) at least one.

[0011] The above method is further improved, the R 3 For n-butyl ( n Bu), cyclohexyl (Cy), phenyl (Ph), p-tolyl ( p -Tolyl), m-tolyl ( m -Tolyl) at least one.

[0012] The above method is further improved, the R 3 For n-butyl ( n Bu), phenyl (Ph), p-tolyl ( p -Tolyl) at least one.

[0013] The above method is further improved, when R 1 and R 2 When all are hydrogen, the chemical reaction equation for preparing the L-seleno-methylselenocysteine ​​is shown in formula (2), which includes the following steps: S1, dissolving dimethyl diselenide, L-serine and organic phosphine in solvent A for reaction to obtain a crude L-seleno-methylselenocysteine ​​product; S2, dissolving the crude L-seleno-methylselenocysteine ​​obtained in step S1 into solvent B, decolorizing, and recrystallizing to obtain L-seleno-methylselenocysteine; (2).

[0014] The above method is further improved, in step S1, the molar ratio of dimethyl diselenide to L-serine is 0.5-5:1; the molar ratio of L-serine to organic phosphine is 1:1-5; the ratio of L-serine to solvent A is 0.01 mol-10 mol:1 L; the 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 0-100°C; and the reaction time is 2 h-24 h.

[0015] The above method is further improved, in step S2, the solvent B is at least one of water, methanol and ethanol; the decolorization is to add activated carbon to the 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°C to 100°C; the decolorization time is 0.5 h to 12 h; the recrystallization is carried out at a temperature of 4°C to 8°C; the recrystallization time is 12h to 24h.

[0016] The above method is further improved, in step S1, the molar ratio of dimethyl diselenide to L-serine is 0.5-2:1; the molar ratio of L-serine to organic phosphine is 1:1-4; the ratio of L-serine to solvent A is 0.1 mol-1 mol:1 L; the 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.

[0017] The above method is further improved, 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°C to 100°C.

[0018] The above method is further improved, in step S1, the molar ratio of dimethyl diselenide to L-serine is 0.5-1:1; the molar ratio of L-serine to organic phosphine is 1:1.2-2; the ratio of L-serine to solvent A is 0.1 mol-0.5 mol:1 L; the solvent A is at least one of tetrahydrofuran, 2-methyl-tetrahydrofuran, and ethylene glycol dimethyl ether; the reaction temperature is 60°C-90°C; and the reaction time is 12 h-16 h.

[0019] The above method is further improved, 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°C to 60°C.

[0020] The above method is further improved, when R 1 Not hydrogen, R 2 Not hydrogen or R 1 and R 2 When both are not hydrogen, the chemical reaction equation for preparing the L-seleno-methylselenocysteine ​​is shown in Formula (3), which comprises the following steps: (1) dissolving dimethyl diselenide, an L-serine derivative and an organic phosphine in a solvent A for reaction to obtain an L-seleno-methylselenocysteine ​​derivative; (2) mixing the L-seleno-methylselenocysteine ​​derivative prepared in step (1) with hydrochloric acid for hydrolysis to obtain a crude L-seleno-methylselenocysteine ​​hydrochloride product; (3) dissolving the crude L-seleno-methylselenocysteine ​​hydrochloride product obtained in step (2) in solvent C, adding an alkalizing agent for alkalization, and obtaining a crude L-seleno-methylselenocysteine ​​product; (4) dissolving the crude L-seleno-methylselenocysteine ​​obtained in step (3) in solvent B, decolorizing, and recrystallizing to obtain L-seleno-methylselenocysteine; (3).

[0021] The above method is further improved, in step (1), the molar ratio of dimethyl diselenide to L-serine derivative is 0.5-5:1; the molar ratio of L-serine derivative to organic phosphine is 1:1-5; the ratio of L-serine derivative to solvent A is 0.01 mol-10 mol:1 L; the 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°C-100°C; and the reaction time is 2 h-24 h.

[0022] The above method is further improved, in step (2), the concentration of the hydrochloric acid is 2 mol / L to 12 mol / L; the hydrolysis is carried out at a temperature of 40°C to 100°C; and the hydrolysis time is 2 h to 24 h.

[0023] The above method is further improved, in which, before the crude L-seleno-methylselenocysteine ​​hydrochloride product is dissolved in solvent C in step (3), the following treatment is further included: dissolving the crude L-seleno-methylselenocysteine ​​hydrochloride product in solvent D, and recrystallizing at -20°C for 12 h to 48 h to obtain L-seleno-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 ether; the solvent C is at least one of methanol and ethanol; the alkalizing agent is at least one of ammonia water, triethylamine, diisopropylamine, and pyridine; the alkalization is carried out at a temperature of 0°C to 40°C; and the pH value of the system after the alkalization is completed is 5.5 to 9.

[0024] The above method is further improved, in step (4), the solvent B is at least one of water, methanol and ethanol; the decolorization is performed by adding activated carbon to the 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 performed at a temperature of 20°C to 100°C; the decolorization time is 0.5 h to 12 h; the recrystallization is performed at a temperature of 4°C to 8°C; and the recrystallization time is 12 h to 24 h.

[0025] The above method is further improved, in step (1), the molar ratio of dimethyl diselenide to L-serine derivative is 0.5-2:1; the molar ratio of L-serine derivative to organic phosphine is 1:1-4; the ratio of L-serine derivative to solvent A is 0.1 mol-1 mol:1 L; the 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°C-100°C; and the reaction time is 6 h-18 h.

[0026] The above method is further improved, in step (2), the concentration of the hydrochloric acid is 4 mol / L to 12 mol / L; the hydrolysis is carried out at a temperature of 60°C to 90°C; and the hydrolysis time is 2 h to 12 h.

[0027] The above method is further improved, 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, and a combination solvent of ethanol and ether; the alkalizing agent is at least one of triethylamine and pyridine; the alkalization is carried out at a temperature of 0°C to 30°C; and the pH value of the system after the alkalization is completed is 6 to 9.

[0028] The above method is further improved, 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°C to 100°C.

[0029] The above method is further improved, in step (1), the molar ratio of dimethyl diselenide to L-serine derivative is 0.5-1:1; the molar ratio of L-serine derivative to organic phosphine is 1:1.2-2; the ratio of L-serine derivative to solvent A is 0.2 mol-0.5 mol:1 L; the 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°C-90°C; and the reaction time is 12 h-16 h.

[0030] The above method is further improved, in step (2), the concentration of the hydrochloric acid is 4 mol / L to 6 mol / L; the hydrolysis is carried out at a temperature of 80°C to 90°C; and the hydrolysis time is 6 h to 12 h.

[0031] The above method is further improved, in step (3), the 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 ether; the alkalizing agent is triethylamine; the alkalization is carried out at a temperature of 0°C to 10°C; and the pH value of the system after the alkalization is completed is 8 to 9.

[0032] The above method is further improved, 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°C to 60°C.

[0033] The principle of preparing L-seleno-methylselenocysteine ​​by organic phosphine reduction is as follows: The present invention is based on the synergistic activation mechanism of organic phosphine: on the one hand, the oxygen-philic property of organic phosphine can be used to effectively activate the hydroxyl group of L-serine (or its derivatives); on the other hand, the strong electron-donating effect of organic phosphine can promote the activation of the Se-Se bond of dimethyl diselenide, thereby realizing the one-step directional construction of the carbon-selenium bond, and finally efficiently synthesizing L-seleno-methylselenocysteine ​​and its derivatives. In addition, when L-seleno-methylselenocysteine ​​is prepared by using L-serine derivatives, the amino / carboxyl protecting groups in the L-seleno-methylselenocysteine ​​derivatives can be removed by hydrolysis under the catalytic condition of hydrochloric acid, and the recrystallization and neutralization process of L-seleno-methylselenocysteine ​​hydrochloride are crucial to improving the purity of the final product, especially during neutralization, the difference between the high solubility of the generated salt in the methanol / ethanol system and the low solubility of the target product can be used to effectively separate the fat-soluble impurities, and then activated carbon adsorption combined with the gradient recrystallization process is used to finally obtain L-seleno-methylselenocysteine ​​with an HPLC purity of more than 99%.

