A kind of production method and device of D,L-p-hydroxyphenylglycine

Abstract

The present invention relates to a production method of D, L-parahydroxyphenylglycine, wherein an aqueous solution of glyoxylic acid, sulfonamide, phenol and a catalyst are stirred and dissolved; a mixed solution is introduced into a multistage tubular reactor, and the temperature of each stage is controlled; a neutralizer is added to the obtained reaction solution according to a pH parameter; the neutralized solution is subjected to solid-liquid separation to obtain D, L-parahydroxyphenylglycine. A production device, a liquid outlet of a material mixing kettle is connected to a liquid inlet of a multistage tubular reactor, a liquid outlet of the multistage tubular reactor is connected to a neutralization kettle, a discharge flow control valve is arranged on the liquid outlet of the material mixing kettle, a flow control valve is arranged between the liquid outlet of a neutralizer flow adding kettle and a neutralization kettle, a liquid outlet of a neutralizer flow adding kettle is connected to a neutralization kettle, a temperature sensor is arranged in each stage of the multistage tubular reactor, and a pH sensor is arranged in a neutralization kettle. The beneficial effect is: the entire production cycle is shortened to 12h, the yield is increased by about 5%, and the purity is increased by about 3%.

Description

Technical Field

[0001] The invention relates to the field of chemical and pharmaceutical production technology, and in particular to a production method and device for D,L-p-hydroxyphenylglycine. Background Art

[0002] DL-p-hydroxyphenylglycine is split to obtain D-p-hydroxyphenylglycine, which is used to synthesize β-lactam antibiotics API intermediates, such as amoxicillin and cefuroxime. Its market demand is large. my country is the main producer and exporter, with an annual output of about 25,000 tons, accounting for more than 60% of the world. This also leads to many problems in my country, such as serious 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.

[0003] The mainstream synthesis route of DL-p-hydroxyphenylglycine uses phenol and glyoxylic acid as the main raw materials, performs an amination reaction under certain conditions, and then obtains the product through neutralization and cooling filtration. The reaction principle is: glyoxylic acid is an active monobasic acid. Under acidic conditions, the carbon atom attacks the para position of the phenol hydroxyl group to generate p-hydroxymandelic acid and o-hydroxymandelic acid, with the para position being the main one. Under heating conditions, the sulfite ion takes away the hydrogen ion, so that the hydroxyl group is further activated, and the ammonium ion attacks the hydroxyl position to generate an amino substituent. The average reaction yield currently reported is only about 67%, and the crude product purity is 95%. During the reaction process, part of the reaction generates o-hydroxyphenylglycine, and part of it decomposes into other organic impurities under strong acid and high temperature conditions. Due to the poor water solubility of phenol and the low mixing degree at low temperature, the reaction is slow. At the same time, the cooling precipitation and filtration product contains more ortho impurities. Therefore, it is necessary to speed up the reaction rate and reduce the damage of the high temperature environment. This requires precise temperature control and increasing the mixing degree of the reaction materials to solve the problem. Currently, almost all patents and papers report that this route is adopted and a kettle reactor is used to synthesize DL-p-hydroxyphenylglycine. The advantage of this method is that it is suitable for large-scale simultaneous preparation, but the disadvantage is that it cannot be continuous, the mixing efficiency is low, the product purity is not high, and the production time is long, generally exceeding 20 hours.

[0004] Patent CN112778146A discloses a method for preparing p-hydroxyphenylglycine in a pulse tubular reactor. The method is reported to be respectively mixing glyoxylic acid and phenol, and mixing glyoxylic acid and aminosulfonic acid, and pumping them into two preheating devices respectively with pumps, and then the two solutions are pumped into a pulse tubular reactor through a metering device to mix and react at 100-150°C, and then cooled and crystallized in a collector to obtain p-hydroxyphenylglycine, while other patents report basically intermittent kettle reactions.

[0005] At present, the gradually mature microchannel and tubular reactors have been widely used in chemical and pharmaceutical production. They have extremely high mixing efficiency, low energy consumption, and easy operation. They also meet the requirements of the D, L-parahydroxyphenylglycine production process. Therefore, using this equipment to optimize the process is a good choice.

