CN102399176B - Preparation method of high-content 2-hydroxy-4-(methylthio) butyl calcium - Google Patents

Abstract

The invention relates to a preparation method of high-content calcium 2-hydroxy-4-methylthiobutyrate. In the current synthesis method, the content of calcium 2-hydroxy-4-methylthiobutyrate obtained is relatively low. In the present invention, 2-hydroxy-4-methylthiobutyronitrile with a content of more than 99.0% is used as a raw material, and concentrated HCl is added for hydrolysis reaction. After the reaction is completed, the pH is adjusted to 7.8-8.0 with alkali, cooled to crystallize, and filtered to obtain 2 -Hydroxy-4-methylthiobutyramide crude product, recrystallized with water to obtain high-content 2-hydroxy-4-methylthiobutyramide; high-content 2-hydroxy-4-methylthiobutyramide was dissolved in water, Then add excess Ca(OH) ₂ , and directly hydrolyze at 80-100°C to generate calcium 2-hydroxy-4-methylthiobutyrate. The yield of the invention is very high, and the content of the obtained calcium 2-hydroxy-4-methylthiobutyrate is more than 99.0%.

Description

A kind of preparation method of high-content calcium 2-hydroxy-4-methylthiobutyrate

technical field

The invention relates to the field of compound synthesis, in particular to a method for preparing high-content calcium 2-hydroxy 4-methylthiobutyrate.

Background technique

Methionine cannot be synthesized in animals and needs to be ingested from food. It is the first limiting amino acid. Adding it to the feed can promote the growth of poultry and livestock, increase the amount of lean meat, and shorten the feeding cycle. 2-Hydroxy 4-methylthiobutyric acid (LMA) is a methionine analogue, which can be absorbed and converted into methionine by animals, and its effect is equivalent to 65% to 88% of that of methionine. At present, LMA is added in ruminant and livestock and poultry feed, and its addition amount is 0.1-0.5%. According to relevant statistics, in recent years, the demand for methionine in the world has grown at a rate of 4% per year, while that in my country has grown at a rate of 7% per year.

According to literature introduction, the synthetic method of 2-hydroxyl 4-methylthiobutyric acid mainly contains following several kinds:

In the patent document with publication number CN1493560, Zhou Jiankang and others proposed to use 2-hydroxy-4-methylthio-butyric acid and calcium oxide or calcium hydroxide as raw materials for neutralization reaction to prepare 2-hydroxy-4-methylthio - Calcium butyrate, then dry and pulverize to obtain a powdery product. There are problems in this method: 1. It is difficult to carry out the reaction thoroughly; 2. The product is difficult to dry, because D, L-2-hydroxy-4-methylthiobutyric acid has 23~24% polymers, and these polymers are somewhat It exists in the form of lactone and acid anhydride, and these polymers are difficult to react with solid Ca(OH) ₂ or CaO, and finally adsorbed on the surface of the product, making the product difficult to dry and affecting the quality of the product.

Publication No. CN101348451 patent literature discloses the following method: take 2-hydroxyl-4-methylthiobutyric acid as raw material, first carry out esterification reaction with alcohol to obtain 2-hydroxyl-4-methylthiobutyrate; The above-mentioned 2-hydroxyl-4-methylthiobutyrate and calcium hydroxide are hydrolyzed into a salt in a solvent to generate 2-hydroxyl-4-methylthiobutyrate calcium. The problems in this method mainly include: 1. During the esterification reaction between 2-hydroxy-4-methylthiobutyric acid and alcohol, 10-50% of the raw material 2-hydroxy-4-methylthiobutyric acid is added If sulfuric acid or p-toluenesulfonic acid is used as a catalyst, some acids will inevitably be brought into the subsequent reaction. Once these acids react with calcium hydroxide, the resulting calcium salt has a very high viscosity and is not easy to remove. It is very inconvenient in the industrial operation process. Product quality is also greatly affected. 2. During the esterification reaction between 2-hydroxy-4-methylthiobutyric acid and alcohol, the amount of alcohol added is 10 to 40 times the amount of D, L-2-hydroxy-4-methylthiobutyric acid, The use of a large amount of alcohol will consume a large amount of heat energy in the subsequent treatment process, which will greatly increase the production cost in the industrial process. 3. Since the 2-hydroxy-4-methylthiobutyric acid on the market is a mixture, the content is only 88%, and there are more than 23% polymers, and the monomer content is only 65%. According to its patent literature introduction , the yield of the esterification reaction alone does not exceed 60%.

