CN110683976A - Method for preparing (R) -selenium methyl selenocysteine - Google Patents
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Abstract
The invention discloses a method for preparing (R) -selenium methyl selenocysteine, which comprises the following steps: firstly, preparing (3S,6S) -3, 6-dichloromethyl-2, 5-diketopiperazine; then, under the atmosphere of nitrogen, taking alcohol as a solvent, and reacting sodium borohydride with dimethyl diselenide to generate sodium methylselenolate; the (3S,6S) -3, 6-dimethylselenomethyl-2, 5-diketopiperazine is generated by the reaction of sodium methylselenolate and (3S,6S) -3, 6-dichloromethyl-2, 5-diketopiperazine, and finally (3S,6S) -3, 6-dimethylselenomethyl-2, 5-diketopiperazine is hydrolyzed to generate (R) -selenomethylselenocysteine. The method has the advantages of easily available raw materials, low price, convenient operation, mild reaction conditions, easy product separation and high yield, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing (R) -selenomethylselenocysteine.
Background
Selenium is a trace element necessary for human bodies, is an important component of various enzymes of the human bodies, has multiple functions of resisting oxidation, preventing cancer, detoxifying, promoting growth, improving immunity and the like, and once an organism lacks selenium, various diseases such as cardiovascular and cerebrovascular diseases, hypertension, metabolic syndrome, gastrointestinal diseases, diabetes, asthma, Parkinson's disease, liver diseases, cancer and the like can be directly caused, so that the huge effect of the selenium on human health cannot be replaced by other substances.
Most areas in the world are selenium-deficient, and 72 percent of areas in China belong to selenium-deficient areas and need to be supplemented with selenium. However, people have limited selenium obtained in daily diet, and the requirement of the human body on selenium cannot be met, so that the selenium supplement is urgently needed. The common selenium nutrition enhancer is L-selenium methyl selenocysteine (or R-configuration), which is a selenium methylated derivative of the 21 st essential amino acid L-selenocysteine for human bodies, widely exists in plants such as astragalus, garlic, onion, broccoli and the like and selenium-enriched yeast, has the advantages of definite chemical structure, low toxicity, high bioavailability, good selenium supplementing effect and the like, has a prevention effect on various tumors (such as breast cancer, prostate cancer, liver cancer and the like), has an auxiliary effect on cancer treatment, and has wide application prospects. In 2002, selenium-methylselenocysteine was recognized by the FDA in the united states as a latest generation of selenium-derived dietary supplement; in 2009, L-selenomethylselenocysteine was approved by the ministry of health in our country as a novel nutritional supplement (new food additive variety No. 11 in 2009).
At present, the synthesis method of the selenium methyl selenocysteine mainly comprises the following steps:
methylselenoacetaldehyde process
The method is a simulated hydantoin method, which comprises the steps of reacting methyl selenol salt with chloroacetaldehyde to prepare methyl selenyl acetaldehyde, cyclizing with cyanide to generate methyl selenyl methyl hydantoin, and then carrying out alkaline hydrolysis ring opening and acidification to obtain DL-selenium-methyl selenocysteine. The method has long reaction steps, uses hypertoxic cyanide, has huge risks in the aspects of safety, environmental protection and occupational health, and simultaneously obtains the product which is raceme and can obtain the L-selenium methyl selenocysteine with single configuration only by splitting.
(Jiangxi Chuanqi pharmaceutical industry Co., Ltd. a method for synthesizing selenium methyl selenocysteine by methyl seleno acetaldehyde, Chinese patent: ZL 200610124942.6).
Addition method of sodium (di) methylselenol and alpha-amino acrylic acid derivative
Firstly, methyl selenol and salt solution thereof and alpha-amino acrylic acid derivative are subjected to addition reaction to generate beta-methyl seleno-alpha-amino propionic acid derivative, then sodium bicarbonate, sodium hydroxide or potassium hydroxide are used for hydrolyzing and saponifying ester group in the beta-methyl seleno-alpha-amino propionic acid derivative, and hydrochloric acid or sulfuric acid is used for acidification to obtain carboxylic acid compound; and then hydrochloric acid or sulfuric acid is used for heating and hydrolyzing to remove amino protecting group-acetyl in the beta-methylseleno-alpha-aminopropionic acid derivative to obtain beta-methylseleno-alpha-aminopropionic acid hydrochloride or sulfate, and finally ammonia gas or triethylamine is used for neutralizing to obtain DL-selenium-methylselenocysteine. The raw material alpha-acetaminoacrylic acid and the derivative of the alpha-acetaminoacrylic acid are difficult to source, expensive and complex in preparation process, and no manufacturer exists in China; the methyl selenol has low boiling point, is easy to volatilize, has high toxicity, is difficult to prepare and is not commercialized, and the salt of the methyl selenol is unstable, is difficult to purify and is not commercialized; the obtained final product is racemate DL-selenium methyl selenocysteine, and the single-configuration L-selenium methyl selenocysteine needs to be obtained by splitting, so that the process is long, the yield is low, the production cost is high, and the industrial production is not facilitated.
