CN109593804B - A kind of method for enzyme-catalyzed rapid synthesis of nitrobenzimidazole derivatives - Google Patents
A kind of method for enzyme-catalyzed rapid synthesis of nitrobenzimidazole derivatives Download PDFInfo
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- 239000002994 raw material Substances 0.000 claims abstract description 30
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- AWAFTONGILRBMM-UHFFFAOYSA-N CCCCOC(=O)CCN1C=NC2=C1C=C(C=C2)[N+](=O)[O-] Chemical compound CCCCOC(=O)CCN1C=NC2=C1C=C(C=C2)[N+](=O)[O-] AWAFTONGILRBMM-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明公开了一种酶催化快速合成硝基苯并咪唑类衍生物的方法，所述方法为：以物质的量之比为1:1～5的6‑硝基苯并咪唑与丙烯酸脂类化合物为原料，以脂肪酶Lipozyme RM IM为催化剂，以DMSO溶剂为反应溶剂，将脂肪酶Lipozyme RM IM均匀填充在微流控通道反应器的反应通道中，所述微流控通道反应器的反应通道内径为0.8～2.4mm，反应通道长为0.5～1.0m；使原料和反应溶剂连续通入反应通道中进行Michael加成反应，控制Michael加成反应温度为40～55℃，Michael加成反应时间为25～40min，在线收集反应液，反应液经常规后处理得到硝基苯并咪唑类衍生物。本发明具有反应时间短、选择性高及产率高的优点。The invention discloses a method for rapidly synthesizing nitrobenzimidazole derivatives by enzymatic catalysis. Compounds are used as raw materials, lipase Lipozyme RM IM is used as catalyst, and DMSO solvent is used as reaction solvent, and lipase Lipozyme RM IM is uniformly filled in the reaction channel of the microfluidic channel reactor. The reaction of the microfluidic channel reactor The inner diameter of the channel is 0.8-2.4mm, and the length of the reaction channel is 0.5-1.0m; the raw materials and the reaction solvent are continuously passed into the reaction channel for Michael addition reaction, and the temperature of the Michael addition reaction is controlled to be 40-55°C, and the Michael addition reaction is carried out. The time is 25-40 min, the reaction solution is collected online, and the reaction solution is subjected to conventional post-treatment to obtain nitrobenzimidazole derivatives. The present invention has the advantages of short reaction time, high selectivity and high yield.
Description
(I) technical field
The invention relates to a method for quickly synthesizing nitrobenzimidazole derivatives through enzyme catalysis.
(II) background of the invention
Imidazole is an important five-membered aromatic heterocycle, shows excellent biological activity due to the unique electrical-rich structure, and is widely applied to the fields of pesticides, medicines, artificial materials, artificial receptors, supramolecular ligands, biomimetic catalysts and the like. In particular, in medicinal chemistry, a large number of mature imidazole compounds are used clinically as anticancer drugs, antimicrobial drugs, anti-inflammatory drugs, antihistamine drugs, anti-neurogenic drugs, hypotensive drugs and the like, and have remarkable curative effects on diseases.
Michael addition, which is one of the important tools for forming C-C, C-N, C-O, C-X bonds, is the classical addition reaction in organic synthesis. The Michael addition reaction is generally carried out under catalysis of strong acid or strong base, and the reaction conditions are harsh, so that the environmental pollution and the energy waste can be caused. In order to find a more efficient synthesis method, a series of metal catalysts such as KF/Al have been developed in recent years2O3、Y(NO3)3·6H2O、CeCl3、Bi(OTf)3Etc., but these catalysts produce environmentally harmful substances with accompanying many side reactions, seriously lowering the selectivity of the reaction and the yield of the objective product. In addition, the reaction is reported to be carried out using a solid supported catalyst, an ionic liquid, or the like, but these reactions have disadvantages such as a long reaction time and a complicated preparation process of the catalyst system. Therefore, the search for a new green synthesis technology of Michael addition reaction is a research hotspot in the field of organic synthesis.
