CN110563623A - Method for synthesizing L- (+) -selenomethionine - Google Patents
Method for synthesizing L- (+) -selenomethionine Download PDFInfo
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Abstract
A method for synthesizing L- (+) -selenomethionine comprises the steps of reacting L- (+) -methionine with methyl iodide to generate a sulfur salt, hydrolyzing the sulfur salt in the presence of inorganic base to obtain homoserine, adding an acetic acid solution of hydrogen bromide into the homoserine, and reacting to obtain bromo L- (+) -homoserine hydrobromide; bromo-L- (+) -homoserine hydrobromide, methanol and thionyl chloride are reacted to generate bromo-L- (+) -homoserine methyl ester hydrochloride; bromo-L- (+) -homoserine methyl ester hydrochloride, selenium powder, methyl lithium and boric acid ester are reacted and then hydrolyzed under alkaline conditions. The invention adopts L- (+) -methionine as a raw material, has wide source and low price, has chirality, and can directly avoid the difficult problems of introducing a chiral center and keeping high stereoselectivity in the subsequent synthesis. The synthetic route of the invention has the advantages of easily obtained raw materials, mild reaction conditions, easy separation and purification and the like.
Description
Technical Field
The invention relates to a method for synthesizing L- (+) -selenomethionine.
Background
Selenium is a trace element that is of great interest to the public and research institutions, and is also one of the essential trace elements for humans and animals. Research as early as 1957 shows that selenium has the function of preventing hepatic necrosis, so that selenium is widely regarded as important. After decades of development, a great deal of research has found that selenium has various immune and biological functions, and research shows that the content of selenium in a body is negatively related to the overall mortality rate of people (directly related to the morbidity of diseases such as cancer, cardiovascular diseases and the like), and reflects the important role of selenium on human bodies. The selenium deficiency of human beings is directly related to the diseases of keshan disease, Kashin-Bek disease, cardiovascular and cerebrovascular diseases and the like, and the proper selenium supplement of human bodies can improve the oxidation resistance of the human bodies, effectively prevent the occurrence of thyroid diseases or relieve corresponding symptoms, prevent chronic diseases such as cardiovascular diseases, diabetes and the like, adjust the immune function, enhance the antiviral ability of the human bodies, adjust the nervous system, effectively reduce the overall incidence of cancers and have the health-care effect on the reproductive systems of the human bodies. The selenium supplement products in the current market are divided into two categories of inorganic selenium and organic selenium, wherein the inorganic selenium mainly comprises sodium selenate and sodium selenite, and the organic selenium mainly comprises selenomethionine. Inorganic selenium is easy to prepare but has low absorption rate and great side effect, and the consequence of excessive eating is far more serious than that of organic selenium. Organic selenium, such as selenomethionine, is a derivative of methionine, is easy to absorb, has few side effects, and is an excellent source of selenium supplement. Therefore, the selenomethionine has higher application value and wide development and popularization prospects.
At present, in the latest synthesis process of L- (+) -selenomethionine, two modes of dimethyl diselenide and selenium powder are mainly introduced into selenium. Dimethyl diselenide was used: dimethyl diselenyl ether is required to react with sodium borohydride to generate methyl seleno-sodium, and then the methyl seleno-sodium reacts with a corresponding substrate to generate selenomethionine (Chinese patent CN 102321004A; Chinese patent CN 1680312A). The dimethyl diselenide is used in the method, the price of the reagent is very high, more than 2 equivalents are needed when the reagent is used in the method, great waste is caused, and meanwhile, the reagent has extremely bad odor, has great pollution to the environment and is not beneficial to industrial production. Selenium powder: the method firstly needs to prepare a substrate before seleno-substitution through 6 steps, then selenium and a methyllithium reagent generate methylselenium, and selenomethionine is obtained by hydrolysis after the reaction of methylselenium and the methyllithium reagent (T.Koch, O.Buchardt, Synthesis,1993,1065). The substrate used by the method needs to be prepared through 6 steps, the process is very complicated, a large amount of HCl gas is used in the esterification step in the production process, the corrosion to equipment is high, the method is not favorable for environmental protection, and meanwhile, the total yield is less than 30% through 7 steps of reaction, so that the industrial large-scale production is difficult to realize.
