CN109824531B - Method for continuously and rapidly preparing DL-phenylglycine and analogues thereof - Google Patents
Method for continuously and rapidly preparing DL-phenylglycine and analogues thereof Download PDFInfo
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Abstract
The invention provides a method for continuously and rapidly preparing DL-phenylglycine and analogues thereof, which comprises the following steps: adding 2-hydroxy-benzyl cyanide and analogs thereof (cyanohydrin for short) and an ammonium bicarbonate aqueous solution into a microchannel reactor for reaction, controlling the reaction temperature to be 80-130 ℃, the pressure to be 0.5-2.0 MPa, and the residence time of reactants in the microchannel to be 1-8 min to obtain 5-phenyl-hydantoin and analogs thereof (hydantoin for short) aqueous solution; adding hydantoin and alkali into a microchannel reactor for reaction, controlling the reaction temperature to be 120-200 ℃, the pressure to be 1.0-3.5 MPa, and the residence time of reactants in the microchannel to be 1-8 min to obtain a phenylglycine and analog salt water solution, and acidifying, neutralizing and crystallizing to obtain the phenylglycine and analog thereof. The method adopts the microchannel reactor, greatly shortens the reaction time, accelerates the reaction rate, reduces the thermal depolymerization of the cyanohydrin, has no byproduct, high product yield, cleanness, environmental protection and reduces the production cost.
Description
Technical Field
The invention relates to the field of chemical industry, in particular to a method for continuously and rapidly preparing DL-phenylglycine and analogues thereof.
Background
DL-phenylglycine and its derivatives are important intermediates for pharmaceutical synthesis, and are mainly used for preparing beta-lactam antibiotics, polypeptide hormones and pesticides. The foreign 60 s begin to produce DL-phenylglycine in batches, and the industrial production of DL-phenylglycine is realized in the early 80 s in China and mainly adopts a sodium cyanide method. The method takes benzaldehyde as a main raw material, and the benzaldehyde reacts with sodium cyanide, solid ammonium salt and the like under the action of a phase transfer catalyst to synthesize the DL-phenylglycine.
Another synthetic method of DL-phenylglycine and derivatives thereof is to adopt a phase transfer catalyst, take benzaldehyde as a main raw material, react with chloroform, sodium hydroxide and ammonium bicarbonate, and synthesize DL-phenylglycine in one step. The production process has a low yield of only 46%, and produces a large amount of salt-containing wastewater and low-value inorganic salts.
Most of the DL-p-hydroxyphenylglycine synthesis processes are prepared by reacting phenol, glyoxylic acid, water and 4-nitrophthalimide in a one-pot method under the action of a phase transfer catalyst quaternary ammonium salt, the synthesis process is complex, and the yield of DL-p-hydroxyphenylglycine is low. And splitting the DL-p-hydroxyphenylglycine to obtain the D-p-hydroxyphenylglycine. D-p-hydroxyphenylglycine is mainly used as a side chain compound of semi-synthetic penicillins and semi-synthetic cephalosporins. The main medicines produced by using the compound are penicillin (amoxicillin), penicillin clavulanate, light ammonia knot, dougutone, head loop and the like, the medicines have wide application, have killing effect on gram-positive bacteria, gram-negative bacteria, toxoplasma, spirochete and the like, and are also applied to the photosensitive field and used as analytical reagents of iron, phosphorus, silicon and the like. The mass production of D-p-hydroxyphenylglycine is carried out in the foreign 70 s, and the D-p-hydroxyphenylglycine is used for producing amoxicillin. In recent years, the annual demand of developed countries such as europe and the united states is over ten thousand tons. The suppliers of D-p-hydroxyphenylglycine, a large-scale side-chain compound, are from DSM in the Netherlands, Derivados in Spain, etc., and Singapore also has a kiloton-scale production apparatus.
The currently mainstream production process of DL-phenylglycine and derivatives thereof is a one-pot Strecker reaction taking benzaldehyde and analogs thereof, sodium cyanide (or potassium cyanide) and ammonium chloride as raw materials, namely a mixed reaction of the formaldehyde and the analogs thereof, the sodium cyanide (or potassium cyanide) and the ammonium chloride to obtain 2-amino-phenylacetonitrile analogs (cyanamide for short), and then acidolysis or alkaline hydrolysis is carried out to obtain the DL-phenylglycine and derivatives thereof. However, the current one-pot method of preparing aniline cyanide analogs using sodium cyanide, ammonium chloride and benzaldehyde and its derivatives is not only low in yield, but also produces a large amount of cyanide-containing wastewater that is difficult to handle. In addition, there are two other hydantoin process technologies.
One is "two-component" cyanhydrin method, that is, using hydrocyanic acid and benzaldehyde and its analogues as raw materials to synthesize 2-hydroxy-benzyl cyanide or 2-hydroxy-benzyl cyanide analogues (cyanhydrin for short), then using cyanhydrin to synthesize hydantoin aqueous solution, then using hydantoin to make alkaline hydrolysis and acidification so as to obtain the invented product. For example, patent CN106380415A discloses a method for preparing D, L-phenylglycine and its analogues, which comprises using benzaldehyde and its analogues, hydrocyanic acid as raw materials, subjecting to cyanidation to generate 2-hydroxy-phenylacetonitrile or 2-hydroxy-phenylacetonitrile analogue (cyanohydrin for short), reacting cyanohydrin with carbon dioxide and ammonia water solution to generate 5-phenyl-hydantoin and its analogues (hydantoin for short); the hydantoin is subjected to steam stripping, alkaline hydrolysis, steam stripping, decoloration, neutralization, crystallization, water washing, centrifugation, drying and other steps to prepare the D, L-phenylglycine and the analogues thereof. Although the use of cyanohydrin in this patent greatly improves the yield of phenylglycine and its analogues, the final process inevitably produces a large amount of sodium chloride or sodium sulfate and a large amount of saline wastewater which is difficult to treat, and is a non-clean and environment-friendly production process.
