CN115872911B - Method for synthesizing selenomethylselenocysteine - Google Patents

Method for synthesizing selenomethylselenocysteine Download PDF

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CN115872911B
CN115872911B CN202111134725.6A CN202111134725A CN115872911B CN 115872911 B CN115872911 B CN 115872911B CN 202111134725 A CN202111134725 A CN 202111134725A CN 115872911 B CN115872911 B CN 115872911B
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triflate
selenomethylselenocysteine
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CN115872911A (en
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胡向平
陈松
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Dalian Institute of Chemical Physics of CAS
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Abstract

The invention aims to provide a synthesis method of selenium methyl selenocysteine, which is used for conveniently and simply synthesizing the selenium methyl selenocysteine by using simple and easily obtained raw materials. The method comprises the following steps: adding solvent and triflate into a system after esterification, dropwise adding methyl selenol under stirring and heating, reacting for 1-3 hours under the condition, concentrating and removing the solvent, adjusting the pH of a water system to 1-3, stirring for 1-3 hours at 50-100 ℃, neutralizing the pH at room temperature to 6-8, stirring for 0.5-2 hours, filtering to obtain crude selenium methyl selenocysteine, and recrystallizing to obtain the target compound. The method is carried out under mild reaction conditions, and has the characteristics of high activity, good selectivity, high yield, low toxicity and the like.

