A method for preparing 6-bromo-2,3-difluorotrifluorotoluene

Abstract

This invention relates to the field of acyclic or carbocyclic compounds and discloses a method for preparing 6-bromo-2,3-difluorotrifluorotoluene, comprising: dissolving 2,3-difluorotrifluorotoluene in a mixed solvent composed of a polar modifier containing a proton acceptor site and a nonpolar solvent; adding a polyether stabilizer and an iron-based catalyst; and dropwise adding liquid bromine to trigger a directional bromination reaction. The method utilizes the protonated ion-pair complex formed by the in-situ generation of hydrogen bromide and the polar modifier, which, in conjunction with the polyether stabilizer, constructs a sterically hindered shielding structure at positions 4 and 5 of the substrate molecule. This invention forces the electrophilic substitution pathway to be directed towards position 6 of the substrate molecule, overcoming the bottleneck of extremely low positioning accuracy in passivated aromatic ring systems, transforming disordered isomers into a single dominant isomer, thereby reducing separation energy consumption.

Description

Technical Field

[0001] This invention relates to a method for preparing 6-bromo-2,3-difluorotrifluorotoluene, belonging to the technical field of acyclic or carbocyclic compounds. Background Technology

[0002] Currently, 2,3-difluorotrifluorotoluene is an important fluorinated aromatic intermediate in the field of fine chemical synthesis. Its mainstream preparation process usually uses liquid bromine as the brominating agent and carries out an electrophilic substitution reaction in halogenated hydrocarbon solvents such as dichloromethane or 1,2-dichloroethane under the action of an iron-based catalyst. Due to the strong electron-withdrawing inductive effect of the trifluoromethyl group and the ortho-fluorine atom, the electron cloud density of the benzene ring decreases, resulting in this type of substrate being in an extremely passivated state. In large-scale industrial production, in order to maintain the reaction rate, the conventional approach is often to increase the reaction temperature or increase the catalyst concentration to overcome the reaction energy barrier. Although this strategy of increasing the system energy improves the conversion efficiency, it causes the bromine electrophile to indiscriminately attack the benzene ring sites. Since the 4- and 5-positions are more open in terms of steric hindrance than the 6-position, the crude product contains a proportion of 4-bromoisomers and 5-bromoisomers.

[0003] Besides the aforementioned attempts to adjust reaction process parameters, researchers have also tried to circumvent the localization problem by starting from the underlying logic of the synthetic route and using multi-step functional group transformations. For example, Chinese invention patent CN116283661A discloses a 2,3-difluoro-6-(trifluoromethyl)-benzonitrile compound and its preparation method. Starting from 1,2,3-trifluoro-6-nitrobenzene, the target skeleton is constructed through cyanolysis, hydrogenation, diazotization, and trifluoromethylation functional group transformation steps. The multi-step linear accumulation strategy theoretically avoids the problem of direct bromination localization of the benzene ring. However, it has revealed significant shortcomings in industrial production: the lengthy reaction steps cause the overall yield to fluctuate greatly due to the cumulative effect of the conversion rates of each step, resulting in low atom economy; the cyanolysis step involves highly toxic cyanide, and the hydrogenation step is also problematic. High-pressure equipment has stringent requirements, diazotization processes pose thermal stability risks, and there are significant safety and environmental pressures, along with high overall costs. This type of technical route is essentially a workaround, failing to overcome the challenge of achieving highly selective direct electrophilic substitution in passivated aromatic ring systems. It cannot efficiently produce the target isomer using inexpensive 2,3-difluorotrifluorotoluene. Industry attempts have tried to suppress isomer formation by optimizing stirring rates or using ultra-low temperature cooling, but in non-polar single solvent systems, uneven charge distribution and surface hotspots caused by localized exothermic reactions still lead to site localization failure. Purifying the product by increasing the distillation reflux ratio results in a surge in energy consumption and low product yield, and it cannot solve the problem of site selectivity fluctuations caused by the lack of directional induction in substrate molecules.

[0004] Therefore, the technical problem to be solved by this invention is how to construct a site shielding mechanism by directional regulation of the intermolecular surface environment in a passivated aromatic ring system, while ensuring catalytic activity, so as to inhibit the substitution reactions at the 4- and 5-positions and improve the selectivity of the 6-position isomer. Summary of the Invention