(Jiangxi Chuanqi pharmaceutical industry Co., Ltd. a method for preparing selenium methyl selenocysteine by using alpha-amino acrylic acid derivatives, Chinese patent: ZL 200710051362.3).
Method for substituting chloropropionic acid or methyl chloropropionate by (tri) methylselenolate sodium
(1) Sodium diselenide method: the method comprises the steps of firstly reacting chloropropionic acid with sodium diselenide to generate selenocysteine, then reducing and cracking Se-Se bonds by using sodium metal/liquid ammonia (-70 ℃), and then methylating to obtain the selenomethylselenocysteine.
（Ioanna A, Wiro M P B, Menge. Synthesis of novel se-substitutedselenocysteine derivatives as potential kidney selective prodrugs ofbiologically active selenol compounds：evaluation of kinetics of β-eliminationreactions in rat renal cytosol. J. Med. Chem, 1996, 39: 2040-2046）。
(2) Sodium methylselenolate method: the method is not beneficial to large-scale production because the source of the raw material of the chloropropionic acid is difficult, the production cost is high, the yield is low.
（Muhammed M, Kalyanam N. Manufacturing processes for se-methyl-L-selenocysteine, US06794537B1, 2002）。
(tetra) N-t-butoxyacyl-L-serine-beta-lactone method
Reacting N-tert-butoxy acyl-L-serine with azodicarbonic diester in the presence of trialkyl (aryl) phosphorus or phosphite to generate beta-lactone, reacting with methyl selenol or its salt to generate tert-butoxy acyl protected selenium methyl selenocysteine, and removing protecting group to obtain selenium methyl selenocysteine. The preparation of the substrate N-tert-butoxy acyl-L-serine-beta-lactone is difficult, and the related reaction raw materials and protective agents have high price, long reaction time and low total yield.
（Julian, E Spallholz. A method of using synthetic L-Se-methylselenocysteine as a nutriceutical and a method of its synthesis,EP1205471A1, 2001）。
(V) substitution, ammonolysis and hydrolysis method of methylselenol sodium and dibromopropionitrile
Firstly, the methyl selenol salt selectively reacts with 2, 3-dihalo propionitrile to generate nucleophilic substitution reaction to generate 2-halogen-3-methyl seleno propionitrile, then acidolysis is carried out to obtain 2-halogen-3-methyl seleno propionic acid, and finally ammoniation is carried out to obtain DL-selenium methyl selenocysteine. In the method, the substrate dibromopropionitrile is prepared by addition of acrylonitrile and liquid bromine, and a large amount of volatile liquid bromine with high toxicity is used, so that the method has the advantages of high operation difficulty, high equipment requirement, serious pollution and high environmental protection cost; the nucleophilic substitution reaction of the selenium alkoxide and the substrate has poor selectivity and low yield; the final product is raceme, and an optically active substance with a single configuration needs to be obtained by resolution, so the process is complicated, long and low in yield, is only suitable for laboratory preparation and is not suitable for industrial production.
(Wangling, a method for synthesizing, racemizing and splitting selenomethylselenocysteine, Chinese patent: CN 201010107900.8).
In summary, these synthetic methods have disadvantages, such as: the raw materials are difficult to source and high in price; the process route is complex and the yield is low; the reaction conditions are harsh, and the equipment requirement is high; relating to highly toxic raw materials and causing serious environmental pollution; and the target product is raceme (DL-configuration), needs to be resolved and the like, so that the problems are difficult to realize large-scale production.
In order to meet the market demand, the improvement of the synthesis method of selenium-methyl selenocysteine is urgently needed, and a new method suitable for industrial production is found.
