CN103641756A - Preparation method of calcium D,L-2-hydroxy-4-methylthiobutyrate having high purity and high bulk density - Google Patents
Preparation method of calcium D,L-2-hydroxy-4-methylthiobutyrate having high purity and high bulk density Download PDFInfo
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Abstract
The invention aims at the chemical industry field, and relates to a preparation method of calcium D,L-2-hydroxy-4-methylthiobutyrate having a high purity and a high bulk density. The method comprises the following steps: fully reacting a hydrocyanic acid mixed gas prepared through an Andrussow method with methylthiopropionaldehyde under the catalysis of an alkali to obtain a 2-hydroxy-4-methylthiobutyronityile system; hydrating the 2-hydroxy-4-methylthiobutyronityile system in the presence of an inorganic acid to obtain D,L-2-hydroxy-4-methylthiobutyramide; and chelating D,L-2-hydroxy-4-methylthiobutyramide with calcium oxide or calcium hydroxide to prepare calcium D,L-2-hydroxy-4-methylthiobutyrate. The method has the advantages of simple synthesis technology and easily available raw materials, the above obtained product has a large bulk density, a high purity and a good fluency, can be effectively mixed with feeds as an animal feed additive to supplement the calcium element and amino acids in the daily ration and improve the endozoic production and immunity performances, and can also be used as a medicinal reagent.
Description
Technical field
The present invention is directed to chemical field, relate to a kind of preparation method of HMBC, be specifically related at D, on L-2-2-hydroxy-4-methylthio butyramide preparation method's basis, prepare the method for HMBC.
Background technology
Methionine hydroxy analog (MHA) claim again D, L-2-hydroxy-4-methylthiobutyric acid, it is a kind of methionine additive, have that toxicity is little, Rumen rate is low, promote rumen microorganism synthetic, save protein in daily ration, improve the production performance of cow, improve production performance and immunological competence, the discharge of minimizing ammonia of animal, the feature such as contaminate environment is less, production technique is simple, price is lower, be the most economical effective a kind of amino acid source of animal.Although methionine hydroxy analog has above-mentioned advantage, on market, replacing gradually more expensive amino acid, but still there is following problem in it: 1) have stronger corrodibility and irritating smell, store, transport, use inconvenience, must use expensive dedicated liquid charging system; 2) viscosity is very large, is difficult for mixing in feed pre-mixing material; 3) meet water and emit a large amount of heats, cause feed to generate heat in storage and transport process and ferment and become sour; Acidity is very large, and pH is about 1, and other composition generation acid-base reactions easily and in feed or premixing feedstuff, damage the nutritive ingredient in feed.
D, L-2-hydroxy-4-methylthiobutyric acid metallo-chelate is a kind of effective way addressing the above problem, it is the necessary metallic element of growth of animal and methionine hydroxy analog effect to be generated to the compound of chelating state, is a kind of trace element replenisher close to natural form in animal body.MHA calcium is a kind of in methionine hydroxy analog metallo-chelate, is a kind of green feed additive.It can provide the source of methionine(Met) for the synthesis of body internal protein, again containing the essential high-quality calcium source of organism, and the needs of growing to meet body growth.
According to Introduction of Literatures, the synthetic method of HMBC mainly contains following several:
Publication number is in the patent documentation of CN1493560, propose to adopt the D of commercial grade, L-2-hydroxy-4-methylthiobutyric acid and calcium oxide or calcium hydroxide carry out neutralization reaction as raw material and prepare D, L-2-2-hydroxy-4-methylthio calcium butyrate, final drying and crushing obtains pulverous HMBC product.The problem that this method exists is mainly: due to commercially available D, the dimer that contains 22% left and right in L-2-hydroxy-4-methylthiobutyric acid and polymer thereof, and these polymers are mainly with the form existence of ester or acid anhydrides, cause these polymers to be difficult to and calcium oxide or calcium hydroxide reaction, finally be adsorbed on product surface, product is difficult to be dried, and then affects product quality.
Publication number is in the patent documentation of CN101348451, discloses with D, and L-2-hydroxy-4-methylthiobutyric acid is raw material, first carries out esterification with alcohol, obtains D, L-2-hydroxy-4-methylthiobutyric acid ester; Make D, L-2-hydroxy-4-methylthiobutyric acid ester and calcium oxide are hydrolyzed and generate HMBC in solvent.The problem that this method exists is mainly: 1) esterification need add raw material D, the sulfuric acid of L-2-hydroxy-4-methylthiobutyric acid amount 10%～50% or P-TOLUENE SULFO ACID 99 are as catalyzer, there is number acid inevitably can bring subsequent reactions into, once and these acid and calcium hydroxide reactions, the calcium salt viscosity generating is very large, be difficult for removing, very inconvenient in industrialization operation, also very large to the quality influence of product; 2) amount of the alcohol that esterification need add is D, 10～40 times of L-2-hydroxy-4-methylthiobutyric acid, and the use of a large amount of alcohol can make to consume a large amount of heat energy in its subsequent processes, and industrial production cost rises greatly; 3) also with commercially available D, L-2-hydroxy-4-methylthiobutyric acid is raw material, and because it is mixture, total content is low and wherein polymer proportion is high, and therefore, being singly that the yield of esterification is the highest is also no more than 60%.
Publication number is in the patent documentation of CN102399176, disclose that to take content be raw material up to more than 99% 2-2-hydroxy-4-methylthio butyronitrile, add concentrated hydrochloric acid hydrolysis, sodium hydroxide neutralization with 30%, water recrystallization obtains the D of high-content, and L-2-2-hydroxy-4-methylthio butyramide, in the calcium hydroxide hydrolysis with excessive, obtain HMBC.The problem that this method exists is mainly: 1) carrying out D, during L-2-2-hydroxy-4-methylthio butyramide purifying, although carried out recrystallization, can not obtain highly purified D, L-2-2-hydroxy-4-methylthio butyramide; 2) waste water and dregs is more, not only contains ammonium chloride in waste water, also contains sodium-chlor, a small amount of D, and L-2-2-hydroxy-4-methylthio butyramide etc., have brought difficulty to wastewater treatment; 3) purity requirement of raw material 2-2-hydroxy-4-methylthio butyronitrile is high, has improved production cost.
Publication number is in the patent documentation of CN102079719, disclose with D, L-2-hydroxy-4-methylthiobutyric acid is starting raw material, generate ammonium salt with ammonia react, and then dehydration obtains D, L-2-2-hydroxy-4-methylthio butyramide, process extraction, concentrated and crystallization purifying, obtain the D that content is greater than 98.5%, L-2-2-hydroxy-4-methylthio butyramide; Hydrolysis generates D again, and L-2-hydroxy-4-methylthiobutyric acid salt finally reacts with inorganic calcium salt and generates HMBC.The problem that this method exists is mainly: 1) D, and the dehydration of L-2-hydroxy-4-methylthiobutyric acid ammonium salt forms D, L-2-2-hydroxy-4-methylthio butyramide, rectification and purification needs high temperature condition of high vacuum degree, and condition is harsh, thereby has limited large-scale industrial production; 2) yield of HMBC is low, only has 70% left and right.
In addition, in actual production, also there is synthetic D in the disclosed method of above-mentioned document, the problems such as L-2-2-hydroxy-4-methylthio calcium butyrate stickiness is large, density is little, fluency is poor, therefore be difficult to fully mix with feed, feed quality is unstable, and then affects feeding effect.
For these reasons and prior art, the present invention improves the preparation method of HMBC.
Summary of the invention
In view of this, the invention provides a kind of preparation method of HMBC, the raw material of the method is cheap and easy to get, intermediate stable in properties, and the HMBC yield that makes is high, purity is high, tap density is large.