The enzyme catalysis reaction is one of effective tools for green chemical synthesis due to high efficiency, green and strong specificity. Its excellent selectivity and mild reaction conditions have led to a wide interest of scientists in the fields of chemistry and chemical engineering, pharmacy, materials and the like. However, the enzymatic reaction has the restriction of solvent to substrate dissolution, solvent polarity to enzyme activity inhibition and the like, the reaction time is usually very long (24-96h), and the conversion rate of a specific substrate is not very high, so that the development of a novel synthesis technology of the enzymatic imidazole compound based on the micro-fluidic technology on the basis of the traditional enzymatic reaction becomes the research target of the people.
In recent years, continuous flow reactors with channel sizes in the micrometer or millimeter range have been widely used in organic synthesis. One of the most significant advantages of microfluidic reactors over conventional chemical reactors is the safety of the use of hazardous reagents. The method is derived from the high specific surface area and the better heat and mass transfer performance of the microreactor, and the local overheating phenomenon is obviously inhibited. At the same time, the smaller dimensions of the microreactor prevent the build-up of hazardous substances inside the reactor. Therefore, microreactor technology provides a unique means of performing ultra-fast exothermic reactions and allows reactions to be performed via highly unstable and even explosive intermediates.
So far, the enzymatic Michael addition reaction in China is in the initial research stage, and has certain defects, and the biological method mostly uses acylase for catalysis, is expensive, needs longer reaction time (24-96h), and is not particularly ideal for the conversion rate of specific substrate reaction. In order to develop a new efficient and green technology for synthesizing imidazole derivatives, a method for synthesizing nitrobenzimidazole derivatives on line under catalysis of lipase in a microchannel reactor is researched, and the new efficient and environment-friendly technology for synthesizing the nitrobenzimidazole derivatives on line is sought.
Disclosure of the invention
The technical problem to be solved by the invention is to provide a novel process for synthesizing the nitrobenzimidazole derivative on line by lipase catalysis in a microfluidic channel reactor, and the novel process has the advantages of short reaction time and high yield.
In order to solve the technical problems, the invention adopts the following technical scheme:
a method for synthesizing nitrobenzimidazole derivatives on line under catalysis of lipase adopts a microfluidic channel reactor, wherein the microfluidic channel reactor comprises an injection pump, an injector, a reaction channel and a product collector, the injector is installed in the injection pump and is communicated with an inlet of the reaction channel through a first interface, the product collector is communicated with an outlet of the reaction channel through a second interface, the inner diameter of the reaction channel is 0.8-2.4 mm, and the length of the reaction channel is 0.5-1.0 m; the method comprises the following steps: the method comprises the steps of uniformly filling a reaction channel with 6-nitrobenzimidazole (RBB) and an acrylate compound shown in a formula 1 as raw materials, lipase Lipozyme RM IM as a catalyst and dimethyl sulfoxide as a reaction solvent, placing the raw materials and the reaction solvent into an injector, continuously introducing the raw materials and the reaction solvent into the reaction channel by the injector under the driving of an injection pump to carry out Michael addition reaction, controlling the reaction temperature to be 40-55 ℃ and the reaction time to be 25-40 min, collecting the reaction liquid on line through a product collector, and respectively obtaining 6-nitrobenzimidazole derivatives shown in a formula 2 and 5-nitrobenzimidazole derivatives shown in a formula 3 through aftertreatment of the reaction liquid; the catalyst is added in an amount of 0.025-0.05 g/mL based on the volume of the reaction solvent within the maximum limit that the reaction channel can accommodate the filled catalyst; in the reaction system, the concentration of the acrylate compound shown in the formula 1 is 0.1-0.5 mmol/mL,
in the formulas 1, 2 and 3, R is CH2CH2CH2CH3Or C (CH)3)3。
Further, the present invention adopts a microfluidic channel reactor, wherein the number of the injectors can be one or more, depending on the specific reaction requirements. The reaction raw materials of the invention are two, preferably two injectors are used, specifically, the injectors are respectively a first injector and a second injector, the first connecting pipeline is a Y-shaped or T-shaped pipeline, the first injector and the second injector are respectively connected with two interfaces of the Y-shaped or T-shaped pipeline and are connected with the reaction channel in series through the Y-shaped or T-shaped pipeline, and the probability of contact and collision of reactant molecules passing through the microchannel is increased, so that two reactant liquid flows are mixed and react in the common reaction channel.
