CN116178272A - Method for preparing 2-methyl-5-nitroimidazole by utilizing microchannel reaction device - Google Patents
Method for preparing 2-methyl-5-nitroimidazole by utilizing microchannel reaction device Download PDFInfo
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- 238000006243 chemical reaction Methods 0.000 title claims abstract description 52
- FFYTTYVSDVWNMY-UHFFFAOYSA-N 2-Methyl-5-nitroimidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1 FFYTTYVSDVWNMY-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 238000000034 method Methods 0.000 title claims abstract description 30
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 claims abstract description 45
- 239000012456 homogeneous solution Substances 0.000 claims abstract description 42
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000012414 tert-butyl nitrite Substances 0.000 claims abstract description 19
- 239000003960 organic solvent Substances 0.000 claims abstract description 16
- 239000003054 catalyst Substances 0.000 claims abstract description 15
- 239000007800 oxidant agent Substances 0.000 claims abstract description 15
- 239000012074 organic phase Substances 0.000 claims abstract description 14
- 230000001590 oxidative effect Effects 0.000 claims abstract description 12
- 238000005086 pumping Methods 0.000 claims abstract description 9
- 238000010438 heat treatment Methods 0.000 claims abstract description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 49
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims description 13
- -1 polytetrafluoroethylene Polymers 0.000 claims description 11
- 229920001343 polytetrafluoroethylene Polymers 0.000 claims description 11
- 239000004810 polytetrafluoroethylene Substances 0.000 claims description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000012043 crude product Substances 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- KLRHPHDUDFIRKB-UHFFFAOYSA-M indium(i) bromide Chemical compound [Br-].[In+] KLRHPHDUDFIRKB-UHFFFAOYSA-M 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- UZFMOKQJFYMBGY-UHFFFAOYSA-N 4-hydroxy-TEMPO Chemical compound CC1(C)CC(O)CC(C)(C)N1[O] UZFMOKQJFYMBGY-UHFFFAOYSA-N 0.000 claims description 2
- 101710134784 Agnoprotein Proteins 0.000 claims description 2
- 229910021617 Indium monochloride Inorganic materials 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- 238000004440 column chromatography Methods 0.000 claims description 2
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 claims description 2
- 239000012969 di-tertiary-butyl peroxide Substances 0.000 claims description 2
- APHGZSBLRQFRCA-UHFFFAOYSA-M indium(1+);chloride Chemical compound [In]Cl APHGZSBLRQFRCA-UHFFFAOYSA-M 0.000 claims description 2
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 claims description 2
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000010025 steaming Methods 0.000 claims 1
- 239000002253 acid Substances 0.000 abstract description 3
- 239000012071 phase Substances 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 239000011259 mixed solution Substances 0.000 description 6
- 238000012216 screening Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 238000002955 isolation Methods 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 229910017604 nitric acid Inorganic materials 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- WAIPAZQMEIHHTJ-UHFFFAOYSA-N [Cr].[Co] Chemical compound [Cr].[Co] WAIPAZQMEIHHTJ-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000008676 import Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- KPQZUUQMTUIKBP-UHFFFAOYSA-N 1-(2-methyl-5-nitro-1-imidazolyl)-2-propanol Chemical compound CC(O)CN1C(C)=NC=C1[N+]([O-])=O KPQZUUQMTUIKBP-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- WGMYEOIMVYADRJ-UHFFFAOYSA-N 6-[2-(diethylamino)ethoxy]-N,N-dimethyl-1,3-benzothiazol-2-amine Chemical compound CCN(CC)CCOC1=CC=C2N=C(N(C)C)SC2=C1 WGMYEOIMVYADRJ-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- HJLSLZFTEKNLFI-UHFFFAOYSA-N Tinidazole Chemical compound CCS(=O)(=O)CCN1C(C)=NC=C1[N+]([O-])=O HJLSLZFTEKNLFI-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229960004462 dimazole Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 229960004076 secnidazole Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960005053 tinidazole Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/91—Nitro radicals
- C07D233/92—Nitro radicals attached in position 4 or 5
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Abstract
The invention discloses a method for preparing 2-methyl-5-nitroimidazole by utilizing a microchannel reaction device, which comprises the steps of dissolving 2-methylimidazole and tert-butyl nitrite in an organic solvent to prepare a homogeneous phase solution A; dissolving an oxidant and a catalyst in an organic solvent to prepare a homogeneous solution B; pumping the homogeneous solution A and the homogeneous solution B into a micro-channel reaction device with a heating function at the same time for reaction; and collecting an organic phase flowing out of the micro-channel reaction device, and concentrating and purifying the organic phase in vacuum to obtain the 2-methyl-5-nitroimidazole. Compared with the existing preparation method, the reaction involved in the invention is a brand new method for synthesizing 2-methyl-5-nitroimidazole, avoids using mixed acid polluting the environment, and has the advantages of simple and convenient reaction operation, mild condition, high yield and environmental friendliness.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to a novel method for preparing 2-methyl-5-nitroimidazole by utilizing a microchannel reaction device.
