A method for synthesizing l-selenium-methylselenocysteine

Abstract

The application provides a synthesis method of L-selenium-methyl selenocysteine, which comprises the following steps: mixing dimethyl diselenide with sodium borohydride, then adding a sodium hydroxide solution to react, to obtain a sodium methyl selenide solution; preparing 3-chloro-L-alanine methyl ester hydrochloride, stirring the prepared 3-chloro-L-alanine methyl ester hydrochloride with the sodium methyl selenide solution to react; acidifying the solution after the stirring reaction, then extracting, removing impurities, heating the water phase, and reducing pressure distillation to obtain solid crystals; using methanol to extract the solid crystals twice, then adding triethylamine to stir and crystallize, to obtain L-selenium-methyl selenocysteine solid crude product; hydrating the L-selenium-methyl selenocysteine solid crude product, then recrystallizing to obtain L-selenium-methyl selenocysteine solid; the L-selenium-methyl selenocysteine synthesized by the application has the advantages of simple process route, mild conditions, high purity and high yield.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, in particular to a synthesis method of L-selenium-methyl selenocysteine. BACKGROUND

[0002] Selenium is an essential trace element for human body, but it cannot be synthesized in the human body and needs to be supplemented completely through external intake. The lack of selenium in the human body can cause the dysfunction of some important organs and lead to the occurrence of many serious diseases. L-selenium-methyl selenocysteine (SeMCYS) is a natural selenium-containing amino acid and also a new generation of approved nutritional fortifier. It has many functions such as inhibiting tumors, resisting oxidation, assisting the treatment of cardiovascular diseases, and detoxification.

[0003] At present, the commonly used method for the synthesis of selenium-methyl selenocysteine is sodium methyl selenide substitution. The prior art usually adopts a nucleophilic substitution reaction between an intermediate of methyl ester or amide group protected alanine and sodium methyl selenide, and then a hydrolysis reaction is required to remove the methyl ester or amide group protection group to obtain the target product. This step-by-step process design leads to the conversion of the key intermediate to the final product through two independent reaction stages of substitution-hydrolysis, which causes the loss of reaction materials and the accumulation of side reactions in multiple steps, resulting in a long process route, low total product yield, and serious constraints on the improvement of production efficiency. In addition, the conventional nucleophilic substitution reaction is carried out in an organic phase reaction system, and a large amount of organic solvents such as tetrahydrofuran, dioxane, and sodium methoxide are used in the reaction process. These solvents significantly increase the production cost and environmental protection management pressure, and the use of strong alkaline reagent sodium methoxide also greatly increases the operation difficulty. SUMMARY

[0004] Therefore, the purpose of the present application is to provide a synthesis method of L-selenium-methyl selenocysteine to solve the problems in the prior art.

[0005] The present application provides a synthesis method of L-selenium-methyl selenocysteine, comprising the following steps:

[0006] S10, dimethyl diselenide and sodium borohydride are added to a first reaction bottle for mixing, and sodium hydroxide solution is added to the mixed first reaction bottle for reaction to obtain a sodium methyl selenide solution;

[0007] S20, 3-chloro-L-alanine methyl ester hydrochloride is prepared, and the prepared 3-chloro-L-alanine methyl ester hydrochloride is added to the first reaction bottle for stirring reaction with the sodium methyl selenide solution;

[0008] S30, the solution after stirring reaction is acidified and extracted, the water phase after removing impurities is heated and distilled under reduced pressure to obtain solid crystals, the solid crystals are extracted with methanol and then stirred and crystallized by adding triethylamine to obtain L-selenium-methyl selenocysteine solid crude product;

[0009] S40, the L-selenium-methyl selenocysteine solid crude product is recrystallized after hydration to obtain L-selenium-methyl selenocysteine solid.

[0010] Preferably, in step S10:

[0011] The molar ratio of dimethyl diselenide, sodium borohydride and sodium hydroxide is (1:5:5)-(5:1:1);

[0012] The initial temperature of the sodium hydroxide solution is less than 10℃;

[0013] The sodium selenomethyl alcohol solution is obtained by reacting in the first reaction bottle for 4h-10h.

[0014] Preferably, the step of preparing 3-chloro-L-alanine methyl ester hydrochloride in step S20 comprises:

[0015] S21, dichloromethane and acetonitrile are added to the second reaction bottle and stirred;

[0016] S22, L-serine methyl ester hydrochloride is prepared, added to the second reaction bottle, and then a water bath at room temperature is performed after adding thionyl chloride;

[0017] S23, the second reaction bottle is heated to a preset temperature, and a supplementary solvent is added dropwise to the second reaction bottle to react at the preset temperature, and a solid is precipitated in the reaction solution;

[0018] S24, the solid in the reaction solution is filtered and washed to obtain 3-chloro-L-alanine methyl ester hydrochloride wet crude product, and 3-chloro-L-alanine methyl ester hydrochloride is obtained after drying the 3-chloro-L-alanine methyl ester hydrochloride wet crude product.