[0006] The first advantage of the tubular reactor is that the mixing is fully uniform, and the reaction mixing degree has a greater impact on the product quality in this process, while the kettle stirred reactor cannot achieve the ideal state of infinite uniform mixing that the tubular reactor approaches. According to the principle of process reaction, if there is no effective collision between molecules and they cannot react in time to enter the para position, the ortho-position impurities will increase and the reaction time will increase; the second advantage is low energy consumption and uniform and rapid heat transfer, which is determined by the structural characteristics of the tubular reactor. Due to the large volume of the kettle stirred reactor, the heat transfer from the jacket or tube to the solution requires full contact and more time, which leads to large heat loss and high energy consumption; the third advantage is that it can be operated continuously, feeding from one end and discharging from the other end, and it can form a dynamic and uninterrupted process from feeding to collection and processing. However, the kettle stirred reactor requires a batch of materials to be discharged after the reaction is completed and then put into another batch, which has an interval time, and each batch may be inconsistent, affecting the quality and low efficiency. Summary of the invention

[0007] The technical problem to be solved by the present invention is to provide a method and device for producing D,L-p-hydroxyphenylglycine to overcome the deficiencies in the above-mentioned prior art.

[0008] The technical solution of the present invention to solve the above technical problem is as follows: a method for producing D,L-p-hydroxyphenylglycine, comprising the following steps:

[0009] S1, stirring and dissolving the glyoxylic acid aqueous solution, sulfonamide, phenol and catalyst to obtain a mixed solution;

[0010] S2, introducing the mixed liquid into a multi-stage tubular reactor and controlling the temperature of each stage;

[0011] S3, adding a neutralizing agent to the reaction solution obtained in S2 according to the pH parameter to obtain a neutralized solution;

[0012] S4. Perform solid-liquid separation on the neutralized liquid to obtain D,L-p-hydroxyphenylglycine.

[0013] Based on the above technical solution, the present invention can also be improved as follows.

[0014] Furthermore, the sulfonamide is one of o-toluenesulfonamide, p-toluenesulfonamide, 2-aminobenzenesulfonic acid, and sulfonic acid amine.

[0015] Furthermore, the catalyst is one of sulfuric acid, benzoic acid, ethylene glycol, p-toluenesulfonamide, and glycine.

[0016] Furthermore, the stirring temperature in S1 is 10°C to 60°C.

[0017] Furthermore, the multistage tubular reactor in S2 has three stages, the temperature of the first stage is 10°C to 30°C, the temperature of the second stage is 20°C to 50°C, and the temperature of the third stage is 50°C to 80°C.

[0018] Furthermore, the neutralizing agent is an aqueous ammonia solution with a concentration of 5% to 27%.

[0019] Furthermore, the pH value is 3.0 to 7.0.

[0020] Furthermore, the neutralization temperature in S3 is 30°C to 70°C.

[0021] Based on the above technical scheme, the present invention also provides a production device of D,L-parahydroxyphenylglycine, comprising: a material mixing kettle, a multistage tubular reactor, a neutralization kettle, a neutralizer flow adding kettle, a PI controller, a discharge flow control valve, a flow control valve, a pH sensor and a temperature sensor, the liquid outlet of the material mixing kettle is connected with the liquid inlet of the multistage tubular reactor through a pipeline, the discharge flow control valve is arranged on the liquid outlet of the material mixing kettle, the liquid outlet of the multistage tubular reactor is connected with the neutralization kettle through a pipeline, the liquid outlet of the neutralizer flow adding kettle is connected with the neutralization kettle through a pipeline, the flow control valve is arranged on the pipeline between the liquid outlet of the neutralizer flow adding kettle and the neutralization kettle, a temperature sensor is arranged in each stage of the multistage tubular reactor, a pH sensor is arranged in the neutralization kettle, and the temperature sensor, the pH sensor, the discharge flow control valve and the flow control valve are electrically connected to the PI controller respectively.

[0022] Furthermore, the multi-stage tubular reactor has three stages, each of which includes: an insulation tank and a coil, the coil is arranged in the insulation tank, a temperature sensor is arranged in the insulation tank of each stage, the coil is connected by multiple sections of U-shaped tubes, and a spoiler baffle is embedded in the connection between each two adjacent sections of U-shaped tubes.

