Process for the synthesis of benzimidazole michael addition derivatives in a continuous flow reactor

Abstract

The application provides a method for synthesizing benzimidazole Michael addition derivatives in a continuous flow reactor, and 2-methylbenzimidazole and alpha, beta-unsaturated olefins are used to catalyze the online synthesis of benzimidazole Michael addition derivatives in a microfluidic channel reactor by using a lipase Lipozyme RM IM. The method not only greatly shortens the reaction time, but also has high conversion rate; meanwhile, the Michael addition reaction of 2-methylbenzimidazole and alpha, beta-unsaturated olefins is catalyzed by using the economical lipase Lipozyme RM IM in methanol, the reaction cost is reduced, the post-processing step is simplified, and the method has the advantages of green environmental protection, economy and efficiency.

Description

Technical Field

[0001] This invention relates to a method for synthesizing benzimidazole Michael addition derivatives in a continuous flow reactor. Background Technology

[0002] Nitrogen-containing organic compounds are widely distributed in nature, and most of them possess important physiological and pharmacological activities in organisms. They are not only prevalent in nature and organisms but also have significant applications in chemistry, pharmacology, biology, materials science, and chemical production. In particular, many pharmacologically active natural products, active drug molecules and intermediates, therapeutic drugs, functional materials, and fluorescent probes are nitrogen-containing heterocyclic compounds. Among these, benzimidazole compounds generally exhibit strong physiological and pharmacological activities and are frequently found in the structural skeletons of various drug molecules and natural products, demonstrating excellent activity in antitumor, anti-inflammatory, and antibacterial applications. Studies have shown that cyano-linked polybrominated benzimidazole compounds have good inhibitory activity against acute lymphoblastic leukemia T lymphocytes (CCRF-CEM and MCF-7), and the alkyl group attached to the cyano group at the N-1 position of benzimidazole significantly affects apoptosis. Clearly, to synthesize such biologically active benzimidazole derivatives, it is necessary to construct CN bonds at specific positions. Therefore, finding novel, efficient, simple, and green CN bond construction methods has become a hot topic in current chemical synthesis methodology and drug research.

[0003] The construction of the CN bond is crucial for the synthesis of N-substituted benzimidazole derivatives. The Michael addition reaction of benzimidazole with α,β-unsaturated olefins has proven to be one of the simplest and most efficient methods for the corresponding adducts. However, benzimidazole, as a poorly nucleophilic Michael addition donor, generally requires strong acid or strong base conditions, high reaction temperatures, and long reaction times.

[0004] Enzymes, as excellent biocatalysts, have attracted widespread attention in organic synthesis, pharmaceuticals, petrochemicals, and materials science. They can be applied to many different reactions, including kinetic resolution, esterification, hydrolysis, ammonolysis, and transesterification. Furthermore, lipases can catalyze Michael addition, Markov addition, and reverse Markov addition reactions to form C-heteroatom and heteroatom-heteroatom bonds. However, enzymatic reactions are limited by solvent solubility in the substrate and the inhibition of enzyme activity by solvent polarity, resulting in long reaction times and relatively low conversion rates for specific substrates. Therefore, developing a novel microfluidic-based synthesis technique for benzimidazole compounds, building upon traditional enzymatic reactions, has become our research objective.

[0005] Compared to conventional chemical reactors, microfluidic reactors offer advantages such as high mixing efficiency, rapid mass and heat transfer, precise parameter control, high reaction selectivity, and good safety. Due to their superior performance, they not only well meet the requirements of green chemistry and fine chemical engineering but also hold promising research and development prospects in chemical synthesis and biocatalysis. Microfluidic reactors are widely used in organic synthesis, catalysis, and extraction. In continuous flow microreactors, many reactions can be rapidly screened under microscale conditions, allowing for safe reactions even under harsh experimental conditions. This significantly saves reaction materials, improves screening efficiency, and aligns more closely with the concept of green chemistry. Continuous flow processing technology in microreactors is finding increasing applications in enzyme biotechnology and biocatalysis.

[0006] To develop a novel, efficient, and environmentally friendly synthetic technique for benzimidazole Michael addition derivatives, we investigated a lipase-catalyzed online synthesis method for benzimidazole Michael addition derivatives in a continuous flow microreactor. Our aim was to find a new, highly efficient, and environmentally friendly synthetic technique for benzimidazole Michael addition derivatives. Summary of the Invention

[0007] The present invention aims to provide a novel method for synthesizing benzimidazole Michael addition derivatives in a continuous flow reactor, which has the advantages of short reaction time and high yield.

[0008] To achieve the above objectives, the technical solution of the present invention is as follows:

[0009] This invention provides a method for synthesizing benzimidazole Michael addition derivatives in a continuous flow reactor. The method employs a microfluidic channel reactor, which includes a syringe, a reaction channel, and a product collector connected in sequence. The syringe is installed in an injection pump and is connected to the inlet of the reaction channel via a first connecting pipe. The product collector is connected to the outlet of the reaction channel via a second connecting pipe. The inner diameter of the reaction channel is 1.6-2.2 mm (preferably 2.0 mm), and the length of the reaction channel is 0.8-1.2 m (preferably 1.0 m).