The other one is the three-component hydantoin method which takes benzaldehyde and its analogues, sodium cyanide and ammonium bicarbonate aqueous solution as raw materials, namely the hydantoin aqueous solution containing sodium carbonate is prepared by taking benzaldehyde and its analogues, sodium cyanide and ammonium bicarbonate aqueous solution as raw materials, and the hydantoin aqueous solution is subjected to alkaline hydrolysis and acidification to obtain the product. For example, patent CN106083628B discloses a method for preparing p-chlorophenyl glycine, which comprises completely reacting p-chlorobenzaldehyde, ammonium bicarbonate and sodium cyanide in a microchannel reactor, and then preparing p-chlorophenyl glycine in a tubular reactor. The method is characterized in that raw materials are subjected to cyclization in a microchannel reactor through a flowmeter to prepare an intermediate p-chlorobenzenehydantoin, the intermediate is subjected to alkaline hydrolysis in a tubular reactor through the flowmeter to prepare p-chlorobenzeneglycine sodium, the reaction can be completed in 8-18 minutes in total, and finally the reaction is conducted in a reaction bottle for acidification and crystallization. The product purity is over 98.0 percent, and the yield is over 95 percent. A patent for a similar process is also described in CN 103086905B. Although sodium cyanide is used as a cyanide source in the method, the method inevitably generates a large amount of sodium chloride or sodium sulfate and a large amount of saline wastewater which is difficult to treat, and is a production process which is not clean and environment-friendly.
In summary, the existing preparation methods of DL-phenylglycine and derivatives thereof, whether the one-pot method is a Strecker reaction or a cyanohydrin hydantoin method or a three-component hydantoin method, have the problems of complex preparation method, long production period, long reaction time, more side reactions, low product yield, poor quality, deep color, more byproduct inorganic salts, greenlessness and environmental protection, discharge of a large amount of salt-containing wastewater, poor product quality and the like.
Disclosure of Invention
In view of the disadvantages of the prior art, the present invention aims to provide a method for continuously and rapidly preparing DL-phenylglycine and analogues thereof, which is used for solving the problems that the reaction time is long, the reaction rate is slow, raw material cyanide is easy to thermally polymerize and produce byproducts, colored impurities are easy to generate, a large amount of cyanide-containing wastewater or a large amount of low-value inorganic salts as byproducts, and a large amount of salt-containing wastewater which is difficult to treat are easily generated in the prior art for preparing DL-phenylglycine and analogues thereof.
To achieve the above and other related objects, there is provided in a first aspect of the present invention a method for continuously and rapidly preparing DL-phenylglycine and the like, comprising: adding 2-hydroxy-benzyl cyanide and analogues (cyanohydrin for short) thereof and an ammonium bicarbonate aqueous solution into a microchannel reactor for reaction, controlling the reaction temperature to be 80-130 ℃, the pressure to be 0.5-2.0 MPa, and keeping reactants in the microchannel for 1-8 min to obtain 5-phenyl-hydantoin and analogues (hydantoin for short) aqueous solution; adding hydantoin and alkali into a microchannel reactor for reaction, controlling the reaction temperature to be 120-200 ℃, the pressure to be 1.0-3.5 MPa, and the residence time of reactants in the microchannel to be 1-8 min to obtain a phenylglycine and analog salt water solution, and acidifying, neutralizing and crystallizing to obtain the phenylglycine and analog thereof.
The chemical structural general formulas of the 2-hydroxy-phenylacetonitrile and the analogues thereof, the 5-phenyl-hydantoin and the analogues thereof, and the DL-phenylglycine and the analogues thereof are shown as follows:
in the formula, R group is ortho-position, meta-position or para-position on a benzene ring, and R group is one or more of hydrogen atom, chlorine atom and fluorine atom; the mass percentage of the hydroxyl-benzyl cyanide and the analogues thereof is 70-99 wt%, the mass percentage of the 5-phenyl-hydantoin and the analogues thereof in the aqueous solution is 10-50 wt%, and the mass percentage of the phenylglycine and the analogues thereof in the aqueous solution is 10-40 wt%.
In some embodiments of the invention, the feeding molar ratio of the 2-hydroxy-phenylacetonitrile and the analogues thereof (referred to as cyanohydrin) to the ammonium bicarbonate aqueous solution is that cyanohydrin/ammonia/carbon dioxide =1: 1.5-2.0: 1.0-1.5, the reaction temperature is controlled to be 100-130 ℃, the pressure is controlled to be 0.5-1.5 MPa, the residence time of reactants in the microchannel is 2-5 min, the ammonium bicarbonate aqueous solution contains 5-10 wt% of ammonia and 8-19.5 wt% of carbon dioxide.
In some embodiments of the present invention, the alkali is at least one selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate, and particularly preferably potassium carbonate aqueous solution, and the mass percentage content is 30wt% to 55 wt%.
In some embodiments of the present invention, the molar ratio of the 5-phenyl-hydantoin and its analog (hydantoin for short) to the potassium carbonate is: hydantoin/potassium ions =1: 1.2-2.5, the reaction temperature is controlled to be 160-180 ℃, the pressure is 1.5-2.5 MPa, and the residence time of reactants in the microchannel is 2-8 min.
In some embodiments of the present invention, the acidifying agent is at least one selected from sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, carbonic acid, carbon dioxide, etc., and particularly preferably carbon dioxide, and the acidifying temperature is 10 to 30 ℃, the pressure is 0.1 to 0.6MPa, and the pH at the acidifying end is 7.0 to 8.5.
In some embodiments of the present invention, the content of ammonia in the aqueous solution of potassium salt of phenylglycine and its analogs is less than 50ppm, and the content of potassium ion is 6.0wt% to 11.5 wt%.
In some embodiments of the present invention, the acidified crystallization mother liquor is a potassium bicarbonate aqueous solution containing phenylglycine and its analogs, the mass percentage of phenylglycine and its analogs is 2wt% to 10wt%, the mass percentage of potassium bicarbonate is 10wt% to 25wt%, the mother liquor is heated, decarburized and concentrated to obtain a mixed aqueous solution of potassium carbonate and potassium salts of phenylglycine and its analogs, the mixed aqueous solution is circulated to hydrolysis of 5-phenyl-hydantoin and its analogs, and after concentration, the mass percentage of potassium ions in the mother liquor is not less than 20 wt%.
In some embodiments of the present invention, the feeding molar ratio of the potassium ions to the (5-phenyl-hydantoin and the like thereof + phenylglycine and the like) is 1.2-2.5: 1.0, the reaction temperature is controlled to be 160-180 ℃, the pressure is controlled to be 1.5-2.5 MPa, and the residence time of the reactants in the microchannel is 2-8 min.
