CN115784913A - Production method and device of D, L-p-hydroxyphenylglycine - Google Patents
Production method and device of D, L-p-hydroxyphenylglycine Download PDFInfo
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- hydroxyphenylglycine
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- LJCWONGJFPCTTL-UHFFFAOYSA-N 4-hydroxyphenylglycine Chemical compound OC(=O)C(N)C1=CC=C(O)C=C1 LJCWONGJFPCTTL-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 26
- 239000007788 liquid Substances 0.000 claims abstract description 56
- 238000006386 neutralization reaction Methods 0.000 claims abstract description 37
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000000463 material Substances 0.000 claims abstract description 26
- 238000002156 mixing Methods 0.000 claims abstract description 25
- 238000003756 stirring Methods 0.000 claims abstract description 17
- 230000003472 neutralizing effect Effects 0.000 claims abstract description 14
- 238000000926 separation method Methods 0.000 claims abstract description 14
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000011259 mixed solution Substances 0.000 claims abstract description 11
- 239000003054 catalyst Substances 0.000 claims abstract description 5
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 4
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000007864 aqueous solution Substances 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 14
- 238000004321 preservation Methods 0.000 claims description 11
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 10
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 9
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical group [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 8
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 8
- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 claims description 6
- 239000004471 Glycine Substances 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- ZMCHBSMFKQYNKA-UHFFFAOYSA-N 2-aminobenzenesulfonic acid Chemical compound NC1=CC=CC=C1S(O)(=O)=O ZMCHBSMFKQYNKA-UHFFFAOYSA-N 0.000 claims description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 3
- YCMLQMDWSXFTIF-UHFFFAOYSA-N 2-methylbenzenesulfonimidic acid Chemical compound CC1=CC=CC=C1S(N)(=O)=O YCMLQMDWSXFTIF-UHFFFAOYSA-N 0.000 claims description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- PQUCIEFHOVEZAU-UHFFFAOYSA-N Diammonium sulfite Chemical compound [NH4+].[NH4+].[O-]S([O-])=O PQUCIEFHOVEZAU-UHFFFAOYSA-N 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 230000005611 electricity Effects 0.000 claims description 2
- 229940124530 sulfonamide Drugs 0.000 claims 1
- 150000003456 sulfonamides Chemical class 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 24
- 239000000243 solution Substances 0.000 abstract description 8
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000001514 detection method Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000007599 discharging Methods 0.000 description 5
- 238000005265 energy consumption Methods 0.000 description 5
- 239000012265 solid product Substances 0.000 description 5
- 239000012535 impurity Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- -1 amine sulfonate Chemical class 0.000 description 3
- 238000003825 pressing Methods 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- LIDYFNYBHXPTJG-UHFFFAOYSA-N 2-azaniumyl-2-(2-hydroxyphenyl)acetate Chemical compound OC(=O)C(N)C1=CC=CC=C1O LIDYFNYBHXPTJG-UHFFFAOYSA-N 0.000 description 2
- TWLSOWAQVSIFIF-UHFFFAOYSA-N 2-hydroxy-2-(2-hydroxyphenyl)acetic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1O TWLSOWAQVSIFIF-UHFFFAOYSA-N 0.000 description 2
- YHXHKYRQLYQUIH-UHFFFAOYSA-N 4-hydroxymandelic acid Chemical compound OC(=O)C(O)C1=CC=C(O)C=C1 YHXHKYRQLYQUIH-UHFFFAOYSA-N 0.000 description 2
- 230000002457 bidirectional effect Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- LJCWONGJFPCTTL-SSDOTTSWSA-N D-4-hydroxyphenylglycine Chemical compound [O-]C(=O)[C@H]([NH3+])C1=CC=C(O)C=C1 LJCWONGJFPCTTL-SSDOTTSWSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 1
- 229960003022 amoxicillin Drugs 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- QYIYFLOTGYLRGG-GPCCPHFNSA-N cefaclor Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 QYIYFLOTGYLRGG-GPCCPHFNSA-N 0.000 description 1
- 229960005361 cefaclor Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/10—Process efficiency
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a production method of D, L-p-hydroxyphenylglycine, which comprises the steps of stirring and dissolving a glyoxylic acid aqueous solution, sulfamide, phenol and a catalyst; introducing the mixed solution into a multistage tubular reactor, and controlling the temperature of each stage; adding a neutralizing agent into the obtained reaction solution according to the pH parameter; and carrying out solid-liquid separation on the neutralized liquid to obtain the D, L-p-hydroxyphenylglycine. The production device comprises a material mixing kettle, a liquid outlet of the material mixing kettle is communicated with a liquid inlet of a multistage tubular reactor, a liquid outlet of the multistage tubular reactor is communicated with a neutralization kettle, a discharge flow control valve is arranged on the liquid outlet of the material mixing kettle, the flow control valve is arranged between the liquid outlet of a neutralizer flow-adding kettle and the neutralization kettle, the liquid outlet of the neutralizer flow-adding kettle is communicated with the neutralization kettle, a temperature sensor is uniformly arranged in each stage of the multistage tubular reactor, and a pH sensor is arranged in the neutralization kettle. The beneficial effects are that: the whole production period is shortened to 12 hours, the yield is improved by about 5 percent, and the purity is improved by about 3 percent.
