A process for the production of alkyl nitroimidazoles

Abstract

The present invention relates to a process for the production of alkyl nitroimidazoles. Generally, the present invention performs a nitration reaction of an alkyl imidazole by contacting a first material comprising an alkyl imidazole, nitric acid, and a second acid component with a second material comprising an ammonium salt and a third acid component in two or more reaction zones. The process of the present invention enables the continuous synthesis of alkyl imidazoles.

Description

TECHNICAL FIELD

[0001] The present invention relates to the field of chemical technology, and in particular to a method for producing an alkyl nitroimidazole. The present invention method enables continuous synthesis of alkyl imidazoles. BACKGROUND

[0002] 2-methyl-5-nitroimidazole is an important intermediate for the synthesis of pharmaceutical drug metronidazole, secnidazole, and veterinary drug dimetridazole. Industrially, 2-methyl-5-nitroimidazole is typically obtained from the nitration of 2-methylimidazole (e.g., by using nitric acid or a mixture of nitric acid and concentrated sulfuric acid as the nitration agent), which has the reaction equation Due to the high reaction temperature, large heat release, and large amount of gas emission during the reaction, the nitration of 2-methylimidazole to synthesize 2-methyl-5-nitroimidazole is a reaction with a hazard level of 5.

[0003] In addition, the feeding of the reaction of nitration of 2-methylimidazole to synthesize 2-methyl-5-nitroimidazole is very difficult, because a large amount of inorganic salt, ammonium sulfate, needs to be added during the reaction. The role of ammonium sulfate is to moderate the oxidizing property of concentrated sulfuric acid and nitric acid, and to reduce the undesirable oxidative degradation of the reactants and products by concentrated sulfuric acid and / or nitric acid. For example, in the reaction, the oxidation product Therefore, the addition of ammonium sulfate generally improves the yield of the target product and reduces the amount of undesirable impurities. However, the use of ammonium sulfate limits the feeding rate. The feeding rate is very important for increasing the production scale and production efficiency.

[0004] Therefore, there is a need in the art for improved methods for the safe and continuous production of alkyl nitroimidazoles (e.g., 2-methyl-5-nitroimidazole), such as methods with improved yield, reduced impurity production, improved feeding rate, etc. SUMMARY

[0005] The present application found that by using a first material comprising an alkyl imidazole, nitric acid, and a second acid component, and a second material comprising an ammonium salt and a third acid component, the impurity production can be effectively reduced, the yield can be improved, and the feeding rate can be improved. The second acid component comprises an organic acid, preferably formic acid, acetic acid, propionic acid, butyric acid, tartaric acid, oxalic acid, malic acid, citric acid, or ascorbic acid, more preferably acetic acid.

[0006] In one aspect, the present invention provides a method for producing an alkyl nitroimidazole, which method specifically comprises the following steps:

[0007] (1) Step 1: providing a first material and a second material, wherein: the first material comprises an alkyl imidazole, nitric acid, and a second acid component; the second material comprises an ammonium salt and a third acid component;

[0008] (2) Step 2: delivering a first portion of the second material into the first reaction zone to contact and react with the first material to form a first reacted material, wherein the first reacted material comprises an alkyl nitroimidazole;

[0009] (3) Step 3: withdrawing the first reacted material from the first reaction zone and delivering the first reacted material into a second reaction zone located downstream from the first reaction zone; delivering a second portion of the second material into the second reaction zone, wherein the second portion of the second material is delivered into the second reaction zone before, after, or concurrently with the delivery of the first reacted material into the second reaction zone; the first reacted material and the second portion of the second material contact and react to form a second reacted material, wherein the second reacted material comprises an alkyl nitroimidazole.

[0010] In one embodiment of the first aspect, the weight parts ratio of alkyl imidazole, nitric acid, and the second acid component in the step 1 first material is (1.0-2.0):(1.0-2.0):1. For the alkyl imidazole, the range of 1.0-2.0 is intended to encompass any value within the range or a sub-range consisting of any of the values, e.g., 1.0, 1.05, 1.10, 1.15, 1.20, 1.25, 1.30, 1.35, 1.40, 1.45, 1.40, 1.45, 1.60, 1.65, 1.70, 1.75, 1.80, 1.85, 1.90, 1.95, 2.0. For the nitric acid, the range of 1.0-2.0 is intended to encompass any value within the range or a sub-range consisting of any of the values, e.g., 1.0, 1.05, 1.10, 1.15, 1.20, 1.25, 1.30, 1.35, 1.40, 1.45, 1.40, 1.45, 1.60, 1.65, 1.70, 1.75, 1.80, 1.85, 1.90, 1.95, 2.0. The weight parts ratio of alkyl imidazole, nitric acid, and the second acid component in the step 1 first material is preferably 1.25:1.25:1.

[0011] In one embodiment of the first aspect, wherein the third acid component in the step 1 second material comprises concentrated sulfuric acid in a mass fraction of 90% or more, e.g., 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, or oleum, preferably 95% or more.