In a second aspect, the present invention provides the above method for preparing DL-phenylglycine and its analogs, wherein the DL-phenylglycine and its analogs are selected from at least one of DL-phenylglycine, DL-o-chlorophenylglycine, DL-m-chlorophenylglycine, DL-p-fluorophenylglycine, DL-o-fluorobenzaldehyde, DL-m-fluorophenylglycine, etc.
As described above, the method for continuously and rapidly preparing DL-phenylglycine and analogues thereof according to the present invention has the following beneficial effects: the method adopts the microchannel reactor, greatly shortens the preparation and alkaline hydrolysis time of the hydantoin, accelerates the reaction, reduces the thermal depolymerization of the cyanohydrin, generates no by-product and salt-containing wastewater, has high product yield, is clean and environment-friendly, and reduces the production cost.
The invention solves the problems that in the prior art, when DL-phenylglycine and analogues thereof are prepared, the reaction time is long, the reaction rate is slow, raw material cyanide is easy to generate thermal polymerization and byproducts, colored impurities are easy to generate, a large amount of cyanide-containing wastewater is generated, a large amount of low-value inorganic salt is generated as a byproduct, a large amount of salt-containing wastewater which is difficult to treat is generated, and the like.
Detailed Description
The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.
The manufacturer of the microchannel reactor used in the following examples is the American Uniz micro technology institute, Germany, model SIMM-V2-SS, with a microchannel internal diameter of 50 μm.
The reactant in the following examples is in liquid form, and it should be noted that the reactant is not limited to the form, and may be in other forms such as gas, and 2-hydroxy-phenylacetonitrile and the like and ammonium bicarbonate aqueous solution or 5-phenyl-hydantoin and the like (hydantoin for short) aqueous solution and alkali can be smoothly reacted in the microchannel reactor.
Example 1
Preparation of DL-phenylglycine:
166.4338 g (1.0 mol) of 2-hydroxy-phenylacetonitrile aqueous solution (cyanhydrin) with the mass percentage of 80wt% and 453.3333 g of ammonium bicarbonate aqueous solution (cyanhydrin: ammonia: carbon dioxide =1.0:2.0: 1.5) with the ammonia and carbon dioxide contents of 7.5wt% and 14.56wt% respectively are simultaneously pumped into a microchannel reactor through a metering pump, the flow rate of the cyanohydrin in the micro-channel is 10.0g/min, the flow rate of the ammonium bicarbonate aqueous solution in the micro-channel is 27.238g/min, the temperature of the reaction is controlled to be 120 ℃, the pressure is controlled to be 1.5MPa, the residence time is 3min (namely the time of the reaction liquid flowing through the micro-channel), the effluent liquid is clear, colorless and transparent 5-phenyl-hydantoin aqueous solution (hydantoin), the hydantoin aqueous solution is obtained by deamination and carbon dioxide, the total amount of the hydantoin aqueous solution is 589.7670 g, the content of 5-phenyl-hydantoin was 29.87wt%, and the yield of 5-phenyl-hydantoin was more than 99.9% (based on cyanohydrin).
The 5-phenyl-hydantoin aqueous solution (hydantoin) obtained in the above and 276 g of potassium carbonate aqueous solution with the mass percentage of 50wt% (hydantoin: potassium ion =1.0: 2.0) are simultaneously pumped into a microchannel reactor through a metering pump, the flow rate of the hydantoin in the microchannel is 58.9g/min, the flow rate of the potassium carbonate aqueous solution in the microchannel is 27.6g/min, the reaction temperature is controlled at 178 ℃, the pressure is controlled at 2.5MPa, the residence time is 4min (namely the time of the reaction liquid flowing through the microchannel), the effluent liquid is a clear light yellow transparent liquid, the liquid is deaminated and carbon dioxide, 458.8235g of potassium phenylglycinate aqueous solution is obtained, wherein the mass percentage of phenylglycine is 32.94wt%, the mass percentage of potassium ion is 17.0wt%, and the yield of phenylglycine is more than 99.9%. The obtained hydrolysate was diluted with water until the potassium ion content was 8.5wt% and the phenylglycine content was 16.47wt%, and 917.647g of hydrolysate was obtained after dilution.
And (2) introducing carbon dioxide gas into the obtained hydrolysate, wherein the pressure of the introduced carbon dioxide gas is 0.2MPa, the neutralization temperature is 20 ℃, the stirring speed is 120r/min, the end point pH of the carbon dioxide gas neutralization is 8.0, filtering out solids, washing with water, and drying to obtain 115.6860g of phenylglycine product, wherein the main content of the phenylglycine product is 98wt%, the product is powdery, a crystalline DL-phenylglycine product is obtained through recrystallization, the purity of the DL-phenylglycine product reaches more than 99.5wt%, and the recrystallization mother liquor is recycled. The filtrate is potassium bicarbonate aqueous solution containing phenylglycine, the mass of the filtrate is 901.78g, wherein the mass percentage of potassium ions is 8.65wt%, the mass percentage of phenylglycine is 4.2wt%, the filtrate is heated, decarburized and concentrated until the mass percentage of potassium ions is about 28.5wt%, and then the filtrate is circulated to the next hydrolysis of hydantoin, and the mass of mother liquor obtained after decarburization and concentration is 273.698 g.
Example 2
Preparation of DL-phenylglycine (recycling of potassium carbonate mother liquor):
166.4338 g (1.0 mol) of 2-hydroxy-phenylacetonitrile aqueous solution (cyanhydrin) with the mass percentage of 80wt% and 340.0 g (cyanhydrin: ammonia: carbon dioxide =1.0:1.5: 1.05) of ammonium bicarbonate aqueous solution with the ammonia and carbon dioxide contents of 7.5wt% and 13.59wt% respectively are pumped into a microchannel reactor through a metering pump simultaneously, the flow rate of the cyanohydrin in the micro-channel is 10.0g/min, the flow rate of the ammonium bicarbonate aqueous solution in the micro-channel is 20.43g/min, the temperature of the reaction is controlled to be 110 ℃, the pressure is 1.2MPa, the residence time is 4min (namely the time of the reaction liquid flowing through the micro-channel), the effluent liquid is clear, colorless and transparent 5-phenyl-hydantoin aqueous solution (hydantoin), the hydantoin aqueous solution is obtained by deamination and carbon dioxide, the total amount of the hydantoin aqueous solution is 450.550 g, the content of 5-phenyl-hydantoin was 39.10wt%, and the yield of 5-phenyl-hydantoin was more than 99.9% (based on cyanohydrin).
