Preparation method for synthesizing bromonitrobenzene using continuous flow reaction

Abstract

The present invention discloses a preparation method for synthesizing bromonitrobenzene by continuous flow reaction. Specifically, the present invention discloses a preparation method for a compound of formula I, comprising the following steps: subjecting a compound of formula II, a compound of formula III and HBr to continuous flow reaction to obtain the compound of formula I; wherein each R1 and R2 are independently halogen, cyano, nitro or hydrogen; R is C 1‑5 The preparation method of the present invention has one or more of the following advantages: simple operation, high selectivity, low energy consumption and high productivity.

Description

Technical Field

[0001] The invention relates to a preparation method for synthesizing bromonitrobenzene by using a continuous flow reaction. Background Art

[0002] Brominonitrobenzene and its derivatives are important chemical intermediates. The carbon-bromine bond in the structure can be used for further functionalization to form various fluorine-containing and amine-containing products, which are used in the fields of pesticides and medicine.

[0003] US20020010170 discloses a method for preparing 2-bromo-1,3-dichloro-5-nitrobenzene, using 2,6-dichloro-4-nitroaniline as a raw material, sodium nitrite / sulfuric acid as a diazo reagent, acetic acid as a solvent, hydrogen bromide and cuprous bromide as brominating agents, to prepare 2-bromo-1,3-dichloro-5-nitrobenzene. In this method, cuprous bromide is not easy to recover, the generation and accumulation of diazonium salts pose safety risks, and the industrialization prospect is not ideal.

[0004] ACS Medicinal Chemistry Letters, 2015, 6(7), 787-792 reported the use of 2,6-dichloro-4-nitroaniline as a raw material, tert-butyl nitrite as a diazotization reagent, and cuprous bromide as a bromine source to prepare 2-bromo-1,3-dichloro-5-nitrobenzene. This method uses cuprous bromide, which leads to high cost and difficulty in recycling the three wastes. Tert-butyl nitrite is unstable and easily decomposes. This reaction is difficult to control and may cause the accumulation of diazonium salts. There are safety issues and it is difficult to industrialize.

[0005] The document Journal of Chemical & Engineering Data (2010), 55(5), 2048-2054 reported a conventional method for synthesizing bromobenzene derivatives, using aniline derivatives as raw materials, first adding hydrogen bromide and sodium nitrite aqueous solution to generate a diazonium salt intermediate, and then adding the obtained diazonium salt intermediate dropwise into a kettle mixed with cuprous bromide as a catalyst and hydrogen bromide as a bromine source, and the yield was 69%.

[0006] Conventional 2-bromo-1,3-dichloro-5-nitrobenzene is generally prepared by the classic Sandmeyer reaction, which includes the following steps: dissolving 2,6-dichloro-4-nitroaniline in water, then adding hydrobromic acid, and then adding sodium nitrite for diazotization to obtain a diazonium salt, and then adding the obtained diazonium salt to an aqueous solution of cuprous bromide and hydrogen bromide, and reacting at 30-40°C to obtain 2-bromo-1,3-dichloro-5-nitrobenzene. However, due to the excessive number of electron-withdrawing groups on 2-bromo-1,3-dichloro-5-nitrobenzene, the diazonium salt formed is also extremely unstable, the reaction is highly exothermic, there are serious local overheating problems and heat exchange problems in the reaction system, there are great safety risks, and the reaction yield is low. Summary of the invention

[0007] The technical problem to be solved by the present invention is to solve one or more disadvantages of high risk, high pollution, complex operation and high cost in the preparation methods of 4-bromonitrobenzene compounds and derivatives thereof in the prior art, and provide a preparation method for synthesizing bromonitrobenzene using a continuous flow reaction. The preparation method of the present invention has one or more advantages of simple operation, high selectivity, low energy consumption and high production capacity.