Background
2-methyl-5-nitroimidazole is an important fine chemical raw material, and is an important intermediate for synthesizing metronidazole, tinidazole, secnidazole and veterinary drug damagetin in the field of medicine and health; in the food manufacturing industry, it is used to make the beverage additive, dimazole. At present, the method for synthesizing the compounds adopts 2-methylimidazole as a raw material, and concentrated nitric acid, concentrated sulfuric acid, sodium sulfate or urea substances are added into a high-temperature reaction kettle to carry out nitration reaction. The method has the following defects in actual operation: (1) the reaction process is complex, and the yield is as high as 60-80%; (2) The reaction is required to be carried out under the high-temperature condition, the temperature is a sensitive index in the reaction kettle, and if the reaction kettle is improperly regulated, the explosion can be caused; (3) The consumption of the acid is large, a large amount of alkali compounds are consumed in the subsequent separation and purification, the production cost is greatly increased, and the environment is polluted. Therefore, the development of a new method and process route for preparing 2-methyl-5-nitroimidazole has become an important topic in the field.
Disclosure of Invention
The invention aims to: in order to overcome the defects, the invention provides a novel method for preparing 2-methyl-5-nitroimidazole by utilizing a microchannel reaction device, so that the yield is greatly improved, the process route is safer and more controllable, the post-reaction treatment is simple and convenient, the method is environment-friendly, and the method has great potential in the aspect of later industrial application.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
a method for preparing 2-methyl-5-nitroimidazole using a microchannel reaction device, comprising the steps of:
(1) 2-methylimidazole shown in a formula 1 and tert-butyl nitrite shown in a formula 2 are dissolved 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 the homogeneous solution A and the homogeneous solution B into a micro-channel reaction device with a heating function to perform reaction;
(3) And collecting an organic phase flowing out of the microchannel reaction device, concentrating the organic phase in vacuum to obtain a crude product, and finally further separating and purifying the crude product to obtain the 2-methyl-5-nitroimidazole shown in the formula 3.
Wherein, the structure of the 2-methylimidazole shown in the formula 1 is as follows:
the tert-butyl nitrite represented by formula 2 has the following structure:
the structure of 2-methyl-5-nitroimidazole represented by formula 3 is as follows:
specifically, in the step (1), the organic solvent is selected from one or more of acetonitrile, ethanol, dichloromethane, dimethyl sulfoxide, N-dimethylformamide, tetrahydrofuran and chlorobenzene; acetonitrile is preferred.
Further, in the step (1), the molar ratio of the 2-methylimidazole to the tert-butyl nitrite is 1 (0.75-1.5), preferably 1:1.2; the concentration of the 2-methylimidazole in the homogeneous solution A is 0.05 to 0.35mol/L, preferably 0.2mol/L.
