阅读说明：本技术 一种脉冲管式反应器中制备对羟基苯甘氨酸的方法 (Method for preparing p-hydroxyphenylglycine in pulse tubular reactor ) 是由 周林利 张跃 严生虎 辜顺林 于 2021-01-08 设计创作，主要内容包括：本发明公开了一种脉冲管式反应器中制备对羟基苯甘氨酸的方法,本发明以乙醛酸、苯酚、氨基磺酸为原料,氮气氛围下在新型脉冲管式反应器中制备对羟基苯甘氨酸,属于有机合成工艺技术领域。物料由计量泵通入脉冲管式反应器后,经预热、混合反应、分离得到对羟基苯甘氨酸产品,与文献报道的工艺相比,本发明的新工艺能大幅度缩短反应时间,提高车间效率,精确控制反应温度,有效减少副产物的生成。而新型脉冲反应器的引入,使得反应的传质传热效果与釜式工艺相比有了质的提升,从而避免相转移催化剂的使用,节约成本。本发明的工艺技术与文献报道的方法相比,在乙醛酸转化率、产品选择性等方面具有显著提升,投产后可替代现有的落后工艺技术。(The invention discloses a method for preparing p-hydroxyphenylglycine in a pulse tubular reactor, which takes glyoxylic acid, phenol and sulfamic acid as raw materials and prepares the p-hydroxyphenylglycine in the novel pulse tubular reactor in a nitrogen atmosphere, belonging to the technical field of organic synthesis processes. After materials are introduced into the pulse tube type reactor through the metering pump, p-hydroxyphenylglycine products are obtained through preheating, mixing reaction and separation. And the introduction of the novel pulse reactor leads the mass and heat transfer effect of the reaction to be qualitatively improved compared with the kettle type process, thereby avoiding the use of a phase transfer catalyst and saving the cost. Compared with the method reported in the literature, the process technology of the invention has obvious improvement in the aspects of glyoxylate conversion rate, product selectivity and the like, and can replace the existing laggard process technology after put into production.)

1. A method for preparing p-hydroxyphenylglycine in a pulse tube reactor is characterized by comprising the following steps: glyoxylic acid, phenol and sulfamic acid are used as raw materials and are continuously reacted in a pulse tube type reactor to generate p-hydroxyphenylglycine;

2. the method for preparing p-hydroxyphenylglycine in a pulsed tubular reactor according to claim 1, wherein:

(1) mixing phenol, sulfamic acid and a reaction solvent according to a certain proportion, and preparing a mixed solution under continuous stirring; respectively taking the mixed solution and the glyoxylic acid as two reaction materials, inputting the reaction materials into a preheating zone of a device, fully preheating the two reaction materials respectively, and then pumping the two reaction materials into a pulse tubular reactor through a metering pump;

(2) the flow of two strands of reaction materials is controlled by a metering pump, so that the preheated materials synchronously enter a pulse tubular reactor for mixing and reaction, after the reaction process is completed, reaction liquid flows out from an outlet of the pulse tubular reactor, reaction liquid is collected, and solid is separated out by cooling to obtain p-hydroxyphenylglycine.

3. The method for preparing p-hydroxyphenylglycine in a pulsed tubular reactor according to claim 2, characterized in that: the preheating temperature and the reaction temperature are 100-150 ℃.

4. The method for preparing p-hydroxyphenylglycine in a pulsed tubular reactor according to claim 2, characterized in that: the reaction time in the pulse tube reactor is 25 min-50 min.

5. The method for preparing p-hydroxyphenylglycine in a pulsed tubular reactor according to claim 2, characterized in that: the reaction solvent is water.

6. The method for preparing p-hydroxyphenylglycine in a pulsed tubular reactor according to claim 2, characterized in that: the molar ratio of the glyoxylic acid to the phenol is as follows: 1:1 to 1: 1.4.

7. The method for preparing p-hydroxyphenylglycine in a pulsed tubular reactor according to claim 2, characterized in that: the molar ratio of the glyoxylic acid to the sulfamic acid is as follows: 1:1 to 1: 1.5.