Description

Method for synthesizing selenomethylselenocysteine
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of 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 not replaced by other substances.
L-selenocysteine (Selenocysteine, CAS: 10236-58-5) is the predominant form of selenium in proteins, which is present in a few enzymes such as glutathione peroxidase, thyroxine 5' -deiodinase, thioredoxin reductase, formate dehydrogenase, glycine reductase, and some hydrogenases, among others. Selenium cysteine has a structure similar to cysteine except that the sulfur atom is replaced with selenium. Selenocysteine is currently considered as the 21 st standard amino acid of human beings, is the only amino acid containing metalloid elements, and has wide research significance. At present, the synthesis of selenium methyl selenocysteine mainly comprises the following methods:
(1) Sodium chloroalanine diselenide method: firstly, reacting chloralanine with sodium diselenide to generate selenocysteine, then, reducing and cracking by using metallic sodium/liquid ammonia (-70 ℃), and then, alkylating by using methyl iodide to obtain selenomethylselenocysteine. The method involves ultralow temperature and active metal sodium, has strict reaction conditions, high requirements on process equipment, high price of chloroalanine raw materials and high production cost (methods enzymol, 1987,143,240-243; J.Med. Chem.,1996,39,2040-2046)
(2) Methylselenylacetaldehyde method: the method is a hydantoin imitation method, which is to prepare methylselenylacetaldehyde by the reaction of methylselenolate and chloroacetaldehyde, then to form methylselenomethylhydantoin by cyclization with cyanide, then to obtain selenomethylselenocysteine by alkali hydrolysis ring opening and acidification. The method has long reaction steps, and the use of highly toxic cyanide has great harm to the environment and human health. (CN 200610124942.6)
(3) Synthesis of alpha-amino acrylic acid derivative: firstly, the beta-methylseleno-alpha-amino acrylic acid derivative is produced by the addition reaction of methyl selenol or methyl selenol salt aqueous solution and alpha-amino acrylic acid derivative, then the ester compound in the derivative is hydrolyzed by alkali, hydrochloric acid or sulfuric acid is acidified to obtain the carboxylic acid compound, then the N-acyl group in the derivative is heated and hydrolyzed by hydrochloric acid or sulfuric acid to remove the beta-methylseleno-alpha-amino propionic acid hydrochloride or sulfate, and finally the selenium methylselenocysteine is obtained by neutralization by triethylamine or ammonia gas. The method has the advantages of high price of the raw material alpha-amino acrylic acid derivative and high production cost. (CN 200710051362.3)
(4) N-Boc-protected serine method: the tert-butoxyacyl serine and azodicarboxylic acid diester react in the presence of trialkyl (aryl) phosphine or phosphite to generate beta-lactone, then react with methyl selenol or its salt to generate tert-butoxyacyl protected selenomethylselenocysteine, and finally deprotecting to obtain the product. The method has the advantages of difficult preparation of the tert-butoxyacyl serine-beta-lactone as the reaction raw material, high price of the involved reaction raw material and protective agent, long reaction time and low yield. (EP 1205471,2001)
(5) Sodium methylselenate substitution chloroalanine method: and replacing chlorine in the chloralanine or chloralanine methyl ester with sodium methyl selenate to obtain selenomethylselenocysteine. The method has high price of the raw material of the chloralanine and high production cost.
(US6794537B1，2004)
(6) Substitution and ammonolysis method of sodium methylselenol and dibromopropionitrile: firstly, a selenite salt selectively reacts with 2, 3-dihalopropionitrile in a nucleophilic substitution reaction to produce 2-halogen-3-methylselenopropionitrile, then acidolysis is carried out to produce 2-halogen-3-methylselenopropionic acid, and finally, selenomethylselenocysteine is obtained by ammoniation. In the method, the preparation of the substrate dibromopropionitrile is that acrylonitrile is added with liquid bromine, a large amount of liquid bromine is used, the environmental pollution is serious, and the equipment requirement is high; the nucleophilic substitution reaction of selenoalkoxide and substrate has poor selectivity and low yield, and is not suitable for industrial production.
(CN201010107900.8)
Disclosure of Invention
The invention aims to provide a nucleophilic substitution reaction system with high efficiency and high activity, which is used for conveniently and simply synthesizing selenomethylselenocysteine through simple and easily obtained raw materials. The trifluoro methanesulfonate is used as a nucleophilic substitution catalyst of hydroxyl in a Lewis acid catalytic substrate, so that efficient alkylation reaction is realized, and the selectivity is as high as 99.5%. The catalyst has extremely strong thermodynamic and chemical stability, is widely applied to the market, and has low cost and little environmental pollution. The method is carried out under mild reaction conditions, and has the characteristics of high activity, good selectivity, high yield, low toxicity and the like.
The invention provides a method for synthesizing selenomethylselenocysteine, which comprises the following steps: adding solvent and triflate into serine methyl ester, heating to 0-80 ℃ under stirring, dropwise adding methyl selenol, after finishing the reaction for 1-5 hours, concentrating to remove the solvent, regulating the pH of a water system to 1-3, keeping stirring for 1-3 hours at 50-100 ℃, neutralizing the pH at room temperature to 6-8, keeping stirring for 0.5-2 hours, cooling the system to room temperature, filtering out solid which is crude product of selenomethylselenocysteine, adding the crude product into water for recrystallization, filtering, washing a filter cake with a small amount of ethanol, and drying to obtain the target compound.
