CN110628839B - Method for preparing L-selenomethylselenocysteine - Google Patents
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Abstract
The invention discloses a green and efficient method for preparing L-selenomethylselenocysteine, which comprises the steps of firstly taking L-serine methyl ester hydrochloride as a starting raw material, synthesizing a reaction substrate by an acetylation, chlorination and methylselenylation one-pot method, and hydrolyzing the obtained reaction substrate under the enzyme catalysis to generate the L-selenomethylselenocysteine. The invention adopts a one-pot method to prepare the reaction substrate, which not only overcomes the instability of the intermediate, but also reduces the complicated steps of intermediate separation, purification and the like; the enzyme catalysis hydrolysis is adopted, so that the environmental pollution and equipment corrosion caused by strong acid hydrolysis are avoided, and the defects of breakage of selenium ether bond, racemization of products and the like are overcome. The invention has the characteristics of easily obtained raw materials, low cost, convenient operation, mild reaction conditions, environmental protection, single product, easy separation, high yield and suitability for industrial production.
Description
Technical Field
The invention belongs to the technical field of food additives, and particularly relates to a method for preparing L-selenomethylselenocysteine.
Background
Selenium is an essential trace element of a human body, is an important component of various enzymes of the human body, has various functions of resisting oxidation, preventing cancer, detoxifying, promoting growth, improving immunity and the like, and once the body lacks selenium, the selenium can directly cause the occurrence of various diseases such as cardiovascular and cerebrovascular diseases, hypertension, metabolic syndrome, gastrointestinal diseases, diabetes, asthma, parkinsonism, liver diseases, cancers and the like, so that the great effect of the selenium on human health is irreplaceable by other substances.
The most part of the world is lack of selenium, and 72% of the world belongs to the selenium-lack area and needs to be supplemented with selenium. However, people have limited selenium obtained in daily diet, so that the requirement of people on selenium can not be met, and the selenium supplement nutrition enhancer is urgently needed to realize the purpose of selenium supplement. The commonly used selenium nutrition enhancer is L-selenium methyl selenocysteine, which is a selenium methylation derivative of 21 st human essential amino acid-L-selenocysteine, widely exists in plants such as astragalus, garlic, onion, broccoli and the like and selenium-enriched yeast, has the advantages of clear chemical structure, low toxicity, high bioavailability, good selenium supplementing effect and the like, has a preventive 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 prospect. In 2002, L-selenomethylselenocysteine was recognized by the us FDA as the latest generation of selenium-derived dietary supplements; in 2009, L-selenomethylselenocysteine was approved by the ministry of health of China as a novel nutrition enhancer (bulletin 11 in 2009 of new variety of food additives).
At present, the synthesis method of the L-selenomethylselenocysteine mainly comprises the following steps:
process for (mono) chloroacetaldehyde
The method is a simulated hydantoin method, and is characterized in that methylselenoacetate is reacted with chloroacetaldehyde to prepare methylselenoacetate, then the methylselenomethylhydantoin is formed by cyclization with cyanide, and then DL-selenium-methylselenocysteine is obtained by alkaline hydrolysis ring opening and acidification. The method has long reaction steps, and the use of the virulent cyanide has huge risks in the aspects of safety, environmental protection and occupational health, and meanwhile, the obtained product is a racemate, and the single-configuration L-selenomethylselenocysteine can be obtained by resolution.
(Jiangxi Chuan pharmaceutical Co., ltd., chinese patent ZL 200610124942.6) a method for synthesizing selenomethylselenocysteine by methylselenoacetate.
Process for (di) alpha-amino acrylic acid derivatives
Firstly, adding a solution of methyl selenol and a salt thereof and an alpha-amino acrylic acid derivative to generate a beta-methyl seleno-alpha-amino propionic acid derivative, then hydrolyzing and saponifying an ester group in the beta-methyl seleno-alpha-amino propionic acid derivative by sodium bicarbonate, sodium hydroxide or potassium hydroxide, and acidifying by hydrochloric acid or sulfuric acid to obtain a carboxylic acid compound; and heating and hydrolyzing with hydrochloric acid or sulfuric acid 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 neutralizing with ammonia gas or triethylamine to obtain DL-selenomethylselenocysteine. The method has the advantages of difficult source of the raw material alpha-acetamido acrylic acid and derivatives, high price, complex preparation process and no manufacturer in China; the methyl selenol has low boiling point, is easy to volatilize, has high toxicity, is difficult to prepare and has no commercialization, and the salt of the methyl selenol is unstable and difficult to purify and has no commercialization; the final product is raceme DL-selenomethylselenocysteine, and the L-selenomethylselenocysteine with a single configuration is needed to be obtained by resolution, so that the process is long, the yield is low, the production cost is high, and the industrial production is not facilitated.
(Jiangxi Sichuan pharmaceutical Co., ltd., a method for preparing selenomethylselenocysteine by using alpha-amino acrylic acid derivative, chinese patent ZL 200710051362.3).
Process for (tri) chloroalanine derivatives
(1) Sodium diselenide process: firstly, reacting chloralanine with sodium diselenide to generate selenocysteine, then, reducing and cracking Se-Se bond by using metal sodium/liquid ammonia (-70 ℃), and then, methylation to obtain selenomethylselenocysteine.