[0008] The present application provides a method for preparing a compound of formula I, comprising the following steps: conducting a continuous flow reaction of a compound of formula II, a compound of formula III and HBr in a solvent to obtain the compound of formula I;

[0009] wherein each R1 and R2 is independently halogen (e.g. fluorine, chlorine, bromine or iodine, also such as chlorine), cyano, nitro or hydrogen;

[0010] R is C 1-5 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-pentyl, isopentyl, n-butyl, sec-butyl, tert-butyl or isobutyl);

[0011]

[0012] In some embodiments, R1 is halogen, such as chlorine.

[0013] In some embodiments, R2 is halogen, such as chlorine.

[0014] In some embodiments, R1 and R2 are the same, for example, R1 and R2 are both chloro.

[0015] In some embodiments, R is isopentyl or tert-butyl.

[0016] In some embodiments, in the preparation method of the present invention, the molar ratio of HBr to the compound of formula II can be a conventional molar ratio for such reactions, preferably (2-5):1, such as 2:1, 3:1, 4:1 or 5:1.

[0017] In some embodiments, in the preparation method of the present invention, the molar ratio of the compound of formula III to the compound of formula II can be a conventional molar ratio for such reactions, preferably (1-1.5):1, such as 1.2:1 or 1.5:1.

[0018] In the continuous flow reaction, the solvent can be a conventional solvent for this type of reaction in the art, such as a mixed solvent of an organic solvent and water. The organic solvent can be a nitrile solvent (such as acetonitrile) and / or a furan solvent (such as tetrahydrofuran and / or 4-methylfuran). In some embodiments, the solvent is a mixed solvent of a nitrile solvent and water, such as a mixed solvent of acetonitrile and water.

[0019] In the preparation method of the present invention, the materials can be mixed in a variety of ways to carry out a continuous flow reaction, for example, the compound of formula II, the compound of formula III and HBr are used as materials I, II and III and are respectively injected simultaneously. Preferably, a mixed solution of HBr and the compound of formula II is used as material a, and a solution of the compound of formula III is used as material b, and materials a and b are injected simultaneously to carry out a continuous flow reaction.

[0020] In some embodiments, in the mixed solution of HBr as material a and the compound of formula II, the solvent can be a conventional solvent for this type of reaction in the art, for example, a mixed solvent of an organic solvent and water. The organic solvent can be a nitrile solvent (e.g., acetonitrile) and / or a furan solvent (e.g., tetrahydrofuran and / or 4-methylfuran). In some embodiments, in the mixed solution of HBr as material a and the compound of formula II, the solvent is a mixed solvent of a nitrile solvent and water, for example, a mixed solvent of acetonitrile and water. The mixed solution of HBr and the compound of formula II can be prepared by using an HBr aqueous solution (e.g., an HBr aqueous solution having a mass fraction of 48%), a compound of formula II, and an organic solvent.

[0021] In some embodiments, in the mixed solution of HBr and the compound of formula II as material a, the mass fraction of the compound of formula II can be 5%-20%, for example, 5.5wt%.

[0022] In some embodiments, in the solution of the compound of formula III as material b, the solvent can be a conventional solvent for this type of reaction in the art, for example, a nitrile solvent (e.g., acetonitrile) or a furan solvent (e.g., furan or 4-methylfuran). In some embodiments, in the solution of the compound of formula III as material b, the solvent is a nitrile solvent, for example, acetonitrile.

[0023] In some embodiments, in the solution of the compound of formula III as material b, the mass fraction of the compound of formula III may be 20%-50%, for example, 23 wt %.

[0024] The mass flow ratio of material a and material b can be adjusted according to the concentration, the molar ratio of the reaction raw materials, etc. In some embodiments, the mass flow ratio of material a and material b is (4-7):1, for example (5-6):1.

[0025] In the preparation method of the present invention, the continuous flow reaction can be carried out in any suitable reactor. Examples of the reactor include a microchannel reactor, such as a microchannel reactor of Corning specification model G1-10FM-SiC.