The mass ratio of the solvent to serine methyl ester in the reaction is as follows: 2-5:1; the molar ratio of the triflate to the serine methyl ester is 0.025-0.005:1, the mass ratio of the methyl selenol to the serine methyl ester is 1-2:1;
The reaction equation is:
the reaction solvent is one or two of dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile and dioxane;
The triflate is one of silver triflate, zinc triflate, aluminum triflate, scandium triflate, titanium triflate, cerium triflate, indium triflate, bismuth triflate and copper triflate;
The crude product of the selenomethylselenocysteine is red or yellow crystal;
The recrystallization solvent is one or more of methanol, ethanol, acetone, water and ethyl acetate;
In summary, under the condition of the invention, the step of synthesizing the target compound is concise, the selenomethylselenoamino acid can be directly synthesized by serine methyl ester through one-step reaction, the chemical yield of the reaction is improved, the chemical yield can reach 74-83%, and meanwhile, the dosage of the methylselenol is reduced (0.82 tons of methylselenol are needed for producing 1 ton of product); the method can reduce the size of equipment, reduce energy consumption, reduce environmental pollution, reduce the generation of byproducts, reduce the corrosion degree of the equipment and prolong the service life of the equipment.
Drawings
The selenium methyl selenocysteine nuclear magnetic hydrogen spectrum is shown in figure 1.
1H NMR(400MHz,Deuterium Oxide)δ3.88(dd,J＝7.0,4.6Hz,1H),3.27–2.78 (m,2H),1.97(s,2H).
Detailed Description
The invention is illustrated by the following examples.
Example 1
200.0Ml of dichloroethane is added into a 1.0 liter four-neck flask, 100.0g of serine methyl ester and 0.5mol% of trifluoro methyl sulfonate are added under stirring, the system is heated to 60 ℃, 220.0g of dichloroethane solution containing methyl selenol (104.0 g) is added dropwise, the reaction is carried out for 2 hours under the condition of keeping the temperature, the solvent is removed by decompression and concentration, 300.0g of water is added, 6N hydrochloric acid is added under stirring to adjust the pH value of the system to 1, the reaction is carried out for 1.5 hours under the condition of heating to 80 ℃, the temperature is reduced to room temperature, 10% sodium hydroxide is added to adjust the pH value to 7, after the stirring is kept for 1 hour, the filtration is carried out, a little ethanol is used for washing a filter cake, and the yellow or red solid is 142.2g of selenium methyl selenocysteine crude product after vacuum drying.
Adding 100.0g of the crude selenomethylselenocysteine into a 500.0ml reaction bottle, adding 250.0g of water, stirring and heating to 80 ℃, cooling to 50 ℃ after the system is dissolved, dropwise adding 50.0g of ethanol, continuously cooling to room temperature, keeping for 1 hour, filtering, washing a filter cake with a small amount of ethanol, and vacuum drying to obtain 89.4g of selenomethylselenocysteine.
Example 2
200.0Ml of acetonitrile is added into a 1.0 liter four-neck flask, 100.0 g of serine methyl ester and 0.5mol% of aluminum triflate are added under stirring, the system is heated to 60 ℃, 220g of acetonitrile solution of methyl selenol (104.0 g containing methyl selenol) is added dropwise, the reaction is carried out for 2 hours under the condition that the temperature is maintained, the solvent is removed by decompression concentration, 300.0g of water is added, 6N hydrochloric acid is added under stirring to adjust the pH of the system to 1, the reaction is carried out for 2.0 hours under the condition that the temperature is 70 ℃, the temperature is reduced to room temperature, 10% sodium hydroxide is added to adjust the pH to 6.8, after the stirring is maintained for 1 hour, the filtration is carried out, a little ethanol is used for washing a filter cake, and the yellow or red solid is 137.6g of selenium methyl selenocysteine crude product after vacuum drying.
Adding 100.0g of the crude selenomethylselenocysteine into a 500.0ml reaction bottle, adding 250.0g of methanol, stirring and heating to 80 ℃, cooling to 50 ℃ after the system is dissolved, dropwise adding 50.0g of acetone, continuously cooling to room temperature, keeping for 1 hour, filtering, washing a filter cake with a small amount of ethanol, and vacuum drying to obtain 89.2g of selenomethylselenocysteine.
Example 3
200.0Ml of dichloroethane is added into a 1.0 liter four-neck flask, 100.0g of serine methyl ester and 1.0mol% of trifluoro methyl sulfonate are added under stirring, the system is heated to 60 ℃, 220g of dichloroethane solution containing methyl selenol (104.0 g) is dripped, the reaction is carried out for 2 hours under the condition of keeping the temperature, the solvent is removed by decompression concentration, 300.0g of water is added, 6N hydrochloric acid is added under stirring to adjust the pH of the system to 1, the reaction is carried out for 1.5 hours under the condition of heating to 60 ℃, the temperature is reduced to room temperature, 10% sodium hydroxide is added to adjust the pH to 6.5, after the stirring is kept for 1 hour, the filtration is carried out, a little ethanol is used for washing a filter cake, and the yellow or red solid is 143.1g of selenium methyl selenocysteine crude product after vacuum drying.