Still further, more specifically, the method of the present invention comprises the steps of:
the method comprises the following steps: taking 6-nitrobenzimidazole and an acrylate compound shown in a formula 1 in a mass ratio of 1: 1-5 as raw materials, taking 0.5-1.0 g of lipase Lipozyme RM IM as a catalyst, taking dimethyl sulfoxide as a reaction solvent, uniformly filling the lipase Lipozyme RM IM in a reaction channel, firstly dissolving the 6-nitrobenzimidazole in the dimethyl sulfoxide, filling the 6-nitrobenzimidazole in a first injector, and dissolving the acrylate compound shown in the formula 1 in the dimethyl sulfoxide, and filling the acrylate compound in a second injector; then, the first injector and the second injector are arranged in the same injection pump, then under the synchronous pushing of the injection pump, raw materials and a reaction solvent are converged through the Y-shaped or T-shaped pipeline and then enter a reaction channel for Michael addition reaction, the reaction temperature is controlled to be 40-55 ℃, the reaction time is 25-40 min, reaction liquid is collected on line through a product collector, and the reaction liquid is subjected to post-treatment to respectively obtain the 6-nitrobenzimidazole derivative shown in the formula 2 and the 5-nitrobenzimidazole derivative shown in the formula 3; in the reaction system, the concentration of the acrylate compound shown in the formula 1 is 0.1-0.5 mmol/mL.
The first syringe and the second syringe have the same specification, and the concentration of the 6-nitrobenzimidazole in the first syringe is usually 0.1 mmol/mL.
Furthermore, the microfluidic channel reactor also comprises a thermostat, and the reaction channel is arranged in the thermostat, so that the reaction temperature can be effectively controlled. The constant temperature box can be selected according to the reaction temperature requirement, such as a water bath constant temperature box and the like.
The material of the reaction channel is not limited, and green and environment-friendly materials such as a silicone tube are recommended; the shape of the reaction channel is preferably curved, so that the reaction liquid can be ensured to stably pass through at a constant speed.
In the present invention, the lipase Lipozyme RM IM is a preparation prepared from microorganisms, using a commercial product manufactured by Novozymes (novozymes), which is a food-grade lipase (EC 3.1.1.3) specific to 1, 3-position on granular silica gel. It is produced by submerged fermentation using a genetically modified Aspergillus oryzae (Aspergillus oryzae) microorganism obtained from Rhizomucor miehei.
The method of the invention uniformly fills the lipase Lipozyme RM IM in the reaction channel, and can directly and uniformly fix the granular catalyst in the reaction channel by a physical method.
Further, the mass ratio of the 6-nitrobenzimidazole to butyl acrylate is preferably 1:3 to 5, and most preferably 1: 4.
Further, the reaction temperature is preferably 40-50 ℃, and most preferably 45 ℃.
Further, the reaction time is preferably 30 to 40min, and most preferably 35 min.
The reaction product can be collected on line, and the obtained reaction liquid can be used for obtaining 3- (5-nitrobenzimidazole) butyl propionate and 3- (6-nitrobenzimidazole) butyl propionate by a conventional post-treatment method. The conventional post-treatment method may be: and (2) distilling the obtained reaction liquid under reduced pressure to remove the solvent, filling the reaction liquid into a column by using a 200-mesh 300-mesh silica gel wet method, wherein the volume ratio of an eluting reagent to ethyl acetate is 4:1, dissolving the obtained sample by using a small amount of an eluting reagent, then loading the sample into the column by using the wet method, collecting eluent, tracking the elution process by using TLC (thin layer chromatography), merging the obtained eluents containing a single product, and evaporating to dryness to obtain the 6-nitrobenzimidazole derivative shown in the formula 2 and the 5-nitrobenzimidazole derivative shown in the formula 3 respectively.
Compared with the prior art, the invention has the beneficial effects that:
according to the invention, the 6-nitrobenzimidazole derivative shown in the formula 2 and the 5-nitrobenzimidazole derivative shown in the formula 3 are synthesized on line in the microfluidic channel reactor by using lipase catalysis, so that the method not only greatly shortens the reaction time, but also has high conversion rate and selectivity; meanwhile, the economical lipase Lipozyme RM IM is used for catalyzing the Michael reaction of the imidazole compounds for the first time, so that the reaction cost is reduced, and the method has the advantages of economy and high efficiency.
