A continuous flow process for the preparation of diaryl urea compounds

Abstract

The application discloses a continuous flow preparation method of a diaryl urea compound, and belongs to the technical field of organic synthesis. The method uses 3-trifluoromethoxy aniline, phenyl chloroformate and 2-(2-hydroxyethyl) aniline as raw materials, and obtains a diaryl urea compound containing formula I through two-stage continuous flow reaction in the presence of triethylamine. The method can reduce the separation and transfer operation of intermediates, is favorable for improving the controllability of a reaction process, can improve the proportion of a target product, reduce the impurity level, and has application potential for further continuous amplification.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a continuous flow preparation method for diarylurea compounds. Background Technology

[0002] Diarylurea compounds are an important class of urea-containing compounds, typically containing Ar-NH-CO-NH-Ar' structural units in their molecules. Because the urea group can form hydrogen bonds, and the aryl groups on both sides can regulate the electronic effects, lipophilicity, and spatial configuration of the compound, diarylurea compounds have high research value in the fields of medicine, pesticides, and fine chemicals.

[0003] Among diarylurea compounds, the compound shown in Formula I, namely 1-[2-(2-hydroxyethyl)phenyl]-3-[3-(trifluoromethoxy)phenyl]urea, is a diarylurea compound containing a trifluoromethoxy-substituted phenyl group and a hydroxyethyl-substituted phenyl group. The trifluoromethoxy group in its structure exhibits a strong electron-withdrawing effect and high lipophilicity, while the hydroxyethyl group can influence the polarity, solubility, and intermolecular interactions of the molecule. These structural characteristics make this compound valuable in the research of bioactive compounds and the development of related applications.

[0004]

[0005] Existing literature has studied the compounds represented by Formula I and their related applications. For example, European patent application EP1461311A2 describes the preparation and related data of the compounds represented by Formula I, and studies urea compounds, including this compound, as VR1 antagonist-related compounds. Another article, "Nisler et al., Diphenylurea-derivedcytokinin oxidase / dehydrogenase inhibitors for biotechnology and agriculture, Journal of Experimental Botany, 2021, 72(2): 355-370," reports that the compounds represented by Formula I belong to the diphenylurea class of cytokinin oxidase / dehydrogenase inhibitors and have application potential in plant tissue culture, plant growth regulation, and agricultural production. Therefore, it is of practical significance to establish a stable, controllable, and scale-up preparation process for the specific compounds represented by Formula I.

[0006] Existing synthetic methods for diarylurea compounds typically include isocyanate methods, phosgene or triphosgene methods, carbonyl diimidazole methods, and urea-forming methods involving chloroformates. Among these, urea-forming methods involving chloroformates usually involve the reaction of an aromatic amine with a chloroformate to form a carbamate intermediate, which then reacts with another aromatic amine to generate an asymmetric diarylurea compound. For the specific compound shown in Formula I, its preparation reaction involves a stepwise conversion between 3-trifluoromethoxyaniline, phenyl chloroformate, and 2-(2-hydroxyethyl)aniline. Different substrate combinations, feeding sequences, reaction temperatures, reaction times, and the type and amount of base can all affect intermediate formation, target product formation, and impurity control.

[0007] In traditional batch reactor preparation processes, materials are typically added to the reaction system in a single addition or dropwise. This process can easily lead to issues such as locally high concentrations, uneven mixing, and insufficient heat transfer efficiency. For the preparation reaction of the compound shown in Formula I, if the formation stage of the carbamate intermediate and the subsequent urea formation stage cannot be effectively controlled separately, it may result in insufficient formation or consumption of the intermediate, leading to a decrease in the proportion of the target product and an increase in raw material residues or impurity levels. As the reaction scales up, the influence of factors such as feeding time, stirring efficiency, temperature control, and material transfer on the reaction results may be further amplified.

[0008] Continuous flow reactions are characterized by low liquid holdup, high mixing efficiency, high heat and mass transfer efficiency, controllable retention time, and ease of continuous scale-up. For multi-stage reactions involving intermediate generation and subsequent transformation, continuous flow processes can improve the stability and controllability of the reaction process by setting up different reaction units, allowing each stage to proceed under suitable conditions.