[0005] To address the problems mentioned in the background art, the technical solution of the present invention is as follows: A method for preparing 6-bromo-2,3-difluorotrifluorotoluene, comprising the following steps: Step S1: 2,3-Difluorotrifluorotoluene is dissolved in a mixed solvent in a reactor; the mixed solvent consists of a nonpolar organic solvent and a polar modifier; the polar modifier is a nonproton polar organic compound containing a proton acceptor site, selected from dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, or sulfolane; wherein the molar ratio of the polar modifier to 2,3-difluorotrifluorotoluene is 0.15:1 to 0.45:1; Step S2: Add a polyether stabilizer and an iron-based catalyst to the system obtained in step S1, and control the system temperature between 0°C and 50°C; the polyether stabilizer constructs a steric shielding structure at the 4 and 5 positions of the 2,3-difluorotrifluorotoluene molecule through proton acceptor sites; Step S3: Liquid bromine is added dropwise to the system obtained in step S2 to carry out a directional bromination reaction; the byproduct hydrogen bromide produced by the directional bromination reaction combines in situ with the polarity regulator to form a protonated ion-pair complex; the protonated ion-pair complex strengthens the steric shielding structure at positions 4 and 5 using the high steric hindrance effect, so that liquid bromine undergoes a substitution reaction at position 6 of the 2,3-difluorotrifluorotoluene molecule to obtain 6-bromo-2,3-difluorotrifluorotoluene.

[0006] Preferably, the nonpolar organic solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform or carbon tetrachloride; the mass percentage concentration of 2,3-difluorotrifluorotoluene in the mixed solvent is 15% to 35%.

[0007] Preferably, the polyether stabilizer is selected from polyethylene glycol dimethyl ether, polyoxyethylene ether, or nonionic surfactants having polyether segments; the amount of polyether stabilizer added is 1% to 5% of the mass of the polarity modifier.

[0008] Preferably, the iron-based catalyst is selected from reduced iron powder, ferrous chloride, ferric chloride, ferrous bromide, or ferric bromide; the amount of the iron-based catalyst is 0.01 to 0.05 times the amount of 2,3-difluorotrifluorotoluene; in step S3, the dropping rate of liquid bromine is 0.05 mol / h to 0.15 mol / h of liquid bromine per mole of substrate.

[0009] Preferably, in step S3, the dropping rate of liquid bromine is adjusted according to the amount of hydrogen bromide generated in real time to maintain the selectivity index. Greater than the preset threshold, selective indicators Satisfying the formula: ,in, The amount of 6-bromo-2,3-difluorotrifluorotoluene produced. This represents the total amount of substance of the monobrominated isomers generated. This represents the real-time amount of hydrogen bromide generated in situ during the directional bromination reaction. This refers to the initial amount of the polarity modifier.

[0010] Preferably, after the directional bromination reaction is completed, a post-processing step is also included: reducing excess liquid bromine with sodium sulfite aqueous solution, taking the organic phase in layers, washing it successively with water and saturated brine, and drying it with anhydrous sodium sulfate.

[0011] Preferably, the post-processing step further includes: performing vacuum distillation at a pressure of 5 kPa to 10 kPa to collect the fraction at 75°C to 82°C.

[0012] Preferably, the polarity modifier is composed of a first modifier and a second modifier; wherein the dipole moment of the first modifier is 1.5D to 2.5D, and the dipole moment of the second modifier is greater than 3.0D.

[0013] Preferably, in step S3, the stirring power density of the reaction system is controlled to be 0.5 kW / m³. 3 Up to 2.0kW / m 3 This is to keep the stirring Reynolds number of the reaction system in the range of 2000 to 5000.

[0014] Preferably, in step S3, after the liquid bromine is added, the mixture is kept at a constant temperature of 25°C to 35°C for 1 to 3 hours to inhibit the isomerization of 6-bromo-2,3-difluorotrifluorotoluene to the 4- or 5-position by utilizing the steric hindrance of the complex by protonated ions.

[0015] Compared with the prior art, the beneficial effects of the present invention are: 1. In the preparation of 6-bromo-2,3-difluorotrifluorotoluene, the polar modifier used utilizes its strong dipole moment to generate directional dipole interactions with the trifluoromethyl and fluorine atoms in the substrate, constructing transient solvation inclusion layers at the 4 and 5 positions of the substrate molecule. Through this surface-scale physical shielding effect, the attack barrier of the bromine electrophile on the passivation site is increased, forcing the electrophilic substitution pathway to the relatively electron-rich 6 position, transforming the reaction product from a multi-site random isomer into a single dominant isomer, eliminating the dependence of subsequent distillation steps on high reflux ratios, and reducing separation energy consumption.

[0016] 2. The reaction byproduct hydrogen bromide is used to generate a large-volume ion-pair complex in situ with a polar regulator that has proton acceptor properties. The high steric hindrance and electrostatic repulsion of this complex dynamically reinforce the shielding structure at positions 4 and 5 during the reaction. This makes the shielding effectiveness automatically increase with the reaction process, effectively resisting the interference of local concentration fluctuations caused by the addition of bromine on selectivity, and achieving a constant distribution of the proportion of the target isomer throughout the entire reaction cycle.