(IV) description of the drawings
Fig. 1 is a schematic structural diagram of a microfluidic channel reactor used in an embodiment of the present invention.
In the figure, 1, 2-injector, 3-reaction channel, 4-product collector, 5-water bath incubator.
(V) detailed description of the preferred embodiments
The scope of the invention is further illustrated by the following examples, but is not limited thereto:
referring to fig. 1, a microfluidic channel reactor used in an embodiment of the present invention includes a syringe pump (not shown), two syringes 1 and 2, a reaction channel 3, a water bath incubator (5, only a schematic plan view thereof is shown), and a product collector 4; two injectors 1 and 2 are installed in the injection pump and are connected with an inlet of a reaction channel 3 through a Y-shaped interface, the reaction channel 3 is arranged in a water bath thermostat 5, the reaction temperature is controlled through the water bath thermostat 5, the inner diameter of the reaction channel 3 is 1.8mm, the length of a tube is 1m, and an outlet of the reaction channel 3 is connected with a product collector 4 through an interface.
Example 1: 3- (5-Nitrobenzimidazole) propionic acid butyl ester, 3- (6-nitrobenzimidazole) propionic acid butyl ester
The device is shown in figure 1: 6-nitrobenzimidazole (1.0mmol) was dissolved in 10mL DMSO and butyl acrylate (4.0mmol) was dissolved in 10mL DMSO, each in a 10mL syringe. 0.87g of lipase Lipozyme RM IM is uniformly filled in the reaction channel, and two paths of reaction liquid are respectively 7.3 mu L/min under the driving of a PHD2000 injection pump-1The flow rate of the reaction solution enters a reaction channel through a Y joint for reaction, the temperature of the reactor is controlled at 45 ℃ through a water bath thermostat, the reaction solution continuously and continuously reacts in the reaction channel for 35min, and the reaction result is tracked and detected through thin-layer chromatography TLC.
Collecting reaction liquid on line through a product collector, distilling under reduced pressure to remove a solvent, filling the reaction liquid into a column by using a 200-mesh 300-mesh silica gel wet method, dissolving a sample in a small amount of an elution reagent, namely petroleum ether and ethyl acetate with the ratio of 4:1, wherein the column height is 35cm, the column diameter is 4.5cm, filling the sample into the column by using the wet method, and collecting eluent at the flow rate of 2 mL/min-1And simultaneously tracking the elution process by TLC (thin layer chromatography), merging the obtained eluents containing the single product and evaporating to obtain syrup-shaped liquid, so as to obtain 3- (5-nitrobenzimidazole) butyl propionate and 3- (6-nitrobenzimidazole) butyl propionate, wherein the conversion rate of 6-nitrobenzimidazole is 74% by HPLC (high performance liquid chromatography).
The nuclear magnetic characterization results were as follows:
3-(6-nitro-benzimidazole-1-yl)-propionic acid Butyl ester and3-(5-nitro-benzimidazole-1-yl)-propionic acid Butyl ester.Yellow oil；1H NMR(500MHz,CDCl3):δ＝8.89(s,1H,Ar-H),8.75(d,1H,J＝2.0Hz,Ar-H),8.63(s,1H,Ar-H),8.51(d,1H,J＝2.0Hz,Ar-H),8.30(m,2H,Ar-H),7.96(d,1H,J＝8.9Hz,Ar-H),7.60(d,1H,J＝8.9Hz,Ar-H),4.68(m,4H,NCH2),4.07(m,4H,OCH2),2.98(m,4H,O＝CCH2),1.67(m,4H,OCH2C 2H),1.28(m,4H,C 2HCH3),0.90(t,J＝7.2Hz,6H,CH2C 3H)；13C NMR(125MHz,CDCl3):δ＝170.36,147.35,146.57,144.30,140.94,137.04,132.28,119.71,119.44,119.21,116.49,110.17,107.28,65.43,41.39,34.25,30.40,18.97,13.58.ESI–MS(m/z):292(M+1).