[0034] Compared with the prior art, the advantages of the present invention are: (1) In the present invention, L-serine or an L-serine derivative is directly used as a chiral source without halogenation, and a single-configuration L-seleno-methylselenocysteine ​​is directly synthesized in one or two steps. The synthetic route is simple and avoids the enzymatic resolution step and the waste of the D-configuration product caused by it.

[0035] (2) In the present invention, the carbon-selenium bond between L-serine or an L-serine derivative and dimethyl diselenide can be constructed by utilizing the oxophilicity and strong reducing property of organic phosphine, without using a borohydride reducing agent or a Grignard reagent with explosion hazard. The reaction conditions are mild, the process is safe and reliable, and the raw materials are cheap and readily available.

[0036] (3) In the present invention, by recrystallizing L-seleno-methylselenocysteine ​​hydrochloride and utilizing the solubility difference between L-seleno-methylselenocysteine ​​hydrochloride and L-seleno-methylselenocysteine, the product can be refined and impurity-removed without using ion exchange resin to remove inorganic salts, and L-seleno-methylselenocysteine ​​with HPLC purity>99% can be prepared. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] In order to make the purpose, technical solution and advantages of the embodiments of the present invention more clear, the technical solution in the embodiments of the present invention will be clearly and completely described below in conjunction with the accompanying drawings in the embodiments of the present invention.

[0038] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of L-seleno-methylselenocysteine ​​prepared in Example 1 of the present invention.

[0039] Figure 2 This is the carbon nuclear magnetic resonance spectrum of L-seleno-methylselenocysteine ​​prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0040] The present invention is further described below in conjunction with the accompanying drawings and specific preferred embodiments of the specification, but the protection scope of the present invention is not limited thereby. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0041] The "range" disclosed in the present invention can be defined in the form of a lower limit and an upper limit, and a given range is defined by selecting a lower limit and an upper limit, and the selected lower limit and upper limit define the boundaries of a particular range. The range defined in this way can be inclusive or exclusive of the end values, and any end value can be included or excluded independently, and can be arbitrarily combined, that is, any lower limit can be combined with any upper limit to form a range. For example, if a range of 60 to 120 and 80 to 110 is listed for a specific parameter, it is understood that a range of 60 to 110 and 80 to 120 is also expected. In addition, if the minimum range values ​​1 and 2 are listed, and if the maximum range values ​​3, 4 and 5 are also listed, the following ranges can all be expected: 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4 and 2 to 5. In the present invention, unless otherwise specified, the numerical range "a to b" represents an abbreviation of any real number combination between a and b, wherein a and b are both real numbers. For example, the numerical range "0-5" means that all real numbers between "0-5" have been listed in this article, and "0-5" is just an abbreviation of these numerical combinations.

[0042] In the present invention, "plurality", "multiple" and the like, unless otherwise specified, refer to a number greater than or equal to 2. For example, "one or more" means one or greater than or equal to two.

[0043] If not otherwise specified, all embodiments and optional embodiments of the present invention can be combined with each other to form a new technical solution. The reference to "embodiment" in this article means that the specific features, structures or characteristics described in conjunction with the embodiment can be included in at least one embodiment or embodiment of the present invention. The appearance of this phrase in various locations in the specification does not necessarily refer to the same embodiment, nor is it an independent or alternative embodiment that is mutually exclusive with other embodiments. It is explicitly and implicitly understood by those skilled in the art that the embodiments described herein can be combined with other embodiments. The "embodiment" mentioned in this article has a similar understanding.

[0044] Those skilled in the art will appreciate that, in the methods of various embodiments or examples, the order in which each step is written does not mean 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 may be performed sequentially or randomly, preferably sequentially. For example, the method includes steps (a) and (b), indicating that the method may include steps (a) and (b) performed sequentially, or may include steps (b) and (a) performed sequentially. For example, the method may also include step (c), indicating that step (c) may be added to the method in any order, for example, the method may include steps (a), (b) and (c), or may include steps (a), (c) and (b), or may include steps (c), (a) and (b), etc. In the present invention, unless otherwise specified, A (such as B) indicates that B is a non-limiting example of A, and it can be understood that A is not limited to B.

[0045] In the present invention, "optionally", "optional", "optional", "further improved" means optional, that is, it means to be selected from any one of the two parallel schemes of "yes" or "no". If there are multiple "options" in a technical solution, unless otherwise specified and there is no contradiction or mutual restriction, each "option" is independent.

[0046] In view of the defects of the existing L-seleno-methylselenocysteine ​​synthesis method, such as complex process, high cost, harsh conditions, low safety factor, low yield and low purity, the present invention creatively proposes a method for preparing L-seleno-methylselenocysteine ​​by reducing with organic phosphine. In the method, a synergistic activation mechanism of organic phosphine is used: on the one hand, the oxygen-philic property of organic phosphine can be used to effectively activate the hydroxyl group of L-serine (or its derivatives); on the other hand, the strong electron-donating effect of organic phosphine can be used to promote the activation of the Se-Se bond of dimethyl diselenide, thereby realizing the one-step directional construction of carbon-selenium bonds, and finally efficiently synthesizing L-seleno-methylselenocysteine ​​and its derivatives. In addition, when L-seleno-methylselenocysteine ​​is prepared from L-serine derivatives, the amino / carboxyl protecting groups in the L-seleno-methylselenocysteine ​​derivatives can be removed by hydrolysis under hydrochloric acid catalysis, and the recrystallization and neutralization process of L-seleno-methylselenocysteine ​​hydrochloride is crucial to improving the purity of the final product. In particular, during neutralization, the difference between the high solubility of the generated salt in the methanol / ethanol system and the low solubility of the target product can be used to effectively separate the fat-soluble impurities, and then activated carbon adsorption combined with a gradient recrystallization process is used to finally obtain L-seleno-methylselenocysteine ​​with an HPLC purity of >99%.

[0047] It can be understood that the method of preparing L-seleno-methylselenocysteine ​​by organic phosphine reduction of the present invention is to use L-serine or an L-serine derivative as a raw material, dimethyl diselenide as a selenium source, and adopt a one-pot method to prepare L-seleno-methylselenocysteine ​​under the reduction action of organic phosphine. The chemical reaction equation is as follows: (1), In formula (1): R 1 is at least one of hydrogen (H), acetyl (Ac), tert-butyloxycarbonyl (Boc), and trityl (Tr); R 2 is 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); R 3 For n-butyl ( n Bu), tert-butyl ( t Bu), cyclohexyl (Cy), phenyl (Ph), p-tolyl ( p -Tolyl), m-tolyl ( m -Tolyl), o-tolyl ( o -Tolyl) at least one.

[0048] In some embodiments, further preferably, R 3 For n-butyl ( n Bu), cyclohexyl (Cy), phenyl (Ph), p-tolyl ( p -Tolyl), m-tolyl ( m -Tolyl) at least one. 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 organic phosphines are tributylphosphine, tricyclohexylphosphine, triphenylphosphine, tri(p-tolyl)phosphine, and tri(m-tolyl)phosphine.

[0049] In some embodiments, more preferably, R 3 For n-butyl ( n Bu), phenyl (Ph), p-tolyl ( p -Tolyl) at least one. As an example, R 3 It can be n-butyl (n Bu), phenyl (Ph), p-tolyl ( p -Tolyl), the corresponding organic phosphines are tributylphosphine, triphenylphosphine, and tri(p-tolyl)phosphine.

[0050] In the present invention, by selecting a suitable type of organic phosphine, it is more conducive to promoting the reaction of L-serine or an L-serine derivative with dimethyl diselenide, and ultimately more conducive to the efficient synthesis of high-quality L-seleno-methylselenocysteine.