[0012] In one embodiment of the first aspect, wherein the alkyl imidazole is C 1-10 alkyl imidazole, preferably 2-C 1-10 alkyl imidazole, 4-C1-10 alkylimidazolium, or 5-C 1-10 Alkyl imidazole, more preferably 2-methylimidazolium, 2-ethylimidazolium, 2-propylimidazolium, 2-isopropylimidazolium, 4-methylimidazolium, 4-ethylimidazolium, 4-propylimidazolium, 4-isopropylimidazolium, 5-methylimidazolium, 5-ethylimidazolium, 5-propylimidazolium, or 5-isopropylimidazolium, with 2-methylimidazolium being the most preferred.

[0013] In one embodiment of this aspect, the nitric acid in the first material of step 1 is nitric acid with a mass fraction of 80% or more, 81% or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, fuming nitric acid, preferably 95% or more, and more preferably fuming nitric acid.

[0014] In one embodiment of this aspect, the ammonium salt in the second material of step 1 includes one or more of ammonium chloride, ammonium fluoride, ammonium iodide, ammonium bromide, ammonium carbonate, ammonium bicarbonate, ammonium phosphate, ammonium hydrogen phosphate, ammonium nitrate, ammonium sulfate, and ammonium bisulfate, preferably ammonium sulfate.

[0015] In one embodiment of this aspect, the second acid component comprises an organic acid, preferably formic acid, acetic acid, propionic acid, butyric acid, tartaric acid, oxalic acid, malic acid, citric acid, or ascorbic acid, more preferably acetic acid.

[0016] In one embodiment of this aspect, the weight parts ratio of the ammonium salt and the third acid component in the Step 1 second material is 1:(0.6-1.6). For the third acid component, the range of 0.6-1.3 is intended to encompass any value within the range or subranges consisting of any value therein, e.g., 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.80, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.90, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1.00, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.10, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.20, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.40, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.50, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.60. The weight parts ratio of the ammonium salt and the third acid component in the Step 1 second material is preferably 1:(1.2-1.5).

[0017] In one embodiment of this aspect, the apparent residence time of the reaction in the first reaction zone is 30-120 s, preferably 30-80 s, more preferably 40-70 s. For example, 30 s, 35 s, 40 s, 45 s, 50 s, 55 s, 60 s, 65 s, 70 s, 75 s, 80 s, 85 s, 90 s, 95 s, 100 s, 105 s, 110 s, 115 s, 120 s.

[0018] In one embodiment of this aspect, the temperature of the reaction in the first reaction zone is 100-200 °C, preferably 100-150 °C, more preferably 140-160 °C. For example, 100 °C, 110 °C, 120 °C, 130 °C, 140 °C, 150 °C, 160 °C, 170 °C, 180 °C, 190 °C, 200 °C.

[0019] In an embodiment of this aspect, the apparent residence time of the reaction in the second reaction zone is 10 s to 50 mins, preferably 10 s to 15 min, more preferably 10 s to 8 min. For example, 10 s, 15 s, 20 s, 25 s, 30 s, 35 s, 40 s, 45 s, 50 s, 55 s, 60 s, 65 s, 70 s, 75 s, 80 s, 85 s, 90 s, 95 s, 100 s, 105 s, 110 s, 115 s, 120 s, 2.5 min, 3 min, 3.5 min, 4 min, 4.5 min, 5 min, 5.5 min, 6 min, 6.5 min, 7 min, 7.5 min, 8 min, 8.5 min, 9 min, 9.5 min, 10 min, 11 min, 12 min, 13 min, 14 min, 15 min, 16 min, 17 min, 18 min, 19 min, 20 min, 25 min, 30 min, 35 min, 40 min, 45 min, 50 min.

[0020] In an embodiment of this aspect, the temperature of the reaction in the second reaction zone is 120 to 220 °C, preferably 120 to 180 °C, more preferably 130 to 150 °C. For example, 120 °C, 130 °C, 140 °C, 150 °C, 160 °C, 170 °C, 180 °C, 190 °C, 200 °C, 210 °C, 220 °C.

[0021] In an embodiment of this aspect, the flow rate of the first material delivered into the first reaction zone in step 2 is 2 to 10000 ml / min, preferably 4 to 5000 ml / min, more preferably 10 to 3000 ml / min. For example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10000 ml / min.

[0022] In one embodiment of this aspect, the flow rate of the first portion of the second material delivered into the first reaction zone in step 2 is between 4 and 20000 ml / min, preferably between 6 and 10000 ml / min, more preferably between 8 and 5000 ml / min. For example, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10000, 11000, 12000, 13000, 14000, 15000, 16000, 17000, 18000, 19000, 20000 ml / min.

[0023] In one embodiment of this aspect, the flow rate of the second portion of the second material delivered into the second reaction zone in step 3 is between 1 and 5000 ml / min, preferably between 2 and 3000 ml / min, more preferably between 2 and 2500 ml / min. For example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3500, 4000, 4500, 5000 ml / min.

[0024] In one embodiment of this aspect, the second material in step 1 is divided into less than or equal to the number of reaction zones. The ratio between the portions is not critical and the portions can be equal or unequal.

