CN112876394A - Preparation method of DL-hydroxyselenomethionine - Google Patents
Preparation method of DL-hydroxyselenomethionine Download PDFInfo
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- CN112876394A CN112876394A CN202110177941.2A CN202110177941A CN112876394A CN 112876394 A CN112876394 A CN 112876394A CN 202110177941 A CN202110177941 A CN 202110177941A CN 112876394 A CN112876394 A CN 112876394A
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- butyrolactone
- hydroxyselenomethionine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C391/00—Compounds containing selenium
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of preparation of organic compounds. The invention provides a preparation method of DL-hydroxyselenomethionine. The method is characterized in that gamma-butyrolactone is used as a raw material, alpha-hydroxy-gamma-butyrolactone is synthesized through alpha-bromination and hydroxylation, and then the alpha-hydroxy-gamma-butyrolactone reacts with sodium methylselenolate to obtain DL-hydroxyselenomethionine. The method has the advantages of easily available raw materials, mild reaction conditions and low cost, and is suitable for mass preparation of DL-hydroxyselenomethionine.
Description
Technical Field
The invention belongs to the field of preparation of organic compounds. The invention relates to a method for preparing DL-hydroxyselenomethionine.
Background
Selenium is an indispensable microelement in human bodies and animal bodies, and has obvious effects on preventing and inhibiting cancers, delaying aging and the like. 42 kinds of diseases such as cancer, cardiovascular and cerebrovascular diseases, children's mental retardation, senile dementia and the like of human beings are related to selenium deficiency. Selenium deficiency in animals can lead to increased mortality, muscle atrophy, and other symptoms. Therefore, the world health organization identified selenium as an essential trace element for humans and animals in 1973. Inorganic selenium is a first-generation selenium source, sodium selenite and sodium selenate can be used as a feed additive, and the inorganic selenium is low in price, but is mainly absorbed in a simple diffusion mode, poor in organism absorption and low in effective utilization rate, can generate toxicity to organisms under the condition of high ingestion, can only meet the requirement of preventing selenium deficiency of animals, and is difficult to realize effective selenium supplement to promote the health and the production performance of the animals. Therefore, the addition of inorganic selenium not only can not achieve the ideal selenium supplementing effect, but also can pollute the environment. DL-hydroxyselenomethionine is a new generation of organic selenium source which is newly developed. Is a selenomethionine hydroxyl analogue, and can be completely converted into L-selenomethionine in organisms through the action of dehydrogenase and transaminase. The compound was approved by the european union as organic selenium in 5 months in 2013 to be applicable to all animal feeds, and was introduced by the company edisu france under the tradename Selisseo in 2014. The organic selenium is derived from chemical synthesis, has purity of over 99.5%, and biological utilization rate remarkably higher than that of yeast selenium and inorganic selenium, and is used as organic selenium source, easy for QC detection and management, and good in batch consistency and stability. The original research process route of DL-hydroxyselenomethionine is that methyl lithium and selenium are prepared into methyl selenol lithium in ether, and then the methyl selenol lithium reacts with alpha-hydroxybutyric lactone to prepare the DL-hydroxyselenomethionine, the process not only uses flammable and explosive methyl lithium and ether, but also uses the alpha-hydroxybutyrolactone which is not easy to obtain as raw materials, and the industrial production cost is high (WO2006008190A 2); the other process route is that methyl selenol and acrolein are reacted to prepare 3-methyl seleno-propionaldehyde, and then the 3-methyl seleno-propionaldehyde is added with a virulent reagent sodium cyanide or hydrogen cyanide and then hydrolyzed to obtain the product, wherein the route not only uses cyanide, hydrogen selenide and various toxic reagents of acrolein, but also has longer reaction route of a selenium-bearing intermediate with poor stability, poor quality control in the process and very strict requirements on industrial production conditions (CN 109232342A). Therefore, the development of a new method for preparing DL-hydroxyselenomethionine with simplicity, high efficiency and low cost has important value for the application and popularization of the emerging selenium source.
Disclosure of Invention
The invention aims to develop a method for preparing DL-hydroxyselenomethionine, which is simple, efficient, mild in condition and low in cost.