(Ioanna A,Wiro M P B,Menge.Synthesis of novel se-substituted selenocysteine derivatives as potential kidney selective prodrugs of biologically active selenol compounds：evaluation of kinetics ofβ-elimination reactions in rat renal cytosol.J.Med.Chem,1996,39:2040-2046)。
(2) Sodium methylselenate method: the selenomethylselenocysteine is prepared by replacing chlorine in 3-chloroalanine and derivatives thereof with methyl selenoalkoxide, and the method is unfavorable for large-scale production due to difficult sources of raw materials of the chloroalanine, high production cost and low yield.
(Muhammed M,Kalyanam N.Manufacturing processes for se-methyl-L-selenocysteine,US06794537B1,2002)。
(IV) N-t-Butoxyacyl-L-serine-beta-lactone method
The N-tert-butoxyacyl-L-serine and azodicarboxylic acid diester react in the presence of trialkyl (aryl) phosphorus or phosphite to generate beta-lactone, then react with methyl selenol or salt thereof to generate tert-butoxyacyl protected selenomethylselenocysteine, and finally deprotecting to obtain the product selenomethylselenocysteine. The substrate N-t-butoxyacyl-L-serine-beta-lactone is difficult to prepare, and the involved 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 anutriceutical and a method of its synthesis,EP1205471A1,2001)。
(five) 2, 3-dihalopropionitrile method
Firstly, the selenite selectively reacts with 2, 3-dihalopropionitrile in a nucleophilic substitution reaction to generate 2-halogen-3-methylselenopropionitrile, then acidolysis is carried out to obtain 2-halogen-3-methylselenopropionic acid, and finally, DL-selenomethylselenocysteine is obtained by ammoniation. In the method, the substrate dibromopropionitrile is prepared by adding acrylonitrile and liquid bromine, and a large amount of liquid bromine which is easy to volatilize and has high toxicity is used, so that the operation difficulty is high, the equipment requirement is high, the pollution is serious, and the environmental protection cost is high; the nucleophilic substitution reaction of selenoalkoxide and substrate has poor selectivity and low yield; the final product is a racemate, and the optical active substance with a single configuration is needed to be resolved, so the process is tedious, tedious and low in yield, and is only suitable for laboratory preparation but not suitable for industrial production.
(Wang Ling A method for synthesizing, racemizing and resolving selenomethylselenocysteine, chinese patent No. CN 201010107900.8).
In summary, these synthetic methods have disadvantages, such as: the raw materials are difficult to source and high in price; the synthesis process is complex and the yield is low; the reaction condition is harsh and the equipment requirement is high; relates to strong acid and highly toxic raw materials, and has serious environmental pollution; and the target molecules are racemates (DL-configuration), and are required to be split, so that the large-scale production of the target molecules is difficult to realize.
In recent years, along with the diversification of selenium supplementing products, the demand of the market for L-selenium methyl selenocysteine is continuously increasing, and a green and efficient synthesis method is needed by manufacturers.
Disclosure of Invention
Based on the defects of the prior art, the invention aims to provide a method for preparing L-selenomethylselenocysteine, which takes L-serine methyl ester hydrochloride as a raw material, prepares L-2-acetamido-3-methylselenopropionic acid by a one-pot method, prepares the L-selenomethylselenocysteine through enzymatic hydrolysis, simplifies the process, reduces the cost and is suitable for industrial production.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
a method for preparing L-selenomethylselenocysteine comprising the steps of:
(1) L-serine methyl ester hydrochloride is used as a starting material, and a reaction substrate (L-2-acetamido-3-methylselenopropionic acid) is synthesized through acetylation, chlorination and methylselenylation in one pot;
(2) And (3) hydrolyzing the reaction substrate obtained in the step (1) under the action of enzyme catalysis to generate L-selenomethylselenocysteine.
Preferably, the step (1) specifically comprises:
(a) Adding L-serine methyl ester hydrochloride into a reaction medium under the stirring condition, and cooling to 0-5 ℃;
(b) Adding an acetylation reagent, stirring for 2-5 hours, adding a chlorination reagent, stirring for 0.5-2 hours, heating to 5-50 ℃, continuously stirring for 2-5 hours, and cooling to-5-0 ℃;
(c) Adding a selenizing reagent, stirring for 2-5 hours, heating to room temperature, and continuously stirring for 10-15 hours to obtain a reaction mixed solution;
(d) And (c) adjusting the pH value of the reaction mixture obtained in the step (c) to be less than 4.0, extracting with ethyl acetate for 2-5 times, combining the extracts, washing with water, drying, filtering, and evaporating the ethyl acetate under reduced pressure to obtain a reaction substrate.
Further, the mol ratio of the L-serine methyl ester hydrochloride to the acetylating reagent to the chlorinating reagent to the selenizing reagent is 1.0 (1.0-1.2): 1.0-1.6): 1.0-1.5.
