CN107935872B - Method for synthesizing 2-amino-5-chlorobenzophenone by using microchannel reactor - Google Patents
Method for synthesizing 2-amino-5-chlorobenzophenone by using microchannel reactor Download PDFInfo
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Abstract
A method for synthesizing 2-amino-5-chlorobenzophenone by a microchannel reactor, belonging to the field of synthesis of mental drugs in organic synthesis. The invention solves the problems of low yield, poor purity, easy generation of danger caused by violent explosion, degradation caused by long reaction time under high temperature and high pressure, low recycling times of a catalyst and the like in the traditional catalytic hydrogenation reaction kettle synthesis process, and provides a method for synthesizing 2-amino-5-chlorobenzophenone by using a microchannel reactor, which specifically comprises the following steps: 1) adding a hydrogenation reaction precursor 5-chloro-3-phenyl-2, 1-benzisoxazole into an organic solvent, then adding activated carbon to load a noble metal catalyst, and taking the obtained mixture as a material I to enter a preheating module of a microreactor; 2) preheating the material I and feeding the material II with hydrogen into a reaction module group of the microreactor for reaction, collecting reaction liquid flowing out of a cooling module, and carrying out aftertreatment to obtain the 2-amino-5-chlorobenzophenone. The invention is suitable for the large-scale production of the 2-amino-5-chlorobenzophenone.
Description
Technical Field
The invention belongs to the field of synthesis of mental drugs in organic synthesis, and particularly relates to a synthesis method of 2-amino-5-chlorobenzophenone.
Background
The 2-amino-5-chlorobenzophenone is an important intermediate for synthesizing benzodiazepine hypnotic and sedative drugs such as diazepam, chlordiazepoxide and oxazepam, and the diazepine hypnotic and sedative drugs are mainly used for treating anxiety disorder and various functional neurosis, insomnia and particularly have excellent treatment effect on the anxiety insomnia. Meanwhile, the 2-amino-5-chlorobenzophenone derivative has wide application in the aspects of resisting cancer, mitosis, receptor antagonist, osteoporosis and the like, and is also an important raw material for synthesizing quinoline by a Friedlander method. As a very common and important intermediate in the fields of medicine and chemical industry, the quality of the synthetic method has important economic significance for improving the quality of a medicine synthetic product and reducing the content of byproducts.
At present, the chemical synthesis methods of 2-amino-5-chlorobenzophenone mainly comprise: 1) friedel-crafts acylation reaction is carried out on p-chloroaniline and benzoyl chloride, but the yield of the generated 2-amino-5-chlorobenzophenone is only about 40 percent, and the method needs harsh absolute anhydrous conditions; 2) the 2-amino-5-chlorobenzophenone is obtained by the addition reaction of the phenylboronic acid and the 2-amino-5-chlorobenzonitrile as raw materials, the yield is improved, but the phenylboronic acid as the raw material is expensive, and the process economic cost is high; 3) the method comprises the steps of firstly condensing phenylacetonitrile and p-chloronitrobenzene under an alkaline condition to obtain an intermediate, and then reducing the intermediate by iron powder under an acidic condition to obtain a target product 2-amino-5-chlorobenzophenone.
Disclosure of Invention
In order to solve the problems of low yield, poor purity, easy occurrence of danger caused by violent explosion, degradation caused by long reaction time at high temperature, low recycling times of a catalyst and the like in the traditional catalytic hydrogenation reaction kettle synthesis process, the invention provides a method for synthesizing 2-amino-5-chlorobenzophenone by using a microchannel reactor, wherein the chemical reaction formula is as follows:
the method specifically comprises the following steps:
1) adding a hydrogenation reaction precursor 5-chloro-3-phenyl-2, 1-benzisoxazole into an organic solvent, then adding activated carbon to load a noble metal catalyst, and taking the obtained mixture as a material I to enter a preheating module of a microreactor;
2) the method comprises the steps of pumping a material I into a preheating module for reaction, introducing hydrogen of the material II into a mixed reaction module of a reaction module group, carrying out hydrogenation reduction reaction on the material I and the material II in the reaction module group of a microchannel reactor, wherein the reaction pressure is 0.5-1.5 MPa, the reaction temperature is 50-100 ℃, the total reaction residence time is 15-40 s, collecting reaction liquid flowing out of a cooling module, the temperature of the cooling module is 20-30 ℃, and carrying out post-treatment to obtain the 2-amino-5-chlorobenzophenone.
