阅读说明：本技术 一种l-硒-甲基硒代半胱氨酸的合成方法 (Synthetic method of L-selenium-methyl selenocysteine ) 是由 贾强 杨金金 王采奕 马天华 蒋京辰 范才文 于 2020-05-23 设计创作，主要内容包括：本发明提供一种合成L-硒-甲基硒代半胱氨酸的方法,该合成方法涉及使用式II化合物或其盐与二甲基二硒醚反应,在MBH-(4)及碱作用下进行“一锅法”反应直接合成L-硒-甲基硒代半胱氨酸,或先合成L-硒-甲基硒代半胱氨酸衍生物,再经水解得到L-硒-甲基硒代半胱氨酸。该合成方法具有应具有反应简单、操作方便、产品收率高、质量好、成本低、适合产业化的优点。(The invention provides a method for synthesizing L-selenium-methyl selenocysteine, which comprises the step of reacting a compound shown in a formula II or a salt thereof with dimethyl diselenide in MBH 4 And alkali, or synthesizing L-selenium-methyl selenocysteine derivative, and hydrolyzing to obtain L-selenium-methyl selenocysteine. The synthesis method has the advantages of simple reaction, convenient operation, high product yield, good quality, low cost and suitability for industrialization.)

1. A synthetic method for synthesizing L-selenium-methyl selenocysteine is characterized in that the synthetic method uses a compound of a formula II or salt thereof to react with dimethyl diselenide in MBH₄And alkali to react in one pot to produce L-selenium-methyl selenocysteine or its derivative, i.e. the compound in the formula I, and the chemical reaction equation is as follows:

wherein the content of the first and second substances,

x is a halogen atom, Cl or Br;

MBH₄is LiBH₄、NaBH₄Or KBH₄；

R is H or C₁-C₆An alkyl group;

the alkali is LiOH, NaOH or KOH.

2. The method of synthesis of claim 1, wherein when R is H, the synthesis of the compound of formula I is L-selenium-methylselenocysteine or a salt thereof comprises the steps of:

step (1): l-serine or salt thereof is synthesized into 3-halogen-L-serine or salt thereof through halogenation reaction;

step (2): synthesizing the product obtained in the step (1) and dimethyl diselenide into L-selenium-methyl selenocysteine or salt thereof by a one-pot method;

the chemical reaction equation of the above 2 steps is as follows:

3. according to claim1, when R is C₁～C₆When the compound of formula I is L-selenium-methylselenocysteine or a salt thereof, the synthesis of L-selenium-methylselenocysteine or a salt thereof comprises the steps of:

step (1): esterification reaction of L-serine or its salt to obtain L-serine ester;

step (2): carrying out halogenation reaction on the product obtained in the step (1) to synthesize and obtain 3-halogen-L-serine ester;

and (3): synthesizing the product obtained in the step (2) and dimethyl diselenide by a one-pot method to obtain the ester of L-selenium-methyl selenocysteine;

and (4): hydrolyzing the product obtained in the step (3) to obtain L-selenium-methyl selenocysteine or salt thereof;

the chemical reaction equation of the above 4 steps is as follows:

Technical Field

The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing L-selenium-methyl selenocysteine.

Background

Selenium element is a trace element necessary for human bodies, but cannot be synthesized in the human bodies and needs to be completely supplemented by external intake, and the selenium deficiency of the human bodies can cause dysfunction of certain important organs, so that a plurality of serious diseases can be caused. Selenium is an important component of various enzymes, plays an important role in participating in metabolism in human bodies, and plays an important role in oxidation resistance, aging resistance, detoxification, prevention of cancerous tumors and the like. In addition, selenium has unique curative effect in resisting virus and strengthening immunity.

Natural L-selenium-methyl selenocysteine (structure shown as below) is a selenium methylated derivative of the 21 st essential amino acid L-selenocysteine for human bodies, is widely present in plants such as astragalus, garlic, onion, yarrow and the like and selenium-enriched yeast, has the characteristics of high toxicity, poor absorption and limited use compared with inorganic selenium, has the advantages of definite chemical structure, low toxicity, high bioavailability, good selenium supplementing effect and the like, and is approved to be popularized and used by FDA and CFDA.