Disclosure of Invention
Based on the defects of the prior art, the invention aims to provide a method for preparing (R) -selenomethylselenocysteine, which adopts a new reaction substrate to prepare the (R) -selenomethylselenocysteine, has the advantages of wide raw material source, low price, simple process and high yield, develops a new synthesis route and realizes the diversification of the synthesis process.
In order to achieve the purpose, the invention adopts the technical scheme that:
a process for preparing (R) -selenomethylselenocysteine comprising the steps of:
(1) preparation of (3S,6S) -3, 6-dichloromethyl-2, 5-diketopiperazine: taking L-serine as a starting material, and sequentially carrying out esterification, cyclization and chlorination to obtain the L-serine;
(2) preparing sodium methylselenolate: under the atmosphere of nitrogen, using alcohol as a solvent, and reacting sodium borohydride with dimethyl diselenide to generate sodium methylselenolate;
(3) nucleophilic substitution: reacting the sodium methylselenolate obtained in the step (1) with the (3S,6S) -3, 6-dichloromethyl-2, 5-diketopiperazine obtained in the step (1) to generate (3S,6S) -3, 6-dimethylselenomethyl-2, 5-diketopiperazine;
(4) hydrolysis: hydrolyzing the (3S,6S) -3, 6-dimethylselenomethyl-2, 5-diketopiperazine obtained in the step (3) to generate (R) -selenomethylselenocysteine.
Preferably, step (1) is specifically:
a) cooling the alcoholic solution to-2 ~ 0 ℃, adding a catalyst under the conditions of stirring and constant temperature, stirring for 0.5 ~ 2 hours, then adding L-serine, stirring for 0.5 ~ 1.5.5 hours at constant temperature, heating to room temperature, continuing stirring for 0.5 ~ 2 hours, refluxing for 2 ~ 5 hours, detecting that the L-serine has completely reacted, stopping stirring, concentrating under reduced pressure, adding ethyl acetate while stirring, separating out a precipitate, performing solid-liquid separation, taking a solid, and drying to obtain an intermediate 1;
b) cyclizing, namely dissolving sodium in an alcohol solution under the stirring condition, adding the intermediate 1 obtained in the step a), stirring, heating and refluxing for 0.5 ~ 2 hours, cooling to room temperature, performing solid-liquid separation, taking filtrate, concentrating, adding toluene, concentrating until the alcohol solution is completely removed, refluxing the residue for 10 ~ 15 hours, performing reduced pressure evaporation to remove the solvent to obtain a brown oily substance, adding the alcohol solution, refluxing for 10 ~ 60 minutes, cooling to room temperature, performing solid-liquid separation, taking a solid, and drying to obtain an intermediate 2;
wherein the mass ratio of sodium to the intermediate 1 is 1:5 ~ 10;
c) and (2) chlorination, namely adding the intermediate 2 obtained in the step b) into a chlorinating agent under the ice bath condition, uniformly stirring, heating to room temperature, continuously stirring for 0.5 ~ 2 hours, further heating to 35 ~ 40 ℃, stirring at constant temperature for 0.5 ~ 2 hours, cooling to room temperature, adding diethyl ether for dilution, filtering, washing with diethyl ether for at least 2 times, standing until the chlorinating agent is completely volatilized, washing with water, filtering, and drying to obtain the 3S,6S) -3, 6-dichloromethyl-2, 5-diketopiperazine.
Preferably, the catalyst in step a) is one of hydrogen chloride, sulfuric acid, benzenesulfonic acid, p-toluenesulfonic acid, thionyl chloride, a strongly acidic ion exchange resin and a lewis acid; the alcoholic solution in the step a) and the step b) is one of methanol, ethanol, tertiary butanol and benzyl alcohol; the chlorinating agent in the step c) is one of phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, trimethyl silicon chloride and thionyl chloride.
Preferably, the step (2) is specifically that under the nitrogen atmosphere and stirring condition, metal sodium is dissolved in an alcohol solution, sodium borohydride is added, after uniform mixing, dimethyl diselenide is added, and stirring reaction is carried out at 55 ~ 65 ℃ for 1 ~ 2 hours, so as to obtain a reaction system containing methyl selenol sodium, wherein the molar ratio of the dimethyl diselenide to the sodium borohydride is 1:1.04 ~ 1.5.5.