Xu Hongbin and others proposed in the research progress of the synthesis of hydroxymethionine and its calcium salt (Modern Biomedicine Advances, 2009 Vol.9 No.7) that 2-hydroxy-4-methylthiobutyric acid was slowly added dropwise to calcium carbonate or In the suspension of calcium hydroxide and water, the temperature is controlled within 25-35°C, and the reaction can be completed within 1-2 hours, then filter off excess calcium carbonate or calcium hydroxide, extract the filtrate with ether, and concentrate the water layer , cooled, precipitated 2-hydroxy-4-methylthiobutyrate calcium, and recrystallized with water to obtain the finished product of 2-hydroxy-4-methylthiobutyrate calcium.

The problem that this method exists is mainly similar to the method in CN1493560, because D, L-2-hydroxyl-4-methylthiobutyric acid has 23~24% polymer, some of these polymers are lactone and acid anhydride However, these polymers are difficult to react with solid Ca(OH) ₂ or CaO, and finally adsorbed on the surface of the product, which makes the product difficult to dry and affects the quality of the product.

Hans L. Nufer etc. proposed in US3272860 to use alkyl glycol monoether as a solvent, adding Ca(OH) ₂ or CaO in the hydrolysis reaction process of 2-hydroxyl-4-methylthiobutyronitrile, prepared 2- Calcium hydroxy-4-methylthiobutyrate, content 98%. The main problem of this method is that 2-hydroxyl-4-methylthiobutyronitrile is unstable in an alkaline environment and is very easy to polymerize. Although 98.5% of -hydroxyl-4-methylthiobutyrate calcium can be obtained, the yield rate has not been reported.

Contents of the invention

The technical problem to be solved by the present invention is to overcome the above-mentioned defects in the prior art and provide an improved preparation method of calcium 2-hydroxy-4-methylthiobutyrate.

For this reason, the technical scheme adopted in the present invention is: use 2-hydroxy-4-methylthiobutyronitrile with a content of more than 99.0% as raw material, slowly add 1.2 to 1.5 times of 36~38% (mass concentration) concentrated HCl of the molar weight of 2-hydroxy-4-methylthiobutyronitrile is hydrolyzed. After the hydrolysis reaction is completed, the pH of the resulting liquid obtained by the hydrolysis reaction is adjusted to 7.8~8.0 with alkali, and the temperature is lowered. Crystallize at -5~5°C for 2~5 hours, filter to obtain the crude product of 2-hydroxy-4-methylthiobutanamide, and then recrystallize with water 2~3 times the weight of 2-hydroxy-4-methylthiobutanamide to obtain High content of 2-hydroxy-4-methylthiobutanamide;

Add high-content 2-hydroxy-4-methylthiobutyramide to 5-10 times its weight in water to dissolve, then add 0.6-1.0 times the molar number of 2-hydroxy-4-methylthiobutanamide Ca(OH) _2. Direct hydrolysis at 80-100°C to generate calcium 2-hydroxy-4-methylthiobutyrate. After the reaction is complete, filter while hot at 50-60°C to remove impurities and unreacted excess Ca(OH) ₂ , lower the temperature to 0-5°C, crystallize for 10-12 hours, filter, and dry the filter cake at 105-110°C for 6-8 hours to obtain a high-content calcium 2-hydroxy-4-methylthiobutyrate product. The crystallization mother liquor of calcium 2-hydroxy-4-methylthiobutyrate can be directly applied to the hydrolysis reaction of the next batch of 2-hydroxy-4-methylthiobutyronitrile with alkali.

Using high-quality 2-hydroxy-4-methylthiobutyronitrile as the starting raw material can ensure that some raw material impurities interfere with the main reaction mechanism in the next reaction process, and obtain the best intermediate quality and reaction yield. In the process of preparing 2-hydroxy-4-methylthiobutanamide by hydrolysis reaction of 2-hydroxy-4-methylthiobutyronitrile, the present invention adopts hydrochloric acid instead of other common acids, and can make full use of sodium chloride and calcium chloride The solubility in water basically does not change with the change of temperature. In the process of extracting 2-hydroxy-4-methylthiobutyramide in the crystallization operation, it is guaranteed that there will be no inorganic salt precipitation, which will affect the intermediate product 2-hydroxy-4-formazan The mass of thiobutanamide. 2-Hydroxy-4-methylthiobutanamide is hydrolyzed by adding Ca(OH) _2. This process adopts normal pressure reaction, which can ensure that the ammonia gas generated in the reaction process can be directly discharged quickly, so that the ammonia gas will not be in the reaction process. Stay in the system, so as to ensure that the hydroxyl group in the chemical structure of the product will not be replaced by the amino group, so as to ensure a high reaction yield.

