A method for preparing 2-methyl-5-nitroimidazole using a microchannel reaction device

Abstract

The invention discloses a method for preparing 2-methyl-5-nitroimidazole using a microchannel reaction device, wherein 2-methylimidazole and tert-butyl nitrite are dissolved in an organic solvent to prepare a homogeneous solution A; an oxidant and a catalyst are dissolved in an organic solvent to prepare a homogeneous solution B; homogeneous solution A and homogeneous solution B are simultaneously pumped into a microchannel reaction device having a heating function for reaction; the organic phase flowing out of the microchannel reaction device is collected, and the organic phase is vacuum concentrated and purified to obtain 2-methyl-5-nitroimidazole. Compared with the existing preparation method, the reaction involved in the present invention is a new method for synthesizing 2-methyl-5-nitroimidazole, which avoids the use of mixed acid that pollutes the environment, has simple reaction operation, mild conditions, high yield, and is environmentally friendly.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical chemical industry, and in particular to a new method for preparing 2-methyl-5-nitroimidazole by utilizing a microchannel reaction device. Background Art

[0002] 2-Methyl-5-nitroimidazole is an important fine chemical raw material. In the field of medicine and health, it is an important intermediate for synthesizing metronidazole, tinidazole, secnidazole and veterinary drug damiprolin. In the food manufacturing industry, it is used to make dimethoazole, a beverage additive. At present, the method for synthesizing such compounds is to use 2-methylimidazole as a raw material, and add concentrated nitric acid, concentrated sulfuric acid, sodium sulfate or urea to a high-temperature reactor for nitration reaction. There are the following disadvantages in the actual operation of such methods: (1) the reaction process is complicated, and the yield is only 60-80%; (2) the reaction needs to be carried out under high temperature conditions, and the temperature is a relatively sensitive indicator in the reactor. If it is not adjusted properly, the reactor will explode; (3) the required amount of acid is large, and a large amount of alkaline compounds need to be consumed in the subsequent separation and purification, which greatly increases the production cost and pollutes the environment. Therefore, the development of a new method and process route for preparing 2-methyl-5-nitroimidazole has become a crucial topic in this field. Summary of the invention

[0003] Purpose of the invention: In order to overcome the above-mentioned defects, the present invention provides a new method for preparing 2-methyl-5-nitroimidazole using a microchannel reaction device, which greatly improves the yield, makes the process route safer and more controllable, and is simple and environmentally friendly after the reaction. It has great potential for later industrial applications.

[0004] In order to achieve the above object, the technical solution adopted by the present invention is as follows:

[0005] A method for preparing 2-methyl-5-nitroimidazole using a microchannel reaction device comprises the following steps:

[0006] (1) dissolving 2-methylimidazole represented by Formula 1 and tert-butyl nitrite represented by Formula 2 in an organic solvent to prepare a homogeneous solution A; dissolving an oxidant and a catalyst in an organic solvent to prepare a homogeneous solution B;

[0007] (2) simultaneously pumping the homogeneous solution A and the homogeneous solution B into a microchannel reaction device with a heating function to react;

[0008] (3) collecting the organic phase flowing out of the microchannel reaction device, concentrating the organic phase under vacuum to obtain a crude product, and finally further separating and purifying the crude product to obtain 2-methyl-5-nitroimidazole as shown in Formula 3.

[0009] Wherein, the structure of 2-methylimidazole shown in formula 1 is as follows:

[0010]

[0011] The structure of tert-butyl nitrite shown in Formula 2 is as follows:

[0012]

[0013] The structure of 2-methyl-5-nitroimidazole shown in formula 3 is as follows:

[0014]

[0015] Specifically, in step (1), the organic solvent is selected from any one of acetonitrile, ethanol, dichloromethane, dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, and chlorobenzene, or a combination of two or more thereof; preferably acetonitrile.

[0016] Furthermore, in step (1), the molar ratio of the 2-methylimidazole to tert-butyl nitrite is 1:(0.75-1.5), preferably 1:1.2; and the concentration of the 2-methylimidazole in the homogeneous solution A is 0.05-0.35 mol / L, preferably 0.2 mol / L.