[0026] In the preparation method of the present invention, the materials of the continuous flow reaction can be transported by various methods, such as pumping. The pumping device can be conventional in the art, such as a horizontal flow pump (such as Shanghai Sanwei specification model MPF1002C horizontal flow pump).

[0027] In some embodiments, in the preparation method of the present invention, the residence time of the continuous flow reaction of the compound of formula II, the compound of formula III and HBr can be 0.15 to 5 min, for example 0.5 min.

[0028] In some embodiments, in the preparation method of the present invention, the continuous flow reaction can be carried out at a temperature of 10 to 40° C. (eg, 20 to 35° C., such as 25° C.).

[0029] In some embodiments, in the preparation method of the present invention, the continuous flow reaction can be carried out at a pressure of 0-1 bar.

[0030] In some embodiments, in the preparation method of the present invention, the flow state of the mixed liquid in the continuous flow reaction can be laminar flow or turbulent flow, such as laminar flow.

[0031] In some embodiments, in the preparation method of the present invention, no metal catalyst such as cuprous bromide is required in the continuous flow reaction system.

[0032] In some embodiments, the preparation method of the present invention may further include a post-treatment step after the continuous flow reaction is completed. The post-treatment step may be conventional in the art, for example, including the following steps: distilling the reaction solution under reduced pressure to obtain the compound of formula I.

[0033] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0034] The reagents and raw materials used in the present invention are commercially available.

[0035] The positive improvement effect of the present invention is that the preparation method of the present invention has one or more of the following advantages:

[0036] (1) It can achieve the purpose of eliminating the need for metal catalysts (such as cuprous bromide), thus reducing the cost of treating the three wastes;

[0037] (2) Compared with the traditional autoclave reaction, it can reduce the side reactions such as diazonium salt coupling and decomposition, and can achieve high purity with simple post-reaction treatment;

[0038] (3) It can achieve a series of advantages such as continuous production, safety, short reaction time, and energy saving, and is more suitable for industrial production. DETAILED DESCRIPTION

[0039] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0040] In the following examples, when the operating temperature is not specified, the operation is carried out at room temperature, which refers to 20-30°C.

[0041] Electronic balance, brand: Shimadzu, specification model: TX3202L.

[0042] Horizontal flow pump, brand: Shanghai Sanwei, specification model: MPF1002C.

[0043] Microchannel reactor, brand: Corning, specification model: G1-10FM-SiC.

[0044] Gas chromatography conditions: inlet temperature: 250°C, split ratio: 20:1, detector temperature: 300°C, flow rate (N2): 1.5ml / min (constant flow), hydrogen flow rate (H2): 40.0ml / min, air flow rate (Air): 400.0ml / min, exhaust flow rate (N2): 25.0ml / min, injection volume: 1ul, heating program: 50°C (1min), 20°C / min, 280°C (4min).

[0045] In the following examples, 2,6-dichloro-4-nitroaniline and 48% hydrobromic acid aqueous solution were added to acetonitrile at a molar ratio of 1:2-5, and stirred at 20-30° C. for 0.5 hour to finally prepare an acetonitrile solution of 2,6-dichloro-4-nitroaniline with a concentration of 5.5 wt %.

[0046] Example 1

[0047] Adjust the temperature of the temperature control device to 25°C; set the pressure to 0-1.0bar;

[0048] 48% hydrobromic acid aqueous solution and 2,6-dichloro-4-nitroaniline were dissolved in acetonitrile solvent at a molar ratio of 2:1 and a flow rate of 40 g / min;

[0049] 23wt% tert-butyl nitrite acetonitrile solution, flow rate 7.1g / min;

[0050] 2,6-dichloro-4-nitroaniline, HBr and tert-butyl nitrite, in a molar ratio of 1:2:1.5;

[0051] The materials were pumped into the reaction system by a metering pump for reaction. According to the reaction requirements, the residence time was controlled to be 30 seconds. The flow state of the mixed liquid when it was pumped into the microreactor was laminar flow.