Preferably: the organic solvent in the step 1) is a mixture of an organic solvent I and an organic solvent II, wherein the organic solvent I is any one of methanol, ethanol and isopropanol, and the solvent II is any one of ethyl acetate, tetrahydrofuran and acetonitrile.
The noble metal-loaded active carbon catalyst in the step 1) is any one or combination of more than one of Pd/C, Pt/C, Rh/C, and the mass of the noble metal in the noble metal-loaded active carbon catalyst accounts for 1-10% of the total mass of the catalyst.
The initial concentration of the 5-chloro-3-phenyl-2, 1-benzisoxazole in the step 1) in the organic solvent is 0.1-0.4 mol/L.
The mass ratio of the 5-chloro-3-phenyl-2, 1-benzisoxazole and the activated carbon supported noble metal catalyst in the step 1) is (1:0.01) - (1: 0.10); the molar ratio of the 5-chloro-3-phenyl-2, 1-benzisoxazole to hydrogen is (1:1.0) - (1: 1.5).
The reaction temperature in step 2) is 80 ℃.
And 2) carrying out aftertreatment, namely filtering the reaction liquid to recover the catalyst, carrying out reduced pressure distillation to recover the solvent, adding an ethanol solution with the volume fraction of 80% into the residue, and recrystallizing to obtain the target product 2-amino-5-chlorobenzophenone.
And hydrogen of the material I and the material II is controlled to enter the reaction module by a slurry pump and a gas flowmeter.
In the method for synthesizing 2-amino-5 chlorobenzophenone by using the microchannel reactor, the microchannel reactor comprises a preheating module group, a reaction module group and a cooling module, wherein the preheating module group comprises a preheating module or more than two preheating modules connected in parallel, the preheating module is of a straight structure or a heart-shaped structure module with two inlets and one outlet, and the preheating module is connected with the reaction module group in series; the reaction module group comprises 1-8 unit modules, all the unit modules are combined in series or in parallel at will, the reaction module and the cooling module are heart-shaped structure modules with two inlets and one outlet or with one inlet and one outlet, and the cooling module is connected with the reaction module group in series.
When the reaction is carried out in the microchannel reactor, the preheating module group and the reaction module group are connected in sequence of a preheating module, a reaction module with a two-in one-out structure, a reaction module with a single-in single-out structure and a cooling module with a single-in single-out structure.
The reaction module is made of one or more of special glass, silicon carbide ceramic, stainless steel metal coated with a corrosion-resistant layer or polytetrafluoroethylene, and the maximum pressure borne by the reaction module is 1.5-1.8 MPa.
Advantageous effects
The reaction type of the invention belongs to the common catalytic hydrogenation reduction reaction in industrial production, noble metals Pd, Pt, Ni and the like are usually used as catalysts, cheap hydrogen is used as a reducing agent for hydrogenation reduction, and the reaction must be carried out at high temperature and high pressure for a long time due to low vapor-liquid-solid three-phase mixing exchange efficiency in the reaction process, otherwise, the complete reaction of raw materials is difficult to ensure. Due to the flammable and explosive properties of hydrogen, if the high-pressure hydrogenation kettle leaks or the temperature is out of control, combustion and explosion are easy to occur, and the potential safety hazard is very large, so the reaction belongs to high-risk reaction in industrial production. Meanwhile, too long reaction time at high temperature can also cause degradation of a large amount of products in the system, so that the purity and yield of final products are affected, the activity of the noble metal catalyst attached to the activated carbon is continuously reduced due to excessive friction and the like in the reaction process, and the recycling difficulty is increased.
Due to the unique micro-structural design of the micro-channel reactor, the vapor-liquid-solid three-phase mixing exchange efficiency of the reaction in the continuous operation process is improved by more than 100 times compared with that of the traditional stirring hydrogenation reaction kettle, three-phase mixing is completed in a short time, the intrinsic reaction speed is greatly improved, the reaction time can be shortened to less than 40 seconds from 10 hours, degraded impurities generated by long-time high temperature in the process can be greatly reduced, meanwhile, the minimum liquid holdup also greatly reduces the potential safety hazard of hydrogen leakage combustion explosion, and the recovery and application efficiency of the catalyst can be greatly improved. Therefore, the reaction for synthesizing the 2-amino-5-chlorobenzophenone by the catalytic hydrogenation of the microchannel or the microreaction method shows stronger green and environmental protection characteristics.