[0017] Furthermore, in step (1), the oxidant is selected from any one or a combination of two or more of TEMPO, 4-OH-TEMPO, 4-MeO-TEMPO, 4-AcO-TEMPO, 4-NHAc-TEMPO, DDQ, BQ, TBHP, and DTBP, preferably TEMPO; and the molar ratio of 2-methylimidazole shown in formula 1 to the oxidant is 1:(1-3), preferably 1:1.5.

[0018] Furthermore, in step (1), the catalyst is selected from BF 3 ·Et 2 O、ZnCl 2 、ZnBr 2 、Zn(OAc) 2 、FeCl 2 、FeCl 3 Sc(OTf) 2 、Yb(OTf) 3 AgNO 3 、AgOTf、InCl 3 、InBr 3 、In(OAc) 3 Any one or a combination of two or more, preferably BF 3 ·Et 2 O; the molar ratio of 2-methylimidazole shown in formula 1 to the catalyst is 1:(0.1-0.8), preferably 1:0.2.

[0019] Furthermore, in step (2), the flow rates of homogeneous solution A and homogeneous solution B are controlled to be 0.5-5 mL / min, preferably 1 mL / min; so that the volume ratio of the two pumped in the same time is 1:(0.8-1.5), preferably 1:1; and the reaction residence time is 3-30 min, preferably 5 min.

[0020] Furthermore, in step (2), the heating temperature in the microchannel reaction device is 90-110°C, preferably 100°C.

[0021] Specifically, in step (2), the microchannel reaction device includes a feed pump, a mixer, a microreactor and a receiver; the mixer, the microreactor and the receiver are connected in series through pipelines; the pipeline of the microreactor is a capillary or a polytetrafluoroethylene tube, the inner diameter of the pipeline is 0.4 to 2 mm, preferably 0.5 mm; the volume is 2 to 10 mL, preferably 10 mL.

[0022] Furthermore, in step (3), the vacuum concentration adopts a vacuum rotary evaporation method; after the reaction effluent is vacuum concentrated, water is added, and extraction is performed with dichloromethane or ethyl acetate, the organic phases are combined, and the crude product is obtained by rotary evaporation again.

[0023] Preferably, in step (3), the extraction adopts dichloromethane or ethyl acetate; and the separation and purification method adopts column chromatography.

[0024] Beneficial effects:

[0025] (1) The present invention is the first to use 2-methylimidazole and tert-butyl nitrite as substrates, and then add a catalyst and an oxidant to prepare 2-methyl-5-nitroimidazole. This method avoids the use of a large amount of mixed acid, and has mild reaction conditions, simple post-treatment, and reduces the generation of a large amount of toxic byproducts, which is environmentally friendly.

[0026] (2) The present invention uses a microchannel reaction device with a heating function to allow the substrate, oxidant and catalyst to fully contact each other, improve the mass transfer and heat transfer rates between the materials, and can achieve precise control of the reaction process, significantly improving the yield of 2-methyl-5-nitroimidazole. Compared with traditional production processes, the temperature of this type of device is more controllable, the operation is simple, and the reaction process and post-treatment are safer and more environmentally friendly. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] The present invention will be further described in detail below in conjunction with specific implementations, and the above and / or other advantages of the present invention will become more clear.

[0028] Figure 1 The invention discloses a synthetic route diagram of 2-methyl-5-nitroimidazole.

[0029] Figure 2 It is the nuclear magnetic resonance image of 2-methyl-5-nitroimidazole synthesized by the present invention. DETAILED DESCRIPTION

[0030] The present invention can be better understood with reference to the following examples.

[0031] like Figure 1 As shown, the present invention uses a microchannel reaction device to prepare 2-methyl-5-nitroimidazole. At 100°C, 2-methylimidazole and tert-butyl nitrite are used as raw materials, TEMPO is used as an oxidant, and BF 3 ·Et 2 O is the catalyst and MeCN is the organic solvent.

[0032] The device adopted by the present invention comprises:

[0033] (1) A microchannel reaction device, comprising a feed pump, a micromixer (slitplate mixer LH25 Hastelloy C), a microreactor (MF-V6), and a receiver; wherein the micromixer (slitplate mixer LH25 Hastelloy C), the microreactor (MF-V6), and the receiver are sequentially connected in series through pipelines, and two feed pumps are connected in parallel at the front end of the micromixer, respectively for pumping homogeneous solution A and homogeneous solution B, respectively serving as the first feed liquid inlet and the second feed liquid inlet, connected to the feed port of the micromixer. The pipeline in the microreactor is a polytetrafluoroethylene tube with an inner diameter of 0.5 mm and a pipeline volume of 10 mL.

