A method for preparing an oxime ether bromide based on a photochemical continuous flow reactor

Abstract

The application discloses a method for preparing an oxime ether bromide based on a photochemical continuous flow reactor, which comprises the following steps: uniformly mixing an organic solution of an oxime ether and an auxiliary agent to obtain raw material A; taking a solution containing bromine as raw material B; feeding the raw material A and the raw material B into the inlets of two pipeline channels of the reactor respectively, wherein the channel of the reaction area of the reactor is made of a light-transmitting material; applying ultraviolet light to the reaction area, controlling the temperature of the reaction area to be 5-55 DEG C, and controlling the flow rates of the raw material A and the raw material B to be both 0.5-10 mL / min to enter the reaction area to react, and obtaining a compound of formula III at the outlet of the reactor. The method can not only effectively reduce the content of Z-type isomers in raw materials and Z-type isomer products and improve the conversion rate, but also precisely control the bromination degree of the target product, reduces the generation of dibromide impurities, and has the advantages of simplicity, safety and high efficiency, significantly reduces the production cost, and has great application potential.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of chemical pharmacy, and particularly relates to a method for preparing an oxime ether bromide intermediate of trifloxystrobin based on a photochemical continuous flow reactor. BACKGROUND

[0002] Trifloxystrobin is a mitochondrial respiration inhibitor, which acts by inhibiting the mitochondrial electron transport chain of fungi. It disrupts normal electron flow, thereby affecting energy production within fungal cells. This disruption of the electron transport chain impairs fungal metabolism and ATP (adenosine triphosphate) production, ultimately leading to the death of fungal cells. Trifloxystrobin also has the advantages of high efficiency, broad spectrum, small harm, resistance to flushing, and long effective period. Trifloxystrobin is particularly effective against powdery mildew and leaf spot, and is mainly used for stem and leaf treatment of grapes, apples, wheat, peanuts, bananas, and vegetables.

[0003] ( E) The oxime ether bromide is a key intermediate for preparing trifloxystrobin, which is mainly prepared by E) The oxime ether and bromine generate under the irradiation of ultraviolet light. Among them, the oxime ether as a raw material is usually obtained by reacting a ketone with O-methylhydroxylamine hydrochloride. In this process, the Z-type isomer (compound of formula II) is inevitably produced, and the reaction process is as follows: E)

[0004] .

[0005] Therefore, the commercialized oxime ether inevitably contains a small amount of (Z E) -oxime ether. ) -oxime ether.

[0006] In the bromination reaction, (Z ) -oxime ether will undergo bromination reaction like (E E) -oxime ether to obtain (Z ) -oxime ether bromide, such as compound of formula V :, thereby affecting the purity of trifloxystrobin in the product. Therefore, the amount of impurity Z-type isomer is often reduced by a purification step of the raw material in the prior art, but obviously the purification step will cause additional cost burden to production.

[0007] In addition, when the (E E) -oxime ether undergoes bromination reaction, not only the target product monobromide is obtained, but also dibromide impurities are produced when the reaction further proceeds, as shown in the following formula:

[0008] .

[0009] ​The compound of formula III is a key intermediate for preparing trifloxystrobin, i.e. the target product, and the compound of formula IV is a dibrominated impurity obtained by excessive bromination.

[0010] Therefore, the control of the reaction process is the key to improve the yield. In the traditional tank process, due to the poor uniformity of light and the slow heat and mass transfer rate, the bromination reaction period is long, and the reaction time is more than 48 h. Moreover, the hydrogen on the benzyl carbon is relatively active, and the generation of dibrominated impurities is difficult to avoid during the reaction process. A large amount of by-products will be generated during the entire reaction process, resulting in low yield of the main product, and the purification operation needs to be carried out in the later stage, which increases the complexity and cost of the process, and there is a problem of poor repeatability. SUMMARY

[0011] The applicant accidentally found that when using a photochemical continuous flow reactor to control the bromination reaction process of oxime ether, the isomerization reaction of the raw material may be triggered due to the regulation of ultraviolet light in the photochemical reaction and the influence of mass transfer and heat transfer efficiency, the Z-type isomer product in the product is reduced, and the dibrominated impurity is also controlled under the premise of greatly improving the raw material conversion rate, thereby effectively reducing the cost of product purification as a whole. Therefore, based on the above findings, the applicant proposes a method for preparing oxime ether bromide based on a photochemical continuous flow reactor, which can reduce Z-type isomer impurities, improve conversion rate and control dibrominated impurities in one step, and reduce production cost, compared with the existing tank process which has the defects of the need for purification of raw materials, long reaction time, low total yield, complex production process, and more "three wastes" (waste residue, waste gas and waste water).