The invention also produces other beneficial technical effects:
1) the high-pressure reaction kettle used in the industrial production of the catalytic hydrogenation reaction has the defects that the reaction must be carried out for a long time at high temperature and high pressure due to poor mixing and exchange effect among heterogeneous phases, and a large amount of degradation and dechlorination byproducts are generated due to long reaction time, so that the yield of the reaction is generally not more than 80 percent when the reaction is operated in the high-pressure reaction kettle, the purity is about 95 percent, and the generation of the byproducts is very difficult to control. The microchannel reactor can greatly shorten the reaction time by means of high-efficiency mixing efficiency, and a special online temperature control technology can greatly reduce degradation and dechlorination byproducts generated by the reaction and improve the yield and purity of the product; and meanwhile, the potential safety hazard caused by the out-of-control reaction temperature is avoided.
2) The reaction time is short, the surface structure of the catalyst cannot be greatly changed due to long-time stirring and friction, the activity of the catalyst can be retained to the maximum extent, the cyclic application result of the catalyst is considered by taking Pd/C and Pt/C as examples in the invention, and experimental data shows that the catalyst still has high activity after 8 cycles. Meanwhile, the reaction time is short, the heat loss is reduced, and the heat energy consumption is reduced.
3) The liquid holding volume is small, the online consumption of hydrogen is low, the production process does not need to worry about the large discharge of hydrogen, the combustion and explosion caused by the leakage are avoided, and the production potential safety hazard of the high-risk reaction is greatly reduced.
4) The method has no amplification effect, can be directly used for amplification production after the pilot plant research data is optimized, shortens the process development period from pilot plant test to production, reduces the research and development cost investment, and has great economic significance.
Drawings
Fig. 1 is a schematic diagram of the shape and structure of a module material flow pipeline of an organic glass material microchannel reactor, wherein (a) is a heart-shaped single-inlet single-outlet module, (b) is a heart-shaped two-inlet single-outlet module, and (c) is a straight module.
FIG. 2 is a schematic diagram of the catalytic hydrogenation reaction process and the connection relationship of the microchannel reactor, wherein A is a gas flowmeter, B is a slurry pump, 1 is a straight preheating module, 2 is a core-type two-in one-out reaction module, 3-5 are core-type single-in single-out reaction modules respectively, and 6 is a core-type single-in single-out cooling module.
Detailed Description
The present invention will be further illustrated with reference to the following specific examples; it should be understood that the following examples are illustrative of the present invention only and are not intended to limit the scope of the present invention; further, it is to be understood that various modifications or changes may be made by those skilled in the art after reading the description of the present invention, but those equivalents are also within the scope of the invention defined by the appended claims.
In the method for synthesizing 2-amino-5 chlorobenzophenone by using the microchannel reactor, the microchannel reactor comprises a preheating module group, a reaction module group and a cooling module, wherein the preheating module group comprises a preheating module or more than two preheating modules connected in parallel, the preheating module is in a straight structure as shown in c in figure 1, or a heart-shaped structure module with two inlets and one outlet as shown in b in figure 1, and the preheating module is connected with the reaction module group in series; the reaction module group comprises 1-8 unit modules, all the unit modules are randomly connected in series or in parallel, the reaction module and the cooling module are heart-shaped structure modules with two inlets and one outlet or one inlet and one outlet, as shown in a in figure 1, the cooling module is connected with the reaction module group in series, and the purpose of the cooling module is to cool high-temperature feed liquid to room temperature on line through the efficient heat transfer effect of the modules, reduce degradation impurities generated due to high temperature in the reaction process and simultaneously facilitate post-treatment operation.
When the reaction is carried out in the microchannel reactor, the preheating module group and the reaction module group are connected in sequence of a preheating module, a reaction module with a two-in one-out structure, a reaction module with a single-in single-out structure and a cooling module with a single-in single-out structure; wherein the two inlet and outlet reaction modules are used for mixing reaction after preheating, and the single inlet and outlet cooling module is used for cooling high-temperature reaction feed liquid.