[0010] The method includes:

[0011] Using methanol as the reaction solvent, 2-methylbenzimidazole (Formula I) and α,β-unsaturated olefin (Formula II) as raw materials, and lipase Lipozyme RM IM as the catalyst, a reaction system was constructed. The raw materials and the reaction solvent were placed in a syringe, and lipase Lipozyme RM IM was uniformly filled into the reaction channel of a microfluidic channel reactor. Under the synchronous push of the injection pump, the raw materials and the reaction solvent were continuously introduced into the reaction channel to carry out the Michael addition reaction. The reaction temperature was controlled at 35-55℃ (preferably 45℃), and the reaction time of the reaction liquid flowing continuously in the reaction channel was 30-50 min (preferably 35 min). The reaction liquid flowing out of the reaction channel was collected online by a product collector. The reaction liquid was post-treated to obtain the benzimidazole Michael addition derivative shown in Formula (III).

[0012]

[0013] In formulas (II) and (III), R is a cyano group or -COOCH3;

[0014] The molar ratio of 2-methylbenzimidazole of formula (I) to α,β-unsaturated olefin of formula (II) is 1:0.5 to 6 (particularly preferred 1:4); the amount of catalyst added, based on the volume of the reaction solvent, is 0.030 g / mL to 0.060 g / mL (preferably 0.04 g / mL) within the maximum capacity of the reaction channel to accommodate the filled catalyst; and the concentration of 2-methylbenzimidazole of formula (I) in the reaction system is 0.1 mmol / mL to 0.4 mmol / mL (preferably 0.25 mmol / mL).

[0015] The lipase Lipozyme RM IM used is a commercial product manufactured by Novozymes. It is a food-grade lipase (EC 3.1.1.3) prepared by microorganisms, specifically for positions 1 and 3, on granular silica gel. It is produced by deep fermentation of a genetically modified Aspergillus oryzae microorganism obtained from Rhizomucor miehei. The lipase Lipozyme RM IM can be prepared by directly and uniformly immobilizing the granular catalyst in the reaction channel using physical methods.

[0016] That is, equation (III) is

[0017] Furthermore, in the microfluidic channel reactor used in this invention, the number of syringes can be one or more, depending on the specific reaction requirements. This invention uses two reaction materials, preferably two syringes. Specifically, the syringes are a first syringe and a second syringe. The first connecting pipe is a Y-shaped or T-shaped pipe. The first syringe and the second syringe are respectively connected to the two ports of the Y-shaped or T-shaped pipe and connected in series with the reaction channel through the Y-shaped or T-shaped pipe. The increased probability of contact and collision between reactant molecules in the microchannel allows the two reaction streams to mix and react in the common reaction channel. That is, the microfluidic channel reactor of this invention includes a first syringe, a second syringe, a reaction channel, and a product collector; the first syringe and the second syringe are connected to the inlet of the reaction channel via Y-shaped or T-shaped pipes, and the product collector is connected to the outlet of the reaction channel via a pipe.

[0018] Furthermore, the 2-methylbenzimidazole shown in formula (I) and the α,β-unsaturated olefin shown in formula (II) are each dissolved in methanol to obtain a 2-methylbenzimidazole solution and an α,β-unsaturated olefin solution, which are then introduced into the reaction channel via the first syringe and the second syringe, respectively. In the 2-methylbenzimidazole solution, the concentration of the 2-methylbenzimidazole shown in formula (I) is 0.2 mmol / mL to 0.8 mmol / mL (preferably 0.5 mmol / mL), and the concentration of the α,β-unsaturated olefin solution shown in formula (II) is 0.25 to 3.0 mmol / mL (preferably 2 mmol / mL).

[0019] Furthermore, this invention recommends a method for synthesizing benzimidazole Michael addition derivatives in a continuous flow reactor. The method employs a microfluidic channel reactor, which includes a syringe, a reaction channel, and a product collector connected in sequence. The syringe is installed in an injection pump and is connected to the inlet of the reaction channel via a first connecting pipe. The product collector is connected to the outlet of the reaction channel via a second connecting pipe. The inner diameter of the reaction channel is 1.6–2.2 mm (preferably 2.0 mm), and the length of the reaction channel is 0.8–1.2 m (preferably 1.0 m). The syringes are a first syringe and a second syringe. The first connecting pipe is a Y-type or T-type pipe. The first syringe and the second syringe are respectively connected to two ports of the Y-type or T-type pipe and connected in series with the reaction channel via the Y-type or T-type pipe.