[0051] In some embodiments, when R 1 and R 2 When all are hydrogen, that is, when L-serine is used as the raw material, the corresponding chemical reaction equation for preparing L-seleno-methylselenocysteine ​​is shown in formula (2), which includes the following steps: S1, dissolving dimethyl diselenide, L-serine and organic phosphine in solvent A for reaction to obtain a crude L-seleno-methylselenocysteine ​​product; S2, dissolving the crude L-seleno-methylselenocysteine ​​obtained in step S1 into solvent B, decolorizing, and recrystallizing to obtain L-seleno-methylselenocysteine; (2).

[0052] In some embodiments, it is further preferred that in step S1, the molar ratio of dimethyl diselenide to L-serine is 0.5 to 5: 1. As an example, the molar ratio of dimethyl diselenide to L-serine may 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, 5: 1, or it may be within the range formed by any two of the above point values ​​as end values, such as the molar ratio of dimethyl diselenide to L-serine is 0.5 to 2: 1, and the molar ratio of dimethyl diselenide to L-serine is 0.5 to 1: 1.

[0053] In some embodiments, further preferably, in step S1, the molar ratio of L-serine to the organic phosphine is 1:1 to 5. As an example, the molar ratio of L-serine to the organic phosphine may 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, 1:5, or may be within the range formed by any two of the above point values ​​as end values, such as the molar ratio of L-serine to the organic phosphine is 1:1 to 4, and the molar ratio of L-serine to the organic phosphine is 1:1.2 to 2.

[0054] In some embodiments, further preferably, in step S1, the ratio of L-serine to solvent A is 0.01 mol to 10 mol: 1 L to 1 L. As an example, the ratio of L-serine to solvent A may 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 : 1 L, 3.8 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, and can also be within the range formed by any two of the above point values ​​as end values, such as the ratio of L-serine to solvent A is 0.1 mol to 1 mol: 1 L, and the ratio of L-serine to solvent A is 0.1 mol to 0.5 mol: 1 L.

[0055] In some embodiments, it is further preferred that in step S1, 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. As an example, solvent A may be tetrahydrofuran, 2-methyl-tetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, methyl tert-butyl ether, N,N-dimethylformamide, acetonitrile, N-methylpyrrolidone, and toluene. It is further preferred that solvent A is at least one of tetrahydrofuran, 2-methyl-tetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, acetonitrile, and N-methylpyrrolidone. As an example, solvent A may be tetrahydrofuran, 2-methyl-tetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, acetonitrile, and N-methylpyrrolidone. Particularly preferably, solvent A 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, and ethylene glycol dimethyl ether.

[0056] In some embodiments, further preferably, in step S1, the reaction temperature is 0°C to 100°C. As an example, the reaction temperature may be 0°C, 10°C, 20°C, 30°C, 40°C, 45°C, 50°C, 55°C, 58°C, 60°C, 63°C, 65°C, 68°C, 70°C, 72°C, 75°C, 77°C, 80°C, 82°C, 86°C, 88°C, 90°C, 91°C, 94°C, 95°C, 96°C, 98°C, 100°C, or any two of the above points may be used as end values. For example, when the reaction temperature is 40°C to 100°C, the reaction temperature is 60°C to 90°C.

[0057] In some embodiments, further preferably, in step S1, the reaction time 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, 24 h, or can be within the range of any two of the above point values ​​as end values, such as the reaction time is 6 h to 18 h, and the reaction time is 12 h to 16 h.

[0058] In some embodiments, further preferably, in step S2, solvent B is at least one of water, methanol and ethanol. As an example, solvent B is water, methanol and ethanol, and can also be a combination of water and methanol, or a combination of water and ethanol, but is not limited thereto.

[0059] In some embodiments, it is further preferred that in step S2, decolorization is performed by adding activated carbon to solvent B to decolorize the crude L-seleno-methylselenocysteine ​​product. In the present invention, the decolorizing agent used may be activated carbon, but is not limited thereto.

[0060] In some embodiments, further preferably, in step S2, the amount of activated carbon added is 1% to 5% of the mass of the theoretical product. 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%, 5% of the mass of the theoretical product, or it can be within the range of any two of the above point values ​​as end values, such as the amount of activated carbon added is 1% to 2% of the mass of the theoretical product, and the amount of activated carbon added is 1% of the mass of the theoretical product.

[0061] In some embodiments, further preferably, in step S2, the bleaching is performed at a temperature of 20°C to 100°C. As an example, the bleaching may be performed at a temperature 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, 100°C, or within a range consisting of any two of the above point values ​​as end values, such as bleaching at a temperature of 40°C to 100°C, or bleaching at a temperature of 40°C to 60°C.

[0062] In some embodiments, further preferably, in step S2, the decolorization time is 0.5 h to 12 h. Further preferably, in step S2, the recrystallization is performed at a temperature of 4° C. to 8° C., and the recrystallization time is 12 h to 24 h.

[0063] In some embodiments, when R 1 Not hydrogen, R 2 Not hydrogen or R 1 and R 2 When neither is hydrogen, that is, when L-serine derivatives are used as raw materials, the corresponding chemical reaction equation for preparing L-seleno-methylselenocysteine ​​is shown in formula (3), which includes the following steps: (1) dissolving dimethyl diselenide, an L-serine derivative and an organic phosphine in a solvent A for reaction to obtain an L-seleno-methylselenocysteine ​​derivative; (2) mixing the L-seleno-methylselenocysteine ​​derivative prepared in step (1) with hydrochloric acid for hydrolysis to obtain a crude L-seleno-methylselenocysteine ​​hydrochloride product; (3) dissolving the crude L-seleno-methylselenocysteine ​​hydrochloride product obtained in step (2) in solvent C, adding an alkalizing agent for alkalization, and obtaining a crude L-seleno-methylselenocysteine ​​product; (4) dissolving the crude L-seleno-methylselenocysteine ​​obtained in step (3) in solvent B, decolorizing, and recrystallizing to obtain L-seleno-methylselenocysteine; (3).

[0064] In some embodiments, it is further preferred that in step (1), the molar ratio of dimethyl diselenide to the L-serine derivative is 0.5 to 5: 1. As an example, the molar ratio of dimethyl diselenide to the L-serine derivative may 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, 5: 1, or may be within the range formed by any two of the above point values ​​as end values, such as the molar ratio of dimethyl diselenide to the L-serine derivative is 0.5 to 2: 1, and the molar ratio of dimethyl diselenide to the L-serine derivative is 0.5 to 1: 1.

[0065] In some embodiments, it is further preferred that in step (1), the molar ratio of the L-serine derivative to the organic phosphine is 1:1 to 5. As an example, the molar ratio of the L-serine derivative to the organic phosphine may 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, 1:5, or may be within the range formed by any two of the above point values ​​as end values, such as the molar ratio of the L-serine derivative to the organic phosphine is 1:1 to 4, and the molar ratio of the L-serine derivative to the organic phosphine is 1:1.2 to 2.

[0066] In some embodiments, it is further preferred that 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 the L-serine derivative to the solvent A may 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 : 1 L, 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, and it can also be within the range formed by any two of the above point values ​​as end values, such as the ratio of L-serine derivative to solvent A is 0.1 mol~1 mol: 1 L, and the ratio of L-serine derivative to solvent A is 0.1 mol~0.5 mol: 1 L.

[0067] In some embodiments, it is further preferred that in step (1), 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. As an example, solvent A may be tetrahydrofuran, 2-methyl-tetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, methyl tert-butyl ether, N,N-dimethylformamide, acetonitrile, N-methylpyrrolidone, and toluene, but is not limited thereto. It is further preferred that 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. As an example, solvent A may be tetrahydrofuran, 2-methyl-tetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, methyl tert-butyl ether, N,N-dimethylformamide, N-methylpyrrolidone. Particularly preferably, solvent A is at least one of tetrahydrofuran, 2-methyl-tetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, and methyl tert-butyl ether. As an example, solvent A may be tetrahydrofuran, 2-methyl-tetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, and methyl tert-butyl ether.