Disclosure of Invention
the invention aims to provide a method for industrially synthesizing L- (+) -selenomethionine, which has the advantages of mild reaction conditions, low raw material price, simple steps, easy operation, environmental protection and economy.
In order to achieve the purpose, the invention adopts the following technical scheme:
A method for synthesizing L- (+) -selenomethionine, comprising the following steps:
(1) L- (+) -methionine reacts with methyl iodide to generate sulfur salt, the sulfur salt is hydrolyzed in the presence of inorganic alkali to obtain homoserine, acetic acid solution of hydrogen bromide is added into the homoserine, and bromo-L- (+) -homoserine hydrobromide is obtained after reaction;
(2) bromo-L- (+) -homoserine hydrobromide, methanol and thionyl chloride are reacted to generate bromo-L- (+) -homoserine methyl ester hydrochloride;
(3) bromo-L- (+) -homoserine methyl ester hydrochloride, selenium powder, methyl lithium and boric acid ester are reacted and then hydrolyzed under alkaline conditions to obtain L- (+) -selenomethionine.
The invention has the further improvement that the specific process of the step (1) is as follows: mixing L- (+) -methionine, methyl iodide, water and methanol, stirring for 12-48h, concentrating to obtain sulfur salt, adding solution of inorganic base into the sulfur salt, heating and refluxing for 12-24h, concentrating and spin-drying to obtain L- (+) -homoserine, reacting the L- (+) -homoserine with acetic acid solution of hydrogen bromide at 50-110 ℃ for 6-12h, and filtering to obtain solid bromo L- (+) -homoserine hydrobromide.
a further improvement of the invention is that the ratio of L- (+) -methionine, methyl iodide, water, methanol and hydrogen bromide in acetic acid solution is 10 g: 10-15 mL: 180-260 mL: 20mL of: 20-38 mL.
In a further improvement of the invention, the inorganic base is sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate or potassium bicarbonate.
The invention is further improved in that the specific process of the step (2) is as follows: dripping thionyl chloride into methanol at the temperature of-15-0 ℃, uniformly stirring, adding a methanol solution of bromo-L- (+) -homoserine hydrobromide, then reacting for 2-12h at the temperature of 20-50 ℃, concentrating and spin-drying to obtain bromo-L- (+) -homoserine methyl ester hydrochloride.
A further improvement of the invention is that the ratio of bromo L- (+) -homoserine hydrobromide, thionyl chloride and methanol is 2.83 g: 1.2-2.4 mL: 20-40 mL.
The invention has the further improvement that the specific process of the step (3) is as follows: under the atmosphere of nitrogen, dropwise adding an ethyl ether solution of methyl lithium into a mixture of selenium powder and tetrahydrofuran at the temperature of-78-0 ℃, returning to room temperature after dropwise adding, adding boric acid ester and N, N-dimethylformamide, adding bromo-L- (+) -homoserine methyl ester hydrochloride after uniformly stirring, carrying out reaction for 5-30 minutes, then spin-drying the solvent, adding a sodium hydroxide solution and methanol, carrying out acidification and spin-drying after uniformly stirring, adding water, filtering, adjusting the pH value of the filtrate to 5.75, adding ethanol, cooling at low temperature, and separating out a white solid, namely L- (+) -selenomethionine.