Description
Technical Field
The invention relates to the technical field of chemical and medicine production, in particular to a method and a device for producing D, L-p-hydroxyphenylglycine.
Background
The D-p-hydroxyphenylglycine is obtained by splitting DL-p-hydroxyphenylglycine, is an intermediate of raw material medicines for synthesizing beta-lactam antibiotics, such as amoxicillin, cefaclor and the like, has large market demand, is a main production country and an export country in China, has annual output of about 2.5 ten thousand tons, and accounts for more than 60 percent of the whole world. This also leads to a great deal of problems in our country such as severe environmental pollution and large energy consumption. Therefore, enterprises need to continuously transform and upgrade, develop new technologies and equipment, improve production efficiency, reduce environmental pollution and reduce energy consumption.
The main flow synthetic route of DL-p-hydroxyphenylglycine adopts phenol and glyoxylic acid as main raw materials, the phenol and the glyoxylic acid are subjected to ammoniation reaction under certain conditions, and then products are obtained through neutralization, cooling and filtration, wherein the reaction principle is as follows: glyoxylic acid is an active monobasic acid, wherein carbon atoms attack phenolic hydroxyl in the monobasic acid to generate p-hydroxymandelic acid and o-hydroxymandelic acid under acidic conditions, and the p-hydroxymandelic acid and the o-hydroxymandelic acid are mainly used. Under heating, the sulfite ion abstracts hydrogen ion, so that the hydroxyl is further activated, and the ammonium ion attacks the hydroxyl position to generate an amino substituent. The average reaction yield reported at present is only about 67%, and the crude product purity is 95%. In the reaction process, part of o-hydroxyphenylglycine is generated by reaction, and part of o-hydroxyphenylglycine is decomposed into other organic impurities under the conditions of strong acid and high temperature, and the reaction is slow due to poor water solubility and low mixing degree at low temperature of phenol, and meanwhile, more ortho-position impurities are contained in the filtered product which is cooled and separated out. Therefore, it is required to accelerate the reaction rate and reduce the damage of high temperature environment, which needs to be solved by precise temperature control and increase of the mixing degree of reaction materials, and almost all the current patents and papers report that the route is adopted and the tank reactor is used for synthesizing DL-p-hydroxyphenylglycine, the method has the advantages of being suitable for large-scale simultaneous preparation, but has the disadvantages of non-continuity, low mixing efficiency, low product purity and long production time generally exceeding 20h.
Patent CN112778146A discloses a method for preparing p-hydroxyphenylglycine in a pulse tube reactor, which reports that glyoxylic acid and phenol are mixed respectively, the glyoxylic acid and sulfamic acid are mixed and pumped into 2 preheating devices respectively by a pump, then 2 solutions are pumped into the pulse tube reactor by metering equipment to be mixed at 100-150 ℃ for reaction, and then the p-hydroxyphenylglycine is obtained by cooling and crystallizing in a collector after the reaction is finished, and other patents report that the p-hydroxyphenylglycine is basically in an intermittent kettle type reaction.