[0012] The present application is realized by the following technical solutions:

[0013] A method for preparing oxime ether bromide based on a photochemical continuous flow reactor, comprising the following steps:

[0014] Mixing the organic solution of oxime ether and the auxiliary agent uniformly to obtain raw material A; mixing the solution containing bromine as raw material B; passing raw material A and raw material B into the inlet of the two pipeline channels of the reactor, and the channel of the reaction area of the reactor is made of light-transmitting material;

[0015] Applying ultraviolet light to the reaction area, and controlling the temperature of the reaction area to be 5-55℃, and controlling the flow rate of the raw material A and the raw material B to be 0.5-10 mL / min into the reaction area for reaction, and obtaining the compound of formula III at the outlet of the reactor.

[0016] The oxime ether is a commercial product of E) -oxime ether, which contains a small amount of (Z ) -oxime ether impurities.

[0017] Preferably, the inner diameter of the channel of the reactor is 0.5-6mm.

[0018] Preferably, the material of the channel of the reaction zone is polyfluorovinyl copolymer (PFA), perfluorovinyl propylene copolymer (FEP) or quartz.

[0019] Preferably, the wavelength of the ultraviolet light is 180-400nm.

[0020] Preferably, the method of controlling the temperature of the reaction zone is to use water bath, oil bath or jacketed heat exchanger.

[0021] Preferably, the solvent of the organic solution of the oxime ether is dichloromethane, dichloroethane, acetonitrile or methanol.

[0022] Preferably, the concentration of the oxime ether in the raw material A is 0.1-2mol / L.

[0023] Preferably, the auxiliary agent is acetophenone or p-toluenesulfonic acid.

[0024] Preferably, the concentration of bromine in the solution of bromine is 0.1-2mol / L.

[0025] Preferably, the solvent of the solution of bromine is dichloromethane, dichloroethane, acetonitrile or methanol.

[0026] Preferably, the ultraviolet light is provided by an ultraviolet LED lamp, and the power of the ultraviolet LED lamp is 80-1000W.

[0027] Preferably, the residence time of the raw material A and the raw material B in the reactor is 0.5-30min.

[0028] Preferably, the flow rate of the raw material A and the raw material B is controlled so that the molar ratio of the oxime ether to bromine entering the reaction zone is 1:1-1.5, preferably 1:1-1.22.

[0029] The beneficial effects of the present application are:

[0030] The present application utilizes continuous flow reaction technology, and adopts a photochemical continuous flow reactor to perform bromination of oxime ether under control of temperature, ultraviolet light, residence time (flow rate), which not only effectively reduces the content of Z-type isomer in raw materials and Z-type isomer product, but also greatly improves the conversion rate of raw materials and controls the bromination degree of target product, reduces the generation of dibromide impurities, greatly shortens the reaction time, effectively solves the problems of traditional kettle type photo-bromination reaction industrialization, including a large amount of raw material remaining, more Z-type isomers and dibromides, low yield of oxime ether bromide (50-60%), difficult product purification, long reaction time (2-3 days), etc., and significantly improves the efficiency of ultraviolet light bromination industrial production. The method of the present application can reduce Z-type isomer impurities, improve conversion rate and control dibromide impurities in one step, and is simple, safe and efficient, significantly reduces production cost, and has great application potential. BRIEF DESCRIPTION OF DRAWINGS

[0031] Figure 1 LC-MS positioning results of the compounds of formula I, formula II, formula III, formula IV and formula V.

[0032] Figure 2 HPLC positioning results of the compounds of formula I, formula II, formula III, formula IV and formula V.

[0033] Figure 3 HPLC determination results of the raw materials.

[0034] Figure 4 HPLC determination results of the product solution in Example 1.

[0035] Figure 5 HPLC determination results of the 24h product solution in Comparative Example 1.

[0036] Figure 6 HPLC determination results of the 48h product solution in Comparative Example 1.

[0037] Figure 7 HPLC determination results of the 72h product solution in Comparative Example 1.

[0038] Figure 8 Conversion rate graph of the oxime ether bromide synthesized by the present application under different solvent conditions in Example 2.

[0039] Figure 9 Conversion rate graph of the oxime ether bromide synthesized by the present application under different molar ratio conditions in Example 3.