[0034] The preparation process of the present invention is as follows:

[0035] (1) dissolving 2-methylimidazole represented by Formula 1 and tert-butyl nitrite represented by Formula 2 in an organic solvent to prepare a homogeneous solution A; dissolving an oxidant and a catalyst in an organic solvent to prepare a homogeneous solution B;

[0036] (2) simultaneously pumping the homogeneous solution A and the homogeneous solution B into a microchannel reaction device with a heating function to react;

[0037] (3) Collecting the organic phase flowing out of the microchannel reaction device, concentrating the organic phase under vacuum to obtain a crude product, and finally further separating and purifying the crude product to obtain 2-methyl-5-nitroimidazole as shown in Formula 3. After obtaining the target product, calculate its yield.

[0038] The screening process of the preparation process of the present invention is as follows:

[0039] (1) Screening of oxidant molar ratio

[0040] The molar ratio of 2-methylimidazole to tert-butyl nitrite is 1:1.2, and the concentration of 2-methylimidazole is 0.2 mol / L; TEMPO is the oxidant of the reaction; 2-methylimidazole and BF 3 ·Et 2 The molar ratio of O is 1:0.2; acetonitrile is the organic solvent.

[0041] Homogeneous solution A is a mixture of 2-methylimidazole, tert-butyl nitrite and acetonitrile, and homogeneous solution B is a mixture of TEMPO and BF 3 ·Et 2 O; homogeneous solution A and homogeneous solution B are pumped into the microchannel reaction device at a flow volume ratio of 1:1, and the flow rate is 1mL / min; after mixing in a micro mixer, they enter a microchannel reactor (polytetrafluoroethylene tube with an inner diameter of 0.5mm and a volume of 10mL) and react at 100°C for 5min; the organic phase flowing out of the receiver is collected, and after vacuum concentration, extraction and column chromatography, 2-methyl-5-nitroimidazole is obtained, and its yield is calculated. The effects of different oxidant contents are shown in Table 1.

[0042] Table 1 Effect of oxidant molar ratio on reaction yield

[0043] Serial number 2-Methylimidazole:TEMPO Isolation yield (%) 1 1:1 82 2 1:1.5 94 3 1:2 91 4 1:3 87

[0044] (2) Screening of catalyst molar ratio

[0045] The molar ratio of 2-methylimidazole to tert-butyl nitrite was 1:1.2, and the concentration of 2-methylimidazole was 0.2 mol / L; the molar ratio of TEMPO to 2-methylimidazole was 1:1.5; acetonitrile was the organic solvent; BF 3 ·Et 2 O is the catalyst for the reaction, and other conditions are the same. The effects of different catalyst contents are shown in Table 2.

[0046] Table 2 Effect of catalyst molar ratio on reaction yield

[0047] Serial number <![CDATA[2-Methylimidazole:BF 3 ·Et 2 O]]> Isolation yield (%) 1 1:0.1 85 1:0.2 94 2 1:0.5 82 3 1:0.8 80

[0048] (3) Temperature screening

[0049] The molar ratio of 2-methylimidazole to TEMPO is 1:1.5, and the molar ratio of 2-methylimidazole to BF 3 ·Et 2 The molar ratio of O is 1:0.2; the reactions were carried out at different temperatures, with other conditions being the same. The effects of different temperatures are shown in Table 3.

[0050] Table 3 Effect of temperature on reaction yield

[0051] Serial number Temperature(℃) Isolation yield (%) 1 80 71 2 90 84 3 100 94 4 110 88 5 120 84

[0052] (4)Solvent screening

[0053] The homogeneous solution A and the homogeneous solution B were dissolved in different solvents, and other conditions were the same. The effects of different solvents are shown in Table 4.

[0054] Table 4 Effect of different solvents on reaction yield

[0055]

[0056]

[0057] (5) Flow rate screening

[0058] The homogeneous solution A and the homogeneous solution B were fully dissolved in acetonitrile; the flow rate of the homogeneous solution was adjusted, and other conditions were the same. The effects of different flow rates are shown in Table 5.