The speed of the above-mentioned rapid stirring is preferably 1000-1200 rpm.

The present invention has the following beneficial effects: the present invention uses 2-hydroxy-4-methylthiobutyronitrile with a content greater than 99.0% as a raw material, and prepares 2-hydroxy-4-methylthiobutyronitrile by hydrolysis reaction in an aqueous system using hydrochloric acid as a catalyst Butyramide is used to avoid the problem that a small amount of sulfuric acid is brought into the subsequent reaction when sulfuric acid is used as a catalyst, and the problem that calcium sulfate is generated is difficult to remove. 2-Hydroxy-4-methylthiobutyramide reaction solution is neutralized, crystallized and purified, the content is more than 99%, and then reacted with calcium hydroxide. The high quality of raw materials ensures that no impurities are mixed in the reaction process, plus the reaction There is no side reaction by itself, and the higher the temperature of calcium hydroxide in water, the smaller its solubility is, and the excess calcium hydroxide is removed in time, so the yield in this reaction process can be very high, thus ensuring the safety of this reaction The mother liquor can be used mechanically all the time, no waste water will be generated, and it is very friendly to the environment.

Detailed ways

The present invention will be described with reference to the following specific examples, which are for illustration only and are not to be construed as limiting the scope of the invention or the method for practicing the invention.

Example 1

Preparation of 2-Hydroxy-4-Methylthiobutanamide

In a 1000mL four-neck flask with mechanical stirring and a thermometer, add 131g (1mol) of 2-hydroxy-4-methylthiobutyronitrile with a content of 99.2%, start stirring, stir rapidly, and slowly stir while cooling. 133ml of 36% concentrated hydrochloric acid (1.2mol) was added, and the reaction was carried out at 5°C until the residue of the raw material 2-hydroxy-4-methylthiobutyronitrile detected by HPLC was less than 0.1%. After the reaction is completed, use 30% sodium hydroxide solution to adjust the pH of the hydrolysis reaction product to 7.8~8.0, put it in an environment of -5°C for cooling and crystallization, and after crystallization for 2 hours, filter to obtain 133.0g of 2-hydroxy-4- Methylthiobutyramide, HPLC content 99.3%, molar yield 89.3%.

Preparation of calcium 2-hydroxy-4-methylthiobutyrate

Put 59.6g (0.4mol) of 2-hydroxy-4-methylthiobutyramide into a 1000ml three-necked flask, then add 596ml of distilled water, and add 29.6g (0.4mol) of calcium hydroxide in batches while stirring. Under nitrogen protection, the reaction was carried out at 80°C until the residual 2-hydroxy-4-methylthiobutyramide was less than 0.1% as detected by sampling HPLC. After the reaction is complete, cool down to 50°C and filter to remove the filter cake, cool the filtrate to 0°C, crystallize for 10 hours, filter to obtain a filter cake, dry the filter cake under vacuum at 110°C for 6 hours, and pulverize to obtain 2-hydroxy-4- Calcium methionate 51.2g (HPLC content 99.75%), yield 75.7%. The filtrate 585ml was applied mechanically to the next batch of reactions.

Example 2

Preparation of 2-Hydroxy-4-Methylthiobutanamide

In a 1000mL four-neck flask with mechanical stirring and a thermometer, add 131g (1mol) of 2-hydroxy-4-methylthiobutyronitrile with a content greater than 99.2%, start stirring, stir rapidly, and slowly stir while cooling. 163.4ml of 36% concentrated hydrochloric acid (1.5mol) was added, and the reaction was carried out at 15°C until the remaining raw material 2-hydroxy-4-methylthiobutyronitrile was detected by HPLC to be less than 0.1%. After the reaction, use 30% sodium hydroxide solution to adjust the pH value of the hydrolysis reaction product to 7.8~8.0, put it into an environment of 5°C for cooling and crystallization, and after crystallization for 5 hours, filter to obtain 126.9g of 2-hydroxyl-4- Methylthiobutanamide, HPLC content 99.7%, molar yield 85.1%.