[0017] 3. By introducing an interface stabilizer into the mixed solvent system, the interaction force between ions and dipoles is used to anchor discrete polarity modifier molecules around specific functional groups of the substrate to form stable solvation clusters. This improves the shielding layer's ability to resist the shear force generated by the high-intensity mechanical stirring of industrial-grade reactors, prevents solvent molecules from being mechanically stripped from the substrate surface, ensures the integrity of the shielding structure under large-scale production conditions, and eliminates the sensitivity of reaction site positioning accuracy to the stirring intensity of the equipment. Attached Figure Description

[0018] Figure 1 This is a flowchart of the fabrication process based on steric shielding and dynamic feedback control of the present invention. Figure 2 This is a trend graph showing the effect of the molar ratio of the polarity modifier of the present invention on selectivity, purity, and yield. Figure 3 This is a schematic diagram illustrating the collaborative interaction and logic between the process operator and the intelligent feedback control system of this invention. Detailed Implementation

[0019] To make the objectives, technical solutions, and advantages of the present invention clearer, the following provides a detailed description of a method for preparing 6-bromo-2,3-difluorotrifluorotoluene. It should be noted that the following embodiments are for illustrative purposes and do not constitute a limitation on the scope of protection of the present invention.

[0020] This invention provides a method for preparing 6-bromo-2,3-difluorotrifluorotoluene. By constructing a solvated inclusion layer based on dipole interactions in a mixed solvent system, combined with a polyether stabilizer and an in-situ generated protonated ion-pair complex, physical steric hindrance shielding is achieved at specific sites on the substrate molecule, thereby directing the electrophilic substitution reaction towards the 6-position of the substrate molecule. In electrophilic bromination reactions targeting extremely passivated aromatic ring systems, the strong electron-withdrawing inductive effect of the trifluoromethyl group and the adjacent fluorine atom reduces the electron cloud density of the benzene ring, leading to relative openness of the steric hindrance at the 4- and 5-positions. Under conventional reaction conditions, isomer impurities are easily generated. To solve the technical problem of low positioning accuracy, this invention's method performs step S1, dissolving 2,3-difluorotrifluorotoluene in a mixed solvent in a reactor. The mixed solvent consists of a nonpolar organic solvent and a polar modifier. The nonpolar organic solvent is selected from one or more of dichloromethane, 1,2-dichloroethane, chloroform, or carbon tetrachloride. The mass percentage concentration of 2,3-difluorotrifluorotoluene in the mixed solvent is set as follows: to The polarity modifier is a non-proton polar organic compound containing a proton acceptor site, selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, or sulfolane, wherein the molar ratio of the polarity modifier to 2,3-difluorotrifluorotoluene is controlled at [value missing]. to In this embodiment of the method, the polarity modifier consists of a first modifier and a second modifier, and the dipole moment of the first modifier is... to The dipole moment of the second regulator is greater than The polar modulator utilizes a strong dipole moment to generate directional dipole interactions with the trifluoromethyl and fluorine atoms in the substrate, constructing transient solvated inclusion layers at the 4- and 5-positions of the substrate molecule, thereby increasing the attack barrier of the bromine electrophile at this site.

[0021] Since the solvation layer in the mixed solvent system needs to be able to withstand high-intensity mechanical stirring and shearing forces, the method of the present invention performs step S2, adding a polyether stabilizer and an iron-based catalyst to the system obtained in step S1, and controlling the system temperature at... to The polyether stabilizer is selected from one or more of polyethylene glycol dimethyl ether, polyoxyethylene ether, or nonionic surfactants with polyether segments. The amount of polyether stabilizer added is set to a certain percentage of the mass of the polarity modifier. to The iron-based catalyst is selected from one or more of reduced iron powder, ferrous chloride, ferric chloride, ferrous bromide, or ferric bromide. The amount of the iron-based catalyst is set to be 2,3-difluorotrifluorotoluene. Doubled To ensure the adhesion strength of the shielding layer under complex flow field environments, polyether stabilizers utilize the ether bond oxygen atoms of the polyoxyethylene units in their molecular chain segments to form ion-dipole interactions with the cation centers in the protonated ion-pair complex, thereby anchoring the solvated inclusion layer to the steric vacancies of the 2,3-difluorotrifluorotoluene molecule and improving the adhesion stability of the shielding layer under shear conditions. Since the electrophilic bromination reaction is accompanied by instantaneous exothermic reactions, local temperature rise can easily lead to desorption of the solvated layer. Therefore, step S3 is performed, adding liquid bromine dropwise to the system obtained in step S2, with a dropwise acceleration rate of [missing information]. to For each mole of liquid bromine substrate, the stirring power density of the reaction system is controlled at [value missing]. to This keeps the Reynolds number of the reaction system at a certain level. to Within the range, the byproduct hydrogen bromide produced by the reaction combines in situ with the polarity regulator to form a protonated ion-pair complex. The protonated ion-pair complex strengthens the steric shielding structure at the 4- and 5-positions using the high steric hindrance effect, allowing liquid bromine to undergo a substitution reaction at the 6-position of the 2,3-difluorotrifluorotoluene molecule.