For achieving the above object, technical scheme of the present invention is:
The preparation method of HMBC, comprises the following steps:
A, take methane, ammonia and oxygen as raw material, adopt iS-One method composition principle, be prepared into prussic acid gas mixture I; Described prussic acid gas mixture I is processed to obtain prussic acid gas mixture II through deamination;
B, described prussic acid gas mixture II and methylthiopropionaldehyde, under the katalysis of alkali, fully react to obtain 2-2-hydroxy-4-methylthio butyronitrile system;
C, described 2-2-hydroxy-4-methylthio butyronitrile system are carried out hydration reaction under the existence of mineral acid, after reaction finishes, with ammonia or ammoniacal liquor, regulate reaction solution pH to 5.0～6.5, crystallisation by cooling, solid-liquid separation obtains D, the crystalline mixture of L-2-2-hydroxy-4-methylthio butyramide and inorganic acid ammonium salt, recrystallization obtains highly purified D, L-2-2-hydroxy-4-methylthio butyramide;
D, by described highly purified D, L-2-2-hydroxy-4-methylthio butyramide is dissolved in water medium, then adds excessive calcium oxide or calcium hydroxide, at 100～120 ℃ of temperature, fully, after hydrolysis, removes by filter residual calcium oxide or calcium hydroxide, obtains filtrate; In described filtrate, add crystallizing agent, crystallisation by cooling, separation, crystal is dried to obtain HMBC.
Described iS-One method (Andrussow method) is the industrial process completing the 1950's, is the main method of producing prussic acid.The main raw material that it adopts has methane, ammonia and oxygen, therefore be again methane oxidation proceses of ammonia.This method is under condition more than normal pressure, l000 ℃, the silk screen that the logical people of material mixed gas is made by platinum, rhodium alloy catalyst platinum and rhodium, or the wire-mesh catalyst bed of being made by platinum iridium alloy, and the oxidative ammonolysis carrying out, its reaction formula is 2CH
4+ 2NH
3+ 30
2→ 2HCN+6H
20.At present, this technology is very ripe, has special prussic acid synthetic tower for the preparation of hydrocyanic acid gas.
Described deamination processing refers to the standby prussic acid gas mixture I of iS-One legal system is passed in acid, sloughs the operation of ammonia.The Main Function that described acid rises is absorbing ammonia G&W steam, so preferably sulfuric acid, the sulfuric acid that further preferred mass mark is 75%～90%.The prussic acid gas mixture of the present invention before and after deamination is processed all can be used for the preparation of 2-2-hydroxy-4-methylthio butyronitrile, and just the prussic acid gas mixture II character after deamination is processed is more excellent.Industrial, special acid tower can be set and for deamination, process.
Further, described prussic acid gas mixture I is preferably comprised of the component of following mass percent: hydrocyanic acid gas 8.8% ± 2%, water vapour 3.9% ± 2%, ammonia 1.6% ± 2%, hydrogen 1.1% ± 2%, nitrogen 76.0% ± 2%, oxygen 1.5% ± 2%, carbon monoxide 5.6% ± 2%, carbonic acid gas 1.1% ± 2%, methane 0.4% ± 2%.Described prussic acid gas mixture II is preferably comprised of the component of following mass percent: hydrocyanic acid gas 9.4% ± 2%, hydrogen 1.6% ± 2%, nitrogen 79.4% ± 2%, oxygen 1.7% ± 2%, carbon monoxide 5.8% ± 2%, carbonic acid gas 1.5% ± 2%, methane 0.6% ± 2%.
Described prussic acid gas mixture II is particularly suitable as the raw material of preparation 2-2-hydroxy-4-methylthio butyronitrile.Its reaction is except making 2-2-hydroxy-4-methylthio butyronitrile, in reaction solution, also contain remaining massfraction and be 0.05%～0.5% prussic acid and 2%～5% water, just because of the existence of residual hydrogen cyanic acid and water, this system (being that 2-2-hydroxy-4-methylthio butyronitrile is together with reaction solution) can long-term storage and is not decomposed.The reaction system of 2-2-hydroxy-4-methylthio butyronitrile also can be further adjusted to pH with acid 2～4 to be deposited, like this, even if still keep at normal temperatures longer stability.The acid of described adjusting pH can be sulfuric acid, phosphoric acid etc., massfraction preferably 85%.2-2-hydroxy-4-methylthio butyronitrile system, without carrying out any separation and purification, can be directly used in the production of MHA.
Further, described methylthiopropionaldehyde is not purified methylthiopropionaldehyde, wherein contains the heavy constituent of the methylthiopropionaldehyde of massfraction 94.5%～96%, the light constituent of massfraction 3.5%～5.3% and massfraction 0.2%～0.5%; Described light constituent is thiomethyl alcohol, methyl alcohol, propenal and water; Described restructuring is divided into dipolymer and the trimer of methylthiopropionaldehyde.
Step B is the nucleophilic addition under base catalysis.The alkali of described katalysis is organic bases and/or mineral alkali; The consumption of the alkali of described katalysis is that the pH that maintains reaction system is 4.0～6.5, and preferably pH is 5.0～5.5.The preferred low-molecular-weight amine compound of described organic bases, the further preferred aminated compounds of 3～20 carbon atoms, this compounds can, with methylthiopropionaldehyde arbitrarily than mixing, be conducive to fast reaction speed.The aminated compounds of described 3～20 carbon atoms comprises triethylamine, tri-isopropanolamine, DMA, imidazoles, picoline, pyridine etc., use wherein one or more can, particularly preferably triethylamine and/or pyridine.Described mineral alkali is one or more in metal hydroxides, metal cyanides, metal carbonate and alkali metal bicarbonate salt, or is ammonia.Described metallic hydrogen oxidation compound, as sodium hydroxide or potassium hydroxide; Metal cyanides, as sodium cyanide or potassium cyanide; Metal carbonate, as sodium carbonate or salt of wormwood; Alkali metal bicarbonate salt, as sodium bicarbonate or saleratus.Independent a kind of mineral alkali or mixed base can.
Further, in the alkali of described katalysis, also add acid, form mixture or the damping fluid of bronsted lowry acids and bases bronsted lowry; Described acid comprises mineral acid and organic acid.Adding or the formation of damping fluid of acid, can make reaction system maintain within the scope of more stable pH value.Described organic acid is a kind of in acetic acid, formic acid, citric acid, Phenylsulfonic acid, trifluoromethanesulfonic acid etc.; Described mineral acid is sulfuric acid or phosphoric acid.The damping fluid that forms is as Trisodium Citrate-sodium hydrate buffer solution, sodium succinate-sodium hydrate buffer solution, acetic acid-sodium hydrate buffer solution etc., optimization citric acid-sodium hydrate buffer solution.
In described step B, the mol ratio of prussic acid and methylthiopropionaldehyde is 1:1.0～1.05; Reaction pressure is 0.09～0.5MPa, and in negative pressure, the environment to malleation can react, for considering of equipment requirements and reaction efficiency, and preferably 0.1～0.3MPa, more preferably 0.1～0.15MPa; Temperature of reaction is 30～80 ℃, preferably 35～60 ℃, and more preferably 40～45 ℃.
In step C, during 2-2-hydroxy-4-methylthio butyronitrile hydration reaction, described mineral acid can be sulfuric acid, phosphoric acid, hydrochloric acid etc., preferably sulfuric acid.When mineral acid is sulfuric acid, the mol ratio of described 2-2-hydroxy-4-methylthio butyronitrile and sulfuric acid is 1:0.5～1, and preferred molar ratio is 1:0.7～1; The massfraction of described sulfuric acid is 50%～80%, and preferred mass mark is 65%～75%; Temperature is controlled at 40～70 ℃, and preferably temperature is 50～65 ℃.Raw material and the product changing conditions of the method monitoring reactions such as available HPLC are stopped reaction until react completely.In above-mentioned sulfuric acid concentration and temperature condition, the hydration reaction time is 0.5～2h, and the preferred reaction time is 1～2h.
After hydration reaction finishes, the adjusting of reaction solution pH except with ammonia or ammoniacal liquor, can also regulate with other mineral alkalis, but the intensity of these alkali to be to destroy D, and the amido linkage in L-2-2-hydroxy-4-methylthio butyramide is limited.The present invention is for the consideration of subsequent purification, and preferred weakly alkaline ammonia or ammoniacal liquor, neutralize and can additionally not introduce other salts simultaneously.While regulating pH, temperature is controlled in 30 ℃, preferably 10～30 ℃, is convenient to obtain accurately the reaction solution of required potential of hydrogen.