[0009] Therefore, for the diarylurea compound shown in Formula I, it is still necessary to develop a continuous flow preparation method that allows for separate control of the stage in which 3-trifluoromethoxyaniline forms a carbamate intermediate with phenyl chloroformate, and the stage in which this intermediate forms a urea with 2-(2-hydroxyethyl)aniline, in order to increase the proportion of the target product, reduce the impurity level, and improve the stability and scale-up applicability of the compound preparation process. Summary of the Invention

[0010] To address the problems of difficult-to-control reaction stages, large local concentration differences, insufficient target product ratio, and insufficient impurity level in the preparation of diarylurea compounds of Formula I using a batch reactor, this invention provides a continuous flow preparation method for diarylurea compounds of Formula I. This invention uses 3-trifluoromethoxyaniline, phenyl chloroformate, and 2-(2-hydroxyethyl)aniline as raw materials. The first-stage reaction and the second-stage urea formation reaction are carried out in different reaction units of a continuous flow reactor. The first reaction solution obtained in the first stage is continuously fed into the second-stage reaction without separation, thereby achieving separate control of the two reaction stages, increasing the formation ratio of the target compound of Formula I, and reducing impurity levels.

[0011] This invention provides a continuous flow preparation method for the diarylurea compound shown in Formula I, comprising the following steps:

[0012] (1) 3-trifluoromethoxyaniline solution, phenyl chloroformate solution and triethylamine solution are continuously introduced into the first reaction unit so that 3-trifluoromethoxyaniline and phenyl chloroformate undergo a first-stage reaction in the presence of triethylamine to generate the first reaction solution;

[0013] (2) The first reaction solution is continuously introduced into the second stage without separation, and is continuously mixed with 2-(2-hydroxyethyl)aniline solution to carry out the second stage reaction, generating a second reaction solution containing the diarylurea compound shown in Formula I;

[0014] The molar ratio of 3-trifluoromethoxyaniline, phenyl chloroformate, 2-(2-hydroxyethyl)aniline and triethylamine is 1.0:(1.0~1.2):(1.0~1.2):(1.5~3.0);

[0015] The retention time for the first stage reaction is 30–45 min, and the retention time for the second stage reaction is 10–20 min.

[0016] The structural formula of Equation I is as follows:

[0017] .

[0018] In this invention, the continuous flow reactor may include a first reaction unit and a second reaction unit connected in sequence. The first reaction unit is used to continuously mix raw material 1, raw material 2 and triethylamine and carry out a first-stage reaction to obtain a first reaction solution; the second reaction unit is used to continuously mix the first reaction solution with a solution of raw material 3 and carry out a second-stage reaction to obtain a second reaction solution containing a diarylurea compound of formula I.

[0019] The first reaction unit and the second reaction unit may each independently include mixing components and reaction components, such as T-type mixers, Y-type mixers, micro mixers, tubular reactors, coil reactors, etc.

[0020] In this invention, the retention time refers to the time during which the reaction solution remains and reacts in the corresponding reaction unit or stage. The retention time can be controlled by adjusting the reactor volume, pipeline volume, feed flow rate, or a combination thereof.

[0021] In some embodiments, the molar ratio of 3-trifluoromethoxyaniline, phenyl chloroformate, 2-(2-hydroxyethyl)aniline, and triethylamine can be 1.0:(1.0–1.2):(1.0–1.2):(1.5–3.0). For example, it can be 1.0:1.0:1.0:1.5, 1.0:1.0:1.0:2.0, 1.0:1.1:1.1:2.0, 1.0:1.2:1.2:2.5, or 1.0:1.2:1.2:3.0; preferably 1.0:1.0:1.0:2.0.

[0022] In some embodiments, the retention time of the first stage reaction can be 30–45 min. For example, it can be 30 min, 35 min, 40 min, or 45 min; preferably 40 min. The retention time of the second stage reaction can be 10–20 min. For example, it can be 10 min, 15 min, or 20 min; preferably 15 min.