The 5-phenyl-hydantoin aqueous solution (hydantoin) obtained above was pumped into a microchannel reactor through a metering pump together with 273.698g of potassium carbonate aqueous solution containing phenylglycine potassium (wherein the potassium ion content is 28.76wt% and the phenylglycine content is 13.838 wt%) recycled in example 1 and 75.348 g of additional potassium carbonate aqueous solution with the mass percentage of 50wt% (hydantoin + phenylglycine): potassium ion =1.0: 2.0), the flow rate in the hydantoin microchannel is 58.9g/min, the flow rate of the potassium carbonate aqueous solution in the microchannel is 45.63g/min, the reaction temperature is controlled to 178 ℃, the pressure is 2.5MPa, the residence time is 4min (i.e. the time for the reaction solution to flow through the microchannel), the effluent liquid is a clear yellowish transparent liquid, the liquid is deaminated and carbon dioxide to obtain 458.8235g of the potassium phenylglycine aqueous solution, wherein the mass percentage of phenylglycine is 41.94wt%, the mass percentage content of potassium ions is 21.64wt%, the yield of phenylglycine is more than 99.9%, the aqueous solution is diluted to 9.5wt% of potassium ions and 18.41wt%, and the total amount of the aqueous solution is 1045.20 g.
Introducing carbon dioxide gas into the obtained hydrolysate, wherein the pressure of the introduced carbon dioxide gas is 0.2MPa, the neutralization temperature is 25 ℃, the stirring speed is 120r/min, the end point pH of the carbon dioxide neutralization is 8.0, filtering out the solid, washing with water, and drying to obtain 147.2682g of phenylglycine product, wherein the main content is 98wt%, the product is powder, and the crystalline DL-phenylglycine product is obtained through recrystallization (the recrystallization solution uses the recrystallization mother liquor and the supplemented water recycled in the example 1), wherein the purity of the crystalline DL-phenylglycine product is more than 99.5wt%, and the recrystallization mother liquor is recycled. The filtrate is potassium bicarbonate aqueous solution containing phenylglycine, the mass of the filtrate is 940.890g, wherein the mass percentage of potassium ions is 10.55wt%, the mass percentage of phenylglycine is 5.11wt%, the filtrate is heated, decarburized and concentrated until the mass percentage of potassium ions is about 28.5wt%, then the filtrate is circulated to the next hydrolysis of hydantoin, and the mass of mother liquor obtained after decarburization and concentration is 348.4778 g.
Example 3
Preparation of DL-o-chlorophenylglycine:
186.2133 g (1.0 mol) of 2-hydroxy-o-chlorobenzene acetonitrile aqueous solution (cyanhydrin) with the mass percentage of 90wt% and 453.3333 g (cyanhydrin: ammonia: carbon dioxide =1.0:2.0: 1.5) of ammonium bicarbonate aqueous solution with the ammonia and carbon dioxide contents of 7.5wt% and 14.56wt% respectively are pumped into a microchannel reactor through a metering pump, the flow rate of the cyanhydrin in the microchannel is 10.0g/min, the flow rate of the ammonium bicarbonate aqueous solution in the microchannel is 27.238g/min, the temperature of the reaction is controlled to be 120 ℃, the pressure is 1.5MPa, the retention time is 3min (namely the time of the reaction liquid flowing through the microchannel), the effluent liquid is clear, colorless and transparent 5- (o-chlorophenyl) -hydantoin aqueous solution (hydantoin, 595.5466 g of the total hydantoin aqueous solution is obtained through deamination and carbon dioxide, wherein the 5- (o-chlorophenyl) -hydantoin content is 35.37wt%, the yield of 5- (o-chlorophenyl) -hydantoin is greater than 99.9% (based on cyanohydrin).
276 g of the obtained 5-o-chlorophenyl-hydantoin aqueous solution (hydantoin) and 50wt% of potassium carbonate aqueous solution (hydantoin: potassium ions =1.0: 2.0) are simultaneously pumped into a microchannel reactor through a metering pump, the flow rate of the hydantoin in a microchannel is 58.9g/min, the flow rate of the potassium carbonate aqueous solution in the microchannel is 27.30g/min, the reaction temperature is 178 ℃, the pressure is 2.5MPa, the retention time is 4min (namely the time for the reaction liquid to flow through the microchannel), the effluent liquid is a clear light yellow transparent liquid, and the liquid is deaminated and carbon dioxide to obtain 478.8255g of an o-chlorophenyl glycine potassium aqueous solution, wherein the mass% of the o-chlorophenyl glycine is 38.76wt%, the mass% of the potassium ions is 16.29wt%, and the yield of the o-chlorophenyl glycine is more than 99.9%. The obtained hydrolysate was diluted with water until the potassium ion content was 9.0wt% and the o-chlorophenylglycine content was 21.41wt%, and 866.6742g of the hydrolysate was obtained after dilution.
And (2) introducing carbon dioxide gas into the obtained hydrolysate, wherein the pressure of the introduced carbon dioxide gas is 0.3MPa, the neutralization temperature is 20 ℃, the stirring speed is 120r/min, the carbon dioxide gas is introduced to neutralize, the end-point pH is 8.2, the solid is obtained by suction filtration, washing with water and drying, 151.5167g of an o-chlorophenyl glycine product with the main content of 98wt% is obtained, the product is in a powder shape, a crystalline DL-o-chlorophenyl glycine product is obtained through recrystallization operation, the purity reaches more than 99.5wt%, and the recrystallization mother liquor is recycled. The filtrate is potassium bicarbonate aqueous solution containing o-chlorophenyl glycine, the mass of the filtrate is 858.5740g, wherein the mass percentage of potassium ions is 9.08wt%, the mass percentage of o-chlorophenyl glycine is 4.32wt%, the filtrate is heated, decarbonized and concentrated until the mass percentage of potassium ions is about 28.5wt%, and then the filtrate is circulated to the next hydrolysis of hydantoin, and the mother liquor obtained after decarbonization and concentration has the mass of 273.5387 g.