Further, in the step (1), the oxidant is selected from any one or more than two of TEMPO, 4-OH-TEMPO, 4-MeO-TEMPO, 4-AcO-TEMPO and 4-NHAc-TEMPO, DDQ, BQ, TBHP, DTBP, preferably TEMPO; the molar ratio of the 2-methylimidazole shown in formula 1 to the oxidant is 1 (1-3), preferably 1:1.5.
Further, 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 represented by formula 1 to the catalyst is 1 (0.1 to 0.8), preferably 1:0.2.
Further, in the step (2), the flow rates of the homogeneous solution A and the homogeneous solution B are controlled to be 0.5-5 mL/min, preferably 1mL/min; so that the volume ratio of the two pumps is 1 (0.8-1.5), preferably 1:1; the reaction residence time is 3 to 30min, preferably 5min.
Further, in the step (2), the heating temperature of the microchannel reactor is 90 to 110 ℃, preferably 100 ℃.
Specifically, in the step (2), the micro-channel reaction device comprises a feed pump, a mixer, a micro-reactor and a receiver; the mixer, the microreactor and the receiver are sequentially connected in series through pipelines; the pipeline of the micro-reactor is a capillary or polytetrafluoroethylene pipe, and the inner diameter of the pipeline is 0.4-2 mm, preferably 0.5mm; the volume is 2-10 mL, preferably 10mL.
Further, in the step (3), the vacuum concentration adopts a vacuum rotary evaporation method; after vacuum concentration of the reaction effluent, water is added, extraction is carried out with dichloromethane or ethyl acetate, the organic phases are combined, and the crude product is obtained by rotary evaporation again.
Preferably, in step (3), the extraction is performed with dichloromethane or ethyl acetate; the separation and purification method adopts a column chromatography mode.
The beneficial effects are that:
(1) According to the method, 2-methylimidazole and tert-butyl nitrite are used as substrates for the first time, and the 2-methyl-5-nitroimidazole is prepared after a catalyst and an oxidant are added, so that the method avoids the use of a large amount of mixed acid, is mild in reaction condition and simple in aftertreatment, reduces the generation of a large amount of toxic byproducts, and is environment-friendly.
(2) The invention adopts the micro-channel reaction device with the heating function, so that the substrate, the oxidant and the catalyst are fully contacted, the mass transfer and heat transfer rate among materials is improved, the reaction process can be accurately controlled, and the yield of the 2-methyl-5-nitroimidazole is obviously improved. Compared with the traditional production process, the device has the advantages of more controllable temperature, simple operation, safer reaction process and post-treatment and environmental protection.
Drawings
The foregoing and/or other advantages of the invention will become more apparent from the following detailed description of the invention when taken in conjunction with the accompanying drawings.
FIG. 1 is a synthetic scheme for 2-methyl-5-nitroimidazole of the invention.
FIG. 2 is a nuclear magnetic resonance image of 2-methyl-5-nitroimidazole synthesized according to the present invention.
Detailed Description
The invention will be better understood from the following examples.
As shown in FIG. 1, the present invention utilizes a microchannel reactor to prepare 2-methyl-5-nitroimidazole. At 100deg.C, 2-methylimidazole and tert-butyl nitrite are used as raw materials, TEMPO is used as oxidant, BF 3 ·Et 2 O is a catalyst, and MeCN is an organic solvent.
The device adopted by the invention comprises:
(1) A microchannel reaction device comprising a feed pump, a micromixer (slitplate mixer LH Hastelloy C), a microreactor (MF-V6), and a receiver; wherein, micromixer (slitplate mixer LH25 Hastelloy C), microreactor (MF-V6) and receiver pass through the pipeline in proper order and connect in series, and two charge pumps are parallelly connected at micromixer front end, are used for pumping homogeneous phase solution A and homogeneous phase solution B respectively, respectively as first feed liquid import and second feed liquid import, are connected with micromixer feed inlet. The pipeline in the microreactor is a polytetrafluoroethylene tube, the inner diameter of the pipeline is 0.5mm, and the volume of the pipeline is 10mL.