[0022] In step S3, the dropping rate of liquid bromine is adjusted according to the real-time amount of hydrogen bromide generated to maintain the selectivity index. Greater than the preset threshold, selective indicators Satisfying the formula: ,in, The amount of 6-bromo-2,3-difluorotrifluorotoluene produced is expressed in units of... , The total amount of substance of the monobrominated isomers generated, in units of , The real-time amount of hydrogen bromide generated in situ during the directed bromination reaction, in units of... , The initial amount of the polarity modifier, in units of ,Establish The correlation matrix between the value and the purity of the finished product was obtained by collecting data at the instantaneous point when liquid bromine was added to the 50.0% conversion point. The numerical value is used to determine the purity of the corresponding distillation product and lock it in. Industrial control alarm threshold The system obtains real-time data from the conductivity sensor. And calculate ,like Determining that the protonated ion pair does not adequately cover the steric hindrance of the complex, the drop acceleration rate is adjusted. The drip rate is decreased in steps, with the step size set to 10% of the initial drip rate. Rebound to target range maintain The system maintains constant density, achieving dynamic closed-loop compensation for site selectivity throughout the entire reaction cycle. The saturation state of the solvation shielding layer's orientation is determined by monitoring the slope change trend of the dielectric parameters, serving as a criterion for triggering catalyst intervention and liquid bromine addition. This resolves the fluctuations in positioning accuracy caused by batch variations in raw materials. A dielectric baseline calibration process is implemented, with a circulating pump driving a 25% concentration substrate solution through the monitoring unit. The average relative permittivity over 10 minutes is collected to define the baseline background value. Real-time monitoring value during the addition of polarity regulator and Differential processing to calculate the first derivative of polarity increment The threshold is determined by the average slope of the derivative over the first 5 minutes before it flattens out from a monotonically increasing trend. In the real-time control program, a moving average window containing 10 sampling points is established to continuously calculate the real-time slope of the dielectric constant. The system records the maximum slope value during the addition of the polarity regulator and uses it as a benchmark. When the real-time slope value within the current window continuously decreases and stabilizes below 5% of the maximum slope value, and this state lasts for more than 120 seconds, it is logically determined that the system has entered a plateau period before arrangement saturation. The average slope value at this time is then locked as the judgment threshold, and the real-time slope drops to a certain level. The following steps trigger the intervention of an iron-based catalyst and the initial addition of liquid bromine to eliminate interference from polar impurities in the raw materials on saturation point identification, ensuring that the solvation shielding layer reaches thermodynamic steady-state arrangement at specific sites; after the liquid bromine addition is completed, in order to suppress product isomerization, the system... to Constant temperature insulation under certain conditions to The steric hindrance of the complex formation by protonated ions was used to suppress the isomerization of 6-bromo-2,3-difluorotrifluorotoluene to the 4- or 5-position. After the reaction was completed, post-treatment was performed by reducing excess liquid bromine with sodium sulfite aqueous solution. The organic phase was separated into layers, washed successively with water and saturated brine, and dried with anhydrous sodium sulfate. to Reduced pressure distillation under pressure to collect to The fraction is used to obtain the finished product.

[0023] Example 1: In using In industrial settings where 2,3-difluorotrifluorotoluene is prepared on a large scale in an enamel-lined reactor, the benzene ring of the molecule is extremely passivated due to the electron-withdrawing effect of the trifluoromethyl group and the adjacent fluorine atom. To maintain the reaction rate, the reaction temperature is increased to [a specific temperature range]. The bromine electrophile tends to attack the 4- and 5-positions on the benzene ring, where steric hindrance is high, resulting in a higher proportion of isomer impurities in the crude product. Furthermore, the target product, 6-bromo-2,3-difluorotrifluorotoluene, has a boiling point very close to that of its isomer impurities, requiring a reflux ratio exceeding [a certain value] during the distillation process. This presents technical challenges such as yield loss and increased energy consumption. To resolve the contradiction between activity and selectivity, the reactor is used to... 2,3-Difluorotrifluorotoluene was dissolved in a mixed solvent consisting of dichloromethane and dimethyl sulfoxide, with the molar ratio of dimethyl sulfoxide to 2,3-difluorotrifluorotoluene controlled at [value missing]. And add relative to the mass of dimethyl sulfoxide Polyethylene glycol dimethyl ether (PEG-DME) is used as a polyether stabilizer. Dimethyl sulfoxide (DMSO) utilizes its strong dipole moment to generate directional dipole interactions with the charge distribution of the substrate molecules, creating solvation shielding layers at the 4- and 5-positions. The anchoring effect of the polyether stabilizer enhances the adhesion stability of the solvation shielding layer under a stirring shear field. The system temperature is adjusted to... And join Reduced iron powder, as an iron-based catalyst, has an on-state power density of Mechanical stirring, to Liquid bromine is added dropwise at a rate of one mole of substrate. Hydrogen bromide, a byproduct of the directional bromination reaction, combines with dimethyl sulfoxide to form a protonated ion-pair complex. The protonated ion-pair complex strengthens the physical shielding at the 4- and 5- positions by utilizing the steric hindrance effect, forcing the bromine electrophile to attack the 6- position, where the electron cloud density is relatively rich.