Preferably, the reaction medium is dichloromethane (CH 2 Cl 2 ) Trichloromethane (CHCl) 3 ) 1, 2-dichloroethane (ClCH) 2 CH 2 Cl), tetrahydrofuran (THF), diethyl ether (Et) 2 O), ethylene glycol dimethyl ether (CH) 3 OCH 2 CH 2 OCH 3 ) Methyl tert-butyl ether ((CH) 3 ) 3 COCH 3 ) Dioxane (C) 4 H 8 O 2 ) Acetonitrile (CH) 3 CN), dimethylformamide (DMF), dimethylsulfoxide (DMSO); the acetylating reagent is acetyl Chloride (CH) 3 COCl), acetyl bromide (CH 3 COBr), acetic anhydride ((CH) 3 CO) 2 O), ethyl acetate (CH) 3 CO 2 Et), acetic acid (CH) 3 COOH); the chlorinating reagent is thionyl chloride (SOCl) 2 ) Carbon oxychloride (COCl) 2 ) Phosphorus oxychloride (POCl) 3 ) Phosphorus trichloride (PCl) 3 ) Phosphorus pentachloride (PCl) 5 ) Mixtures of triphenylphosphine with N-chlorosuccinimide (Ph 3 P+ncs), a mixture of triphenylphosphine and carbon tetrachloride (Ph 3 P+CCl 4 ) Trimethylchlorosilane (Me) 3 SiCl); the chemical formula of the selenizing reagent is CH 3 SeM, wherein M is selected from H, na, K or Li.
Further, the reaction medium is tetrahydrofuran, the acetylation reagent is acetyl chloride, the chlorination reagent is thionyl chloride, and the selenizing reagent is sodium selenite.
Preferably, the acid binding agent is added before the step (b) is added to the acetylating agent and before the step (c) is added to the selenizing agent.
Further, the acid binding agent is selected from triethylamine (Et) 3 N), pyridine (C) 5 H 5 N), sodium methoxide (CH) 3 ONa), sodium ethoxide (EtONa), potassium tert-butoxide (t-BuOK), sodium bicarbonate (NaHCO) 3 ) Potassium bicarbonate (KHCO) 3 ) Sodium carbonate (Na) 2 CO 3 ) Potassium carbonate (K) 2 CO 3 ) One of sodium hydroxide (NaOH), potassium hydroxide (KOH).
Preferably, the step (2) specifically comprises: dissolving the reaction substrate obtained in the step (1) in cobalt chloride aqueous solution, regulating the pH to 7.0-8.0, adding acylated amino acid hydrolase, stirring and reacting for 4-110 hours at 20-40 ℃, regulating the pH to 5.0-6.0, adding active carbon, stirring for 0.3-1.5 hours at 80-85 ℃, carrying out solid-liquid separation, concentrating the liquid under reduced pressure, separating and purifying by strong acid cation exchange resin, and recrystallizing the water-alcohol solution to obtain the L-selenomethylselenocysteine.
Preferably, the concentration of the cobalt chloride solution is 0.3-1 mmol/L, the addition amount of the reaction substrate in the cobalt chloride solution is 22.4-67.2 g/L, the addition amount of the acylated amino acid hydrolase is 1.9-2.4% of the mass of the reaction substrate, and the addition amount of the activated carbon is 0.1-0.5% of the mass of the reaction substrate.
Further, when the strong acid cation exchange resin is used for separation and purification, water and 3-8% ammonia water are sequentially used for elution, the ammonia water eluent is taken for reduced pressure evaporation to dryness, and then water-ethanol recrystallization is carried out.
The raw materials used in the method are all common commercial products, wherein the acylated amino acid hydrolase (Aminoacylase) adopts acyl amino acid amidase I (EC 3.5.1.14), and the strong acid cation exchange resin adopts 732 type strong acid cation exchange resin.
The invention relates to a method for preparing L-selenomethylselenocysteine, which comprises the following synthetic route:
the invention adopts a chemical enzyme method to prepare L-selenomethylselenocysteine, combines the advantages of the chemical method and the enzyme method, firstly takes low-cost and easily-obtained L-serine methyl ester hydrochloride as a raw material, adopts a one-pot method in chemical synthesis to prepare an enzyme action substrate L-2-acetamido-3-methylselenopropionic acid, and then carries out enzymatic hydrolysis to directly obtain the optically pure L-selenomethylselenocysteine.
The invention has the advantages that the reaction substrate is prepared by a one-pot method, so that the instability of an intermediate is overcome, and complicated steps of separation, purification and the like of the intermediate are reduced; and by adopting enzyme catalytic hydrolysis, the defects of environmental pollution, equipment corrosion, selenium ether bond fracture, racemization of products and the like caused by strong acid hydrolysis can be avoided. The process has the characteristics of easily available raw materials, low cost, convenient operation, mild reaction conditions, environmental protection, single product, easy separation, high yield and suitability for industrial production.
Drawings
FIG. 1 is an elemental analysis map of L-selenomethylselenocysteine obtained in example 1;
FIG. 2 is an XRD pattern of L-selenomethylselenocysteine obtained in example 1;
FIG. 3 is a mass spectrum of L-selenomethylselenocysteine obtained in example 1;
FIG. 4 is an infrared spectrum of L-selenomethylselenocysteine obtained in example 1;
FIG. 5 is a diagram of L-selenomethylselenocysteine obtained in example 1 1 H nuclear magnetic resonance diagram;
FIG. 6 is a diagram of L-selenomethylselenocysteine obtained in example 1 13 C nuclear magnetic resonance image.
