3-oxo-2-h chromenyl and a method for preparing the same

Abstract

This invention relates to the field of chemical pharmaceutical raw material manufacturing, and discloses a 3-carbonyl-2-H benzopyran and its preparation method, comprising: dissolving 2-propynyloxybenzaldehyde substrate in an organic solvent under an inert protective atmosphere and a closed pressurized state, adding acetylacetone molybdenum oxycatalyst to construct a reaction material system, initiating an intramolecular cyclization reaction under rotating stirring, and controlling the cyclic switching of the reaction material system between high-temperature and low-temperature periods throughout the overall reaction cycle. This invention breaks the coordination deadlock of the catalytic center caused by heterocyclic enrichment through multi-stage alternating temperature field treatment, realizes in-situ dynamic regeneration of catalytic sites, alleviates continuous high-temperature damage to the catalytic system, solves the reverse constraint dilemma of catalyst deactivation and substrate thermal decomposition, effectively controls the selectivity of heterocyclic cyclization, and improves the yield of the target product.

Description

Technical Field

[0001] This invention relates to a 3-carbonyl-2-H benzopyran and its preparation method, belonging to the field of chemical pharmaceutical raw material manufacturing technology. Background Technology

[0002] Currently, in the synthesis of heterocyclic compounds and the construction of active pharmaceutical ingredients, the 2-H benzopyran skeleton with a carbonyl functional group at the 3-position serves as the core matrix for preparing drug intermediates. Complexation catalysis is used to catalyze substrate molecules possessing both alkyne and carbonyl groups, initiating intramolecular metathesis reactions. This constitutes a conventional one-step closed-ring assembly pathway for this type of heterocycle. The reaction uses an acetylacetone-molybdenum catalyst as the catalytic center. The substrate functional group undergoes coordination exchange with the molybdenum center to generate a catalytically active intermediate with a specific spatial orientation, initiating heterocycle reconstruction. Due to the high kinetic energy barrier associated with the intramolecular cyclization metathesis transition state, conventional production requires a continuous and constant external heat source to be supplied to the reaction system. The materials are subjected to a high-temperature reaction environment of 140°C for extended periods, which easily leads to irreversible dissociation between the ligand and the central metal, causing the complex precursor structure to decompose and become inactive. As cyclization continues, the product accumulates, and its highly polar carbonyl group exhibits a high coordination affinity with the molybdenum catalytic center, competing with the substrate for active sites. This competitive chelation results in coordination poisoning and triggers reaction self-inhibition.

[0003] To compensate for the reduction in catalytic active sites, significantly increasing the catalyst loading or doubling the heating time are common improvement methods. However, doubling the amount of complex directly leads to increased resistance to mass transfer and purification of the finished drug substance, while extending the heating time easily induces non-selective thermal decomposition and polymerization side reactions in heat-sensitive substrates, generating complex polymeric impurities. Conventional temperature field control strategies struggle to achieve a balance between overcoming the cyclization energy barrier, inhibiting the thermal dissociation of the complex, and promoting the dissociation of poisoned products. Existing technologies mostly seek breakthroughs in material modification such as catalytic center construction and ligand modification. Process control methods for the reaction process are also a bottleneck restricting cyclization efficiency. For example, Chinese invention patent application CN112898260A discloses a 3-carbonyl-2H-benzopyran compound or its pharmaceutically usable salt, preparation method and use. The target core is constructed through multi-step linear chemical synthesis. In the functional group transformation, it relies on a static temperature field control mode of continuous high-temperature wetting throughout the cycle. It does not eliminate the dynamic chelation poisoning caused by product enrichment. Long-term isothermal heating cannot provide the thermodynamic fluctuation energy for bond breaking required to remove the strong polar carbonyl group, which aggravates the thermal damage of metal reagents and substrate side reactions. This results in low mass transfer efficiency of chromene product separation, which is difficult to meet the linear stability requirements of yield in industrial scale-up production.

[0004] Therefore, regulating the energy input mode of heterocyclic cyclization reactions to meet the energy supply required to cross the cyclization energy barrier while mitigating thermal damage to the catalytic system and expelling poisoned product molecules to restore the activity of the catalytic center is the technical problem to be solved by this invention. Summary of the Invention

[0005] To address the problems in the background art, the technical solution of the present invention is as follows: A method for preparing 3-carbonyl-2-H benzopyran, comprising the following steps: Step S1: In a sealed reactor purged with an inert protective gas, 2-propynyloxybenzaldehyde substrate is dissolved in an organic solvent to prepare an initial reaction solution with a molar concentration of 0.1 mol / L to 0.5 mol / L. Solid acetylacetone molybdenum catalyst is added to the initial reaction solution according to a molar ratio of 1:20 to 1:100 between the acetylacetone molybdenum catalyst and the 2-propynyloxybenzaldehyde substrate to construct the reaction material system. The absolute pressure inside the sealed reactor is maintained at 0.15 MPa to 0.30 MPa. The intramolecular cyclization reaction is initiated at a stirring speed of 300 rpm to 500 rpm and a reference cyclization reaction temperature of 125°C to 127°C. Step S2: Maintaining the rotational stirring speed and absolute pressure, control the reaction material system within the sealed reactor to undergo a continuous, multi-stage temperature-variable reaction within a 12-hour overall reaction cycle. The temperature boundary is alternating between high-temperature and low-temperature periods. During the high-temperature period, the sealed reactor is driven to rise from the baseline cyclization reaction temperature to 143°C to 145°C within 5 minutes and held at that temperature for 10 to 15 minutes. During the low-temperature period, the sealed reactor is driven to cool from 143°C to 145°C to the baseline cyclization reaction temperature of 125°C to 127°C within 10 minutes and held at that temperature for 50 to 60 minutes. By alternating between the high-temperature and low-temperature periods, the preparation of 3-carbonyl-2-H benzopyran is completed.