The further improvement of the invention is that the ratio of bromo-L- (+) -homoserine methyl ester hydrochloride, selenium powder, tetrahydrofuran, diethyl ether solution of lithium reagent, borate, N-dimethylformamide, sodium hydroxide solution and methanol is 2.33 g: 0.79-1.6 g: 15-30 mL: 7.7-15 mL: 2.95-5 mL: 5-25 mL: 38-50 mL: 38-50 mL.
in a further improvement of the invention, the lithium reagent is methyl lithium, ethyl lithium, propyl lithium, n-butyl lithium, tert-butyl lithium, aryl lithium and other lithium reagents, preferably methyl lithium;
The borate is trimethyl borate, triethyl borate, tripropyl borate, tributyl borate or tri-tert-butyl borate.
The invention is further improved in that the concentration of the aether solution of the lithium reagent is 1.3 mol/L;
The concentration of the sodium hydroxide solution was 1 mol/L.
compared with the prior art, the invention has the following beneficial effects: the L- (+) -methionine is adopted as a raw material, and the raw material has wide source, low price and chirality, so that the problems of introducing a chiral center in subsequent synthesis and keeping high stereoselectivity can be directly avoided. Secondly, the step of introducing a selenium source is usually the most cost factor in synthesizing a target product, and the invention selects the cheap and easily-obtained selenium powder as the selenium source, so that the raw materials are widely and easily obtained, the expensive and odor dimethyl selenide reagent used in the traditional method is well avoided, and the obvious advantages of environmental protection, economy and environmental protection are fully displayed. Finally, compared with the traditional synthetic route, the synthetic route of the invention has the advantages of easily obtained raw materials, simple steps, easy operation, mild reaction conditions, easy separation and purification, suitability for industrial large-scale production and the like.
Drawings
FIG. 1 shows the results of TLC detection of twice recrystallized product. Wherein, the adopted solvent is a mixture of n-butanol, glacial acetic acid and water, and the volume ratio of n-butanol: glacial acetic acid: water-8: 1: in the figure, the left side is the first recrystallized product and the right side is the second recrystallized product.
FIG. 2 is a high performance liquid chromatogram of the second recrystallized product.
Detailed Description
The present invention will be described in detail below.
The invention provides a method for synthesizing L- (+) -selenomethionine, which has the following reaction equation:
The synthesis steps are as follows:
(1) Taking L- (+) -methionine as a raw material, reacting with methyl iodide to generate a sulfur salt, hydrolyzing under the condition of inorganic base, and adding an acetic acid solution of hydrogen bromide to obtain bromo-L- (+) -homoserine hydrobromide, wherein the molar ratio of L- (+) -methionine to methyl iodide is 1: 1-2.4; the specific process is as follows: mixing L- (+) -methionine, methyl iodide, water and methanol, stirring for 12-48h, concentrating to obtain sulfur salt, adding an aqueous solution of inorganic base into the sulfur salt, heating and refluxing for 12-24h, concentrating and spin-drying to obtain L- (+) -homoserine, reacting the L- (+) -homoserine with an acetic acid solution of hydrogen bromide at 50-110 ℃ for 6-12h, and filtering to obtain a solid, namely bromo-L- (+) -homoserine hydrobromide.
wherein the ratio of the L- (+) -methionine, methyl iodide, water, methanol and acetic acid solution of hydrogen bromide is 10 g: 10-15 mL: 180-260 mL: 20mL of: 20-38 mL.
The inorganic base is sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate or potassium bicarbonate.
(2) bromo-L- (+) -homoserine hydrobromide is subjected to methanol and thionyl chloride to generate bromo-L- (+) -homoserine methyl ester hydrochloride, wherein the molar ratio of bromo-L- (+) -homoserine hydrobromide to thionyl chloride is 1: 1-1.5; the specific process is as follows: dripping thionyl chloride into methanol at the temperature of-15-0 ℃, uniformly stirring, adding a methanol solution of bromo-L- (+) -homoserine hydrobromide, then reacting for 2-12h at the temperature of 20-50 ℃, concentrating and spin-drying to obtain bromo-L- (+) -homoserine methyl ester hydrochloride.