Detailed Description
In order to make the technical objects, technical solutions and advantageous effects of the present invention more apparent, the technical solutions of the present invention will be further described with reference to specific examples, which are intended to illustrate the present invention but are not to be construed as limiting the present invention, and specific techniques or conditions are not specified in the examples, and are performed according to techniques or conditions described in the literature in the art or according to the product specifications.
The instruments used in the examples below were all commercially available products. Wherein L-serine methyl ester hydrochloride is purchased from source leaf organisms (S20131-100 g), CAS number: 5680-80-8; the aminoacylases were purchased from source foliar organisms (acylating enzymes, S51676-100 g), CAS number: 9012-37-7, the enzyme activity is more than or equal to 30000u/g; the sodium methylselenate is prepared temporarily (prepared by reacting tetrahydrofuran as solvent, methanol as activating agent and sodium borohydride as reducing agent with dimethyl diselenide under ice bath and nitrogen atmosphere), and specifically comprises the following steps: to a three-necked flask equipped with a stirrer and a nitrogen gas guide tube, 300mL of tetrahydrofuran, 30.0g of dimethyl diselenide and 12.5g of sodium borohydride are added, and under the ice bath cooling and nitrogen protection, 60mL of methanol is slowly added dropwise, the dropwise is completed for about 0.5h, and stirring reaction is continued for 0.5h after the dropwise is completed, so as to obtain a sodium selenite tetrahydrofuran solution.
Example 1
A method for preparing L-selenomethylselenocysteine comprising the steps of:
(a) Adding 50g L-serine methyl ester hydrochloride into 300mL of tetrahydrofuran under stirring, and cooling to 0-5 ℃;
(b) 70.8g of triethylamine is added, 26.5g of acetyl chloride is added dropwise after the mixture is stirred uniformly (about 1 hour of adding dropwise is finished), and stirring is continued for 3 hours after the adding is finished; slowly dripping 34.4g of thionyl chloride (dripping is completed within 0.5 h), continuously stirring for 1h after dripping, heating to 45 ℃, stirring for 3h, and cooling to 0 ℃;
(c) 600mL of sodium bicarbonate saturated solution is added, after stirring for 0.5h, 300mL of sodium selenite tetrahydrofuran solution (containing 37.3g of sodium selenite) is added dropwise, after about 2h of dropwise addition, stirring is continued for 3h, after heating to room temperature, stirring is carried out for 12h, and a reaction mixture is obtained;
(d) After the pH of the reaction mixture was adjusted to <4.0 by slowly adding 6.0mol/LHCl, extraction was performed 3 times with ethyl acetate, the extracts were combined, washed with water, dried over anhydrous sodium sulfate, filtered, and ethyl acetate was removed under reduced pressure to give 50g of a pale yellow solid, i.e., the reaction substrate: the crude L-2-acetamido-3-methylselenopropionic acid does not need to be purified;
(e) Dissolving 50g of the reaction substrate obtained in the step (d) in 1000mL of 0.5mmol/L cobalt chloride aqueous solution, regulating the pH to 7.5 by using 2mol/L NaOH solution, adding 1.0g of acylated amino acid hydrolase, controlling the temperature to 37 ℃, stirring for 48 hours, and neutralizing the pH to 5.0-6.0 by using acetic acid; adding 0.2g of active carbon, heating and stirring for 0.5h at 80-85 ℃, filtering while the active carbon is still hot, concentrating the filtrate under reduced pressure to 300mL, separating by 732 type cation exchange resin, eluting by water and 5% ammonia water in sequence, evaporating 5% ammonia water eluent under reduced pressure to dryness, and recrystallizing by water-ethanol (1:1) to obtain 38.2g of product (L-selenomethylselenocysteine) with the yield of 94.0%.
The reaction equation of the above method is as follows:
and (3) carrying out physical property analysis, element analysis, X-ray diffraction detection, high-resolution mass spectrum detection, infrared detection and nuclear magnetic resonance detection on the product obtained in the step (e), wherein an element analysis chart, an XRD chart, a mass spectrogram, an infrared spectrogram and a nuclear magnetic resonance chart are respectively shown in figures 1-6.
The specific detection results are as follows:
m.p.179.8-180.2 ℃; specific rotation [ alpha ]] D 20 ＝-14.0°(C＝1,H 2 O)。
Elemental analysis (%), measured values: c26.31; h5.071; n7.952; theoretical value: c26.39; h4.98; n7.69; ESI-MS, M/z: [ M+H ]] + Measured value 183.9874; theoretical value 183.9877.
IR(KBr,cm -1 )3341(N-H),3130-3021,2927(C-H),2700-2500,1619(C＝O),1579,1489,1414(C-O),1377(C-H)。
1 HNMR(400MHz,D 2 O),δ(ppm):3.904-3.875(1H,dd,J＝4.7,6.8Hz,-CH-),3.028-2.924(2H,m,-CH 2 -),1.982(3H,s,-CH 3 )；
13 CNMR(D 2 O),δ(ppm):173.0(-COOH),53.7(-CH-),24.9(-CH 2 -),4.43(-CH 3 )；
77 SeNMR(D 2 O),δ(ppm):240.1(SeCH 3 )。
By analyzing the detection result, the method can obtain:
(1) the X-ray powder diffraction result of the sample shows that the sample is crystalline powder.