The reaction module is made of one or more of special glass, silicon carbide ceramic, stainless steel metal coated with a corrosion-resistant layer or polytetrafluoroethylene, and the maximum pressure borne by the reaction module is 1.5-1.8 MPa.
The following describes the synthesis of 2-amino-5 chlorobenzophenone with the microchannel reactor of the present invention.
Example 1. Microchannel reactor Synthesis of 2-amino-5 chlorobenzophenone.
1) Weighing 150g of raw material 5-chloro-3-phenyl-2, 1-benzisoxazole, adding 1.2L of anhydrous methanol and 1.2L of tetrahydrofuran, stirring to dissolve, adding 5g of Pt/C catalyst with 5% of Pt content, fully stirring and mixing to form a material I, adjusting the flow rate of a slurry pump to enable the flow rate of the material I to be 45.0g/min, and entering a preheating module of a microreactor.
2) Adjusting H2The flow rate of the gas flow meter is 400ml/min, the gas flow meter directly enters the reaction module group without preheating and carries out catalytic hydrogenation reaction with the material I, as shown in figure 2, the molar ratio of 5-chloro-3-phenyl-2, 1-benzisoxazole to hydrogen is 1:1.2, the reaction temperature is 50 ℃, the reaction residence time is 30s, and the reaction pressure is 1.5 Mpa; and then the reaction solution enters a cooling module, the temperature of the cooling module is 20 ℃, the reaction solution flowing out of an outlet of the cooling module is collected, the catalyst is filtered and recovered, the solvent is recovered by reduced pressure distillation, the residue is added with an ethanol solution with the volume fraction of 80 percent for recrystallization, 134.75g of the target product 2-amino-5-chlorobenzophenone is obtained, the yield is 89.05 percent, and the purity is 99.23 percent.
Example 2. Microchannel reactor Synthesis of 2-amino-5 chlorobenzophenone.
1) Weighing 180g of raw material 5-chloro-3-phenyl-2, 1-benzisoxazole, adding 1.5L of absolute ethyl alcohol and 1.5L of ethyl acetate, stirring to dissolve, adding 9g of Pd/C catalyst with 10% of Pd content, fully stirring and mixing to form a material I, adjusting the flow rate of a slurry pump to enable the flow rate of the material I to be 42.0g/min, and entering a preheating module of a microreactor.
2) Adjusting H2The flow rate of the gas flow meter is 350ml/min, the reaction mixture directly enters the reaction module group without preheating and is subjected to catalytic hydrogenation reaction with the material I, as shown in figure 2, the molar ratio of 5-chloro-3-phenyl-2, 1-benzisoxazole to hydrogen is 1:1.1, the reaction temperature is 80 ℃, the reaction residence time is 32s, and the reaction pressure is 1.2 Mpa; then the reaction solution enters a cooling module, the temperature of the cooling module is 20 ℃, the reaction solution flowing out of an outlet of the cooling module is collected, the catalyst is filtered and recovered, and the solvent is recovered by reduced pressure distillationAnd adding an ethanol solution with the volume fraction of 80% into the residue to recrystallize to obtain 170.27g of the target product 2-amino-5-chlorobenzophenone, wherein the yield is 93.77% and the purity is 99.79%.
Example 3. Microchannel reactor Synthesis of 2-amino-5 chlorobenzophenone.
1) Weighing 200g of raw material 5-chloro-3-phenyl-2, 1-benzisoxazole, adding 1.5L of anhydrous methanol and 1.5L of tetrahydrofuran, stirring to dissolve, adding 20g of Pd/C catalyst with 3% of Pd content, fully stirring and mixing to form a material I, adjusting the flow rate of a slurry pump to enable the flow rate of the material I to be 40.0g/min, and entering a preheating module of a microreactor.