[0068] In some embodiments, it is further preferred that in step (1), the reaction temperature is 0°C to 100°C. As an example, the reaction temperature may be 0°C, 10°C, 20°C, 30°C, 40°C, 45°C, 50°C, 55°C, 58°C, 60°C, 63°C, 65°C, 68°C, 70°C, 72°C, 75°C, 77°C, 80°C, 82°C, 86°C, 88°C, 90°C, 91°C, 94°C, 95°C, 96°C, 98°C, 100°C, or may be within the range formed by any two of the above point values ​​as end values, such as when the reaction temperature is 40°C to 100°C, the reaction temperature may be 60°C to 90°C.

[0069] In some embodiments, it is further preferred that in step (1), the reaction time 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, 24 h, or can be within the range formed by any two of the above point values ​​as end values, such as the reaction time is 6 h to 18 h, and the reaction time is 12 h to 16 h.

[0070] In some embodiments, it is further preferred that 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, 4mol / 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, 12 mol / L, or it can be within the range formed by any two of the above point values ​​as end values, such as if the concentration of hydrochloric acid is 4 mol / L to 12 mol / L, the concentration of hydrochloric acid is 4 mol / L to 6 mol / L.

[0071] In some embodiments, it is further preferred that in step (2), the hydrolysis is carried out at a temperature of 40°C to 100°C. As an example, the hydrolysis can be carried out at a temperature of 40°C, 45°C, 50°C, 55°C, 58°C, 60°C, 63°C, 65°C, 68°C, 70°C, 72°C, 75°C, 77°C, 80°C, 82°C, 86°C, 88°C, 90°C, 91°C, 94°C, 95°C, 96°C, 98°C, 100°C, or within a range consisting of any two of the above point values ​​as end values, such as the hydrolysis is carried out at a temperature of 60°C to 90°C, or the hydrolysis is carried out at a temperature of 80°C to 90°C.

[0072] In some embodiments, it is further preferred that in step (2), the hydrolysis time 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, 24 h, or it can be within the range formed by any two of the above point values ​​as end values, such as the hydrolysis time is 2 h to 12 h, and the hydrolysis time is 6 h to 12 h.

[0073] In some embodiments, it is further preferred that in step (3), before the crude L-seleno-methylselenocysteine ​​hydrochloride product is dissolved in solvent C, the following treatment is further included: dissolving the crude L-seleno-methylselenocysteine ​​hydrochloride product in solvent D, and recrystallizing at -20°C for 12 h to 48 h to obtain L-seleno-methylselenocysteine ​​hydrochloride.

[0074] In some embodiments, it is further preferred that solvent D is at least one of dichloromethane, methanol, ethanol, ethyl acetate, acetone, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, n-hexane, petroleum ether, and ether. As an example, solvent D may be dichloromethane, methanol, ethanol, ethyl acetate, acetone, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, n-hexane, petroleum ether, and ether, but is not limited thereto. Further 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 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 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 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 ether.

[0075] Unless otherwise specified, the "combination of reagents" and "combination of solvents" used in the present invention refer to reagents or solvents used at the same time.

[0076] In some embodiments, it is further preferred that in step (3), solvent C is at least one of methanol and ethanol. As an example, solvent C can be methanol or ethanol.

[0077] In some embodiments, it is further preferred that in step (3), the alkalizing agent is at least one of ammonia water, triethylamine, diisopropylamine, and pyridine. As an example, the alkalizing agent may be ammonia water, triethylamine, diisopropylamine, and pyridine. It is further preferred that the alkalizing agent is at least one of triethylamine and pyridine. It is particularly preferred that the alkalizing agent is triethylamine.

[0078] In some embodiments, it is further preferred that in step (3), the alkalization is carried out at a temperature of 0°C to 40°C. As an example, the alkalization can be carried out at a temperature of 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C.

[0079] In some embodiments, it is further preferred that 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, 9, or any two of the above point values ​​as end values. For example, the pH value of the system after alkalization is 6 to 9, and the pH value of the system after alkalization is 8 to 9.

[0080] In some embodiments, it is further preferred that in step (4), solvent B is at least one of water, methanol and ethanol. As an example, solvent B is water, methanol and ethanol, and may also be a combination of water and methanol, or a combination of water and ethanol, but is not limited thereto.

[0081] In some embodiments, it is further preferred that in step (4), the decolorization is performed by adding activated carbon to the solvent B to decolorize the crude L-seleno-methylselenocysteine ​​product. In the present invention, the decolorizing agent used may be activated carbon, but is not limited thereto.

[0082] In some embodiments, it is further preferred that in step (4), the amount of activated carbon added is 1% to 5% of the mass of the theoretical product. As an example, the amount of activated carbon added may 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%, 5% of the mass of the theoretical product, or may be within the range formed by any two of the above point values ​​as end values, such as the amount of activated carbon added is 1% to 2% of the mass of the theoretical product, and the amount of activated carbon added is 1% of the mass of the theoretical product.

[0083] In some embodiments, it is further preferred that in step (4), the bleaching is carried out at a temperature of 20°C to 100°C. As an example, the bleaching can be carried out at a temperature 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, 100°C, or within a range consisting of any two of the above point values ​​as end values, such as bleaching at a temperature of 40°C to 100°C, or bleaching at a temperature of 40°C to 60°C.

[0084] In some embodiments, it is further preferred that in step (4), the decolorization time is 0.5 h to 12 h; the recrystallization is carried out at a temperature of 4°C to 8°C; and the recrystallization time is 12 h to 24 h.

[0085] The embodiments of the present invention are described in detail below.

[0086] Embodiment 1: A method for preparing L-seleno-methylselenocysteine ​​by reducing with an organic phosphine, specifically comprising: using L-serine as a raw material and dimethyl diselenide as a selenium source, and preparing L-seleno-methylselenocysteine ​​by a one-pot method under the reduction of an organic phosphine, comprising the following steps: Dissolve 112.8 g (0.6 mol, 0.6 equiv.) of dimethyl diselenide and 105 g (1.0 mol, 1.0 equiv.) of L-serine in 2000 ml of tetrahydrofuran (i.e., solvent A). Slowly add 242.4 g (1.2 mol, 1.2 equiv.) of tributylphosphine under vigorous stirring at room temperature. Heat to 60 °C and stir to react. As the reaction proceeds, the color of the solution gradually changes from orange-red to colorless, and a large amount of white solid precipitates. Stir the reaction for 18 hours until the reaction of L-serine is complete (TLC monitoring). Filter the reaction system, wash the residue with ethanol three times, 100 ml each time, and obtain 165 g of yellow-white powdery solid, which is the crude product of L-seleno-methylselenocysteine. The yellow-white powder solid was mixed with water (i.e., solvent B) to dissolve the yellow-white powder solid in the water, and the temperature was raised to 60°C. 1.82 g of activated carbon (1% of the theoretical mass of the product) was added and stirred for 1 hour to decolorize L-seleno-methylselenocysteine. The mixture was filtered with suction, and ethanol (i.e., solvent B) was added to the filtrate. When the system temperature dropped to room temperature, it was transferred to a cool cabinet at 4°C to 8°C for crystallization for 12 hours. After filtration, the filter residue was washed three times with ethanol, 100 ml each time, to obtain 140.1 g of white powder solid, i.e., L-seleno-methylselenocysteine, wherein the yield of the product was 77% and the HPLC purity was 99%.

[0087] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of L-seleno-methylselenocysteine ​​prepared in Example 1 of the present invention. Figure 1 In the reaction, the deuterated solvent is D2O.

[0088] Figure 2 This is the carbon nuclear magnetic resonance spectrum of L-seleno-methylselenocysteine ​​prepared in Example 1 of the present invention. Figure 2 The deuterated solvent is D2O. Figure 1-Figure 2 It can be seen that: [α] D 20 =-14.1 (c = 1.0 in H2O); ESI-HRMS: Calcd. for C4H9NO2SeNa + (M + Na + ) = 205.9691, measured value 205.9696; 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). 13 C NMR (151 M, D2O) δ 173.04, 53.69, 24.82, 4.38. It can be seen that the preparation method in Example 1 of the present invention can prepare L-seleno-methylselenocysteine.