[0023] In continuous flow preparation, each reactant solution can enter the corresponding reaction unit at a set flow rate via a metering pump or other continuous delivery device. The flow rate refers to the volumetric flow rate of each reactant solution entering the corresponding reaction unit or reaction stage. The flow rate can be adjusted according to the reaction unit volume, pipeline volume, and target retention time.

[0024] In some embodiments, under the condition that the retention times of the first stage reaction and the second stage reaction are satisfied, in the first stage, the flow rates of the 3-trifluoromethoxyaniline solution, the phenyl chloroformate solution, and the triethylamine solution are each independently 3.0 to 5.0 mL / min, for example, 3.0 mL / min, 3.5 mL / min, 3.75 mL / min, 4.0 mL / min, 4.5 mL / min, or 5.0 mL / min; preferably 3.5 to 4.5 mL / min; more preferably 3.75 mL / min. In the second stage, the flow rate of the 2-(2-hydroxyethyl)aniline solution can be 8.0 to 12.0 mL / min, for example, 8.0 mL / min, 9.0 mL / min, 10.0 mL / min, 11.0 mL / min, or 12.0 mL / min; preferably 9.0 to 11.0 mL / min; more preferably 10.0 mL / min.

[0025] In some embodiments, the 3-trifluoromethoxyaniline solution, phenyl chloroformate solution, 2-(2-hydroxyethyl)aniline solution, and triethylamine solution are all prepared using organic solvents. The organic solvent can be one or more of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, acetonitrile, ethyl acetate, toluene, or N,N-dimethylformamide; preferably dichloromethane.

[0026] In some embodiments, the temperature of the first stage reaction can be -10 to 30°C. For example, it can be -10°C, 0°C, 10°C, 20°C or 30°C; preferably -5 to 5°C; more preferably 0°C.

[0027] In some embodiments, the temperature of the second stage reaction can be 30–80°C. For example, it can be 30°C, 40°C, 50°C, 60°C, 70°C, or 80°C; preferably 50–70°C; more preferably 60°C.

[0028] In some embodiments, the continuous flow preparation method can be carried out under back pressure conditions. The back pressure can be 0.3 to 0.6 MPa. For example, it can be 0.3 MPa, 0.4 MPa, 0.5 MPa, or 0.6 MPa; preferably 0.5 MPa. The back pressure can be achieved by a back pressure valve or other device capable of maintaining the system pressure.

[0029] In some embodiments, the concentrations of the 3-trifluoromethoxyaniline solution, the phenyl chloroformate solution, and the 2-(2-hydroxyethyl)aniline solution are each independently 0.5 to 1.5 mmol / mL. For example, they can be 0.5 mmol / mL, 0.8 mmol / mL, 1.0 mmol / mL, 1.2 mmol / mL, or 1.5 mmol / mL; preferably 0.8 to 1.2 mmol / mL; more preferably 1.0 mmol / mL.

[0030] In some embodiments, the concentration of the triethylamine solution can be 0.5–2.5 mmol / mL. For example, it can be 0.5 mmol / mL, 1.0 mmol / mL, 1.5 mmol / mL, 2.0 mmol / mL, or 2.5 mmol / mL; preferably 1.5–2.5 mmol / mL; more preferably 2.0 mmol / mL.

[0031] In some embodiments, the second reaction solution can be post-processed to obtain the diarylurea compound of Formula I. The post-processing includes, but is not limited to, washing, extraction, separation, concentration, crystallization, recrystallization, pulping, column chromatography, filtration, or drying. It should be noted that the post-processing method can be selected based on the composition of the second reaction solution and the purification requirements of the target product, and does not affect the continuous flow reaction process of this invention itself.