[0019] Preferably, in step S21, the addition ratio of dichloromethane to acetonitrile is 1:3-3:1;

[0020] In step S23, the preset temperature is room temperature to 50℃, the supplementary solvent is a mixed solvent of dichloromethane and acetonitrile, and the solution in the second reaction bottle is reacted at the preset temperature for 6h-10h, then the heating is turned off and the stirring is stopped, and the solid is precipitated after cold storage;

[0021] In step S24, the solid precipitated in step S23 is washed with dichloromethane.

[0022] Preferably, the step of preparing L-serine methyl ester hydrochloride in step S22 includes:

[0023] S221, after adding methanol to the third reaction flask, the mixture is placed in an ice-water bath. Thionyl chloride is then added to the third reaction flask in the ice-water bath and stirred to obtain the intermediate product.

[0024] S222, the obtained intermediate product is mixed with L-serine and then heated and stirred for reaction;

[0025] S223, after the stirring reaction is completed, the reaction solution is concentrated under reduced pressure and evaporated with methanol until no liquid evaporates from the third reaction flask, to obtain the wet crude product of L-serine methyl ester hydrochloride. The wet crude product of L-serine methyl ester hydrochloride is dried to obtain L-serine methyl ester hydrochloride.

[0026] Preferably, in step S221, the temperature of the ice-water bath is 0℃-10℃, and the stirring reaction time is 0.5h-1h;

[0027] In step S222, the intermediate product is mixed with L-serine and then heated to 40℃-50℃. The stirring reaction time after heating is 2h-3h. The molar ratio of L-serine, thionyl chloride and methanol is (1:0.8:10) to (1:1.2:15).

[0028] Preferably, in step S20, the step of adding the prepared 3-chloro-L-alanine methyl ester hydrochloride to the first reaction flask and stirring it with sodium methyl selenoolate solution includes:

[0029] Cool the sodium methyl selenoside solution obtained in step S10 to below 10°C and stir for 10-15 minutes.

[0030] Add 3-chloro-L-alanine methyl ester hydrochloride to the first reaction flask and stir for 10-15 minutes.

[0031] The solution in the first reaction flask is heated to 25℃-35℃ and reacted for 8h-15h.

[0032] Preferably, step S30 specifically includes:

[0033] S31, cool the reaction solution after step S20 to below 10°C, add hydrochloric acid to adjust the pH value of the reaction solution, and stir for 1-2 hours;

[0034] S32 was extracted with ethyl acetate 2-3 times, and the aqueous phase was retained and then subjected to heating and vacuum distillation to obtain solid crystals.

[0035] S33, a methanol solution is used to perform a secondary extraction on the solid crystals, and the remaining solid is filtered off to obtain the methanol extract;

[0036] S34, under water bath conditions, heat up, add triethylamine dropwise to methanol extract, adjust the pH of the solution, cool down and stir until the solid is completely precipitated, then filter.

[0037] S35: Collect the filter cake from S34, wash it with methanol, and obtain L-seleno-methylselenocysteine ​​solid crude product.

[0038] Preferably, in step 31, the pH of the reaction solution is adjusted to 1-2 using hydrochloric acid;

[0039] In step 32, the volume ratio of the extractant ethyl acetate to the reaction solution to be extracted is 2:1 to 1:2;

[0040] In step 33, the ratio of the mass m of the solid crystals to the volume v of the extractant methanol solution is m:v = 1:1 - 1:5;

[0041] In step 34, the water bath temperature is raised to 45℃-55℃, the pH of the solution is adjusted to 5.5-6.5 using triethylamine, and the temperature of the cooling and stirring is lower than 15℃-20℃.

[0042] Preferably, step S40 specifically includes:

[0043] S41, add the crude L-seleno-methylselenocysteine ​​solid to purified water and dissolve it completely at 55℃-65℃.

[0044] S42, add activated carbon to the dissolved solution and filter to decolorize;

[0045] S43, heat and distill the decolorized filtrate under reduced pressure until saturation, add ethanol dropwise under a water bath at 45℃-55℃ until turbidity appears, then stop and stir for 25min-30min.

[0046] S44, after stirring, continue to add ethanol dropwise and stir for 0.5h-4.0h, let stand and cool naturally, stir to crystallize until the solid is completely precipitated, filter, collect the filter cake, wash the filter cake with ethanol to obtain L-seleno-methylselenocysteine ​​solid.

[0047] The beneficial effects of this invention are as follows: The method for synthesizing L-seleno-methylselenocysteine ​​provided in this application exhibits outstanding innovation and technological advancement: First, by innovatively adopting an aqueous reaction system to replace the traditional organic phase reaction system, a one-step direct conversion from chiral L-serine as the starting material to 3-chloro-L-alanine methyl ester hydrochloride is achieved. This avoids the hydrolysis step in existing technologies while reducing steps such as group protection, hydroxyl activation, and subsequent deprotection, significantly shortening the process route and greatly improving the overall reaction yield. Second, the in-situ generation strategy of sodium methylselenool effectively solves the technical bottlenecks of poor stability and difficult separation and purification of this intermediate, simplifying the operation process while ensuring the reliability of the reaction system. Third, the selected raw materials are inexpensive and readily available, the reaction medium is environmentally friendly, and the process conditions are mild and controllable, resulting in significant economic benefits and environmental friendliness. The synergistic effect of the above technical features makes this solution particularly suitable for industrial continuous production, possessing significant application value in the field of L-seleno-methylselenocysteine ​​synthesis, and suitable for widespread promotion.