Example 4
Preparation of DL-p-chlorophenyl glycine:
223.4560 g (1.0 mol) of 2-hydroxy-o-chlorobenzene acetonitrile aqueous solution (cyanohydrin) with the mass percentage of 75wt% is preheated to 60 ℃, then is pumped into a microchannel reactor together with 340.0 g (cyanohydrin: carbon dioxide =1.0:1.5: 1.05) of ammonium bicarbonate aqueous solution with the ammonia and carbon dioxide contents of 7.5wt% and 13.59wt%, respectively, through a metering pump, the flow rate of the cyanohydrin in the microchannel is 10.0g/min, the flow rate of the ammonium bicarbonate aqueous solution in the microchannel is 15.22g/min, the reaction temperature is controlled to be 100 ℃, the pressure is 1.0MPa, the retention time is 5min (namely the time of the reaction liquid flowing through the microchannel), the effluent liquid is clear, colorless and transparent 5- (p-chlorophenyl) -hydantoin aqueous solution (hydantoin, 545.5466 g of the total hydantoin aqueous solution is obtained through deamination and carbon dioxide, wherein the content of the 5- (p-chlorophenyl) -hydantoin is 38.61wt%, the yield of 5- (p-chlorophenyl) -hydantoin is greater than 99.9% (based on cyanohydrin).
Pumping 207 g of the obtained 5- (p-chlorophenyl) -hydantoin aqueous solution (hydantoin) and 207 g of 50wt% potassium carbonate aqueous solution (hydantoin: potassium ion =1.0: 1.5) into a microchannel reactor through a metering pump at the same time, wherein the flow rate of the hydantoin in a microchannel is 58.9g/min, the flow rate of the potassium carbonate aqueous solution in the microchannel is 22.35g/min, the reaction temperature is controlled at 178 ℃, the pressure is controlled at 2.5MPa, the residence time is 4min (namely the time of a reaction liquid flowing through the microchannel), the effluent liquid is a clear light yellow transparent liquid, and the liquid is deaminated and carbon dioxide to obtain 598.550g of a p-chlorophenyl glycine potassium aqueous solution, wherein the mass% of the p-chlorophenyl glycine is 31.0wt%, the mass% of the potassium ion is 9.8wt%, and the yield of the p-chlorophenyl glycine is more than 99.9%.
And (2) introducing carbon dioxide gas into the obtained hydrolysate, wherein the pressure of the introduced carbon dioxide gas is 0.3MPa, the neutralization temperature is 30 ℃, the stirring speed is 120r/min, the carbon dioxide gas is introduced for neutralization, the end-point pH is 8.2, the solid is obtained by suction filtration, washing and drying are carried out, 123.1074g of p-chlorophenyl glycine product with the main content of 98wt% is obtained, the product is in a powder shape, a crystalline DL-p-chlorophenyl glycine product is obtained through recrystallization operation, the purity reaches more than 99.5wt%, and the recrystallization mother liquor is recycled. The filtrate is potassium bicarbonate aqueous solution containing parachlorophenylglycine, the mass of the filtrate is 580.5560g, wherein the mass percentage of potassium ions is 10.1wt%, the mass percentage of the parachlorophenylglycine is 11.19wt%, the filtrate is heated, decarburized and concentrated until the mass percentage of the potassium ions is about 28.5wt%, and then the filtrate is circulated to the next time of hydantoin hydrolysis, and the mass of mother liquor obtained after decarburization and concentration is 205.8710 g.
Example 5
Preparation of DL-m-chlorophenyl glycine:
186.2133 g (1.0 mol) of 2-hydroxy-m-chlorobenzene acetonitrile aqueous solution (cyanhydrin) with the mass percentage of 90wt% and 453.3333 g (cyanhydrin: ammonia: carbon dioxide =1.0:2.0: 1.5) of ammonium bicarbonate aqueous solution with the ammonia and carbon dioxide contents of 7.5wt% and 14.56wt% respectively are pumped into a microchannel reactor through a metering pump, the flow rate of the cyanhydrin in the microchannel is 10.0g/min, the flow rate of the ammonium bicarbonate aqueous solution in the microchannel is 27.238g/min, the temperature of the reaction is controlled to be 120 ℃, the pressure is 1.5MPa, the residence time is 3min (namely the time of the reaction liquid flowing through the microchannel), the effluent liquid is clear, colorless and transparent 5- (m-chlorophenyl) -hydantoin aqueous solution (hydantoin, 595.5466 g of the total hydantoin aqueous solution is obtained through deamination and carbon dioxide, wherein the 5- (m-chlorophenyl) -hydantoin content is 35.37wt%, the yield of 5- (m-chlorophenyl) -hydantoin is greater than 99.9% (based on cyanohydrin).
The 5-m-chlorophenyl-hydantoin aqueous solution (hydantoin) obtained above and 276 g of potassium carbonate aqueous solution with the mass percentage of 50wt% (hydantoin: potassium ion =1.0: 2.0) are simultaneously pumped into a microchannel reactor through a metering pump, the flow rate of the hydantoin in the microchannel is 58.9g/min, the flow rate of the potassium carbonate aqueous solution in the microchannel is 27.30g/min, the reaction temperature is controlled at 178 ℃, the pressure is 2.5MPa, the residence time is 4min (namely the time of a reaction liquid flowing through the microchannel), the effluent liquid is a clear light yellow transparent liquid, the liquid is deaminated and carbon dioxide, 478.8255g of potassium m-chlorophenyl glycinate aqueous solution is obtained, wherein the mass percentage of m-chlorophenyl glycinate is 38.76wt%, the mass percentage of potassium ion is 16.29wt%, and the yield of m-chlorophenyl glycinate is more than 99.9%. The obtained hydrolysate was diluted with water until the potassium ion content was 9.0wt% and the m-chlorophenylglycine content was 21.41wt%, and 866.6742g of the hydrolysate was obtained after dilution.