Further, described step C is to D, and the purifying of the crystalline mixture of L-2-2-hydroxy-4-methylthio butyramide and inorganic acid ammonium salt, comprises the following steps:
1) by D, the hydration of the crystalline mixture of L-2-2-hydroxy-4-methylthio butyramide and inorganic acid ammonium salt and 5～10 ℃ also, stirring and dissolving inorganic acid ammonium salt, solid-liquid separation obtains D, L-2-2-hydroxy-4-methylthio butyramide work in-process;
2) described D, the water dissolution of 2～4 times of crude product quality for L-2-2-hydroxy-4-methylthio butyramide work in-process, crystallisation by cooling, separated crystallization and the recrystallization mother liquor I of obtaining; Crystallization is dried, and obtains highly purified D, L-2-2-hydroxy-4-methylthio butyramide finished product.
Described in step 1), the consumption of water preferably makes inorganic acid ammonium salt dissolve the amount reaching capacity.Step 2) described recrystallization mother liquor I is capable of circulation to step 1), dissolving for the next crude product inorganic acid ammonium salt of producing, be circulated to D while producing next time, the washing of the crystalline mixture of L-2-2-hydroxy-4-methylthio butyramide and inorganic acid ammonium salt, product in mother liquor is further recycled like this, also reduce water consumption, avoided the discharge of waste liquid simultaneously.
In described step D, the consumption of preferably water medium is D, 5～8 times of L-2-2-hydroxy-4-methylthio butyramide quality, and preferred D, the mol ratio of L-2-2-hydroxy-4-methylthio butyramide and calcium oxide or calcium hydroxide is 1: 0.55～0.80.Wherein, described crystallizing agent has the character of tensio-active agent, and such crystallizing agent and water effect can form even, the regular cellular template in aperture, when crystallization, forms gradually big or small even, the regular crystal of profile in template.One or more in described crystallizing agent optimization citric acid, lactic acid, Walocel MT 20.000PV, Natvosol and Aluctyl; Its consumption is preferably D, 50～3000ppm of L-2-2-hydroxy-4-methylthio butyramide quality.During HMBC crystallisation by cooling, preferably 0～5 ℃ of Tc; The crystalline mother solution II obtaining after separated, can be used as water medium, D while being circulated to next step D production, the dissolving of L-2-2-hydroxy-4-methylthio butyramide.
The present invention also provides a kind of D of utilization, L-2-2-hydroxy-4-methylthio calcium butyrate production equipment is prepared D, the method of L-2-2-hydroxy-4-methylthio calcium butyrate, the method is simple to operate, controllability is strong, production cost is low, the D making, L-2-2-hydroxy-4-methylthio calcium butyrate yield is high, purity is high, tap density is large, and mother liquid recycling rate is high, environmental protection and energy saving.The technical scheme adopting is:
Utilize D, L-2-2-hydroxy-4-methylthio calcium butyrate production equipment is prepared D, the method of L-2-2-hydroxy-4-methylthio calcium butyrate, described production equipment comprises prussic acid synthetic tower, acid tower, reactor, tripping device and crystallization kettle, in described acid tower, fill massfraction and be 75%～90% sulfuric acid, described reactor is provided with pressure and temperature regulates supplementary unit, the air outlet of prussic acid synthetic tower is communicated with the inlet mouth of acid tower by pipeline, and the air outlet of acid tower is communicated with reactor by being provided with the pipeline of throttling valve;
A, take methane, ammonia and oxygen as raw material, adopt iS-One method composition principle, by prussic acid synthetic tower, prepare prussic acid gas mixture I; Described prussic acid gas mixture I passes into acid tower and sloughs ammonia and water vapour, obtains prussic acid gas mixture II;
B, described prussic acid gas mixture II, under throttle valve control, pass in the methylthiopropionaldehyde in reactor with the speed of 250～350L/min, under the katalysis of alkali, fully react to obtain 2-2-hydroxy-4-methylthio butyronitrile system;
Under C, vigorous stirring, in reactor, add mineral acid to mix with 2-2-hydroxy-4-methylthio butyronitrile system, carry out hydration reaction, after reaction finishes, with ammonia or ammoniacal liquor, regulate reaction solution pH to 5.0～6.5, crystallisation by cooling, through the separated D that obtains of tripping device, the crystalline mixture of L-2-2-hydroxy-4-methylthio butyramide and inorganic acid ammonium salt, with the water washing crystalline mixture of 5～10 ℃, obtain D, L-2-2-hydroxy-4-methylthio butyramide work in-process; Described D, L-2-2-hydroxy-4-methylthio butyramide work in-process proceed to recrystallization in crystallization kettle, through separated crystal and the crystalline mother solution I of obtaining of tripping device; Wash crystallization mixture when described crystalline mother solution I is circulated to next step C production; Described crystal is highly purified D, L-2-2-hydroxy-4-methylthio butyramide;
D, by described highly purified D, L-2-2-hydroxy-4-methylthio butyramide proceeds to crystallization kettle again, water medium dissolves, add again excessive calcium oxide or calcium hydroxide, at 100～120 ℃ of temperature, fully, after hydrolysis, through tripping device separation, remove residual calcium oxide or calcium hydroxide, obtain filtrate; Described filtrate proceeds to again crystallization kettle, adds crystallizing agent, and crystallisation by cooling, through separated crystal and the crystalline mother solution II of obtaining of tripping device; Described crystalline mother solution II is as water medium, D when being circulated to next step D and producing, the dissolving of L-2-2-hydroxy-4-methylthio butyramide; Described crystal proceeds to drying plant and dries, and obtains HMBC.
In described step C, when mineral acid mixes with 2-2-hydroxy-4-methylthio butyronitrile system, the sequencing adding does not affect the carrying out of reaction.When mineral acid is sulfuric acid, the consideration for sulfuric acid dilution heat release for preventing bumping, preferably drips 2-2-hydroxy-4-methylthio butyronitrile in sulfuric acid.
Described tripping device can be whizzer, suction filter, gets rid of worry machine etc.Wherein, the functions such as that described reactor possesses is synthetic, hydration, neutralization, are separately also correspondingly equipped with the utility appliance such as cooling, heating, supercharging, but reactor used in the present invention is not limited to this.The reaction conditions of optimizing in preceding method, is also applicable to the method for this part band production equipment.
Useful technique effect of the present invention is:
(1) adopt standby prussic acid gas mixture and the not purified methylthiopropionaldehyde of iS-One legal system, raw material, without rectifying purifying, is saved the production time, has improved production efficiency, has also reduced production cost; The 2-2-hydroxy-4-methylthio butyronitrile system preparing, stable in properties, can long-term storage, is more conducive to the production of subsequent product.
(2) the 2-2-hydroxy-4-methylthio butyronitrile system obtaining just can be directly used in D without separation and purification, the preparation of L-2-2-hydroxy-4-methylthio butyramide, and the D obtaining, L-2-2-hydroxy-4-methylthio butyramide can obtain high yield and high purity through simple recrystallization, simple to operate.
(3) utilize D obtained above, L-2-2-hydroxy-4-methylthio butyramide makes HMBC again, and whole production process is simple, and production cost is low, and purification process is simple and easy.The HMBC purity obtaining is more than 99.2%, and yield is more than 99%, and have powder crystal formation, tap density is greater than 0.65, solved in actual production process, D, L-2-2-hydroxy-4-methylthio calcium butyrate yield is low, and purity is not high, and filter cake is sticky, hard-pumped filter, the problems such as after drying, finished product is loose, and density is little, and fluency is poor.Can be used as animal feedstuff additive, effectively mix with feed, supplement calcium constituent and amino acid in daily ration, improve production performance and immune performance in animal body; And, due to its high purity and high-bulk-density, also can be used as pharmaceutical reagent and use.
Accompanying drawing explanation
Fig. 1 is HMBC production equipment structural representation.
Embodiment
Hereinafter with reference to accompanying drawing, the preferred embodiments of the present invention are described in detail.The experimental technique of unreceipted actual conditions in preferred embodiment, conventionally according to normal condition.Embodiment 1-8 is the preparation of 2-2-hydroxy-4-methylthio butyronitrile; Embodiment 9～14 is the preparation of 2-2-hydroxy-4-methylthio butyramide; The preparation that embodiment 15～20 is HMBC.