Preparation of calcium 2-hydroxy-4-methylthiobutyrate

Put 59.6g (0.4mol) of 2-hydroxy-4-methylthiobutyramide into a 1000ml three-necked flask, then add 417ml of the reaction filtrate from the previous batch, and add 17.8g (0.24mol) of calcium hydroxide in batches while stirring. Under nitrogen protection, the reaction was carried out at 100°C until the residual 2-hydroxy-4-methylthiobutyramide was less than 0.1% as detected by sampling HPLC. After the reaction is complete, cool down to 60°C and filter to remove the filter cake, cool the filtrate to 5°C, crystallize for 12 hours, filter to obtain a filter cake, dry the filter cake under vacuum at 105°C for 8 hours, and pulverize to obtain 2-hydroxy-4- Calcium methionate 67.1g (HPLC content 99.65%), yield 99.3%. The filtrate can be applied to the next batch of reactions.

Example 3

Preparation of 2-Hydroxy-4-Methylthiobutanamide

In a 1000mL four-neck flask with mechanical stirring and a thermometer, add 131g (1mol) of 2-hydroxy-4-methylthiobutyronitrile with a content greater than 99.2%, start stirring, stir rapidly, and slowly stir while cooling. 141.6ml of 36% concentrated hydrochloric acid (1.3mol) was added, and the reaction was carried out at 10°C until the remaining raw material 2-hydroxy-4-methylthiobutyronitrile was detected by HPLC to be less than 0.1%. After the reaction, use 30% sodium hydroxide solution to adjust the pH value of the hydrolysis reaction product to 7.8~8.0, put it in an environment of 0°C for cooling and crystallization, and after crystallization for 3 hours, filter to obtain 130.6g of 2-hydroxy-4- Methylthiobutanamide, HPLC content 99.6%, molar yield 87.6%.

Preparation of calcium 2-hydroxy-4-methylthiobutyrate

Put 59.6g (0.4mol) of 2-hydroxy-4-methylthiobutyramide into a 1000ml three-necked flask, then add 298ml of the reaction filtrate from the previous batch, and add 23.7g (0.32mol) of calcium hydroxide in batches while stirring. Under nitrogen protection, the reaction was carried out at 100°C until the residual 2-hydroxy-4-methylthiobutyramide was less than 0.1% as detected by sampling HPLC. After the reaction is complete, cool down to 55°C and filter to remove the filter cake, cool the filtrate to 5°C, crystallize for 12 hours, filter to obtain a filter cake, dry the filter cake under vacuum at 105°C for 8 hours, and pulverize to obtain 2-hydroxy-4- Calcium methionate 67.4g (HPLC content 99.62%), yield 99.7%. The filtrate can be applied to the next batch of reactions.

Claims (3)

1. a preparation method of 2-hydroxyl-4-methylthiobutyrate calcium is characterized in that, with content reaching more than 99.0% 2-hydroxyl-4-methylthiobutyronitrile as raw material, under rapid stirring, Slowly add 36-38% concentrated HCl of 1.2-1.5 times the molar weight of 2-hydroxy-4-methylthiobutyronitrile under the condition of 5-15°C to carry out normal pressure hydrolysis reaction. The pH of the solution was adjusted to 7.8-8.0 with alkali, and the temperature was lowered to -5-5°C to crystallize for 2-5 hours, and the crude product of 2-hydroxy-4-methylthiobutyramide was obtained by filtration, and then 2-3 times of 2-hydroxy-4- Water recrystallization of the weight of methylthiobutanamide obtains high content of 2-hydroxy-4-methylthiobutanamide; Add high-content 2-hydroxy-4-methylthiobutyramide to 5 to 10 times its weight in water to dissolve, and then add 0.6 to 1.0 times the molar number of 2-hydroxy-4-methylthiobutanamide Ca(OH) _2. Direct hydrolysis at 80-100°C to generate calcium 2-hydroxy-4-methylthiobutyrate. After the reaction is complete, filter while hot at 50-60°C to remove impurities and unreacted excess Ca(OH) ₂ , lower the temperature to 0-5°C, crystallize for 10-12 hours, filter, and dry the filter cake at 105-110°C for 6-8 hours to obtain a high-content calcium 2-hydroxy-4-methylthiobutyrate product. 2. the preparation method of 2-hydroxyl-4-methylthiobutyrate calcium according to claim 1, is characterized in that, the speed of rapid stirring is 1000-1200 rev/min. 3. the preparation method of 2-hydroxyl-4-methylthiobutyrate calcium according to claim 1 is characterized in that, the crystallization mother liquor of 2-hydroxyl-4-methylthiobutyrate calcium directly applies mechanically to next batch 2-Hydroxy-4-methylthiobutyronitrile plus alkali hydrolysis reaction.