The invention is characterized in that: using gamma-butyrolactone as raw material, firstly synthesizing alpha-hydroxy-gamma-butyrolactone through alpha-bromination and hydroxylation, then reacting with methyl sodium selenol to obtain DL-hydroxyselenomethionine. The method has the advantages of easily available raw materials, mild reaction conditions and low cost, and is suitable for mass preparation of DL-hydroxyselenomethionine.
The structure of the synthesized DL-hydroxyselenomethionine is characterized in that: represented by the formula
The invention adopts the following technical scheme:
1) the gamma-butyrolactone is used as a raw material and reacts with liquid bromine to obtain the alpha-bromo-gamma-butyrolactone.
2) The alpha-bromine-gamma-butyrolactone is hydrolyzed in potassium carbonate to obtain the alpha-hydroxy-gamma-butyrolactone.
3) Reacting alpha-hydroxy-gamma-butyrolactone with sodium methylselenolate, and acidifying to obtain DL-hydroxyselenomethionine.
Detailed Description
The synthesis of DL-hydroxyselenomethionine adopts gamma-butyrolactone as a raw material, firstly, the gamma-butyrolactone reacts with liquid bromine to obtain alpha-bromo-gamma-butyrolactone, then the alpha-bromo-gamma-butyrolactone is hydrolyzed in potassium carbonate to obtain alpha-hydroxy-gamma-butyrolactone, and finally, the alpha-hydroxy-gamma-butyrolactone reacts with sodium methylselenolate and is acidified to obtain DL-hydroxyselenomethionine.
In the invention, the preparation of the alpha-bromo-gamma-butyrolactone can be completed by selecting no catalyst or using a catalyst, wherein the catalyst used can be phosphorus or sulfur or phosphorus tribromide; in the last nucleophilic ring-opening preparation of DL-hydroxyselenomethionine, dry methyl selenol sodium or methyl selenol sodium solution can be used, and the solvent for reaction can be non-proton solvent such as tetrahydrofuran, methyl tetrahydrofuran, 1, 4-dioxane and the like or proton solvent such as methanol, ethanol and the like.
Example of the implementation
The present invention will be described in detail below with reference to examples. However, the present invention is not limited to the embodiments shown in the embodiments, and the specific embodiments may be variously modified within the scope of the description of the specific embodiments of the present invention.
Preparation of 1 alpha-bromo-gamma-butyrolactone
Adding 2.2ml of phosphorus tribromide into 100g of gamma-butyrolactone, heating to 100 ℃ under the protection of nitrogen, slowly dripping 176.4g of bromine, continuing to keep the temperature and stir for reaction for 4 hours after the dripping is finished, and performing reduced pressure concentration to remove low-boiling-point substances after the reaction to obtain 172.5g of alpha-bromo-gamma-butyrolactone crude product which is directly used for the next reaction.
Preparation of 2 alpha-hydroxy-gamma-butyrolactone
217g of potassium carbonate is dissolved in 1L of deionized water, heated to reflux, 172.5g of the crude product of alpha-bromo-gamma-butyrolactone obtained in example 1 is slowly added dropwise, the mixture is kept at the temperature and stirred for reaction for 2 hours after the addition, the reaction temperature is reduced to room temperature after the reaction is finished, 177mL of concentrated hydrochloric acid is added dropwise, and then the reaction mixture is concentrated to dryness under reduced pressure. Adding 500mL of absolute ethyl alcohol into the residue, stirring and pulping for 30 minutes, filtering to remove insoluble substances, concentrating the filtrate under reduced pressure to remove the solvent to obtain a crude product, and distilling under reduced pressure to obtain 90.1g of alpha-hydroxy-gamma-butyrolactone colorless oily liquid.1H NMR (400MHz,CDCl3)：δ＝4.48(dd,J＝10.1,8.5Hz,1H),4.33(td,J＝9.1,2.1Hz,1H), 4.19-4.13(m,1H),2.56-2.49(m,1H),2.24-2.13(m,1H),1.96(bs,1H)。
Preparation of 3 DL-alpha-hydroxyselenomethionine (1)