The micro-channel and tubular reactor which are gradually mature at present are widely applied to chemical and medical production, have extremely high mixing efficiency, low energy consumption and convenient operation, and also meet the requirements of the production process of D, L-p-hydroxyphenylglycine, so that the optimization process of the equipment is a good choice.
The tubular reactor has the advantages that the mixing is fully and uniformly, the reaction mixing degree is the reaction degree which has great influence on the product quality in the process, and the kettle type stirring reactor cannot reach the ideal infinite uniform mixing state which is close to the tubular reactor. According to the process reaction principle, effective collision can not occur between molecules and the molecules react in time to enter contraposition, so that the adjacent position impurities are increased, and the reaction time is prolonged; the kettle type stirring reactor has the advantages that the energy consumption is low, the heat transfer is uniform and rapid, the structure characteristics of the tubular reactor determine, and the kettle type stirring reactor has large volume, so that the heat is transferred to the solution from the jacket or the tube and needs to be fully contacted and more time, and the heat loss is large, and the energy consumption is high; the device has the advantages that the device can be continuously operated, the material is fed from one end, the material is discharged from the other end, and the device can form dynamic uninterrupted state from feeding to collecting treatment. The kettle type stirring reactor needs to discharge materials after one batch of materials is reacted and then put into another batch of materials, so that the batch time exists, and each batch of materials may be inconsistent to influence the quality and have low efficiency.
Disclosure of Invention
The invention aims to solve the technical problem of providing a method and a device for producing D, L-p-hydroxyphenylglycine, so as to overcome the defects in the prior art.
The technical scheme for solving the technical problems is as follows: a production method of D, L-p-hydroxyphenylglycine comprises the following steps:
s1, stirring and dissolving a glyoxylic acid aqueous solution, sulfamide, phenol and a catalyst to obtain a mixed solution;
s2, introducing the mixed solution into a multistage tubular reactor, and controlling the temperature of each stage;
s3, adding a neutralizer into the reaction liquid obtained in the S2 according to the pH parameter to obtain a neutralization liquid;
s4, carrying out solid-liquid separation on the neutralized liquid to obtain D, L-p-hydroxyphenylglycine.
On the basis of the technical scheme, the invention can be improved as follows.
Furthermore, the sulfamide is one of o-toluenesulfonamide, p-toluenesulfonamide, 2-aminobenzenesulfonic acid and ammonium sulfonate.
Further, the catalyst is one of sulfuric acid, benzoic acid, ethylene glycol, p-toluene sulfonamide and glycine.
Further, the stirring temperature in S1 is 10 ℃ to 60 ℃.
Further, the multi-stage tubular reactor in the S2 has three stages, wherein the first-stage temperature is 10-30 ℃, the second-stage temperature is 20-50 ℃, and the third-stage temperature is 50-80 ℃.
Further, the neutralizer is ammonia solution with the concentration of 5-27%.
Further, the pH value is 3.0 to 7.0.
Further, the neutralization temperature in S3 is 30 ℃ to 70 ℃.
Based on the technical scheme, the invention also provides a device for producing the D, L-p-hydroxyphenylglycine, which comprises: the material mixing kettle, multistage tubular reactor, the neutralization kettle, the neutralizer flows with the cauldron, the PI controller, ejection of compact flow control valve, pH sensor and temperature sensor, the liquid outlet of material mixing kettle passes through the inlet intercommunication of pipeline with multistage tubular reactor, ejection of compact flow control valve sets up on the liquid outlet of material mixing kettle, the liquid outlet of multistage tubular reactor passes through the pipeline and communicates with the neutralization kettle, the liquid outlet of neutralizer flow with the cauldron passes through the pipeline and communicates with the neutralization kettle, flow control valve sets up on the pipeline between the liquid outlet of neutralizer flow with the cauldron and the neutralization kettle, temperature sensor is put to multistage tubular reactor's every grade equipartition, pH sensor arranges in the neutralization kettle, temperature sensor, pH sensor, ejection of compact flow control valve, flow control valve is connected with the PI controller electricity respectively.