To detecting from prussic acid synthetic tower prussic acid gas mixture I out, the consisting of of prussic acid gas mixture I: hydrocyanic acid gas 8.87%, water vapour 3.88%, ammonia 1.64%, hydrogen 1.13%, nitrogen 76.01%, oxygen 1.48%, carbon monoxide 5.67%, carbonic acid gas 1.13%, methane 0.39%.
Prussic acid gas mixture I after 75% sulfuric acid tower absorbs the ammonia and water vapour thereof in gas mixture, the consisting of of the prussic acid gas mixture II obtaining: hydrocyanic acid gas 9.35%, hydrogen 1.57%, nitrogen 79.44%, oxygen 1.71%, carbon monoxide 5.79%, carbonic acid gas 1.50%, methane 0.64%.
Embodiment 2
It is in 94.5% methylthiopropionaldehyde that prussic acid gas mixture II is passed into 223.3g massfraction, contains 3.3g pyridine in methylthiopropionaldehyde.Under normal pressure, react, controlling temperature of reaction is 45 ℃, and draft speed is 300L/min, and tail gas absorbs with sodium hydroxide, with the residual volume of HPLC monitoring methylthiopropionaldehyde.When methylthiopropionaldehyde residual volume is less than 0.5%, be reaction end, can stop passing into.Be total to obtain weak yellow liquid 270.64g, the content of 2-2-hydroxy-4-methylthio butyronitrile is 98%, prussic acid remnants 0.5%.
Embodiment 3
It is in 94.5% methylthiopropionaldehyde that prussic acid gas mixture II is passed into 223.3g massfraction, contains the water of 2.2g pyridine and 10g in methylthiopropionaldehyde.Under 0.15MPa, controlling temperature of reaction is 42 ℃, and draft speed is 280L/min, and tail gas absorbs with sodium hydroxide, with the residual volume of HPLC monitoring methylthiopropionaldehyde.When methylthiopropionaldehyde residual volume is less than 0.5%, be reaction end, can stop passing into.Be total to obtain weak yellow liquid 279.54g, the content of 2-2-hydroxy-4-methylthio butyronitrile is 98%, prussic acid remnants 0.07%.
Embodiment 4
It is in 94.5% methylthiopropionaldehyde that prussic acid gas mixture II is passed into 247.2g massfraction, contains the water of 2.2g pyridine and 15g in methylthiopropionaldehyde.Under 0.5MPa, controlling temperature of reaction is 45 ℃, and draft speed is 280L/min, and tail gas absorbs with sodium hydroxide, with the residual volume of HPLC monitoring methylthiopropionaldehyde.When methylthiopropionaldehyde residual volume is less than 0.5%, be reaction end, can stop passing into.Be total to obtain weak yellow liquid 294.54g, the content of 2-2-hydroxy-4-methylthio butyronitrile is 98%, prussic acid remnants 0.07%.
It is in 94.5% methylthiopropionaldehyde that prussic acid gas mixture II is passed into 227.3g massfraction, contains the water of 3.3g pyridine and 4g in methylthiopropionaldehyde.Under 0.09MPa, controlling temperature of reaction is 80 ℃, and draft speed is 350L/min, and tail gas carries out burning disposal, and incineration temperature is higher than 1000 ℃.With the residual volume of HPLC monitoring methylthiopropionaldehyde, when methylthiopropionaldehyde residual volume is less than 0.5%, be reaction end, can stop passing into.Be total to obtain weak yellow liquid 277.4g, the content of 2-2-hydroxy-4-methylthio butyronitrile is 97%, prussic acid remnants 0.06%, moisture content 2%.
Embodiment 6
It is in 94.5% methylthiopropionaldehyde that prussic acid gas mixture II is passed into 237.3g massfraction, contains 8.5g water in methylthiopropionaldehyde, in mixed system, adds a certain amount of catalyzer carbonic acid sodium, and the pH that keeps system in passing into prussic acid gas mixture process is 5.5.Under 0.5MPa, controlling temperature of reaction is 30 ℃, and draft speed is 350L/min, and tail gas carries out burning disposal, and incineration temperature is higher than 1000 ℃.With the residual volume of HPLC monitoring methylthiopropionaldehyde, when methylthiopropionaldehyde residual volume is less than 0.2%, be reaction end, can stop passing into.Be total to obtain weak yellow liquid 287.4g, the content of 2-2-hydroxy-4-methylthio butyronitrile is 96%, prussic acid remnants 0.06%, moisture content 3%.
Embodiment 7
It is in 94.5% methylthiopropionaldehyde that prussic acid gas mixture II is passed into 233.3g massfraction, contains 8.5g water in methylthiopropionaldehyde, in mixed system, adds a certain amount of catalyst of triethylamine, and the pH that keeps system in passing into prussic acid gas mixture process is 5.5.Under normal pressure, react, controlling temperature of reaction is 40 ℃, and draft speed is 350L/min, and tail gas carries out burning disposal, and incineration temperature is higher than 1000 ℃.With the residual volume of HPLC monitoring methylthiopropionaldehyde, when methylthiopropionaldehyde residual volume is less than 0.2%, be reaction end, can stop passing into.Be total to obtain weak yellow liquid 287.4g, the content of 2-2-hydroxy-4-methylthio butyronitrile is 96%, prussic acid remnants 0.06%, moisture content 3%.
Embodiment 8
It is in 94.5% methylthiopropionaldehyde that prussic acid gas mixture II is passed into 223.3g massfraction, and to the damping fluid that adds a certain amount of sodium hydroxide and citric acid to form in mixed system, in logical prussic acid gas mixture process, keeping the pH of system is 5.0.Under normal pressure, react, controlling temperature of reaction is 45 ℃, and draft speed is 350L/min, and tail gas carries out burning disposal, and incineration temperature is higher than 1000 ℃.With the residual volume of HPLC monitoring methylthiopropionaldehyde, when methylthiopropionaldehyde residual volume is less than 0.5%, be reaction end, can stop passing into.Be total to obtain weak yellow liquid 287.4g, the content of 2-2-hydroxy-4-methylthio butyronitrile is 97%, prussic acid remnants 0.06%, moisture content 2%.The 2-2-hydroxy-4-methylthio butyronitrile obtaining is divided into two parts together with reaction solution (being 2-2-hydroxy-4-methylthio butyronitrile system).Portion wherein adds 8.5g water, under 3 ℃ of conditions, preserves 120 days, has no decomposition; Another part adds 8.5g water wherein, then with 85% sulfuric acid acidation to pH be 3, under 20 ℃ of conditions, preserve 120 days, 2-2-hydroxy-4-methylthio butyronitrile rate of decomposition is 0.1%.
Embodiment 9
Under vigorous stirring, at 50 ℃, in reactor, add the sulfuric acid (1.5mol) that people 210g massfraction is 70%, in this temperature and vigorous stirring and cooling under add the synthetic 2-2-hydroxy-4-methylthio butyronitrile 270.64g of embodiment 2, control temperature of reaction at 55 ℃.When dropwising, at 55 ℃, react again 60 minutes, by the residual quantity of HPLC monitoring 2-2-hydroxy-4-methylthio butyronitrile, when 2-2-hydroxy-4-methylthio butyronitrile is transformed into 2-2-hydroxy-4-methylthio butyramide completely, be reaction end, the transformation efficiency of 2-2-hydroxy-4-methylthio butyronitrile is more than 99%.Then slowly in 2-2-hydroxy-4-methylthio butyramide vitriol reactant, add 25% ammoniacal liquor, neutralization reaction temperature is no more than 30 ℃, in and terminal pH be controlled at 6.0, after neutralization, non-shock chilling to 0 ℃ crystallization, suction filtration, obtains D, L-2-2-hydroxy-4-methylthio butyramide crude product (is D, the mixed crystal of L-2-2-hydroxy-4-methylthio butyramide and ammonium sulfate, wet product) amount to 450g, by analysis, 2-2-hydroxy-4-methylthio butyramide is containing 65.7%, and ammonium sulfate is containing 26.7%.