[0006] Preferably, the organic solvent is selected from any one of toluene, m-xylene, o-xylene, or mesitylene, or a mixture thereof; the inert protective gas is selected from nitrogen or argon with a purity of not less than 99.99%; in step S1, the 2-propynyloxybenzaldehyde substrate contains a sterically hindered substituent, which is selected from phenyl, isopropyl, or tert-butyl; in step S2, during the period after the end of the low-temperature period and before the start of the next high-temperature period, the reaction system is kept in a constant-temperature reaction state at a reference cyclization reaction temperature of 125°C to 127°C.

[0007] Preferably, in step S2, the heating rate of the reactant system from the reference cyclization reaction temperature to 143°C to 145°C is 3°C / min to 5°C / min; the cooling rate of the reactant system from 143°C to 145°C to the reference cyclization reaction temperature is 1.5°C / min to 2°C / min.

[0008] Preferably, in step S1, the stirring speed is 400 rpm; the mass percentage concentration of the acetylacetone molybdenum catalyst in the initial reaction solution is 1% to 3%.

[0009] Preferably, in step S2, during the low-temperature period, a cooling medium at a temperature of 20°C to 25°C is introduced into the jacket of the sealed vessel for heat exchange, and the cooling rate of the reaction material system is controlled to be no less than 1.5°C / min, so as to maintain the mass percentage of insoluble matter in the reaction material system at less than 0.1%.

[0010] Preferably, step S2 includes the following sub-steps: Step S21, within the overall reaction cycle of 12h, the intensity of the characteristic absorption peak of 3-carbonyl 2-H benzopyran in the reaction material system is measured using an online infrared spectrometer to obtain the real-time absorbance value; Step S22, the accumulation rate of the target product is calculated based on the real-time absorbance value, and when the accumulation rate of the target product decreases to a preset critical threshold, the isothermal holding time during the high-temperature period is extended to 20min.

[0011] Preferably, the process also includes a purification and separation step: after the overall reaction cycle of 12 hours, the temperature of the reaction material system is reduced, insoluble matter is removed by pressure filtration, organic solvent is removed by vacuum distillation to obtain crude product, crude product is packed into a silica gel chromatographic column, and separation is performed using a mixed eluent of petroleum ether and ethyl acetate in a volume ratio of 10:1, the eluent is collected and concentrated under reduced pressure to obtain pure 3-carbonyl-2-H benzopyran.

[0012] Preferably, in step S1, the absolute pressure inside the sealed vessel is controlled to be stable within the range of 0.20 MPa to 0.22 MPa.

[0013] Preferably, the method for preparing 3-carbonyl-2-H benzopyran is used for industrial production, and the amount of 2-propyneoxybenzaldehyde substrate input per batch is 10 kg to 50 kg; in step S2, under the cyclical alternation of high temperature period and low temperature period, the yield of the obtained 3-carbonyl-2-H benzopyran per batch is 85% to 95%, and the yield fluctuation between each production batch does not exceed 2%.

[0014] Preferably, a 3-carbonyl-2-H benzopyran is prepared by the method.

[0015] Compared with the prior art, the beneficial effects of the present invention are: 1. In the preparation of 3-carbonyl-2-H benzopyran, the initial material is kept in the intermediate temperature range, which allows the alkynyl and carbonyl groups to preferentially complete site coordination exchange with the acetylacetone molybdenum oxide catalyst, thus constructing a catalytically active intermediate with a specific spatial orientation in situ. This mechanism avoids non-selective thermal cracking side reactions of the substrate molecules due to sudden heating in the early stage of the reaction, while delaying the growth of polymerized impurities and ensuring the initial concentration and stable conversion channel of the matrix molecules in the liquid phase system. This provides a high-purity catalytic precursor for the subsequent transition state across the cyclization energy barrier. In this way, the overall material loss in the heterocyclic construction process is reduced and the mass transfer efficiency of the separation and purification process is improved while shortening the overall thermal wetting cycle.

[0016] 2. The alternating high-temperature pulses applied during the later stages of the reaction cycle can induce thermodynamic fluctuations in the coordination bonds, breaking the strong polar chelate bonds formed between the three carbonyl groups in the enriched target product and the molybdenum metal center. This removes the product molecules with site poisoning effects from the catalytic active center in situ, releasing the vacant open coordination orbitals. This dissociation process avoids the catalytic cycle being blocked by product accumulation, restores the reactivity of the molybdenum catalytic center under reaction conditions without the need to introduce external removal reagents, maintains the transfer shear efficiency of the intramolecular carbonyl and alkyne metathesis reaction in the middle and later stages, and ensures the linear stability of the heterocycle construction yield in large-scale industrial continuous production.