At present, the synthesis methods mainly comprise the following steps:

document J.Med.chem., 1996, 39, 2040 reports a synthesis method of L-selenium-methylselenocysteine, and the synthesis route is shown as follows, wherein 3-chlorine-L-serine is used as a starting material, reacts with sodium diselenide to generate selenocysteine, and then is subjected to reduction cracking by using sodium metal/liquid nitrogen (-70 ℃) and alkylation by using methyl iodide to obtain the L-selenium-methylselenocysteine. The method uses raw materials which are not easy to obtain, relates to ultralow-temperature and active dangerous metal sodium, has harsh reaction conditions and high requirements on process equipment, and is not suitable for industrial production.

European patent EP1205471 discloses a synthesis process of L-selenium-methyl selenocysteine, which includes the condensation reaction of N-tert-butoxy acyl-L-serine as material and azodicarbonic diester in the presence of trialkyl (aryl) phosphate or phosphite to produce beta-lactone, the reaction with methyl selenol or its salt to produce N-tert-butoxy acyl-L-selenium-methyl selenocysteine, and final deprotection to obtain L-selenium-methyl selenocysteine product. In the route, the preparation of the N-tert-butoxy acyl-L-serine-beta-lactone is difficult, the price of the related protective agent and reagent is high, the reaction time is long, the yield of the second step is only 28 percent, and the total yield of the process is low; the methyl selenol has low boiling point, easy volatilization, high toxicity, difficult preparation and no commercialization, and the salt thereof is unstable and difficult to purify.

Chinese patent CN101033208 discloses a synthetic method of DL-selenium-methyl selenocysteine, and the synthetic route is as follows. Taking alpha-amino acrylic acid derivatives as initial raw materials, firstly carrying out addition reaction with methyl selenol or methyl selenol salt under the action of sodium bicarbonate to produce beta-methyl seleno-alpha-amino acrylic acid derivatives, and then carrying out hydrolysis, saponification and acidification to obtain carboxylic acid compounds; then hydrochloric acid or sulfuric acid is heated and hydrolyzed to remove acetyl protecting group of amino, and finally DL-selenium-methyl selenocysteine is obtained by ammonia gas or triethylamine neutralization. The source of the initial raw material of the route is difficult, the commercialization is not existed in China, the self-synthesis process is complex and the cost is high; the methyl selenol has low boiling point, is easy to volatilize, has high toxicity, is difficult to prepare and is not commercialized, and the salt thereof is unstable, difficult to purify and is not commercialized; the obtained final product is DL-selenium-methyl selenocysteine, and the target product L-selenium-methyl selenocysteine needs to be obtained by splitting, so that the whole process has long route, low yield and high production cost, and is not beneficial to industrial production.

Chinese patent CN102146050 discloses a synthetic method of DL-selenium-methylselenocysteine, and the synthetic route is as follows. The method comprises the steps of firstly, carrying out nucleophilic substitution reaction on methyl selenol salt and 2, 3-dihalo propionitrile selectively to produce 2-halogen-3-methyl seleno propionitrile, then carrying out acidolysis to obtain 2-halogen-3-methyl seleno propionic acid, carrying out ammoniation to obtain DL-selenium-methyl selenocysteine, and carrying out enzyme resolution to obtain an optical pure target. The reaction methoselenol salt is unstable, difficult to purify and not commercialized. The selectivity of the first step reaction is poor, and the yield is low; the process needs to be separated to obtain the optical active substance with a single configuration, so the process operation is complicated and tedious, the overall yield is low, and the process cost is high.

When the splitting route is used, the racemate synthesis method is complex and long in steps, splitting reagents are required to be additionally consumed during splitting, reaction steps and treatment links are increased, and yield loss is serious, so that the production cost of the splitting preparation method is high. When a direct chemical synthesis preparation method is adopted, the method has certain advantages, but has the problems of difficult obtainment of raw materials and reagents, high price, unstable self-made reagents, poor purity, harsh process reaction conditions, long reaction time and the like. Therefore, it is highly desirable to develop routes and processes that are more suitable for industrialization.

Disclosure of Invention

In order to solve the defects of the prior art, the invention provides a method for synthesizing L-selenium-methyl selenocysteine, which has the advantages of simple reaction, convenient operation, high product yield, good quality, low cost and suitability for industrialization.

According to the purpose of the invention, the invention provides a synthetic method of L-selenium-methyl selenocysteine, which is characterized in that the synthetic method uses a compound shown in a formula II and a salt thereof to react with dimethyl diselenide in MBH₄And alkali to react in one pot to produce L-selenium-methyl selenocysteine or its derivative, i.e. the compound in the formula I, and the chemical reaction equation is as follows:

wherein the content of the first and second substances,

x is a halogen atom, Cl or Br;

MBH₄is LiBH₄、NaBH₄Or KBH₄；

R is H or C₁-C₆An alkyl group;

the alkali is LiOH, NaOH or KOH.