Under the protection of nitrogen at room temperature, 10g of alpha-hydroxy-gamma-butyrolactone is dripped into 200mL of methanol solution containing 17g of sodium methylselenolate, and after the dripping is finished, the temperature is raised to reflux and the reaction is continued overnight. Then decompressing and concentrating the reaction liquid to be dry, putting the residue into ice water, dropwise adding concentrated hydrochloric acid to adjust the pH value to be less than or equal to 1, extracting tert-butyl methyl ether, drying anhydrous sodium sulfate, and concentrating to obtain 14.1g of product, namely yellow oily liquid.1H NMR(400MHz,CDCl3)：δ＝ 4.46(dd,J＝8.1,3.8Hz,1H),2.72(m,2H),2.25(m,1H),2.10(m,1H),2.04(s, 3H)。
Preparation of 4 DL-alpha-hydroxyselenomethionine (2)
Under the protection of nitrogen at room temperature, 8g of dry sodium methylselenolate is dispersed into 100mL of anhydrous tetrahydrofuran solution, 5g of alpha-hydroxy-gamma-butyrolactone is slowly dripped, and the temperature is raised to reflux after the dripping is finished, and the reaction is continued overnight. Then, the reaction solution is decompressed and concentrated to be dry, the residue is put into ice water, concentrated hydrochloric acid is dripped to adjust the pH value to be less than or equal to 1, and the anhydrous sodium sulfate is dried after the methyl tetrahydrofuran is extracted, and the product is concentrated to obtain 7.3 g.
Claims (3)
1. A preparation method of DL-hydroxyselenomethionine is characterized in that: using gamma-butyrolactone as raw material, firstly synthesizing alpha-hydroxy-gamma-butyrolactone through alpha-bromination and hydroxylation, then reacting with methyl sodium selenol to obtain DL-hydroxyselenomethionine.
2. The method of synthesizing DL-hydroxyselenomethionine according to claim 1, wherein: the preparation of α -bromo- γ -butyrolactone can optionally be carried out without or with a catalyst, which may be phosphorus or sulfur or phosphorus tribromide.
3. The method of synthesizing DL-hydroxyselenomethionine according to claim 1, wherein: when the alpha-hydroxy-gamma-butyrolactone is subjected to nucleophilic ring opening by sodium methylselenolate, dry sodium methylselenolate or sodium methylselenolate solution can be used, and the solvent for the reaction can be tetrahydrofuran, methyltetrahydrofuran, 1, 4-dioxane aprotic solvent or methanol or ethanol protic solvent.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114181177A (en) * | 2021-11-25 | 2022-03-15 | 烟台泽湃新材料科技有限公司 | Production method of novel alpha-bromo-gamma-butyrolactone |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101098879A (en) * | 2004-07-23 | 2008-01-02 | 四面体公司 | New selenohydroxy acids and their derivatives applications in nutrition, cosmetics and pharmaceutics |
| CN101506153A (en) * | 2006-08-24 | 2009-08-12 | 赢创德固赛有限责任公司 | Method for the production of D,l-2-hydroxy-4-alkylthio butyric acid |
| CN109232342A (en) * | 2018-10-15 | 2019-01-18 | 禄丰天宝磷化工有限公司 | A kind of preparation method of selenomethionine hydroxy analogs |
-
2021
- 2021-02-09 CN CN202110177941.2A patent/CN112876394A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101098879A (en) * | 2004-07-23 | 2008-01-02 | 四面体公司 | New selenohydroxy acids and their derivatives applications in nutrition, cosmetics and pharmaceutics |
| CN101506153A (en) * | 2006-08-24 | 2009-08-12 | 赢创德固赛有限责任公司 | Method for the production of D,l-2-hydroxy-4-alkylthio butyric acid |
| CN109232342A (en) * | 2018-10-15 | 2019-01-18 | 禄丰天宝磷化工有限公司 | A kind of preparation method of selenomethionine hydroxy analogs |
Non-Patent Citations (1)
| Title |
|---|
| O. P. GOEL 等: "AN IMPROVED PREPARATION OF (±) 3-HYDROXY-2-PYRROLIDINONE", 《ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL: THE NEW JOURNAL FOR ORGANIC SYNTHESIS》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114181177A (en) * | 2021-11-25 | 2022-03-15 | 烟台泽湃新材料科技有限公司 | Production method of novel alpha-bromo-gamma-butyrolactone |
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Application publication date: 20210601 |