[0020] The method is as follows: 2-methylbenzimidazole of formula (I) and α,β-unsaturated olefin of formula (II) are dissolved in methanol to obtain a 2-methylbenzimidazole solution of formula (I) with a concentration of 0.2 mmol / mL to 0.8 mmol / mL (preferably 0.5 mmol / mL) and an α,β-unsaturated olefin solution of formula (II) with a concentration of 0.25 to 3.0 mmol / mL (preferably 2 mmol / mL); the 2-methylbenzimidazole solution of formula (I) and the α,β-unsaturated olefin solution of formula (II) are respectively loaded into the first syringe and the second syringe, and the first syringe and the second syringe are loaded into the same injection pump; lipase Lipozyme RM After IM is uniformly filled into the reaction channel of the microfluidic channel reactor, the 2-methylbenzimidazole solution shown in formula (I) and the α,β-unsaturated olefin solution shown in formula (II) are continuously and synchronously introduced into the reaction channel under the synchronous push of the injection pump to carry out the Michael addition reaction. The reaction temperature is controlled at 35-55°C (preferably 45°C), and the reaction time in which the reaction solution flows continuously in the reaction channel is 30-50 min (preferably 35 min). The reaction solution flowing out of the reaction channel is collected online by the product collector. The reaction solution is post-processed to obtain the benzimidazole Michael addition derivative shown in formula (III). The concentration ratio of the 2-methylbenzimidazole solution shown in formula (I) to the α,β-unsaturated olefin solution shown in formula (II) is 1:0.5-6 (particularly preferred 1:4). Within the maximum limit that the reaction channel can accommodate the filled catalyst, the amount of catalyst added is 0.03 g / mL to 0.06 g / mL (preferably 0.04 g / mL) based on the volume of the reaction medium.

[0021] Further, the post-processing is as follows: after removing the solvent from the reaction solution under reduced pressure, silica gel column chromatography is performed using a mixed solution of methanol and dichloromethane with a volume ratio of 1:60 as the eluent, the eluent containing the target compound is collected, evaporated to dryness, and the benzimidazole Michael addition derivative shown in formula (III) is obtained.

[0022] Specifically, the silica gel column used in the silica gel column chromatography was prepared by wet packing with 200-300 mesh silica gel, with a column height of 35 cm and a column diameter of 4.5 cm. The specific operation was as follows: after evaporating the solvent, the sample was dissolved in a small amount of eluent and then loaded onto the column using a wet packing method. The eluent was collected at a flow rate of 2 mL / min. -1 Meanwhile, TLC was used to track the elution process, and the resulting eluents containing a single target compound were combined, evaporated to dryness, and the benzimidazole Michael addition derivative shown in formula (III) was obtained.

[0023] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0024] This invention enables the online synthesis of benzimidazole Michael addition derivatives in a microfluidic channel reactor. This method not only significantly shortens the reaction time but also achieves high conversion rates. The post-processed product has a purity of over 99% and can be considered a pure product. Furthermore, it is the first time that the economical lipase Lipozyme RM IM has been used to catalyze the Michael addition reaction of 2-methylbenzimidazole with α,β-unsaturated olefins, reducing reaction costs and demonstrating economic and high efficiency. Attached Figure Description

[0025] Figure 1 This is a schematic diagram of the microfluidic channel reactor used in an embodiment of the present invention.

[0026] In the diagram, 1-first syringe, 2-second syringe, 3-reaction channel, 4-product collector, 5-water bath thermostat. Detailed Implementation

[0027] The present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto:

[0028] Structural reference of the microfluidic channel reactor used in the embodiments of the present invention Figure 1 The system includes a syringe pump (not shown), two syringes 1 and 2, a reaction channel 3, a water bath thermostat (5, only its plan view is shown), and a product collector 4. The two syringes 1 and 2 are installed in the syringe pump and connected to the inlet of the reaction channel 3 through a Y-type interface. The reaction channel 3 is placed in the water bath thermostat 5, and the reaction temperature is controlled by the water bath thermostat 5. The inner diameter of the reaction channel 3 is 2.0 mm, and the tube length is 1.0 m. The outlet of the reaction channel 3 is connected to the product collector 4 through an interface.

[0029] Example 1: Synthesis of 3-(2-methyl-benzimidazolyl)propionitrile

[0030]

[0031] Device Reference Figure 1 2-Methylbenzimidazole (5.0 mmol, 0.661 g) and acrylonitrile (20.0 mmol, 1.061 g) were dissolved in 10 mL of methanol, and then each was placed into a 10 mL syringe for later use. 0.87 g of Lipozyme RM IM was uniformly filled into the reaction channel. Using a PHD 2000 syringe pump, the two reaction solutions were dispensed at a rate of 8.91 μL / min. -1 The flow rate enters the reaction channel through the "Y" connector to carry out the reaction. The reactor temperature is controlled at 45℃ by a water bath constant temperature box. The reaction solution flows continuously in the reaction channel for 35 minutes. The reaction results are tracked and detected by thin-layer chromatography (TLC).