8. The method for preparing p-hydroxyphenylglycine in a pulsed tubular reactor according to claim 2, characterized in that: the preheating and the reaction are protected by nitrogen in the whole process.

9. The method for preparing p-hydroxyphenylglycine in a pulsed tubular reactor according to claim 2, characterized in that: and a plurality of thorn-shaped protruding structures are arranged on the inner wall of the pipeline of the pulse tubular reactor at intervals along the circumferential direction.

Technical Field

The invention belongs to the technical field of chemical processes, and particularly relates to a method for continuously preparing p-hydroxyphenylglycine in a pulse tubular reactor by taking glyoxylic acid, phenol and sulfamic acid as raw materials in the tubular reactor under the nitrogen atmosphere.

Background

P-hydroxyphenylglycine is a medical intermediate, plays a very important role in medicine synthesis, is mainly used for synthesizing compounds of side chains of cephalosporin medicines and medicines such as penicillin and the like, such as cefoperazone, cefoperazine, amoxicillin and the like, and can also be applied to analytical reagents of phosphorus, iron, silicon and the like and the application in some photosensitive fields. There are five routes appearing in the mainstream reports of p-hydroxyphenylglycine at home and abroad, and the 4 synthetic methods are listed below. (1) Strecker amino acid synthesis; (2) carrying out electrophilic substitution reaction on phenol and glyoxylic acid to generate hydroxymandelic acid, and then carrying out aminolysis; (3) phenol, glyoxylic acid and ammonium salt are directly reacted to prepare the product; (4) the p-hydroxyphenylglycine is prepared by a one-step synthesis method, wherein electrophilic substitution reaction is carried out on phenol and glyoxylic acid, and nucleophilic reaction is carried out on an active amide compound.

Chinese patent CN102050752A discloses a method for preparing p-hydroxyphenylglycine, which is characterized in that glyoxylic acid, phenol and a catalyst are respectively added into an intermittent reaction kettle and then heated, the reaction temperature is controlled to be 35-70 ℃, and the reaction time is 5-20 hours. And adding reducing substances for decoloring, adjusting the pH value by using alkali, and crystallizing for 1-10 hours at 0-40 ℃ to obtain a product, wherein the process has low selectivity and yield and increases side reactions after too long reaction time.

Chinese patent CN101362703B discloses a synthesis method of p-hydroxyphenylglycine, which is characterized in that glyoxylic acid, phenol and a catalyst are respectively added into an intermittent reaction kettle, then the mixture is heated, the reaction temperature is controlled to be 50-70 ℃, and the reaction time is 5-15 hours. According to the method, the p-hydroxyphenylglycine is prepared by taking benzenesulfonic acid, p-toluenesulfonic acid or o-toluenesulfonic acid as a catalyst, and the yield is 56-65%. The process has low selectivity and yield, and has long reaction time and increased side reactions.

Chinese patent CN102050752A discloses a synthesis method of p-hydroxyphenylglycine, which is characterized in that glyoxylic acid, phenol and a catalyst are respectively added into an intermittent reaction kettle, then the mixture is heated, the reaction temperature is controlled to be 70-100 ℃, and the reaction time is 5-10 hours. The p-hydroxyphenylglycine is obtained by taking organic sulfonic acid such as benzenesulfonic acid, p-toluenesulfonic acid or o-toluenesulfonic acid and the like as a catalyst, and the yield is less than or equal to 60%. Too long reaction time, poor selectivity, complex post-treatment and low yield.

US4175206 discloses a synthesis method of p-hydroxyphenylglycine, which is characterized in that glyoxylic acid, phenol and ammonium acetate are used as raw materials, a one-pot method is adopted to synthesize the p-hydroxyphenylglycine, the reaction is carried out for 48 hours at 30-35 ℃, and the product yield is 50.4%; however, this method has a long reaction time, a low yield, and many by-products.