[0048] Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. Attached Figure Description

[0049] Figure 1 Flowchart of the method for synthesizing L-seleno-methylselenocysteine ​​provided by the present invention;

[0050] Figure 2 High-resolution mass spectrum of the L-serine methyl ester hydrochloride sample prepared for the invention;

[0051] Figure 3 Infrared spectral analysis of the L-serine methyl ester hydrochloride sample prepared for the invention;

[0052] Figure 4 The standard proton NMR spectrum of L-seleno-methylselenocysteine;

[0053] Figure 5 The standard carbon spectrum of L-seleno-methylselenocysteine;

[0054] Figure 6 The hydrogen spectrum of L-seleno-methylselenocysteine ​​prepared in this invention;

[0055] Figure 7 The carbon spectrum of L-seleno-methylselenocysteine ​​prepared in this invention.

[0056] The following detailed description, in conjunction with the accompanying drawings, will further illustrate the present invention. Detailed Implementation

[0057] To facilitate understanding of the present invention, a more complete description will be given below with reference to the accompanying drawings. Several embodiments of the invention are illustrated in the drawings. However, the invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.

[0058] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the description of the invention is for the purpose of describing alternative embodiments only and is not intended to be limiting of the invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0059] Example 1

[0060] This embodiment provides a method for synthesizing L-seleno-methylselenocysteine, such as... Figure 1 As shown, the preparation method includes steps S10-S40:

[0061] S10, add dimethyl diselenyl ether and sodium borohydride to the first reaction flask for mixing, then add sodium hydroxide solution to the first reaction flask after mixing to react and obtain sodium methyl diselenyl alcohol solution.

[0062] S20, prepare 3-chloro-L-alanine methyl ester hydrochloride, add the prepared 3-chloro-L-alanine methyl ester hydrochloride into the first reaction flask and stir to react with sodium methyl selenoolate solution;

[0063] S30, after acidification of the solution after stirring and reaction, extraction is performed to remove impurities. The aqueous phase is then heated and distilled under reduced pressure to obtain solid crystals. The solid crystals are then extracted a second time with methanol and triethylamine is added for stirring and crystallization to obtain crude L-seleno-methylselenocysteine.

[0064] S40 is used to hydrate and recrystallize crude L-selen-methylselenocysteine ​​solid to obtain L-selen-methylselenocysteine ​​solid.

[0065] In this embodiment, step S10 specifically includes: adding dimethyl diselenyl ether and sodium borohydride in a molar ratio of 1:2 to a 250ml reaction flask, then preparing an aqueous solution of sodium hydroxide with a molar ratio of sodium borohydride to sodium hydroxide of 1:1; that is, the molar ratio of dimethyl diselenyl ether, sodium borohydride, and sodium hydroxide is 1:2:2; pre-cooling the sodium hydroxide solution to 8°C to absorb the exothermic reaction when dimethyl diselenyl ether, sodium borohydride, and sodium hydroxide come into contact, preventing the solution temperature from becoming too high; then stirring and allowing the reaction to proceed naturally to room temperature (understandably, room temperature is ambient temperature), with a reaction time of 8 hours, to obtain an aqueous solution of sodium methylselenool. This application prepares sodium methylselenool through an in-situ generation strategy, effectively solving the technical bottlenecks of poor stability and difficult separation and purification of this intermediate, simplifying the operation process while ensuring the reliability of the reaction system.

[0066] The step of preparing 3-chloro-L-alanine methyl ester hydrochloride in step S20 includes:

[0067] S21, add dichloromethane and acetonitrile to the second reaction flask and stir;

[0068] S22, to prepare L-serine methyl ester hydrochloride, L-serine methyl ester hydrochloride is added to the second reaction flask, and thionyl chloride is added and then placed in a room temperature water bath.

[0069] S23, the second reaction flask is heated to a preset temperature, and supplementary solvent is added dropwise to the second reaction flask to allow it to react at the preset temperature, and a solid is precipitated in the reaction solution;

[0070] S24, the solid in the reaction solution is filtered out and washed to obtain a wet crude product of 3-chloro-L-alanine methyl ester hydrochloride. The wet crude product of 3-chloro-L-alanine methyl ester hydrochloride is dried to obtain 3-chloro-L-alanine methyl ester hydrochloride.