2) Adjusting H2The flow rate of the gas flow meter is 500ml/min, the reaction mixture directly enters the reaction module group without preheating and is subjected to catalytic hydrogenation reaction with the material I, as shown in figure 2, the molar ratio of 5-chloro-3-phenyl-2, 1-benzisoxazole to hydrogen is 1:1.5, the reaction temperature is 90 ℃, the reaction residence time is 40s, and the reaction pressure is 0.6 Mpa; and then the reaction solution enters a cooling module, the temperature of the cooling module is 25 ℃, the reaction solution flowing out of an outlet of the cooling module is collected, the catalyst is filtered and recovered, the solvent is recovered by reduced pressure distillation, the residue is added with an ethanol solution with the volume fraction of 80 percent for recrystallization, 179.58g of the target product 2-amino-5-chlorobenzophenone is obtained, the yield is 89.01 percent, and the purity is 99.15 percent.
Example 4. Microchannel reactor Synthesis of 2-amino-5 chlorobenzophenone.
1) Weighing 150g of raw material 5-chloro-3-phenyl-2, 1-benzisoxazole, adding 1.2L of anhydrous isopropanol and 1.2L of tetrahydrofuran, stirring to dissolve, adding 4g of Pt/C catalyst with the Pt content of 10%, fully stirring and mixing to form a material I, adjusting the flow rate of a slurry pump to enable the flow rate of the material I to be 30.0g/min, and entering a preheating module of a micro-reactor.
2) Adjusting H2The flow rate of the gas flow meter is 300ml/min, the gas flow meter directly enters the reaction module group without preheating and carries out catalytic hydrogenation reaction with the material I, as shown in figure 2, the molar ratio of 5-chloro-3-phenyl-2, 1-benzisoxazole to hydrogen is 1:1.0, the reaction temperature is 80 ℃, the residence time of the reaction is 40s, and the reaction pressure is 1.4 Mpa; then enters a cooling moduleAnd collecting the reaction liquid flowing out of the outlet of the cooling module at the temperature of 25 ℃, filtering and recovering the catalyst, carrying out reduced pressure distillation to recover the solvent, adding an ethanol solution with the volume fraction of 80% into the residue, and recrystallizing to obtain 140.18g of the target product 2-amino-5-chlorobenzophenone, wherein the yield is 92.64%, and the purity is 99.80%.
Example 5. Synthesis of 2-amino-5-chlorobenzophenone by a microchannel reactor.
1) Weighing 200g of raw material 5-chloro-3-phenyl-2, 1-benzisoxazole, adding 1.8L of absolute ethyl alcohol and 1.8L of ethyl acetate, stirring to dissolve, adding 8g of Pd/C catalyst with 5% of Pd content, fully stirring and mixing to form a material I, adjusting the flow rate of a slurry pump to enable the flow rate of the material I to be 50.0g/min, and entering a preheating module of a microreactor.
2) Adjusting H2The flow rate of the gas flow meter is 600ml/min, the gas flow meter directly enters the reaction module group without preheating and carries out catalytic hydrogenation reaction with the material I, as shown in figure 2, the molar ratio of 5-chloro-3-phenyl-2, 1-benzisoxazole to hydrogen is 1:1.4, the reaction temperature is 100 ℃, the residence time of the reaction is 15s, and the reaction pressure is 0.8 Mpa; and then the reaction solution enters a cooling module, the temperature of the cooling module is 30 ℃, the reaction solution flowing out of an outlet of the cooling module is collected, the catalyst is filtered and recovered, the solvent is recovered by reduced pressure distillation, the residue is added with an ethanol solution with the volume fraction of 80 percent for recrystallization, 179.30g of the target product 2-amino-5-chlorobenzophenone is obtained, the yield is 88.87 percent, and the purity is 98.94 percent.
Example 6. Synthesis of 2-amino-5-chlorobenzophenone by a microchannel reactor.
1) Weighing 180g of raw material 5-chloro-3-phenyl-2, 1-benzisoxazole, adding 1.5L of anhydrous methanol and 1.5L of acetonitrile, stirring to dissolve, adding 10g of Pd/C catalyst with 3% of Pd content, fully stirring and mixing to form a material I, adjusting the flow rate of a slurry pump to enable the flow rate of the material I to be 40.0g/min, and entering a preheating module of a microreactor.