[0025] When two or more reactor zones are present, the reaction zones described herein can be connected in series and / or in parallel. When two or more reaction zones are connected in parallel, they can be used in the form of multiple (e.g., two, three, four, or five) production runs connected in parallel, where each production run includes one or more reaction zones connected in series. In another aspect, one or more reaction zones connected in series can also be used herein, each of which is optionally parallel to one or more additional reaction zones.

[0026] In the present context, the term "alkyl" denotes a straight-chain or branched saturated aliphatic hydrocarbon group having 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms. Exemplary straight-chain alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, and hexyl. Exemplary branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, t-butyl, isopentyl, t-pentyl, isohexyl, and neohexyl. In the present context, the term "alkyl imidazole" includes C 1-10 alkyl imidazole, preferably 2-C 1-10 alkyl imidazole, 4-C 1-10 alkyl imidazole, or 5-C 1-10 alkyl imidazole, more preferably, for example, 2-methyl imidazole, 2-ethyl imidazole, 2-propyl imidazole, 2-isopropyl imidazole, 4-methyl imidazole, 4-ethyl imidazole, 4-propyl imidazole, 4-isopropyl imidazole, 5-methyl imidazole, 5-ethyl imidazole, 5-propyl imidazole, or 5-isopropyl imidazole, more preferably 2-methyl imidazole.

[0027] In an optional embodiment, the nitrogen atom at position 1 of the alkyl nitroimidazole can be unsubstituted or substituted with optional substituents including, but not limited to, methyl, hydroxyethyl, 2-hydroxyprop-1-yl, 3-chloro-2-hydroxyprop-1-yl, ethyl(sulfonyl)ethyl.

[0028] In the present context, the expression "second acid component" is intended to describe an additional acid that is different from nitric acid in the first material. The expression "third acid component" is intended to describe an acid component in the second material without otherwise limiting. In some embodiments, the "second acid component" and the "third acid component" can be the same or different. In some embodiments, the "second acid component" can comprise one or more acids. In some embodiments, the "third acid component" can comprise one or more acids.

[0029] In the present context, the term "acid" in the expression "second acid component" includes, but is not limited to, organic acids and inorganic acids. Among the organic acids are included natural organic acids and synthetic organic acids, non-limiting examples of organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, butyric acid, tartaric acid, oxalic acid, malic acid, citric acid, ascorbic acid, and the like, aromatic organic acids such as benzoic acid, salicylic acid, caffeic acid, and the like. Non-limiting examples of inorganic acids include, but are not limited to, hydrochloric acid, sulfuric acid, nitric acid, boric acid, carbonic acid, phosphoric acid, and the like.

[0030] In the present context, the term "acid" in the expression "third acid component" includes, but is not limited to, organic acids and inorganic acids. Among the organic acids are included natural organic acids and synthetic organic acids, non-limiting examples of organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, butyric acid, tartaric acid, oxalic acid, malic acid, citric acid, ascorbic acid, and the like, aromatic organic acids such as benzoic acid, salicylic acid, caffeic acid, and the like. Non-limiting examples of inorganic acids include, but are not limited to, hydrochloric acid, sulfuric acid, nitric acid, boric acid, carbonic acid, phosphoric acid, and the like.

[0031] In the present context, the term "sulfuric acid" encompasses sulfuric acid (H2SO4) at any concentration. In some embodiments, the sulfuric acid described herein is sulfuric acid at a mass fraction of 90% or more, including, but not limited to, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sulfuric acid, or fuming sulfuric acid.

[0032] In the present context, the term "nitric acid" encompasses nitric acid (HNO3) at any concentration. In some embodiments, the nitric acid described herein is nitric acid at a mass fraction of 80% or more, 81% or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, fuming nitric acid, preferably 95% or more, more preferably fuming nitric acid.

[0033] As used herein, the term "parts by weight" is intended to mean the relative amounts of the materials involved, based on the pure substance in the material provided, especially for materials in the form of a liquid mixture. For example, sulfuric acid is based on the number of molecules of sulfuric acid in the sulfuric acid provided, and nitric acid is based on the number of molecules of nitric acid in the nitric acid provided. For example, when 1000 grams of 90% by mass sulfuric acid is used, the weight of the sulfuric acid is based on 900 grams. For feed materials other than sulfuric acid and nitric acid, especially for feed materials in solid form, purity is not considered in the calculations herein, unless otherwise specified, because the purity of commercially available reagents is already sufficient to meet the requirements of the present application. For fuming nitric acid (e.g., nitric acid having a mass fraction of 98% or more) or fuming sulfuric acid, the mass fraction is not considered in the calculations herein.

[0034] The isolated yield of 2-methyl-5-nitroimidazole described herein is based on the number of moles of starting material 2-methylimidazole.

[0035] As used herein, the terms "acetic acid" and "acetic acid" are interchangeable.

[0036] As used herein, the term "ammonium salt" refers to an ionic compound composed of an ammonium ion and an acid ion, non-limiting examples of "ammonium salts" include, but are not limited to, ammonium chloride, ammonium fluoride, ammonium iodide, ammonium bromide, ammonium carbonate, ammonium bicarbonate, ammonium phosphate, ammonium hydrogen phosphate, ammonium nitrate, ammonium sulfate, and ammonium bisulfate, preferably ammonium sulfate, and the like. In some preferred embodiments, ammonium sulfate is preferably used.