[0032] In a preferred embodiment, the molar ratio of 3-trifluoromethoxyaniline, phenyl chloroformate, 2-(2-hydroxyethyl)aniline, and triethylamine is 1.0:1.0:1.0:2.0; the organic solvent is dichloromethane; the concentrations of the 3-trifluoromethoxyaniline solution, phenyl chloroformate solution, and 2-(2-hydroxyethyl)aniline solution are all 1.0 mmol / mL, and the concentration of the triethylamine solution is 2.0 mmol / mL; in the first stage, the flow rates of the 3-trifluoromethoxyaniline solution, phenyl chloroformate solution, and triethylamine solution are each 3.75 mL / min; in the second stage, the flow rate of the 2-(2-hydroxyethyl)aniline solution is 10.0 mL / min; the reaction temperature in the first stage is 0°C, and the retention time in the first stage is 40 min; the reaction temperature in the second stage is 60°C, and the retention time in the second stage is 15 min; the back pressure is 0.5 MPa.

[0033] Compared with the prior art, the present invention has at least the following beneficial effects:

[0034] (1) This invention targets a specific substrate system composed of 3-trifluoromethoxyaniline, phenyl chloroformate and 2-(2-hydroxyethyl)aniline, and uses a continuous flow method to prepare the diarylurea compound shown in Formula I, so that the first-stage activation reaction and the second-stage urea formation reaction can be controlled separately, which is beneficial to improving the stability and controllability of the reaction process.

[0035] (2) The present invention enables the first reaction liquid containing carbamate intermediates obtained in the first stage to continuously enter the second stage reaction without separation, which reduces the separation, transfer and exposure of intermediates, simplifies the process flow, and is conducive to the continuous preparation of diarylurea compounds shown in Formula I.

[0036] (3) The present invention addresses the specific preparation process of the diarylurea compound shown in Formula I. By controlling the molar ratio of reactants, the retention time of the first stage, the retention time of the second stage, and continuous flow parameters such as feed concentration, triethylamine concentration, reaction temperature, and back pressure, it is beneficial to increase the product ratio of the target compound shown in Formula I and reduce the impurity level. Under better conditions, the target product ratio obtained by HPLC detection of the reaction solution can be increased to about 90%, and impurities 1 and 2 can be reduced to below 3%. Attached Figure Description

[0037] Figure 1 The image shows the 1H NMR spectrum of impurity 1.

[0038] Figure 2 The image shows the 1H NMR spectrum of impurity 2.

[0039] Figure 3 The 1H NMR spectrum of the diarylurea compound shown in Formula I is shown below.

[0040] Figure 4 This is the HPLC chromatogram of the second reaction solution obtained in Example 3, No. 2. Detailed Implementation

[0041] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention. All features disclosed in this specification, or steps in all disclosed methods or processes, except for mutually exclusive features and / or steps, can be combined in any way.

[0042] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0043] In the following examples, the target compound is a diarylurea compound of Formula I, namely 1-[2-(2-hydroxyethyl)phenyl]-3-[3-(trifluoromethoxy)phenyl]urea, whose structural formula is as follows:

[0044]

[0045] For ease of description, 3-trifluoromethoxyaniline is designated as raw material 1, phenyl chloroformate as raw material 2, and 2-(2-hydroxyethyl)aniline as raw material 3. The specific structures of raw materials 1, 2, and 3 are as shown in the reaction formula.

[0046] The reaction route of the target compound is as follows:

[0047] Raw material 1 + Raw material 2 + Triethylamine → First reaction solution;

[0048]

[0049] First reaction solution + raw material 3 → diarylurea compound as shown in Formula I.

[0050]

[0051] The continuous flow preparation process of the present invention includes two continuous reaction stages: in the first stage, raw material 1, raw material 2 and triethylamine are continuously mixed and reacted to obtain a first reaction solution; in the second stage, the first reaction solution is continuously mixed and reacted with the raw material 3 solution without separation or purification to obtain a second reaction solution containing the diarylurea compound shown in Formula I.

[0052] To facilitate comparison of reaction effects under different continuous flow reaction conditions, the following examples use the normalized peak area ratio obtained by HPLC detection of the reaction solution as the evaluation index. Unless otherwise stated, "Raw Material 1", "Raw Material 2", "Raw Material 3", "Product", "Impurity 1", and "Impurity 2" all refer to the normalized peak area ratio of the corresponding chromatographic peaks. Among them, "Product" refers to the chromatographic peak corresponding to the diarylurea compound shown in Formula I, and "Impurity 1" and "Impurity 2" refer to the two main impurity peaks observed under the same HPLC detection conditions.