[0032] The reaction solution was collected online using a product collector. The solvent was removed by vacuum distillation. The solution was then packed into a column using a wet method with 200-300 mesh silica gel. The eluent was methanol:dichloromethane (v / v) = 1:60. The column height was 35 cm and the column diameter was 4.5 cm. The sample was dissolved in a small amount of the eluent and then loaded onto the column using a wet method. The eluent was collected at a flow rate of 2 mL / min. -1 Meanwhile, TLC was used to track the elution process, and the eluents containing a single product were combined and evaporated to dryness to obtain 0.842 g of white solid, with a separation yield of 91%.

[0033] The NMR characterization results are as follows: 1 H NMR (400MHz, DMSO-d6) δ7.65–7.58(m,1H),7.58–7.49(m,1H),7.18(pd,J=7.2,1.4Hz,2H),4.52(t,J=6.6Hz,2H),3.05(t,J=6.6Hz,2H),2.59(s,3H). 13 C NMR (101MHz, DMSO-d6) δ151.84,142.36,134.70,121.69,121.57,118.80,118.31,110.04,38.72,17.87,13.50.

[0034] Examples 2-6

[0035] The solvent in the microfluidic microchannel reactor was changed, while other aspects remained the same as in Example 1. The results are shown in Table 1.

[0036] Table 1 Effect of solvent on reaction

[0037] Example solvent Conversion rate [%) Production [g] 1 Methanol (20 mL) 91 0.842 2 tert-amyl alcohol (20 mL) 20 0.185 3 Acetonitrile (20 mL) 25 0.232 4 Cyclohexane (20 mL) nd 0 5 DMF (20mL) 47 0.435 6 DMSO (20 mL) 50 0.463

[0038] The results in Table 1 show that when the molar ratio of 2-methylbenzimidazole to acrylonitrile is 1:4 and the flow rate is 17.8 μL·min, the desired effect is achieved. -1 The reaction time was 35 min and the reaction temperature was 45 °C. The conversion rate was optimal when methanol was used as the organic solvent in the reactor. Therefore, methanol is the optimal solvent in the microfluidic microchannel reactor of this invention.

[0039] Examples 7-10

[0040] The temperature of the microfluidic channel reactor was changed, and other aspects remained the same as in Example 1. The reaction results are shown in Table 2.

[0041] Table 2: Effect of temperature on the reaction

[0042] Example Temperature [°C] Conversion rate [%) Production [g] 7 35 69 0.639 8 40 85 0.787 1 45 91 0.842 9 50 86 0.796 10 55 81 0.750

[0043] The results in Table 2 show that when the flow rate is 17.8 μL·min -1 The reaction time was 35 min, methanol was used as the organic solvent, and the molar ratio of 2-methylbenzimidazole to acrylonitrile was 1:4. The conversion rate was optimal at a reaction temperature of 45℃. Temperatures that were too high or too low would affect enzyme activity. Therefore, the optimal temperature in the microfluidic microchannel reactor of this invention was 45℃.

[0044] Examples 11-14

[0045] Using the amount of 2-methylbenzimidazole as a baseline, the molar ratio of benzimidazole to acrylonitrile in the microfluidic microchannel reactor was varied, while other aspects remained the same as in Example 1. The results are shown in Table 3.

[0046] Table 3 Effect of substrate molar ratio on the reaction

[0047] Example 2-Methylbenzimidazole and acrylonitrile Conversion rate [%) Production [g] 11 1:0.5(5.0mmol:2.5mmol,0.661g:0.133g) 44 0.407 12 1:1(5.0mmol:5.0mmol,0.661g:0.265g) 73 0.676 13 1:2(5.0mmol:10.0mmol,0.661g:0.531g) 81 0.750 1 1:4(5.0mmol:20.0mmol,0.661g:1.061g) 91 0.842 14 1:6(5.0mmol:30.0mmol,0.661g:1.592g) 86 0.795

[0048] The results in Table 3 show that when the flow rate is 17.8 μL·min -1 The reaction time was 35 min and the reaction temperature was 45 °C. Methanol was used as the organic solvent in the reactor. As the amount of acrylonitrile increased, the conversion rate of the reaction also increased. The conversion rate was optimal when the substrate ratio of 2-methylbenzimidazole to acrylonitrile was 1:4. Therefore, the optimal substrate molar ratio in the microfluidic microchannel reactor of this invention is 1:4.

[0049] Examples 15-20

[0050] The reaction time of the microfluidic channel reactor was changed, while other aspects remained the same as in Example 1. The reaction results are shown in Table 4.