The ratio of bromo-L- (+) -homoserine hydrobromide, thionyl chloride and methanol was 2.83 g: 1.2-2.4 mL: 20-40 mL;
In the methanol solution of bromo-L- (+) -homoserine hydrobromide, the ratio of bromo-L- (+) -homoserine hydrobromide to methanol was 2.83 g: 20-40 mL.
(3) bromo-L- (+) -homoserine methyl ester hydrochloride, selenium powder, a lithium reagent and boric acid ester are reacted and then hydrolyzed under alkaline conditions to obtain L- (+) -selenomethionine, wherein the molar ratio of selenium to methyllithium to the boric acid ester is 1:1: 1-1.2;
The specific process is as follows: under the atmosphere of nitrogen, dropwise adding an ethyl ether solution of methyl lithium into a mixture of selenium powder and tetrahydrofuran at the temperature of-78-0 ℃, returning to room temperature after dropwise adding, adding boric acid ester and N, N-dimethylformamide, adding bromo-L- (+) -homoserine methyl ester hydrochloride after uniformly stirring, carrying out reaction for 5-30 minutes, then spin-drying the solvent, adding a sodium hydroxide solution and methanol, carrying out acidification and spin-drying after uniformly stirring, adding water, filtering, adjusting the pH value of the filtrate to 5.75, adding ethanol, cooling at low temperature, and separating out a white solid, namely L- (+) -selenomethionine.
the inorganic base is sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, etc., preferably sodium bicarbonate.
The lithium reagent is a lithium reagent such as methyl lithium, ethyl lithium, propyl lithium, n-butyl lithium, tert-butyl lithium, aryl lithium and the like, and methyl lithium is preferred.
The boric acid ester is trimethyl borate, triethyl borate, tripropyl borate, tributyl borate, tri-tert-butyl borate, etc., and tributyl borate is preferred.
the concentration of the diethyl ether solution of the lithium reagent is 1.3 mol/L;
the concentration of the sodium hydroxide solution was 1 mol/L.
Example 1
(1) Synthesis of bromo-L- (+) -homoserine hydrobromide
adding 10g L- (+) -methionine and 10mL methyl iodide, 180mL water and 26mL methanol into a 500mL single-neck flask, stirring for 26h, concentrating to one third of the original volume, adding 5.6g sodium bicarbonate and 66mL water, heating and refluxing for 12h, concentrating and spin-drying, adding 20mL water and 200mL acetone, cooling, performing suction filtration to obtain L- (+) -homoserine white solid, adding 80mL hydrogen bromide acetic acid solution, reacting for 10h at 80 ℃, continuing stirring for 4h at room temperature, performing suction filtration, and washing a filter cake with 30mL diethyl ether to obtain 10.22g white solid. The yield thereof was found to be 55%.
Nuclear magnetic data:1H NMR(400MHz,D2O)δ:4.17(t,1H,J＝5.2Hz),3.60-3.48(m,2H),2.53-2.44(m,1H),2.36-2.27(m,1H).
(2) Synthesis of bromo-L- (+) -homoserine methyl ester hydrochloride
In a 100mL single-neck flask, dripping 1.2mL of thionyl chloride into 20mL of methanol at 0 ℃, stirring for 30min to obtain a reaction solution, adding 2.83g of methyl alcohol (20mL) solution of bromo-L- (+) -homoserine hydrobromide into the reaction solution, heating to 35 ℃ for reaction for 11h, concentrating and spin-drying to obtain a light yellow solid. The yield thereof was found to be 100%.
Nuclear magnetic data:1H NMR(400MHz,D2O)δ:4.27(t,1H,J＝6.4Hz),3.76(s,3H),3.59-3.48(m,2H),2.52-2.46(m,1H),2.36-2.29(m,1H).