The preparation process of the invention comprises the following steps:
(1) 2-methylimidazole shown in a formula 1 and tert-butyl nitrite shown in a formula 2 are dissolved 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 the homogeneous solution A and the homogeneous solution B into a micro-channel reaction device with a heating function to perform reaction;
(3) And collecting an organic phase flowing out of the microchannel reaction device, concentrating the organic phase in vacuum to obtain a crude product, and finally further separating and purifying the crude product to obtain the 2-methyl-5-nitroimidazole shown in the formula 3, and calculating the yield of the target product after obtaining the target product.
The screening process of the preparation process of the invention is as follows:
(1) Screening of oxidant molar ratios
The molar ratio of the 2-methylimidazole to the tert-butyl nitrite is 1:1.2, and the concentration of the 2-methylimidazole is 0.2mol/L; TEMPO is the reactive oxidant; 2-methylimidazole and BF 3 ·Et 2 The molar ratio of O is 1:0.2; acetonitrile is an organic solvent.
The homogeneous solution A is a mixed solution of 2-methylimidazole, tert-butyl nitrite and acetonitrile, and the homogeneous solution B is TEMPO and BF 3 ·Et 2 A mixed solution of O; pumping the homogeneous solution A and the homogeneous solution B into a micro-channel reaction device according to the flow volume ratio of 1:1, wherein the flow rates are respectively 1mL/min; mixing by a micromixer, and then entering a microchannel reactor (the inner diameter of a polytetrafluoroethylene tube is 0.5mm, and the volume of the polytetrafluoroethylene tube is 10 mL) to react for 5min at 100 ℃; the organic phase flowing out of the receiver was collected, concentrated in vacuo, extracted and column chromatographed to give 2-methyl-5-nitroimidazole, the yield of which was calculated. The effect of different levels of oxidizing agent is shown in table 1.
TABLE 1 influence of the molar ratio of the oxidizing agent on the reaction yield
| Sequence number | 2-methylimidazole TEMPO | Isolation yield (%) |
| 1 | 1:1 | 82 |
| 2 | 1:1.5 | 94 |
| 3 | 1:2 | 91 |
| 4 | 1:3 | 87 |
(2) Screening of catalyst molar ratios
The molar ratio of the 2-methylimidazole to the tert-butyl nitrite is 1:1.2, and the concentration of the 2-methylimidazole is 0.2mol/L; the molar ratio of TEMPO to 2-methylimidazole is 1:1.5; acetonitrile is an organic solvent; BF (BF) 3 ·Et 2 O is the catalyst for this reaction, and the other conditions are the same. The effect of different levels of catalyst is shown in Table 2.
TABLE 2 influence of the molar ratio of the catalyst on the reaction yield
| Sequence number | 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 |
(3) Temperature screening
The molar ratio of 2-methylimidazole to TEMPO is 1:1.5, 2-methylimidazole to BF 3 ·Et 2 The molar ratio of O is 1:0.2; the reaction was carried out at different temperatures, the other conditions being the same. The effect of the different temperatures is shown in Table 3.
TABLE 3 influence of temperature on reaction yield
| Sequence number | Temperature (. Degree. C.) | Isolation yield (%) |
| 1 | 80 | 71 |
| 2 | 90 | 84 |
| 3 | 100 | 94 |
| 4 | 110 | 88 |
| 5 | 120 | 84 |
(4) Screening of solvents
Homogeneous solution a and homogeneous solution B were dissolved in different solvents, the other conditions being the same. The effect of the different solvents is shown in table 4.
TABLE 4 influence of different solvents on reaction yield
(5) Screening of flow rates
Fully dissolving the homogeneous solution A and the homogeneous solution B in acetonitrile; the flow rate of the homogeneous solution was adjusted, and the other conditions were the same. The effect of the different flow rates is shown in table 5.
TABLE 5 influence of different flow rates on reaction yield
| Sequence 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 |
Example 1
The molar ratio of the 2-methylimidazole to the tert-butyl nitrite is 1:1.2, and the concentration of the 2-methylimidazole is 0.2mol/L; the molar ratio of the 2-methylimidazole to the TEMPO is 1:1.5; 2-methylimidazole and BF 3 ·Et 2 The molar ratio of O is 1:0.2; acetonitrile is an organic solvent.