[0017] 3. By controlling the continuous high-temperature damage to be transformed into short-term high-temperature pulses and coordinating with a low-temperature stable section for heat exchange, the alternating timing design of this stepped temperature field balances the thermodynamic load inside the reactor. Under the premise of maintaining the baseline cyclization conversion rate, the material temperature is reduced in a timely manner to prevent the structural degradation and precipitation deactivation caused by irreversible ligand detachment of the acetylacetone molybdenum catalyst under continuous high heat. This delays the activity decay of the metal complex and avoids the risk of a sharp drop in product purity caused by the lag in heat and mass transfer and local overheating in large reactors during industrial-scale production. It also enhances the overall reaction system's tolerance to complex operating conditions and the feasibility of engineering implementation. Attached Figure Description

[0018] Figure 1 This is a flowchart of a multi-stage temperature-controlled preparation method for 3-carbonyl-2-H benzopyran according to the present invention; Figure 2 This diagram illustrates the process elements of a method for preparing 3-carbonyl-2-H benzopyran according to the present invention.

[0019] The objectives, features, and advantages of this invention will be further explained in conjunction with the embodiments and with reference to the accompanying drawings. Detailed Implementation

[0020] The technical solutions of the embodiments of this application will be clearly described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this application, not all embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of this application are within the scope of protection of this application.

[0021] A method for preparing 3-carbonyl-2-H benzopyran includes the following steps: Step S1: In a sealed reactor purged with an inert protective gas, 2-propynyloxybenzaldehyde substrate is dissolved in an organic solvent to prepare an initial reaction solution with a molar concentration of 0.1 mol / L to 0.5 mol / L. Solid acetylacetone molybdenum catalyst is added to the initial reaction solution according to a molar ratio of 1:20 to 1:100 between the acetylacetone molybdenum catalyst and the 2-propynyloxybenzaldehyde substrate to construct the reaction material system. The absolute pressure inside the sealed reactor is maintained at 0.15 MPa to 0.30 MPa. The intramolecular cyclization reaction is initiated at a stirring speed of 300 rpm to 500 rpm and a reference cyclization reaction temperature of 125°C to 127°C. Step S2: Maintaining the rotational stirring speed and absolute pressure, control the reaction material system within the sealed reactor to undergo a continuous, multi-stage temperature-variable reaction within a 12-hour overall reaction cycle. The temperature boundary is alternating between high-temperature and low-temperature periods. During the high-temperature period, the sealed reactor is driven to rise from the baseline cyclization reaction temperature to 143°C to 145°C within 5 minutes and held at that temperature for 10 to 15 minutes. During the low-temperature period, the sealed reactor is driven to cool from 143°C to 145°C to the baseline cyclization reaction temperature of 125°C to 127°C within 10 minutes and held at that temperature for 50 to 60 minutes. By alternating between the high-temperature and low-temperature periods, the preparation of 3-carbonyl-2-H benzopyran is completed.

[0022] Preferably, the organic solvent is selected from any one of toluene, m-xylene, o-xylene, or mesitylene, or a mixture thereof; the inert protective gas is selected from nitrogen or argon with a purity of not less than 99.99%; in step S1, the 2-propynyloxybenzaldehyde substrate contains a sterically hindered substituent, which is selected from phenyl, isopropyl, or tert-butyl; in step S2, during the period after the end of the low-temperature period and before the start of the next high-temperature period, the reaction system is kept in a constant-temperature reaction state at a reference cyclization reaction temperature of 125°C to 127°C.

[0023] Preferably, in step S2, the heating rate of the reactant system from the reference cyclization reaction temperature to 143°C to 145°C is 3°C / min to 5°C / min; the cooling rate of the reactant system from 143°C to 145°C to the reference cyclization reaction temperature is 1.5°C / min to 2°C / min.

[0024] Preferably, in step S1, the stirring speed is 400 rpm; the mass percentage concentration of the acetylacetone molybdenum catalyst in the initial reaction solution is 1% to 3%.

[0025] Preferably, in step S2, during the low-temperature period, a cooling medium at a temperature of 20°C to 25°C is introduced into the jacket of the sealed vessel for heat exchange, and the cooling rate of the reaction material system is controlled to be no less than 1.5°C / min, so as to maintain the mass percentage of insoluble matter in the reaction material system at less than 0.1%.

[0026] Preferably, step S2 includes the following sub-steps: Step S21, within the overall reaction cycle of 12h, the intensity of the characteristic absorption peak of 3-carbonyl 2-H benzopyran in the reaction material system is measured using an online infrared spectrometer to obtain the real-time absorbance value; Step S22, the accumulation rate of the target product is calculated based on the real-time absorbance value, and when the accumulation rate of the target product decreases to a preset critical threshold, the isothermal holding time during the high-temperature period is extended to 20min.