examples 2 to 4
The temperature of the microfluidic channel reactor was changed, and the reaction results are shown in table 1 as in example 1:
table 1: influence of temperature on the reaction
The results in Table 1 show that when the flow rate is 7.3. mu.L.min-1When the reaction time is 35min, the conversion rate is obviously increased along with the increase of the reaction temperature, when the reaction temperature reaches 45 ℃, the conversion rate of the reaction is optimal, and if the temperature is continuously increased, the enzyme activity is reduced, so that the conversion rate and the selectivity of the reaction are reduced, and therefore, the optimal reaction temperature of the butyl 3- (5-nitrobenzimidazole) propionate and the optimal reaction temperature of the butyl 3- (6-nitrobenzimidazole) propionate in the microfluidic microchannel reactor are 45 ℃.
Examples 5 to 8
The results are shown in Table 2, except that the temperature is controlled at 45 ℃ in the microfluidic microchannel reactor by changing the ratio of the 6-nitrobenzimidazole to the butyl acrylate substrate in reference to the 6-nitrobenzimidazole dosage, and the results are shown in the same manner as in example 1:
TABLE 2 influence of the molar ratio of 6-nitrobenzimidazole to butyl acrylate substrate on the reaction
| Examples | Butyl acrylate: 6-nitrobenzimidazole molar ratio | Conversion [% ]] |
| 5 | 1:1 | 21 |
| 6 | 2:1 | 50 |
| 7 | 3:1 | 66 |
| 1 | 4:1 | 74 |
| 8 | 5:1 | 72 |
The results in Table 2 show that the flow rate was 7.3. mu.L.min-1The reaction time is 35min, the reaction temperature is 45 ℃, DMSO is used as an organic solvent in the reactor, the conversion rate of the reaction is increased along with the increase of butyl acrylate serving as a reactant, and when the substrate ratio of 6-nitrobenzimidazole to butyl acrylate is 1:4, the conversion rate of the reaction is optimal, so that the ratio of the optimal substrate amount in the microfluidic microchannel reactor is 1: 4.
Examples 9 to 11
The reaction time of the microfluidic channel reactor was changed, and the reaction results are shown in Table 3 as in example 1:
table 3: influence of reaction time on the reaction
| Examples | Reaction time [ min ]] | Conversion [% ]] |
| 9 | 25 | 51 |
| 10 | 30 | 65 |
| 1 | 35 | 74 |
| 11 | 40 | 72 |
The results in Table 3 show that 65% of butyl 3- (5-nitrobenzimidazole) propionate and butyl 3- (6-nitrobenzimidazole) propionate can be obtained after 30min of reaction, and 6-nitrobenzimidazole is basically converted into butyl 3- (5-nitrobenzimidazole) propionate and butyl 3- (6-nitrobenzimidazole) propionate. The conversion rate of the reaction is gradually increased along with the increase of the reaction time, when the reaction is carried out for 35min, the conversion rate of the butyl 3- (5-nitrobenzimidazole) propionate and the butyl 3- (6-nitrobenzimidazole) propionate can reach 74%, and at the moment, if the reaction time is continuously prolonged, the reduction of the conversion rate and the selectivity of the reaction is caused, so that the optimal time for synthesizing the butyl 3- (5-nitrobenzimidazole) propionate and the butyl 3- (6-nitrobenzimidazole) propionate in the microfluidic channel reactor is 35 min.
Comparative examples 1 to 4
The results are shown in Table 4 for the same samples as example 1 except that the catalysts in the microfluidic microchannel reactor were changed to porcine pancreatic lipase PPL (comparative example 1), lipase Novozym 435 (comparative example 2), subtilisin alkaline protease (comparative example 3), Lipozyme TL IM (comparative example 4), respectively.