[0040] Figure 10 Conversion rate graph of the oxime ether bromide synthesized by the present application under different temperature and residence time conditions in Example 4. DETAILED DESCRIPTION

[0041] The application will be described in further detail below with reference to the accompanying drawings.

[0042] The mixture of the compounds of formula I, formula II, formula III, formula IV, formula V was prepared and located by LC-MS, and the results are shown in Table 1. Figure 1 The HPLC location results are shown in Table 2. Figure 2

[0043] HPLC instrument parameters: Example 1

[0044] The reaction area of the pipeline photochemical continuous flow reactor was placed under the illumination of ultraviolet light at a wavelength of 365 nm, the temperature of the reaction area was controlled to be 25°C by a constant temperature water bath, and the mixture of the compounds of formula I, formula II, formula III, formula IV, formula V was prepared. E) The DCE (1,2-dichloroethane) solution of the oxime ether was mixed with the auxiliary as raw material A, wherein the concentration of the oxime ether was 0.75 mol / L. E) The DCE solution of bromine was used as raw material B, wherein the concentration of bromine was 1 mol / L. Raw material A and raw material B were respectively introduced into the two inlets of the photochemical continuous flow reactor, the flow rate of raw material A was controlled to be 1.16 ml / min, the flow rate of raw material B was controlled to be 1.16 ml / min, the residence time was 8.6 min for reaction, and the product solution was obtained at the outlet of the microchannel reactor.

[0045] Under the determination conditions described above, the raw material (such as shown in Table 1) was determined by high performance liquid chromatography (HPLC), and the mass fraction of the compound of formula II (Z-type isomer) in the oxime ether was 1.96%. E) Figure 3 In the product solution obtained after the reaction (such as shown in Table 2), the content of the compound of formula I was 0%, and the content of the compound of formula II was 0%, indicating that the raw material of any configuration had been fully reacted.

[0046] In the product solution obtained after the reaction (such as shown in Table 2), the content of the compound of formula I was 0%, and the content of the compound of formula II was 0%, indicating that the raw material of any configuration had been fully reacted. Figure 4 In the product solution, the content of the target product, the compound of formula III, was 91.19%, and the content of the dibrominated impurity, the compound of formula IV, was 6.65%.

[0047] In the product solution, the content of the Z-type isomer brominated product, the compound of formula V, was 0.13%, compared with the Z-type raw material ratio of 1.96% in the raw material, most of the Z-type raw material was converted into the E-type brominated product.

[0048] Comparative Example 1

[0049] As a comparison, the oxime ether bromination reaction was carried out by using the traditional kettle process as follows:

[0050]

[0051] ​​​The same raw materials as in Example 1 were used, and raw material A and raw material B were additionally put into a tank reactor, and a reaction was carried out under stirring and irradiation of ultraviolet light at 25°C and a wavelength of 365 nm to obtain a comparative product solution. The oxime ether (10.0 g, 0.048 mol) and p-toluenesulfonic acid (0.95 g) were added to dichloromethane (64 ml), and bromine (8.15 g, 0.05 mol) was added dropwise to the dichloromethane solution under irradiation of 365 nm ultraviolet light at 25°C for 2 hours. The stirring was continued, and samples were taken at 24 h, 48 h and 72 h, and the contents of various substances in the product solution were detected by HPLC. The results are shown in Table 1 and Table 2. o The contents of various substances in the product solution were detected by HPLC. The results are shown in Table 1 and Table 2. Figure 3 、 5

[0052] Table 1 Contents of various substances in raw materials and product after 72 h of tank reaction

[0053]

[0054] As can be seen from Table 1, even after 72 h of reaction, the traditional tank process still cannot be completely reacted. And the dibromination degree of the tank process is still significantly higher even at a lower conversion rate.

[0055] As for the Z-type isomer, the content of 0.33% of the Z-type impurity is also significantly higher than the content of 0.13% in Example 1 under the premise of a lower conversion rate.

[0056] It can be seen that the method of the present application not only can effectively improve the yield of the product compound of formula III, reduce the content of the dibromination impurity compound of formula IV, but also can reduce the content of the Z-type isomer and its bromide (Z-type impurity) at the same time. The one-step reaction improves the reaction conversion rate, reduces two kinds of impurities, improves the product purity and reduces the purification cost.