Further, the alcohol solution is methanol or ethanol, and the adding amount of the metal sodium in the alcohol solution is 5 ~ 10 g/L.
Preferably, the step (3) is specifically to cool the reaction system containing the methylselenol sodium obtained in the step (2) to 45 ~ 50 ℃, add the (3S,6S) -3, 6-dichloromethyl-2, 5-diketopiperazine obtained in the step (1), heat and reflux for 3 ~ 24 hours under stirring conditions, detect by TLC that the (3S,6S) -3, 6-bis-chloromethyl-2, 5-diketopiperazine has reacted completely, filter, place the filtrate at 0 ~ 7 ℃ for 6 ~ 15 hours, separate solid and liquid, wash the solid with water, and dry the solid to obtain the (3S,6S) -3, 6-dimethylselenomethyl-2, 5-diketopiperazine, wherein the molar ratio of the methylselenol sodium to the (3S,6S) -3, 6-dichloromethyl-2, 5-diketopiperazine is 1:0.4 ~ 0.46.46.
Further, the step (4) is specifically that (3S,6S) -3, 6-dimethylselenomethyl-2, 5-diketopiperazine obtained in the step (3) is added into hydrochloric acid solution, heated at 50 ~ 120 ℃ for 3 ~ 50 hours under the stirring condition, the (3S,6S) -3, 6-di-methylselenomethyl-2, 5-diketopiperazine is completely hydrolyzed through TLC detection, the solvent is evaporated under reduced pressure and dissolved by water, the pH value of the system is adjusted to 5.0 ~ 6.5.5 by using a pH value regulator, the system is placed at 0 ~ 7 ℃ for 6 ~ 15 hours, solid-liquid separation is carried out, solid water is taken out, and water-ethanol recrystallization is carried out to obtain the (R) -selenomethylselenocysteine.
Preferably, (3S,6S) -3, 6-dimethylselenomethyl-2, 5-diketopiperazine is added in an amount of 0.05 ~ 0.1.1 g/mL in hydrochloric acid solution.
Preferably, the hydrochloric acid concentration is 4.0 ~ 12.0.0 mol/L.
Preferably, the pH value regulator is triethylamine, pyridine or ammonia water.
The method for preparing (R) -selenium methyl selenocysteine has the following synthetic route:
（1）
（2）
（3）
（4）
the raw materials used in the method are all common commercial products.
The preparation method takes the prepared (3S,6S) -3, 6-dichloromethyl-2, 5-diketopiperazine as a raw material, and prepares the (R) -selenomethylselenocysteine by nucleophilic substitution, hydrolysis and neutralization with the methylselenol sodium, wherein the preparation of the methylselenol sodium and the nucleophilic substitution reaction with the (3S,6S) -3, 6-dichloromethyl-2, 5-diketopiperazine adopt a one-pot method, so that the defects of instability and difficult separation and purification of the methylselenol sodium can be overcome; meanwhile, the obtained product is a single optical active substance, so that the complicated and tedious resolution process can be overcome. The method has the advantages of easily obtained and cheap raw materials, easy preparation of the intermediate, convenient operation, mild reaction conditions, easy separation of the product, high yield and suitability for industrial production.
Detailed Description
In order to make the technical purpose, technical solutions and advantages of the present invention clearer, the technical solutions of the present invention are further described with reference to specific examples, which are intended to explain the present invention and are not to be construed as limiting the present invention, and those who do not specify a specific technique or condition in the examples follow the techniques or conditions described in the literature in the art or follow the product specification.