[0053] In this invention, the HPLC detection method for determining the normalized peak area ratio of each component in the reaction solution can be performed under the following conditions: take the reaction solution sample, dilute it with methanol and then perform HPLC detection; use water as mobile phase A and acetonitrile as mobile phase B, and the elution gradient is shown in Table 1; use a stainless steel chromatographic column with C18 as packing material and use an ultraviolet detector at a wavelength of 250 nm for detection.

[0054] Table 1 Elution gradient

[0055]

[0056] Under the above HPLC detection conditions, the retention times of the main compounds and impurity peaks are shown in Table 2.

[0057] Table 2 Retention times of compounds

[0058]

[0059] Note: Raw material 2 was not tested.

[0060] Among them, impurity 1 and impurity 2 are the main impurity peaks with retention times of 20.28 min and 21.37 min, respectively, under the above HPLC detection conditions.

[0061] The structural formula of impurity 1 is as follows:

[0062] ;

[0063] The structural formula of impurity 2 is as follows:

[0064] .

[0065] To further clarify the attribution of the main impurity peaks, proton NMR spectra of impurities 1 and 2 were analyzed. The proton NMR spectrum of impurity 1 is shown below. Figure 1 As shown, the proton NMR spectrum of impurity 2 is as follows: Figure 2 As shown. Combined with Figure 1 and Figure 2 It can be seen that the 1H NMR signals of impurity 1 and impurity 2 are consistent with their corresponding structures, and can be used to explain the attribution of the main impurity peaks with retention times of 20.28 min and 21.37 min, respectively, under the above HPLC detection conditions.

[0066] Based on the above HPLC detection method, the effects of different continuous flow process conditions on the formation and impurity control of the diarylurea compound shown in Formula I were investigated through single-stage continuous flow reaction screening, two-stage continuous flow reaction screening, and further optimization under high concentration and back pressure conditions.

[0067] Example 1: Single-stage continuous flow reaction screening

[0068] This embodiment is used to investigate the reaction when raw material 1, raw material 2, raw material 3 and acid-binding agent are simultaneously introduced into the same continuous flow reactor.

[0069] According to the conditions shown in Table 3, solutions of raw material 1, raw material 2, raw material 3, and the acid-binding agent were prepared respectively. Each of the raw material 1, raw material 2, raw material 3, and acid-binding agent solutions was connected to a metering pump, and the flow rate of each metering pump was set to 5 mL / min. The solutions were then simultaneously introduced into a continuous flow reactor for reaction. After the system stabilized, the reaction solution was collected, and samples were taken for HPLC analysis. The results are shown in Table 4.

[0070] Table 3 Single-stage continuous flow reaction conditions

[0071]

[0072] Table 4. HPLC Detection Results of Single-Stage Continuous Flow Reaction

[0073]

[0074] Tables 3 and 4 show that the diarylurea compound shown in Formula I can be generated using a single-stage continuous flow method. When triethylamine is used as the acid-binding agent, the overall proportion of the target product is relatively high; under the conditions of a feed concentration of 0.5 mmol / mL, a triethylamine concentration of 0.5 mmol / mL, a temperature of 30℃, and a retention time of 30 min, the product proportion can reach 77%.

[0075] However, in the single-stage continuous flow method, feedstock 1, feedstock 2, feedstock 3, and the acid-binding agent enter the same reactor simultaneously. The formation stage of the carbamate intermediate and the subsequent urea formation stage cannot be controlled separately, and under certain conditions, the proportion of impurity 2 remains relatively high. This indicates that although the single-stage continuous flow method can achieve the generation of the target product, further optimization of the reaction stage control method is still necessary.

[0076] Example 2: Two-stage continuous flow reaction screening

[0077] This embodiment is used to examine a two-stage continuous flow reaction method in which raw material 1 and raw material 2 are reacted first to generate a carbamate intermediate, and then reacted with raw material 3 to generate the target product.