[0057] Example 2

[0058] The conditions of this example and Example 1 are the same, and the only difference is that:

[0059] The concentration of the oxime ether in raw material A is 0.3 mol / L, and the concentration of bromine in raw material B is 0.33 mol / L.

[0060] And dichloromethane (DCM), 1,2-dichloroethane (DCE), acetonitrile (MeCN) and methanol (MeOH) were used as solvents for raw material A and raw material B.

[0061] As can be seen from Table 2, the dibromination degree of the product obtained by the method of the present application is significantly lower than that of the product obtained by the traditional tank process. Figure 8 ​As shown, under the same reaction time, the reaction efficiency of oxime ethers was higher in dichloromethane and 1,2-dichloroethane, reaching 90% conversion and 79% yield of the oxime ether bromide after 16 min; the results in acetonitrile were poor, with a conversion of 49% and a yield of 79% of the oxime ether bromide after 16 min; in methanol, the conversion was only 14% and the yield was only 10% after 16 min. Furthermore, due to the very low boiling point of dichloromethane (38.8°C), it is difficult to increase the reaction temperature when using dichloromethane as a solvent. Therefore, 1,2-dichloroethane is the optimal solvent in this invention.

[0062] Example 3

[0063] The conditions in this embodiment are the same as in Example 1, except that the residence time is 4 min, the concentration of oxime ether in raw material A is 0.3 mol / L, and the concentrations of bromine in raw material B are 0.3, 0.33, 0.37, 0.41, and 0.45 mol / L, respectively, i.e., the molar ratio of bromine to oxime ether is 1:1, 1.1:1, 1.22:1, 1.35:1, and 1.5:1. The solvent is 1,2-dichloroethane.

[0064] like Figure 9 As shown, the conversion rate of oxime ether increases with increasing molar ratio. When the molar ratio increases to 1.5:1, the conversion rate of oxime ether reaches 93% within 4 minutes. However, increasing the molar ratio also reduces selectivity. The selectivity decreases from 88.9% under the 1:1 molar ratio condition to 75.2% under the 1.5:1 molar ratio condition. When the molar ratio increases from 1:1 to 1.22:1, the selectivity only decreases from 88.9% to 84.1%. Therefore, from the perspective of selectivity, the optimal molar ratio range of this invention is 1~1.22:1 at 25°C, a residence time of 4 minutes, and an oxime ether solution concentration of 0.5 mol / L.

[0065] Example 4

[0066] The conditions in this embodiment are the same as in Embodiment 1, except that a constant temperature water bath is used to control the temperature at 5, 10, 20, 35, 45, and 55°C. The concentration of the oxime ether solution is 0.3 mol / L, and the concentration of the bromine solution is 0.33 mol / L, i.e., the molar ratio is 1.1:1. The residence time is controlled at 4, 6, 8, 11, and 16 minutes.

[0067] like Figure 10 As shown, the conversion rate of oxime ethers increases with the extension of residence time, while the selectivity of oxime ether bromides first increases and then decreases.

[0068] like Figure 10As shown, the conversion rate of oxime ethers increases with increasing reaction temperature, while the selectivity of oxime ether bromides first increases and then decreases.

[0069] like Figure 10 As shown, when the reaction temperature is 35℃ and the residence time is 11 min, the yield of the oxime ether bromide reaches the maximum value in the figure, namely 83.6%. Therefore, it can be concluded that the optimal reaction conditions of this invention are 35℃ and 11 min when the concentration of the oxime ether solution is 0.3 mol / L and the concentration of the bromine solution is 0.33 mol / L.

[0070] Example 5

[0071] The conditions in this embodiment are the same as in Example 1, except that: in this embodiment, a constant temperature water bath is used to control the temperature at 35°C, and the residence time is controlled at 4, 6, 8, 11, and 16 minutes. The concentration of the oxime ether solution is 0.3 mol / L, and the concentration of the bromine solution is 0.33 mol / L, i.e., the molar ratio is 1.1:1. Acetophenone (photoinitiator) or p-toluenesulfonic acid (acid catalyst) is added to the oxime ether solution at a concentration of 1 mol% of the oxime ether solution.

[0072] Both acetophenone and p-toluenesulfonic acid can improve the conversion rate of oxime ethers. With increasing residence time, the selectivity of oxime ether bromides initially increases and then decreases.

[0073] When p-toluenesulfonic acid was used, the yield of the oxime ether bromide reached 86.4% at 11 min, which was higher than that of the control group without the auxiliaries and the control group using acetophenone. This indicates that p-toluenesulfonic acid promotes the photobromination process of oxime ethers.