(3) Synthesis of L- (+) -selenomethionine
In a 250mL single-neck flask, 0.79g of selenium powder and 15mL of dry tetrahydrofuran are added under the atmosphere of nitrogen, stirred for 15min at-78 ℃, slowly adding 7.7mL of methyl lithium ether solution (1.3mol/L) dropwise, returning to room temperature after the dropwise addition is finished, adding 2.95mL of tributyl borate, 20mL of N, N-dimethylformamide, stirring for 5 minutes, adding 2.33g of bromo-L- (+) -homoserine methyl ester hydrochloride, reacting for 10 minutes, spin-drying the solvent, adding 38mL of 1mol/L sodium hydroxide solution and 38mL of methanol, stirring for 10 minutes, acidifying and spin-drying the solution, adding 8mL of water, filtering, adjusting the pH value of the filtrate to be between 5.75, adding 25mL of ethanol, cooling at low temperature, precipitating a large amount of white solid after 5h, and drying a filter cake after suction filtration to obtain 1.27g of a white product, namely L- (+) -selenomethionine. The yield thereof was found to be 66%.
Recrystallizing the white product again, firstly adding 5ml of absolute ethyl alcohol, dropwise adding water under the water bath heating condition of 70 ℃ until the white product is completely dissolved, precisely adjusting the pH value to 5.75, then cooling at low temperature, precipitating a large amount of white solid after 5h, performing suction filtration, and drying a filter cake to obtain 0.9g of the white product, wherein the yield is 71%, and no other impurities exist through TLC detection, as shown in figure 1. Purity of L-configuration: 99.8% purity of L-configuration Fmoc-protected L-selenomethionine, a derivative of L-selenomethionine, was assayed by high performance liquid chromatography with a retention time of 6.961min, a flow rate v of 1ml/min, Column: CHIRALPAK IC, Mobile phase: Hexane/IPA/TFA of 70/10/0.5(v/v/v), as shown in figure 2. Nuclear magnetic data:1H NMR(400MHz,D2O)δ:3.77(t,1H,J＝5.6Hz),,2.57-2.53(m,2H),2.18-2.09(m,2H),1.95(s,3H)；ESI-MS m/z calc.197.0,found198.1(M+1)+；[α]D＝+20.0°,(c＝0.02,2N HCl).
Example 2
(1) Mixing L- (+) -methionine, methyl iodide, water and methanol, stirring for 12h, concentrating to obtain a sulfur salt, adding a solution of inorganic base into the sulfur salt, heating and refluxing for 18h, concentrating and spin-drying to obtain L- (+) -homoserine, reacting the L- (+) -homoserine with an acetic acid solution of hydrogen bromide at 50 ℃ for 12h, and filtering to obtain a solid, namely bromo-L- (+) -homoserine hydrobromide.
Wherein the ratio of the L- (+) -methionine, methyl iodide, water, methanol and acetic acid solution of hydrogen bromide is 10 g: 15mL of: 260mL of: 20mL of: 20 mL.
The inorganic base is sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate or potassium bicarbonate. Sodium bicarbonate is preferred.
(2) dripping thionyl chloride into methanol at the temperature of-15-0 ℃, uniformly stirring, adding a methanol solution of bromo-L- (+) -homoserine hydrobromide, then reacting for 12 hours at the temperature of 20 ℃, concentrating and spin-drying to obtain bromo-L- (+) -homoserine methyl ester hydrochloride.
The ratio of bromo-L- (+) -homoserine hydrobromide, thionyl chloride and methanol was 2.83 g: 1.2 mL: 20 mL;
(3) Dropwise adding 1.3mol/L of diethyl ether solution of a lithium reagent into a mixture of selenium powder and tetrahydrofuran at the temperature of-78-0 ℃ in a nitrogen atmosphere, recovering to room temperature after dropwise adding, adding boric acid ester and N, N-dimethylformamide, adding bromo-L- (+) -homoserine methyl ester hydrochloride after uniformly stirring, carrying out spin-drying on the solvent after reacting for 5 minutes, adding 1mol/L of sodium hydroxide solution and methanol, carrying out acidification and spin-drying after uniformly stirring, adding water, filtering, adjusting the pH value of the filtrate to 5, adding ethanol, cooling at low temperature, and separating out a white solid, namely L- (+) -selenomethionine.