To D obtained above, L-2-2-hydroxy-4-methylthio butyramide crude product adds the water of 5 ℃ of 150g, under 5 ℃ of conditions, stirs, then suction filtration, obtain 2-2-hydroxy-4-methylthio butyramide work in-process 330g(wet product), 2-2-hydroxy-4-methylthio butyramide content is 87.8%, ammonium sulfate content is 3%.
2-2-hydroxy-4-methylthio butyramide work in-process 330g obtained above is added to water, be heated to 85 ℃, 2-2-hydroxy-4-methylthio butyramide just completely dissolves and is as the criterion.Be cooled to 0 ℃, crystallization, suction filtration obtains crystal and crystalline mother solution, and crystal is dried and is obtained 2-2-hydroxy-4-methylthio butyramide 289.7g, and yield is 96%, and purity is 99.5%.Crystalline mother solution is applied mechanically to next batch D, the washing of L-2-2-hydroxy-4-methylthio butyramide crude product.
Embodiment 10
Under vigorous stirring, at 50 ℃, in reactor, add the sulfuric acid (1.57mol) that people 219.8g massfraction is 70%, in this temperature and vigorous stirring and cooling under add the synthetic 2-2-hydroxy-4-methylthio butyronitrile 279.54g of embodiment 3, control temperature of reaction at 55 ℃.When dropwising, at 55 ℃, react again 60 minutes, by the residual quantity of HPLC monitoring 2-2-hydroxy-4-methylthio butyronitrile, when 2-2-hydroxy-4-methylthio butyronitrile is transformed into 2-2-hydroxy-4-methylthio butyramide completely, be reaction end, the transformation efficiency of 2-2-hydroxy-4-methylthio butyronitrile is more than 99%.Then slowly in 2-2-hydroxy-4-methylthio butyramide vitriol reactant, add 25% ammoniacal liquor, neutralization reaction temperature is no more than 30 ℃, in and terminal pH be controlled at 6.0, after neutralization, non-shock chilling to 0 ℃ crystallization, suction filtration, obtains D, L-2-2-hydroxy-4-methylthio butyramide crude product (is D, the mixed crystal of L-2-2-hydroxy-4-methylthio butyramide and ammonium sulfate, wet product) amount to 451g, by analysis, 2-2-hydroxy-4-methylthio butyramide is containing 69.2%, and ammonium sulfate is containing 25.7%.
To D obtained above, it (is the crystalline mother solution of embodiment 9 that L-2-2-hydroxy-4-methylthio butyramide crude product adds the water of 5 ℃ of 156g, the not enough clear water polishing of using), under 5 ℃ of conditions, stir, then suction filtration, obtain 2-2-hydroxy-4-methylthio butyramide work in-process 335g(wet product), 2-2-hydroxy-4-methylthio butyramide content is 91.2%, ammonium sulfate content is 3.4%.
2-2-hydroxy-4-methylthio butyramide work in-process 335g obtained above is added to water, be heated to 85 ℃, 2-2-hydroxy-4-methylthio butyramide just completely dissolves and is as the criterion.Be cooled to 0 ℃, crystallization, suction filtration obtains crystal and crystalline mother solution, and crystal is dried and is obtained 2-2-hydroxy-4-methylthio butyramide 300.7g, and yield is 96.5%, and purity is 99.5%.Crystalline mother solution is applied mechanically to next batch D, the washing of L-2-2-hydroxy-4-methylthio butyramide crude product.
Embodiment 11
Under vigorous stirring, at 45 ℃, in reactor, add the sulfuric acid (2.1mol) that people 257.2g massfraction is 80%, in this temperature and vigorous stirring and cooling under add the synthetic 2-2-hydroxy-4-methylthio butyronitrile 294.54g of embodiment 4, control temperature of reaction at 45 ℃.When dropwising, at 45 ℃, react again 90 minutes, by the residual quantity of HPLC monitoring 2-2-hydroxy-4-methylthio butyronitrile, when 2-2-hydroxy-4-methylthio butyronitrile is transformed into 2-2-hydroxy-4-methylthio butyramide completely, be reaction end, the transformation efficiency of 2-2-hydroxy-4-methylthio butyronitrile is more than 99.8%.Then slowly in 2-2-hydroxy-4-methylthio butyramide vitriol reactant, add 25% ammoniacal liquor, neutralization reaction temperature is no more than 20 ℃, in and terminal pH be controlled at 5.0, after neutralization, non-shock chilling to 0 ℃ crystallization, suction filtration, obtains D, L-2-2-hydroxy-4-methylthio butyramide crude product (is D, the mixed crystal of L-2-2-hydroxy-4-methylthio butyramide and ammonium sulfate, wet product) amount to 687.5g, by analysis, 2-2-hydroxy-4-methylthio butyramide is containing 47.66%, and ammonium sulfate is containing 39.67%.
To D obtained above, it (is the crystalline mother solution of embodiment 10 that L-2-2-hydroxy-4-methylthio butyramide crude product adds the water of 10 ℃ of 160g, the not enough clear water polishing of using), under 10 ℃ of conditions, stir, then suction filtration, obtain 2-2-hydroxy-4-methylthio butyramide work in-process 354.82g(wet product), 2-2-hydroxy-4-methylthio butyramide content is 90.50%, ammonium sulfate content is 5.56%.
2-2-hydroxy-4-methylthio butyramide work in-process 354.82g obtained above is added to water, be heated to 85 ℃, 2-2-hydroxy-4-methylthio butyramide just completely dissolves and is as the criterion.Be cooled to 0 ℃, crystallization, suction filtration obtains crystal and crystalline mother solution, and crystal is dried and is obtained 2-2-hydroxy-4-methylthio butyramide 318.44g, and yield is 96.7%, and purity is 99.5%.Crystalline mother solution is applied mechanically to next batch D, the washing of L-2-2-hydroxy-4-methylthio butyramide crude product.
Embodiment 12
Under vigorous stirring, at 50 ℃, in reactor, add the sulfuric acid (1.54mol) that people 215.7g massfraction is 70%, in this temperature and vigorous stirring and cooling under add the synthetic 2-2-hydroxy-4-methylthio butyronitrile 277.4g of embodiment 5, control temperature of reaction at 50 ℃.When dropwising, at 50 ℃, react again 60 minutes, by the residual quantity of HPLC monitoring 2-2-hydroxy-4-methylthio butyronitrile, when 2-2-hydroxy-4-methylthio butyronitrile is transformed into 2-2-hydroxy-4-methylthio butyramide completely, be reaction end, the transformation efficiency of 2-2-hydroxy-4-methylthio butyronitrile is more than 99.8%.Then slowly in 2-2-hydroxy-4-methylthio butyramide vitriol reactant, add 25% ammoniacal liquor, neutralization reaction temperature is no more than 20 ℃, in and terminal pH be controlled at 6.5, after neutralization, non-shock chilling to 0 ℃ crystallization, suction filtration, obtains D, L-2-2-hydroxy-4-methylthio butyramide crude product (is D, the mixed crystal of L-2-2-hydroxy-4-methylthio butyramide and ammonium sulfate, wet product) amount to 460g, by analysis, 2-2-hydroxy-4-methylthio butyramide is containing 65.2%, and ammonium sulfate is containing 26.0%.
To D obtained above, it (is the crystalline mother solution of embodiment 11 that L-2-2-hydroxy-4-methylthio butyramide crude product adds the water of 5 ℃ of 160g, the not enough clear water polishing of using), under 5 ℃ of conditions, stir, then suction filtration, obtain 2-2-hydroxy-4-methylthio butyramide work in-process 350g(wet product), 2-2-hydroxy-4-methylthio butyramide content is 84%, ammonium sulfate content is 7.4%
2-2-hydroxy-4-methylthio butyramide work in-process 335g obtained above is added to water, be heated to 85 ℃, 2-2-hydroxy-4-methylthio butyramide just completely dissolves and is as the criterion.Be cooled to 0 ℃, crystallization, suction filtration obtains crystal and crystalline mother solution, and crystal is dried and is obtained 2-2-hydroxy-4-methylthio butyramide 313g, and yield is 95.3%, and purity is 99.5%.Crystalline mother solution is applied mechanically to next batch D, the washing of L-2-2-hydroxy-4-methylthio butyramide crude product.
