CN102399176A - Preparation method of high-content 2-hydroxy-4-(methylthio) butyl calcium - Google Patents
Preparation method of high-content 2-hydroxy-4-(methylthio) butyl calcium Download PDFInfo
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Abstract
The invention relates to a preparation method of high-content 2-hydroxy-4-(methylthio) butyl calcium. The content of 2-hydroxy-4-(methylthio) butyl calcium prepared by the traditional synthesis method is lower. The preparation method provided by the invention comprises the following steps of: adding 2-hydroxy-4-methionine nitrile with content higher than 99.0% used as a raw material in concentrated HCl (hydrochloric acid) for carrying out hydrolysis reaction; after the reaction is finished, regulating pH with alkali till pH is between 7.8-8.0, cooling, crystallizing and filtering to obtain a 2-hydroxy-4-(methylthio) butyric amide crude product; recrystallizing with water to obtain high-content 2-hydroxy-4-(methylthio) butyric amide; and dissolving the high-content 2-hydroxy-4-(methylthio) butyric amide in water, adding excess Ca(OH)2 and directly hydrolyzing at 80-100 DEG C to generate 2-hydroxy-4-(methylthio) butyl calcium. The yield of the preparation method is very high, and the content of the prepared 2-hydroxy-4-(methylthio) butyl calcium is higher than 99.0%.
Description
Technical field
The present invention relates to the synthetic field of compound, specifically a kind of preparation method of high-content 2-hydroxyl 4-methylthio calcium butyrate.
Background technology
Methionine(Met) can't synthesize in animal body, needs from food, to take in, and be first limiting amino acid.It is added in the feed, can promote that the fowl dirty swine is long, increase cutability, shorten breeding cycle.2-hydroxyl 4-methylmercapto butyric acid (LMA) is the methionine(Met) analogue, can be absorbed by animal to be converted into methionine(Met), and its effect is equivalent to 65%～88% of methionine(Met).At present, in ruminating animal and fowl poultry kind feed, all add LMA, its addition is 0.1 ~ 0.5%.According to the related data statistics, methionine(Met) demand in the world's is with annual 4% speed increment in recent years, and the methionine(Met) demand of China is then with annual 7% speed increment.
According to the document introduction, the compound method of 2-hydroxyl 4-methylmercapto butyric acid mainly contains following several kinds:
At publication number is in the patent documentation of CN1493560; Propositions such as Zhou Jiankang are adopted 2-2-hydroxy-4-methylthio-butyric acid and quicklime or calcium hydroxide to do raw material to carry out neutralization reaction and prepare 2-2-hydroxy-4-methylthio-Calcium Butyrate, carry out drying and crushing then and obtain powdery product.These method existing problems: 1, reaction is difficult to thoroughly; 2, product is difficult to dryly, because D, the L-2-hydroxy-4-methylthiobutyric acid has 23 ~ 24% polymer, and these polymers are that the form with lactone and acid anhydrides exists a bit, and these polymers are difficult to solid Ca (OH)
2Or CaO reacts, and is adsorbed on the product surface at last, and it is dry to cause product to be difficult to, and influences product quality.
Publication number is the openly following method of the patent documentation of CN101348451: with the 2-hydroxy-4-methylthiobutyric acid is raw material, carries out esterification with alcohol earlier, obtains 2-hydroxy-4-methylthiobutyric acid ester; Make above-mentioned 2-hydroxy-4-methylthiobutyric acid ester and calcium hydroxide hydrolysis salify in solvent generate the 2-2-hydroxy-4-methylthio calcium butyrate again.The problem that this method exists mainly contains: 1, carry out in the esterification reaction process at 2-hydroxy-4-methylthiobutyric acid and alcohol; The sulfuric acid or the tosic acid that have added raw material 2-hydroxy-4-methylthiobutyric acid amount 10 ~ 50% unavoidably have number acid and bring subsequent reactions into as catalyzer, and these acid in case and calcium hydroxide reactions; The calcium salt viscosity that generates is very big; Be difficult for removing, in very inconvenience of industriallization operating process, also bigger to the quality product influence.2, carry out in the esterification reaction process at 2-hydroxy-4-methylthiobutyric acid and alcohol; The alcohol amount that adds is D; 10 ~ 40 times of L-2-hydroxy-4-methylthiobutyric acid amount, the uses of a large amount of alcohol can make a large amount of heat energy of consumption in the subsequent processes, at course of industrialization production cost are risen greatly.3, because the 2-hydroxy-4-methylthiobutyric acid on the market is a mixture, and content has only 88%, and wherein also have the polymer more than 23%, monomer content has only 65%, introduces according to its patent documentation, and singly being that the esterification yield is the highest is no more than 60%.