[0051] Table 4. Effect of reaction time on the reaction

[0052] Example Time [min] Conversion rate [%) Production [g] 15 20 55 0.509 16 25 73 0.676 17 30 87 0.805 1 35 91 0.842 18 40 86 0.796 19 45 85 0.787 20 50 83 0.768

[0053] The results in Table 4 show that when methanol is used as the organic solvent in the reactor, the molar ratio of the reactants 2-methylbenzimidazole and acrylonitrile is 1:4, the reaction temperature is 45℃, and the reaction time is 35 min, the conversion rate is 91%. Therefore, the optimal reaction time in the microfluidic microchannel reactor of this invention is 35 min.

[0054] Comparative Examples 1-4

[0055] The type of benzimidazole in the microfluidic channel reactor was changed, replacing 2-methylbenzimidazole with 5-aminobenzimidazole, 5-carboxylic acid benzimidazole, 6-benzylaminopurine, and 2-phenylbenzimidazole. Other reactions were the same as in Example 1. The reaction results are shown in Table 5.

[0056] Table 5. Effect of different benzimidazoles on reaction conversion rate

[0057]

[0058]

[0059] The results showed that the structure of different benzimidazoles had a significant impact on the conversion rate of the Michael addition of benzimidazole to acrylonitrile. The conversion rates of 5-aminobenzimidazole, 5-carboxylic acid benzimidazole, 6-benzylaminopurine, and 2-phenylbenzimidazole for the Michael addition were less than 5%, while the conversion rate of 2-methylbenzimidazole as a reactant reached 91%.

[0060] Comparative Examples 5-8

[0061] The type of acrylonitrile in the microfluidic channel reactor was changed to 3-phenylacrylonitrile, 3-(dimethylamino)acrylonitrile, 2-butenonitrile, or 2-methyl-2-butenonitrile, while other aspects remained the same as in Example 1. The reaction results are shown in Table 6.

[0062] Table 6. Effect of different acrylonitriles on reaction conversion rate

[0063] Comparative Example Acrylonitrile Conversion rate [%) 5 3-Phenylacetonitrile (20.0 mmol, 2.583 g) 18 6 3-(dimethylamino)acrylonitrile (20.0 mmol, 1.922 g) <5 7 2-Butenonitrile (20.0 mmol, 1.341 g) <5 8 2-Methyl-2-butenonitrile (20.0 mmol, 1.622 g) <5 Example 1 Acrylonitrile (20.0 mmol, 1.061 g) 91

[0064] The results showed that the structure of different acrylonitriles had a significant impact on the conversion rate of the Michael addition of 2-methylbenzimidazole to acrylonitrile. Among 3-(dimethylamino)acrylonitrile, 2-butenonitrile, and 2-methyl-2-butenonitrile, the conversion rate of benzimidazole to Michael addition was less than 5%, while the conversion rate of acrylonitrile as a reactant reached 91%.

[0065] Comparative Examples 9-12

[0066] The catalyst in the microfluidic microchannel reactor was changed to porcine pancreatic lipase PPL, lipase Novozym435, Bacillus subtilis alkaline protease, and lipase TM IM, respectively. Other aspects were the same as in Example 1. The results are shown in Table 7.

[0067] Table 7. Effects of different enzymes on reaction conversion rate and selectivity

[0068] Comparative Example enzyme source Conversion rate [%) Selectivity [%) 9 PPL 19 100 10 Novozym435 45 100 11 Bacillus subtilis alkaline protease ＜5 100 12 Lipase™ IM 50 100 Example 1 Lipase RM IM 91 100

[0069] The results showed that different enzymes had a significant impact on the Michael addition reaction of 2-methylbenzimidazole and acrylonitrile in a microfluidic channel reactor. Using lipase™ IM to catalyze the reaction, the conversion rate of 2-methylbenzimidazole was 50%. However, using PPL to catalyze the reaction, the conversion rate was only 19%. Therefore, the optimal enzyme source for the microfluidic channel reactor in this invention is lipase RM IM.

[0070] Example 21: Synthesis of methyl 3-(2-methyl-benzimidazolyl)propionate

[0071]

[0072] Device Reference Figure 1 2-Methylbenzimidazole (5.0 mmol, 0.661 g) and methyl acrylate (20.0 mmol, 1.722 g) were dissolved in 10 mL of methanol and then separately placed into 10 mL syringes for later use. 0.87 g of Lipozyme RM IM was uniformly filled into the reaction channel. Using a PHD 2000 syringe pump, the two reaction solutions were dispensed at a rate of 8.91 μL / min. -1 The flow rate enters the reaction channel through the "Y" connector to carry out the reaction. The reactor temperature is controlled at 45℃ by a water bath constant temperature box. The reaction solution flows continuously in the reaction channel for 35 minutes. The reaction results are tracked and detected by thin-layer chromatography (TLC).