Salts of the compounds of formula I include salts of inorganic acids such as hydrohalic acids (e.g., hydrochloric or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid, and salts of organic acids. Pharmaceutical salts can be obtained by reacting a compound with an organic acid, such as an aliphatic or aromatic carboxylic or sulfonic acid, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, salicylic or naphthalenesulfonic acid.

When R is H, the compound of formula I is L-selenium-methylselenocysteine or a salt thereof, and the synthesis of L-selenium-methylselenocysteine or a salt thereof comprises the following steps:

step (1): l-serine or salt thereof is synthesized into 3-halogen-L-serine or salt thereof through halogenation reaction;

step (2): synthesizing the product obtained in the step (1) and dimethyl diselenide into L-selenium-methyl selenocysteine or salt thereof by a one-pot method;

the chemical reaction equation of the above 2 steps is as follows:

the halogenation reaction of step (1) may employ conventional halogenating reagents, including but not limited to SOCl₂、SOBr₂、POCl₃And POBr₃And the like are obtained by direct halogenation.

In the step (2), 3-halogen-L-serine, dimethyl diselenide and MBH₄The molar ratio of the alkali to the alkali is 1 to (1-5) to (2-10).

When R is C₁～C₆When the compound of formula I is L-selenium-methylselenocysteine or a salt thereof, the synthesis of L-selenium-methylselenocysteine or a salt thereof comprises the steps of:

step (1): esterification reaction of L-serine or its salt to obtain L-serine ester;

step (2): carrying out halogenation reaction on the product obtained in the step (1) to synthesize and obtain 3-halogen-L-serine ester;

and (3): synthesizing the product obtained in the step (2) and dimethyl diselenide by a one-pot method to obtain the ester of L-selenium-methyl selenocysteine;

and (4): hydrolyzing the product obtained in the step (3) to obtain L-selenium-methyl selenocysteine or salt thereof;

the chemical reaction equation of the above 4 steps is as follows:

the esterification reaction in step (1) can be carried out by reacting with alcohol in the presence of a catalyst (concentrated sulfuric acid, hydrogen chloride gas or SOCl)₂Etc.) under the action of the acid.

The halogenation reaction of step (2) may employ conventional halogenating reagents, including but not limited to SOCl₂、SOBr₂、POCl₃And POBr₃And the like are obtained by direct halogenation.

3-halo-L-serine ester, dimethyl diselenide, MBH in step (3)₄The molar ratio of the alkali to the alkali is 1 to (1-5) to (2-10).

In the method for synthesizing the L-selenium-methyl selenocysteine ester in the step (3), solvents used for reaction are N, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, acetonitrile, methyltetrahydrofuran and N-methylpyrrolidone.

In the method for synthesizing the L-selenium-methyl selenocysteine ester in the step (3), the reaction temperature is 0-50 ℃.

In the method for synthesizing the L-selenium-methyl selenocysteine ester in the step (3), the reaction time is 2-8 hours.

In the method for synthesizing the L-selenium-methyl selenocysteine in the step (4), the hydrolysis reaction comprises acidic hydrolysis and alkaline hydrolysis reaction, the reaction temperature is 0-60 ℃, and the reaction solvent is an alcohol solvent.

In the prior art: the preparation of the L-selenium-methyl selenocysteine has the problems of long process route, difficult obtainment of raw materials and reagents, high price, unstable self-made reagents, poor purity, harsh process reaction conditions, long reaction time and the like.

The preparation method of the L-selenium-methyl selenocysteine has the following remarkable advantages: the method has the advantages of short route, easily obtained raw materials, mild reaction conditions, simple process operation, high product quality, high yield, low cost, no generation of a large amount of waste water and solid waste in the process, greenness, environmental protection and suitability for industrial production.

Detailed Description

Embodiments of the present invention are described in detail below with reference to specific examples, but it should be understood by those skilled in the art that the examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention.

The examples, in which specific conditions are not specified, were conducted under conventional conditions, conditions recommended by the manufacturer or supplier. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.

Example 1

Synthesis of 3-chloro-L-serine hydrochloride: 10g L-serine was added to a 250mL reaction flask, followed by 60mL SOCl₂Heating to 70 ℃ for reflux reaction for 4-6 hours, taking attention to the absorption of hydrogen chloride tail gas during the reflux reaction, and removing most SOCl by reduced pressure distillation after the reaction is finished₂And slowly adding the residue into 100mL of ethanol at the temperature of 0-5 ℃, stirring and filtering to obtain 14.5g of 3-chloro-L-serine hydrochloride with the yield of 95.3%.