[0037] As used herein, delivery described herein includes, but is not limited to, delivery using a pump, extrusion, osmosis, spraying, and the like. In some embodiments, delivery described herein is delivery using a pump, such as a pump conventional in the art.

[0038] As used herein, the term "downstream" is intended to merely describe the flow of the reaction material first through a first reaction zone and then through a second reaction zone, without any other limitation. The first reaction zone and the second reaction zone described herein are intended to describe different reaction areas in the direction of the flow of the reaction material, without any other limitation. If necessary, one skilled in the art can provide more reaction zones (e.g., a third reaction zone, a fourth reaction zone, etc.) (e.g., according to the extent of the reaction). The first reaction zone and the second reaction zone should never be understood as limiting the present application to only two reaction zones.

[0039] The method described herein can be carried out in a continuous manner or in a batch manner, preferably in a continuous manner.

[0040] The reaction zone described herein can comprise a reactor. The reactor can be a tank reactor, a pipe reactor, a microchannel reactor (e.g., SiC / tetrafluoro microchannel reactor, available from Corning, Inc.), a high flux reactor (e.g., high flux reactor available from Corning, Inc., such as high flux reactor assembled from "G1" modules (AFR-G1), or high flux reactor assembled from "G5" modules (AFR-G5)), a flow reactor. One reaction zone described herein can comprise one or more reactors.

[0041] In the present context, the term "microchannel reactor" refers to a microreactor whose internal structure is mainly composed of microscale (typically 10-300 μm) channels.

[0042] In the present context, the term "(LC) analysis" refers to liquid chromatography (LC) analysis method.

[0043] The process described herein can be carried out at normal pressure or elevated pressure. The pressure of any reaction zone of the process described herein can be 0.1-5 MPa, preferably 0.1-2 MPa, for example, 0.1 MPa, 0.2 MPa, 0.3 MPa, 0.4 MPa, 0.5 MPa, 0.6 MPa, 0.7 MPa, 0.8 MPa, 0.9 MPa, 1.0 MPa, 2.0 MPa, 3.0 MPa, 4.0 MPa, or 5.0 MPa.

[0044] The temperature described herein refers to Celsius. The concentration / amount / usage / portion described herein can be concentration / amount / usage / portion expressed in mass, volume, mole, mass / volume, volume / mass, as needed.

[0045] The temperature in different reaction zones described herein can be the same or different. When a reaction zone comprises multiple reactors, the temperature in different reactors in the same reaction zone can be the same or different.

[0046] The process described herein can be carried out in adiabatic or non-adiabatic state.

[0047] The process described herein can be carried out in isothermal or non-isothermal state. The isothermal described herein refers to the reaction temperature varying within ±5°C (preferably ±4, 3, 2, 1, 0.5°C) of the set temperature value.

[0048] The second material described herein can be prepared before, simultaneously with, or after the preparation of the first material.

[0049] In a preferred embodiment, the alkyl imidazole is 2-methylimidazole; the alkyl nitroimidazole is 2-methyl-5-nitroimidazole; the second acid component is acetic acid; the third acid component is sulfuric acid; and the ammonium salt is ammonium sulfate.

[0050] In one preferred embodiment, the present application relates to a method for producing 2-methyl-5-nitroimidazole, the method comprising the steps of:

[0051] (1) Step 1: providing a first material and a second material, wherein: the first material comprises 2-methylimidazole, nitric acid, and a second acid component, wherein the second acid component is formic acid, acetic acid, propionic acid, or butyric acid; the second material comprises ammonium sulfate and sulfuric acid;

[0052] (2) Step 2: delivering a first portion of the first material and the second material into a first reaction zone to contact and react to form a first reacted material, wherein the first reacted material comprises 2-methyl-5-nitroimidazole;

[0053] (3) Step 3: discharging the first reacted material from the first reaction zone and delivering the first reacted material into a second reaction zone located downstream of the first reaction zone; delivering a second portion of the second material into the second reaction zone, wherein the second portion of the second material is delivered into the second reaction zone before, after, or simultaneously with the delivery of the first reacted material into the second reaction zone; the first reacted material and the second portion of the second material contact and react to form a second reacted material, wherein the second reacted material comprises 2-methyl-5-nitroimidazole.

[0054] The method described herein achieves the following excellent technical effects.

[0055] (1) It is advantageous to provide the second material in two or more portions, which can both increase the yield of the product alkyl nitroimidazole and increase the purity of the alkyl nitroimidazole.

[0056] (2) The use of a second acid component such as acetic acid reduces oxidation impurities and / or increases yield, which increases the feed rate. BRIEF DESCRIPTION OF DRAWINGS

[0057] Figure 1 : AFR-G1 (AFR: Advanced Flow Reactor) device schematic diagram, wherein A1 is the first material, A2 is the first portion of the second material, and A3 is the second portion of the second material. T1 is a first temperature zone having a first temperature, and T2 is a second temperature zone having a second temperature. BPR (BPR: Background Pressure Regulator) is a back pressure valve. IPC (In-process-control) is in-process control.