Example 1
A process for preparing (R) -selenomethylselenocysteine comprising the steps of:
(1) preparation of (3S,6S) -3, 6-dichloromethyl-2, 5-diketopiperazine:
a) esterification: in a reaction flask equipped with an electric stirrer, a reflux condenser, a thermometer and a constant pressure dropping funnel, 400 mL of anhydrous methanol and ice are addedCooling the bath to below 0 ℃, starting stirring, slowly dropwise adding 80 mL of freshly distilled thionyl chloride, keeping the system temperature below 0 ℃ in the dropwise adding process, continuing stirring for 1 h after the dropwise adding is finished, then adding 50 g of L-serine (adding in batches), stirring at constant temperature for reaction for 45 min after the dropwise adding is finished, then heating to room temperature for reaction for 1 h, refluxing for 3 h (TCL detects that the L-serine is completely reacted), concentrating under reduced pressure to a small volume, adding 200 mL of ethyl acetate while stirring, precipitating white precipitate, performing suction filtration and drying to obtain 68 g of a product (an intermediate 1, namely L-serine methyl ester hydrochloride), wherein the yield is 92%, m.p.159-161 ℃, and [ alpha ] is 92]D 22=+4.5（C2.0，CH3OH）；
b) Cyclization: adding 500 mL of methanol and 10 g of metal sodium into a reaction flask provided with an electric stirrer and a reflux condenser, adding 62.2 g of the intermediate 1 after the sodium is completely dissolved, stirring, heating and refluxing for 1 h, cooling to room temperature, filtering, concentrating the filtrate to a small volume, adding 500 mL of toluene, concentrating again until the methanol is removed, refluxing the residue for 12h, stopping the reaction, evaporating under reduced pressure to remove the solvent to obtain brown oily matter, adding 100 mL of methanol, refluxing for 20 min, cooling to room temperature, filtering to obtain 40.6 g of light yellow solid (intermediate 2), wherein the yield is 52.3%, m.p.229.3-230.1 ℃, directly using for the next reaction without purification;
c) chlorination: adding 300 mL of thionyl chloride into a three-neck flask with an electric stirring and reflux condenser, slowly adding 40 g of the intermediate 2 obtained in the step b) under ice-bath cooling, uniformly stirring, slowly heating to room temperature, stirring for 1 h, further continuously heating to 37 ℃, stirring for 1 h, cooling to room temperature, adding 300 mL of anhydrous ether for dilution, filtering, washing twice with ether, placing in a fume hood, after the thionyl chloride is volatilized, washing with water, filtering, and drying to obtain 45 g of a faint yellow 3, 6-bis-chloromethyl-2, 5-diketopiperazine product, wherein the yield is 94.5% and m.p.241 ℃.
(2) Preparing sodium methylselenolate, namely adding 1000 mL of methanol and 10.0 g of metal sodium into a three-neck flask provided with a stirrer and a nitrogen gas guide tube, adding 21.0 g of sodium borohydride after the sodium is dissolved under the stirring condition in the nitrogen atmosphere, dropwise adding 41.2 g of dimethyl diselenide after uniform mixing, and stirring and reacting at 58 ~ 60 ℃ for 1 h after completing dropwise adding to obtain a reaction system containing the sodium methylselenolate;
(3) nucleophilic substitution, namely cooling the reaction system containing the methylselenol sodium obtained in the step (2) to 45 ~ 50 ℃, adding 48.0 g of (3S,6S) -3, 6-dichloromethyl-2, 5-diketopiperazine obtained in the step (1), heating and refluxing for 3 h under the stirring condition, detecting that (3S,6S) -3, 6-bis-chloromethyl-2, 5-diketopiperazine has reacted completely by TLC, filtering while hot, taking the filtrate, standing the filtrate at 0 ~ 5 ℃ for 12h, separating out a white solid, performing suction filtration, washing a filter cake with water, and drying to obtain 57.6 g of a crude product, namely (3S,6S) -3, 6-dimethylselenomethyl-2, 5-diketopiperazine (without purification);
(4) and (3) hydrolysis, namely taking 50.0 g of the crude product obtained in the step (3), adding 500 mL of hydrochloric acid with the concentration of 6.0 mol/L, heating and refluxing for 3 h under the stirring condition, detecting that (3S,6S) -3, 6-di-methylselenomethyl-2, 5-diketopiperazine is completely hydrolyzed by TLC, evaporating the solvent to dryness under reduced pressure until free HCl is completely removed to obtain a white solid, dissolving the white solid with 200 mL of water, dropwise adding pyridine to adjust the pH of the system to 5.0 ~ 6.0.0, standing the solution at 0 ~ 5 ℃ for 12h, filtering, washing a filter cake with water, and recrystallizing with water-ethanol (1: 1) to obtain 45.4 g of the product (R) -selenomethylselenocysteine with the yield of 82.5%.
The synthetic route of example 1 is as follows:
and (4) performing physical property analysis and structure characterization on the product obtained in the step (4), wherein the result is as follows:
m.p.179.5-180.2℃；[ɑ]D 20=-14.0゜(C=1,H2O)。
elemental analysis (%), found: c26.27; h5.036; n7.794, theoretical: c26.39; h4.98; n7.69; ESI-MS, M/z: [ M + H ]]+Found 183.9874; theoretical value 183.9877.