TABLE 4 Effect of different enzymes on the conversion of the reaction
| Comparative example | Enzyme source | Conversion (%) |
| 1 | PPL | 20 |
| 2 | Novozym 435 | 16 |
| 3 | Bacillus subtilis alkaline protease | 26 |
| 4 | Lipozyme TL IM | 55 |
| Example 1 | Lipozyme RM IM | 74 |
The results in table 4 show that for the Michael addition reaction of enzymatic imidazoles in microfluidic channel reactors, different enzymes have a very significant effect on the reaction. The Lipozyme TL IM catalyzed reaction, the conversion rate of 3- (5-nitrobenzimidazole) butyl propionate and 3- (6-nitrobenzimidazole) butyl propionate is 55%. The conversion of butyl 3- (5-nitrobenzimidazole) propionate and butyl 3- (6-nitrobenzimidazole) propionate was only 16% when Novozym 435 catalyzed the reaction. From the results in table 4, the most effective catalyst for Michael of enzymatic imidazoles in microfluidic reactors was the lipase Lipozyme RM IM, with a conversion of 74% for butyl 3- (5-nitrobenzimidazole) propionate, butyl 3- (6-nitrobenzimidazole) propionate.
Example 12: tert-butyl 3- (5-nitrobenzimidazole) propionate, tert-butyl 3- (6-nitrobenzimidazole) propionate
6-Nitrobenzimidazole (1.0mmol) was dissolved in 10mL of DMSO, tert-butyl acrylate (4.0mmol) was dissolved in 10mL of DMSO, and the solutions were separately filled in 10mL syringesAnd (4) preparing for later use. 0.87g of lipase Lipozyme RM IM is uniformly filled in the reaction channel, and two paths of reaction liquid are respectively 7.3 mu L/min under the driving of a PHD2000 injection pump-1The flow rate of the reaction solution enters a reaction channel through a Y joint for reaction, the temperature of the reactor is controlled at 45 ℃ through a water bath thermostat, the reaction solution continuously and continuously reacts in the reaction channel for 35min, and the reaction result is tracked and detected through thin-layer chromatography TLC.
Collecting reaction liquid on line through a product collector, distilling under reduced pressure to remove a solvent, filling the reaction liquid into a column by using a 200-mesh 300-mesh silica gel wet method, dissolving a sample in a small amount of an elution reagent, namely petroleum ether and ethyl acetate with the ratio of 4:1, wherein the column height is 35cm, the column diameter is 4.5cm, filling the sample into the column by using the wet method, and collecting eluent at the flow rate of 2 mL/min-1And simultaneously tracking the elution process by TLC (thin layer chromatography), merging the obtained eluents containing the single product and evaporating to obtain syrup-shaped liquid, so as to obtain the tert-butyl 3- (5-nitrobenzimidazole) propionate and the tert-butyl 3- (6-nitrobenzimidazole) propionate, and detecting the conversion rate of the 6-nitrobenzimidazole by HPLC (high performance liquid chromatography) to be 59%.
The nuclear magnetic characterization results were as follows:
3-(6-nitro-benzimidazole-1-yl)-propionic acid tert-butyl ester and3-(5-nitro-benzimidazole-1-yl)-propionic acid tert-butyl ester.Yellow oil；1H NMR(500MHz,CDCl3):δ＝8.72(d,1H,J＝2.0Hz,Ar-H),8.42(d,1H,J＝2.0Hz,Ar-H),8.29-8.21(m,4H,Ar-H),7.88(d,1H,J＝8.9Hz,Ar-H),7.51(d,1H,J＝8.9Hz,Ar-H),4.55(m,4H,NCH2),2.84(m,4H,O＝CCH2),1.39(s,18H,OC(CH3)3)；13C NMR(125MHz,CDCl3):δ＝169.48,147.91,146.77,143.98,142.94,137.57,132.78,120.53,118.90,118.21,117.17,109.61,106.65,82.28,82.25,41.09,41.03,35.46,35.39,27.96.ESI–MS(m/z):292(M+1).
examples 13 to 15
The temperature of the microfluidic channel reactor was changed, and the reaction results are shown in Table 5 as in example 12:
table 5: influence of temperature on the reaction
The results in Table 5 show that the flow rate was 7.3. mu.L.min-1When the reaction time is 35min, the reaction is obviously improved along with the increase of the temperature, the conversion rate of the reaction is optimal when the reaction temperature reaches 45 ℃, and if the temperature is continuously increased, the enzyme activity is reduced, so that the conversion rate and the selectivity of the reaction are reduced, and the optimal reaction temperature of the tert-butyl 3- (5-nitrobenzimidazole) propionate and the tert-butyl 3- (6-nitrobenzimidazole) propionate in the microfluidic microchannel reactor is 45 ℃.