(2) Specific optical rotation measurement of sample: -14.0 ° (c=1, h 2 O) is consistent with the value of L-selenomethylselenocysteine, indicating that the sample is in the L-configuration.
(3) High resolution mass spectrometry analysis shows excimer ion peak [ M+H ] of sample] + 183.9874, L-selenomethylselenocysteineTheoretical exact molecular weight of amino acids [ M+H ]] + 183.9877, the theoretical value is less than 3ppm error compared with the measured value, and the element matching result shows that the element composition is C 4 H 10 NO 2 Se, can be deduced to have the molecular formula C 4 H 9 NO 2 Se is consistent with the structure of L-selenomethylselenocysteine, and the cleavage fragments of the secondary mass spectrum are consistent with the cleavage rule of the L-selenomethylselenocysteine, so that the element composition is correct.
④IR 3441cm -1 ：NH 2 Stretching and vibrating of NH, 3130-3021cm -1 ：NH 3 + CH(CH 2 SeCH 3 )COO - Middle NH 3 + Is stretched asymmetrically and vibrated at 2700-2500cm -1 ：NH 3 + CH(CH 2 SeCH 3 )COO - Middle NH 3 + They are ammonium peaks in amino acids; 1579,1489cm -1 ：NH 3 + CH(CH 2 SeCH 3 )COO - Middle NH 3 + The bending vibration of (2) indicates that the molecule contains an amino acid fragment. 1619cm -1 ：COO - Is 1414cm -1 : the COO-symmetrical stretching vibration indicates that the molecule contains amino acid fragments.
⑤IR 1619cm -1 ：COO - C=o stretching vibration 1414cm -1 ：COO - The C-O of the device stretches and vibrates, 13 delta 173.0 (quaternary carbon) ppm in CNMR is the C-5 carboxycarbonyl carbon in the molecule.
⑥IR:2927cm -1 ：CH,CH 2 ,CH 3 C-H stretching vibration 1377cm -1 ：CH,CH 2 ,CH 3 C-H bending vibration in the molecule, which proves that CH and CH are in the molecule 2 ,CH 3 。 1 H NMR、 13 C NMR spectrum also proves that the molecule contains 1 CH and 1 CH 2 1 CH 3 。
In summary, the product molecule obtained in the step (e) contains 3 active protons, 6 inactive protons and 4 carbons, which are consistent with the structure of L-selenomethylselenocysteine; UV, IR, sample, 1 H NMR、 13 The C NMR and HR-MS spectra can be reasonably explained by the structure of the L-selenomethylselenocysteine, and the sample structure is proved to be consistent with the structure of the L-selenomethylselenocysteine.
Example 2
A method for preparing L-selenomethylselenocysteine comprising the steps of:
(a) Adding 50g L-serine methyl ester hydrochloride into 300mL of tetrahydrofuran under stirring, and cooling to 0-5 ℃;
(b) 70.8g of triethylamine is added, 26.5g of acetyl chloride is added dropwise after the mixture is stirred uniformly (about 1 hour of adding dropwise is finished), and stirring is continued for 4 hours after the adding is finished; slowly dropwise adding 36.1g of thionyl chloride (dropwise adding is completed in 0.5 h), continuously stirring for 1h after the dropwise adding is completed, heating to 45 ℃, stirring for 3h for reaction, and cooling to 0 ℃;
(c) 600mL of sodium bicarbonate saturated solution is added, after stirring for 0.5h, 300mL of sodium selenite tetrahydrofuran solution (containing 37.3g of sodium selenite) is added dropwise, after about 2h of dropwise addition, stirring is continued for 3h, after heating to room temperature, stirring is carried out for 12h, and a reaction mixture is obtained;
(d) After the pH of the reaction mixture is regulated to be less than 4.0 by slowly adding 6.0mol/L HCl, extracting with ethyl acetate for 3 times, combining the extracts, washing with water, drying with anhydrous sodium sulfate, filtering, and removing the ethyl acetate under reduced pressure to obtain 46g of light yellow solid, namely a reaction substrate: the crude L-2-acetamido-3-methylselenopropionic acid does not need to be purified;
(e) Dissolving 46g of the reaction substrate obtained in the step (d) in 1000mL of 0.5mmol/L cobalt chloride aqueous solution, regulating the pH to 7.0 by using 2mol/L NaOH solution, adding 0.9g of acylated amino acid hydrolase, controlling the temperature to 37 ℃, stirring for 48 hours, and neutralizing the pH to 5.0-6.0 by using acetic acid; adding 0.2g of active carbon, heating and stirring for 0.5h at 80-85 ℃, filtering while the active carbon is still hot, concentrating the filtrate under reduced pressure to 300mL, separating by 732 type cation exchange resin, eluting by water and 5% ammonia water in sequence, evaporating 5% ammonia water eluent under reduced pressure to dryness, and recrystallizing by water-ethanol (1:1) to obtain 37.0g of L-selenomethylselenocysteine with the yield of 91.1%.