Wherein the lithium reagent is ethyl lithium.
The borate is triethyl borate.
Example 3
(1) mixing L- (+) -methionine, methyl iodide, water and methanol, stirring for 48h, concentrating to obtain a sulfur salt, adding a solution of inorganic base into the sulfur salt, heating and refluxing for 12h, concentrating and spin-drying to obtain L- (+) -homoserine, reacting the L- (+) -homoserine with an acetic acid solution of hydrogen bromide at 110 ℃ for 6h, and filtering to obtain a solid, namely bromo-L- (+) -homoserine hydrobromide.
Wherein the ratio of the L- (+) -methionine, methyl iodide, water, methanol and acetic acid solution of hydrogen bromide is 10 g: 10mL of: 200mL of: 20mL of: 38 mL.
The inorganic base is sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate or potassium bicarbonate. Sodium bicarbonate is preferred.
(2) Dripping thionyl chloride into methanol at the temperature of-15-0 ℃, uniformly stirring, adding a methanol solution of bromo-L- (+) -homoserine hydrobromide, then reacting for 10 hours at the temperature of 30 ℃, concentrating and spin-drying to obtain bromo-L- (+) -homoserine methyl ester hydrochloride.
The ratio of bromo-L- (+) -homoserine hydrobromide, thionyl chloride and methanol was 2.83 g: 1.5 mL: 30 mL;
(3) Dropwise adding 1.3mol/L of diethyl ether solution of a lithium reagent into a mixture of selenium powder and tetrahydrofuran at the temperature of-78-0 ℃ in a nitrogen atmosphere, recovering to room temperature after dropwise adding, adding boric acid ester and N, N-dimethylformamide, adding bromo-L- (+) -homoserine methyl ester hydrochloride after uniformly stirring, carrying out spin-drying on the solvent after reacting for 5 minutes, adding 1mol/L of sodium hydroxide solution and methanol, carrying out acidification and spin-drying after uniformly stirring, adding water, filtering, adjusting the pH value of the filtrate to 5, adding ethanol, cooling at low temperature, and separating out a white solid, namely L- (+) -selenomethionine.
wherein the lithium reagent is n-butyllithium.
The borate is tripropyl borate.
Example 4
(1) mixing L- (+) -methionine, methyl iodide, water and methanol, stirring for 20h, concentrating to obtain a sulfur salt, adding a solution of inorganic base into the sulfur salt, heating and refluxing for 20h, concentrating and spin-drying to obtain L- (+) -homoserine, reacting the L- (+) -homoserine with an acetic acid solution of hydrogen bromide at 70 ℃ for 10h, and filtering to obtain a solid, namely bromo-L- (+) -homoserine hydrobromide.
wherein the ratio of the L- (+) -methionine, methyl iodide, water, methanol and acetic acid solution of hydrogen bromide is 10 g: 12mL of: 180 mL: 20mL of: 25 mL.
The inorganic base is sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate or potassium bicarbonate. Sodium bicarbonate is preferred.
(2) dripping thionyl chloride into methanol at the temperature of-15-0 ℃, uniformly stirring, adding a methanol solution of bromo-L- (+) -homoserine hydrobromide, then reacting for 5 hours at the temperature of 40 ℃, concentrating and spin-drying to obtain bromo-L- (+) -homoserine methyl ester hydrochloride.