[0074] Example 6

[0075] The conditions in this embodiment are the same as in Example 1, except that the concentration of the oxime ether solution is controlled at 0.1, 0.2, 0.3, 0.4, 0.5, and 0.6 mol / L, and the concentration of the bromine solution is 0.11, 0.22, 0.33, 0.44, 0.55, and 0.66 mol / L, i.e., a molar ratio of 1.1:1. The temperature is controlled at 35°C.

[0076] With the increase of the initial concentration of oxime ether, the conversion rate of oxime ether shows an upward trend, when the initial concentration of oxime ether is 0.5 mol / L, the yield and selectivity of oxime ether bromide reach the maximum, the yield is 86.5%, and the selectivity is 89.9%. Then, the initial concentration of oxime ether is further increased, the yield and selectivity of oxime ether bromide slightly decrease. Therefore, the initial concentration of oxime ether is increased to 0.5 mol / L under the condition of the molar ratio of 1.1:1 and the temperature of 35℃, the product oxime ether bromide has higher yield and selectivity. Compared with the reaction time of 72h of the existing batch operation, the reaction time of the photochemical microreactor is shortened to 11min, and the efficiency is greatly improved.

[0077] Example 7

[0078] The conditions of the present example are the same as those of example 1, and the only difference is that the present example will use a 600W LED light source, and the temperature is controlled at 15℃, and the dichloroethane solution containing oxime ether and the dichloroethane solution containing bromine are injected into the pipeline microreactor respectively to complete the photo-bromination reaction.

[0079] The flow rate of the dichloroethane solution containing oxime ether and the dichloroethane solution containing bromine is 0.25-4ml / min.

[0080] The concentration of oxime ether in the reaction system is 0.65 mol / L, and the concentration of bromine is 0.78 mol / L.

[0081] Compared with the reaction result of 80W LED (11min, yield of 86.5%, selectivity of 89.9%), the yield under the irradiation of 600W LED is increased to 91%, and the selectivity is increased to 93%. The reaction time is reduced to 8.6min. Therefore, the continuous flow photochemical microreactor equipped with 600W of the present application has excellent yield and selectivity for the photo-bromination reaction of oxime ether.

[0082] The above specific embodiments can be adjusted in different ways by those skilled in the art without departing from the principles and purposes of the present application, the protection scope of the present application is subject to the claims and is not limited by the above specific embodiments, and the constraints of the present application are within the scope thereof.

Claims

1. A method for the preparation of an oxime ether bromide based on a photochemical continuous flow reactor, characterized in that, The method comprises the following steps: The organic solution of the oxime ether, the auxiliary agent are uniformly mixed to obtain raw material A; the solution containing bromine is used as raw material B; the raw material A and the raw material B are respectively introduced into the inlets of the two pipeline channels of the reactor, and the channel of the reaction area of the reactor is made of light-transmitting material; The reaction region is irradiated with ultraviolet light, and the temperature of the reaction region is controlled to be 5-55°C. The flow rates of the raw material A and the raw material B are both controlled to be 0.5-10 mL / min into the reaction region to react, and a compound of formula III is obtained at the outlet of the reactor ; The oxime ether is commercially available as E containing small amounts of Z oxime ether impurities. The solvent of the organic solution of the oxime ether or the solvent of the solution of bromine is dichloromethane or dichloroethane; The auxiliary agent is acetophenone or p-toluenesulfonic acid.

2. The method of claim 1, wherein, The inner diameter of the channel of the reactor is 0.5-6 mm.

3. The method of claim 1, wherein, The material of the channel of the reaction area is polyvinyl fluoride copolymer, perfluoroethylene propylene copolymer or quartz.

4. The method of claim 1, wherein, The wavelength of the ultraviolet light is 180-400 nm.

5. The method of claim 1, wherein, The concentration of the oxime ether in the raw material A is 0.1-2 mol / L.

6. The method of claim 1, wherein, The concentration of bromine in the solution of bromine is 0.1-2 mol / L.

7. The method of claim 1, wherein, The residence time of the raw material A and the raw material B in the reactor is 0.5-30 min.

8. The method of claim 1, wherein, The flow rates of the raw material A and the raw material B are controlled so that the molar ratio of the oxime ether to bromine entering the reaction area is 1:1-1.

5.

9. The method of claim 8, wherein, The molar ratio of the oxime ether to bromine entering the reaction area is 1:1-1.22.

Images