Embodiment 13
Under vigorous stirring, at 65 ℃, in reactor, add the sulfuric acid (1.2mol) that people 180.9g massfraction is 65%, in this temperature and vigorous stirring and cooling under add the synthetic 2-2-hydroxy-4-methylthio butyronitrile 287.4g of embodiment 6, control temperature of reaction at 65 ℃.When dropwising, at 65 ℃, react again 60 minutes, by the residual quantity of HPLC monitoring 2-2-hydroxy-4-methylthio butyronitrile, when 2-2-hydroxy-4-methylthio butyronitrile is transformed into 2-2-hydroxy-4-methylthio butyramide completely, be reaction end, the transformation efficiency of 2-2-hydroxy-4-methylthio butyronitrile is more than 99%.Then slowly in 2-2-hydroxy-4-methylthio butyramide vitriol reactant, add 25% ammoniacal liquor, neutralization reaction temperature is no more than 30 ℃, in and terminal pH be controlled at 6.5, after neutralization, non-shock chilling to 0 ℃ crystallization, suction filtration, obtains D, L-2-2-hydroxy-4-methylthio butyramide crude product (is D, the mixed crystal of L-2-2-hydroxy-4-methylthio butyramide and ammonium sulfate, wet product) amount to 488.28g, by analysis, 2-2-hydroxy-4-methylthio butyramide is containing 63.63%, and ammonium sulfate is containing 32.44%.
To D obtained above, it (is the crystalline mother solution of embodiment 12 that L-2-2-hydroxy-4-methylthio butyramide crude product adds the water of 5 ℃ of 160g, the not enough clear water polishing of using), under 5 ℃ of conditions, stir, then suction filtration, obtain 2-2-hydroxy-4-methylthio butyramide work in-process 346.95g(wet product), 2-2-hydroxy-4-methylthio butyramide content is 89.55%, ammonium sulfate content is 5.72%.
2-2-hydroxy-4-methylthio butyramide work in-process 346.95g obtained above is added to water, be heated to 85 ℃, 2-2-hydroxy-4-methylthio butyramide just completely dissolves and is as the criterion.Be cooled to 0 ℃, crystallization, suction filtration obtains crystal and crystalline mother solution, and crystal is dried and is obtained 2-2-hydroxy-4-methylthio butyramide 304.90g, and yield is 97.65%, and purity is 99.5%.Crystalline mother solution is applied mechanically to next batch D, the washing of L-2-2-hydroxy-4-methylthio butyramide crude product.
Embodiment 14
Under vigorous stirring, at 70 ℃, in reactor, add the sulfuric acid (1.8mol) that people 235.2g massfraction is 75%, in this temperature and vigorous stirring and cooling under add the synthetic 2-2-hydroxy-4-methylthio butyronitrile 287.4g of embodiment 7, control temperature of reaction at 70 ℃.When dropwising, at 70 ℃, react again 30 minutes, by the residual quantity of HPLC monitoring 2-2-hydroxy-4-methylthio butyronitrile, when 2-2-hydroxy-4-methylthio butyronitrile is transformed into 2-2-hydroxy-4-methylthio butyramide completely, be reaction end, the transformation efficiency of 2-2-hydroxy-4-methylthio butyronitrile is more than 99%.Then slowly in 2-2-hydroxy-4-methylthio butyramide vitriol reactant, add 25% ammoniacal liquor, neutralization reaction temperature is no more than 20 ℃, in and terminal pH be controlled at 6.0, after neutralization, non-shock chilling to 0 ℃ crystallization, suction filtration, obtains D, L-2-2-hydroxy-4-methylthio butyramide crude product (is D, the mixed crystal of L-2-2-hydroxy-4-methylthio butyramide and ammonium sulfate, wet product) amount to 624.18g, by analysis, 2-2-hydroxy-4-methylthio butyramide is containing 49.77%, and ammonium sulfate is containing 38.06%.
To D obtained above, it (is the crystalline mother solution of embodiment 13 that L-2-2-hydroxy-4-methylthio butyramide crude product adds the water of 8 ℃ of 160g, the not enough clear water polishing of using), under 8 ℃ of conditions, stir, then suction filtration, obtain 2-2-hydroxy-4-methylthio butyramide work in-process 346.95g(wet product), 2-2-hydroxy-4-methylthio butyramide content is 89.55%, ammonium sulfate content is 5.72%.
2-2-hydroxy-4-methylthio butyramide work in-process 346.95g obtained above is added to water, be heated to 85 ℃, 2-2-hydroxy-4-methylthio butyramide just completely dissolves and is as the criterion.Be cooled to 0 ℃, crystallization, suction filtration obtains crystal and crystalline mother solution, and crystal is dried and is obtained 2-2-hydroxy-4-methylthio butyramide 304.90g, and yield is 97.65%, and purity is 99.5%.Crystalline mother solution is applied mechanically to next batch D, the washing of L-2-2-hydroxy-4-methylthio butyramide crude product.
Embodiment 15
The 2-2-hydroxy-4-methylthio butyramide 289.7g(1.93mol that adds embodiment 9 gained in reactor), add water 1200ml, under stirring, add in batches calcium hydroxide 115.1g(1.54mol).Neutralization reaction is reacted in 100 ℃, until sampling high performance liquid chromatography detects the residual volume of 2-2-hydroxy-4-methylthio butyramide lower than 0.1%.After completion of the reaction, be cooled to 60 ℃, the calcium hydroxide of filtration residue, the filtrate obtaining adds the Natvosol of 2-2-hydroxy-4-methylthio butyramide quality 100ppm, be cooled to again 0 ℃ of crystallisation by cooling, suction filtration obtains crystal and crystalline mother solution, and 100 ℃, crystal vacuum is dry, obtains D, the Powdered crystal 327.4g of L-2-2-hydroxy-4-methylthio calcium butyrate, purity is that 99.7%(HPLC measures), yield is 99.7%, tap density (g/ml) is 0.72.Crystalline mother solution can be applied mechanically to next batch and react.
Embodiment 16
The 2-2-hydroxy-4-methylthio butyramide 300.7g(2.0mol that adds embodiment 10 gained in reactor), add embodiment 15 crystalline mother solution 1200ml, under stirring, add in batches calcium hydroxide 112.1g(1.5mol).Neutralization reaction is reacted in 100 ℃, until sampling high performance liquid chromatography detects the residual volume of 2-2-hydroxy-4-methylthio butyramide lower than 0.1%.After completion of the reaction, be cooled to 60 ℃, the calcium hydroxide of filtration residue, the filtrate obtaining adds the Natvosol of 2-2-hydroxy-4-methylthio butyramide quality 300ppm, be cooled to again 0 ℃ of crystallisation by cooling, suction filtration obtains crystal and crystalline mother solution, and 100 ℃, crystal vacuum is dry, obtains D, the Powdered crystal 337.9g of L-2-2-hydroxy-4-methylthio calcium butyrate, purity is that 99.7%(HPLC measures), yield is 99.5%, tap density (g/ml) is 0.70.Crystalline mother solution can be applied mechanically to next batch and react.
Embodiment 17
The 2-2-hydroxy-4-methylthio butyramide 313g(2.09mol that adds embodiment 12 gained in reactor), add embodiment 16 crystalline mother solution 1200ml, under stirring, add in batches calcium hydroxide 117.2g(1.57mol).Neutralization reaction is reacted in 100 ℃, until sampling high performance liquid chromatography detects the residual volume of 2-2-hydroxy-4-methylthio butyramide lower than 0.1%.After completion of the reaction, be cooled to 60 ℃, the calcium hydroxide of filtration residue, the filtrate obtaining adds the Walocel MT 20.000PV of 2-2-hydroxy-4-methylthio butyramide quality 100ppm, be cooled to again 0 ℃ of crystallisation by cooling, suction filtration obtains crystal and crystalline mother solution, and 100 ℃, crystal vacuum is dry, obtains D, the Powdered crystal 353.1g of L-2-2-hydroxy-4-methylthio calcium butyrate, purity is that 99.7%(HPLC measures), yield is 99.5%, tap density (g/ml) is 0.69.Crystalline mother solution can be applied mechanically to next batch and react.