[0073] The reaction solution was collected online using a product collector. The solvent was removed by vacuum distillation. The solution was then packed into a column using a wet method with 200-300 mesh silica gel. The eluent was methanol:dichloromethane (v / v) = 1:60. The column height was 35 cm and the column diameter was 4.5 cm. The sample was dissolved in a small amount of the eluent and then loaded onto the column using a wet method. The eluent was collected at a flow rate of 2 mL / min. -1 Meanwhile, TLC was used to track the elution process, and the eluents containing a single product were combined and evaporated to dryness to obtain 1.004 g of colorless oily liquid, with a separation yield of 92%.

[0074] The NMR characterization results are as follows: 1 H NMR (400MHz, DMSO-d6) δ7.58–7.45(m,2H),7.16(pd,J=7.2,1.4Hz,2H),4.43(t,J=7.0Hz,2H),3.56(s,3H),2.85(t,J=6.9Hz,2H),2.55(s,3H). 13C NMR (101MHz, DMSO-d6) δ171.24,151.81,142.43,134.75,121.48,121.25,118.24,109.86,51.56,38.99,33.35,13.40.

[0075] Examples 22-26

[0076] The solvent in the microfluidic microchannel reactor was changed, while other aspects remained the same as in Example 21. The results are shown in Table 8.

[0077] Table 8. Effect of solvent on the reaction

[0078] Example solvent Conversion rate [%) Production [g] 21 Methanol (20 mL) 92 1.004 22 Ethanol (20 mL) 37 0.403 23 Isopropanol (20 mL) 31 0.338 24 Cyclohexane (20 mL) nd 0 25 DMF (20mL) 39 0.425 26 DMSO (20 mL) 48 0.523

[0079] The results in Table 8 show that when the molar ratio of 2-methylbenzimidazole to methyl acrylate is 1:4 and the flow rate is 17.8 μL·min, the desired effect is achieved. -1 The reaction time was 35 min and the reaction temperature was 45 °C. The conversion rate was optimal when methanol was used as the organic solvent in the reactor. Therefore, methanol is the optimal solvent in the microfluidic microchannel reactor of this invention.

[0080] Examples 27-30

[0081] The temperature of the microfluidic channel reactor was changed, and other aspects were the same as in Example 21. The reaction results are shown in Table 9.

[0082] Table 9 Effect of temperature on the reaction

[0083] Example Temperature [°C] Conversion rate [%) Production [g] 27 35 64 0.698 28 40 80 0.873 21 45 92 1.004 29 50 85 0.927 30 55 80 0.873

[0084] The results in Table 9 show that when the flow rate is 17.8 μL·min -1 The reaction time was 35 min, methanol was used as the organic solvent, and the molar ratio of 2-methylbenzimidazole to methyl acrylate was 1:4. The conversion rate was optimal at a reaction temperature of 45°C; temperatures that were too high or too low would affect enzyme activity. Therefore, the optimal temperature in the microfluidic microchannel reactor of this invention was 45°C.

[0085] Examples 31-34

[0086] Using the amount of 2-methylbenzimidazole as a baseline, the molar ratio of 2-methylbenzimidazole to methyl acrylate in the microfluidic microchannel reactor was varied, while other aspects remained the same as in Example 21. The results are shown in Table 10.

[0087] Table 10 Effect of substrate molar ratio on the reaction

[0088]

[0089]

[0090] The results in Table 10 show that when the flow rate is 17.8 μL·min -1 The reaction time was 35 min and the reaction temperature was 45 °C. Methanol was used as the organic solvent in the reactor. As the reactant methyl acrylate increased, the conversion rate of the reaction also increased. The conversion rate was optimal when the substrate ratio of 2-methylbenzimidazole to methyl acrylate was 1:4. Therefore, the optimal substrate molar ratio in the microfluidic microchannel reactor of this invention is 1:4.

[0091] Examples 35-40

[0092] The reaction time of the microfluidic channel reactor was changed, while other aspects remained the same as in Example 21. The reaction results are shown in Table 11.

[0093] Table 11 Effect of reaction time on the reaction

[0094] Example Time [min] Conversion rate [%) Production [g] 35 20 50 0.545 36 25 63 0.687 37 30 80 0.873 21 35 92 1.004 38 40 90 0.982 39 45 88 0.960 40 50 86 0.938

[0095] The results in Table 11 show that when methanol is used as the organic solvent in the reactor, the molar ratio of reactants 2-benzimidazole and methyl acrylate is 1:4, the reaction temperature is 45℃, and the reaction time is 35 min, the reaction conversion rate is 92%. Therefore, the optimal reaction time in the microfluidic microchannel reactor of this invention is 35 min.

[0096] Comparative Examples 13-16

[0097] The type of benzimidazole in the microfluidic channel reactor was changed, replacing 2-methylbenzimidazole with 5-aminobenzimidazole, 5-carboxylic acid benzimidazole, 6-benzylaminopurine, and 2-phenylbenzimidazole. Other reactions were the same as in Example 21. The reaction results are shown in Table 12.