[0078] According to the conditions shown in Table 5, solutions of raw material 1, raw material 2, raw material 3, and triethylamine were prepared respectively. The raw material 1 solution, raw material 2 solution, and triethylamine solution were continuously fed into the first reactor (flow rate 10 mL / min) for the first stage reaction to obtain the first reaction solution. The first reaction solution and raw material 3 solution were continuously fed into the second reactor (flow rate 10 mL / min) for the second stage reaction to obtain the second reaction solution containing the diarylurea compound shown in Formula I.

[0079] Adjust the raw material concentration, triethylamine concentration, first-stage reaction temperature (reaction temperature 1), second-stage reaction temperature (reaction temperature 2), first-stage retention time (retention time 1), and second-stage retention time (retention time 2) according to the conditions shown in Table 5. After the system stabilizes, collect the second reaction solution, take a sample for HPLC analysis, and the results are shown in Table 6.

[0080] Table 5. Reaction conditions for two-stage continuous flow

[0081]

[0082] Table 6. HPLC Detection Results of Two-Stage Continuous Flow Reaction

[0083]

[0084] Tables 5 and 6 show that by splitting the reaction into two continuous flow stages, the activation reaction in the first stage and the urea formation reaction in the second stage can be controlled separately. Tables 1-5 show that when the temperature in the first stage is 20-40℃ and the retention time in the first stage is 15 min, the proportion of impurity 1 is relatively high, while the proportion of the target product is relatively low. Specifically, in table 5, when both the temperature in the first and second stages is 40℃, the product proportion is only 40%, while impurity 1 reaches 45%.

[0085] Reactions 6-8 show that lowering the first-stage reaction temperature is beneficial for reducing the proportion of impurity 1. Specifically, in reaction 8, with a first-stage temperature of 0°C, a second-stage temperature of 40°C, a first-stage retention time of 30 min, and a second-stage retention time of 15 min, the product proportion increased to 78%, and impurity 1 decreased to 7%. Reaction 10 further extended the first-stage retention time to 40 min, increasing the product proportion to 80% and reducing impurity 1 to 6%.

[0086] This demonstrates that in a two-stage continuous flow reaction, using a lower temperature and appropriately extending the retention time in the first stage is beneficial for controlling impurity formation and increasing the proportion of the target product.

[0087] Example 3: Optimization of Two-Stage Continuous Flow Reaction

[0088] Based on Example 2, this embodiment further increases the raw material concentration and sets back pressure to examine the reaction effect of the two-stage continuous flow reaction under higher concentration conditions.

[0089] According to the conditions shown in Table 7, solutions of raw material 1, raw material 2, raw material 3, and triethylamine were prepared respectively. The back pressure of the continuous flow reaction system was set to 0.5 MPa. The raw material 1 solution, raw material 2 solution, and triethylamine solution were continuously fed into the first reactor (flow rate of 3.75 mL / min) for the first stage reaction to obtain the first reaction solution; the first reaction solution and raw material 3 solution were continuously fed into the second reactor (flow rate of 10 mL / min) for the second stage reaction to obtain the second reaction solution containing the diarylurea compound shown in Formula I.

[0090] Adjust the triethylamine concentration and the second-stage reaction temperature according to the conditions shown in Table 7. After the system stabilizes, collect the second reaction solution, take a sample for HPLC analysis, and the results are shown in Table 8.

[0091] Table 7 Optimization conditions for two-stage continuous flow reaction

[0092]

[0093] Table 8 HPLC Detection Results

[0094]

[0095] As shown in Tables 7 and 8, the two-stage continuous flow reaction can proceed stably under the following conditions: the concentrations of raw materials 1, 2 and 3 are all 1.0 mmol / mL, the back pressure is 0.5 MPa, the temperature of the first stage is 0℃, the retention time of the first stage is 40 min, and the retention time of the second stage is 15 min.