[0024] During the dropping process, the concentration of hydrogen bromide in the system was continuously monitored and the selectivity index was calculated. The dynamic maintenance response is in a high-selectivity region, and the selectivity index The calculation satisfies the formula: ,in, The amount of 6-bromo-2,3-difluorotrifluorotoluene produced is expressed in units of... , The total amount of substance of the monobrominated isomers generated, in units of , The real-time amount of hydrogen bromide generated in situ during the directed bromination reaction, in units of... , The initial amount of dimethyl sulfoxide, in units of... After the addition is complete, the system is in Under-insulation After reducing excess liquid bromine with sodium sulfite aqueous solution, washing, and drying with anhydrous sodium sulfate, vacuum distillation is performed. Cutting under pressure to The fraction was extracted to obtain the finished product, and the purity of the finished product was measured to be [value missing]. The overall yield is improved compared to the single solvent process. The steric shielding structure synergistically constructed by polarity modifiers, polyether stabilizers, and protonated ion-pair complexes achieves directional protection of passivation sites, converts the electrophilic substitution pathway into the dominant 6-position substitution pathway, and keeps the selectivity of 6-bromo-2,3-difluorotrifluorotoluene stable throughout the entire conversion cycle.

[0025] Example 2: In a volume of And possess Inside a glass-jacketed reactor with precise temperature control, the dynamic process of the conversion of 2,3-difluorotrifluorotoluene to its monobrominated isomer was monitored using an online infrared spectrometer. The raw input data used in the experiment were acquired from the real-time spectral peak positions and intensities of the substrate in the mixed solvent system. The liquid bromine droplet acceleration rate was set based on a technical trade-off of maintaining the activity of the electrophilic reagent. When the rate of attenuation of the substrate's characteristic peaks monitored by the online spectrometer exceeded... To prevent thermal desorption of the shielding layer due to localized heat release, the system lowers the droplet acceleration rate to the lower limit of its range. By adjusting the ratio gradient of polarity modifier and polyether stabilizer, reaction performance indicators under different operating conditions were obtained to verify the effect of steric shielding structure on the selectivity of 6-position monobromination reaction. To confirm the synergistic effect of polarity modifier, polyether stabilizer and protonated ion-paired complex, the experiment included a control group, an experimental group and an out-of-range control group. The data are shown in Table 1.

[0026] Table 1: Reaction performance data under different ratio schemes By comparing the data of experimental group 2 and control group 2, under the same polarity modifier dosage, the selectivity index of control group 2 (without added polyether stabilizer) was [data missing]. Only The purity of the finished product decreased compared to test group 2. This data deviation confirms a nonlinear synergistic effect between polyether stabilizers and polar modifiers, namely, that the interfacial locking mechanism formed by ion-dipole interactions alters the hydrodynamic stability of the shielding layer; according to the data shown in Table 1, when the molar ratio of polar modifier to substrate is at... to When combined with polyether stabilizers, the product purity is maintained at a certain range. The above applies when the molar ratio is below the lower limit. When the substrate molecule's 4- and 5-position shielding coverage is insufficient, the content of byproducts increases, especially when the molar ratio exceeds the upper limit. At that time, the product yield decreased to The results showed that excessive polar modifiers caused over-solventization and encapsulation of iron-based catalysts, inhibiting catalytic activity. During the directed bromination reaction, the system dynamically adjusted the liquid bromine droplet acceleration rate based on the real-time generation of hydrogen bromide to maintain selectivity. Greater than the preset threshold, selective indicators Satisfying the formula: ,in, The amount of 6-bromo-2,3-difluorotrifluorotoluene produced is expressed in units of... , The total amount of substance of the monobrominated isomers generated, in units of , The real-time amount of hydrogen bromide generated in situ during the directed bromination reaction, in units of... , The initial amount of the polarity modifier, in units of .