IR(KBr,cm-1)3330(N-H),3136-3020,2920(C-H),2710-2500,1623(C=O),1570,1482,1410(C-O),1380(C-H)。
1HNMR (D2O,300MHz),δ(ppm):4.10 (t,1H,-CH-) , 3.08 (dd, 2H,-CH2-) ,2.00(s,3H,-CH3)；
13CNMR(D2O ),δ(ppm):173.4(-COOH),53.8(-CH-),25.0(-CH2-),4.53( -CH3)；
77SeNMR (D2O ),δ(ppm): 240.0(SeCH3)。
The analysis of the detection result confirms that the structure of the product completely conforms to the structure of the (R) -selenomethylselenocysteine.
Example 2
A process for preparing (R) -selenomethylselenocysteine comprising the steps of:
(1) preparation of (3S,6S) -3, 6-dichloromethyl-2, 5-diketopiperazine: the same as example 1;
(2) preparing sodium methylselenolate, namely adding 2000 mL of methanol and 10.0 g of metal sodium into a three-neck flask provided with a stirrer and a nitrogen gas guide tube, adding 21.0 g of sodium borohydride after the sodium is dissolved under the stirring condition in the nitrogen atmosphere, dropwise adding 41.2 g of dimethyl diselenide after uniform mixing, and stirring and reacting at 58 ~ 60 ℃ for 1 h after completing dropwise adding to obtain a reaction system containing the sodium methylselenolate;
(3) nucleophilic substitution, namely cooling the reaction system containing the methylselenol sodium obtained in the step (2) to 45 ~ 50 ℃, adding 48.0 g of (3S,6S) -3, 6-dichloromethyl-2, 5-diketopiperazine obtained in the step (1), heating and refluxing for 3 h under the stirring condition, detecting that (3S,6S) -3, 6-bis-chloromethyl-2, 5-diketopiperazine has reacted completely by TLC, filtering while hot, taking the filtrate, standing the filtrate at 0 ~ 5 ℃ for 12h, separating out a white solid, performing suction filtration, washing a filter cake with water, and drying to obtain 55.0 g of a crude product, namely (3S,6S) -3, 6-dimethylselenomethyl-2, 5-diketopiperazine (without purification);
(4) and (3) hydrolysis, namely taking 50.0 g of the crude product obtained in the step (3), adding 750 mL of hydrochloric acid with the concentration of 6.0 mol/L, heating and refluxing for 3 h under the stirring condition, detecting by TLC that (3S,6S) -3, 6-di-methylselenomethyl-2, 5-diketopiperazine is completely hydrolyzed, evaporating the solvent to dryness under reduced pressure until free HCl is completely removed to obtain a white solid, dissolving the white solid with 200 mL of water, dropwise adding pyridine to adjust the pH of the system to 5.0 ~ 6.0.0, standing the solution at 0 ~ 5 ℃ for 12h, filtering, washing a filter cake with water, and recrystallizing with water-ethanol (1: 1) to obtain 47.0 g of the product (R) -selenomethylselenocysteine with the yield of 85.8%.
Example 2 differs from example 1 in that: the dosage of the methanol in the step (2) and the dosage of the hydrochloric acid in the step (4) are changed.
And (5) performing physical property analysis and structural characterization on the product obtained in the step (4), wherein the result is the same as that of the example 1.