[0052] Sampling was performed for gas phase analysis, and the reaction conversion rate was 93.3%. 13.21 g of 2-bromo-1,3-dichloro-5-nitrobenzene was obtained by vacuum distillation, and the yield was 96.4%.

[0053] Example 2

[0054] Adjust the temperature of the temperature control device to 25°C; set the pressure to 0-1.0bar;

[0055] 48% hydrobromic acid aqueous solution and 2,6-dichloro-4-nitroaniline were dissolved in acetonitrile solvent with a molar ratio of 3:1 and a flow rate of 40 g / min;

[0056] 23wt% tert-butyl nitrite acetonitrile solution, flow rate 7.1g / min;

[0057] 2,6-dichloro-4-nitroaniline, HBr and tert-butyl nitrite, in a molar ratio of 1:3:1.5, are pumped into the reaction system by a metering pump for reaction. According to the reaction requirements, the reaction time is controlled to be 30s. When the mixed liquid is pumped into the microreactor, the flow state is laminar flow.

[0058] Sampling was performed for gas phase analysis, and the reaction conversion rate was 82.1%. 10.96 g of 2-bromo-1,3-dichloro-5-nitrobenzene was obtained by vacuum distillation, and the yield was 80.2%.

[0059] Example 3

[0060] Adjust the temperature of the temperature control device to 25°C; set the pressure to 0-1.0bar;

[0061] 48% hydrobromic acid aqueous solution and 2,6-dichloro-4-nitroaniline were dissolved in acetonitrile solvent at a molar ratio of 4:1 and a flow rate of 40 g / min;

[0062] 23wt% tert-butyl nitrite acetonitrile solution, flow rate 7.1g / min;

[0063] 2,6-dichloro-4-nitroaniline, HBr and tert-butyl nitrite, in a molar ratio of 1:4:1.5;

[0064] The materials were pumped into the reaction system with a metering pump for reaction. The reaction time was controlled to be 30 s according to the reaction requirements.

[0065] Sampling was performed for gas phase analysis, and the reaction conversion rate was 85.9%. 11.23 g of 2-bromo-1,3-dichloro-5-nitrobenzene was obtained by vacuum distillation, and the yield was 82.3%.

[0066] Example 4

[0067] Adjust the temperature of the temperature control device to 25°C; set the pressure to 0-1.0bar;

[0068] 48% hydrobromic acid aqueous solution and 2,6-dichloro-4-nitroaniline were dissolved in acetonitrile solvent at a molar ratio of 5:1 and a flow rate of 40 g / min;

[0069] 23wt% tert-butyl nitrite acetonitrile solution, flow rate 7.1g / min;

[0070] 2,6-Dichloro-4-nitroaniline, HBr and tert-butyl nitrite, in a molar ratio of 1:5:1.5, are pumped into the reaction system with a metering pump for reaction. According to the reaction requirements, the reaction time is controlled to be 30 seconds.

[0071] Sampling was performed for gas phase analysis, and the reaction conversion rate was 86.1%. 13.43 g of 2-bromo-1,3-dichloro-5-nitrobenzene was obtained by vacuum distillation, and the yield was 84.2%.

[0072] Example 5

[0073] Adjust the temperature of the temperature control device to 25°C; set the pressure to 0-1.0bar;

[0074] 48% hydrobromic acid aqueous solution and 2,6-dichloro-4-nitroaniline were dissolved in acetonitrile solvent at a molar ratio of 5:1 and a flow rate of 40 g / min;

[0075] 23wt% isoamyl nitrite acetonitrile solution, flow rate 6.5g / min;

[0076] The molar ratio of 2,6-dichloro-4-nitroaniline, HBr and isoamyl nitrite is 1:5:1.2. The materials are pumped into the reaction system with a metering pump for reaction. According to the reaction requirements, the reaction time is controlled to be 30 seconds.