[0027] To verify the reliability of this method under industrial noise disturbance, the experiment actively introduced noise during the operation of test group 5. Temperature fluctuations and stirring rate The pulse interference, monitoring data shows that the distribution fluctuation of the 6-position isomer is less than This confirmed the compensating ability of the protonated ion-pair complex to environmental changes. After the reaction, the system remained in... Under-insulation To inhibit the isomerization of the product to the 4- or 5-position, after reduction with sodium sulfite aqueous solution, washing with water, and drying with anhydrous sodium sulfate, in... Reduced pressure distillation under pressure, to extract to The fraction was used to obtain the final product. Through comparison of experimental data at different gradients, it was confirmed that the component range constituted the working window for performance gain. The directional protection mechanism at the molecular level was used to achieve the directional guidance of the 6-position substitution pathway of 2,3-difluorotrifluorotoluene, which reduced the subsequent separation load and improved the overall yield of the final product.

[0028] Example 3: This example combines Figures 1 to 3 A method for preparing 6-bromo-2,3-difluorotrifluorotoluene is described, as follows: Figure 1As shown, raw material preparation is carried out by adding 2,3-difluorotrifluorotoluene to the mixed solvent dissolution step S1. In the system composed of a nonpolar solvent and a polar regulator containing a proton acceptor site, a preliminary solvation layer is formed by dipole interaction. Then, the process proceeds to the shielding structure construction step S2, where a polyether stabilizer and an iron-based catalyst are added to construct a steric shielding structure at the 4 and 5 positions of the substrate. Subsequently, the directional bromination reaction is carried out by adding liquid bromine dropwise and using the in-situ generation of protonated ions to reinforce the steric shielding of the complex, thereby forcing directional substitution at the 6-position. During this process, the dynamic feedback control unit monitors the real-time HBr generation and feeds it back to the rate control unit to dynamically adjust the liquid bromine drop rate to maintain the selectivity index S greater than the threshold. After the reaction, the process proceeds to the post-processing and distillation stage. After reducing excess liquid bromine, separating and washing, and vacuum distillation, 6-bromo-2,3-difluorotrifluorotoluene is finally output.

[0029] like Figure 2 As shown in the figure, the horizontal axis represents the molar ratio of polar modifier to substrate, the left vertical axis represents the selectivity index S, and the right vertical axis represents purity / yield %. The three curves in the figure reflect the numerical relationships of selectivity index S, product purity, and product yield with the molar ratio in this reaction system. Selectivity index S increases with increasing molar ratio and then levels off within a certain range. Product purity remains at a high level, while product yield decreases significantly after the molar ratio exceeds a certain value. Figure 3 As shown, the process operator and the intelligent feedback control system perform operations through interactive collaboration. The operation process includes performing sensor baseline calibration and constructing a solvation shielding system, in which a polyether stabilizer is anchored. During the directional bromination reaction stage, real-time data is obtained by monitoring the amount of HBr generated / conductivity, and then the selectivity index S is calculated. The intelligent feedback control system dynamically adjusts the liquid bromine dropping rate based on this index to ensure that the reaction runs under optimal conditions until the reaction is completed and post-processing and purification are carried out.

[0030] Example 4: A batch of 2,3-difluorotrifluorotoluene contained a mass fraction of In industrial preparation scenarios involving polar impurities, the presence of these impurities at the proton acceptor sites of polar modifiers leads to localized structural vacancies in the solvation shielding layer. This results in random fluctuations in the selectivity of the 6-position monobromination reaction. To adjust the effectiveness of the shielding layer, in applications with a capacity of [missing information], [missing information]. The reactor exhaust port is equipped with a tail gas absorption tower filled with deionized water, and the conductivity of the absorption liquid is measured using an online conductivity sensor. Based on the calibrated mapping function between conductivity and hydrogen bromide mass concentration The mass of hydrogen bromide released in real time was obtained, combined with the dissolution equilibrium constant in the reaction solution. Calculate the real-time amount of hydrogen bromide generated in situ during the directed bromination reaction. ,in, This is the real-time conductivity value of the absorbent, in units of... , This is a linear mapping function of conductivity and concentration. This represents the gas-liquid equilibrium constant of hydrogen bromide at the current reaction temperature and pressure. The initial amount of polarity modifier In addition to real-time product distribution data, the process is performed using a selection index-based approach. Real-time calculations were performed, and an offline calibration process was executed before adding liquid bromine. 2,3-Difluorotrifluorotoluene was dissolved in a non-polar organic solvent. The rate of addition of a polarity modifier and the recording of the system's dielectric constant were observed. Calculate the first derivative based on the changing trend. Take the period before the derivative value changes from a monotonically increasing trend to a plateau approaching zero. The average slope is used as the discrimination threshold. In actual production, when the slope of the detected real-time dielectric constant decreases to The following conditions trigger the addition of the iron-based catalyst and the initial dropwise addition of liquid bromine, wherein, Let be the relative permittivity of the reaction system, which is dimensionless. For time, the unit is , This is the preset threshold for determining saturation in the layout.