[0058] Figure 2AFR-G5 (AFR: Advanced Flow Reactor) device schematic, where Al is a first material, A2 is a first portion of a second material, A3 is a second portion of the second material. T1 is a first temperature zone having a first temperature, T2 is a second temperature zone having a second temperature. DETAILED DESCRIPTION

[0059] The technical solutions of the present application will now be described in conjunction with specific examples. It should be understood that the following examples are only used to illustrate the present application and are not intended to limit the scope of the present application. Unless otherwise specified, the reagents described in the examples are commercially available.

[0060] 2-methylimidazole was purchased from Macklin Reagent. Nitric acid was purchased from National Pharmaceutical Reagent, with a specification of 98% fuming nitric acid. Sulfuric acid was purchased from National Pharmaceutical Reagent, with a specification of 98% concentrated sulfuric acid. Ammonium sulfate was purchased from National Pharmaceutical Reagent. Formic acid was purchased from Aldrich Reagent (88%). Acetic acid was purchased from National Pharmaceutical Reagent. Propionic acid was purchased from Aldrich. Butyric acid was purchased from Aldrich. Malic acid was purchased from Aldrich.

[0061] The G1 reactor used is a commercially available process development and production platform produced by Corning Inc.

[0062] The G5 reactor used is a commercially available industrial scale-up production device produced by Corning Inc.

[0063] The LC analyzer is an LC-20AD high-performance liquid chromatograph produced by Shimadzu Corporation.

[0064] General Method

[0065] The methods described herein were performed using the following general method.

[0066] Step 1: Mix the alkyl imidazole, nitric acid, and acetic acid under stirring to form a first material comprising the alkyl imidazole, the nitric acid, and the acetic acid. Mix the ammonium sulfate and the sulfuric acid under stirring to form a second material, and divide the second material into multiple portions.

[0067] Step 2: Deliver the first material and a first portion of the second material into a first reaction zone to contact and react to form a first reacted material, wherein the first reacted material comprises an alkyl nitroimidazole.

[0068] Step 3: discharging a first reacted material from the first reaction zone and delivering the first reacted material into a second reaction zone located downstream of the first reaction zone; delivering a second portion of the second material into the second reaction zone, wherein the second portion of the second material is delivered into the second reaction zone before, after or simultaneously with the delivery of the first reacted material into the second reaction zone; the first reacted material and the second portion of the second material being contacted to react to form a second reacted material, wherein the second reacted material comprises an alkyl nitroimidazole.

[0069] Example 1

[0070] 1000 g of 2-methylimidazole (white powder, molecular weight: 82), 1000 g of nitric acid (mass fraction: 98%) and 800 g of acetic acid (volume: 762 ml; density: 1.05 g / ml) were mixed under stirring to obtain a first material. 1000 g of ammonium sulfate (white granules, molecular weight: 132) and 1500 g of sulfuric acid (mass fraction: 90%) were mixed under stirring to form a second material.

[0071] Pump 1 for delivering the first material was set to feed at a rate of 28 g / min (21.5 ml / min).

[0072] Pump 2 for delivering the first portion of the second material was set to feed at a rate of 23 g / min (13.2 ml / min).

[0073] Pump 3 for delivering the second portion of the second material was set to feed at a rate of 3.5 g / min (2 ml / min).

[0074] The temperature of the first reaction zone was 150°C. The reaction zone was a Gl reactor. The internal volume of the reactor was 40 mL (5 modules) and the apparent residence time was about 67 s.

[0075] The temperature of the second reaction zone was 150°C. The reaction zone was a Gl reactor. The internal volume of the reactor was 40 mL (5 modules) and the apparent residence time was about 67 s.

[0076] Back pressure valves were used to apply a back pressure to the first and second reaction zones at the outlet of the reactor material, the material delivered by the pumps providing a pressure of 0.8 MPa of back pressure to increase the actual residence time of the material.

[0077] The LC analysis showed that 3 mol% of 2-methylimidazole remained unreacted compared to the feed. The reaction solution was quenched with water, neutralized with ammonia, filtered, washed, dried, and the isolated yield of 2-methyl-5-nitroimidazole was 91 mol%. The LC analysis showed that the purity of 2-methyl-5-nitroimidazole was 99.7%.

[0078] Example 2

[0079] A first material was obtained by mixing 1000 g of 2-methylimidazole (white powder, molecular weight: 82), 1000 g of nitric acid (mass fraction: 98%), and 800 g of acetic acid (volume: 762 ml; density: 1.05 g / ml) under stirring. A second material was obtained by mixing 1000 g of ammonium sulfate (white granules, molecular weight: 132) and 1500 g of sulfuric acid (mass fraction: 98%) under stirring.

[0080] The pump 1 for delivering the first material was set to feed at a rate of 28 g / min (21.5 ml / min).

[0081] The pump 2 for delivering the first part of the second material was set to feed at a rate of 23 g / min (13.2 ml / min).

[0082] The pump 3 for delivering the second part of the second material was set to feed at a rate of 3.5 g / min (2 ml / min).