[0077] Sampling was performed for gas phase analysis, and the reaction conversion rate was 82.1%. 11.67 g of 2-bromo-1,3-dichloro-5-nitrobenzene was obtained by vacuum distillation, and the yield was 73.3%.

Claims

1. A method for preparing a compound of formula I, comprising the following steps: reacting a compound of formula II, a compound of formula III and HBr in a continuous flow reaction to obtain the compound of formula I; wherein each R1 and R2 is independently chlorine; R is isopentyl or tert-butyl; The molar ratio of HBr to the compound of formula II is (2-5):1; The molar ratio of the compound of formula III to the compound of formula II is (1-1.5):1; The continuous flow reaction was carried out at a temperature of 25 °C; The continuous flow reaction was carried out at a pressure of 0-1 bar; The compound of formula II, the compound of formula III and HBr are respectively injected simultaneously as materials I, II and III to carry out a continuous flow reaction; or, a mixed solution of HBr and the compound of formula II is used as material a, and a solution of the compound of formula III is used as material b, and materials a and b are injected simultaneously to carry out a continuous flow reaction, wherein, The mass flow ratio of material a and material b is (4-7):1; There is no metal catalyst in the continuous flow reaction system.

2. The preparation method according to claim 1, characterized in that The solvent system for the continuous flow reaction is a mixed solvent of an organic solvent and water; And / or, the residence time of the continuous flow reaction of the compound of formula II, the compound of formula III and HBr is 0.15 to 5 minutes.

3. The preparation method according to claim 2, characterized in that: The organic solvent is a nitrile solvent and / or a furan solvent; And / or, the residence time of the continuous flow reaction of the compound of formula II, the compound of formula III and HBr is 0.5 min.

4. The preparation method according to claim 1, characterized in that: The molar ratio of HBr to the compound of formula II is 2:1, 3:1, 4:1 or 5:1; And / or, the molar ratio of the compound of formula III to the compound of formula II is 1.2:1 or 1.5:

1.

5. The preparation method according to claim 3, characterized in that: The nitrile solvent is acetonitrile; And / or, the furan solvent is tetrahydrofuran and / or 4-methylfuran.

6. The preparation method according to claim 1, characterized in that: In the mixed solution of HBr and the compound of formula II as material a, the solvent is a mixed solvent of an organic solvent and water; the organic solvent is a nitrile solvent and / or a furan solvent; and / or, in the mixed solution of HBr and the compound of formula II as material a, the mass fraction of the compound of formula II is 5%-20%; and / or, in the solution of the compound of formula III as material b, the solvent is a nitrile solvent or a furan solvent; And / or, in the solution of the compound of formula III as material b, the mass fraction of the compound of formula III is 20%-50%.

7. The preparation method according to claim 6, characterized in that: The nitrile solvent is acetonitrile; And / or, the furan solvent is tetrahydrofuran and / or 4-methylfuran; and / or, in the mixed solution of HBr and the compound of formula II as material a, the mass fraction of the compound of formula II is 5.5%; and / or, in the solution of the compound of formula III as material b, the mass fraction of the compound of formula III is 23wt%; And / or, the mass flow ratio of material a and material b is (5-6):

1.

8. The preparation method according to any one of claims 1 to 7, characterized in that The continuous flow reaction is carried out in a microchannel reactor; and / or, the materials of the continuous flow reaction are transported by pumping; And / or, the flow state of the mixed liquid in the continuous flow reaction is laminar flow; And / or, the preparation method further comprises a post-treatment step after the continuous flow reaction is completed, and the post-treatment step comprises the following steps: distilling the reaction solution under reduced pressure to obtain the compound of formula I.

9. The preparation method according to claim 8, characterized in that: The microchannel reactor is a microchannel reactor of Corning specification model G1-10FM-SiC.

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