[0031] During the reaction process, the system operates based on selectivity indicators. Dynamically correct liquid bromine droplet acceleration due to fluctuations Set the target selectivity range as to When calculated in real time Below At this time, it indicates that the generated protonated ions have not yet formed sufficient steric hindrance over the complex, and the system will... Decrease the step size, setting it to be equal to the initial drip rate. ,when When within the target range, maintain Constant, if Exceed And if the temperature control system has sufficient load margin, then Increasing step length to improve production intensity, among which, The real-time dropping rate of liquid bromine is expressed in units of... The application of the aforementioned online compensation calibration procedure suppressed the uneven shielding layer performance caused by fluctuations in raw material purity. Under the interference of raw material impurities, the dielectric parameter slope is triggered in real time and... The closed-loop feedback indicates that the purity deviation of 6-bromo-2,3-difluorotrifluorotoluene is due to the control group. Shrink to The compensation calibration procedure transforms the steric hindrance shielding mechanism into an automated program that can be executed by the sensor system, thereby improving the stability of high regional selectivity under long-term operation.

[0032] Example 5: During the initial operation of the reaction monitoring device or when the absorbent was replaced, to establish the mathematical mapping relationship between the conductivity of the absorbent and the mass of escaping hydrogen bromide, an offline calibration procedure was performed. Hydrogen bromide standard gas with a purity of not less than 99.9% was uniformly introduced into an absorption tower containing 1000g of deionized water at a constant temperature of 25°C. The real-time readings of the conductivity sensor were recorded as the introduced flow rate increased from 0.1g to 5.0g. The mapping coefficient kcal was calculated through linear regression, and a mathematical model satisfying the following formula was established: ,in, The mass of the hydrogen bromide that escaped is expressed in grams. This is the mapping coefficient between conductivity and the mass of hydrogen bromide, in units of... ; This is the real-time conductivity value, in units of S / m. Based on this, repeated verification was performed on absorbents with different dilution ratios to ensure that the measurement deviation across the entire range was less than 0.5%. This procedure represents the real-time amount of hydrogen bromide generated in situ during the directional bromination reaction. The accounting provides a physical quantity traceability benchmark.

[0033] When the system faces the objective condition of raw material batch switching, in order to reduce the impact of impurities in the raw materials on the saturation judgment threshold... To mitigate the impact of the addition of iron-based catalysts, a baseline calibration procedure was performed, and the batch of 2,3-difluorotrifluorotoluene to be processed was calibrated according to the following mass percentages: The concentration is dissolved in a nonpolar organic solvent. The circulation pump is turned on to allow the material to flow through the dielectric constant monitoring unit, and the data is continuously recorded. The average relative permittivity within the range is defined as the reference background value. The relative permittivity monitored in real time during the addition of the polarity modifier. All relative to the reference background value Perform difference processing to make the derivative term The computational path is only controlled by the polarity increments generated by the directional arrangement, where, The real-time relative permittivity of the reaction system is dimensionless. For time, the unit is Measurement data show that this baseline calibration procedure reduces the saturation point identification deviation for different raw material sources to [value missing]. The system then enters a steady state of 6-position monobromination reaction dominated by steric shielding structure.

[0034] Example 6: In offline parameter-finding mode for determining critical process control boundaries, selectivity indices are established by creating an association matrix with product purity and yield as target variables. Control lower limit threshold The optimal molar ratio range of the polarity modifier and the substrate 2,3-difluorotrifluorotoluene; maintaining the amount of iron-based catalyst added at a rate equal to the amount of substrate. The reaction temperature is [number] times ... The content of polyether stabilizers is equal to the mass of polarity modifiers. The molar ratio of the polarity modifier was changed sequentially, and the results were recorded as liquid bromine was added dropwise. instantaneous at the conversion point The corresponding data for the values ​​and the purity of the final product after distillation, among which... The real-time acquisition cycle of the value is set to To cover the dynamic changes of the shielding layer.

[0035] Measurement data shows that when Maintain at At the above levels, the purity of the obtained 6-bromo-2,3-difluorotrifluorotoluene product is within the range of... to The interval, and when Descending to When the content of isomerization impurities increases non-linearly, the control alarm threshold in industrial preparation is adjusted accordingly. Locked to This determination eliminates the risk of positioning failure due to component concentration deviations; before applying this method to enamel-lined reactors of different specifications, a standardized pre-stability testing procedure is performed to balance the active release of the iron-based catalyst and the thermal desorption rate of the protonated ions on the complex. to Within the range To conduct gradient heating experiments, the real-time changes in the dielectric parameters of the system and the total amount of hydrogen bromide generated in situ were monitored simultaneously. The binding energy constant of the shielding layer at different temperature levels was calculated. Establish the upper limit of the liquid bromine dropping rate under this reactor configuration; measurement data show that at a power density of Under stirring conditions, when the system temperature exceeds And the liquid bromine dropping rate reached At that time, the reconstruction rate of the protonated shielding structure is lower than its thermal desorption rate, resulting in a decrease in 6-site directional selectivity. .