People such as Xu Hongbin are in study on the synthesis progress (the modern biomedical progress of hydroxy methionine and calcium salt thereof; Vol.9 No.7 in 2009) propose in the 2-hydroxy-4-methylthiobutyric acid slowly is added drop-wise in the suspension liquid of lime carbonate or calcium hydroxide and water, temperature is controlled in 25～35 ℃, and 1-2h just can react completely; Excessive lime carbonate or the calcium hydroxide of elimination then; Filtrating is used extracted with diethyl ether again, water layer is concentrated cooling; Separate out the 2-2-hydroxy-4-methylthio calcium butyrate, the water recrystallization obtains 2-2-hydroxy-4-methylthio calcium butyrate finished product.
The problem that this method exists main with CN1493560 in method similar, owing to D, the L-2-hydroxy-4-methylthiobutyric acid has 23 ~ 24% polymer, these polymers are that the form with lactone and acid anhydrides exists a bit, and these polymers are difficult to solid Ca (OH)
2Or CaO reacts, and is adsorbed on the product surface at last, and it is dry to cause product to be difficult to, and influences product quality.
People such as Hans L. Nufer propose to be solvent, in 2-2-hydroxy-4-methylthio butyronitrile hydrolysis reaction, to add Ca (OH) with the alkyl glycol monoether in US3272860
2Or CaO, prepared the 2-2-hydroxy-4-methylthio calcium butyrate, content 98%.The topmost problem of this method is that 2-2-hydroxy-4-methylthio butyronitrile is unstable in alkaline environment, very easily polymerization, though can obtain 98.5%-2-hydroxy-4-methylthio calcium butyrate, yield does not appear in the newspapers.
Summary of the invention
Technical problem to be solved by this invention is to overcome the defective that above-mentioned prior art exists, and a kind of preparation method of improved 2-2-hydroxy-4-methylthio calcium butyrate is provided.
For this reason; The technical scheme that the present invention adopts is: the 2-2-hydroxy-4-methylthio butyronitrile that reaches more than 99.0% with content is a raw material; Stirring fast down, the dense HCl of 36 ~ 38% (mass concentrations) that under 5 ~ 15 ℃ of conditions, slowly adds 1.2 ~ 1.5 times of 2-2-hydroxy-4-methylthio butyronitrile molar weights reaction that is hydrolyzed is after the hydrolysis reaction end; The Generation Liquid that hydrolysis reaction is obtained is with adjusting PH with base to 7.8 ~ 8.0; Be cooled to-5 ~ 5 ℃ of crystallizations 2 ~ 5 hours, filter and obtain 2-2-hydroxy-4-methylthio yulocrotine bullion, use the water recrystallization of 2 ~ 3 times of 2-2-hydroxy-4-methylthio yulocrotine weight to obtain high-load 2-2-hydroxy-4-methylthio yulocrotine again;
With the water dissolution of 5 ~ 10 times of high-load its weight of 2-2-hydroxy-4-methylthio yulocrotine adding, add the Ca (OH) of 0.6 ~ 1.0 times of 2-2-hydroxy-4-methylthio yulocrotine mole number again
2, direct hydrolysis generates the 2-2-hydroxy-4-methylthio calcium butyrate under 80-100 ℃ of temperature, and reaction is finished, and filtered while hot is removed impurity and unreacted excess amount of Ca (OH) under 50 ~ 60 ℃ of conditions
2, being cooled to 0 ~ 5 ℃, crystallization 10 ~ 12 hours is filtered, and filter cake obtained high-load 2-2-hydroxy-4-methylthio calcium butyrate product in 6 ~ 8 hours in 105 ~ 110 ℃ of dryings.The crystalline mother solution of 2-2-hydroxy-4-methylthio calcium butyrate can directly apply mechanically under criticize in the 2-2-hydroxy-4-methylthio butyronitrile alkaline hydrolysis reaction.