Synthesizing L-selenium-methyl selenocysteine: adding 10g of 3-chloro-L-serine hydrochloride, 100mL of acetonitrile, a NaOH aqueous solution (7.7g of NaOH, 15g of water) and 18g of dimethyl diselenide into a 250mL reaction bottle, cooling to 0-5 ℃, and finally adding 3.5g of NaBH₄After the addition, the temperature was gradually raised to 40 ℃ and the reaction was carried out for 4 hours, during which the progress of the reaction was monitored by TLC. After the reaction is finished, adjusting the pH value to 7-8 by using dilute hydrochloric acid, distilling to remove acetonitrile, adding 100mL of ethyl acetate and 50mL of water, extracting the water phase by using 50mL of multiplied by 2 ethyl acetate, discarding the organic phase, adding 50mL of ethanol into the water phase, stirring, recrystallizing, filtering, and drying to obtain 10.6g of a target product with the yield of 93.1%.

¹HNMR(D₂O)，δ(ppm)：2.05(s，3H)，3.07(dd，2H)，4.13(t，1H)。

Example 2

Synthesis of L-serine methyl ester hydrochloride: adding 100mL of methanol into a 250mL reaction bottle, cooling to 0 ℃, and dropwise adding 15mL of SOCl₂Stirring for 1 hour at 0-5 ℃, adding 10g L-serine, heating to 50-55 ℃, reacting for 5-6 hours, after the reaction is finished, distilling under reduced pressure, adding 100mL of isopropanol into the residue, recrystallizing and filtering to obtain 9.2g of L-serine methyl ester hydrochloride with the yield of 83.6%.

Synthesis of 3-chloro-L-serine methyl ester hydrochloride: 9g L-serine methyl ester hydrochloride was added to a 250mL reaction flask, followed by 60mL SOCl₂Heating to 70 ℃ for reflux reaction for 5-6 hours, taking attention to the absorption of hydrogen chloride tail gas during the reflux reaction, and removing most SOCl by reduced pressure distillation after the reaction is finished₂And slowly adding the residue into 100mL of isopropanol at the temperature of between O and 5 ℃, stirring and filtering to obtain 9.4g of 3-chloro-L-serine methyl ester hydrochloride with the yield of 93.4 percent.

Synthesizing L-selenium-methyl selenocysteine methyl ester hydrochloride: adding 9g of 3-chloro-L-serine methyl ester hydrochloride, 100mL of N, N-dimethylformamide, 30g of dimethyl diselenide and KOH aqueous solution (18g of KOH and 36g of water) into a 250mL reaction bottle, cooling to 0-5 ℃, and adding 7.0g of KBH₄After the addition was complete, the reaction was allowed to proceed for 4 hours during which time the progress of the reaction was monitored by TLC. After the reaction is finished, 100mL of ethyl acetate and 50mL of water are added for extraction, the water phase is extracted by 50mL of multiplied by 2 ethyl acetate, the organic phases are combined, the temperature is cooled to 0-5 ℃, 6mL of concentrated hydrochloric acid is dropwise added, solid is separated out, the solid is filtered and dried, and 11.1g L-selenium-methyl selenocysteine methyl ester hydrochloride is obtained, wherein the yield is 92.2%.

¹HNMR(CDCl₃)，δ(ppm)：8.8(brs，3H)，4.53(brs，1H)，3.86(s，3H)，3.27(brs，2H)，2.12(s， 3H)。

Synthesizing L-selenium-methyl selenocysteine hydrochloride: 10g L-Se-methylselenocysteine methyl ester hydrochloride, 50mL of ethanol and 20mL of water were put into a 250mL reaction flask, and then an aqueous NaOH solution (3.5g of NaOH and 10.5g of water) was added thereto, followed by stirring at 30 ℃ for 2 hours. After the reaction is finished, adjusting the pH value to 7-8 by 6N hydrochloric acid, adding 100mL of ethanol, cooling to 0-5 ℃, crystallizing, filtering, and drying to obtain 7.4g of L-selenium-methyl selenocysteine with the yield of 94.5%.

¹HNMR(D₂O)，δ(ppm)：2.05(s，3H)，3.07(dd，2H)，4.13(t，1H)。