Homogeneous solution A is mixed solution of 2-methylimidazole, tert-butyl nitrite and acetonitrile, and homogeneous solution B is BF 3 ·Et 2 O, TEMPO and acetonitrile; pumping the homogeneous solution A and the homogeneous solution B into a micro-channel reaction device according to the flow volume ratio of 1:1, wherein the flow rates are respectively 1mL/min; mixing by a micromixer, and then entering a microchannel reactor (the inner diameter of a polytetrafluoroethylene tube is 0.5mm, and the volume of the polytetrafluoroethylene tube is 10 mL) to react for 5min at 100 ℃; the organic phase flowing out of the receiver was collected, concentrated in vacuo, extracted and column chromatographed to give 2-methyl-5-nitroimidazole in 94% yield.
The nuclear magnetic diagram is shown in fig. 2:1H NMR (400 MHz, DMSO-d 6) delta 12.93 (s, 1H), 8.21-8.06 (m, 1H), 2.29 (s, 3H); 13C NMR (101 MHz, DMSO-d 6) delta 147.2,145.2,119.4,14.1; HRMS (ESI-TOF) m/z calcd for C 4 H 6 N 3 O 2 [M+Na] + 128.0565,Found 128.0582.
Example 2
The molar ratio of the 2-methylimidazole to the tert-butyl nitrite is 1:1.2, and the concentration of the 2-methylimidazole is 0.2mol/L; the molar ratio of the 2-methylimidazole to the DDQ is 1:1.5; 2-methylimidazole and BF 3 ·Et 2 The molar ratio of O is 1:0.2; acetonitrile is an organic solvent.
The homogeneous solution A is a mixed solution of 2-methylimidazole, tert-butyl nitrite and acetonitrile, and the homogeneous solution B is OH-TEMPO and BF 3 ·Et 2 A mixed solution of O and acetonitrile; pumping the homogeneous solution A and the homogeneous solution B into a micro-channel reaction device according to the flow volume ratio of 1:1, wherein the flow rates are respectively 1mL/min; mixing by a micromixer, and then entering a microchannel reactor (the inner diameter of a polytetrafluoroethylene tube is 0.5mm, and the volume of the polytetrafluoroethylene tube is 10 mL) to react for 5min at 100 ℃; the organic phase flowing out of the receiver was collected, concentrated in vacuo, extracted and column chromatographed to give 2-methyl-5-nitroimidazole in 93% yield.
Example 3
The molar ratio of the 2-methylimidazole to the tert-butyl nitrite is 1:1.2, and the concentration of the 2-methylimidazole is 0.2mol/L; the molar ratio of the 2-methylimidazole to the TEMPO is 1:1.5; 2-methylimidazole and ZnBr 2 The molar ratio of (2) is 1:0.2; acetonitrile is an organic solvent.
The homogeneous solution A is a mixed solution of 2-methylimidazole, tert-butyl nitrite and acetonitrile, and the homogeneous solution B is TEMPO or ZnBr 2 And acetonitrile; pumping the homogeneous solution A and the homogeneous solution B into a micro-channel reaction device according to the flow volume ratio of 1:1, wherein the flow rates are respectively 1mL/min; mixing by a micromixer, and then entering a microchannel reactor (the inner diameter of a polytetrafluoroethylene tube is 0.5mm, and the volume of the polytetrafluoroethylene tube is 10 mL) to react for 5min at 100 ℃; the organic phase flowing out of the receiver was collected, concentrated in vacuo, extracted and column chromatographed to give 2-methyl-5-nitroimidazole in 91% yield.