[0023] The beneficial effects of the present invention are:

[0024] 1) The present invention adopts a multi-stage tubular reactor graded temperature control method, first synthesizes more intermediates under mild conditions, and gradually controls the temperature increase within a certain range to avoid product degradation and impurity generation caused by high temperature reaction, and the high mixing efficiency of the tubular reactor also increases the reaction rate;

[0025] 2) The present invention adopts continuous neutralization and controls solid-liquid separation at a certain temperature. It is found through previous studies that the water solubility of the ortho-position by-product increases at a certain temperature and is not easy to precipitate, while the solubility of the para-position product is almost unaffected. Therefore, the purity of the product after separation at a certain temperature is higher, and the ortho-position product is almost dissolved in the filtrate. At the same time, the solid-liquid separation is faster than at room temperature;

[0026] 3) Using a tank reactor to synthesize D,L-p-hydroxyphenylglycine, the production time of this method is long, generally more than 20 hours, while the method of the present invention greatly improves the reaction efficiency, shortens the entire production cycle to 12 hours, that is, shortens the reaction time by 8 hours, and in addition, the yield is increased by about 5% and the purity is increased by about 3%. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 The liquid phase detection spectrum of crude D,L-p-hydroxyphenylglycine synthesized by the method of the present invention has a product peak retention time of 7.571 and a peak area of ​​98.25%, which can be equivalent to the product content;

[0028] Figure 2 The present invention is a structural diagram of the production device of D, L-parahydroxyphenylglycine.

[0029] In the accompanying drawings, the components represented by the reference numerals are listed as follows:

[0030] 1. Material mixing kettle, 2. Multi-stage tubular reactor, 210. Insulation tank, 220. Coil, 221. Baffle, 3. Neutralization kettle, 4. Neutralizer flow adding kettle, 5. PI controller, 6. Discharge flow control valve, 7. pH sensor, 8. Flow control valve, 9. Temperature sensor. DETAILED DESCRIPTION

[0031] The principles and features of the present invention are described below in conjunction with the accompanying drawings. The examples given are only used to explain the present invention and are not used to limit the scope of the present invention.

[0032] Example 1

[0033] A method for producing D,L-p-hydroxyphenylglycine comprises the following steps:

[0034] S1, 50 kg of 50% glyoxylic acid, 55 L of water, 27 kg of p-toluenesulfonamide, 32 kg of phenol, and 0.1 kg of ethylene glycol are sequentially added into a material mixing kettle 1, and stirred at 30°C to dissolve to obtain a mixed solution;

[0035] S2, open the temperature control equipment in advance to make the first stage temperature of the multi-stage tubular reactor 2 20 ± 2 ° C, the second stage temperature 35 ± 2 ° C, the third stage temperature 65 ± 2 ° C, and control the 1m 3 / h flow rate so that the mixed liquid continuously enters from the first-stage tubular reactor of the multi-stage tubular reactor 2, and continuously passes through the second-stage and third-stage tubular reactors, and the discharge liquid at the end of the third-stage tubular reactor continuously flows into the neutralization kettle 3;

[0036] S3, start the neutralization kettle 3 to stir, set the pH to 4.0±0.5, the PI controller 5 adjusts the amount of ammonia added according to the pH value measured in real time by the pH sensor 7, and controls the temperature at 35°C to 45°C (also maintained at this temperature during subsequent solid-liquid separation) to obtain a neutralized solution;

[0037] S4. After the neutralization liquid reaches the predetermined liquid level of the neutralization kettle 3, for example, half of the volume, the control valve at the bottom of the neutralization kettle 3 is opened, and the feed liquid continuously flows to the filtering facility for solid-liquid separation. The solid-liquid separation can be carried out by centrifuge or filter press, suction filtration, etc., and the mother liquor is filtered out to obtain the solid product D, L-p-hydroxyphenylglycine, with a yield of 73.3% and a content of 97.6% detected by HPLC.