Compared with example 1, example 2 mainly changes in that: the reaction time of acetylation and the addition amount of thionyl chloride in the step (b) are increased, the yield of reaction substrates is reduced, and the acylated amino acid hydrolase is reduced.
And (3) detecting and analyzing the product obtained in the step (e), wherein the result is as follows:
m.p.180-180.2 ℃; specific rotation [ alpha ]] D 20 ＝-13.5°(C＝1,H 2 O)。
Elemental analysis (%), measured values: c26.29; h5.504; n7.873; theoretical value: c26.39; h4.98; n7.69; ESI-MS, M/z: [ M+H ]] + Measured value 183.9874; theoretical value 183.9877.
IR(KBr,cm -1 )3341(N-H),3130-3021,2927(C-H),2700-2500,1619(C＝O),1579,1489,1414(C-O),
1377(C-H)。
1 HNMR(400MHz,D 2 O),δ(ppm):3.904-3.875(1H,dd,J＝4.7,6.8Hz,-CH-),3.028-2.924(2H,m,-CH 2 -),1.982(3H,s,-CH 3 )；
13 CNMR(D 2 O),δ(ppm):173.0(-COOH),53.7(-CH-),24.9(-CH 2 -),4.43(-CH 3 )；
77 SeNMR(D 2 O),δ(ppm):240.1(SeCH 3 )。
Example 3
A method for preparing L-selenomethylselenocysteine comprising the steps of:
(a) Adding 50g L-serine methyl ester hydrochloride into 300mL of tetrahydrofuran under stirring, and cooling to 0-5 ℃;
(b) 70.8g of triethylamine is added, after the mixture is stirred uniformly, 27.8g of acetyl chloride is added dropwise (about 1 hour of adding is finished), and stirring is continued for 4 hours after the adding is finished; slowly dripping 37.8g of thionyl chloride (dripping is completed within 0.5 h), continuously stirring for 1h after dripping is completed, heating to 45 ℃, stirring for 3h, and then cooling to 0 ℃;
(c) 600mL of sodium bicarbonate saturated solution is added, after stirring for 0.5h, 300mL of sodium selenite tetrahydrofuran solution (containing 37.3g of sodium selenite) is added dropwise, after about 2h of dropwise addition, stirring is continued for 3h, after heating to room temperature, stirring is carried out for 12h, and a reaction mixture is obtained;
(d) After the pH of the reaction mixture is regulated to be less than 4.0 by slowly adding 6.0mol/L HCl, the mixture is extracted for 3 times by ethyl acetate, the extracts are combined, washed by water, dried by anhydrous sodium sulfate, filtered and decompressed to remove the ethyl acetate, and 47g of light yellow solid is obtained, namely a reaction substrate: the crude L-2-acetamido-3-methylselenopropionic acid does not need to be purified;
(e) Dissolving 47g of the reaction substrate obtained in the step (d) in 1000mL of 0.5mmol/L cobalt chloride aqueous solution, regulating the pH to 7.0 by using 2mol/L NaOH solution, adding 0.9g of acylated amino acid hydrolase, controlling the temperature to 37 ℃, stirring for 48 hours, and neutralizing the pH to 5.0-6.0 by using acetic acid; adding 0.2g of active carbon, heating and stirring for 0.5h at 80-85 ℃, filtering while the active carbon is still hot, concentrating the filtrate under reduced pressure to 300mL, separating by 732 type cation exchange resin, eluting by water and 5% ammonia water in sequence, evaporating 5% ammonia water eluent under reduced pressure to dryness, and recrystallizing by water-ethanol (1:1) to obtain 37.2g of L-selenomethylselenocysteine with the yield of 91.6%.
Compared with example 1, example 3 mainly changes in that: the reaction time of acetylation and the addition amount of acetyl chloride in the step (b) are increased, the yield of reaction substrates is reduced, and the acylated amino acid hydrolase is reduced.
And (3) detecting and analyzing the product obtained in the step (e), wherein the result is as follows:
m.p.179.5-180.3 ℃; specific rotation [ alpha ]] D 20 ＝-13.8°(C＝1,H 2 O)。
Elemental analysis (%), measured values: c26.29; h5.504; n7.873; theoretical value: c26.39; h4.98; n7.69; ESI-MS, M/z: [ M+H ]] + Measured value 183.9874; theoretical value 183.9877.
