CN1369483A

CN1369483A - Methyleneseleno propanel method for preparing selenoic methionine

Info

Publication number: CN1369483A
Application number: CN 02104260
Authority: CN
Inventors: 董国臣
Original assignee: Individual
Current assignee: Individual
Priority date: 2002-02-28
Filing date: 2002-02-28
Publication date: 2002-09-18
Anticipated expiration: 2022-02-28
Also published as: CN1219760C

Abstract

A process for preparing selenoic methionine by methyleneseleno propanal method includes preparing the important intermediate, methyleneseleno propanel, from methyleneselenol, acroleic acid relative compounds by chemical synthesis, and chemically synthesizing selenoic methionic from it along with se and methionine by conventional process. The resultant product has excellent more bioactivities and the insulin-like action, so it can be used for treating diabetes.

Description

Method for preparing selenomethionine by methylselenopropionaldehyde

The technical field is as follows:

the invention belongs to the field of amino acid medicaments, and relates to a method for preparing selenomethionine by a chemical synthesis intermediate methylselenopropionaldehyde method;

the invention also relates to a technology for treating diabetes by the insulin-like action of the biological trace element and amino acid complex selenomethionine.

(II) background technology:

as is well known, the important bioactivity of trace element selenium exists in the form of selenium-containing amino acid in organisms, and particularly selenomethionine is widely applied to the departments of medicine, health care, agriculture, nutrition and the like, so that the preparation method of selenomethionine is paid attention.

1. The prior art is as follows:

(1) liquid ammonia process (Na/lig NH)₄) Preparing selenomethionine: to obtain selenomethionine, the benzyl group is generally removed by reductive cleavage with sodium/liquid ammonia using (selenium) -benzylselenohomocysteine and remethylation. (Xue Hui Bi Master code. chemistry, biochemistry of selenium and its use in Life sciences. page 50, Wuhan: university of Chinese university Press, 1994.)

(2) The biological synthesis method is used for preparing selenomethionine: the selenomethionine is produced by a fermentation method and an enzyme method. The fermentation method has the advantages of difficult management of process conditions, low product yield and small large-scale production yield.

2. The defects of the prior art are as follows:

the existing selenomethionine preparation method has complex process conditions and difficult management no matter the chemical synthesis method or the biological synthesis method is used for reaction; the product concentration is low and the yield is low; large equipment scale and low profit. Therefore, selenomethionine products do not meet the market demand and limit the development of selenomethionine analogues.

(III) the invention content:

1. the problems to be solved by the invention are as follows:

the invention aims to realize the production of selenomethionine by a process route for producing methionine by synthesizing an important intermediate methylselenopropionaldehyde to replace methylthiopropionaldehyde in a technical route for methionine (methionine), which is called a methylselenopropionaldehyde method.

Another purpose of the invention is to provide selenomethionine with insulin-like effect, which is prepared into oral hypoglycemic agents to replace insulin and other hypoglycemic agents to treat diabetes through preparation technology.

2. The solution to the problem is as follows:

the technical scheme of the invention is realized by synthesizing the important intermediate methylselenopropionaldehyde to replace methylthiopropanal according to the characteristic that organic compounds containing selenium and sulfur-containing amino acid have similarity in chemical properties and synthetic methods. The method is the main link of chemical synthesis of precursor in the process of selenomethionine, namely, the important intermediate methylselenopropionaldehyde synthesized by the reaction of acrolein and methylselenol. Specifically, thiourea is first used to prepare selenourea (Zhang Sai et al, synthesis of organic reagents, Beijing: ocean Press, 1984.), and then methyl selenol is further prepared according to the production process of methyl mercaptan. Wherein, dimethyl selenate can be used for replacing dimethyl sulfate in the selenourea methylation reaction.