[0096] Among them, when No. 1 was tested at a second-stage temperature of 50℃ and a triethylamine concentration of 1.0 mmol / mL, the product ratio was 86%, impurity 1 was 5%, and impurity 2 was 9%. When No. 2 was tested at a second-stage temperature of 60℃ and a triethylamine concentration of 2.0 mmol / mL, the product ratio increased by nearly 90%, impurity 1 was 0.35%, and impurity 2 was 2.47%. These results indicate that, based on the above two-stage continuous flow processes, increasing the second-stage temperature and increasing the triethylamine concentration is beneficial to further increase the target product ratio and reduce the proportion of impurity 2.

[0097] To further confirm the structure of the obtained product, the diarylurea compound of formula I obtained by post-processing the second reaction solution obtained in Example 3, No. 2, was subjected to 1H NMR spectroscopy. Its 1H NMR spectrum is shown below. Figure 3 .Depend on Figure 3 It can be seen that the nuclear magnetic resonance hydrogen spectrum signal of the obtained product is consistent with the structure of the diarylurea compound shown in Formula I, indicating that the continuous flow preparation method of the present invention can prepare the target compound shown in Formula I.

[0098] Furthermore, the second reaction solution obtained in Example 3, No. 2, was analyzed by HPLC, and its HPLC chromatogram and peak table are shown below. Figure 4 .Depend on Figure 4 The retention time of the target product peak is approximately 16.16 min, with a peak area normalization ratio of approximately 89.59%; the retention time of impurity 1 peak is approximately 20.28 min, with a peak area normalization ratio of approximately 0.35%; and the retention time of impurity 2 peak is approximately 21.37 min, with a peak area normalization ratio of approximately 2.47%. This indicates that under these conditions, a second reaction solution with a high proportion of the target product and a low level of impurities can be obtained.

[0099] In summary, the screening results of Examples 1-3 show that, compared to a single-stage continuous flow reaction, a two-stage continuous flow approach, dividing the reaction into a first-stage activation reaction and a second-stage urea formation reaction, is more advantageous for controlling the formation of the target compound and impurity levels. In the existing screening data, the optimal reaction conditions are: reactant 1 concentration of 1.0 mmol / mL, reactant 2 concentration of 1.0 mmol / mL, reactant 3 concentration of 1.0 mmol / mL, triethylamine as the acid-binding agent with a concentration of 2.0 mmol / mL, back pressure of 0.5 MPa, first-stage reaction temperature of 0°C, first-stage retention time of 40 min, and second-stage reaction temperature of 60°C with a second-stage retention time of 15 min. Under these conditions, HPLC detection results showed no significant residues of reactants 1, 2, and 3, the target product ratio was 89.59%, and impurities 1 and 2 were 0.35% and 2.47%, respectively, indicating that these conditions are the optimal continuous flow preparation conditions obtained through screening.

[0100] Comparative Example 1

[0101] To examine the reaction performance of the two-stage continuous flow preparation method of the present invention compared with the two-stage batch feeding method, Comparative Example 1 was set up. Comparative Example 1 followed the feeding logic of phenyl chloroformate participating in the urea formation reaction in CN122036733A, and carried out a two-stage batch reaction under the same target substrate system, and compared it with the two-stage continuous flow feeding method under the optimized conditions of Example 3.

[0102] In Comparative Example 1, raw material 1 (44.2 g, 1.0 eq) was dissolved in 1000 mL of dichloromethane, pyridine (40 g, 2.0 eq) was added, followed by raw material 2 (39.1 g, 1.0 eq). The first stage reaction was carried out at 0 °C for 40 min. After the first stage reaction, raw material 3 (34.3 g, 1.0 eq), which had been pre-dissolved in 500 mL of dichloromethane, was added, and the temperature was raised to 20 °C for the second stage reaction for 30 min. After the reaction, the reaction solution was analyzed according to the HPLC detection method described above.

[0103] In addition, the two-stage continuous flow feeding method under the optimized conditions of Embodiment 3 of the present invention refers to the following: the concentrations of raw material 1, raw material 2 and raw material 3 are all 1.0 mmol / mL, the concentration of triethylamine is 2.0 mmol / mL, and the back pressure is 0.5 MPa; the solutions of raw material 1, raw material 2 and triethylamine are continuously fed into the first reaction unit, and the first stage reaction is carried out at 0°C for 40 min to obtain a first reaction solution containing a carbamate intermediate; then the first reaction solution is continuously fed into the second stage without separation, and after continuous mixing with the raw material 3 solution, the second stage reaction is carried out at 60°C for 15 min to obtain a second reaction solution containing the diarylurea compound shown in Formula I.