Example 3
A process for preparing (R) -selenomethylselenocysteine comprising the steps of:
(1) preparation of (3S,6S) -3, 6-dichloromethyl-2, 5-diketopiperazine: the same as example 1;
(2) preparing sodium methylselenolate, namely adding 1000 mL of methanol and 10.0 g of metal sodium into a three-neck flask provided with a stirrer and a nitrogen gas guide tube, adding 21.0 g of sodium borohydride after the sodium is dissolved under the stirring condition in the nitrogen atmosphere, dropwise adding 41.2 g of dimethyl diselenide after uniform mixing, and stirring and reacting at 58 ~ 60 ℃ for 1 h after completing dropwise adding to obtain a reaction system containing the sodium methylselenolate;
(3) nucleophilic substitution, namely cooling the reaction system containing the methylselenol sodium obtained in the step (2) to 45 ~ 50 ℃, adding 48.0 g of (3S,6S) -3, 6-dichloromethyl-2, 5-diketopiperazine obtained in the step (1), heating and refluxing for 10 h under the stirring condition, detecting that (3S,6S) -3, 6-bis-chloromethyl-2, 5-diketopiperazine has reacted completely by TLC, filtering while hot, taking the filtrate, standing the filtrate at 0 ~ 5 ℃ for 12h, separating out a white solid, performing suction filtration, washing a filter cake with water, and drying to obtain 53.0 g of a crude product, namely (3S,6S) -3, 6-dimethylselenomethyl-2, 5-diketopiperazine (without purification);
(4) and (3) hydrolysis, namely adding 50.0 g of the crude product obtained in the step (3) into 1000 mL of hydrochloric acid with the concentration of 6.0 mol/L, heating and refluxing for 6 h under the stirring condition, detecting that (3S,6S) -3, 6-di-methylselenomethyl-2, 5-diketopiperazine is completely hydrolyzed by TLC, evaporating the solvent to dryness under reduced pressure until free HCl is completely removed to obtain a white solid, dissolving the white solid with 200 mL of water, dropwise adding pyridine to adjust the pH of the system to 5.0 ~ 6.0.0, standing the solution at 0 ~ 5 ℃ for 12h, filtering, washing a filter cake with water, and recrystallizing with water-ethanol (1: 1) to obtain 43.4 g of the product (R) -selenomethylselenocysteine with the yield of 78.2%.
Example 3 differs from example 1 in that: the dosage of the hydrochloric acid in the step (4) and the reflux time are changed.
And (5) performing physical property analysis and structural characterization on the product obtained in the step (4), wherein the result is the same as that of the example 1.
In conclusion, in example 1 ~ 3, (R) -selenomethylselenocysteine is prepared from (3S,6S) -3, 6-dichloromethyl-2, 5-diketopiperazine, and the product is easy to separate, high in yield and economical and feasible.
Claims (10)
1. A method for preparing (R) -selenomethylselenocysteine, which is characterized by comprising the following steps:
(1) preparation of (3S,6S) -3, 6-dichloromethyl-2, 5-diketopiperazine: taking L-serine as a starting material, and sequentially carrying out esterification, cyclization and chlorination to obtain the L-serine;
(2) preparing sodium methylselenolate: under the atmosphere of nitrogen, using alcohol as a solvent, and reacting sodium borohydride with dimethyl diselenide to generate sodium methylselenolate;
(3) nucleophilic substitution: reacting the sodium methylselenolate obtained in the step (1) with the (3S,6S) -3, 6-dichloromethyl-2, 5-diketopiperazine obtained in the step (1) to generate (3S,6S) -3, 6-dimethylselenomethyl-2, 5-diketopiperazine;
(4) hydrolysis: hydrolyzing the (3S,6S) -3, 6-dimethylselenomethyl-2, 5-diketopiperazine obtained in the step (3) to generate (R) -selenomethylselenocysteine.
2. The method for preparing (R) -selenomethylselenocysteine according to claim 1, wherein the step (1) is specifically:
a) cooling the alcoholic solution to-2 ~ 0 ℃, adding a catalyst under the conditions of stirring and constant temperature, stirring for 0.5 ~ 2 hours, then adding L-serine, stirring for 0.5 ~ 1.5.5 hours at constant temperature, heating to room temperature, continuing stirring for 0.5 ~ 2 hours, refluxing for 2 ~ 5 hours, detecting that the L-serine has completely reacted, stopping stirring, concentrating under reduced pressure, adding ethyl acetate while stirring, separating out a precipitate, performing solid-liquid separation, taking a solid, and drying to obtain an intermediate 1;
b) cyclizing, namely dissolving sodium in an alcohol solution under the stirring condition, adding the intermediate 1 obtained in the step a), stirring, heating and refluxing for 0.5 ~ 2 hours, cooling to room temperature, performing solid-liquid separation, taking filtrate, concentrating, adding toluene, concentrating until the alcohol solution is completely removed, refluxing the residue for 10 ~ 15 hours, performing reduced pressure evaporation to remove the solvent to obtain a brown oily substance, adding the alcohol solution, refluxing for 10 ~ 60 minutes, cooling to room temperature, performing solid-liquid separation, taking a solid, and drying to obtain an intermediate 2;
wherein the mass ratio of sodium to the intermediate 1 is 1:5 ~ 10;
c) and (2) chlorination, namely adding the intermediate 2 obtained in the step b) into a chlorinating agent under the ice bath condition, uniformly stirring, heating to room temperature, continuously stirring for 0.5 ~ 2 hours, further continuously heating to 35 ~ 40 ℃, stirring at constant temperature for 0.5 ~ 2 hours, cooling to room temperature, adding diethyl ether for dilution, filtering, washing with diethyl ether for at least 2 times, standing until the chlorinating agent is completely volatilized, washing with water, filtering, and drying to obtain (3S,6S) -3, 6-dichloromethyl-2, 5-diketopiperazine.