Chenhongbiao et al (D/L-p-hydroxyphenyl hydantoin's "one-pot" synthesis [ J ]. chemical world, 2002(5): 249-251.) disclose a synthesis method of p-hydroxyphenylglycine, which is characterized in that phenol, urea and glyoxylic acid are used as raw materials, concentrated sulfuric acid is used as a catalyst to obtain p-hydroxyphenylhydantoin, and then the p-hydroxyphenylhydantoin is obtained by heating and hydrolyzing under the action of sodium hydroxide, but the method has long reaction time and low yield, and the alkaline hydrolysis step needs to be carried out under high pressure, so the method has high requirements on equipment and high production cost, and has certain limitation in practical application.

In the prior art, in the process of synthesizing the p-hydroxyphenylglycine by taking glyoxylic acid, phenol and sulfamic acid as raw materials, a proper catalyst is mostly added to further improve the yield and efficiency of the p-hydroxyphenylglycine, but even under the catalyst, the reaction yield can only reach about 60 percent, generally does not exceed 70 percent, and the reaction time is longer. If no catalyst is added, not only is the yield low, but the reaction rate is slower. Therefore, how to use no catalyst, further improve the reaction efficiency and yield, and improve the product quality is the focus of the research of the invention.

Aiming at the problems, the invention utilizes the novel pulse variable-diameter tubular reactor to continuously synthesize the p-hydroxyphenylglycine product, is an important improvement of the 4-hydroxyphenylglycine synthesis process, and can solve a plurality of defects of the prior art in many aspects. Although some pulse tube reactors exist in the prior art, such as pulse diameter-variable rectangular flat pipe (including round cake type pulse diameter-variable rectangular flat pipe, oblique square cake type pulse diameter-variable rectangular flat pipe, reinforced hybrid round cake type rectangular flat pipe, reinforced hybrid oblique square cake type rectangular flat pipe) channel reactors. Although the reactor utilizes a pulse structure, the flow velocity of fluid in a pipeline is constantly changed, and the mixing effect is enhanced to a certain extent, the result of synthesizing 4-hydroxyphenylglycine is not satisfactory, and the conversion rate of raw materials is not high all the time.

The tubular reactor that this application design obtained is equivalent to a plurality of little batch reactor and establishes ties and forms, compares with conventional batch reactor, and it is big to have a specific surface area, and is small, easily enlargies, and the flash mixed is effectual, and heat transfer effect is good, advantages such as high temperature resistant high pressure. The internal structure is improved, a plurality of protruding structures (see the cross section of the reactor in figure 3) are arranged on the inner wall of the pipeline, and the continuous flow tubular reactor adopting the specific structure can effectively control the mixing, mass transfer and heat transfer processes of reaction materials, thereby avoiding the use of catalysts. The process can skip the step-by-step amplification test, directly carry out amplification production, and has flexible production and high safety performance. The new process technology greatly shortens the reaction time, improves the equipment efficiency, and carries out N in a tubular reactor₂The protection is very easy to operate, the oxidation of the raw material phenol and the product is avoided, and the reaction selectivity and the yield are improved. Compared with the traditional intermittent production method, the method for synthesizing p-hydroxyphenylglycine by adopting the tubular continuous method has obvious advantages in the aspects of safety, cost, energy consumption, equipment efficiency and the like, and can provide an important scheme for industrial continuous production.

Disclosure of Invention

Aiming at the defects of the hydroxyphenylglycine synthesis process in the prior art, the invention provides a method for continuously preparing p-hydroxyphenylglycine (DL-p-hydroxyphenylglycine) by using a tubular process.

In order to achieve the purpose, the invention adopts the technical scheme that: a method for continuously preparing p-hydroxyphenylglycine comprises the following steps:

(1) in a pulse tubular reactor system, the temperature of heat exchange liquid is set to a certain temperature, raw materials of phenol, sulfamic acid and water are mixed according to a certain proportion and prepared into a mixed solution under continuous stirring, and glyoxylic acid and the mixed solution are respectively used as two reaction materials and are respectively pumped into a tubular reactor through a metering pump, the temperature of the heat exchange liquid is controlled by an external heat exchanger, and a back pressure valve is arranged at an outlet of the reactor.

(2) The flow of the materials is controlled by a metering pump, so that the preheated two materials synchronously enter a reaction module in a tubular reactor for mixing and reaction, after the reaction process is finished, the reaction liquid flows out from an outlet of the pulse tubular reactor, the reaction liquid is collected, white solid is separated out by cooling, and the product is analyzed by high performance liquid chromatography.