The ratio of bromo-L- (+) -homoserine hydrobromide, thionyl chloride and methanol was 2.83 g: 2mL of: 25 mL;
(3) Dropwise adding 1.3mol/L of diethyl ether solution of a lithium reagent into a mixture of selenium powder and tetrahydrofuran at the temperature of-78-0 ℃ in a nitrogen atmosphere, recovering to room temperature after dropwise adding, adding boric acid ester and N, N-dimethylformamide, adding bromo-L- (+) -homoserine methyl ester hydrochloride after uniformly stirring, carrying out spin-drying on a solvent after reacting for 20 minutes, adding 1mol/L of sodium hydroxide solution and methanol, carrying out acidification and spin-drying after uniformly stirring, adding water, filtering, adjusting the pH value of the filtrate to 5, adding ethanol, cooling at low temperature, and separating out a white solid, namely L- (+) -selenomethionine.
Wherein the lithium reagent is tert-butyllithium.
The borate ester is tributyl borate.
Example 5
(1) Mixing L- (+) -methionine, methyl iodide, water and methanol, stirring for 30h, concentrating to obtain a sulfur salt, adding a solution of inorganic base into the sulfur salt, heating and refluxing for 24h, concentrating and spin-drying to obtain L- (+) -homoserine, reacting the L- (+) -homoserine with an acetic acid solution of hydrogen bromide at 90 ℃ for 8h, and filtering to obtain a solid, namely bromo-L- (+) -homoserine hydrobromide.
Wherein the ratio of the L- (+) -methionine, methyl iodide, water, methanol and acetic acid solution of hydrogen bromide is 10 g: 13mL of: 170mL of: 20mL of: 30 mL.
The inorganic base is sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate or potassium bicarbonate. Sodium bicarbonate is preferred.
(2) Dripping thionyl chloride into methanol at the temperature of-15-0 ℃, uniformly stirring, adding a methanol solution of bromo-L- (+) -homoserine hydrobromide, reacting for 2 hours at the temperature of 50 ℃, concentrating and spin-drying to obtain bromo-L- (+) -homoserine methyl ester hydrochloride.
The ratio of bromo-L- (+) -homoserine hydrobromide, thionyl chloride and methanol was 2.83 g: 2.4 mL: 40 mL;
(3) Dropwise adding 1.3mol/L of diethyl ether solution of a lithium reagent into a mixture of selenium powder and tetrahydrofuran at the temperature of-78-0 ℃ in a nitrogen atmosphere, recovering to room temperature after dropwise adding, adding boric acid ester and N, N-dimethylformamide, adding bromo-L- (+) -homoserine methyl ester hydrochloride after uniformly stirring, carrying out spin-drying on the solvent after 10 minutes of reaction, adding 1mol/L of sodium hydroxide solution and methanol, carrying out acidification and spin-drying after uniformly stirring, adding water, filtering, adjusting the pH value of the filtrate to 5.5, adding ethanol, cooling at low temperature, and separating out a white solid, namely L- (+) -selenomethionine.
wherein the lithium reagent is aryl lithium.
The borate is tri-tert-butyl borate.
Claims (10)
1. A method for synthesizing L- (+) -selenomethionine, which is characterized by comprising the following steps:
(1) L- (+) -methionine reacts with methyl iodide to generate sulfur salt, the sulfur salt is hydrolyzed in the presence of inorganic alkali to obtain homoserine, acetic acid solution of hydrogen bromide is added into the homoserine, and bromo-L- (+) -homoserine hydrobromide is obtained after reaction;
(2) bromo-L- (+) -homoserine hydrobromide, methanol and thionyl chloride are reacted to generate bromo-L- (+) -homoserine methyl ester hydrochloride;
(3) bromo-L- (+) -homoserine methyl ester hydrochloride, selenium powder, methyl lithium and boric acid ester are reacted and then hydrolyzed under alkaline conditions to obtain L- (+) -selenomethionine.