Adopt high-quality 2-2-hydroxy-4-methylthio butyronitrile as starting raw material, can guarantee that some raw material impurities obtain best midbody quality and reaction yield to the interference of main reaction mechanism in next step reaction process.2-2-hydroxy-4-methylthio butyronitrile hydrolysis reaction prepares in the 2-2-hydroxy-4-methylthio yulocrotine process; The present invention adopts hydrochloric acid rather than other some common acid; Can make full use of the temperature-independent basically characteristic of sodium-chlor, calcium chloride solubleness in water; In the process of crystallization operation extraction 2-2-hydroxy-4-methylthio yulocrotine, guarantee that not having inorganic salt separates out, thereby influence the quality of midbody product 2-2-hydroxy-4-methylthio yulocrotine.2-2-hydroxy-4-methylthio yulocrotine adds Ca (OH)
2In the process that is hydrolyzed; This process using synthesis under normal pressure can guarantee directly the ammonia that generates in the reaction process to be discharged fast, and ammonia can not stopped in reaction system; Thereby guarantee that the hydroxyl in the product chemical structure can not replaced by amino, thereby guarantee to get very high reaction yield.
The speed of above-mentioned quick stirring is preferably 1000-1200 rev/min.
The present invention has following beneficial effect: it is raw material greater than 99.0% 2-2-hydroxy-4-methylthio butyronitrile that the present invention adopts content; With hydrochloric acid as the aqueous systems of catalyzer in hydrolysis reaction prepare 2-2-hydroxy-4-methylthio yulocrotine; A small amount of sulfuric acid is brought subsequent reactions into when having avoided use sulfuric acid as catalyzer, generates the problem that calcium sulfate is difficult to remove.2-2-hydroxy-4-methylthio yulocrotine reaction solution is after neutralization, crystallization and purification, and content is greater than 99%, again with calcium hydroxide reaction; The high quality of raw material has guaranteed not have in the reaction process impurity to sneak into, and adds that reaction itself does not have side reaction to produce, and utilizes calcium hydroxide temperature in water high more again; The special property that its solubleness is more little; In time remove unnecessary calcium hydroxide, so yield can be very high in this reaction process, thereby the mother liquor that has guaranteed this reaction can be applied mechanically always; Can not produce waste water, very friendly to environment.
Embodiment
The present invention will describe with reference to following specific examples, and these instances just can not be regarded as limiting the method for scope of the present invention or embodiment of the present invention for elaboration.
Embodiment 1
The preparation of 2-2-hydroxy-4-methylthio yulocrotine
In having the 1000mL four-hole boiling flask of mechanical stirring, TM; Adding 131g (1mol) content is 99.2% 2-2-hydroxy-4-methylthio butyronitrile; Start stirring, stir fast, under cooling situation while stirring, slowly add the concentrated hydrochloric acid (1.2mol) of 133ml 36%; React in 5 ℃, it is residual less than 0.1% to detect raw material 2-2-hydroxy-4-methylthio butyronitrile until HPLC.Reaction is finished, and separates reaction solution pH to 7.8 ~ 8.0 with 30% sodium hydroxide solution water transfer, and the environment of putting into-5 ℃ carries out decrease temperature crystalline; After the crystallization 2 hours; Filtration obtains 133.0g 2-2-hydroxy-4-methylthio yulocrotine, HPLC content 99.3%, molar yield 89.3%.
The preparation of 2-2-hydroxy-4-methylthio calcium butyrate
In the 1000ml there-necked flask, drop into 2-2-hydroxy-4-methylthio yulocrotine 59.6g (0.4mol), add 596ml zero(ppm) water again, add calcium hydroxide 29.6g (0.4mol) under stirring in batches.Logical nitrogen protection is reacted in 80 ℃, and it is residual less than 0.1% to detect 2-2-hydroxy-4-methylthio yulocrotine until sampling HPLC.Reaction is finished, and is cooled to 50 ℃ of filtrations, removes filter cake, and filtrating is cooled to 0 ℃; Crystallization 10 hours is filtered, and obtains filter cake, and filter cake dried by the fire 6 hours under 110 ℃ of conditions of vacuum; Pulverize, get 2-hydroxyl-4-first sulphur butyl acid calcium 51.2g (HPLC content 99.75%), yield 75.7%.Filtrating 585ml applies mechanically to next batch and reacts.