Further, the reaction in the step (1) uses the following solvents: water; wherein the molar ratio of the glyoxylic acid to the phenol is as follows: 1: 1-1: 1.4, wherein the molar ratio of glyoxylic acid to sulfamic acid is as follows: 1: 1-1: 1.5, the preheating temperature and the reaction temperature are 100-150 ℃, and the retention time in the tubular reactor is 25-50 min.

Further, the air inside the reactor is firstly N₂Is exhausted and then is in N₂Preheating raw materials and reacting under the atmosphere.

Further, the residence time, i.e. the reaction time, is controlled by the length of the pipeline and the flow rate of the liquid, and the reactor can realize the reaction at the temperature higher than the atmospheric boiling point of the solvent by pressurization.

Further, a plurality of (preferably 3) thorn-shaped protruding structures are arranged on the inner wall of the pipeline of the pulse pipe type reactor at intervals around the circumferential direction, the thorn-shaped protruding structures are arranged in the process that the pulse pipe is thickened from thin to thick, materials flow forwards along the thorn-shaped protruding structures, and the protruding structures are used for forming vortex at the edges of the protruding structures, so that the mixing between the materials is enhanced.

Compared with the prior art, the invention mainly has the following advantages:

1. the invention adopts a continuous production method, has short reaction time, short production period and more stable reaction process, does not need to use a catalyst, and can be beneficial to obviously improving the selectivity of products and the conversion rate of raw materials and obviously improving the reaction efficiency.

2. The selected pulse tubular reactor can enhance the mass transfer and heat transfer performance, keep the reaction temperature constant, avoid the temperature runaway phenomenon, reduce the generation of by-products and improve the safety of the reaction process.

3. The invention has simple operation, wide application range and flexible production, and can enlarge the production scale by connecting the reaction devices in parallel.

Drawings

FIG. 1 is a diagram of a continuous flow reactor apparatus used in the present invention:

1, 2-raw material pump batching zone, 3, 4-raw material metering pump, 5, 6-preheating zone, 7, 8-tubular reactor system and 9-quenching zone.

FIG. 2 is a schematic diagram of a pulsed tubular reactor;

FIG. 3 is a schematic cross-sectional view of a pulse tube reactor.

Detailed Description

The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It should be noted that the described embodiments are only a part of the invention, not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The invention is further illustrated by the following examples, which are intended to explain and complement the invention and do not limit the scope of the invention, according to the requirements of the process of the invention, in tubular or microchannel reactors, respectively. In the present invention, the conversion rate is not particularly limited, and the conversion rate refers to the conversion rate of glyoxylic acid.

Example 1

The tubular continuous flow reactor of the present invention consists of a preheating zone, a reaction zone and a quenching zone. Controlling the reaction residence time to be 40min by adjusting the flow of the pump and the tubular volume, setting the preheating temperature and the reaction temperature to be 100 ℃, and N₂Under protection, mixed liquor of raw materials of phenol, sulfamic acid and water is input into a preheating zone A of a device through a metering pump 1, glyoxylic acid is input into a preheating zone B of the device through a pump 2, and the mixture enters a reaction zone for mixing reaction after the two materials are respectively and fully preheated.

Wherein the molar ratio of the glyoxylic acid to the phenol is as follows: 1:1.2, the molar ratio of glyoxylic acid to sulfamic acid is as follows: 1:1.3, continuously discharging the p-hydroxyphenylglycine product from an outlet, collecting the p-hydroxyphenylglycine product into a product collector, cooling and crystallizing to obtain a product, and analyzing the product by HPLC to ensure that the product is consistent with the peak time of a standard product on HPLC. The conversion rate is 86.9%, the selectivity is 96.4%, and the product separation yield is 78.1%.

Example 2

The control residence time is 40min, N by adjusting the flow of the pump and the module number of the tubular volume or the microchannel₂Under protection, mixed liquid obtained by mixing raw materials of phenol, sulfamic acid and water is input into a preheating zone A of a device through a metering pump 1, glyoxylic acid is input into a preheating zone B of the device through a pump 2, and the mixture enters a reaction zone for mixing reaction after the two materials are respectively and fully preheated.