Examples 16 to 19
The results are shown in Table 6, except that the temperature is controlled at 45 ℃ in the microfluidic microchannel reactor by changing the ratio of the substrate substances of 6-nitrobenzimidazole and tert-butyl acrylate based on the amount of 6-nitrobenzimidazole, and the results are the same as in example 12:
TABLE 6 influence of the molar ratio of 6-nitrobenzimidazole to tert-butyl acrylate substrate on the reaction
The results in Table 6 show that the flow rate was 7.3. mu.L.min-1The reaction time is 35min, the reaction temperature is 45 ℃, DMSO is used as an organic solvent in the reactor, the conversion rate of the reaction is increased along with the increase of the reactant tert-butyl acrylate, and when the substrate ratio of 6-nitrobenzimidazole to tert-butyl acrylate is 1:4, the conversion rate of the reaction is optimal, so that the ratio of the optimal substrate amount in the microfluidic microchannel reactor is 1: 4.
Examples 20 to 11
The reaction time of the microfluidic channel reactor was changed, and the reaction results are shown in Table 7 as in example 12:
table 7: influence of reaction time on the reaction
| Examples | Reaction time [ min ]] | Conversion [% ]] |
| 20 | 25 | 39 |
| 21 | 30 | 51 |
| 12 | 35 | 59 |
| 22 | 40 | 57 |
The results in Table 7 show that reaction time of 30min gave 51% of tert-butyl 3- (5-nitrobenzimidazole) propionate and tert-butyl 3- (6-nitrobenzimidazole) propionate, with the 6-nitrobenzimidazole being essentially converted to tert-butyl 3- (5-nitrobenzimidazole) propionate and tert-butyl 3- (6-nitrobenzimidazole) propionate. The conversion rate of the reaction gradually increases along with the increase of the reaction time, when the reaction is carried out for 35min, the conversion rate of the tert-butyl 3- (5-nitrobenzimidazole) propionate and the tert-butyl 3- (6-nitrobenzimidazole) propionate can reach 59%, and at the moment, if the reaction time is continuously prolonged, the reduction of the conversion rate and the selectivity of the reaction can be caused, so that the optimal time for synthesizing the tert-butyl 3- (5-nitrobenzimidazole) propionate and the tert-butyl 3- (6-nitrobenzimidazole) propionate in the microfluidic channel reactor is 35 min.
Comparative examples 1 to 4
The results are shown in Table 8 for the same samples as example 12 except that the catalysts in the microfluidic microchannel reactor were changed to porcine pancreatic lipase PPL (comparative example 1), lipase Novozym 435 (comparative example 2), subtilisin alkaline protease (comparative example 3), Lipozyme TL IM (comparative example 4), respectively.
TABLE 8 Effect of different enzymes on the conversion of the reaction
| Comparative example | Enzyme source | Conversion (%) |
| 1 | PPL | 18 |
| 2 | Novozym 435 | 12 |
| 3 | Bacillus subtilis alkaline protease | 21 |
| 4 | Lipozyme TL IM | 38 |
| Example 1 | Lipozyme RM IM | 59 |
The results in table 8 show that for the Michael addition reaction of enzymatic imidazoles in microfluidic channel reactors, different enzymes have a very significant effect on the reaction. The Lipozyme TL IM catalyzed reaction, the conversion rate of 3- (5-nitrobenzimidazole) butyl propionate and 3- (6-nitrobenzimidazole) butyl propionate is 38%. The reaction was catalyzed by Novozym 435, and the conversion of tert-butyl 3- (5-nitrobenzimidazole) propionate and tert-butyl 3- (6-nitrobenzimidazole) propionate was only 12%. From the results in Table 8, the most effective catalyst for Michael of enzymatic imidazoles in microfluidic reactors is the lipase Lipozyme RM IM, with 59% conversion of tert-butyl 3- (5-nitrobenzimidazole) propionate, tert-butyl 3- (6-nitrobenzimidazole) propionate.
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