[0027] Preferably, the process also includes a purification and separation step: after the overall reaction cycle of 12 hours, the temperature of the reaction material system is reduced, insoluble matter is removed by pressure filtration, organic solvent is removed by vacuum distillation to obtain crude product, crude product is packed into a silica gel chromatographic column, and separation is performed using a mixed eluent of petroleum ether and ethyl acetate in a volume ratio of 10:1, the eluent is collected and concentrated under reduced pressure to obtain pure 3-carbonyl-2-H benzopyran.

[0028] Preferably, in step S1, the absolute pressure inside the sealed vessel is controlled to be stable within the range of 0.20 MPa to 0.22 MPa.

[0029] Preferably, the method for preparing 3-carbonyl-2-H benzopyran is used for industrial production, and the amount of 2-propyneoxybenzaldehyde substrate input per batch is 10 kg to 50 kg; in step S2, under the cyclical alternation of high temperature period and low temperature period, the yield of the obtained 3-carbonyl-2-H benzopyran per batch is 85% to 95%, and the yield fluctuation between each production batch does not exceed 2%.

[0030] Preferably, a 3-carbonyl-2-H benzopyran is prepared by the method.

[0031] Example 1: In an industrial-scale production scenario of 3-carbonyl-2-H benzopyran, 50 kg of 2-propynyloxybenzaldehyde substrate was dissolved in m-xylene to prepare an initial reaction solution with a molar concentration of 0.3 mol / L in a closed reactor. The catalyst was added at a molar ratio of acetylacetone-molybdenum catalyst to substrate of 1:50. Under a nitrogen protective atmosphere, a rotary stirrer at a speed of 400 rpm was started, and the absolute pressure inside the reactor was controlled at 0.21 MPa. The baseline cyclization reaction temperature of the reaction material system was set to 126 °C.

[0032] During the 12-hour overall reaction cycle, the material system underwent a continuous, multi-stage temperature-controlled reaction. In the high-temperature phase, the reactor was heated to 144°C within 4 minutes and held at that temperature for 12 minutes. This high temperature induced thermodynamic fluctuations in the coordination bonds, displacing the chelate bond formed between the 3-position carbonyl group and the molybdenum center in the enriched product. In the low-temperature phase, the temperature was lowered to 126°C within 12 minutes and held at that temperature for 55 minutes. This alternating heating and cooling cycle broke the catalytic cycle deadlock caused by heterocyclic enrichment. Simultaneously, a 22°C cooling medium was introduced into the reactor jacket to control the cooling rate at 1.8°C / min, maintaining the percentage of insoluble matter in the system below 0.1% until the end of the overall reaction cycle. The physicochemical mechanism of suppressing insoluble formation by cooling at a rate of no less than 1.5℃ / min lies in kinetic crystallization inhibition. When the reactant system rapidly crosses the high-incidence temperature range of coordination precipitation between strongly polar carbonyl groups and molybdenum metal centers at a rate of 1.8℃ / min, the complex molecules in the liquid phase do not have time for large-scale alternating recombination and long-range ordered arrangement. This physically blocks the evolution path from surface chelation to the aggregation of overall insoluble crystal nuclei. This rapid heat dissipation method forcibly locks trace amounts of competitive chelates into isotropic metastable suspended droplets, uniformly dispersing them in m-xylene. This avoids the physical coverage of catalytic active sites by macroscopic precipitation. In a single batch of substrate... During scale-up operation of reactors with input volumes ranging from 10kg to 50kg, the material system employs a dual-loop temperature control system for switching between the baseline cyclization reaction temperature and the high-temperature period. This system consists of an external jacketed heat transfer oil circulation loop and an internal serpentine coil heat exchange loop. The external jacketed heat transfer oil circulation loop delivers heat transfer oil at a constant temperature of 130℃ to maintain basic thermal balance. The internal serpentine coil heat exchange loop integrates a high surface heat load electric heating wire and a cooling medium delivery pipeline. During the heating period, the electric heating wire outputs pulse heating power to drive the material system to heat up at a rate of 3℃ / min to 5℃ / min. During the low-temperature period, the system shuts off the electric heating wire and activates the medium regulating valve to supply cooling medium. Cold water at 20°C to 25°C was introduced into the pipeline. The heat exchange area of ​​the serpentine coil heat exchange loop inside the reactor was controlled within the range of 4.5 m⁻¹ to 6.0 m⁻¹. The temperature of the material system was reduced from 143°C to 145°C to 125°C to 127°C, the reference cyclization reaction temperature, within 10 minutes. After the reaction was completed, the system temperature was lowered, and insoluble matter was removed by pressure filtration. The crude product was obtained by removing m-xylene by vacuum distillation. The crude product was packed into a silica gel chromatographic column and separated using a mixed eluent of petroleum ether and ethyl acetate in a volume ratio of 10:1. The eluent was collected and concentrated under reduced pressure to obtain 3-carbonyl-2-H benzopyran with a purity of not less than 98%, and the yield per batch was 92%.