[0059] Table 5 Effect of different flow rates on reaction yield

[0060] Serial number Flow rate (mL / min) Isolation yield (%) 1 0.5 73 2 1 94 3 1.5 88 4 2 78 5 2.5 70

[0061] Example 1

[0062] The molar ratio of 2-methylimidazole to tert-butyl nitrite was 1:1.2, and the concentration of 2-methylimidazole was 0.2 mol / L; the molar ratio of 2-methylimidazole to TEMPO was 1:1.5; the molar ratio of 2-methylimidazole to BF 3 ·Et 2 The molar ratio of O is 1:0.2; acetonitrile is the organic solvent.

[0063] Homogeneous solution A is a mixture of 2-methylimidazole, tert-butyl nitrite and acetonitrile, and homogeneous solution B is BF 3 ·Et 2 O, TEMPO and acetonitrile; homogeneous solution A and homogeneous solution B are pumped into a microchannel reaction device at a flow volume ratio of 1:1, and the flow rates are 1 mL / min respectively; after mixing in a micro mixer, they enter a microchannel reactor (the inner diameter of a polytetrafluoroethylene tube is 0.5 mm and its volume is 10 mL) and react at 100° C. for 5 minutes; the organic phase flowing out of the receiver is collected, and after vacuum concentration, extraction and column chromatography, 2-methyl-5-nitroimidazole is obtained with a yield of 94%.

[0064] Its NMR is shown in Figure 2: 1H NMR (400MHz, DMSO-d6) δ12.93 (s, 1H), 8.21-8.06 (m, 1H), 2.29 (s, 3H); 13C NMR (101MHz, DMSO-d6) δ 147.2, 145.2, 119.4, 14.1; HRMS (ESI-TOF): m / z calcdfor C 4 H 6 N 3 O 2 [M+Na] + 128.0565,Found 128.0582.

[0065] Example 2

[0066] The molar ratio of 2-methylimidazole to tert-butyl nitrite was 1:1.2, and the concentration of 2-methylimidazole was 0.2 mol / L; the molar ratio of 2-methylimidazole to DDQ was 1:1.5; the molar ratio of 2-methylimidazole to BF 3 ·Et 2 The molar ratio of O is 1:0.2; acetonitrile is the organic solvent.

[0067] Homogeneous solution A is a mixture of 2-methylimidazole, tert-butyl nitrite and acetonitrile, and homogeneous solution B is a mixture of OH-TEMPO, BF 3 ·Et 2 O and acetonitrile; homogeneous solution A and homogeneous solution B are pumped into a microchannel reaction device at a flow volume ratio of 1:1, and the flow rates are 1 mL / min respectively; after mixing in a micro mixer, they enter a microchannel reactor (the inner diameter of a polytetrafluoroethylene tube is 0.5 mm and its volume is 10 mL) and react at 100° C. for 5 minutes; the organic phase flowing out of the receiver is collected, and after vacuum concentration, extraction and column chromatography, 2-methyl-5-nitroimidazole is obtained with a yield of 93%.

[0068] Example 3

[0069] The molar ratio of 2-methylimidazole to tert-butyl nitrite was 1:1.2, and the concentration of 2-methylimidazole was 0.2 mol / L; the molar ratio of 2-methylimidazole to TEMPO was 1:1.5; the molar ratio of 2-methylimidazole to ZnBr 2 The molar ratio is 1:0.2; acetonitrile is the organic solvent.

[0070] Homogeneous solution A is a mixture of 2-methylimidazole, tert-butyl nitrite and acetonitrile, and homogeneous solution B is a mixture of TEMPO, ZnBr 2and acetonitrile; pumping homogeneous solution A and homogeneous solution B into a microchannel reaction device at a flow volume ratio of 1:1, with a flow rate of 1 mL / min; after mixing in a micro mixer, entering a microchannel reactor (the inner diameter of a polytetrafluoroethylene tube is 0.5 mm and its volume is 10 mL) to react at 100° C. for 5 min; collecting the organic phase flowing out of the receiver, and after vacuum concentration, extraction and column chromatography, obtaining 2-methyl-5-nitroimidazole with a yield of 91%.