[0071] In this embodiment, 200 ml of dichloromethane and 300 ml of acetonitrile were first added to the reaction flask, with a dichloromethane to acetonitrile ratio of 1:1.5. The mixture was stirred until homogeneous at a stirring speed of 260 r / min. Then, 100 g of L-serine methyl ester hydrochloride and 91.8 g of thionyl chloride were added to the reaction flask. The water bath temperature was 30°C. The temperature was then raised to 45°C. After 50 min, 150 ml of dichloromethane and 150 ml of acetonitrile were added dropwise to the reaction flask as a supplementary solvent. The reagent was used to react the mixture at 45°C. The reaction was carried out for a total of 7 hours after the temperature was raised from the reaction flask to 45°C. The stirring parameter during the reaction was 380 r / min. Then the heating was turned off and the stirring was stopped. After refrigerating overnight, the solid precipitated. The next day, the reaction solution was filtered to remove the brown filtrate, and a brownish-yellow filter cake was obtained. The brownish-yellow filter cake was washed with dichloromethane to obtain a wet crude product of 3-chloro-L-alanine methyl ester hydrochloride. The wet crude product of 3-chloro-L-alanine methyl ester hydrochloride was dried to obtain 3-chloro-L-alanine methyl ester hydrochloride.

[0072] The step of preparing L-serine methyl ester hydrochloride in step S22 includes:

[0073] S221, after adding methanol to the third reaction flask, the mixture is placed in an ice-water bath. Thionyl chloride is then added to the third reaction flask in the ice-water bath and stirred to obtain the intermediate product.

[0074] S222, the obtained intermediate product is mixed with L-serine and then heated and stirred for reaction;

[0075] S223, after the reaction is completed, the reaction solution is concentrated to dryness under reduced pressure and then evaporated with methanol until no liquid evaporates from the third reaction flask to obtain the wet crude product of L-serine methyl ester hydrochloride. The wet crude product of L-serine methyl ester hydrochloride is dried to obtain L-serine methyl ester hydrochloride.

[0076] In this embodiment, 1320 ml of methanol was added to a 2 L four-necked flask and stirred in an ice-water bath at 5 °C at a stirring rate of 260 r / min. Then, 148.8 g of thionyl chloride was weighed and slowly added to the system. After the addition of thionyl chloride was completed, the mixture was stirred in an ice-water bath for 0.5 h to obtain an intermediate product. 110.1 g of L-serine was weighed and mixed with the intermediate product, and the mixture was heated to 45 °C and stirred at 45 °C for 3 h. The molar ratio of L-serine, thionyl chloride, and methanol was 1:1.2:12. After the reaction is complete, turn off the heating device, allow it to cool naturally, and stir overnight at room temperature at a stirring rate of 200 r / min. The next day, concentrate the reaction solution to dryness under reduced pressure, repeatedly add 500 ml of methanol and evaporate to dryness twice until no liquid evaporates from the flask, to obtain a wet crude product of L-serine methyl ester hydrochloride. Dry the wet crude product of L-serine methyl ester hydrochloride to obtain L-serine methyl ester hydrochloride. The chemical name of L-serine methyl ester hydrochloride is L-2-amino-3-hydroxypropionic acid methyl ester hydrochloride, and its molecular formula is C4H4H4O2. 10 ClNO3; Optional, in this embodiment, the prepared sample is subjected to high-resolution mass spectrometry and infrared spectroscopy analysis, and the analysis results are as follows: Figure 2 and Figure 3 As shown, the ESI positive ion mode high-resolution primary mass spectrometry of the sample shows the target peak as hydrogen addition C4H9NO3H[M+H] + The measured mass-to-charge ratio was 120.0655, consistent with the theoretical mass-to-charge ratio of 120.0655 for hydrogenated L-serine methyl ester. The infrared spectrum of the sample showed characteristic absorption peaks of hydroxyl, amino, alkyl, carbonyl, ester, and amine salt groups, which are consistent with the structure of the compound L-serine methyl ester hydrochloride.

[0077] In this application, an aqueous phase reaction system is innovatively used to replace the traditional organic phase reaction system, realizing a one-step direct conversion of chiral L-serine as the starting material to 3-chloro-L-alanine methyl ester hydrochloride. While avoiding the methyl ester hydrolysis process in the prior art, the process route is significantly shortened, reducing the loss of reactant materials and the accumulation of side reactions caused by multiple reaction steps, and improving the overall reaction yield.

[0078] In step S20, the step of adding the prepared 3-chloro-L-alanine methyl ester hydrochloride to the first reaction flask and stirring it with sodium methyl selenoside solution includes:

[0079] Cool the sodium methyl selenoside solution obtained in step S10 to 8°C and stir for 10 min;

[0080] Add 3-chloro-L-alanine methyl ester hydrochloride to the first reaction flask and stir for 10 min.

[0081] The solution in the first reaction flask was heated to 30°C and reacted for 10 hours.

[0082] In this application, the intermediates L-serine methyl ester hydrochloride and 3-chloro-L-alanine methyl ester hydrochloride are prepared separately, ensuring the quality and stability of the intermediates and ultimately improving the product quality. 3-chloro-L-alanine methyl ester hydrochloride is prepared by chiral synthesis technology, with readily available and inexpensive raw materials, convenient operation, mild and environmentally friendly reaction conditions, a single product that is easy to separate, has a high yield, is suitable for industrial production, and has good quality. The process conditions are mild and controllable, resulting in significant economic benefits and environmental friendliness.