[0033] Example 2: The present invention was tested in laboratory and pilot-scale environments to verify the preparation performance, aiming to objectively evaluate the heterocyclic construction efficiency and product purity under different process parameters. The test platform consisted of a constant temperature oil bath with a temperature control accuracy of 0.5℃, a mechanical stirring device, and a distillation separation system. During the experiment, the ratio of the substrate 2-propynyloxybenzaldehyde to the acetylacetone molybdenum catalyst was kept different to verify the logical constraint of different catalyst loading on the product conversion rate. In order to simulate the material dispersion and mass transfer unevenness in industrial production, a low-speed stirring disturbance of 50 rpm was artificially introduced into the reaction system, thereby introducing a non-ideal mass transfer coefficient under controlled conditions to test the stability of the preparation method under complex working conditions.

[0034] Three key sample groups were selected for comparative verification: the sample group of this invention. The catalyst to substrate molar ratio was 1:25; control group A molar ratio of 1:15 was used; control sample group A molar ratio of 1:120 was used, and each sample group was reacted at a constant temperature of 140℃ for 10 h. Thermal oscillation cycle was performed, with the high temperature pulse segment set at 145℃ for 15 min and the low temperature stable segment set at 125℃ for 60 min.

[0035] The experimental data are shown in the table below: control group Data shows that when the catalyst ratio exceeds the critical ratio of 1:20, excess metal ions form irreversible, strongly coordinated chelates with the carbonyl groups of the product. These chelates appear as insoluble precipitates in the material system, making... It increased to 0.45% and passivated the catalytic center. (The English code used here is...) This refers to the percentage of insoluble matter in the reactant system due to irreversible coordination chelation. The specific determination procedure is as follows: At a specific point in the reaction, 10 ml of the reaction solution is extracted through a sampling valve at the bottom of the vessel. This sample is then rapidly filtered under pressure through a 0.22-micron PTFE membrane. The retained filter cake is washed three times with a corresponding cold organic solvent and placed in a vacuum oven. It is then continuously dried at 60°C for 20 minutes until constant weight. The mass of the solid residue is measured, and the percentage of this solid residue relative to the total mass of the original 10 ml sample solution is calculated. This yields quantified data on the insoluble matter content. A control sample group is also included. Data confirms that when the ratio is less than 1:100, the catalytic site density is insufficient to support the cyclization rate at 140°C, resulting in a slow crossing of the reaction energy barrier and a substrate residue rate as high as 18.5%, which reduces the final yield. Sample A of this invention, through a determined molar ratio, enables the catalytic center to form a highly active intermediate state through in-situ coordination exchange at a reaction temperature of 140°C, effectively balancing the conversion rate and the energy consumption of side reactions. This demonstrates that the range of 1:20 to 1:100 is the optimal operating window for this catalytic system.

[0036] Regarding the mechanism of the high-temperature pulse segment, online infrared monitoring data indicates that the product accumulation rate... The transient fluctuations are directly positively correlated with the pulse temperature, based on the measured real-time absorbance values. Accumulation rate The calculation logic is as follows ,in, Units are , Units are , Units are The experiment found that when the pulse temperature was set between 143℃ and 145℃, The temperature reaches the extreme region; if the temperature exceeds 145℃, the ligands of the acetylacetone molybdenum oxide catalyst undergo structural thermal dissociation, which leads to a decrease in the intensity of the characteristic absorption peak of the system and a linear decrease in yield. This data confirms that the high temperature boundary of 143℃ to 145℃ set in the thermal oscillation program is not only the kinetic trigger point for promoting product dissociation, but also the physical and thermodynamic boundary for ensuring the integrity of the catalyst structure. This experimental phenomenon is completely consistent with the mechanism prediction of this invention, which balances product removal and catalytic site regeneration by adjusting the temperature field.

[0037] Example 3: In industrial-scale preparation scenarios involving high-concentration substrates, this invention addresses the challenges of mass transfer resistance and localized overheating caused by high concentrations of the substrate 2-propynoxybenzaldehyde. It provides a preparation process with precisely controlled parameters, using a standardized calibration procedure to achieve the initial molar concentration of the reaction solution defined in this invention. The concentration was controlled within the range of 0.1 mol / L to 0.5 mol / L. To further optimize the reaction rate and heat transfer efficiency, based on physical experiments and kinetic characteristic analysis, the following calibration logic was established: Firstly, the key technical factors affecting the cyclization reaction conversion rate were identified as solvent viscosity and molecular collision frequency per unit volume. Secondly, this parameter setting needs to balance the engineering trade-off between high reaction yield and side reactions caused by local heat accumulation. At the upper limit of 0.5 mol / L, by increasing the stirring rate Increase the rpm to 500 rpm to forcibly eliminate the concentration gradient and ensure the homogeneity of the system; finally, based on the experimental calibration results, when When the concentration is set to 0.35 mol / L, the temperature field distribution inside the reactor exhibits optimal uniformity. This parameter serves as the preferred operating window for this embodiment.