2. the method for synthesizing L- (+) -selenomethionine according to claim 1, wherein the specific process of step (1) is: mixing L- (+) -methionine, methyl iodide, water and methanol, stirring for 12-48h, concentrating to obtain sulfur salt, adding solution of inorganic base into the sulfur salt, heating and refluxing for 12-24h, concentrating and spin-drying to obtain L- (+) -homoserine, reacting the L- (+) -homoserine with acetic acid solution of hydrogen bromide at 50-110 ℃ for 6-12h, and filtering to obtain solid bromo L- (+) -homoserine hydrobromide.
3. The method of claim 2, wherein the ratio of L- (+) -methionine, methyl iodide, water, methanol and hydrogen bromide in acetic acid is 10 g: 10-15 mL: 180-260 mL: 20mL of: 20-38 mL.
4. the method of claim 2, wherein the inorganic base is sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate or potassium bicarbonate.
5. The method for synthesizing L- (+) -selenomethionine according to claim 1, wherein the specific process of step (2) is as follows: dripping thionyl chloride into methanol at the temperature of-15-0 ℃, uniformly stirring, adding a methanol solution of bromo-L- (+) -homoserine hydrobromide, then reacting for 2-12h at the temperature of 20-50 ℃, concentrating and spin-drying to obtain bromo-L- (+) -homoserine methyl ester hydrochloride.
6. The method of claim 5, wherein the ratio of bromo-L- (+) -homoserine hydrobromide, thionyl chloride and methanol is 2.83 g: 1.2-2.4 mL: 20-40 mL.
7. The method for synthesizing L- (+) -selenomethionine according to claim 1, wherein the specific process of step (3) is: under the atmosphere of nitrogen, dropwise adding an ethyl ether solution of methyl lithium into a mixture of selenium powder and tetrahydrofuran at the temperature of-78-0 ℃, returning to room temperature after dropwise adding, adding boric acid ester and N, N-dimethylformamide, adding bromo-L- (+) -homoserine methyl ester hydrochloride after uniformly stirring, carrying out reaction for 5-30 minutes, then spin-drying the solvent, adding a sodium hydroxide solution and methanol, carrying out acidification and spin-drying after uniformly stirring, adding water, filtering, adjusting the pH value of the filtrate to 5.75, adding ethanol, cooling at low temperature, and separating out a white solid, namely L- (+) -selenomethionine.
8. The method for synthesizing L- (+) -selenomethionine according to claim 7, wherein the ratio of bromo L- (+) -homoserine methyl ester hydrochloride, selenium powder, tetrahydrofuran, diethyl ether solution of lithium reagent, borate N, N-dimethylformamide, sodium hydroxide solution and methanol is 2.33 g: 0.79-1.6 g: 15-30 mL: 7.7-15 mL: 2.95-5 mL: 5-25 mL: 38-50 mL: 38-50 mL.
9. The method for synthesizing L- (+) -selenomethionine according to claim 5, wherein said lithium reagent is methyl lithium, ethyl lithium, propyl lithium, n-butyl lithium, tert-butyl lithium, aryl lithium or other lithium reagent, preferably methyl lithium;
The borate is trimethyl borate, triethyl borate, tripropyl borate, tributyl borate or tri-tert-butyl borate.
10. The method of claim 5, wherein the concentration of the solution of lithium reagent in diethyl ether is 1.3 mol/L;
the concentration of the sodium hydroxide solution was 1 mol/L.
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| CN113603623A (en) * | 2021-08-13 | 2021-11-05 | 暨南大学 | Synthetic method and device of selenomethionine |
| CN114163471A (en) * | 2020-09-11 | 2022-03-11 | 南京华狮新材料有限公司 | Preparation method of long-chain homoserine derivative |
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| CN114163471A (en) * | 2020-09-11 | 2022-03-11 | 南京华狮新材料有限公司 | Preparation method of long-chain homoserine derivative |
| CN113603623A (en) * | 2021-08-13 | 2021-11-05 | 暨南大学 | Synthetic method and device of selenomethionine |
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