[0071] Comparative Example 1

[0072] Use concentrated sulfuric acid as the medium to fully dissolve 2-methylimidazole. The concentration of 2-methylimidazole is 0.2 mol / L. Add sodium sulfate, heat to 150°C, slowly drop concentrated nitric acid, and continue stirring for 2 hours. The molar ratio of 2-methylimidazole: sodium sulfate: concentrated nitric acid is 1:1.2:1.2. After the reaction is completed, take out the reaction solution, stop heating, adjust the pH value to 3.5-4 with ammonia water, filter while hot, wash with water, and dry to obtain 2-methyl-5-nitroimidazole with a yield of 68%. The specific reaction formula is as follows:

[0073]

[0074] The present invention provides a novel method for preparing 2-methyl-5-nitroimidazole using a microchannel reaction device. There are many methods and approaches to implement the technical solution. The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the protection scope of the present invention. All components not specified in this embodiment can be implemented by existing technologies.

Claims

1. A method for preparing 2-methyl-5-nitroimidazole using a microchannel reaction device, characterized in that: The following steps are involved: (1) dissolving 2-methylimidazole represented by Formula 1 and tert-butyl nitrite represented by Formula 2 in an organic solvent to prepare a homogeneous solution A; dissolving an oxidant and a catalyst in an organic solvent to prepare a homogeneous solution B; (2) Pumping homogeneous solution A and homogeneous solution B simultaneously into a microchannel reaction device with a heating function to react; (3) collecting the organic phase flowing out of the microchannel reaction device, concentrating the organic phase under vacuum to obtain a crude product, and further separating and purifying the crude product to obtain 2-methyl-5-nitroimidazole as shown in Formula 3; Wherein, the structure of 2-methylimidazole shown in formula 1 is as follows: ； Formula 1; The structure of tert-butyl nitrite shown in Formula 2 is as follows: ； Formula 2; The structure of 2-methyl-5-nitroimidazole shown in formula 3 is as follows: ； Formula 3; In step (1), the oxidant is selected from any one of TEMPO, 4-OH-TEMPO, 4-MeO-TEMPO, 4-AcO-TEMPO, 4-NHAc-TEMPO, and DDQ, or a combination of two or more thereof; the molar ratio of 2-methylimidazole to the oxidant shown in formula 1 is 1:(1-3); In step (1), the catalyst is selected from any one of BF3·Et2O, ZnCl2, and ZnBr2, or a combination of two or more thereof; the molar ratio of 2-methylimidazole to the catalyst as shown in formula 1 is 1:(0.1-0.8).

2. The method for preparing 2-methyl-5-nitroimidazole using a microchannel reaction device according to claim 1, characterized in that: In step (1), the organic solvent is selected from any one or a combination of two or more of acetonitrile, ethanol, dichloromethane, dimethyl sulfoxide, N, N-dimethylformamide, tetrahydrofuran, and chlorobenzene.

3. The method for preparing 2-methyl-5-nitroimidazole using a microchannel reaction device according to claim 1, characterized in that: In step (1), the molar ratio of the 2-methylimidazole to tert-butyl nitrite is 1:(0.75-1.5); the concentration of the 2-methylimidazole in the homogeneous solution A is 0.05-0.35 mol / L.

4. The method for preparing 2-methyl-5-nitroimidazole using a microchannel reaction device according to claim 1, characterized in that: In step (2), the flow rates of homogeneous solution A and homogeneous solution B are controlled to be 0.5-5 mL / min; the volume ratio of the two pumped in at the same time is 1:(0.8-1.5); and the reaction residence time is 3-30 min.

5. The method for preparing 2-methyl-5-nitroimidazole using a microchannel reaction device according to claim 1, characterized in that: In step (2), the heating temperature of the microchannel reaction device is 90~110°C.

6. The method for preparing 2-methyl-5-nitroimidazole using a microchannel reaction device according to claim 1, characterized in that: In step (2), the microchannel reaction device comprises a feed pump, a mixer, a microreactor and a receiver; the mixer, the microreactor and the receiver are sequentially connected in series through pipelines; the pipeline of the microreactor is a capillary or a polytetrafluoroethylene tube, the inner diameter of the pipeline is 0.4~2 mm, and the volume is 2~10 mL.

7. The method for preparing 2-methyl-5-nitroimidazole using a microchannel reaction device according to claim 1, characterized in that: In step (3), the reaction effluent is concentrated in vacuo, water is added, and extraction is performed with dichloromethane or ethyl acetate. The organic phases are combined and rotary evaporated again to obtain a crude product.

8. The method for preparing 2-methyl-5-nitroimidazole using a microchannel reaction device according to claim 1, characterized in that: In step (3), the separation and purification is carried out by column chromatography.

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