Embodiment 2
The preparation of 2-2-hydroxy-4-methylthio yulocrotine
In having the 1000mL four-hole boiling flask of mechanical stirring, TM; Add 131g (1mol) content greater than 99.2% 2-2-hydroxy-4-methylthio butyronitrile; Start stirring, stir fast, under cooling situation while stirring, slowly add the concentrated hydrochloric acid (1.5mol) of 163.4ml 36%; React in 15 ℃, it is residual less than 0.1% to detect raw material 2-2-hydroxy-4-methylthio butyronitrile until HPLC.Reaction is finished, and separates reaction solution pH value to 7.8 ~ 8.0 with 30% sodium hydroxide solution water transfer, and the environment of putting into 5 ℃ carries out decrease temperature crystalline; After the crystallization 5 hours; Filtration obtains 126.9g 2-2-hydroxy-4-methylthio yulocrotine, HPLC content 99.7%, molar yield 85.1%.
The preparation of 2-2-hydroxy-4-methylthio calcium butyrate
In the 1000ml there-necked flask, drop into 2-2-hydroxy-4-methylthio yulocrotine 59.6g (0.4mol), add and go up batch reaction filtrating 417ml, stirring adds calcium hydroxide 17.8g (0.24mol) down in batches.Logical nitrogen protection is reacted in 100 ℃, and it is residual less than 0.1% to detect 2-2-hydroxy-4-methylthio yulocrotine until sampling HPLC.Reaction is finished, and is cooled to 60 ℃ of filtrations, removes filter cake, and filtrating is cooled to 5 ℃; Crystallization 12 hours is filtered, and obtains filter cake, and filter cake dried by the fire 8 hours under 105 ℃ of conditions of vacuum; Pulverize, get 2-hydroxyl-4-first sulphur butyl acid calcium 67.1g (HPLC content 99.65%), yield 99.3%.Filtrating can be applied mechanically to next batch and reacted.
Embodiment 3
The preparation of 2-2-hydroxy-4-methylthio yulocrotine
In having the 1000mL four-hole boiling flask of mechanical stirring, TM; Add 131g (1mol) content greater than 99.2% 2-2-hydroxy-4-methylthio butyronitrile; Start stirring, stir fast, under cooling situation while stirring, slowly add the concentrated hydrochloric acid (1.3mol) of 141.6ml 36%; React in 10 ℃, it is residual less than 0.1% to detect raw material 2-2-hydroxy-4-methylthio butyronitrile until HPLC.Reaction is finished, and separates reaction solution pH value to 7.8 ~ 8.0 with 30% sodium hydroxide solution water transfer, and the environment of putting into 0 ℃ carries out decrease temperature crystalline; After the crystallization 3 hours; Filtration obtains 130.6g 2-2-hydroxy-4-methylthio yulocrotine, HPLC content 99.6%, molar yield 87.6%.
The preparation of 2-2-hydroxy-4-methylthio calcium butyrate
In the 1000ml there-necked flask, drop into 2-2-hydroxy-4-methylthio yulocrotine 59.6g (0.4mol), add and go up batch reaction filtrating 298ml, stirring adds calcium hydroxide 23.7g (0.32mol) down in batches.Logical nitrogen protection is reacted in 100 ℃, and it is residual less than 0.1% to detect 2-2-hydroxy-4-methylthio yulocrotine until sampling HPLC.Reaction is finished, and is cooled to 55 ℃ of filtrations, removes filter cake, and filtrating is cooled to 5 ℃; Crystallization 12 hours is filtered, and obtains filter cake, and filter cake dried by the fire 8 hours under 105 ℃ of conditions of vacuum; Pulverize, get 2-hydroxyl-4-first sulphur butyl acid calcium 67.4g (HPLC content 99.62%), yield 99.7%.Filtrating can be applied mechanically to next batch and reacted.
Claims (3)
1. the preparation method of a high-content 2-hydroxyl-4-first sulphur butyl acid calcium; It is characterized in that; The 2-2-hydroxy-4-methylthio butyronitrile that reaches more than 99.0% with content is a raw material, in 36 ~ 38% dense HCl that stir fast down, under 5 ~ 15 ℃ of conditions, slowly add 1.2 ~ 1.5 times of 2-2-hydroxy-4-methylthio butyronitrile molar weights reaction that is hydrolyzed, after the hydrolysis reaction end; The Generation Liquid that hydrolysis reaction is obtained is with adjusting PH with base to 7.8 ~ 8.0; Be cooled to-5 ~ 5 ℃ of crystallizations 2 ~ 5 hours, filter and obtain 2-2-hydroxy-4-methylthio yulocrotine bullion, use the water recrystallization of 2 ~ 3 times of 2-2-hydroxy-4-methylthio yulocrotine weight to obtain high-load 2-2-hydroxy-4-methylthio yulocrotine again;
With the water dissolution of 5 ~ 10 times of high-load its weight of 2-2-hydroxy-4-methylthio yulocrotine adding, add the Ca (OH) of 0.6 ~ 1.0 times of 2-2-hydroxy-4-methylthio yulocrotine mole number again
2, direct hydrolysis generates the 2-2-hydroxy-4-methylthio calcium butyrate under 80-100 ℃ of temperature, and reaction is finished, and filtered while hot is removed impurity and unreacted excess amount of Ca (OH) under 50 ~ 60 ℃ of conditions
2, being cooled to 0 ~ 5 ℃, crystallization 10 ~ 12 hours is filtered, and filter cake obtained high-load 2-2-hydroxy-4-methylthio calcium butyrate product in 6 ~ 8 hours in 105 ~ 110 ℃ of dryings.