Wherein the molar ratio of the glyoxylic acid to the phenol is as follows: 1:1.2, the molar ratio of glyoxylic acid to sulfamic acid is as follows: 1:1.3, continuously discharging the p-hydroxyphenylglycine product from an outlet, collecting the p-hydroxyphenylglycine product into a product collector, cooling and crystallizing to obtain a product, and analyzing the product by HPLC to ensure that the product is consistent with the peak time of a standard product on HPLC. The reaction temperature is selected to be more suitable by different experiments, and the obtained results are shown in the table 1:

TABLE 1 results for p-hydroxyphenylglycine preparation at different temperatures

As can be seen from Table 1, the preferred temperature of p-hydroxyphenylglycine is 100-140 ℃, and the yield can reach more than 78% at the temperature.

Example 3

The tubular continuous flow reactor consists of a preheating zone, a reaction zone and a quenching zone. Setting the preheating temperature and the reaction temperature at 100 ℃, N₂Under protection, mixed liquid obtained by mixing raw materials of phenol, sulfamic acid and water is input into a preheating zone A of a device through a metering pump 1, glyoxylic acid is input into a preheating zone B of the device through a pump 2, and the mixture enters a reaction zone for mixing reaction after the two materials are respectively and fully preheated.

Wherein the molar ratio of the glyoxylic acid to the phenol is as follows: 1:1.2, the molar ratio of glyoxylic acid to sulfamic acid is as follows: 1:1.3, continuously discharging the p-hydroxyphenylglycine product from an outlet, collecting the p-hydroxyphenylglycine product into a product collector, cooling and crystallizing to obtain a product, and analyzing the product by HPLC to ensure that the product is consistent with the peak time of a standard product on HPLC. By adopting the method, the more appropriate retention time is screened, and the obtained result is shown in the table 2:

table 2. p-hydroxyphenylglycine preparation results at different residence times:

the results in the table above show that: within 1-50 min, the reaction can reach more than 75% yield, and the yield tends to increase first and then slightly decrease, but the efficiency is reduced due to too long retention time, so the invention does not make further research on prolonging the time.

Example 4

Controlling the reaction residence time to be 45min by adjusting the flow of the pump and the tubular volume, setting the preheating temperature and the reaction temperature to be 120 ℃, and N₂Under protection, the mixed liquid of the raw materials of phenol, sulfamic acid and water is input into a preheating zone A of a device through a metering pump 1, glyoxylic acid is input into a preheating zone B of the device through a pump 2, and the two materials are respectively and fully preheated and then enter a reaction zone for mixing reaction. Discharging the p-hydroxyphenylglycine product continuously from the outlet, collecting the product in a product collector, and coolingCrystallization gave the product, which was analyzed by HPLC and which gave a time to peak on HPLC consistent with the standard. By adopting the method, the more suitable molar ratio of the glyoxylic acid to the phenol to the sulfamic acid is screened, and the obtained results are shown in a table 3:

TABLE 3 results for p-hydroxyphenylglycine prepared at different glyoxylic acid to phenol to sulfamic acid molar ratios

Example 5 results of carrying out the reactions according to the invention in different reactors

In order to examine the actual effect of the reaction of the invention in different reactors, the invention uses the pulse reducing type rectangular flat pipeline reactors described in CN201810780744.8 and CN201810815654.8 for comparison, and the results obtained by the test on different reactors according to the process condition of serial number 6 in example 2 are shown in Table 4:

TABLE 4 results obtained with the same process conditions in the different reactors

As can be seen from the above table, the reactor of the present invention is more suitable for the synthesis of p-hydroxyphenylglycine, and has significant advantages in terms of conversion rate.

As can be seen from the above embodiments, the method provided by the present invention has at least the following advantages:

compared with the traditional kettle type operation reported in documents such as CN102050752A and the like, the method has obvious advantages in the aspects of raw materials, mass and heat transfer, energy consumption and equipment efficiency; also has significant advantages in terms of conversion, selectivity and yield.

The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.