[0038] Example 2

[0039] A method for producing D,L-p-hydroxyphenylglycine comprises the following steps:

[0040] S1, 50 kg of 50% glyoxylic acid, 50 L of water, 28 kg of 2-aminobenzenesulfonic acid, 30 kg of phenol, and 0.2 kg of p-toluenesulfonamide are sequentially added into a material mixing kettle 1, and stirred at 45°C to dissolve to obtain a mixed solution;

[0041] S2, open the temperature control equipment in advance to make the first stage temperature of the multi-stage tubular reactor 2 25 ± 2 ° C, the second stage temperature 45 ± 2 ° C, the third stage temperature 75 ± 2 ° C, and control the 1.5m 3 / h flow rate so that the mixed liquid continuously enters from the first-stage tubular reactor of the multi-stage tubular reactor 2, and continuously passes through the second-stage and third-stage tubular reactors, and the discharge liquid at the end of the third-stage tubular reactor continuously flows into the neutralization kettle 3;

[0042] S3, start the neutralization kettle 3 for stirring, set the pH to 5.0±0.5, and adjust the amount of ammonia water added according to the pH value measured in real time by the pH sensor 7. The ammonia water concentration is 10%, and the temperature is controlled at 45°C to 55°C (also maintained at this temperature during subsequent solid-liquid separation) to obtain a neutralized solution;

[0043] S4. After the neutralization liquid reaches the predetermined liquid level of the neutralization kettle 3, for example, half of the volume, the control valve at the bottom of the neutralization kettle 3 is opened, and the feed liquid continuously flows to the filtering facility for solid-liquid separation. The solid-liquid separation can be carried out by centrifuge or filter press, suction filtration, etc., and the mother liquor is filtered out to obtain the solid product D, L-p-hydroxyphenylglycine, with a yield of 73.1% and a content of 97.9% detected by HPLC.

[0044] Example 3

[0045] A method for producing D,L-p-hydroxyphenylglycine comprises the following steps:

[0046] S1, 50 kg of 50% glyoxylic acid, 50 L of water, 25 kg of sulfonic acid amine, 30 kg of phenol, and 0.1 kg of glycine are sequentially added into a material mixing kettle 1, and stirred at 55°C to dissolve to obtain a mixed solution;

[0047] S2, open the temperature control equipment in advance to make the first stage temperature of the multi-stage tubular reactor 2 18±2℃, the second stage temperature 48±2℃, the third stage temperature 78±2℃, and control the 3m 3 / h flow rate so that the mixed liquid continuously enters from the first-stage tubular reactor of the multi-stage tubular reactor 2, and continuously passes through the second-stage and third-stage tubular reactors, and the discharge liquid at the end of the third-stage tubular reactor continuously flows into the neutralization kettle 3;

[0048] S3, start the neutralization kettle 3 for stirring, set the pH to 6.0±0.5, and adjust the amount of ammonia water added according to the pH value measured in real time by the pH sensor 7. The ammonia concentration is 20%, and the temperature is controlled at 55°C to 65°C (also maintained at this temperature during subsequent solid-liquid separation) to obtain a neutralized solution;

[0049] S4. After the neutralization liquid reaches the predetermined liquid level of the neutralization kettle 3, for example, half of the volume, the control valve at the bottom of the neutralization kettle 3 is opened, and the feed liquid continuously flows to the filtering facility for solid-liquid separation. The solid-liquid separation can be carried out by centrifuge or filter press, suction filtration, etc., and the mother liquor is filtered out to obtain the solid product D, L-p-hydroxyphenylglycine, with a yield of 72.6% and a content of 98.1% detected by HPLC.

[0050] Comparative Example 1

[0051] 50 kg of 50% glyoxylic acid, 50 L of water, 25 kg of sulfonic acid amine, 30 kg of phenol, and 0.1 kg of glycine were sequentially put into a 500 L reactor or tank and stirred for reaction. The reaction was carried out at 25°C for 15 h. The jacket steam was opened and the temperature was raised to 85±2°C until the residual intermediate did not exceed 1%. The material was transferred to the neutralization kettle, stirred and cooled to 40±2°C, and ammonia water was introduced. Pay attention to heat control and cool the jacket with cold water. After neutralization, the temperature was lowered to room temperature and allowed to stand for 6 h. The solid product D, L-p-hydroxyphenylglycine was obtained by centrifugation and filtration. The yield was 67.5%, and the content was 95.2% by HPLC.