Introducing carbon dioxide gas into the obtained hydrolysate, wherein the pressure of the introduced carbon dioxide gas is 0.3MPa, the neutralization temperature is 20 ℃, the stirring speed is 120r/min, the end point pH of the carbon dioxide gas neutralization is 8.2, filtering out solids, washing with water, and drying to obtain 151.5167g of m-chlorophenyl glycine product, wherein the main content is 98wt%, the product is in a powder shape, and a crystalline DL-m-chlorophenyl glycine product is obtained through recrystallization, the purity of the product reaches more than 99.5wt%, and the recrystallization mother liquor is recycled. The filtrate is potassium bicarbonate aqueous solution containing m-chlorobenzene glycine, the mass of the filtrate is 858.5740g, wherein the mass percentage of potassium ions is 9.08wt%, the mass percentage of m-chlorobenzene glycine is 4.32wt%, the filtrate is heated, decarbonized and concentrated until the mass percentage of potassium ions is about 28.5wt%, and then the filtrate is circulated to the next time of hydantoin hydrolysis, and the mass of mother liquor obtained after decarbonization and concentration is 273.5387 g.
Example 6
Preparation of DL-p-fluorophenylglycine:
167.9311 g (1.0 mol) of a 90wt% aqueous 2-hydroxy-p-fluorophenylacetonitrile solution (cyanohydrin) and 453.3333 g (cyanohydrin: carbon dioxide =1.0:2.0: 1.5) of an aqueous ammonium bicarbonate solution (cyanohydrin: carbon dioxide =1.0:2.0: 1.5) containing 7.5wt% and 14.56wt% of ammonia and carbon dioxide, respectively, were simultaneously pumped into a microchannel reactor through a metering pump, the flow rate of the cyanohydrin in the microchannel was 10.0g/min, the flow rate of the aqueous ammonium bicarbonate solution in the microchannel was 27.0g/min, the temperature of the reaction was controlled at 120 ℃, the pressure was 1.5MPa, the residence time was 3min (i.e., the time during which the reaction liquid flowed through the microchannel), the liquid flowed out was a clear, colorless, transparent aqueous 5- (p-fluorophenyl) -hydantoin solution (hydantoin, 582.2641 g in total was obtained by deaminizing and carbon dioxide, wherein the content of the aqueous 5- (p-fluorophenyl) -hydantoin was 33.35wt%, the yield of 5- (p-fluorophenyl) -hydantoin is greater than 99.9% (based on cyanohydrin).
Pumping 276 g of the obtained 5- (p-fluorophenyl) -hydantoin aqueous solution (hydantoin) and 50wt% of potassium carbonate aqueous solution (hydantoin: potassium ions =1.0: 2.0) into a microchannel reactor through a metering pump at the same time, wherein the flow rate of the hydantoin in a microchannel is 58.9g/min, the flow rate of the potassium carbonate aqueous solution in the microchannel is 27.92g/min, the reaction temperature is 178 ℃, the pressure is 2.5MPa, the residence time is 4min (namely the time of a reaction liquid flowing through the microchannel), the effluent liquid is a clear light yellow transparent liquid, and the liquid is deaminated and carbon dioxide to obtain 745.2641g of p-fluorophenyl glycine potassium aqueous solution, wherein the mass% of the p-fluorophenyl glycine is 22.70wt%, the mass% of the potassium ions is 10.47wt%, and the yield of the p-fluorophenyl glycine is more than 99.9%. The obtained hydrolysate was diluted with water until the content of potassium ions was 8.5wt% and the content of p-fluorophenylglycine was 18.43wt%, and 917.990g of hydrolysate was obtained after dilution.
And introducing carbon dioxide gas into the obtained hydrolysate, wherein the pressure of the introduced carbon dioxide gas is 0.3MPa, the neutralization temperature is 20 ℃, the stirring speed is 120r/min, the carbon dioxide gas is introduced for neutralization, the end-point pH is 7.8, the solid is obtained by suction filtration, washing with water and drying, 138.0841g of p-fluorophenylglycine product with the main content of 98wt% is obtained, the product is in powder form, a crystalline DL-p-fluorophenylglycine product is obtained through recrystallization operation, the purity reaches more than 99.5wt%, and the recrystallization mother liquor is recycled. The filtrate is a potassium bicarbonate aqueous solution containing the p-fluorophenyl glycine, the mass of the filtrate is 860.5740g, wherein the mass percentage of potassium ions is 9.06wt%, the mass percentage of the p-fluorophenyl glycine is 3.93wt%, the filtrate is heated, decarburized and concentrated until the mass percentage of the potassium ions is 30wt%, and then the filtrate is circulated to the next hydrolysis of hydantoin, and the mass of mother liquor obtained after decarburization and concentration is 259.9136 g.
Example 7
Preparation of DL-o-fluorophenylglycine:
167.9311 g (1.0 mol) of a 90wt% aqueous 2-hydroxy-o-fluorophenylacetonitrile solution (cyanohydrin) and 453.3333 g (cyanohydrin: carbon dioxide =1.0:2.0: 1.5) of an aqueous ammonium bicarbonate solution (cyanohydrin: carbon dioxide: 1.0:2.0: 1.5) containing 7.5wt% and 14.56wt% of ammonia and carbon dioxide, respectively, were simultaneously pumped into a microchannel reactor through a metering pump, the flow rate of the cyanohydrin in the microchannel was 10.0g/min, the flow rate of the aqueous ammonium bicarbonate solution in the microchannel was 27.0g/min, the temperature of the reaction was controlled at 120 ℃, the pressure was 1.5MPa, the residence time was 3min (i.e., the time during which the reaction liquid flowed through the microchannel), the liquid flowed out was a clear, colorless, transparent aqueous 5- (o-fluorophenyl) -hydantoin solution (hydantoin), 582.2641 g in total was obtained by deaminizing and carbon dioxide, in which the content of the aqueous 5- (o-fluorophenyl) -hydantoin was 33.35wt%, the yield of 5- (o-fluorophenyl) -hydantoin is greater than 99.9% (based on cyanohydrin).