Further, the multistage tubular reactor has three stages, each of which includes: the heat preservation device comprises a heat preservation tank and a coil, wherein the coil is arranged in the heat preservation tank, temperature sensors are uniformly arranged in each stage of heat preservation tank, the coil is formed by connecting multiple sections of U-shaped pipes, and a turbulence baffle is embedded in the joint of every two adjacent sections of U-shaped pipes.
The invention has the beneficial effects that:
1) According to the invention, a multistage tubular reactor graded temperature control method is adopted, more intermediates are synthesized under mild conditions, and the temperature is gradually increased and controlled within a certain range, so that product degradation and impurity generation caused by high-temperature reaction are avoided, and the reaction rate is improved due to the high mixing efficiency of the tubular reactor;
2) According to the invention, continuous neutralization is adopted, solid-liquid separation is carried out at a certain temperature, early-stage research shows that the water solubility of the ortho-position byproducts is increased at a certain temperature, the ortho-position byproducts are not easy to separate out, and the solubility of the para-position products is almost not influenced, so that the purity of the products separated at a certain temperature is higher, the ortho-position products are almost all dissolved in the filtrate, and meanwhile, the solid-liquid separation speed is higher than that at normal temperature;
3) The method for synthesizing the D, L-p-hydroxyphenylglycine has the advantages that the production time is generally more than 20 hours, the reaction efficiency is greatly improved, the whole production period is shortened to 12 hours, namely the reaction time is shortened by 8 hours, in addition, the yield is improved by about 5 percent, and the purity is improved by about 3 percent.
Drawings
FIG. 1 is a liquid phase detection spectrum of crude D, L-p-hydroxyphenylglycine synthesized by the method, wherein the peak retention time of the product is 7.571, and the peak area of 98.25% can be equal to the product content;
FIG. 2 is a block diagram of a D, L-hydroxyphenylglycine production apparatus according to the invention.
In the drawings, the components represented by the respective reference numerals are listed below:
1. the device comprises a material mixing kettle, 2, a multistage tubular reactor, 210, a heat preservation tank, 220, a coil pipe, 221, a turbulence baffle, 3, a neutralization kettle, 4, a neutralizer feeding kettle, 5, a P I controller, 6, a discharge flow control valve, 7, a pH sensor, 8, a flow control valve, 9 and a temperature sensor.
Detailed Description
The principles and features of this invention are described below in conjunction with the following drawings, which are set forth by way of illustration only and are not intended to limit the scope of the invention.
Example 1
A production method of D, L-p-hydroxyphenylglycine comprises the following steps:
s1, sequentially adding 50Kg of 50% glyoxylic acid, 55L of water, 27Kg of p-toluenesulfonamide, 32Kg of phenol and 0.1Kg of ethylene glycol into a material mixing kettle 1, and stirring and dissolving the materials clearly at 30 ℃ to obtain a mixed solution;
s2, opening the temperature control equipment in advance to enable the primary temperature of the multistage tubular reactor 2 to be 20 +/-2 ℃, the secondary temperature to be 35 +/-2 ℃, the tertiary temperature to be 65 +/-2 ℃, and controlling 1m through the discharge flow control valve 6 3 The flow rate per hour ensures that the mixed solution continuously enters from the first-stage tubular reactor of the multistage tubular reactor 2, continuously passes through the second-stage tubular reactor and the third-stage tubular reactor, and the discharging solution at the tail end of the third-stage tubular reactor continuously flows into the neutralization kettle 3;
s3, starting a neutralization kettle 3 for stirring, setting the pH value to be 4.0 +/-0.5, adjusting the adding amount of ammonia water by a PI controller 5 according to the real-time pH value measured by a pH sensor 7, and controlling the temperature to be 35-45 ℃ (the temperature is also kept at the temperature during subsequent solid-liquid separation) to obtain a neutralized liquid;
s4, after the neutralizing liquid reaches the preset liquid level of the neutralizing kettle 3, for example, half of the volume, a control valve at the bottom of the neutralizing kettle 3 is opened, the continuous flow of the feed liquid is sent to a filtering facility for solid-liquid separation, the solid-liquid separation can be realized by using a centrifuge or a filter pressing, suction filtration and other modes, the mother liquid is filtered to obtain a solid product D, L-p-hydroxyphenylglycine, the yield is 73.3%, and the HPLC detection content is 97.6%.