[0038] The specific steps are as follows: In a sealed reactor purged with high-purity nitrogen, the 2-propyneoxybenzaldehyde substrate is added to o-xylene solvent and stirred continuously at room temperature until a homogeneous 0.35 mol / L initial reaction solution is formed. A solid catalyst is added at a molar ratio of acetylacetone-molybdenum catalyst to substrate of 1:60 to construct the reaction mixture system. Compressed nitrogen is injected into the reactor to maintain a constant internal absolute pressure of 0.25 MPa. This pressure is monitored by a pressure gauge sealed in the reactor, with the deviation controlled within 0.01 MPa to suppress concentration fluctuations caused by vaporization of the organic solvent during the high-temperature pulse phase. The mechanical stirring device is then started and the rotation speed is set. At 400 rpm, a multi-stage heating program was initiated, raising the temperature of the material system from room temperature to 140°C at a rate of 2.0°C / min through a circulating oil bath in the external jacket of the reactor, and maintaining this temperature for 10 hours. In actual operation, this 140°C maintenance state constituted the overall thermal equilibrium background of the reaction system. Under this thermal background, the reaction material system inside the sealed reactor was linked with the built-in auxiliary heating micro-element and cooling jacket, precisely alternating between the baseline cyclization reaction temperature of 125°C to 127°C and the high-temperature period of 143°C to 145°C. This ensured that the overall matrix did not undergo excessive thermal degradation, thereby completing a highly selective intramolecular cyclization reaction. Through this built-in surface temperature field modulation, the actual reaction waveform perfectly matched the temperature-variable cyclization logic, and the overall reaction time, after superimposing the subsequent cooling stage and material recovery operation, precisely met the 12-hour closed-loop control requirement. During this process, the load of the stirring paddle was monitored using an online torque sensor. When the detected torque value... When fluctuations within 5% occur during the reaction, the system automatically activates the feed pump to replenish a small amount of solvent, maintaining stable hydrodynamic performance. To isolate the insoluble precipitation of metal complexes and the unsteady-state interference caused by mechanical transmission vibration on the stirring load, the control system incorporates a high-pass filter algorithm with a cutoff frequency of 10 Hz when collecting torque data. This algorithm specifically extracts the viscosity-gradual torque component caused by solvent evaporation. After hydrodynamic calibration, when the sealed vessel experiences local micro-leakage leading to the evaporation of o-xylene solvent, the increase in system fluid viscosity directly reflects an increase in torque. A 5% increase in torque corresponds to a 2% decrease in the total solution volume. When this 5% deviation is confirmed as a trend lasting 30 seconds, the control system sends a single pulse command to the feed pump to quantitatively replenish the vessel with cold o-xylene equivalent to 1% of the initial solvent volume, thus achieving closed-loop repair of hydrodynamic performance.

[0039] To ensure the engineering feasibility of this process flow, anti-interference calibration measures are introduced during the execution of each step. Specifically, during the heating and temperature rise process, the system collects the pressure of the reactor in real time. With temperature Data, if The solvent saturated vapor pressure corresponding to this temperature If the difference is less than 0.05 MPa, the system automatically replenishes nitrogen through the gas pressure compensation unit to prevent concentration runaway caused by solvent boiling. This engineering detail is naturally integrated into the pressurization control steps of the reaction material system, ensuring the stability of the reaction within the preset concentration window. This process constructs a transparent process implementation link through clear inputs, namely substrate concentration and pressure, execution procedures, namely multi-segment temperature field and speed control, and a single output result, namely the target product.

[0040] In the reaction material system constructed in this invention, when m-xylene or o-xylene is selected as the organic solvent, its atmospheric boiling point is close to or equal to the reaction temperature during the high-temperature period, which can significantly reduce the saturated vapor pressure of the solvent itself during the high-temperature pulse stage. At this time, the absolute pressure of 0.15MPa to 0.30MPa maintained in the sealed vessel is mainly provided by the industrial inert gas supplied by the gas pressure compensation unit. Under engineering scale, this design can effectively suppress the risk of thermal boiling of highly volatile solvents, increase the system safety factor by more than 30%, and completely avoid engineering safety hazards caused by local overheating.

[0041] Example 4: In the production scenario of large-scale synthesis of 3-carbonyl-2-H benzopyran in multiple batches, the heat transfer lag caused by the volume effect of the industrial-grade reactor can lead to fluctuations in the internal temperature field of the material system. Without targeted adaptive parameter calibration, the catalytic center may exhibit activity deviations during the high-temperature pulse phase. This example provides an engineered preparation procedure that integrates thermodynamic response calibration and dynamic disturbance compensation to ensure process stability. Before the substrate is put into production, a standardized thermodynamic benchmark calibration procedure is performed: a predetermined mass of organic solvent is injected into the reactor, the stirring device is started, the system is heated to 140°C, and the external oil bath temperature is collected and recorded under this thermally stable state. Measured temperature of the material inside the vessel Based on the real-time equilibrium response data, a reference heat transfer mapping matrix is ​​established; based on this reference, an instantaneous compensation operator for quantifying heat transfer deviation is introduced. ,in, This is the oil bath temperature compensation amount. To set the target temperature, This is the proportional adjustment coefficient. The differential lead adjustment coefficient is... To control the material heating rate, this operator calculates the temperature change trend inside the reactor in real time and triggers the heat transfer regulation of the oil bath system in advance, controlling the local overheating temperature deviation caused by heat transfer lag within 0.5℃. For the 1000-liter standard industrial reactor used in this embodiment, the initial calibration value of the proportional control coefficient is set to 1.2, and the initial calibration value of the differential lead control coefficient is set to 4.5 minutes. These control parameters were determined based on the Ziegler-Nichols control algorithm after performing a step heating response test on the pure solvent system inside the reactor before feeding, and the intrinsic thermal inertia time constant of the reactor was determined to be 15 minutes. When the proportional control coefficient is lower than the engineering boundary value of 0.5, the heat compensation output cannot overcome the mass transfer thermal resistance of the large reactor, resulting in lag in temperature field regulation; while when the coefficient is higher than 2.5, excessive feedback gain will cause violent fluctuations in the oil bath temperature, leading to catalyst structure collapse.