[0089] Embodiment 2~7: A method for preparing L-seleno-methylselenocysteine ​​by reducing with an organic phosphine, specifically comprising: using L-serine as a raw material and dimethyl diselenide as a selenium source, and preparing L-seleno-methylselenocysteine ​​by a one-pot method under the reduction of an organic phosphine, which is basically the same as Example 1, except that a different organic phosphine is used, as shown in Table 1.

[0090]

[0091] As shown in Table 1, when other organic phosphine is used instead of tributylphosphine in Example 1, high-yield and high-purity L-selenium-methylselenocysteine ​​can also be prepared. Specifically, when the organic phosphine is triphenylphosphine and tri(p-tolyl)phosphine, the yield of L-selenium-methylselenocysteine ​​is 75% and 76%, respectively, and the HPLC purity is 99.1% and 99%, respectively; in addition, when the organic phosphine is tricyclohexylphosphine and tri(m-tolyl)phosphine, although the yield and purity of the product are reduced, they are still relatively high. By comparison, it can be seen that when the organic phosphine is tributylphosphine, triphenylphosphine, and tri(p-tolyl)phosphine, it is beneficial to obtain higher yield and higher purity L-selenium-methylselenocysteine, because they have less steric hindrance and stronger electronegativity, which is more conducive to the activation of hydroxyl groups and the reduction of dimethyl diselenide, so the reaction yield and purity are both high.

[0092] Embodiments 8 to 20: A method for preparing L-seleno-methylselenocysteine ​​by reducing with an organic phosphine, specifically comprising: using L-serine as a raw material and dimethyl diselenide as a selenium source, and preparing L-seleno-methylselenocysteine ​​by a one-pot method under the reduction of an organic phosphine, which is basically the same as Example 1, except that a different solvent A is used, as shown in Table 2.

[0093]

[0094] As can be seen from Table 2, when other reaction solvents are used instead of solvent A (tetrahydrofuran) in Example 1, high-yield and high-purity 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, acetonitrile, and N-methylpyrrolidone, the yield of L-seleno-methylselenocysteine ​​is 55%, 56%, 48%, 51%, and 42%, respectively, all of which are above 40%, and the HPLC purity is 99%, 98%, 98.6%, 98.4%, and 97.6%, respectively. This shows that when a highly polar organic solvent is used as a reaction solvent, the reaction can be promoted and it is beneficial to obtain L-seleno-methylselenocysteine ​​with higher yield and higher purity. In addition, when solvent A is methyl tert-butyl ether, toluene, ether, or dichloromethane, the yield of L-seleno-methylselenocysteine ​​is significantly reduced, and the purity is also reduced. This is because methyl tert-butyl ether, toluene, and ether have extremely poor solubility for L-serine, which makes the reaction impossible, and dichloromethane has a low boiling point, which makes the reaction impossible. In addition, when solvent A is methanol, ethanol, or water, L-seleno-methylselenocysteine ​​is basically not generated. This is because methanol and ethanol have active hydroxyl groups that are preferentially activated by organic phosphine. Although water can dissolve L-serine well, dimethyl diselenide and organic phosphine cannot be dissolved, which makes the reaction impossible. It can be seen that when solvent A is tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, acetonitrile, or N-methylpyrrolidone, it is beneficial to prepare high-yield, high-purity L-seleno-methylselenocysteine. In particular, when solvent A is tetrahydrofuran, 2-methyltetrahydrofuran, or ethylene glycol dimethyl ether, L-seleno-methylselenocysteine ​​with higher yield and higher purity can be obtained.

[0095] Embodiment 21-23: A method for preparing L-seleno-methylselenocysteine ​​by reducing an organic phosphine, specifically comprising: using L-serine as a raw material and dimethyl diselenide as a selenium source, and preparing L-seleno-methylselenocysteine ​​by a one-pot method under the reduction of an organic phosphine, which is basically the same as Example 1, except that the molar ratio (a:b:c) of dimethyl diselenide, L-serine and the organic phosphine is different, as shown in Table 3.

[0096]

[0097] As can be seen from Table 3, by optimizing the molar ratio of dimethyl diselenide, L-serine and organic phosphine, it is beneficial to quickly convert more L-serine and dimethyl diselenide into L-seleno-methylselenocysteine, and it will significantly affect the formation of impurity products. As a result, high-purity L-seleno-methylselenocysteine ​​can be obtained while improving the product yield. At the same time, combined with Table 3, it can be seen that when the amount of organic phosphine is small, the reaction yield and purity will decrease, because L-serine is not completely converted, which in turn affects the yield and purity; and when the amount of organic phosphine is too much, it will also lead to a decrease in purity; in addition, increasing the amount of dimethyl diselenide will not further increase the yield of the product. Therefore, in the present invention, by optimizing the molar ratio of dimethyl diselenide to L-serine to 0.5-5:1 and the molar ratio of L-serine to organic phosphine to 1:1-5, it is beneficial to obtain high-yield and high-purity L-seleno-methylselenocysteine. In particular, when the molar ratio of dimethyl diselenide to L-serine is 0.5-1:1 and the molar ratio of L-serine to organic phosphine is 1:1.2-2, not only the utilization rate of raw materials can be significantly improved, but also L-seleno-methylselenocysteine ​​with higher yield and higher purity can be obtained.

[0098] Embodiment 24: A method for preparing L-seleno-methylselenocysteine ​​by reducing with an organic phosphine, specifically comprising: using an L-serine derivative (N-acetyl-L-serine methyl ester) as a raw material and dimethyl diselenide as a selenium source, and preparing L-seleno-methylselenocysteine ​​by a one-pot method under the reduction of an organic phosphine, comprising the following steps: Dissolve 112.8 g (0.6 mol, 0.6 equiv.) of dimethyl diselenide and 161 g (1.0 mol, 1.0 equiv.) of N-acetyl-L-serine methyl ester in 2000 ml of tetrahydrofuran (solvent A), slowly add 242.4 g (1.2 mol, 1.2 equiv.) of tributylphosphine under vigorous stirring at room temperature, heat to 60 °C and stir to react. As the reaction proceeds, the color of the solution gradually changes from orange-red to colorless. Stir and react for 12 hours until the reaction of N-acetyl-L-serine methyl ester is complete (TLC monitoring). After the reaction is completed, concentrate by rotary evaporation to obtain a light yellow viscous liquid, which is N-acetyl-L-seleno-methylselenocysteine ​​methyl ester.

[0099] Add 1000 ml of 4 mol / L hydrochloric acid to the N-acetyl-L-seleno-methylselenocysteine ​​methyl ester prepared in the previous step at room temperature, equip with a condensing reflux device and heat to 90 °C for 6 hours. As the reaction proceeds, the oil in the system gradually decreases, the color of the solution changes from colorless to light red and then to light yellow, and a pungent odor is emitted. After the reaction is completed, the excess hydrochloric acid and solvent are evaporated under reduced pressure to obtain a yellow-white solid, which is the crude product of L-seleno-methylselenocysteine ​​hydrochloride. Add 200 ml of ethanol (solvent D) to dissolve and heat to boiling, then add 200 ml of petroleum ether (solvent D), slowly cool to room temperature, then transfer to -20 °C for cooling and crystallization, filter out the solid, which is the pure product of L-seleno-methylselenocysteine ​​hydrochloride. The pure L-seleno-methylselenocysteine ​​hydrochloride was dissolved in ethanol (solvent C), and triethylamine (alkalizing agent) was added at 0 °C to alkalize to pH 8-9. The product was precipitated from ethanol. The triethylamine hydrochloride was dissolved in ethanol and filtered off. The filter residue was washed three times with ethanol, 100 ml each time, to obtain crude L-seleno-methylselenocysteine. The product was dissolved in an appropriate amount of water (solvent B), heated to 60 °C, 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 suction filtration, ethanol (solvent B) was added to the filtrate. After the system temperature dropped to room temperature, it was transferred to a cool cabinet at 4-8 °C for crystallization for 12 hours. After filtration, the filter residue was washed three times with ethanol, 100 ml each time, to obtain 158.3 g of white powdery solid, namely L-seleno-methylselenocysteine. The yield of the product was 87%, and the HPLC purity was 99.4%.