Example 2
A production method of D, L-p-hydroxyphenylglycine comprises the following steps:
s1, sequentially adding 50Kg of 50% glyoxylic acid, 50L of water, 28Kg of 2-aminobenzenesulfonic acid, 30Kg of phenol and 0.2Kg of p-toluenesulfonamide into a material mixing kettle 1, and stirring and dissolving at 45 ℃ to obtain a mixed solution;
s2, opening the temperature control equipment in advance to enable the primary temperature of the multistage tubular reactor 2 to be 25 +/-2 ℃, the secondary temperature to be 45 +/-2 ℃, the tertiary temperature to be 75 +/-2 ℃, and controlling the temperature to be 1.5m through the discharge flow control valve 6 3 The flow rate of the flow is that the mixed liquid continuously enters from the first-stage tubular reactor of the multistage tubular reactor 2, continuously passes through the second-stage tubular reactor and the third-stage tubular reactor, and the discharging liquid at the tail end of the third-stage tubular reactor continuously flows into the neutralization kettle 3;
s3, starting a neutralization kettle 3 for stirring, setting the pH value to be 5.0 +/-0.5, adjusting the adding amount of ammonia water by a PI controller 5 according to the pH value measured by a pH sensor 7 in real time, controlling the concentration of the ammonia water to be 10 percent and the temperature to be 45-55 ℃ (keeping the temperature during subsequent solid-liquid separation), and obtaining a neutralization solution;
s4, after the neutralizing liquid reaches the preset liquid level of the neutralizing kettle 3, for example, half of the volume, a control valve at the bottom of the neutralizing kettle 3 is opened, the continuous flow of the feed liquid is sent to a filtering facility for solid-liquid separation, the solid-liquid separation can be realized by using a centrifuge or a filter pressing, suction filtration and other modes, the mother liquid is filtered to obtain a solid product D, L-p-hydroxyphenylglycine, the yield is 73.1%, and the HPLC detection content is 97.9%.
Example 3
A production method of D, L-p-hydroxyphenylglycine comprises the following steps:
s1, sequentially adding 50Kg of 50% glyoxylic acid, 50L of water, 25Kg of amine sulfonate, 30Kg of phenol and 0.1Kg of glycine into a material mixing kettle 1, and stirring and dissolving the materials clearly at 55 ℃ to obtain a mixed solution;
s2, opening the temperature control equipment in advance to enable the primary temperature of the multistage tubular reactor 2 to be 18 +/-2 ℃, the secondary temperature to be 48 +/-2 ℃ and the tertiary temperature to be 78 +/-2 ℃, and controlling the temperature to be 3m through the discharge flow control valve 6 3 The flow rate of the mixed solution is that the mixed solution continuously enters from the first-stage tubular reactor of the multistage tubular reactor 2 and continuously passes through the second-stage tubular reactor and the third-stage tubular reactor, and the discharged solution at the tail end of the third-stage tubular reactor continuously flows into the neutralization kettle 3;
s3, starting a neutralization kettle 3 for stirring, setting the pH value to be 6.0 +/-0.5, adjusting the adding amount of ammonia water by a PI controller 5 according to the pH value measured by a pH sensor 7 in real time, controlling the concentration of the ammonia water to be 20 percent, and controlling the temperature to be 55-65 ℃ (keeping the temperature during subsequent solid-liquid separation) to obtain a neutralization solution;
s4, after the neutralizing liquid reaches the preset liquid level of the neutralizing kettle 3, for example, half of the volume, a control valve at the bottom of the neutralizing kettle 3 is opened, the continuous flow of the feed liquid is conveyed to a filtering facility for solid-liquid separation, the solid-liquid separation can be realized by using a centrifugal machine or a filter pressing, suction filtration and other modes, the mother liquid is filtered to obtain a solid product D, L-p-hydroxyphenylglycine, the yield is 72.6 percent, and the HPLC detection content is 98.1 percent.