Embodiment 18
The 2-2-hydroxy-4-methylthio butyramide 285.2g(1.90mol that adds embodiment 11 gained in reactor), add embodiment 17 crystalline mother solution 1200ml, under stirring, add in batches calcium hydroxide 99.7g(1.33mol).Neutralization reaction is reacted in 100 ℃, until sampling high performance liquid chromatography detects the residual volume of 2-2-hydroxy-4-methylthio butyramide lower than 0.1%.After completion of the reaction, be cooled to 60 ℃, the calcium hydroxide of filtration residue, the filtrate obtaining adds the Natvosol of 2-2-hydroxy-4-methylthio butyramide quality 50ppm, be cooled to again 0 ℃ of crystallisation by cooling, suction filtration obtains crystal and crystalline mother solution, and 100 ℃, crystal vacuum is dry, obtains D, the Powdered crystal 322.3g of L-2-2-hydroxy-4-methylthio calcium butyrate, purity is that 99.7%(HPLC measures), yield is 99.9%, tap density (g/ml) is 0.71.Crystalline mother solution can be applied mechanically to next batch and react.
Embodiment 19
The 2-2-hydroxy-4-methylthio butyramide 304.90g(2.04mol that adds embodiment 13 gained in reactor), add embodiment 18 crystalline mother solution 1400ml, under stirring, add in batches calcium oxide 61.6g(1.1mol).Neutralization reaction is reacted in 120 ℃, until sampling high performance liquid chromatography detects the residual volume of 2-2-hydroxy-4-methylthio butyramide lower than 0.1%.After completion of the reaction, be cooled to 60 ℃, the calcium hydroxide of filtration residue, the filtrate obtaining adds the citric acid of 2-2-hydroxy-4-methylthio butyramide quality 500ppm, be cooled to again 5 ℃ of crystallisation by cooling, suction filtration obtains crystal and crystalline mother solution, and 100 ℃, crystal vacuum is dry, obtains D, the Powdered crystal 347.14g of L-2-2-hydroxy-4-methylthio calcium butyrate, purity is that 99.7%(HPLC measures), yield is 99.9%, tap density (g/ml) is 0.72.Crystalline mother solution can be applied mechanically to next batch and react.
Embodiment 20
The 2-2-hydroxy-4-methylthio butyramide 304.90g(2.04mol that adds embodiment 14 gained in reactor), add embodiment 19 crystalline mother solution 1600ml, under stirring, add in batches calcium oxide 84g(1.5mol).Neutralization reaction is reacted in 110 ℃, until sampling high performance liquid chromatography detects the residual volume of 2-2-hydroxy-4-methylthio butyramide lower than 0.1%.After completion of the reaction, be cooled to 60 ℃, the calcium hydroxide of filtration residue, the filtrate obtaining adds the lactic acid of 2-2-hydroxy-4-methylthio butyramide quality 2500ppm, be cooled to again 5 ℃ of crystallisation by cooling, suction filtration obtains crystal and crystalline mother solution, and 100 ℃, crystal vacuum is dry, obtains D, the Powdered crystal 347.14g of L-2-2-hydroxy-4-methylthio calcium butyrate, purity is that 99.7%(HPLC measures), yield is 99.9%, tap density (g/ml) is 0.72.Crystalline mother solution can be applied mechanically to next batch and react.
Embodiment 21 utilizes HMBC production equipment to prepare HMBC
As shown in Figure 1, HMBC production equipment comprises prussic acid synthetic tower 1, acid tower 2, reactor 3, tripping device 4-suction filtration machine and crystallization kettle 5, fills massfraction and be 75%～90% sulfuric acid in described acid tower 2; Described reactor 3 is provided with pressure and temperature regulates supplementary unit, and the air outlet of prussic acid synthetic tower 1 is communicated with the inlet mouth of acid tower 2 by pipeline, and the air outlet of acid tower 2 is communicated with reactor 3 by being provided with the pipeline of throttling valve.
According to the synthetic prussic acid requirement of iS-One method, to prussic acid synthetic tower 1, send into raw material, react to obtain prussic acid gas mixture I, prussic acid gas mixture I passes into acid tower 2 and sloughs ammonia and water vapour, obtains prussic acid gas mixture II.Prussic acid gas mixture II is under throttle valve control, and the speed of 350L/min of take passes in the methylthiopropionaldehyde that in reactor 3,223.3kg massfraction is 94.5%, contains 3.3kg pyridine and 4kg water in methylthiopropionaldehyde.Under 0.09MPa, controlling temperature of reaction is 80 ℃, and tail gas absorbs with sodium hydroxide, with the residual volume of HPLC monitoring methylthiopropionaldehyde.When methylthiopropionaldehyde residual volume is less than 0.2%, be reaction end, can stop passing into.Be total to obtain weak yellow liquid 287.4kg, the content of 2-2-hydroxy-4-methylthio butyronitrile is 97%, prussic acid remnants 0.06%, moisture content 2%.
Under vigorous stirring, in 50 ℃, in reactor 3, add the sulfuric acid that people 223.45kg massfraction is 70%, add simultaneously, carry out coolingly, temperature is controlled at 50 ℃.Add complete, in 50 ℃, react again 60 minutes, by the residual quantity of HPLC monitoring 2-2-hydroxy-4-methylthio butyronitrile, when 2-2-hydroxy-4-methylthio butyronitrile is transformed into 2-2-hydroxy-4-methylthio butyramide completely, be reaction end, the transformation efficiency of 2-2-hydroxy-4-methylthio butyronitrile is up to more than 99.8%.Then slowly in 2-2-hydroxy-4-methylthio butyramide vitriol reactant, add 25% ammoniacal liquor, neutralization reaction temperature is no more than 20 ℃, in and terminal pH be controlled at 6.5, after neutralization, non-shock chilling to 0 ℃ crystallization, suction filtration, obtain D, L-2-2-hydroxy-4-methylthio butyramide crude product (being D, the mixed crystal of L-2-2-hydroxy-4-methylthio butyramide and ammonium sulfate, filter cake) amounts to 480.8kg, by analysis, D, L-2-2-hydroxy-4-methylthio butyramide is containing 63.90%, and ammonium sulfate is containing 30.12%.To the water of 5 ℃ that adds 201kg in the filter cake of suction filtration machine, stirring and dissolving ammonium sulfate, then suction filtration under 5 ℃ of conditions, obtain D, L-2-2-hydroxy-4-methylthio butyramide work in-process 335.77kg(wet product), D, L-2-2-hydroxy-4-methylthio butyramide content is 91.5%, and ammonium sulfate content is 3.45%.
D obtained above, L-2-2-hydroxy-4-methylthio butyramide work in-process proceed in crystallization kettle 5, are dissolved in water, and are heated to 85 ℃, and amount of water is with D, and L-2-2-hydroxy-4-methylthio butyramide just completely dissolves and is as the criterion.Be cooled to 0 ℃, crystallization, suction filtration, obtains crystallization and crystalline mother solution.Crystallization is transferred to drying plant and dries, and obtains D, L-2-2-hydroxy-4-methylthio butyramide 304.65kg, and yield is 95.6%, purity is 99.5%.Crystalline mother solution is applied mechanically to next batch D, the washing of L-2-2-hydroxy-4-methylthio butyramide crude product.
Highly purified D obtained above, L-2-2-hydroxy-4-methylthio butyramide proceeds to crystallization kettle 5 again, uses 1300kg water dissolution, adds in batches calcium hydroxide 84.5kg under stirring.Carry out neutralization reaction in 100 ℃, until sampling high performance liquid chromatography detects the residual volume of 2-2-hydroxy-4-methylthio butyramide lower than 0.1%.After completion of the reaction, be cooled to 60 ℃, suction filtration is removed residual calcium hydroxide, the filtrate obtaining is returned in crystallization kettle 5, add the Natvosol of 2-2-hydroxy-4-methylthio butyramide quality 100ppm, then be cooled to 0 ℃ of crystallisation by cooling, suction filtration obtains crystal and crystalline mother solution; Crystal is transferred to drying plant, and 100 ℃, vacuum is dry, obtains the Powdered crystal 341.4g of HMBC, and purity is that 99.7%(HPLC measures), yield is 99%, tap density (g/ml) is 0.72.Crystalline mother solution can be applied mechanically to next batch and react.