2) Adjusting H2The flow rate of the gas flow meter is 350ml/min, the reaction mixture directly enters the reaction module group without preheating and undergoes catalytic hydrogenation reaction with the material I, as shown in figure 2, the molar ratio of 5-chloro-3-phenyl-2, 1-benzisoxazole to hydrogen is 1:1.2, and the reaction temperature isThe reaction residence time is 35s at the temperature of 80 ℃, and the reaction pressure is 1.0 Mpa; and then the reaction solution enters a cooling module, the temperature of the cooling module is 30 ℃, the reaction solution flowing out of an outlet of the cooling module is collected, the catalyst is filtered and recovered, the solvent is recovered by reduced pressure distillation, the residue is added with an ethanol solution with the volume fraction of 80 percent for recrystallization, 168.96g of the target product 2-amino-5-chlorobenzophenone is obtained, the yield is 92.79 percent, and the purity is 99.68 percent.
Example 7. Synthesis of 2-amino-5-chlorobenzophenone by a microchannel reactor.
1) Weighing 180g of raw material 5-chloro-3-phenyl-2, 1-benzisoxazole, adding 1.5L of anhydrous methanol and 1.5L of acetonitrile, stirring to dissolve, adding 8g of Pd/C catalyst with 5% of Pd content, fully stirring and mixing to form a material I, adjusting the flow rate of a slurry pump to enable the flow rate of the material I to be 45.0g/min, and entering a preheating module of a microreactor.
2) Adjusting H2The flow rate of the gas flow meter is 450ml/min, the gas flow meter directly enters the reaction module group without preheating and carries out catalytic hydrogenation reaction with the material I, as shown in figure 2, the molar ratio of 5-chloro-3-phenyl-2, 1-benzisoxazole to hydrogen is 1:1.4, the reaction temperature is 70 ℃, the reaction residence time is 25s, and the reaction pressure is 1.0 Mpa; and then the reaction solution enters a cooling module, the temperature of the cooling module is 25 ℃, the reaction solution flowing out of an outlet of the cooling module is collected, the catalyst is filtered and recovered, the solvent is recovered by reduced pressure distillation, the residue is added with an ethanol solution with the volume fraction of 80 percent for recrystallization, 162.63g of the target product 2-amino-5-chlorobenzophenone is obtained, the yield is 89.56 percent, and the purity is 99.27 percent.
Example 8. Microchannel reactor Synthesis of 2-amino-5 chlorobenzophenone.
1) Weighing 200g of raw material 5-chloro-3-phenyl-2, 1-benzisoxazole, adding 1.8L of isopropanol and 1.8L of tetrahydrofuran, stirring to dissolve, adding 15g of Pt/C catalyst with 5% of Pt, fully stirring and mixing to form a material I, adjusting the flow rate of a slurry pump to enable the flow rate of the material I to be 38.0g/min, and entering a preheating module of a microreactor.
2) Adjusting H2The flow rate of the gas flow meter is 380ml/min, and the gas flow meter directly enters the reaction module group without preheating to perform catalytic hydrogenation reaction with the material IAs shown in fig. 2, the molar ratio of 5-chloro-3-phenyl-2, 1-benzisoxazole to hydrogen is 1:1.3, the reaction temperature is 60 ℃, the reaction residence time is 33s, and the reaction pressure is 1.4 Mpa; and then the reaction solution enters a cooling module, the temperature of the cooling module is 30 ℃, the reaction solution flowing out of an outlet of the cooling module is collected, the catalyst is filtered and recovered, the solvent is recovered by reduced pressure distillation, the residue is added with an ethanol solution with the volume fraction of 80 percent for recrystallization, 180.35g of the target product 2-amino-5-chlorobenzophenone is obtained, the yield is 89.39 percent, and the purity is 99.11 percent.
Example 9. Synthesis of 2-amino-5-chlorobenzophenone by a microchannel reactor.
1) Weighing 180g of raw material 5-chloro-3-phenyl-2, 1-benzisoxazole, adding 1.5L of absolute ethanol and 1.5L of acetonitrile, stirring to dissolve, adding 18g of Rh/C catalyst with the Rh content of 1%, fully stirring and mixing to form a material I, adjusting the flow rate of a slurry pump to enable the flow rate of the material I to be 30.0g/min, and entering a preheating module of a microreactor.