[0083] Step S30 specifically includes:

[0084] S31, cool the reaction solution after step S20 to 8°C, add hydrochloric acid to adjust the pH of the reaction solution to 1, and stir for 1 hour;

[0085] S32 was extracted twice with ethyl acetate, with a volume ratio of ethyl acetate to the reaction solution to be extracted of 1:2. The aqueous phase was retained and subjected to heating and vacuum distillation to obtain solid crystals.

[0086] S33, a methanol solution is used to perform a secondary extraction on the solid crystals. The ratio of the mass m (g) of the solid crystals to the volume v (ml) of the methanol solution is 1:3. After filtering out the remaining solid, a methanol extract is obtained.

[0087] S34, under water bath conditions, heat to 50°C, add triethylamine dropwise to methanol extract, adjust the pH of the solution to 6, then cool to 15°C and stir until the solid is completely precipitated, then filter.

[0088] S35: Collect the filter cake from S34, wash it with methanol, and obtain L-seleno-methylselenocysteine ​​solid crude product.

[0089] Step S40 specifically includes:

[0090] S41, add 5g of crude L-seleno-methylselenocysteine ​​solid to 50ml of purified water and dissolve completely at 60℃;

[0091] S42, add activated carbon to the dissolved solution and filter to decolorize;

[0092] S43, the decolorized filtrate is heated and distilled under reduced pressure until saturation, and ethanol is added dropwise under 50℃ water bath conditions until turbidity appears and then stopped, and stirred for 30 min;

[0093] S44, after stirring, continue to add ethanol dropwise and stir for 2 hours, let stand and cool naturally, stir to crystallize until the solid is completely precipitated, filter, collect the filter cake, wash the filter cake with 50 ml of ethanol to obtain L-seleno-methylselenocysteine ​​solid.

[0094] Optionally, the standard proton and carbon spectra of L-seleno-methylselenocysteine ​​are as follows:Figure 4 and Figure 5 As shown, the proton and carbon spectra of L-seleno-methylselenocysteine ​​prepared in this embodiment are as follows. Figure 6 and Figure 7 As shown, through comparison Figure 4 and Figure 6 as well as Figure 5 and Figure 7 It can be seen that the hydrogen spectrum and carbon spectrum of L-seleno-methylselenocysteine ​​prepared in this embodiment are almost identical to those of standard L-seleno-methylselenocysteine, which means that the L-seleno-methylselenocysteine ​​prepared in this embodiment has high purity.

[0095] Example 2

[0096] The difference between this embodiment and Embodiment 1 is that:

[0097] Step S10 specifically includes:

[0098] The molar ratio of dimethyl diselenyl ether, sodium borohydride, and sodium hydroxide is 1:5:5; the sodium hydroxide solution is preheated to 5°C, and the reaction time is 4 hours to obtain sodium methylselenoolate solution.

[0099] The specific steps in step S20 for preparing 3-chloro-L-alanine methyl ester hydrochloride include:

[0100] In step S21, the ratio of added dichloromethane to acetonitrile is 1:3;

[0101] In step S22, 80g of L-serine methyl ester hydrochloride and 75g of thionyl chloride are added;

[0102] In step S23, the preset temperature is 25°C, and the supplementary solvent is a mixed solvent of 100 ml dichloromethane and 150 ml acetonitrile. After the solution in the second reaction flask reacts at 25°C for 6 hours, the heating is turned off and the stirring is stopped. After refrigeration, a solid is precipitated.

[0103] The preparation of L-serine methyl ester hydrochloride in step S22 specifically includes:

[0104] In step S221, the temperature of the ice-water bath is 8°C, and the stirring reaction time is 0.7 h;

[0105] In step S222, the intermediate product is mixed with L-serine and then heated to 40°C. The stirring reaction time after heating is 2 hours. The molar ratio of L-serine, thionyl chloride and methanol is 1:0.8:10.

[0106] Step S20, which involves adding the prepared 3-chloro-L-alanine methyl ester hydrochloride to the first reaction flask and stirring it with sodium methyl selenoside solution, specifically includes:

[0107] The sodium methyl selenoside solution obtained in step S10 was cooled to 5°C and stirred for 12 min.

[0108] Add 3-chloro-L-alanine methyl ester hydrochloride to the first reaction flask and stir for 13 min.

[0109] The solution in the first reaction flask was heated to 25°C and reacted for 8 hours.

[0110] Step S30 specifically includes:

[0111] S31, cool the reaction solution after step S20 to 5°C, add hydrochloric acid to adjust the pH of the reaction solution to 1.5, and stir for 1.5 hours;

[0112] S32 was extracted three times with ethyl acetate at a volume ratio of 1:1 to the reaction solution to be extracted. The aqueous phase was then heated and distilled under reduced pressure to obtain solid crystals.

[0113] S33, a methanol solution is used to perform a secondary extraction on the solid crystals. The ratio of the mass m (g) of the solid crystals to the volume v (ml) of the methanol solution is 1:1. After filtering out the remaining solids, a methanol extract is obtained.