[0083] The temperature of the first reaction zone was 150°C. The reaction zone was a G1 reactor. The internal volume of the reactor was 40 mL (5 modules) and the apparent residence time was about 67 s.

[0084] The temperature of the second reaction zone was 150°C. The reaction zone was a G1 reactor. The internal volume of the reactor was 40 mL (5 modules) and the apparent residence time was about 67 s.

[0085] A back pressure valve was used to apply a back pressure to the first and second reaction zones at the outlet of the reactor material, the material delivered by the pumps providing a pressure of 0.8 MPa to increase the actual residence time of the material.

[0086] The LC analysis showed that 2 mol% of 2-methylimidazole remained unreacted compared to the feed. The reaction solution was quenched with water, neutralized with ammonia, filtered, washed, dried, and the isolated yield of 2-methyl-5-nitroimidazole was 92.5 mol%. The LC analysis showed that the purity of 2-methyl-5-nitroimidazole was 99.7%.

[0087] Example 3

[0088] 1000 Kg of 2-methylimidazole (white powder, molecular weight: 82), 1000 Kg of nitric acid (mass fraction: 98%) and 800 Kg of acetic acid (volume: 762 L; density: 1.05 g / ml) were mixed under stirring to obtain a first material. 1000 Kg of ammonium sulfate (white granules, molecular weight: 132) and 1500 Kg of sulfuric acid (mass fraction: 98%) were mixed under stirring to form a second material.

[0089] The pump 1 for delivering the first material was set to feed at a rate of 2800 g / min (2150 ml / min).

[0090] The pump 2 for delivering the first part of the second material was set to feed at a rate of 2300 g / min (1320 ml / min).

[0091] The pump 3 for delivering the second part of the second material was set to feed at a rate of 350 g / min (200 ml / min).

[0092] The temperature of the first reaction zone was 150°C. The reaction zone was a G5 reactor. The internal volume of the reactor was 4 L and the apparent residence time was about 67 s.

[0093] The temperature of the second reaction zone was 150°C. The reaction zone was a G5 reactor. The internal volume of the reactor was 4 L and the apparent residence time was about 67 s.

[0094] A back pressure valve was used to impose a back pressure on the first and second reaction zones at the outlet of the reactor material, the material delivered by the pumps providing a pressure of 0.8 MPa of back pressure to increase the actual residence time of the material.

[0095] The sample collected at the outlet of the reaction was subjected to LC analysis after 5 minutes. The LC analysis showed that 2 mol% of 2-methylimidazole remained unreacted compared to the feed. The reaction liquid was quenched with water, neutralized with ammonia, filtered, washed, dried and the separation yield of 2-methyl-5-nitroimidazole was 91 mol%. The LC analysis showed that the product had a purity of 99%.

[0096] Example 4

[0097] 1000 g of 2-methylimidazole (white powder, molecular weight: 82), 1000 g of nitric acid (mass fraction: 98%) and 800 g of formic acid (volume: 746 ml; density: 1.22 g / ml mass fraction 88%) were mixed under stirring to obtain a first material. 1000 g of ammonium sulfate (white granules, molecular weight: 132) and 1500 g of sulfuric acid (mass fraction: 98%) were mixed under stirring to form a second material.

[0098] Pump 1 for delivering the first material was set to feed at a rate of 28 g / min (21.1 ml / min).

[0099] Pump 2 for delivering the first part of the second material was set to feed at a rate of 23 g / min (13.2 ml / min).

[0100] Pump 3 for delivering the second part of the second material was set to feed at a rate of 3.5 g / min (2 ml / min).

[0101] The temperature of the first reaction zone was 150 °C. The reaction zone was a Gl reactor. The internal volume of the reactor was 40 mL (5 modules) and the apparent residence time was approximately 67 s.

[0102] The temperature of the second reaction zone was 150 °C. The reaction zone was a Gl reactor. The internal volume of the reactor was 40 mL (5 modules) and the apparent residence time was approximately 67 s.

[0103] Back pressure was applied to the first and second reaction zones at the reactor material outlet using a back pressure valve, the material delivered by the pumps providing a pressure of 0.8 MPa to increase the actual residence time of the material.

[0104] LC analysis of the sample collected at the reaction outlet showed that 2 mol% of 2-methylimidazole remained unreacted compared to the feed. The reaction was quenched with water, neutralised using ammonia, filtered, washed, dried and the 2-methyl-5-nitroimidazole was isolated in a yield of 88 mol%. LC analysis showed that the purity of the 2-methyl-5-nitroimidazole was 99.5%.

[0105] Example 5

[0106] 1000 g of 2-methylimidazole (white powder, molecular weight: 82), 1000 g of nitric acid (mass fraction: 98%) and 800 g of n-propionic acid (volume: 808 ml; density: 0.99 g / ml; oily liquid) were mixed under stirring to obtain the first material. 1000 g of ammonium sulfate (white granules, molecular weight: 132) and 1500 g of sulfuric acid (mass fraction: 98%) were mixed under stirring to form the second material.

[0107] Pump 1 for delivering the first material was set to feed at a rate of 28 g / min (21.7 ml / min).