[0098] Table 12 Effect of different benzimidazoles on reaction conversion rate

[0099] Comparative Example Acrylonitrile Conversion rate [%) 13 5-Aminobenzimidazole (5.0 mmol, 0.666 g) <5 14 5-Carboxylic acid benzimidazole (5.0 mmol, 0.811 g) <5 15 6-Benzylaminopurine (5.0 mmol, 1.126 g) <5 16 2-Phenylenimazole (5.0 mmol, 0.971 g) <5 Example 21 2-Methylbenzimidazole (5.0 mmol, 0.661 g) 92

[0100] The results showed that the structure of different benzimidazoles had a significant impact on the conversion rate of the Michael addition of benzimidazole with methyl acrylate. The conversion rates of 5-aminobenzimidazole, 5-carboxylic acid benzimidazole, 6-benzylaminopurine, and 2-phenylbenzimidazole with methyl acrylate were less than 5%, while the conversion rate of 2-methylbenzimidazole as a reactant reached 92%.

[0101] Comparative Examples 17-20

[0102] The type of acrylate in the microfluidic channel reactor was changed, with methyl acrylate replaced by butyl acrylate, tert-butyl acrylate, methyl methacrylate, and tert-butyl methacrylate, while other aspects remained the same as in Example 21. The reaction results are shown in Table 13.

[0103] Table 13 Effect of different acrylates on reaction conversion rate

[0104]

[0105]

[0106] The results showed that the structure of different acrylates had a significant impact on the conversion rate of the Michael addition of 2-methylbenzimidazole. In methyl methacrylate and tert-butyl methacrylate, the conversion rate of 2-methylbenzimidazole by the Michael addition was less than 5%, while the conversion rate of 2-methylbenzimidazole reached 92% when methyl methacrylate was used as a reactant.

[0107] Comparative Examples 21-24

[0108] The catalyst in the microfluidic microchannel reactor was changed to porcine pancreatic lipase PPL, lipase Novozym435, Bacillus subtilis alkaline protease, and lipase TM IM, respectively. Other aspects were the same as in Example 21. The results are shown in Table 14.

[0109] Table 14 Effects of different enzymes on reaction conversion rate and selectivity

[0110] Comparative Example enzyme source Conversion rate [%) Selectivity [%) 21 PPL 20 100 22 Novozym 435 27 100 23 Bacillus subtilis alkaline protease <5 100 24 Lipase™ IM 50 100 Example 21 Lipase RM IM 92 100

[0111] The results showed that different enzymes had a significant impact on the enzymatic Michael addition reaction of 2-methylbenzimidazole with methyl acrylate in a microfluidic reactor. Using Novozym 435 as a catalyst, the conversion rate of 2-methylbenzimidazole was only 35%. Using PPL as a catalyst, the conversion rate was only 20%. Therefore, the most effective catalyst for the enzymatic online synthesis of benzimidazole Michael addition derivatives in a microfluidic reactor is the lipase Lipozyme RM IM, which achieved a 2-methylbenzimidazole conversion rate of 92%.

Claims

1. A method for synthesizing benzimidazole Michael addition derivatives in a continuous flow reactor, characterized in that: The method employs a microfluidic channel reactor, which includes a syringe, a reaction channel, and a product collector connected in sequence. The syringe is installed in an injection pump and is connected to the inlet of the reaction channel via a first connecting pipe. The product collector is connected to the outlet of the reaction channel via a second connecting pipe. The inner diameter of the reaction channel is 1.6-2.2 mm, and the length of the reaction channel is 0.8-1.2 m. The method includes: Using methanol as the reaction solvent, 2-methylbenzimidazole (Formula I) and α,β-unsaturated olefin (Formula II) as raw materials, and lipase Lipozyme RM IM as the catalyst, a reaction system was constructed. The raw materials and the reaction solvent were placed in a syringe, and lipase Lipozyme RM IM was uniformly filled into the reaction channel of a microfluidic channel reactor. Under the synchronous push of the injection pump, the raw materials and the reaction solvent were continuously introduced into the reaction channel to carry out the Michael addition reaction. The reaction temperature was controlled at 35-55°C, and the reaction time of the reaction liquid flowing continuously in the reaction channel was 30-50 min. The reaction liquid flowing out of the reaction channel was collected online by a product collector. The reaction liquid was post-treated to obtain the benzimidazole Michael addition derivative shown in Formula (III). In formulas (II) and (III), R is a cyano group or -COOCH3; The molar ratio of 2-methylbenzimidazole of formula (I) to α,β-unsaturated olefin of formula (II) is 1:0.5 to 6; within the maximum extent that the reaction channel can accommodate the filled catalyst, the amount of catalyst added is 0.030 g / mL to 0.060 g / mL based on the volume of the reaction solvent; in the reaction system, the concentration of 2-methylbenzimidazole of formula (I) is 0.1 mmol / mL to 0.4 mmol / mL.

2. The method for synthesizing benzimidazole Michael addition derivatives in a continuous flow reactor as described in claim 1, characterized in that: The reaction temperature is 45°C.