[0114] S34, under water bath conditions, heat to 45°C, add triethylamine dropwise to methanol extract, adjust the pH of the solution to 5.5, then cool to 18°C ​​and stir until the solid is completely precipitated, then filter.

[0115] S35: Collect the filter cake from S34, wash it with methanol, and obtain L-seleno-methylselenocysteine ​​solid crude product.

[0116] Step S40 specifically includes:

[0117] S41, add the crude L-seleno-methylselenocysteine ​​solid to purified water and dissolve it completely at 55°C;

[0118] S42, add activated carbon to the dissolved solution and filter to decolorize;

[0119] S43, the decolorized filtrate is heated and distilled under reduced pressure until saturation, and ethanol is added dropwise under a 45℃ water bath until turbidity appears and then stopped, and stirred for 25 min;

[0120] S44, after stirring, continue to add ethanol dropwise and stir for 0.5 h, let stand and cool naturally, stir to crystallize until the solid is completely precipitated, filter, collect the filter cake, wash the filter cake with ethanol to obtain L-seleno-methylselenocysteine ​​solid.

[0121] Example 3

[0122] Step S10 specifically includes:

[0123] The molar ratio of dimethyl diselenyl ether, sodium borohydride, and sodium hydroxide is 5:1:1; the sodium hydroxide solution is cooled to 6°C beforehand, and the reaction time is 10 hours to obtain sodium methylselenoolate solution.

[0124] The specific steps in step S20 for preparing 3-chloro-L-alanine methyl ester hydrochloride include:

[0125] In step S21, the ratio of added dichloromethane to acetonitrile is 3:1;

[0126] In step S22, 120g of L-serine methyl ester hydrochloride and 105g of thionyl chloride were added;

[0127] In step S23, the preset temperature is 50°C, and the supplementary solvent is a mixture of 300 ml of dichloromethane and 200 ml of acetonitrile. After the solution in the second reaction flask reacts at 50°C for 10 h, the heating is turned off and the stirring is stopped. After refrigeration, a solid is precipitated.

[0128] The preparation of L-serine methyl ester hydrochloride in step S22 specifically includes:

[0129] In step S221, the temperature of the ice-water bath is 6°C, and the stirring reaction time is 1 hour;

[0130] In step S222, the intermediate product is mixed with L-serine and then heated to 50°C. The stirring reaction time after heating is 2.5 h. The molar ratio of L-serine, thionyl chloride and methanol is 1:1.2:15.

[0131] Step S20, which involves adding the prepared 3-chloro-L-alanine methyl ester hydrochloride to the first reaction flask and stirring it with sodium methyl selenoside solution, specifically includes:

[0132] The sodium methyl selenoside solution obtained in step S10 was cooled to 6°C and stirred for 15 min.

[0133] Add 3-chloro-L-alanine methyl ester hydrochloride to the first reaction flask and stir for 15 min.

[0134] The solution in the first reaction flask was heated to 35°C and reacted for 15 hours.

[0135] Step S30 specifically includes:

[0136] S31, cool the reaction solution after step S20 to 5°C, add hydrochloric acid to adjust the pH of the reaction solution to 2, and stir for 2 hours;

[0137] S32 was extracted three times with ethyl acetate at a volume ratio of 2:1 to the reaction solution to be extracted. The aqueous phase was then heated and distilled under reduced pressure to obtain solid crystals.

[0138] S33, a methanol solution is used to perform a secondary extraction on the solid crystals. The ratio of the mass m (g) of the solid crystals to the volume v (ml) of the methanol solution is 1:5. After filtering out the remaining solids, a methanol extract is obtained.

[0139] S34, under water bath conditions, heat to 55°C, add triethylamine dropwise to methanol extract, adjust the pH of the solution to 6.5, then cool to 20°C and stir until the solid is completely precipitated, then filter.

[0140] S35: Collect the filter cake from S34, wash it with methanol, and obtain L-seleno-methylselenocysteine ​​solid crude product.

[0141] Step S40 specifically includes:

[0142] S41, add the crude L-seleno-methylselenocysteine ​​solid to purified water and dissolve it completely at 65°C;

[0143] S42, add activated carbon to the dissolved solution and filter to decolorize;

[0144] S43, the decolorized filtrate is heated and distilled under reduced pressure until saturation, and ethanol is added dropwise under a 55℃ water bath until turbidity appears and then the mixture is stirred for 28 min.

[0145] S44, after stirring, ethanol was added dropwise and stirred for 4 hours. The mixture was allowed to cool naturally and then stirred until the solid crystallized completely. The mixture was filtered, the filter cake was collected, and the filter cake was washed with ethanol to obtain L-seleno-methylselenocysteine ​​solid.

[0146] Comparative Example

[0147] This comparative example uses the conventional method for synthesizing L-seleno-methylselenocysteine, specifically including the following steps:

[0148] (a) Under stirring conditions, L-serine methyl ester hydrochloride was added to tetrahydrofuran and cooled to 0~5°C;

[0149] (b) Add triethylamine (acid-binding agent), stir evenly, then add acetyl chloride dropwise. After the reaction is complete, add thionyl chloride dropwise, heat to 45°C, and then cool to 0°C after the reaction is complete to obtain an amide-protected alanine intermediate.