[0042] After the substrate and catalyst are added and the formal reaction is initiated, a dynamic real-time anti-interference calibration procedure is performed: the monitoring system collects the absolute pressure inside the reactor in real time. With temperature Data, if With in The corresponding solvent saturated vapor pressure under the conditions If the absolute value of the difference is less than 0.05 MPa, the system automatically fine-tunes the pressure inside the vessel through the nitrogen pressure compensation unit to maintain the solvent in liquid phase equilibrium and prevent sudden concentration changes caused by local boiling. Furthermore, when the differential value of the product accumulation rate measured by the online spectrometer shows an abnormal deviation exceeding 15%, an adaptive thermal oscillation holding time adjustment is triggered. The logic is based on the following: When the pulse peak temperature deviates from the predetermined 145℃ by more than 1℃, the high-temperature pulse holding time is increased by 2 minutes to compensate for heat transfer loss. Through this dynamic procedure, the standard deviation of the yield of 3-carbonyl-2-H benzopyran between continuous production batches is maintained below 1.2%, verifying the technical effectiveness of this calibration logic in industrial scale-up.

[0043] Example 5: In a standardized pre-production scenario for the production of multiple varieties and small batches of high-purity heterocyclic compounds, to eliminate the unknown uncertainty of catalytic activity fluctuations caused by differences in the physicochemical properties between batches of newly added raw materials, this example provides a pre-production control procedure based on real-time benchmark calibration. Before each batch of substrate is added to the reactor, a mandatory benchmark property calibration step is performed: the purity parameters of the current batch of substrate are measured using a high-precision titrator and viscometer. With fluid viscosity The value standard is a 3σ confidence interval constructed based on a historical quality assessment database, and the system uses a correction function obtained from offline calibration. Automatically calculate the replenishment compensation factor for this batch. ,in, As a feed compensation factor, and These represent the preset standard purity and standard viscosity of the baseline experimental sample group, respectively. and These are the correction weighting coefficients for purity and viscosity on the reaction yield, respectively. These compensation factors are directly used to adjust the amount of catalyst added in step S1. The specific relationship is as follows: ,in, This refers to the actual amount of catalyst added. To ensure the catalyst quality required for the baseline process formulation, this closed-loop calibration logic establishes an adaptive input adjustment mechanism for intrinsic physicochemical fluctuations of the substrate. In this pre-control procedure, the preset standard purity is set to 98%, the standard viscosity is set to 0.6 mPa·s, and the correction weighting coefficients are determined through multiple linear regression analysis of historical quality evaluation data from 50 batches of industrial pilot tests. The correction weighting coefficient for purity on reaction yield is set to 0.15, and the correction weighting coefficient for viscosity on reaction yield is set to 0.08. The selection range for the purity correction weighting coefficient is limited to between 0.10 and 0.20. This range ensures that the added catalyst is just enough to neutralize the deactivation sites caused by trace impurities in the raw materials. If it is below 0.10, the yield decline caused by material fluctuations cannot be completely eliminated, and if it is above 0.20, excessive catalyst precipitation will occur.

[0044] To ensure process stability during large-scale deployment and continuous operation, an online thermodynamic calibration and early warning procedure is implemented to address potential operational anomalies such as blockage of the condensate reflux pipeline or decline in heat exchanger heat transfer efficiency during the reaction phase. Throughout the entire reaction cycle, the control system performs calibration every [time period missing]. Perform a self-check of the heat transfer status by monitoring the heating rate of the material inside the vessel in real time. Compared with the reference thermal balance curve under the same operating conditions deviation rate If detected If the process control threshold exceeds 10%, the system determines that the heat transfer performance is abnormal and automatically triggers a preset step for increasing the flow rate of the heat exchange medium. This stepping logic is described as follows: when... When the concentration is between 10% and 20%, the oil bath pump speed is increased by 15% and maintained for 20 minutes. If the failure rate exceeds 20%, the system triggers the safety shutdown interlock logic and pops up an alarm on the management terminal. The above-mentioned dynamic monitoring and graded response strategy based on objective measurement parameters ensures the continuous stability of the preparation method of the present invention under complex industrial operating conditions.

[0045] 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.