[0036] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the present invention can be implemented in other specific forms without departing from the spirit or essential characteristics of the present invention.

[0037] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.

Claims

1. A process for the preparation of 6-bromo-2,3-difluorobenzotrifluoride, characterized in that, Includes the following steps: Step S1: 2,3-Difluorotrifluorotoluene is dissolved in a mixed solvent in a reactor; the mixed solvent consists of a nonpolar organic solvent and a polar modifier; the polar modifier is a nonproton polar organic compound containing a proton acceptor site, selected from dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, or sulfolane; wherein the molar ratio of the polar modifier to 2,3-difluorotrifluorotoluene is 0.15:1 to 0.45:1; Step S2: Add a polyether stabilizer and an iron-based catalyst to the system obtained in step S1, and control the system temperature between 0°C and 50°C; the polyether stabilizer constructs a steric shielding structure at the 4 and 5 positions of the 2,3-difluorotrifluorotoluene molecule through proton acceptor sites; Step S3: Liquid bromine is added dropwise to the system obtained in step S2 to carry out a directional bromination reaction; the byproduct hydrogen bromide produced by the directional bromination reaction combines in situ with the polarity regulator to form a protonated ion-pair complex; the protonated ion-pair complex strengthens the steric shielding structure at positions 4 and 5 using the high steric hindrance effect, so that liquid bromine undergoes a substitution reaction at position 6 of the 2,3-difluorotrifluorotoluene molecule to obtain 6-bromo-2,3-difluorotrifluorotoluene.

2. The process for the preparation of 6-bromo-2,3-difluorobenzotrifluoride according to claim 1, characterized in that, The nonpolar organic solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, or carbon tetrachloride; the mass percentage concentration of 2,3-difluorotrifluorotoluene in the mixed solvent is 15% to 35%.

3. The process for the preparation of 6-bromo-2,3-difluorobenzotrifluoride according to claim 1, characterized in that, The polyether stabilizer is selected from polyethylene glycol dimethyl ether, polyoxyethylene ether, or nonionic surfactants with polyether segments; the amount of polyether stabilizer added is 1% to 5% of the mass of the polarity modifier.

4. The process for the preparation of 6-bromo-2,3-difluorobenzotrifluoride according to claim 1, characterized in that, The iron-based catalyst is selected from reduced iron powder, ferrous chloride, ferric chloride, ferrous bromide, or ferric bromide; the amount of the iron-based catalyst is 0.01 to 0.05 times the amount of 2,3-difluorotrifluorotoluene; in step S3, the dropping rate of liquid bromine is 0.05 mol / h to 0.15 mol / h of liquid bromine per mole of substrate.

5. The method for preparing 6-bromo-2,3-difluorotrifluorotoluene according to claim 1, characterized in that, In step S3, the dropping rate of liquid bromine is adjusted according to the amount of hydrogen bromide generated in real time to maintain the selectivity index. Greater than the preset threshold, selective indicators Satisfying the formula: ,in, The amount of 6-bromo-2,3-difluorotrifluorotoluene produced. This represents the total amount of substance of the monobrominated isomers generated. This represents the real-time amount of hydrogen bromide generated in situ during the directional bromination reaction. This refers to the initial amount of the polarity modifier.

6. The method for preparing 6-bromo-2,3-difluorotrifluorotoluene according to claim 1, characterized in that, After the directional bromination reaction is completed, a post-processing step is also included: excess liquid bromine is reduced with sodium sulfite aqueous solution, the organic phase is separated into layers, washed successively with water and saturated brine, and dried with anhydrous sodium sulfate.

7. The method for preparing 6-bromo-2,3-difluorotrifluorotoluene according to claim 6, characterized in that, The post-processing steps also include: vacuum distillation at a pressure of 5 kPa to 10 kPa to collect the fraction at 75°C to 82°C.

8. The method for preparing 6-bromo-2,3-difluorotrifluorotoluene according to claim 1, characterized in that, The polarity modifier consists of a first modifier and a second modifier; wherein the dipole moment of the first modifier is 1.5D to 2.5D, and the dipole moment of the second modifier is greater than 3.0D.

9. The method for preparing 6-bromo-2,3-difluorotrifluorotoluene according to claim 1, characterized in that, In step S3, the stirring power density of the reaction system is controlled to be 0.5 kW / m 3 to 2.0 kW / m 3 so that the stirring Reynolds number of the reaction system is in the interval of 2000 to 5000.

10. The method for preparing 6-bromo-2,3-difluorotrifluorotoluene according to claim 1, characterized in that, In step S3, after the liquid bromine is added, the mixture is kept at a constant temperature of 25°C to 35°C for 1 to 3 hours to inhibit the isomerization of 6-bromo-2,3-difluorotrifluorotoluene to the 4- or 5-position by utilizing the steric hindrance of the complex by protonated ions.

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