[0052] Comparative Example 2

[0053] Put 50Kg of 50% glyoxylic acid, 50L of water, 25kg of sulfonic acid amine, 30kg of phenol, and 0.1kg of glycine into a 500L reactor or tank in sequence and stir to react. Control the temperature at 20°C to react for 4h, then open the jacket steam and heat it to 50±2°C to react for 6h, then heat it to 90±2°C to react for 2h, transfer the material to the neutralization kettle and cool it to 50±2°C, stir and pass ammonia water, pay attention to heat control, cool the jacket with cold water, stir and cool to room temperature after neutralization is completed for 6h, and centrifuge to obtain a solid product D, L-p-hydroxyphenylglycine with a yield of 68.4% and a content of 96.8% detected by HPLC.

[0054] The experimental data show that the method of the present invention significantly improves the product conversion rate, as shown in Table 1 below.

[0055]

[0056]

[0057] The liquid phase detection spectrum of crude D,L-p-hydroxyphenylglycine synthesized by the method of the present invention is as follows: Figure 1 .

[0058] like Figure 2 As shown, a production device for D,L-p-hydroxyphenylglycine comprises:

[0059] Material mixing kettle 1, multi-stage tubular reactor 2, neutralization kettle 3, neutralizer flow adding kettle 4, PI controller 5, discharge flow control valve 6, flow control valve 8, pH sensor 7 and temperature sensor 9;

[0060] The liquid outlet of the material mixing kettle 1 is connected with the liquid inlet of the multistage tubular reactor 2 through a pipeline, the discharge 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 connected with the neutralization kettle 3 through a pipeline, the liquid outlet of the neutralizer flow adding kettle 4 is connected 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 flow adding kettle 4 and the neutralization kettle 3; a temperature sensor 9 is arranged in each stage of the multistage tubular reactor 2, and the temperature sensor 9 in each stage of the multistage tubular reactor 2 is used to measure the temperature of the stage, a pH sensor 7 is arranged in the neutralization kettle 3, and the pH sensor 7 is used to measure the pH value in the neutralization kettle 3, the signal output of the temperature sensor 9 is electrically connected to the signal input of the PI controller 5, the signal output of the pH sensor 7 is electrically connected to the signal input of the PI controller 5, the discharge flow control valve 6 is bidirectionally electrically connected to the PI controller 5, and the flow control valve 8 is bidirectionally electrically connected to the PI controller 5.

[0061] Furthermore: the multi-stage tubular reactor 2 has three stages, each stage is independently temperature controlled, and each stage includes: an insulation tank 210 and a coil 220. The coil 220 is arranged in the insulation tank 210. A temperature sensor 9 is arranged in the insulation tank 210 of each stage. The coil 220 is connected by multiple sections of U-shaped tubes. A spoiler baffle 221 is embedded at the connection between each two adjacent sections of U-shaped tubes. The spoiler baffle 221 is used to increase the mixing degree of the solution. The spoiler baffle 221 can be a perforated plate. In addition, the length of the coil 220 can be selected to be 20-200m.

[0062] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A method for producing D,L-p-hydroxyphenylglycine, characterized in that: The steps include: S1, stirring and dissolving the glyoxylic acid aqueous solution, sulfonamide, phenol, and catalyst at a stirring temperature of 10°C to 60°C to obtain a mixed solution, wherein the sulfonamide is one of o-toluenesulfonamide, p-toluenesulfonamide, 2-aminobenzenesulfonic acid, and sulfonic acid amine, and the catalyst is one of sulfuric acid, benzoic acid, ethylene glycol, p-toluenesulfonamide, and glycine; S2, introducing the mixed liquid into a multistage tubular reactor, the multistage tubular reactor has three stages, the mixed liquid continuously enters from the first-stage tubular reactor of the multistage tubular reactor, and continuously passes through the second-stage and third-stage tubular reactors, and the discharge liquid at the end of the third-stage tubular reactor continuously flows into the neutralization kettle, and the temperature of each stage is controlled, the temperature of the first stage is 10°C to 30°C, the temperature of the second stage is 20°C to 50°C, and the temperature of the third stage is 50°C to 80°C; S3, according to the pH parameter, the pH value is 3.0-7.0, adding a neutralizer to the reaction solution obtained in S2, the neutralizer is an ammonia solution, the concentration is 5%-27%, the neutralization temperature is 30°C-70°C, and a neutralized solution is obtained; S4. Performing solid-liquid separation on the neutralized liquid at a temperature range that is the same as the neutralization temperature to obtain D,L-p-hydroxyphenylglycine.

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