IR(KBr,cm -1 )3341(N-H),3130-3021,2927(C-H),2700-2500,1619(C＝O),1579,1489,1414(C-O),
1377(C-H)。
1 HNMR(400MHz,D 2 O),δ(ppm):3.904-3.875(1H,dd,J＝4.7,6.8Hz,-CH-),3.028-2.924(2H,m,-CH 2 -),1.982(3H,s,-CH 3 )；
13 CNMR(D 2 O),δ(ppm):173.0(-COOH),53.7(-CH-),24.9(-CH 2 -),4.43(-CH 3 )；
77 SeNMR(D 2 O),δ(ppm):240.1(SeCH 3 )。
Example 4
A method for preparing L-selenomethylselenocysteine comprising the steps of:
(a) Adding 50g L-serine methyl ester hydrochloride into 300mL of tetrahydrofuran under stirring, and cooling to 0-5 ℃;
(b) 68.3g of triethylamine is added, 26.5g of acetyl chloride is added dropwise after being stirred uniformly (about 1 hour of dropwise addition is finished), and stirring is continued for 3 hours after dropwise addition is finished; slowly dripping 34.4g of thionyl chloride (dripping is completed within 0.5 h), continuously stirring for 1h after dripping, heating to 45 ℃, stirring for 3h, and cooling to 0 ℃;
(c) 600mL of sodium bicarbonate saturated solution is added, after stirring for 0.5h, 300mL of sodium selenite tetrahydrofuran solution (containing 37.3g of sodium selenite) is added dropwise, after about 2h of dropwise addition, stirring is continued for 3h, after heating to room temperature, stirring is carried out for 12h, and a reaction mixture is obtained;
(d) After the pH of the reaction mixture is regulated to be less than 4.0 by slowly adding 6.0mol/L HCl, extracting with ethyl acetate for 3 times, combining the extracts, washing with water, drying with anhydrous sodium sulfate, filtering, and removing the ethyl acetate under reduced pressure to obtain 50g of light yellow solid, namely a reaction substrate: the crude L-2-acetamido-3-methylselenopropionic acid does not need to be purified;
(e) Dissolving 50g of the reaction substrate obtained in the step (d) in 1000mL of 0.5mmol/L cobalt chloride aqueous solution, regulating the pH to 7.0 by using 2mol/L NaOH solution, adding 1.0g of acylated amino acid hydrolase, controlling the temperature to 37 ℃, stirring for 48 hours, and neutralizing the pH to 5.0-6.0 by using acetic acid; adding 0.2g of active carbon, heating and stirring for 0.5h at 80-85 ℃, filtering while the active carbon is still hot, concentrating the filtrate under reduced pressure to 300mL, separating by 732 type cation exchange resin, eluting by water and 5% ammonia water in sequence, evaporating 5% ammonia water eluent under reduced pressure to dryness, and recrystallizing by water-ethanol (1:1) to obtain 38.0g of L-selenomethylselenocysteine with the yield of 93.5%.
Compared with example 1, example 4 mainly changed in that: the addition amount of triethylamine is reduced.
And (3) detecting and analyzing the product obtained in the step (e), wherein the result is as follows:
m.p.179.8-180.2 ℃; specific rotation [ alpha ]] D 20 ＝-14.0°(C＝1,H 2 O)。
Elemental analysis (%), measured values: c26.29; h5.504; n7.873; theoretical value: c26.39; h4.98; n7.69; ESI-MS, M/z: [ M+H ]] + Measured value 183.9874; theoretical value 183.9877.
IR(KBr,cm -1 )3341(N-H),3130-3021,2927(C-H),2700-2500,1619(C＝O),1579,1489,1414(C-O),
1377(C-H)。
1 HNMR(400MHz,D 2 O),δ(ppm):3.904-3.875(1H,dd,J＝4.7,6.8Hz,-CH-),3.028-2.924(2H,m,-CH 2 -),1.982(3H,s,-CH 3 )；
13 CNMR(D 2 O),δ(ppm):173.0(-COOH),53.7(-CH-),24.9(-CH 2 -),4.43(-CH 3 )；
77 SeNMR(D 2 O),δ(ppm):240.1(SeCH 3 )。
Example 5
A method for preparing L-selenomethylselenocysteine comprising the steps of:
(a) Adding 50g L-serine methyl ester hydrochloride into 300mL of tetrahydrofuran under stirring, and cooling to 0-5 ℃;
(b) 68.3g of triethylamine is added, 26.5g of acetyl chloride is added dropwise after being stirred uniformly (about 1 hour of dropwise addition is finished), and stirring is continued for 3 hours after dropwise addition is finished; slowly dripping 34.4g of thionyl chloride (dripping is completed within 0.5 h), continuously stirring for 1h after dripping, heating to 45 ℃, stirring for 3h, and cooling to 0 ℃;
(e) 600mL of sodium bicarbonate saturated solution is added, after stirring for 0.5h, 300mL of sodium selenite tetrahydrofuran solution (containing 37.3g of sodium selenite) is added dropwise, after about 2h of dropwise addition, stirring is continued for 3h, after heating to room temperature, stirring is carried out for 12h, and a reaction mixture is obtained;
(d) After the pH of the reaction mixture is regulated to be less than 4.0 by slowly adding 6.0mol/L HCl, extracting with ethyl acetate for 3 times, combining the extracts, washing with water, drying with anhydrous sodium sulfate, filtering, and removing the ethyl acetate under reduced pressure to obtain 50g of light yellow solid, namely a reaction substrate: the crude L-2-acetamido-3-methylselenopropionic acid does not need to be purified;
(e) Dissolving 50g of the reaction substrate obtained in the step (d) in 1000mL of 0.5mmol/L cobalt chloride aqueous solution, regulating the pH to 7.0 by using 2mol/LNaOH solution, adding 1.2g of acylated amino acid hydrolase, controlling the temperature to 37 ℃, stirring for 48 hours, and neutralizing the pH to 5.0-6.0 by using acetic acid; adding 0.2g of active carbon, heating and stirring for 0.5h at 80-85 ℃, filtering while the active carbon is still hot, concentrating the filtrate under reduced pressure to 300mL, separating by 732 type cation exchange resin, eluting by water and 5% ammonia water in sequence, evaporating 5% ammonia water eluent under reduced pressure to dryness, and recrystallizing by water-ethanol (1:1) to obtain 38.5g of L-selenomethylselenocysteine with the yield of 94.8%.