Comparative example 1
50Kg of 50 percent glyoxylic acid, 50L of water, 25Kg of amine sulfonate, 30Kg of phenol and 0.1Kg of glycine are sequentially put into a 500L reaction kettle or tank for stirring reaction, the reaction is carried out for 15h at the temperature of 25 ℃, jacket steam is opened, the temperature is raised to 85 +/-2 ℃ until the residue of an intermediate is not more than 1 percent, the intermediate is transferred to a neutralization kettle, the temperature is reduced to 40 +/-2 ℃ by stirring, ammonia water is introduced, the heat is controlled, the jacket cold water is cooled, the temperature is reduced to room temperature after the neutralization is finished, the mixture is kept stand for 6h, the solid product D, L-p-hydroxyphenylglycine is obtained by centrifugal filtration, the yield is 67.5 percent, and the HPLC detection content is 95.2 percent.
Comparative example 2
50Kg of 50 percent glyoxylic acid, 50L of water, 25Kg of amine sulfonate, 30Kg of phenol and 0.1Kg of glycine are sequentially put into a 500L reaction kettle or a 500L reaction tank to be stirred and reacted, the temperature is controlled to react for 4h at 20 ℃, then jacket steam is opened to heat to 50 +/-2 ℃ to react for 6h, the temperature is raised to 90 +/-2 ℃ to react for 2h, the materials are transferred to a neutralization kettle to be cooled to 50 +/-2 ℃, ammonia is stirred and introduced, attention is paid to heat control, the jacket cold water is cooled, after neutralization is finished, the temperature is stirred and cooled to room temperature to maintain for 6h, and a solid product D, L-p-hydroxyphenylglycine are obtained by centrifugal filtration, the yield is 68.4 percent, and the content is 96.8 percent by HPLC (high performance liquid chromatography).
The experimental data show that the process of the present invention significantly improves product conversion as shown in table 1 below.
A liquid phase detection map of the D, L-p-hydroxyphenylglycine crude product synthesized by the method disclosed by the invention is shown in figure 1.
As shown in fig. 2, an apparatus for producing D, L-p-hydroxyphenylglycine comprises:
the system comprises a material mixing kettle 1, a multistage tubular reactor 2, a neutralizing kettle 3, a neutralizing agent feeding kettle 4, a P I controller 5, a discharging flow control valve 6, a flow control valve 8, a pH sensor 7 and a temperature sensor 9;
the liquid outlet of the material mixing kettle 1 is communicated with the liquid inlet of the multistage tubular reactor 2 through a pipeline, the discharging flow control valve 6 is arranged on the liquid outlet of the material mixing kettle 1, the liquid outlet of the multistage tubular reactor 2 is communicated with the neutralization kettle 3 through a pipeline, the liquid outlet of the neutralizer feeding kettle 4 is communicated with the neutralization kettle 3 through a pipeline, and the flow control valve 8 is arranged on the pipeline between the liquid outlet of the neutralizer feeding kettle 4 and the neutralization kettle 3; a temperature sensor 9 is arranged in each stage of the multistage tubular reactor 2, the temperature sensor 9 in each stage of the multistage tubular reactor 2 is used for measuring the temperature of the stage, a pH sensor 7 is arranged in the neutralization kettle 3, the pH sensor 7 is used for measuring the pH value in the neutralization kettle 3, the signal output of the temperature sensor 9 is electrically connected with the signal input of the P I controller 5, the signal output of the pH sensor 7 is electrically connected with the signal input of the P I controller 5, the discharging flow control valve 6 is electrically connected with the P I controller 5 in a bidirectional mode, and the flow control valve 8 is electrically connected with the P I controller 5 in a bidirectional mode.