3. The method for synthesizing benzimidazole Michael addition derivatives in a continuous flow reactor as described in claim 1, characterized in that: The molar ratio of 2-methylbenzimidazole shown in formula (I) to α,β-unsaturated olefin shown in formula (II) is 1:

4.

4. The method for synthesizing benzimidazole Michael addition derivatives in a continuous flow reactor as described in claim 1, characterized in that: The amount of catalyst added was 0.04 g / mL based on the volume of the reaction solvent.

5. The method for synthesizing benzimidazole Michael addition derivatives in a continuous flow reactor as described in claim 1, characterized in that: In the reaction system, the concentration of 2-methylbenzimidazole shown in formula (I) is 0.25 mmol / mL.

6. The method for synthesizing benzimidazole Michael addition derivatives in a continuous flow reactor as described in claim 1, characterized in that: The number of syringes is two.

7. The method for synthesizing benzimidazole Michael addition derivatives in a continuous flow reactor as described in claim 6, characterized in that: The syringes are a first syringe and a second syringe. The first connecting tube is a Y-shaped or T-shaped tube. The first syringe and the second syringe are respectively connected to two ports of the Y-shaped or T-shaped tube and connected in series with the reaction channel through the Y-shaped or T-shaped tube.

8. The method for synthesizing benzimidazole Michael addition derivatives in a continuous flow reactor as described in claim 7, characterized in that: The 2-methylbenzimidazole shown in formula (I) and the α,β-unsaturated olefin shown in formula (II) are each dissolved in methanol to obtain a 2-methylbenzimidazole solution and an α,β-unsaturated olefin solution, respectively, which are then introduced into the reaction channel through the first syringe and the second syringe; in the 2-methylbenzimidazole solution, the concentration of the 2-methylbenzimidazole shown in formula (I) is [missing information]. The concentration of the α,β-unsaturated olefin solution shown in formula (II) is 0.2 mmol / mL to 0.8 mmol / mL, and the concentration is 0.25 to 3.0 mmol / mL.

9. The method for synthesizing benzimidazole Michael addition derivatives in a continuous flow reactor as described in claim 6, characterized in that: The method employs a microfluidic channel reactor, which includes a syringe, a reaction channel, and a product collector connected in sequence. The syringe is installed in an injection pump and is connected to the inlet of the reaction channel via a first connecting pipe. The product collector is connected to the outlet of the reaction channel via a second connecting pipe. The inner diameter of the reaction channel is 1.6–2.2 mm, and the length of the reaction channel is 0.8–1.2 m. The syringes are a first syringe and a second syringe. The first connecting pipe is a Y-type or T-type pipe. The first syringe and the second syringe are respectively connected to two ports of the Y-type or T-type pipe and connected in series with the reaction channel via the Y-type or T-type pipe. The method is as follows: 2-methylbenzimidazole of formula (I) and α,β-unsaturated olefin of formula (II) are dissolved in methanol to obtain a 2-methylbenzimidazole solution of formula (I) with a concentration of 0.2 mmol / mL to 0.8 mmol / mL and an α,β-unsaturated olefin solution of formula (II) with a concentration of 0.25 to 3.0 mmol / mL; the 2-methylbenzimidazole solution of formula (I) and the α,β-unsaturated olefin solution of formula (II) are respectively loaded into the first syringe and the second syringe, and the first syringe and the second syringe are loaded into the same injection pump; After uniformly filling the reaction channel of the microfluidic channel reactor with lipase Lipozyme RM IM, the 2-methylbenzimidazole solution shown in formula (I) and the α,β-unsaturated olefin solution shown in formula (II) were continuously and synchronously introduced into the reaction channel under the synchronous push of the injection pump to carry out the Michael addition reaction. The reaction temperature was controlled at 35-55℃, and the reaction time of the reaction solution flowing continuously in the reaction channel was 30-50 min. The reaction solution flowing out of the reaction channel was collected online by the product collector. The reaction solution was post-processed to obtain the benzimidazole Michael addition derivative shown in formula (III). The concentration ratio of the 2-methylbenzimidazole solution shown in formula (I) to the α,β-unsaturated olefin solution shown in formula (II) was 1:0.5-6. Within the maximum limit that the reaction channel can accommodate the filled catalyst, the amount of catalyst added was 0.03 g / mL to 0.06 g / mL based on the volume of the reaction medium.

10. The method for synthesizing benzimidazole Michael addition derivatives in a continuous flow reactor according to any one of claims 1-9, characterized in that: The post-processing is as follows: after removing the solvent from the reaction solution under reduced pressure, silica gel column chromatography is performed using a mixed solution of methanol and dichloromethane with a volume ratio of 1:60 as the eluent. The eluent containing the target compound is collected, evaporated to dryness, and the benzimidazole Michael addition derivative shown in formula (III) is obtained.

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