Compared with example 1, example 5 is mainly modified in that: the addition amount of the aminoacylase is increased.
And (3) detecting and analyzing the product obtained in the step (e), wherein the result is as follows:
m.p.179.6-180.0 ℃; specific rotation [ alpha ]] D 20 ＝-14.0°(C＝1,H 2 O)。
Elemental analysis (%), measured values: c26.29; h5.504; n7.873, theoretical value: c26.39; h4.98; n7.69; ESI-MS, M/z: [ M+H ]] + Measured value 183.9874; theoretical value 183.9877.
IR(KBr,cm -1 )3341(N-H),3130-3021,2927(C-H),2700-2500,1619(C＝O),1579,1489,1414(C-O),
1377(C-H)。
1 HNMR(400MHz,D 2 O),δ(ppm):3.904-3.875(1H,dd,J＝4.7,6.8Hz,-CH-),3.028-2.924(2H,m,-CH 2 -),1.982(3H,s,-CH 3 )；
13 CNMR(D 2 O),δ(ppm):173.0(-COOH),53.7(-CH-),24.9(-CH 2 -),4.43(-CH 3 )；
77 SeNMR(D 2 O),δ(ppm):240.1(SeCH 3 )。
In summary, examples 1 to 5, which employ both one-pot and enzymatic hydrolysis methods, effectively synthesize L-selenomethylselenocysteine with high yield, economical feasibility and reduced environmental pollution.
Claims (4)
1. A method for preparing L-selenomethylselenocysteine comprising the steps of:
(1) L-serine methyl ester hydrochloride is used as a starting material, and a reaction substrate is synthesized by an acetylation, chlorination and methylselenylation one-pot method;
(2) Hydrolyzing the reaction substrate obtained in the step (1) under the action of enzyme catalysis to generate L-selenomethylselenocysteine;
the step (1) comprises the following steps:
(a) Adding L-serine methyl ester hydrochloride into a reaction medium under the stirring condition, and cooling to 0-5 ℃;
(b) Adding an acetylation reagent, stirring for 2-5 hours, adding a chlorination reagent, stirring for 0.5-2 hours, heating to 5-50 ℃, continuously stirring for 2-5 hours, and cooling to-5-0 ℃;
(c) Adding the selenizing reagent, stirring for 2-5 hours, heating to room temperature, and continuously stirring for 10-15 hours to obtain a reaction mixed solution;
(d) Adjusting the pH value of the reaction mixed solution obtained in the step (c) to be less than 4.0, extracting with ethyl acetate for 2-5 times, combining the extracts, washing with water, drying, filtering, and evaporating the ethyl acetate under reduced pressure to obtain a reaction substrate;
wherein, before the step (b) is added with an acetylation reagent and before the step (c) is added with a selenization reagent, an acid binding agent is added, and the reaction substrate is L-2-acetamido-3-methylselenopropionic acid;
the step (2) comprises the following steps: dissolving the reaction substrate obtained in the step (1) in cobalt chloride aqueous solution, regulating the pH to 7.0-8.0, adding acylated amino acid hydrolase, stirring and reacting for 4-110 hours at 20-40 ℃, regulating the pH to 5.0-6.0, adding active carbon, stirring for 0.3-1.5 hours at 80-85 ℃, carrying out solid-liquid separation, concentrating the liquid under reduced pressure, separating and purifying by strong acid cation exchange resin, and recrystallizing the water-alcohol solution to obtain the L-selenomethylselenocysteine;
the mol ratio of the L-serine methyl ester hydrochloride to the acetylating reagent to the chlorinating reagent to the selenizing reagent is 1.0 (1.0-1.2): 1.0-1.6): 1.0-1.5;
the reaction medium is tetrahydrofuran, the acetylation reagent is acetyl chloride, the chlorination reagent is thionyl chloride, and the selenizing reagent is sodium selenite.
2. The method for preparing L-selenomethylselenocysteine according to claim 1, wherein: the acid binding agent is selected from one of triethylamine, pyridine, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.
3. The method for preparing L-selenomethylselenocysteine according to claim 1, wherein: the concentration of the cobalt chloride solution is 0.3-1 mmol/L, the addition of the reaction substrate in the cobalt chloride solution is 22.4-67.2 g/L, the addition of the acylated amino acid hydrolase is 1.9-2.4% of the mass of the reaction substrate, and the addition of the activated carbon is 0.1-0.5% of the mass of the reaction substrate.
4. A process for the preparation of L-selenomethylselenocysteine according to claim 1 or 3, characterized in that: when the strong acid cation exchange resin is used for separation and purification, water and 3-8% ammonia water are adopted for sequential elution, ammonia water eluent is taken for decompression and evaporation, and then water-ethanol recrystallization is carried out.
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