[0150] (c) Add a saturated sodium bicarbonate solution, stir well, and then add a tetrahydrofuran solution of sodium methylselenool to carry out a nucleophilic substitution reaction. After the addition is complete, continue stirring and let the temperature rise naturally to room temperature to obtain a reaction mixture.

[0151] (d) After slowly adding HCl to adjust the pH of the reaction mixture to <4.0, extract with ethyl acetate three times, combine the extracts, wash with water, dry with anhydrous sodium sulfate, filter, and remove ethyl acetate under reduced pressure to obtain crude L-2-acetamido-3-methylselenopropionic acid.

[0152] (e) Dissolve the crude product obtained in step (d) in an aqueous solution of cobalt chloride, adjust the pH to 7.5 with NaOH solution, add acylated amino acid hydrolase to carry out hydrolysis reaction to remove the protecting group, control the temperature at 37 °C, stir and hydrolyze until the pH is 5.0~6.0, add activated carbon and heat to decolorize, concentrate the filtrate under reduced pressure, and then separate with cation exchange resin, elute with water and ammonia water in sequence, evaporate the ammonia water eluent to dryness under reduced pressure, and recrystallize with water-ethanol to obtain L-selenomethylselenocysteine.

[0153] The L-seleno-methylselenocysteine ​​synthesized in the embodiments and comparative examples of this application are shown in Table 1;

[0154] Table 1

[0155]

[0156] As shown in Table 1, the L-seleno-methylselenocysteine ​​synthesis method provided in this application produces L-seleno-methylselenocysteine ​​with higher purity, a total product yield of over 90%, and a shorter overall reaction time, thus improving preparation efficiency.

[0157] In summary, the method for synthesizing L-seleno-methylselenocysteine ​​provided in this application demonstrates outstanding innovation and technological advancement: First, by innovatively employing an aqueous reaction system instead of the traditional organic phase reaction system, a one-step direct conversion from chiral L-serine as the starting material to 3-chloro-L-alanine methyl ester hydrochloride is achieved. This avoids the methyl ester hydrolysis step in existing technologies, significantly shortening the process route and increasing the overall reaction yield to over 90%. Second, the in-situ generation strategy of sodium methylselenool effectively solves the technical bottlenecks of poor stability and difficult separation and purification of this intermediate, simplifying the operation process while ensuring the reliability of the reaction system. Third, the reaction process reduces the use of tetrahydrofuran and sodium methoxide, the selected raw materials are inexpensive and readily available, the reaction medium is environmentally friendly, and the process conditions are mild and controllable, resulting in significant economic benefits and environmental friendliness. The synergistic effect of these technical features makes this scheme particularly suitable for industrial continuous production and has important application value in the field of L-seleno-methylselenocysteine ​​synthesis.

[0158] It should be noted that the above implementation process is only to illustrate the feasibility of this application, but it does not mean that the L-seleno-methylselenocysteine ​​synthesis method of this application has the above-mentioned implementation process. On the contrary, as long as the L-seleno-methylselenocysteine ​​synthesis method of this application can be implemented, it can be included in the feasible implementation scheme of this application.

[0159] In the description of this specification, references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0160] The above embodiments merely illustrate several implementation methods of the present invention, and their descriptions are relatively specific and detailed, but they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this patent should be determined by the appended claims.