Finally explanation is, above embodiment is only unrestricted in order to technical scheme of the present invention to be described, although the present invention is had been described in detail with reference to preferred embodiment, those of ordinary skill in the art is to be understood that, can modify or be equal to replacement technical scheme of the present invention, and not departing from aim and the scope of technical solution of the present invention, it all should be encompassed in the middle of claim scope of the present invention.
Claims (10)
1.D, the preparation method of L-2-2-hydroxy-4-methylthio calcium butyrate, is characterized in that: comprise the following steps:
A, take methane, ammonia and oxygen as raw material, adopt iS-One method composition principle, be prepared into prussic acid gas mixture I; Described prussic acid gas mixture I is processed to obtain prussic acid gas mixture II through deamination;
B, described prussic acid gas mixture II and methylthiopropionaldehyde, under the katalysis of alkali, fully react to obtain 2-2-hydroxy-4-methylthio butyronitrile system;
C, described 2-2-hydroxy-4-methylthio butyronitrile system are carried out hydration reaction under the existence of mineral acid, after reaction finishes, with ammonia or ammoniacal liquor, regulate reaction solution pH to 5.0～6.5, crystallisation by cooling, solid-liquid separation obtains D, the crystalline mixture of L-2-2-hydroxy-4-methylthio butyramide and inorganic acid ammonium salt, recrystallization obtains highly purified D, L-2-2-hydroxy-4-methylthio butyramide;
D, by described highly purified D, L-2-2-hydroxy-4-methylthio butyramide is dissolved in water medium, then adds excessive calcium oxide or calcium hydroxide, at 100～120 ℃ of temperature, fully, after hydrolysis, removes by filter residual calcium oxide or calcium hydroxide, obtains filtrate; In described filtrate, add crystallizing agent, crystallisation by cooling, separation, crystal is dried to obtain HMBC.
2. the preparation method of HMBC according to claim 1, is characterized in that: it is that prussic acid gas mixture I is passed into massfraction is that 75%～90% sulfuric acid carries out deamination processing that the deamination described in steps A is processed.
3. D according to claim 1, the preparation method of L-2-2-hydroxy-4-methylthio calcium butyrate, it is characterized in that: the methylthiopropionaldehyde described in step B is not purified methylthiopropionaldehyde, wherein contain the heavy constituent of the methylthiopropionaldehyde of massfraction 94.5%～96%, the light constituent of massfraction 3.5%～5.3% and massfraction 0.2%～0.5%; Described light constituent is thiomethyl alcohol, methyl alcohol, propenal and water; Described restructuring is divided into dipolymer and the trimer of methylthiopropionaldehyde.
4. the preparation method of HMBC according to claim 1, is characterized in that: the alkali described in step B is organic bases and/or mineral alkali; The consumption of described alkali is that the pH that maintains reaction system is 4.0～6.5.
5. D according to claim 1, the preparation method of L-2-2-hydroxy-4-methylthio calcium butyrate, is characterized in that: in described step B, the mol ratio of prussic acid and methylthiopropionaldehyde is 1:1.0～1.05, reaction pressure is 0.09～0.5MPa, and temperature of reaction is 30～80 ℃.
6. the preparation method of HMBC according to claim 1, is characterized in that: in described step C, described mineral acid is sulfuric acid, and the mol ratio of 2-2-hydroxy-4-methylthio butyronitrile and sulfuric acid is 1:0.5～1; The massfraction of described sulfuric acid is 50%～80%, and temperature of reaction is controlled at 40～70 ℃.
7. the preparation method of HMBC according to claim 1, is characterized in that: in described step D, the consumption of water medium is D, 5～8 times of L-2-2-hydroxy-4-methylthio butyramide quality; D, the mol ratio of L-2-2-hydroxy-4-methylthio butyramide and calcium oxide or calcium hydroxide is 1:0.55～0.80.
8. the preparation method of HMBC according to claim 1, is characterized in that: the crystallizing agent described in step D is one or more in citric acid, lactic acid, Walocel MT 20.000PV, Natvosol and Aluctyl.
9. the preparation method of HMBC according to claim 1, is characterized in that: in described step D, the consumption of crystallizing agent is D 50～3000ppm of L-2-2-hydroxy-4-methylthio butyramide quality.
10. utilize D, L-2-2-hydroxy-4-methylthio calcium butyrate production equipment is prepared D, the method of L-2-2-hydroxy-4-methylthio calcium butyrate, it is characterized in that: described production equipment comprises prussic acid synthetic tower (1), acid tower (2), reactor (3), tripping device (4) and crystallization kettle (5), in described acid tower (2), fill massfraction and be 75%～90% sulfuric acid, described reactor (3) is provided with pressure and temperature regulates supplementary unit, the air outlet of prussic acid synthetic tower (1) is communicated with the inlet mouth of acid tower (2) by pipeline, the air outlet of acid tower (2) is communicated with reactor (3) by being provided with the pipeline of throttling valve,
A, take methane, ammonia and oxygen as raw material, adopt iS-One method composition principle, by prussic acid synthetic tower (1), prepare prussic acid gas mixture I; Described prussic acid gas mixture I passes into acid tower (2) and sloughs ammonia and water vapour, obtains prussic acid gas mixture II;
B, described prussic acid gas mixture II, under throttle valve control, pass in the methylthiopropionaldehyde in reactor (3) with the speed of 250～350L/min, under the katalysis of alkali, fully react to obtain 2-2-hydroxy-4-methylthio butyronitrile system;
Under C, vigorous stirring, in reactor (3), add mineral acid to mix with 2-2-hydroxy-4-methylthio butyronitrile system, carry out hydration reaction, after reaction finishes, with ammonia or ammoniacal liquor, regulate reaction solution pH to 5.0～6.5, crystallisation by cooling, through the separated D that obtains of tripping device (4), the crystalline mixture of L-2-2-hydroxy-4-methylthio butyramide and inorganic acid ammonium salt, with the water washing crystalline mixture of 5～10 ℃, obtain D, L-2-2-hydroxy-4-methylthio butyramide work in-process; Described D, L-2-2-hydroxy-4-methylthio butyramide work in-process proceed to recrystallization in crystallization kettle (5), through separated crystal and the crystalline mother solution I of obtaining of tripping device (4); Wash crystallization mixture when described crystalline mother solution I is circulated to next step C production; Described crystal is highly purified D, L-2-2-hydroxy-4-methylthio butyramide;
D, by described highly purified D, L-2-2-hydroxy-4-methylthio butyramide proceeds to crystallization kettle (5) again, water medium dissolves, add again excessive calcium oxide or calcium hydroxide, at 100～120 ℃ of temperature, fully, after hydrolysis, through tripping device (4) separation, remove residual calcium oxide or calcium hydroxide, obtain filtrate; Described filtrate proceeds to again crystallization kettle (5), adds crystallizing agent, and crystallisation by cooling, through separated crystal and the crystalline mother solution II of obtaining of tripping device (4); Described crystalline mother solution II is as water medium, D when being circulated to next step D and producing, the dissolving of L-2-2-hydroxy-4-methylthio butyramide; Described crystal proceeds to drying plant and dries, and obtains HMBC.
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| CN114223789A (en) * | 2021-12-22 | 2022-03-25 | 天宝动物营养科技股份有限公司 | Raw material composition and method for preparing methionine hydroxy analogue without separating by-product salt by using same |
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| CN103347854A (en) * | 2011-02-23 | 2013-10-09 | 赢创德固赛有限公司 | Method for producing 2-hydroxy-4-(methylthio)butanenitrile from 3-(methylthio)propanal and hydrogen cyanide |
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| CN114223789B (en) * | 2021-12-22 | 2024-03-12 | 天宝动物营养科技股份有限公司 | Raw material composition and method for preparing methionine hydroxy analogue without separating byproduct salt by using same |
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Effective date of registration: 20160729 Address after: 755000 the Ningxia Hui Autonomous Region central defender, Shapotou District, Guangzhou Road West Patentee after: NINGXIA ZIGUANG TIANHUA METHIONINE CO., LTD. Address before: 402161 Yongchuan District, Chongqing Chemical Road, No. 426 Patentee before: Chongqing Unisplendour Chemical Co., Ltd. |