276 g of the obtained 5- (o-fluorophenyl) -hydantoin aqueous solution (hydantoin) and 50wt% of potassium carbonate aqueous solution (hydantoin: potassium ions =1.0: 2.0) are simultaneously pumped into a microchannel reactor through a metering pump, the flow rate of the hydantoin in a microchannel is 58.9g/min, the flow rate of the potassium carbonate aqueous solution in the microchannel is 27.92g/min, the reaction temperature is 178 ℃, the pressure is 2.5MPa, the retention time is 4min (namely the time for the reaction liquid to flow through the microchannel), the effluent liquid is a clear light yellow transparent liquid, and the liquid is deaminated and carbon dioxide to obtain 745.2641g of o-fluorophenyl glycine potassium aqueous solution, wherein the mass% of o-fluorophenyl glycine is 22.70wt%, the mass% of potassium ions is 10.47wt%, and the yield of the o-fluorophenyl glycine is more than 99.9%. The obtained hydrolysate was diluted with water until the potassium ion content was 8.5wt% and the o-fluorophenylglycine content was 18.43wt%, and 917.990g of the hydrolysate was obtained after dilution.
And introducing carbon dioxide gas into the obtained hydrolysate, wherein the pressure of the introduced carbon dioxide gas is 0.3MPa, the neutralization temperature is 20 ℃, the stirring speed is 120r/min, the carbon dioxide gas is introduced for neutralization, the end-point pH is 7.8, the solid is obtained by suction filtration, washing with water and drying, 138.0841g of o-fluorophenylglycine product with the main content of 98wt% is obtained, the product is in powder form, a crystalline DL-o-fluorophenylglycine product is obtained through recrystallization operation, the purity reaches more than 99.5wt%, and the recrystallization mother liquor is recycled. The filtrate is potassium bicarbonate water solution containing o-fluoro phenylglycine, the mass of the filtrate is 860.5740g, wherein the mass percentage of potassium ions is 9.06wt%, the mass percentage of o-fluoro phenylglycine is 3.93wt%, the filtrate is heated, decarburized and concentrated until the mass percentage of potassium ions is 30wt%, and then the filtrate is circulated to the next hydrolysis of hydantoin, and the mass of mother liquor obtained after decarburizing and concentrating is 259.9136 g.
Example 8
Preparation of DL-m-fluorophenyl glycine:
215.9114 g (1.0 mol) of an aqueous 2-hydroxy-m-fluorophenylacetonitrile solution (cyanohydrin) having a mass% of 70wt% and 453.3333 g (cyanohydrin: ammonia: carbon dioxide =1.0:2.0: 1.5) of an aqueous ammonium carbonate solution having ammonia and carbon dioxide contents of 7.5wt% and 14.56wt%, respectively, were simultaneously pumped into a microchannel reactor through a metering pump, the flow rate of the cyanohydrin in the microchannel was 10.0g/min, the flow rate of the aqueous ammonium carbonate solution in the microchannel was 21.0g/min, the temperature of the reaction was controlled at 110 ℃, the pressure was 1.3MPa, the residence time was 6min (i.e., the time during which the reaction liquid flowed through the microchannel), the liquid flowed out was a clear, colorless and transparent aqueous 5- (m-fluorophenyl) -hydantoin solution (hydantoin, 630.2447 g in total was obtained by deaminizing and carbon dioxide, wherein the content of the aqueous 5- (m-fluorophenyl) -hydantoin was 30.81wt%, the yield of 5- (m-fluorophenyl) -hydantoin is greater than 99.9% (based on cyanohydrin).
The 5- (m-fluorophenyl) -hydantoin aqueous solution (hydantoin) obtained in the above and 276 g of potassium carbonate aqueous solution with the mass percentage of 50wt% (hydantoin: potassium ion =1.0: 2.0) are simultaneously pumped into a microchannel reactor through a metering pump, the flow rate of the hydantoin in the microchannel is 58.9g/min, the flow rate of the potassium carbonate aqueous solution in the microchannel is 25.79g/min, the reaction temperature is controlled at 168 ℃, the pressure is controlled at 2.0MPa, the residence time is 4min (namely the time of a reaction liquid flowing through the microchannel), the effluent liquid is a clear light yellow transparent liquid, and the liquid is deaminated and carbon dioxide to obtain 845.2447g of potassium m-fluorophenyl glycinate aqueous solution, wherein the mass percentage of m-fluorophenyl glycinate is 20.01wt%, the mass percentage of potassium ion is 9.23wt%, and the yield of m-fluorophenyl glycinate is more than 99.9%.
And introducing carbon dioxide gas into the obtained hydrolysate, wherein the pressure of the introduced carbon dioxide gas is 0.3MPa, the neutralization temperature is 20 ℃, the stirring speed is 120r/min, the carbon dioxide gas is introduced for neutralization, the end-point pH is 7.8, the solid is obtained by suction filtration, washing with water and drying, 138.0841g of m-fluorophenylglycine product with the main content of 98wt% is obtained, the product is in powder form, a crystalline DL-o-fluorophenylglycine product is obtained through recrystallization operation, the purity reaches more than 99.5wt%, and the recrystallization mother liquor is recycled. The filtrate is potassium bicarbonate aqueous solution containing o-fluorophenylglycine, the mass of the filtrate is 760.5740g, wherein the mass percentage of potassium ions is 10.26wt%, the mass percentage of m-fluorophenylglycine is 4.45wt%, the filtrate is heated, decarburized, concentrated to 30wt% of the mass percentage of potassium ions, and then circulated to the next hydrolysis of hydantoin, the mass of mother liquor obtained after decarburizing and concentrating is 260.1142g, and the mass percentage of m-fluorophenylglycine is 13.0 wt%.
In conclusion, the microchannel reactor is adopted, so that the preparation and alkaline hydrolysis time of hydantoin is greatly shortened, the reaction is accelerated, the thermal depolymerization of cyanohydrin is reduced, no by-product and salt-containing wastewater are generated, the product yield is high, the microchannel reactor is clean and environment-friendly, and the production cost is reduced. In the embodiment, a Germany IMM microchannel reactor (50-300 mu m) is used as an experimental platform, and the mass transfer and heat transfer speed of the microreactor is high, so that when 2-hydroxy-phenylacetonitrile and analogues thereof and ammonium bicarbonate aqueous solution pass through the microchannel reactor, the mass transfer and heat transfer effects are obvious, the collision among molecules is increased, the mixing among materials is fully and uniformly, the heat transfer is fully realized, the reaction pressure is increased to promote the reaction to proceed towards the product direction, the cyclization time is shortened, and the thermolysis polymerization and byproduct generation of the 2-hydroxy-phenylacetonitrile and analogues thereof are effectively reduced; the cyclization reaction and hydrolysis reaction rate are accelerated, the 2-hydroxy-phenylacetonitrile and the analogues thereof are converted into hydantoin to the maximum extent, the hydantoin is completely hydrolyzed and converted into phenylglycine and the analogues thereof, potassium carbonate is used for hydrolysis, and a potassium carbonate mother solution is recycled, so that no by-product and salt-containing wastewater are generated, the product yield is high, the method is clean and environment-friendly, and the production cost is reduced.