[0104] Table 9 HPLC Comparison Results

[0105]

[0106] As shown in Table 9, when the reaction was carried out using the two-stage batch reactor method of Comparative Example 1, the target product ratio was 57.91%, and the impurity 1 ratio was 30.56%. However, when the two-stage continuous flow feed method under the optimized conditions of Example 3 was used, the target product ratio increased to 89.59%, and the impurity 1 ratio decreased to 0.35%. The above results show that, compared with the two-stage batch reactor method of CN122036733A, the present invention, through two-stage continuous flow reaction and corresponding control of temperature, retention time, feed concentration, flow rate, and back pressure conditions, can increase the product ratio of the diarylurea compound shown in Formula I and significantly reduce the level of impurity 1.

[0107] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A continuous flow preparation method for a diarylurea compound of Formula I, characterized in that, Includes the following steps: (1) 3-trifluoromethoxyaniline solution, phenyl chloroformate solution and triethylamine solution are continuously introduced into the first reaction unit so that 3-trifluoromethoxyaniline and phenyl chloroformate undergo a first-stage reaction in the presence of triethylamine to generate the first reaction solution; (2) The first reaction solution is continuously introduced into the second stage without separation, and is continuously mixed with 2-(2-hydroxyethyl)aniline solution to carry out the second stage reaction, generating a second reaction solution containing the diarylurea compound shown in Formula I; The molar ratio of 3-trifluoromethoxyaniline, phenyl chloroformate, 2-(2-hydroxyethyl)aniline and triethylamine is 1.0:(1.0~1.2):(1.0~1.2):(1.5~3.0); The retention time for the first stage reaction is 30–45 min, and the retention time for the second stage reaction is 10–20 min. The structural formula of Equation I is as follows: 。 2. The continuous flow preparation method according to claim 1, characterized in that, The molar ratio of 3-trifluoromethoxyaniline, phenyl chloroformate, 2-(2-hydroxyethyl)aniline and triethylamine is 1.0:1.0:1.0:2.

0.

3. The continuous flow preparation method according to claim 1, characterized in that, The retention time for the first stage reaction is 40 min, and the retention time for the second stage reaction is 15 min.

4. The continuous flow preparation method according to claim 1, characterized in that, In the first stage, the flow rates of the 3-trifluoromethoxyaniline solution, phenyl chloroformate solution, and triethylamine solution are each independently 3.0–5.0 mL / min; In the second stage, the flow rate of the 2-(2-hydroxyethyl)aniline solution is 8.0–12.0 mL / min.

5. The continuous flow preparation method according to claim 1, characterized in that, The 3-trifluoromethoxyaniline solution, phenyl chloroformate solution, 2-(2-hydroxyethyl)aniline solution, and triethylamine solution are all prepared using organic solvents; the organic solvents are selected from one or more of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, acetonitrile, ethyl acetate, toluene, or N,N-dimethylformamide.

6. The continuous flow preparation method according to claim 1, characterized in that, The temperature of the first stage reaction is -5 to 5℃.

7. The continuous flow preparation method according to claim 1, characterized in that, The temperature of the second stage reaction is 50–70°C.

8. The continuous flow preparation method according to claim 1, characterized in that, The continuous flow preparation method is carried out under back pressure conditions, wherein the back pressure is 0.3 to 0.6 MPa.

9. The continuous flow preparation method according to claim 1, characterized in that, The concentrations of the 3-trifluoromethoxyaniline solution, phenyl chloroformate solution, and 2-(2-hydroxyethyl)aniline solution are each independently 0.8–1.2 mmol / mL.

10. The continuous flow preparation method according to claim 1, characterized in that, The concentration of the triethylamine solution is 1.5–2.5 mmol / mL.

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