[0108] Pump 2 for delivering the first part of the second material was set to feed at a rate of 23 g / min (13.2 ml / min).

[0109] The pump 3 for delivering the second part of the second material was set to feed at a rate of 3.5 g / min (2 ml / min).

[0110] The temperature of the first reaction zone was 150 °C. The reaction zone was a G1 reactor. The internal volume of the reactor was 40 mL (5 modules) and the apparent residence time was about 67 s.

[0111] The temperature of the second reaction zone was 150 °C. The reaction zone was a G1 reactor. The internal volume of the reactor was 40 mL (5 modules) and the apparent residence time was about 67 s.

[0112] A back pressure valve was used to impose a back pressure on the first and second reaction zones at the outlet of the reactor material, the material delivered by the pump providing a pressure of 0.8 MPa to increase the actual residence time of the material.

[0113] LC analysis of the sample collected at the reaction outlet showed that 2 mol% of 2-methylimidazole remained unreacted compared to the feed. The reaction liquid was quenched with water, neutralized using ammonia, filtered, washed, dried and the separation yield of 2-methyl-5-nitroimidazole was 87 mol%. LC analysis showed that the purity of 2-methyl-5-nitroimidazole was 99.3%.

[0114] Example 6

[0115] 1000 g of 2-methylimidazole (white powder, molecular weight: 82) and 1000 g of nitric acid (mass fraction: 98%) were mixed under stirring to obtain a first material. 1000 g of ammonium sulfate (white granules, molecular weight: 132) and 1500 g of sulfuric acid (mass fraction: 90%) were mixed under stirring to form a second material.

[0116] The pump 1 for delivering the first material was set to feed at a rate of 20 g / min (15.5 ml / min).

[0117] The pump 2 for delivering the first part of the second material was set to feed at a rate of 23 g / min (13.2 ml / min).

[0118] The pump 3 for delivering the second part of the second material was set to feed at a rate of 3.5 g / min (2 ml / min).

[0119] The temperature of the first reaction zone was 150 °C. The reaction zone was a G1 reactor. The internal volume of the reactor was 40 mL (5 modules) and the apparent residence time was about 67 s.

[0120] The temperature of the second reaction zone was 150°C. The reaction zone was a G1 reactor. The internal volume of the reactor was 40 mL (5 modules) and the apparent residence time was about 67 s.

[0121] Back pressure was applied to the first and second reaction zones at the reactor material outlet using back pressure valves. The material delivered by the pumps provided a back pressure of 0.8 MPa to increase the actual residence time of the material.

[0122] LC analysis of the sample collected at the reaction outlet after 5 minutes from the first sample being discharged at the reaction outlet showed that 2 mol% of 2-methylimidazole remained unreacted compared to the feed. The reaction liquid was quenched with water, neutralized using ammonia, filtered, washed, dried and the isolated yield of 2-methyl-5-nitroimidazole was only 83 mol%. LC analysis showed that the purity of 2-methyl-5-nitroimidazole was 99.5%.

[0123] The low isolated yield suggests that in this experiment a significant amount of 2-methylimidazole was reacted to impurities such as oxidation impurities rather than the target product 2-methyl-5-nitroimidazole.

[0124] Example 7

[0125] 1000 g of 2-methylimidazole (white powder, molecular weight: 82), 1000 g of nitric acid (mass fraction: 98%) and 800 g of n-butyl acid (volume: 833 ml; density: 0.96 g / ml; oily liquid) were mixed under stirring to obtain a first material. 1000 g of ammonium sulfate (white granules, molecular weight: 132) and 1500 g of sulfuric acid (mass fraction: 98%) were mixed under stirring to form a second material.

[0126] Pump 1 for delivering the first material was set to feed at a rate of 28 g / min (21.4 ml / min).

[0127] Pump 2 for delivering the first part of the second material was set to feed at a rate of 23 g / min (13.2 ml / min).

[0128] Pump 3 for delivering the second part of the second material was set to feed at a rate of 3.5 g / min (2 ml / min).

[0129] The temperature of the first reaction zone was 150°C. The reaction zone was a G1 reactor. The internal volume of the reactor was 40 mL (5 modules) and the apparent residence time was about 67 s.

[0130] The temperature of the second reaction zone was 150°C. The reaction zone was a G1 reactor. The internal volume of the reactor was 40 mL (5 modules) and the apparent residence time was about 67 s.

[0131] A back pressure valve was used to apply back pressure to the first and second reaction zones at the reactor material outlet, the material delivered by the pumps provided a pressure of 0.8 MPa to increase the effective residence time of the material.

[0132] LC analysis of the sample collected at the reaction outlet after 5 minutes from the first sample being discharged from the reaction outlet showed that 2 mol% of 2-methylimidazole remained unreacted compared to the feed. The reaction solution was quenched with water, neutralised using ammonia, filtered, washed and dried to give a 84 mol% isolated yield of 2-methyl-5-nitroimidazole. LC analysis showed that the purity of the 2-methyl-5-nitroimidazole was 99.5%.