Claims

1. A method for synthesizing L-seleno-methylselenocysteine, characterized in that, Includes the following steps: S10, add dimethyl diselenyl ether and sodium borohydride to the first reaction flask for mixing, then add sodium hydroxide solution to the first reaction flask after mixing to react and obtain sodium methyl diselenyl alcohol solution. S20, prepare 3-chloro-L-alanine methyl ester hydrochloride, add the prepared 3-chloro-L-alanine methyl ester hydrochloride into the first reaction flask and stir to react with sodium methyl selenoolate solution; S30, after acidification of the solution after stirring and reaction, extraction is performed to remove impurities. The aqueous phase is then heated and distilled under reduced pressure to obtain solid crystals. The solid crystals are then extracted a second time with methanol and triethylamine is added for stirring and crystallization to obtain crude L-seleno-methylselenocysteine. S40, the crude L-selen-methylselenocysteine ​​solid was hydrated and then recrystallized to obtain L-selen-methylselenocysteine ​​solid. The step of preparing 3-chloro-L-alanine methyl ester hydrochloride in step S20 includes: S21, add dichloromethane and acetonitrile to the second reaction flask and stir; S22, to prepare L-serine methyl ester hydrochloride, L-serine methyl ester hydrochloride is added to the second reaction flask, and thionyl chloride is added and then placed in a room temperature water bath. S23, the second reaction flask is heated to a preset temperature, and supplementary solvent is added dropwise to the second reaction flask to allow it to react at the preset temperature, and a solid is precipitated in the reaction solution; S24, filter out the solid in the reaction solution and wash it to obtain the wet crude product of 3-chloro-L-alanine methyl ester hydrochloride. After drying the wet crude product of 3-chloro-L-alanine methyl ester hydrochloride, 3-chloro-L-alanine methyl ester hydrochloride is obtained. The step of preparing L-serine methyl ester hydrochloride in step S22 includes: S221, after adding methanol to the third reaction flask, the mixture is placed in an ice-water bath. Thionyl chloride is then added to the third reaction flask in the ice-water bath and stirred to obtain the intermediate product. S222, the obtained intermediate product is mixed with L-serine and then heated and stirred for reaction; S223, after the stirring reaction is completed, the reaction solution is concentrated under reduced pressure and evaporated with methanol until no liquid evaporates from the third reaction flask to obtain the wet crude product of L-serine methyl ester hydrochloride. The wet crude product of L-serine methyl ester hydrochloride is dried to obtain L-serine methyl ester hydrochloride. Step S30 specifically includes: S31, cool the reaction solution after step S20 to below 10°C, add hydrochloric acid to adjust the pH value of the reaction solution, and stir for 1-2 hours; S32 was extracted with ethyl acetate 2-3 times, and the aqueous phase was retained and then subjected to heating and vacuum distillation to obtain solid crystals. S33, a methanol solution is used to perform a secondary extraction on the solid crystals, and the remaining solid is filtered off to obtain the methanol extract; S34, under water bath conditions, heat up, add triethylamine dropwise to methanol extract, adjust the pH of the solution, cool down and stir until the solid is completely precipitated, then filter. S35: Collect the filter cake from S34, wash it with methanol, and obtain L-seleno-methylselenocysteine ​​solid crude product.

2. The method for synthesizing L-seleno-methylselenocysteine ​​according to claim 1, characterized in that, In step S10: The molar ratio of dimethyl diselenyl ether, sodium borohydride, and sodium hydroxide is (1:5:5) - (5:1:1). The initial temperature of the sodium hydroxide solution is less than 10℃; The reaction was carried out in the first reaction flask for 4-10 hours to obtain a sodium methylselenoolate solution.

3. The method for synthesizing L-seleno-methylselenocysteine ​​according to claim 1, characterized in that, In step S21, the ratio of dichloromethane to acetonitrile is 1:3 to 3:1; In step S23, the preset temperature is room temperature to 50°C, the supplementary solvent is a mixed solvent of dichloromethane and acetonitrile, the solution in the second reaction flask reacts at the preset temperature for 6-10 hours, then the heating is turned off and the stirring is stopped, and the solid precipitates after refrigeration; In step S24, dichloromethane is used to wash the solid precipitated in step S23.

4. The method for synthesizing L-seleno-methylselenocysteine ​​according to claim 1, characterized in that, In step S221, the temperature of the ice-water bath is 0℃-10℃, and the stirring reaction time is 0.5h-1h; In step S222, the intermediate product is mixed with L-serine and then heated to 40℃-50℃. The stirring reaction time after heating is 2h-3h. The molar ratio of L-serine, thionyl chloride and methanol is (1:0.8:10) to (1:1.2:15).

5. The method for synthesizing L-seleno-methylselenocysteine ​​according to claim 1, characterized in that, In step S20, the step of adding the prepared 3-chloro-L-alanine methyl ester hydrochloride to the first reaction flask and stirring it with sodium methyl selenoside solution includes: Cool the sodium methyl selenoside solution obtained in step S10 to below 10°C and stir for 10-15 minutes. Add 3-chloro-L-alanine methyl ester hydrochloride to the first reaction flask and stir for 10-15 minutes. The solution in the first reaction flask is heated to 25℃-35℃ and reacted for 8h-15h.

6. The method for synthesizing L-seleno-methylselenocysteine ​​according to claim 1, characterized in that, In step 31, the pH of the reaction solution is adjusted to 1-2 using hydrochloric acid; In step 32, the volume ratio of the extractant ethyl acetate to the reaction solution to be extracted is 2:1 to 1:2; In step 33, the ratio of the mass m of the solid crystals to the volume v of the extractant methanol solution is m:v = 1:1 - 1:5; In step 34, the water bath temperature is raised to 45℃-55℃, the pH of the solution is adjusted to 5.5-6.5 using triethylamine, and the temperature of the cooling and stirring is lower than 15℃-20℃.

7. The method for synthesizing L-seleno-methylselenocysteine ​​according to claim 1, characterized in that, Step S40 specifically includes: S41, add the crude L-seleno-methylselenocysteine ​​solid to purified water and dissolve it completely at 55℃-65℃. S42, add activated carbon to the dissolved solution and filter to decolorize; S43, heat and distill the decolorized filtrate under reduced pressure until saturation, add ethanol dropwise under a water bath at 45℃-55℃ until turbidity appears, then stop and stir for 25min-30min. S44, after stirring, continue to add ethanol dropwise and stir for 0.5h-4.0h, let stand and cool naturally, stir to crystallize until the solid is completely precipitated, filter, collect the filter cake, wash the filter cake with ethanol to obtain L-seleno-methylselenocysteine ​​solid.

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