Adding 100.0g of the crude selenomethylselenocysteine into a 1.0L reaction bottle, adding 600.0g of ethyl acetate, stirring and heating to 80 ℃, cooling to room temperature after the system is dissolved, keeping the temperature for 1 hour, filtering, washing a filter cake with a small amount of ethanol, and vacuum drying to obtain 83.5g of selenomethylselenocysteine.
Example 4
200.0Ml of tetrahydrofuran is added into a 1.0 liter four-neck flask, 100.0g of serine methyl ester and 1.5mol% of indium triflate are added under stirring, the system is heated to 65 ℃, 220g of tetrahydrofuran solution of methyl selenol (104.0 g containing methyl selenol) is added dropwise, the reaction is carried out for 2 hours under the condition that the temperature is maintained, the solvent is removed by decompression concentration, 300.0g of water is added, 6N hydrochloric acid is added under stirring to adjust the pH of the system to 1, the reaction is carried out for 1.5 hours under the condition that the temperature is heated to 80 ℃, the temperature is reduced to room temperature, 10% sodium hydroxide is added to adjust the pH to 7.5, after the stirring is maintained for 1 hour, the filtration is carried out, a little ethanol is used for washing a filter cake, and vacuum drying is carried out to obtain yellow or red solid which is 134.5g of selenium methyl selenocysteine crude product.
Adding 100.0g of the crude selenomethylselenocysteine into a 1.0L reaction bottle, adding 500.0g of water, stirring and heating to 80 ℃, cooling to room temperature after the system is dissolved, keeping for 1 hour, filtering, washing a filter cake with a small amount of acetone, and vacuum drying to obtain 82.3g of selenomethylselenocysteine.
Example 5
200.0Ml of dichloroethane is added into a 1.0 liter four-neck flask, 100.0 g of serine methyl ester and 2.5mol% of copper triflate are added under stirring, the system is heated to 70 ℃,220 g of dichloroethane solution containing methyl selenol (104.0 g) is added dropwise, the reaction is carried out for 2 hours under the condition that the temperature is maintained, the solvent is removed by decompression concentration, 300.0g of water is added, 6N hydrochloric acid is added under stirring to adjust the pH of the system to 3, the reaction is carried out for 1.5 hours under the condition that the temperature is heated to 80 ℃, the temperature is reduced to room temperature, 10% sodium hydroxide is added to adjust the pH to 7, after the stirring is kept for 1 hour, the filtration is carried out, a little ethanol is used for washing a filter cake, and the yellow or red solid is 126.9g of selenium methyl selenocysteine crude product after vacuum drying.
Adding 100.0g of the crude selenomethylselenocysteine into a 500.0ml reaction bottle, adding 250.0g of water, stirring and heating to 80 ℃, cooling to 50 ℃ after the system is dissolved, dropwise adding 50.0g of ethanol, continuously cooling to room temperature, keeping for 1 hour, filtering, washing a filter cake with a small amount of ethanol, and vacuum drying to obtain 88.6g of selenomethylselenocysteine.
Example 6
200.0Ml of methylene dichloride is added into a 1.0 liter four-neck flask, 100.0g of serine methyl ester and 0.5mol% of zinc triflate are added under stirring, the system is heated to 45 ℃, 200.0g of methylene dichloride solution containing methyl selenol (104.0 g) is added dropwise, the reaction is carried out for 2 hours under the condition that the temperature is maintained, the solvent is removed by decompression concentration, 300.0g of water is added, 6N hydrochloric acid is added under stirring to adjust the pH of the system to 1, the reaction is carried out for 1.5 hours under the condition that the temperature is heated to 80 ℃, the temperature is reduced to room temperature, 10% sodium hydroxide is added to adjust the pH to 7, after the stirring is maintained for 1 hour, the filtration is carried out, a little ethanol is used for washing a filter cake, and a yellow or red solid is obtained, namely, the selenium methyl selenocysteine crude product is 140.2g.
Adding 100.0g of the crude selenomethylselenocysteine into a 500.0ml reaction bottle, adding 250.0g of methanol, stirring and heating to 80 ℃, cooling to room temperature after the system is dissolved, keeping for 1 hour, filtering, washing a filter cake with a small amount of methanol, and vacuum drying to obtain 83.6g of selenomethylselenocysteine.
Example 7
200.0Ml of dioxane is added into a 1.0 liter four-neck flask, 100.0g of serine methyl ester and 0.5mol% of silver triflate are added under stirring, the system is heated to 65 ℃, 220.0g of dioxane solution of methyl selenol (containing 104.0g of methyl selenol) is added dropwise, the reaction is carried out for 2 hours under the condition that the temperature is maintained, the solvent is removed through decompression and concentration, 300.0g of water is added, 6N hydrochloric acid is added under stirring to adjust the pH value of the system to 1, the reaction is carried out for 1.5 hours under the condition that the temperature is heated to 80 ℃, the temperature is reduced to the room temperature, 10% sodium hydroxide is added to adjust the pH value to 7, the mixture is kept under stirring for 1 hour, the mixture is filtered, a little ethanol is used for washing a filter cake, and the yellow or red solid is 123.1g of selenium methyl selenocysteine crude product after vacuum drying.
Adding 100.0g of the crude selenomethylselenocysteine into a 500.0ml reaction bottle, adding 200.0g of water, stirring and heating to 80 ℃, cooling to 50 ℃ after the system is dissolved, dropwise adding 100.0g of ethanol, continuously cooling to room temperature, keeping for 1 hour, filtering, washing a filter cake with a small amount of ethanol, and vacuum drying to obtain 80.4g of selenomethylselenocysteine.