[0133] Example 8

[0134] 1000 g of 2-methylimidazole (white powder, molecular weight: 82), 1000 g of nitric acid (mass fraction: 98%) and 800 g of L-malic acid (white crystalline solid; molecular weight: 134) were mixed under heating with stirring to give a first material. 1000 g of ammonium sulfate and 1500 g of sulfuric acid (mass fraction: 98%) were mixed under stirring to form a second material.

[0135] Pump 1 for delivering the first material was set to feed at a rate of 28 g / min (21.5 ml / min).

[0136] Pump 2 for delivering the first part of the second material was set to feed at a rate of 23 g / min (13.2 ml / min).

[0137] Pump 3 for delivering the second part of the second material was set to feed at a rate of 3.5 g / min (2 ml / min).

[0138] The temperature of the first reaction zone was 150 °C. The reaction zone was a G1 reactor. The internal volume of the reactor was 40 mL (5 modules) and the apparent residence time was approximately 67 s.

[0139] The temperature of the second reaction zone was 150 °C. The reaction zone was a G1 reactor. The internal volume of the reactor was 40 mL (5 modules) and the apparent residence time was approximately 67 s.

[0140] A back pressure valve was used to apply back pressure to the first and second reaction zones at the reactor material outlet, the material delivered by the pumps provided a pressure of 0.8 MPa to increase the effective residence time of the material.

[0141] Timing was started from the first sample discharge at the reaction outlet, and LC analysis was performed on the sample collected at the reaction outlet after 5 minutes. LC analysis showed that 2 mol% of 2-methylimidazole remained unreacted compared to the feed. The reaction solution was quenched with water, neutralized with ammonia, filtered, washed, dried, and the separation yield of 2-methyl-5-nitroimidazole was 82 mol%. LC analysis showed that the purity of 2-methyl-5-nitroimidazole was 99.7%.

[0142] The foregoing description of the examples and embodiments should be considered as illustrative only of the principles of the application. The specific embodiments described are merely exemplary and are not intended to limit the scope of the application, which is defined by the claims. Any change and further modification that comes within the meaning of the claims are to be embraced by the application.

Claims

1. A method for producing 2-methyl-5-nitroimidazole, the method comprising the following steps: (1) Step 1: Provide a first material and a second material, wherein: the first material contains 2-methylimidazole, nitric acid and acetic acid; the second material contains ammonium sulfate and sulfuric acid; (2) Step 2: The first material and the first part of the second material are delivered into the first reaction zone to react and form a first reacted material, wherein the first reacted material contains 2-methyl-5-nitroimidazole; (3) Step 3: Discharge the first reacted material from the first reaction zone and deliver the first reacted material into a second reaction zone located downstream of the first reaction zone; deliver a second portion of the second material into the second reaction zone, wherein the second portion of the second material is delivered into the second reaction zone before, after, or simultaneously with the delivery of the first reacted material into the second reaction zone; the first reacted material and the second portion of the second material react to form the second reacted material, wherein the second reacted material contains 2-methyl-5-nitroimidazole. The reaction temperature in the first reaction zone is 140-160℃, and the apparent residence time in the first reaction zone is 40-70s; furthermore, the first reaction zone is a high-throughput reactor. The reaction temperature in the second reaction zone is 130-150℃, and the apparent residence time in the second reaction zone is 10s-8min; furthermore, the second reaction zone is one or more high-throughput reactors. In step 2, the flow rate of the first material delivered into the first reaction zone is 2100-10000 ml / min; In step 2, the flow rate of the first portion of the second material entering the first reaction zone is 1300-20000 ml / min; In step 3, the flow rate of the second portion of the second material entering the second reaction zone is 200-5000 ml / min; In step 1, the weight ratio of 2-methylimidazole, nitric acid, and acetic acid in the first material is (1.0-2.0):(1.0-2.0):

1. In step 1, the weight ratio of ammonium sulfate to sulfuric acid in the second material is 1:(0.6-1.6).

2. The method according to any one of the preceding claims, wherein the sulfuric acid in the second material of step 1 comprises concentrated sulfuric acid with a mass fraction of 90% or more.

3. The method according to any one of the preceding claims, wherein the nitric acid in the first material in step 1 is nitric acid with a mass fraction of 80% or more.

4. The method according to any one of the preceding claims, wherein the second material in step 1 is divided into a number of parts less than or equal to the number of reaction zones.

5. The method according to claim 2, wherein the weight ratio of 2-methylimidazole, nitric acid and acetic acid in the first material of step 1 is 1.25:1.25:

1.

6. The method according to claim 3, wherein the sulfuric acid in the second material of step 1 comprises concentrated sulfuric acid with a mass fraction of 95% or more.

7. The method according to claim 4, wherein the nitric acid in the first material in step 1 is nitric acid with a mass fraction of 95% or more.

8. The method according to claim 4, wherein the nitric acid in the first material in step 1 is fuming nitric acid.

9. The method according to claim 5, wherein the weight ratio of ammonium sulfate to sulfuric acid in the second material of step 1 is 1:(1.2-1.5).

10. The method of claim 1, wherein the high-throughput reactor is an AFR-G1 reactor or an AFR-G5 reactor.

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