2. the preparation method of high-content 2-hydroxyl according to claim 1-4-first sulphur butyl acid calcium is characterized in that the speed that stirs fast is 1000-1200 rev/min.
3. the preparation method of high-content 2-hydroxyl according to claim 1-4-first sulphur butyl acid calcium is characterized in that the crystalline mother solution of 2-2-hydroxy-4-methylthio calcium butyrate is directly applied mechanically to following batch 2-2-hydroxy-4-methylthio butyronitrile alkaline hydrolysis reaction.
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Cited By (5)
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| CN103641754A (en) * | 2013-11-19 | 2014-03-19 | 重庆紫光化工股份有限公司 | Preparation method of medicinal D,L-2-hydroxy-4-methylthiobutyric acid metal chelate |
| CN103641756A (en) * | 2013-11-19 | 2014-03-19 | 重庆紫光化工股份有限公司 | Preparation method of calcium D,L-2-hydroxy-4-methylthiobutyrate having high purity and high bulk density |
| CN103641760A (en) * | 2013-11-19 | 2014-03-19 | 重庆紫光化工股份有限公司 | Preparation method of cheap highly-pure D,L-2-hydroxy-4-methylthiobutyramide |
| CN104098490A (en) * | 2013-04-03 | 2014-10-15 | 天津金耀集团有限公司 | New crystal form of racemic methionine hydroxyl analog-Ca and preparation method thereof |
| CN110577479A (en) * | 2019-09-25 | 2019-12-17 | 福安药业集团重庆博圣制药有限公司 | Novel crystal form A of racemic hydroxy methionine calcium and preparation method and application thereof |
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| CN104098490A (en) * | 2013-04-03 | 2014-10-15 | 天津金耀集团有限公司 | New crystal form of racemic methionine hydroxyl analog-Ca and preparation method thereof |
| CN104098490B (en) * | 2013-04-03 | 2017-08-11 | 天津金耀集团有限公司 | A kind of racemization methionine hydroxy calcium novel crystal forms and preparation method thereof |
| CN103641754A (en) * | 2013-11-19 | 2014-03-19 | 重庆紫光化工股份有限公司 | Preparation method of medicinal D,L-2-hydroxy-4-methylthiobutyric acid metal chelate |
| CN103641756A (en) * | 2013-11-19 | 2014-03-19 | 重庆紫光化工股份有限公司 | Preparation method of calcium D,L-2-hydroxy-4-methylthiobutyrate having high purity and high bulk density |
| CN103641760A (en) * | 2013-11-19 | 2014-03-19 | 重庆紫光化工股份有限公司 | Preparation method of cheap highly-pure D,L-2-hydroxy-4-methylthiobutyramide |
| CN103641756B (en) * | 2013-11-19 | 2016-03-30 | 重庆紫光化工股份有限公司 | The preparation method of high purity and high-bulk-density HMBC |
| CN103641760B (en) * | 2013-11-19 | 2016-03-30 | 重庆紫光化工股份有限公司 | The preparation method of cheap highly purified D, L-2-2-hydroxy-4-methylthio butyramide |
| CN103641754B (en) * | 2013-11-19 | 2016-08-24 | 宁夏紫光天化蛋氨酸有限责任公司 | The preparation method of medicinal D, L-2-hydroxy-4-methylthiobutyric acid metallo-chelate |
| CN110577479A (en) * | 2019-09-25 | 2019-12-17 | 福安药业集团重庆博圣制药有限公司 | Novel crystal form A of racemic hydroxy methionine calcium and preparation method and application thereof |
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