Claims (4)

1. A method for synthesizing selenomethylselenocysteine is characterized in that:
(1) Adding solvent and triflate into serine methyl ester, and heating to 45-80deg.C under stirring;
(2) Dropwise adding methyl selenol, keeping the reaction for 1 to 5 hours after the adding, and concentrating to remove the solvent;
(3) Regulating pH of the system to 1-3 with 6N hydrochloric acid, and stirring at 50-100deg.C for 1-3 hr;
(4) Cooling to room temperature, neutralizing pH to 6-8 with 10% sodium hydroxide, and stirring for 0.5-2 hr;
(5) Filtering out solid to obtain crude selenomethylselenocysteine, and recrystallizing the crude selenomethylselenocysteine;
the mass ratio of the solvent to serine methyl ester in the reaction is as follows: 2-5:1;
The molar ratio of the triflate to the serine methyl ester is 0.025-0.005:1, a step of;
The mass ratio of the methyl selenol to the serine methyl ester is 1-2:1;
The reaction equation is:
The triflate is one or more of silver triflate, zinc triflate, aluminum triflate, scandium triflate, titanium triflate, cerium triflate, indium triflate, bismuth triflate and copper triflate.
2. The method for synthesizing selenomethylselenocysteine according to claim 1, wherein: the solvent is one or more of dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile and dioxane.
3. The method for synthesizing selenomethylselenocysteine according to claim 1, wherein: the crude product of the selenomethylselenocysteine is red or yellow crystal.
4. The method for synthesizing selenomethylselenocysteine according to claim 1, wherein: the recrystallization solvent is one or more of methanol, ethanol, acetone, water and ethyl acetate.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102558005A (en) * 2012-01-11 2012-07-11 张家港阿拉宁生化技术有限公司 Environmentally-friendly method for synthesizing selenomethionine
CN110683976A (en) * 2019-11-04 2020-01-14 济源市万洋华康生物科技有限公司 Method for preparing (R) -selenium methyl selenocysteine

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160221941A1 (en) * 2015-02-02 2016-08-04 University Of Vermont And State Agricultural College Selenocystine derivatives, alpha-methylselenocysteine, alpha-methylselenocysteine derivatives, and methods of making and using same

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102558005A (en) * 2012-01-11 2012-07-11 张家港阿拉宁生化技术有限公司 Environmentally-friendly method for synthesizing selenomethionine
CN110683976A (en) * 2019-11-04 2020-01-14 济源市万洋华康生物科技有限公司 Method for preparing (R) -selenium methyl selenocysteine

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