The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.
Claims (9)
1. A process for the preparation of DL-phenylglycine and its analogues, characterized in that: the method comprises the following steps: adding 2-hydroxy-phenylacetonitrile and analogues thereof and an ammonium bicarbonate aqueous solution into a microchannel reactor for reaction, controlling the reaction temperature to be 80-130 ℃, the pressure to be 0.5-2.0 MPa, and the residence time of reactants in the microchannel to be 1-8 min to obtain a 5-phenyl-hydantoin and analogues thereof aqueous solution; adding hydantoin and alkali into a microchannel reactor for reaction, controlling the reaction temperature to be 120-200 ℃, the pressure to be 1.0-3.5 MPa, and the residence time of reactants in a microchannel to be 1-8 min to obtain a phenylglycine and analog salt water solution, and acidifying, neutralizing and crystallizing to obtain DL-phenylglycine and analog thereof; the 2-hydroxy-benzyl cyanide and the analogues thereof are referred to as cyanohydrin for short, and the 5-phenyl-hydantoin and the analogues thereof are referred to as hydantoin for short;
the base is selected from potassium carbonate aqueous solution;
the acidified crystallization mother liquor is a potassium bicarbonate aqueous solution containing phenylglycine and analogues thereof, the mother liquor is heated, decarburized and concentrated to obtain a mixed aqueous solution of potassium carbonate and phenylglycine and analogues potassium salt, the mixed aqueous solution is circulated to 5-phenyl-hydantoin and analogues thereof for hydrolysis, and after concentration, the mass percentage content of potassium ions in the mother liquor is not lower than 20 wt%;
the DL-phenylglycine and the analogues thereof are selected from at least one of DL-phenylglycine, DL-o-chlorophenylglycine, DL-m-chlorophenylglycine, DL-p-fluorophenylglycine, DL-o-fluorophenylglycine and DL-m-fluorophenylglycine.
2. The process for the preparation of DL-phenylglycine and its analogs as claimed in claim 1, wherein: the chemical structural general formulas of the 2-hydroxy-phenylacetonitrile and the analogues thereof, the 5-phenyl-hydantoin and the analogues thereof, and the DL-phenylglycine and the analogues thereof are shown as follows:
in the formula, R group is ortho-position, meta-position or para-position on a benzene ring, and R group is one of hydrogen atom, chlorine atom and fluorine atom; the 2-hydroxy-benzyl cyanide and the analogues thereof are in liquid or solid state, the mass percentage of the 2-hydroxy-benzyl cyanide and the analogues thereof is 70-99 wt%, the mass percentage of the 5-phenyl-hydantoin and the analogues thereof in the aqueous solution of the 5-phenyl-hydantoin and the analogues thereof is 10-50 wt%, and the mass percentage of the phenylglycine and the analogues thereof in the aqueous solution of the phenylglycine and the analogues thereof is 10-40 wt%.
3. The process for the preparation of DL-phenylglycine and its analogs as claimed in claim 1, wherein: the feeding molar ratio of the 2-hydroxy-phenylacetonitrile and the analogues thereof to the ammonium bicarbonate aqueous solution is that cyanohydrin/ammonia/carbon dioxide =1: 1.5-2.0: 1.0-1.5, the reaction temperature is controlled to be 100-130 ℃, the pressure is 0.5-1.5 MPa, the residence time of reactants in a microchannel is 2-5 min, the mass percentage of ammonia in the ammonium bicarbonate aqueous solution is 5-10 wt%, and the mass percentage of carbon dioxide is 8-19.5 wt%.
4. The process for the preparation of DL-phenylglycine and its analogs as claimed in claim 1, wherein: the alkali is selected from potassium carbonate aqueous solution, and the mass percentage content is 30wt% -55 wt%.
5. The process for preparing DL-phenylglycine and its analogues according to claim 1 or 4, wherein: the feeding molar ratio of the 5-phenyl-hydantoin and the analogs thereof to the potassium carbonate is as follows: hydantoin/potassium ions =1: 1.2-2.5, the reaction temperature is controlled to be 160-180 ℃, the pressure is 1.5-2.5 MPa, and the residence time of reactants in the microchannel is 2-8 min.
6. The process for preparing DL-phenylglycine and its analogs as claimed in claim 1, wherein: the acidifying agent is at least one selected from sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, carbonic acid and carbon dioxide.
7. The process for preparing DL-phenylglycine and its analogues according to claim 1 or 6, wherein: in the phenylglycine and analog potassium salt water solution, the ammonia content is lower than 50ppm, and the mass percentage of potassium ions is 6.0-11.5 wt%.
8. The process for the preparation of DL-phenylglycine and its analogs as claimed in claim 1, wherein: the acidified crystallization mother liquor is a potassium bicarbonate aqueous solution containing phenylglycine and analogues thereof, the mass percentage of the phenylglycine and the analogues thereof is 2wt% -10 wt%, the mass percentage of the potassium bicarbonate is 10wt% -25 wt%, the mother liquor is heated, decarburized and concentrated to obtain a mixed aqueous solution of potassium carbonate and potassium salts of the phenylglycine and the analogues thereof, the mixed aqueous solution is circulated to the hydrolysis of the 5-phenyl-hydantoin and the analogues thereof, and the mass percentage of potassium ions in the mother liquor is not lower than 20wt% after the concentration.
9. The process for preparing DL-phenylglycine and its analogs as claimed in claim 1 or 8, wherein: the feeding molar ratio of the potassium ions to the (5-phenyl-hydantoin and the analogs thereof plus the phenylglycine and the analogs thereof) is 1.2-2.5: 1.0, the reaction temperature is controlled to be 160-180 ℃, the pressure is controlled to be 1.5-2.5 MPa, and the residence time of reactants in the microchannel is 2-8 min.
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