Further, the method comprises the following steps: the multistage tubular reactor 2 has three stages, each of which independently controls temperature, each of which includes: the temperature sensor comprises a heat preservation tank 210 and a coil 220, wherein the coil 220 is arranged in the heat preservation tank 210, a temperature sensor 9 is arranged in each stage of the heat preservation tank 210, the coil 220 is formed by connecting a plurality of sections of U-shaped pipes, a turbulent flow baffle 221 is embedded at the joint of each two adjacent sections of U-shaped pipes, the turbulent flow baffle 221 is used for increasing the mixing degree of solution, the turbulent flow baffle 221 can be a pore plate, and in addition, the length of the coil 220 can be selected to be 20-200m.
Although embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are exemplary and not to be construed as limiting the present invention, and that changes, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
1. A production method of D, L-p-hydroxyphenylglycine is characterized by comprising the following steps:
s1, stirring and dissolving a glyoxylic acid aqueous solution, sulfamide, phenol and a catalyst to obtain a mixed solution;
s2, introducing the mixed solution into a multistage tubular reactor, and controlling the temperature of each stage;
s3, adding a neutralizing agent into the reaction liquid obtained in the S2 according to the pH parameter to obtain a neutralized liquid;
s4, carrying out solid-liquid separation on the neutralized liquid to obtain D, L-p-hydroxyphenylglycine.
2. The method for producing D, L-p-hydroxyphenylglycine according to claim 1, wherein the sulfonamide is one of o-toluenesulfonamide, p-toluenesulfonamide, 2-aminobenzenesulfonic acid and ammonium sulfonate.
3. The method for producing D, L-p-hydroxyphenylglycine according to claim 1, wherein the catalyst is one of sulfuric acid, benzoic acid, ethylene glycol, p-toluenesulfonamide and glycine.
4. The method for producing D, L-p-hydroxyphenylglycine according to claim 1, wherein the stirring temperature in S1 is 10 to 60 ℃.
5. The process for producing D, L-p-hydroxyphenylglycine according to claim 1, wherein the multistage tubular reactor in S2 has three stages, a first stage temperature of 10 ℃ to 30 ℃, a second stage temperature of 20 ℃ to 50 ℃, and a third stage temperature of 50 ℃ to 80 ℃.
6. The method for producing D, L-p-hydroxyphenylglycine according to claim 1, wherein the neutralizing agent is an aqueous ammonia solution with a concentration of 5% to 27%.
7. The method for producing D, L-p-hydroxyphenylglycine according to claim 1, wherein the pH is 3.0 to 7.0.
8. The method for producing D, L-p-hydroxyphenylglycine according to claim 1, wherein the neutralization temperature in S3 is from 30 ℃ to 70 ℃.
9. The utility model provides a D, L-p hydroxyphenylglycine's apparatus for producing which characterized in that includes: material mixing kettle (1), multistage tubular reactor (2), neutralization kettle (3), neutralizer flow with cauldron (4), PI controller (5), ejection of compact flow control valve (6), flow control valve (8), pH sensor (7) and temperature sensor (9), the liquid outlet of material mixing kettle (1) pass through the pipeline with the inlet intercommunication of multistage tubular reactor (2), ejection of compact flow control valve (6) set up on the liquid outlet of material mixing kettle (1), the liquid outlet of multistage tubular reactor (2) pass through the pipeline with neutralization kettle (3) intercommunication, the liquid outlet of neutralizer flow with cauldron (4) pass through the pipeline with neutralization kettle (3) intercommunication, flow control valve (8) set up on the pipeline between the liquid outlet of neutralizer flow with cauldron (4) and neutralization kettle (3), temperature sensor (9) are put to each level of multistage tubular reactor (2) equipartition, pH sensor (7) arrange in neutralization kettle (3), temperature sensor (9), pH sensor (7), pH sensor (6), PI controller (5) electricity respectively control.
10. A plant for the production of D, L-p-hydroxyphenylglycine according to claim 9, characterized in that the multistage tubular reactor (2) has three stages, each comprising: heat preservation groove (210) and coil pipe (220), coil pipe (220) are arranged in heat preservation groove (210), and temperature sensor (9) are put to equipartition in heat preservation groove (210) of every level, coil pipe (220) are formed by the connection of multistage U type pipe, and vortex baffle (221) all imbeds in the junction of every adjacent two sections U type pipe.
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