The preparation method of the methylselenopropionaldehyde comprises the following steps:

the reaction equation is as follows:

(Acrylene) (Methylselenol) (Methylselenopropionaldehyde)

[ attached to)]Synthesis of methylselenol

In 12 months in 1983, the production simplification of important methylthio propionaldehyde is shown in the international chemical process and equipment exposition of Paris, France, and a new process for producing methionine is generated, namely, the technical process and the process for producing methionine by the hydantoin method which are widely used at home and abroad. Therefore, the methylselenopropionaldehyde method of the invention transplants the production of selenomethionine to the process route and process of hydantoin method for chemical synthesis of methionine, and can also use chemical synthesis methods such as malonate method, etc.

(IV) specific embodiment:

the chemical synthesis method for producing methionine mainly comprises a Strecker method, a malonate method, an aminolactone method and a hydantoin method, and the hydantoin method is adopted at home and abroad. Among them, the important intermediate methylthio propionaldehyde of hydantoin method and malonate method uses methylselenol to substitute methyl mercaptan and make it react with acrolein to synthesize methylselenopropionaldehyde intermediate so as to implement chemical synthesis of selenomethionine on methionine production line, i.e. methylselenopropionaldehyde method is used to prepare selenomethionine.

The manufacturing method comprises the following steps:

the process route is as follows:

the process comprises the following steps:

1. and (3) dehydrating: the yield is 95% (calculated by propylene) or 70% (calculated by glycerin), and the mixture ratio is 1: 0.5: 0.26. Firstly, putting 1/7 mass of glycerol, all potassium bisulfate and potassium sulfate into a reaction kettle, heating to 190 ℃, beginning to drop the rest glycerol, leading acrolein gas generated by reaction to be condensed by a condenser, and collecting in a storage tank to obtain crude acrolein.

And adding 10% ammonium bicarbonate solution into the crude product, regulating the pH value to 6, fractionating, collecting 50-75 degrees of fractions, namely the refinedacrolein, 75-90 degrees of fractions, which are high-boiling-point substances, keeping for next batch of combined fractionation, and discarding residual liquid with the temperature of more than 95 degrees.

2. Addition: the yield is 94% (to acrolein), and the mixture ratio of acrolein, methyl selenol, copper acetate and formic acid is 1: 0.1: 0.01: 0.024.

Adding acrolein and formic acid into an addition tower (namely a methylselenopropionaldehyde synthesis tower), adding copper acetate while stirring, heating to 35-41 ℃, introducing selenol into the synthesis tower for reaction, and finishing the reaction when the specific weight of a reaction solution reaches 1.066-1.074/20 ℃ to obtain the methylselenopropionaldehyde.

3. Cyclization: the mixture ratio is methylselenopropionaldehyde, sodium cyanide and ammonium hydrogen carbonate is 1: 0.52: 1.75.

Adding ammonium bicarbonate into a reaction tank, adding normal water with the weight 4 times that of the ammonium bicarbonate, stirring to dissolve the ammonium bicarbonate, dissolving sodium cyanide with normal water with the weight 3 times that of the sodium cyanide, adding the sodium cyanide into the reaction tank, stirring uniformly, slowly and dropwise adding methylselenopropionaldehyde under stirring, titrating, heating to 75-80 ℃, and reacting for 3 hours to obtain a methylselenoethylhydantoin solution (ureide for short).

4. Hydrolysis: the mixing ratio of ureide (calculated by methylselenopropionaldehyde) to sodium hydroxide (28%) to active carbon is 1: 2.75: 0.1.

Adding ureide and sodium hydroxide solution (28%) into high-pressure kettle, heating for hydrolysis, discharging ammonia for 1 hr, closing throttle, heating to 160 deg.C, and gradually heating to 5.5kg/cm²Reacting for 1 hour under pressure to obtain selenomethionine salt.