2) Adjusting H2The flow rate of the gas flow meter is 420ml/min, the reaction mixture directly enters the reaction module group without preheating and undergoes catalytic hydrogenation reaction with the raw material, as shown in fig. 2, the molar ratio of 5-chloro-3-phenyl-2, 1-benzisoxazole to hydrogen is 1:1.5, the reaction temperature is 80 ℃, the residence time of the reaction is 28s, and the reaction pressure is 1.1 Mpa; and then the reaction solution enters a cooling module, the temperature of the cooling module is 25 ℃, the reaction solution flowing out of an outlet of the cooling module is collected, the catalyst is filtered and recovered, the solvent is recovered by reduced pressure distillation, the residue is added with an ethanol solution with the volume fraction of 80 percent for recrystallization, 168.06g of the target product 2-amino-5-chlorobenzophenone is obtained, the yield is 92.55 percent, and the purity is 99.75 percent.
TABLE 1 statistics of the yield, yield and purity of 2-amino-5-chlorobenzophenone obtained by the process of the present invention
As can be seen from Table 1, the reaction temperature between 50-100 ℃ can ensure higher purity and yield, from the overall law, the reaction temperature within the range of change has little effect on purity and yield, but 80 ℃ is selected, the reaction product yield and purity and the numerical value appears a great amount change, and does not accord with the overall law, the beneficial effect is unpredictably before the technical scheme and technical effect of the application are not known, so the reaction temperature is most preferably 80 ℃.
Detecting the recycling efficiency of the catalyst:
in order to examine the recycling efficiency of the catalyst, Pd/C and Pt/C are respectively selected as the catalyst, the reaction temperature is 80 ℃, the hydrogen consumption is 3.2eq, the reaction pressure is 1.5MPa, the retention time is 30s in each recycling process of the catalyst, a metal catalyst with the metal content of 10 percent is selected, the consumption is 5 percent of the raw material, the experiment content of recycling for 8 times is designed, the relationship between Pt/C, Pd/C which is recycled for many times and the reaction yield and the product purity is considered, and the result is shown in the following graph:
TABLE 2 Pd/C catalyst recycle experiment
| Experiment number | Purity of | Yield of |
| Example 10 | 99.68％ | 92.33％ |
| Example 11 | 99.75％ | 92.19％ |
| Example 12 | 99.64％ | 91.95％ |
| Example 13 | 99.59％ | 92.38％ |
| Example 14 | 99.81％ | 92.41％ |
| Example 15 | 99.72％ | 92.97％ |
| Example 16 | 99.73％ | 92.69％ |
| Example 17 | 99.68％ | 91.88％ |
TABLE 3 Pt/C catalyst recycle experiment
| Experiment number | Purity of | Yield of |
| Example 18 | 99.59％ | 92.28％ |
| Example 19 | 99.79％ | 92.13％ |
| Example 20 | 99.74％ | 92.07％ |
| Example 21 | 99.68％ | 91.98％ |
| Example 22 | 99.72％ | 92.21％ |
| Example 23 | 99.69％ | 92.27％ |
| Example 24 | 99.59％ | 92.09％ |
| Example 25 | 99.80％ | 91.91％ |
The above examples show that no matter the catalyst is selected from Pd/C or Pt/C, the catalyst still has good activity after being recycled for 8 times, and can ensure higher product yield and purity.
Comparative example a method for producing 2-amino-5-chlorobenzophenone in a conventional autoclave.
Adding 150g of 5-chloro-3-phenyl-2, 1-benzisoxazole into a 5L autoclave, adding 1.2L of anhydrous methanol and 1.2L of tetrahydrofuran, stirring to dissolve, adding 20g of Pd/C catalyst with 10% Pd content, and introducing H into the autoclave2And ensuring that the pressure in the reaction kettle is 2.0-3.0 Mpa, heating to 120 ℃, carrying out heat preservation reaction for 12 hours, cooling to room temperature after the reaction is finished, filtering to recover the catalyst, carrying out reduced pressure distillation to remove the solvent, and recrystallizing the residue with an ethanol solution with the volume fraction of 80% to obtain 125.28g of the target product 2-amino-5-chlorobenzophenone, wherein the yield is 82.79%, and the purity is 96.68%.