3. The process for preparing (R) -selenomethylselenocysteine according to claim 2, characterized in that: the catalyst in the step a) is one of hydrogen chloride, sulfuric acid, benzenesulfonic acid, p-toluenesulfonic acid, thionyl chloride, strong acid ion exchange resin and Lewis acid; the alcoholic solution in the step a) and the step b) is one of methanol, ethanol, tertiary butanol and benzyl alcohol; the chlorinating agent in the step c) is one of phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, trimethyl silicon chloride and thionyl chloride.
4. The method for preparing (R) -selenomethylselenocysteine according to claim 1, wherein the step (2) is specifically that under the nitrogen atmosphere and stirring condition, metal sodium is dissolved in an alcohol solution, sodium borohydride is added, after uniform mixing, dimethyl diselenide is added, stirring reaction is carried out at 55 ~ 65 ℃ for 1 ~ 2 hours, and a reaction system containing methylselenol sodium is obtained, wherein the molar ratio of the dimethyl diselenide to the sodium borohydride is 1:1.04 ~ 1.5.5.
5. The method for preparing (R) -selenomethylselenocysteine according to claim 4, wherein the alcohol solution is methanol or ethanol, and the amount of sodium metal added in the alcohol solution is 5 ~ 10 g/L.
6. The method for preparing (R) -selenomethylselenocysteine according to claim 4, wherein the step (3) is specifically that the reaction system containing the sodium methylselenolate obtained in the step (2) is cooled to 45 ~ 50 ℃, the (3S,6S) -3, 6-dichloromethyl-2, 5-diketopiperazine obtained in the step (1) is added, the mixture is heated and refluxed for 3 ~ 24 hours under stirring, the (3S,6S) -3, 6-bis-chloromethyl-2, 5-diketopiperazine is detected by TLC to be completely reacted, the mixture is filtered, the filtrate is taken and placed at 0 ~ 7 ℃ for 6 ~ 15 hours, solid-liquid separation is carried out, the solid is taken and washed with water, and the mixture is dried, so as to obtain the (3S,6S) -3, 6-dimethylselenomethyl-2, 5-diketopiperazine, wherein the molar ratio of the sodium methylselenolate to the (3S,6S) -3, 6-dichloromethyl-2, 5-diketopiperazine is 1:0.4 ~ 0.46.46.
7. The method for preparing (R) -selenomethylselenocysteine according to any one of claims 1 to 6, wherein the step (4) is specifically that (3S,6S) -3, 6-dimethylselenomethyl-2, 5-diketopiperazine obtained in the step (3) is added into hydrochloric acid solution, heated at 50 ~ 120 ℃ for 3 ~ 50 hours under the condition of stirring, the (3S,6S) -3, 6-di-methylselenomethyl-2, 5-diketopiperazine is completely hydrolyzed by TLC detection, the solvent is evaporated under reduced pressure and dissolved by water, the pH value of the system is adjusted to 5.0 ~ 6.5.5 by using a pH value regulator, the system is placed at 0 ~ 7 ℃ for 6 ~ 15 hours, solid-liquid separation is carried out, solid water is washed, and water-ethanol recrystallization is carried out to obtain the (R) -selenomethylselenocysteine.
8. The method for preparing (R) -selenomethylselenocysteine according to claim 7, wherein the amount of (3S,6S) -3, 6-dimethylselenomethyl-2, 5-diketopiperazine added to the hydrochloric acid solution is 0.05 ~ 0.1.1 g/mL.
9. The process for preparing (R) -selenomethylselenocysteine according to claim 7, wherein the hydrochloric acid concentration is 4.0 ~ 12.0.0 mol/L.
10. The process for preparing (R) -selenomethylselenocysteine according to claim 7, wherein: the pH value regulator is triethylamine, pyridine or ammonia water.
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