Comparative example 1
Fully dissolving 2-methylimidazole by taking concentrated sulfuric acid as a medium, adding sodium sulfate with the concentration of 0.2mol/L, heating to 150 ℃, slowly dropwise adding concentrated nitric acid, and continuously stirring for 2 hours after the dropwise adding is finished; wherein, 2-methylimidazole: sodium sulfate: the molar ratio of the concentrated nitric acid is 1:1.2:1.2. After the reaction is finished, the reaction solution is taken out, heating is stopped, the pH value is regulated to 3.5-4 by ammonia water, and the 2-methyl-5-nitroimidazole is obtained through hot filtration, water washing and drying, wherein the yield is 68%. The specific reaction formula is as follows:
the present invention provides a new method for preparing 2-methyl-5-nitroimidazole by using a microchannel reaction device, and the method and the way for realizing the technical scheme are numerous, the above description is only a preferred embodiment of the present invention, and it should be pointed out that, for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and the improvements and modifications should also be regarded as the protection scope of the present invention. The components not explicitly described in this embodiment can be implemented by using the prior art.
Claims (10)
1. A method for preparing 2-methyl-5-nitroimidazole by using a microchannel reaction device, comprising the following steps:
(1) 2-methylimidazole shown in a formula 1 and tert-butyl nitrite shown in a formula 2 are dissolved 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 the homogeneous solution A and the homogeneous solution B into a micro-channel reaction device with a heating function to perform reaction;
(3) Collecting an organic phase flowing out of the micro-channel reaction device, concentrating the organic phase in vacuum to obtain a crude product, and finally further separating and purifying the crude product to obtain 2-methyl-5-nitroimidazole shown in a formula 3;
wherein, the structure of the 2-methylimidazole shown in the formula 1 is as follows:
the tert-butyl nitrite represented by formula 2 has the following structure:
the structure of 2-methyl-5-nitroimidazole represented by formula 3 is as follows:
2. the method for preparing 2-methyl-5-nitroimidazole according to claim 1, wherein in the step (1), the organic solvent is selected from any one or a combination of two or more of acetonitrile, ethanol, dichloromethane, dimethyl sulfoxide, N-dimethylformamide, tetrahydrofuran and chlorobenzene.
3. The method for preparing 2-methyl-5-nitroimidazole by using a microchannel reactor according to claim 1, wherein in the step (1), the molar ratio of 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 by using a microchannel reactor according to claim 1, wherein in the step (1), the oxidizing agent is any one or more selected from TEMPO, 4-OH-TEMPO, 4-MeO-TEMPO, 4-AcO-TEMPO, and 4-NHAc-TEMPO, DDQ, BQ, TBHP, DTBP; the molar ratio of the 2-methylimidazole shown in the formula 1 to the oxidant is 1 (1-3).
5. The method for preparing 2-methyl-5-nitroimidazole by using a microchannel reactor according to claim 1, wherein in the step (1), the catalyst is selected from the group consisting of 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 of them; the molar ratio of the 2-methylimidazole shown in the formula 1 to the catalyst is 1 (0.1-0.8).
6. The method for preparing 2-methyl-5-nitroimidazole by using a microchannel reactor according to claim 1, wherein in the step (2), the flow rate of the homogeneous solution A and the homogeneous solution B is controlled to be 0.5-5 mL/min; the volume ratio of the two pumps is 1 (0.8-1.5) in the same time; the reaction residence time is 3-30 min.
7. The method for producing 2-methyl-5-nitroimidazole according to claim 1, wherein in the step (2), the microchannel reactor is heated at a temperature of 90 to 110 ℃.
8. The method for preparing 2-methyl-5-nitroimidazole according to claim 1, wherein 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 polytetrafluoroethylene pipe, the inner diameter of the pipeline is 0.4-2 mm, and the volume is 2-10 mL.
9. The method for preparing 2-methyl-5-nitroimidazole by using a microchannel reactor according to claim 1, wherein in the step (3), after concentrating the reaction effluent in vacuo, adding water, extracting with dichloromethane or ethyl acetate, combining organic phases, and steaming again to obtain a crude product.
10. The method for preparing 2-methyl-5-nitroimidazole by using a microchannel reactor according to claim 1, wherein in the step (3), the separation and purification are performed by column chromatography.
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