The results show that compared with the conventional high-pressure reaction kettle, the microchannel reactor has the advantages of high reaction speed, small liquid holdup, safety, environmental protection and the like, the contents of degraded impurities and dechlorination byproducts in the reaction process can be greatly reduced, and the final product has high yield and better quality.
Claims (6)
1. A method for synthesizing 2-amino-5 chlorobenzophenone by a microchannel reactor is characterized by comprising the following steps:
1) adding a hydrogenation reaction precursor 5-chloro-3-phenyl-2, 1-benzisoxazole into an organic solvent, then adding activated carbon to load a noble metal catalyst, and taking the obtained mixture as a material I to enter a preheating module of a microreactor;
2) pumping a material I into a preheating module for reaction, introducing hydrogen gas of the material II into a mixed reaction module of a reaction module group, carrying out hydrogenation reduction reaction on the material I and the material II in the reaction module group of the microchannel reactor, wherein the reaction pressure is 0.5-1.5 MPa, the reaction temperature is 50-100 ℃, the total reaction residence time is 15-40 s, collecting reaction liquid flowing out of a cooling module, the temperature of the cooling module is 20-30 ℃, and carrying out post-treatment to obtain 2-amino-5-chlorobenzophenone;
the organic solvent in the step 1) is a mixture of an organic solvent I and an organic solvent II, wherein the organic solvent I is any one of methanol, ethanol and isopropanol, and the solvent II is any one of ethyl acetate, tetrahydrofuran and acetonitrile;
step 1), the active carbon supported noble metal catalyst is any one or combination of more than one of Pd/C, Pt/C, Rh/C, and the mass of noble metal in the active carbon supported noble metal catalyst accounts for 1-10% of the total mass of the catalyst;
the initial concentration of the 5-chloro-3-phenyl-2, 1-benzisoxazole in the organic solvent in the step 1) is 0.1-0.4 mol/L;
the mass ratio of the 5-chloro-3-phenyl-2, 1-benzisoxazole and the activated carbon supported noble metal catalyst in the step 1) is (1:0.01) - (1: 0.10); the molar ratio of the 5-chloro-3-phenyl-2, 1-benzisoxazole to hydrogen is (1:1.0) - (1: 1.5).
2. The method for synthesizing 2-amino-5-chlorobenzophenone with the microchannel reactor as claimed in claim 1, wherein the reaction temperature in step 2) is 80 ℃.
3. The method for synthesizing 2-amino-5-chlorobenzophenone in a microchannel reactor as claimed in claim 1, wherein the post-treatment in step 2) is to filter the reaction solution to recover the catalyst, to distill under reduced pressure to recover the solvent, and to add 80 vol% ethanol solution to the residue to recrystallize to obtain the target product 2-amino-5-chlorobenzophenone.
4. The method for synthesizing 2-amino-5-chlorobenzophenone with a microchannel reactor as claimed in claim 1, wherein the hydrogen gas of the material I and the hydrogen gas of the material II are controlled to enter the reaction module by a slurry pump and a gas flow meter.
5. The method for synthesizing 2-amino-5 chlorobenzophenone with a microchannel reactor as claimed in claim 1, wherein the microchannel reactor comprises a preheating module set, a reaction module set and a cooling module, the preheating module set comprises one preheating module or more than two preheating modules connected in parallel, the preheating module is a straight structure or a two-in-one-out heart-shaped structure module, and the preheating module is connected in series with the reaction module set; the reaction module group comprises 1-8 unit modules, all the unit modules are combined in series or in parallel at will, the reaction module and the cooling module are heart-shaped structure modules with two inlets and one outlet or with one inlet and one outlet, and the cooling module is connected with the reaction module group in series; when the reaction is carried out in the microchannel reactor, the preheating module group and the reaction module group are connected in sequence of a preheating module, a reaction module with a two-in one-out structure, a reaction module with a single-in single-out structure and a cooling module with a single-in single-out structure.
6. The method for synthesizing 2-amino-5 chlorobenzophenone with the microchannel reactor according to claim 1, wherein the reaction module is made of at least one of special glass, silicon carbide ceramic, stainless steel metal coated with a corrosion-resistant layer, or poly-tetrachloroethylene, and the maximum pressure applied to the reaction module is 1.5 to 1.8 MPa.
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