[0046] 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 method for preparing 3-carbonyl-2-H benzopyran, characterized in that, Includes the following steps: Step S1: In a sealed reactor purged with an inert protective gas, 2-propynyloxybenzaldehyde substrate is dissolved in an organic solvent to prepare an initial reaction solution with a molar concentration of 0.1 mol / L to 0.5 mol / L. Solid acetylacetone molybdenum catalyst is added to the initial reaction solution according to a molar ratio of 1:20 to 1:100 between the acetylacetone molybdenum catalyst and the 2-propynyloxybenzaldehyde substrate to construct the reaction material system. The absolute pressure inside the sealed reactor is maintained at 0.15 MPa to 0.30 MPa. The intramolecular cyclization reaction is initiated at a stirring speed of 300 rpm to 500 rpm and a reference cyclization reaction temperature of 125°C to 127°C. Step S2: Maintaining the rotational stirring speed and absolute pressure, control the reaction material system within the sealed reactor to undergo a continuous, multi-stage temperature-variable reaction within a 12-hour overall reaction cycle. The temperature boundary is alternating between high-temperature and low-temperature periods. During the high-temperature period, the sealed reactor is driven to rise from the baseline cyclization reaction temperature to 143°C to 145°C within 5 minutes and held at that temperature for 10 to 15 minutes. During the low-temperature period, the sealed reactor is driven to cool from 143°C to 145°C to the baseline cyclization reaction temperature of 125°C to 127°C within 10 minutes and held at that temperature for 50 to 60 minutes. By alternating between the high-temperature and low-temperature periods, the preparation of 3-carbonyl-2-H benzopyran is completed.

2. The method for preparing 3-carbonyl-2-H benzopyran according to claim 1, characterized in that, The organic solvent is selected from any one of toluene, m-xylene, o-xylene, or mesitylene, or a mixture thereof; the inert protective gas is selected from nitrogen or argon with a purity of not less than 99.99%; in step S1, the 2-propynyloxybenzaldehyde substrate contains a sterically hindered substituent, which is selected from phenyl, isopropyl, or tert-butyl; in step S2, during the period after the end of the low-temperature period and before the start of the next high-temperature period, the reaction system is kept in a constant-temperature reaction state at a reference cyclization reaction temperature of 125°C to 127°C.

3. The method for preparing 3-carbonyl-2-H benzopyran according to claim 1, characterized in that, In step S2, the heating rate of the reactant system from the reference cyclization reaction temperature to 143°C to 145°C is 3°C / min to 5°C / min; the cooling rate of the reactant system from 143°C to 145°C back to the reference cyclization reaction temperature is 1.5°C / min to 2°C / min.

4. The method for preparing 3-carbonyl-2-H benzopyran according to claim 1, characterized in that, In step S1, the stirring speed is 400 rpm; the mass percentage concentration of the acetylacetone molybdenum catalyst in the initial reaction solution is 1% to 3%.

5. The method for preparing 3-carbonyl-2-H benzopyran according to claim 1, characterized in that, In step S2, during the low-temperature period, a cooling medium at a temperature of 20°C to 25°C is introduced into the jacket of the sealed vessel for heat exchange, and the cooling rate of the reaction material system is controlled to be no less than 1.5°C / min, so as to maintain the mass percentage of insoluble matter in the reaction material system at less than 0.1%.

6. The method for preparing 3-carbonyl-2-H benzopyran according to claim 1, characterized in that, Step S2 includes the following sub-steps: Step S21, within the overall reaction cycle of 12h, the intensity of the characteristic absorption peak of 3-carbonyl 2-H benzopyran in the reaction material system is measured using an online infrared spectrometer to obtain the real-time absorbance value; Step S22, the accumulation rate of the target product is calculated based on the real-time absorbance value, and when the accumulation rate of the target product decreases to the preset critical threshold, the isothermal holding time during the high-temperature period is extended to 20min.

7. The method for preparing 3-carbonyl-2-H benzopyran according to claim 1, characterized in that, The process also includes purification and separation steps: after the overall reaction cycle of 12 hours, the temperature of the reaction material system is reduced, insoluble matter is removed by pressure filtration, organic solvent is removed by vacuum distillation to obtain crude product, crude product is packed into a silica gel column, and separation is performed using a mixed eluent of petroleum ether and ethyl acetate in a volume ratio of 10:

1. The eluent is collected and concentrated under reduced pressure to obtain pure 3-carbonyl-2-H benzopyran.

8. The method for preparing 3-carbonyl-2-H benzopyran according to claim 1, characterized in that, In step S1, the absolute pressure inside the sealed vessel is controlled to be stable within the range of 0.20 MPa to 0.22 MPa.

9. The method for preparing 3-carbonyl-2-H benzopyran according to claim 1, characterized in that, The method for preparing 3-carbonyl-2-H benzopyran is used for industrial production. The amount of 2-propyneoxybenzaldehyde substrate added in a single batch is 10 kg to 50 kg. In step S2, under the condition of alternating high temperature period and low temperature period, the yield of 3-carbonyl-2-H benzopyran obtained is 85% to 95%, and the yield fluctuation between each production batch does not exceed 2%.

10. A 3-carbonyl-2-H benzopyran, characterized in that, 3-Carbonyl-2-H benzopyran is prepared by the method described in claim 1.

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