5. Neutralizing: placing selenomethionine salt into a neutralization tank, adding a proper amount of distilled water for dilution until no crystals are formed, adding hydrochloric acid for adjusting the pH to 5-6, adding activated carbon for boiling for 45 minutes for decolorization, filtering, concentrating filtrate to separate out crystals, transferring the crystals into a crystallization tank, stirring, boiling, decolorizing for 1.5 hours, preserving heat at 15-20 ℃, filtering, cooling filtrate for crystallization, and drying to obtain a finished product of selenomethionine.

Selenomethionine is a selenium-containing compound with various biological effects, is unique in aspects of free radical removal through antioxidation, anticancer effect, nutrition effect, prevention and treatment of endemic diseases, application in agriculture and animal husbandry and the like, is not possessed by methionine, particularly has insulin-like effect in the process of finding that selenide has the functions of reducing blood sugar and regulating and controlling insulin-mediated metabolism in recent years, and can replace insulin to treat diabetes. Selenomethionine is far more remarkable than sodium selenite and the like in various biological activities, and particularly, the preparation and application (patent application No. 98120472.4) of selenomethionine chromium applied by the inventor before has more effective effect of replacing insulin.

The results of the test for the hypoglycemic effect of the compound selenomethionine of the present invention are described below.

Acute toxicity test: the Minimal Lethal Dose (MLD) of DL-selenomethionine injected into the abdominal cavity of a rat is 10.54mg/kg body weight.

Hypoglycemic drug effect test: rats (body weight 200-.

10 rats were fasted for 6 hours before the test, and after measuring the blood glucose level, they were randomly divided into a treatment group and a control group, each of which was divided into 5 rats, and the hyperglycemia of the rats was induced by the chemical agent of alloxan.

In the treatment group, 15 mu mol/kg body weight of selenomethionine is injected into the abdominal cavity of a diabetic rat for 16 days continuously; the results of the control diabetic rats administered the same amount of water for injection into the abdominal cavity are shown in the table.

TABLE test results of selenomethionine for lowering blood sugar of diabetic rats

Pre-treatment rat blood glucose (mg/dl) post-treatment rat blood glucose (mg/dl) group P value

The number of normal rats X + -S diabetic rats X + -S selenomethionine constitutes 5201 + -205204 + -23<0.01 control group 5198 + -185268 + -35

The blood sugar of the rats in the treatment group is recovered to the normal value level, the blood sugar value of the rats with diabetes in the control group still maintains the high blood sugar level, the difference of the two groups is obvious, and P is less than 0.01. Therefore, selenomethionine can be judged to replace insulin to regulate blood sugar metabolism in vivo, and experiments prove that selenomethionine has insulin-like effect.

The experiments indicate that the insulin-like function displayed by the selenomethionine can replace insulin to treat diabetes, and the selenomethionine chromium complex synthesized by the selenomethionine and the life trace element trivalent chromium provides a new prospect scheme for treating diabetes.

(V) effects of the invention:

the methylselenopropionaldehyde shown in the invention is an important intermediate in theprocess of preparing selenomethionine, and the final target compound can be easily prepared by using the methylselenopropionaldehyde as the important intermediate for preparing methionine, so that the chemical synthesis of methylselenopropionaldehyde is realized in a mature process route for producing methionine.

Selenomethionine shows excellent multiple biological activity, especially insulin-like action, and the invention is used for treating diabetes to replace insulin.

Claims

1. In view of the similarity of organic compounds of selenium and sulfur, the invention prepares selenomethionine by the methylselenopropionaldehyde method of amino acid seleno analogs generated by the reaction of biological trace amount of selenium and sulfur-containing amino acids, which is characterized in that the methylselenopropionaldehyde, which is an important intermediate synthesized by acrolein and related compounds, is used for replacing the methylthiopropanal which is an intermediate in the methionine production process route, the selenomethionine is easily produced, the chemical synthesis of the methylselenopropionaldehyde method is realized in the methionine production process route to prepare the selenomethionine, and the selenomethionine shows excellent various biological activities and insulin-like effects and is used for treating diabetes.