[0100] The test results of specific rotation test, high resolution mass spectrometry test, nuclear magnetic resonance hydrogen spectrum and nuclear magnetic resonance carbon spectrum show that: [α] D 20 =-13.8 (c = 1.0 in H2O); ESI-HRMS: Calcd. for C4H9NO2SeNa + (M + Na + ) = 205.9691, measured value 205.9687; 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). 13 C NMR (151 M, D2O) δ 173.04, 53.69, 24.82, 4.38. It can be seen that the preparation method in Example 24 of the present invention can prepare L-seleno-methylselenocysteine.

[0101] Embodiment 25-30: A method for preparing L-seleno-methylselenocysteine ​​by reducing with an organic phosphine, specifically comprising: using an L-serine derivative (N-acetyl-L-serine methyl ester) as a raw material and dimethyl diselenide as a selenium source, and preparing L-seleno-methylselenocysteine ​​by a one-pot method under the reduction action of an organic phosphine, which is basically the same as Example 24, except that the type of organic phosphine used is different, as shown in Table 4.

[0102]

[0103] It can be seen from Table 4 that when other organic phosphines are used instead of tributyl phosphine in Example 24, high-yield and high-purity L-selenium-methylselenocysteine ​​can also be prepared. Specifically, when the organic phosphine is triphenylphosphine or tri(p-tolyl)phosphine, the yield of L-selenium-methylselenocysteine ​​is 87% and 86%, respectively, and the HPLC purity is 99.3% and 99.3%, respectively; in addition, when the organic phosphine is tricyclohexylphosphine or tri(m-tolyl)phosphine, the yield of the product decreases, but is still relatively high, and the purity is above 99%. In addition, when the organic phosphine is tri-tert-butyl phosphine or tri-(o-tolyl) phosphine, the yield of the product is significantly reduced. The reason is that when N-acetyl-L-serine methyl ester is used as a raw material, the steric hindrance next to the hydroxyl group increases, causing the reaction to be more sensitive to the structure of the organic phosphine. In particular, tri-tert-butyl phosphine and tri-(o-tolyl) phosphine have greater steric hindrance, so when tri-tert-butyl phosphine and tri-(o-tolyl) phosphine with greater steric hindrance are used as organic phosphine, the yield of the product is greatly reduced. By comparison, it can be seen that when the organic phosphine is tributyl phosphine, triphenyl phosphine, or tri-(p-tolyl) phosphine, it is beneficial to obtain higher yield and higher purity L-selenium-methyl selenocysteine. In addition, hydrochloric acid is introduced into the method of the present invention for hydrolysis, and the hydrochloride generated after the hydrolysis is recrystallized and alkalized. The generated salts and other impurities can be effectively removed by recrystallization and alkalization, which is beneficial to improve the purity of the product, and finally L-selenium-methyl selenocysteine ​​with higher purity can be obtained.

[0104] Embodiment 31~43: A method for preparing L-seleno-methylselenocysteine ​​by reducing with an organic phosphine, specifically comprising: using an L-serine derivative (N-acetyl-L-serine methyl ester) as a raw material and dimethyl diselenide as a selenium source, and preparing L-seleno-methylselenocysteine ​​by a one-pot method under the reduction action of an organic phosphine, which is basically the same as Example 24, except that the type of solvent A is different, as shown in Table 5.

[0105]

[0106] It can be seen from Table 5 that when other reaction solvents are used instead of solvent A (tetrahydrofuran) in Example 24, high-yield and high-purity 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, and methyl tert-butyl ether, the yield of L-seleno-methylselenocysteine ​​is 80%, 77%, 78%, 67%, 63%, and 81%, respectively, all of which are above 60%, and the HPLC purity is 99%, 98%, 98.6%, 97%, 97.6%, and 96%, respectively. This shows that when an organic solvent with a stronger polarity is used as a reaction solvent, the reaction can be promoted and it is beneficial to obtain L-seleno-methylselenocysteine ​​with a higher yield and higher purity. In addition, when solvent A is toluene, ether, or dichloromethane, the yield of L-seleno-methylselenocysteine ​​is significantly reduced, and the purity is also reduced, which indicates that the reaction is almost impossible to occur in a low-boiling point, non-polar solvent. In addition, when solvent A is methanol, ethanol, or water, L-seleno-methylselenocysteine ​​is basically not generated. This is because the reaction cannot be promoted when methanol and ethanol are used as solvents, and when water is used as a solvent, the reaction is difficult to occur because the raw materials cannot be dissolved. It can be seen that when solvent A is tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, N,N-dimethylformamide, N-methylpyrrolidone, or methyl tert-butyl ether, it is beneficial to prepare high-yield, high-purity L-seleno-methylselenocysteine, especially when solvent A is tetrahydrofuran or 2-methyltetrahydrofuran, L-seleno-methylselenocysteine ​​with higher yield and higher purity can be obtained.

[0107] Embodiments 44 to 48: A method for preparing L-seleno-methylselenocysteine ​​by reducing with an organic phosphine, specifically comprising: using an L-serine derivative (N-acetyl-L-serine methyl ester) as a raw material and dimethyl diselenide as a selenium source, and preparing L-seleno-methylselenocysteine ​​by a one-pot method under the reduction of an organic phosphine, which is basically the same as Example 24, except that the reaction temperatures of dimethyl diselenide and N-acetyl-L-serine methyl ester are different, as shown in Table 6.

[0108]

[0109] As shown in Table 6, when the reaction temperature is low (such as 0°C), the reaction activity is poor and basically no reaction occurs; when the reaction temperature is above 20°C, the reaction can be promoted. Further, when the reaction temperature is above 40°C, the yield and purity of the product are significantly improved, especially when the reaction temperature is 60°C~90°C, the yield of the product exceeds 80%, and the purity is above 99%. In addition, as shown in Table 6, when the reaction temperature is too high (such as 100°C), side reactions will occur, which will lead to a significant decrease in yield, and it is easy to introduce new impurities, or a new impurity removal process needs to be introduced, which is not conducive to reducing production energy consumption, simplifying the production process and reducing production costs. It can be seen that when the reaction temperature is 60°C~90°C, L-seleno-methylselenocysteine ​​with higher yield and higher purity can be obtained.

[0110] Embodiments 49-60: A method for preparing L-seleno-methylselenocysteine ​​by using organic phosphine reduction, specifically: using L-serine derivative (N-acetyl-L-serine methyl ester) as raw material, dimethyl diselenide as selenium source, and preparing L-seleno-methylselenocysteine ​​by a one-pot method under the reduction action of organic phosphine, which is basically the same as Example 24, except that: the corresponding solvent D is different when the crude L-seleno-methylselenocysteine ​​hydrochloride product is recrystallized, as shown in Table 7.

[0111]

[0112] As shown in Table 7, when different solvents D are used instead of ethanol / petroleum ether in Example 24, high-yield and high-purity L-seleno-methylselenocysteine ​​can also be prepared, but the yield is reduced. Specifically, when solvent D is dichloromethane, methanol, ethanol, ethyl acetate, acetone, tetrahydrofuran, dichloromethane / n-hexane, ethanol / n-hexane, and ethanol / ether, the corresponding yields of L-seleno-methylselenocysteine ​​are 70%, 78%, 81%, 75%, and 76%, respectively. , 79%, 76%, 85%, 86%, all more than 70%, and the purity is successively 97%, 99.3%, 99.4%, 96%, 99.2%, 93%, 97%, 99.3%, 99.4%, all more than 93%, in particular, when solvent D is methanol, ethanol, acetone, ethanol / n-hexane, ethanol / ether, the yield is more than 76%, and the purity is more than 99%, and the yield is higher and the purity is higher than 99%, and the L-selenium-methyl selenocysteine ​​with higher yield and higher purity can be obtained. In addition, when solvent D is N, N-dimethylformamide or acetonitrile, even if the product after hydrolysis is recrystallized, it is difficult to improve the yield and purity of L-selenium-methyl selenocysteine. In addition, if the product after hydrolysis is not recrystallized, that is, the product after hydrolysis is directly alkalized, the purity of the product will be greatly reduced. It can be seen that when L-serine derivative (N-acetyl-L-serine methyl ester) is used as a raw material for preparing L-seleno-methylselenocysteine, the crude L-seleno-methylselenocysteine ​​hydrochloride needs to be recrystallized, and when the solvent D is dichloromethane, methanol, ethanol, ethyl acetate, acetone, tetrahydrofuran, dichloromethane / n-hexane, ethanol / n-hexane, ethanol / ethyl ether, ethanol / petroleum ether, it is conducive to preparing high-yield and high-purity L-seleno-methylselenocysteine.

[0113] Embodiment 61-69: A method for preparing L-seleno-methylselenocysteine ​​by reducing with an organic phosphine, specifically comprising: using an L-serine derivative (N-acetyl-L-serine methyl ester) as a raw material and dimethyl diselenide as a selenium source, and preparing L-seleno-methylselenocysteine ​​by a one-pot method under the reduction action of an organic phosphine, which is basically the same as Example 24, except that: the solvent C and the alkalizing agent used are different, as shown in Table 8.

[0114]

[0115] It can be seen from Table 8 that when solvent C is methanol and ethanol, it is beneficial to obtain high-yield and high-purity L-seleno-methylselenocysteine, while when solvent C is water, the yield and purity of L-seleno-methylselenocysteine ​​are significantly reduced; at the same time, it can be seen from Table 8 that when the alkalizing agent is ammonia water, triethylamine, diisopropylamine, and pyridine, it is also beneficial to obtain high-yield and high-purity L-seleno-methylselenocysteine, while when the alkalizing agent is NaOH, NaHCO3, and Na2CO3, L-seleno-methyl The yield and purity of selenocysteine ​​were significantly reduced. The possible reasons were: when methanol and ethanol were used as solvents, L-seleno-methylselenocysteine ​​hydrochloride was soluble, while L-seleno-methylselenocysteine ​​had low solubility. On the other hand, the hydrochloride of organic base was soluble in ethanol while the hydrochloride of inorganic base was insoluble. At the same time, if an organic solvent was used for alkalization with an inorganic base, the generated inorganic salt and L-seleno-methylselenocysteine ​​would be precipitated at the same time, and the purification purpose could not be achieved, resulting in a decrease in the purity of the product.

[0116] Embodiment 70~77: A method for preparing L-seleno-methylselenocysteine ​​by reducing with an organic phosphine, specifically comprising: using an L-serine derivative (N-acetyl-L-serine methyl ester) as a raw material and dimethyl diselenide as a selenium source, and preparing L-seleno-methylselenocysteine ​​by a one-pot method under the reduction of an organic phosphine, which is basically the same as Example 24, except that the amount of activated carbon used and the decolorization conditions are different, as shown in Table 9.

[0117]

[0118] As shown in Table 9, if decolorization is not performed, the purity of L-seleno-methylselenocysteine ​​is low; further, with the increase of the amount of activated carbon, the yield of the product will decrease. The reason may be that too much activated carbon will adsorb more products, resulting in a decrease in yield, but the yield of the product is still above 76%, and the purity is above 99%. Considering the cost of raw materials, when the amount of activated carbon added is 1% to 5% of the theoretical product mass, the maximum economic benefit can be obtained. At the same time, as shown in Table 9, the decolorization temperature is 40 ℃ ~ 60 ℃, and the decolorization time is 1 h ~ 2 h, which is more conducive to obtaining high yield and high purity L-seleno-methylselenocysteine. This is because: when the decolorization temperature is too low, it will lead to incomplete adsorption, and when the adsorption temperature is too high, it will lead to oxidation of the product and cause the purity to decrease; in addition, when the decolorization time is too short, the adsorption effect is poor, which will lead to a decrease in purity, and the extension of the adsorption time cannot further improve the purity.

[0119] Embodiment 78: A method for preparing L-seleno-methylselenocysteine ​​by reducing with an organic phosphine, specifically comprising: using a serine derivative (N-tert-butyloxycarbonyl-L-serine methyl ester) as a raw material and dimethyl diselenide as a selenium source, and preparing L-seleno-methylselenocysteine ​​by a one-pot method under the reduction of an organic phosphine, comprising the following steps: 112.8 g (0.6 mol, 0.6 equiv.) of dimethyl diselenide and 219 g (1.0 mol, 1.0 equiv.) of N-tert-butyloxycarbonyl-L-serine methyl ester were dissolved in 2000 ml of tetrahydrofuran (solvent A). 314.4 g (1.2 mol, 1.2 equiv.) of triphenylphosphine were slowly added under vigorous stirring at room temperature. The temperature was raised to 60 °C and stirred for reaction. As the reaction proceeded, the color of the solution gradually changed from orange-red to colorless. The reaction was stirred for 12 hours until the reaction of N-tert-butyloxycarbonyl-L-serine methyl ester was complete (TLC monitoring). After the reaction was completed, 400 g of calcium bromide was added, stirred at room temperature for 3 hours, and the triphenylphosphine oxide / calcium bromide complex precipitate was removed by filtration. The filtrate was concentrated by rotary evaporation to obtain a light yellow viscous liquid, and the crude product of N-tert-butyloxycarbonyl-L-seleno-methylselenocysteine ​​methyl ester was obtained.

[0120] Add 1000 ml of 4 mol / L hydrochloric acid to the crude N-tert-butyloxycarbonyl-L-seleno-methylselenocysteine ​​methyl ester obtained in the previous step at room temperature, stir at room temperature until no bubbles are generated, and heat to 90 °C with a condensation reflux device for 6 hours. As the reaction proceeds, the oil in the system gradually decreases, and the color of the solution changes from colorless to light red and then to light yellow, while emitting a pungent odor. After the reaction is completed, the excess hydrochloric acid and solvent are evaporated under reduced pressure to obtain a yellow-white solid, and 200 ml of ethanol (solvent D) is added to dissolve and heated to boiling, and then 200 ml of ether (solvent D) is added, and the temperature is slowly cooled to room temperature, and then transferred to -20 °C for cooling and crystallization for 24 hours, and the solid is filtered out, which is the pure L-seleno-methylselenocysteine ​​hydrochloride. The hydrochloride was dissolved in ethanol (solvent C), and triethylamine (alkalizing agent) was added at 0 °C to alkalize to pH 8-9. The product was precipitated from ethanol. The triethylamine hydrochloride was dissolved in ethanol and filtered out. The filter residue was washed three times with ethanol, 100 ml each time. The product was dissolved in an appropriate amount of water (solvent B), heated to 60 °C, 1.82 g of activated carbon was added, and stirred for 1 hour for decolorization. After suction filtration, ethanol (solvent B) was added to the filtrate. After the system temperature dropped to room temperature, it was transferred to a cool cabinet at 4-8 °C for crystallization for 12 hours. After filtration, the filter residue was washed three times with ethanol, 100 ml each time, and 156.5 g of white powdery solid was obtained, which was L-seleno-methylselenocysteine. The yield of the product was 86.0%, and the HPLC purity was 99.4%.

[0121] The test results of specific rotation test, high resolution mass spectrometry test, nuclear magnetic resonance hydrogen spectrum and nuclear magnetic resonance carbon spectrum show that: [α] D 20 =-13.9 (c = 1.0 in H2O); ESI-HRMS: Calcd. for C4H9NO2SeNa + (M + Na + ) = 205.9691, measured value 205.9690; 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). 13 C NMR (151 M, D2O) δ 173.04, 53.69, 24.82, 4.38. It can be seen that the preparation method in Example 78 of the present invention can prepare L-seleno-methylselenocysteine.

[0122] In summary, it can be clearly seen from all the above embodiments that when the method of the present invention is adopted, that is, a composite reaction system composed of dimethyl diselenide, L-serine or an L-serine derivative and an organic phosphine is used, a high-yield L-seleno-methylselenocysteine ​​can be obtained directly through a one-step or two-step reaction. At the same time, the above embodiments also prove that the refining and purification scheme adopted by the present invention can greatly improve the purity of L-seleno-methylselenocysteine; in addition, the preparation method of the present invention also has the advantages of a simple synthetic route, no need to use a borohydride reducing agent or a Grignard reagent with explosion hazards, mild reaction conditions, safe and reliable process, cheap and easy-to-obtain raw materials, high product yield, high purity, etc., which plays an important role in promoting the large-scale industrial application of L-seleno-methylselenocysteine.

[0123] The above embodiments are only preferred implementations of the present invention, and the protection scope of the present invention is not limited to the above embodiments. All technical solutions under the concept of the present invention belong to the protection scope of the present invention. It should be pointed out that for ordinary technicians in this technical field, improvements and modifications without departing from the principle of the present invention should also be regarded as the protection scope of the present invention.

Claims

1. A method for preparing L-seleno-methylselenocysteine ​​by reduction with an organic phosphine, characterized in that: L-Serine or L-serine derivatives are used as raw materials, dimethyl diselenide is used as a selenium source, and L-Se-methylselenocysteine ​​is prepared by a one-pot method under the reduction of organic phosphine. The chemical reaction equation is as follows: （1）， In formula (1): The R 1 is at least one of hydrogen, acetyl, tert-butyloxycarbonyl, and trityl; The R 2 is at least one of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl; The R 3 It is at least one of n-butyl, tert-butyl, cyclohexyl, phenyl, p-tolyl, m-tolyl and o-tolyl.

2. The method according to claim 1, characterized in that: The R 3 It is at least one of n-butyl, cyclohexyl, phenyl, p-tolyl and m-tolyl.

3. The method according to claim 2, characterized in that The R 3 It is at least one of n-butyl, phenyl and p-tolyl.

4. The method according to any one of claims 1 to 3, characterized in that When R 1 and R 2 When all are hydrogen, the chemical reaction equation for preparing the L-seleno-methylselenocysteine ​​is shown in formula (2), which includes the following steps: S1, dissolving dimethyl diselenide, L-serine and organic phosphine in solvent A for reaction to obtain a crude L-seleno-methylselenocysteine ​​product; S2, dissolving the crude L-seleno-methylselenocysteine ​​obtained in step S1 into solvent B, decolorizing, and recrystallizing to obtain L-seleno-methylselenocysteine; （2）； When R 1 Not hydrogen, R 2 Not hydrogen or R 1 and R 2 When both are not hydrogen, the chemical reaction equation for preparing the L-seleno-methylselenocysteine ​​is shown in Formula (3), which comprises the following steps: (1) dissolving dimethyl diselenide, an L-serine derivative and an organic phosphine in a solvent A for reaction to obtain an L-seleno-methylselenocysteine ​​derivative; (2) mixing the L-seleno-methylselenocysteine ​​derivative prepared in step (1) with hydrochloric acid for hydrolysis to obtain a crude L-seleno-methylselenocysteine ​​hydrochloride product; (3) dissolving the crude L-seleno-methylselenocysteine ​​hydrochloride product obtained in step (2) in solvent C, adding an alkalizing agent for alkalization, and obtaining a crude L-seleno-methylselenocysteine ​​product; (4) dissolving the crude L-seleno-methylselenocysteine ​​obtained in step (3) in solvent B, decolorizing, and recrystallizing to obtain L-seleno-methylselenocysteine; （3）。 5. The method according to claim 4, characterized in that In step S1, the molar ratio of dimethyl diselenide to L-serine is 0.5-5:1; the molar ratio of L-serine to organic phosphine is 1:1-5; the ratio of L-serine to solvent A is 0.01 mol-10 mol:1 L; the 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 0-100°C; the reaction time is 2 h-24 h; In step S2, the solvent B is at least one of water, methanol and ethanol; the decolorization is to add activated carbon to the 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°C to 100°C; the decolorization time is 0.5 h to 12 h; the recrystallization is carried out at a temperature of 4°C to 8°C; and the recrystallization time is 12 h to 24 h.

6. The method according to claim 5, characterized in that In step S1, the molar ratio of dimethyl diselenide to L-serine is 0.5-2:1; the molar ratio of L-serine to organic phosphine is 1:1-4; the ratio of L-serine to solvent A is 0.1 mol-1 mol:1 L; the 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; the reaction time is 6 h-18 h; 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°C to 100°C.

7. The method according to claim 6, characterized in that In step S1, the molar ratio of dimethyl diselenide to L-serine is 0.5-1:1; the molar ratio of L-serine to organic phosphine is 1:1.2-2; the ratio of L-serine to solvent A is 0.1 mol-0.5 mol:1 L; the solvent A is at least one of tetrahydrofuran, 2-methyl-tetrahydrofuran, and ethylene glycol dimethyl ether; the reaction temperature is 60°C-90°C; the reaction time is 12 h-16 h; 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°C to 60°C.

8. The method according to claim 4, characterized in that In step (1), the molar ratio of dimethyl diselenide to L-serine derivative is 0.5-5:1; the molar ratio of L-serine derivative to organic phosphine is 1:1-5; the ratio of L-serine derivative to solvent A is 0.01 mol-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°C-100°C; the reaction time is 2 h-24 h; In step (2), the concentration of the hydrochloric acid is 2 mol / L to 12 mol / L; the hydrolysis is carried out at a temperature of 40°C to 100°C; and the hydrolysis time is 2 h to 24 h; In step (3), before the crude L-seleno-methylselenocysteine ​​hydrochloride product is dissolved in solvent C, the following treatment is further included: dissolving the crude L-seleno-methylselenocysteine ​​hydrochloride product in solvent D, and recrystallizing at -20°C for 12h to 48h to obtain L-seleno-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 ether; the solvent C is at least one of methanol and ethanol; the alkalizing agent is at least one of ammonia water, triethylamine, diisopropylamine, and pyridine; the alkalization is carried out at a temperature of 0°C to 40°C; the pH value of the system after the alkalization is completed is 5.5 to 9; In step (4), the solvent B is at least one of water, methanol and ethanol; the decolorization is performed by adding activated carbon to the 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 performed at a temperature of 20°C to 100°C; the decolorization time is 0.5 h to 12 h; the recrystallization is performed at a temperature of 4°C to 8°C; and the recrystallization time is 12 h to 24 h.

9. The method according to claim 8, characterized in that In step (1), the molar ratio of dimethyl diselenide to L-serine derivative is 0.5-2:1; the molar ratio of L-serine derivative to organic phosphine is 1:1-4; the ratio of L-serine derivative to solvent A is 0.1 mol-1 mol:1 L; the 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°C-100°C; the reaction time is 6 h-18 h; In step (2), the concentration of the hydrochloric acid is 4 mol / L to 12 mol / L; the hydrolysis is carried out at a temperature of 60°C to 90°C; and the hydrolysis time is 2 h to 12 h; In step (3), the solvent D is one of ethanol, a combination of ethanol and n-hexane, a combination of ethanol and petroleum ether, and a combination of ethanol and ether; the alkalizing agent is at least one of triethylamine and pyridine; the alkalization is performed at a temperature of 0°C to 30°C; the pH value of the system after the alkalization is completed is 6 to 9; 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°C to 100°C.

10. The method according to claim 9, characterized in that In step (1), the molar ratio of dimethyl diselenide to L-serine derivative is 0.5-1:1; the molar ratio of L-serine derivative to organic phosphine is 1:1.2-2; the ratio of L-serine derivative to solvent A is 0.2 mol-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°C-90°C; the reaction time is 12 h-16 h; In step (2), the concentration of the hydrochloric acid is 4 mol / L to 6 mol / L; the hydrolysis is carried out at a temperature of 80°C to 90°C; and the hydrolysis time is 6 h to 12 h; In step (3), the 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 ether; the alkalizing agent is triethylamine; the alkalization is carried out at a temperature of 0°C to 10°C; the pH value of the system after the alkalization is completed is 8 to 9; 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°C to 60°C.

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