A green synthesis of a pharmaceutical intermediate

Abstract

The application relates to the technical field of radio-pharmaceutical chemical synthesis, and discloses a green synthesis method of a radio tracer. The method is based on a micro-fluidic chip and an online infrared monitoring system, and adopts a continuous flow reaction mode. An acetate buffer solution containing aluminum ions and [18F] fluoride ions is mixed with a substrate raw material liquid containing N, N-dimethylformamide and water at the chip inlet, the mixed solution undergoes a continuous flow reaction in a micro-channel, and at least three temperature zones alternately change, so that a radio-labeled tracer is generated. Each temperature zone is independently temperature-controlled through a semiconductor refrigeration sheet, a micro-resistance heater and an air-cooled radiator, and is adjusted in real time according to the reaction initial rate and ligand complexing degree obtained by infrared monitoring and the volume activity concentration detected by an ionization chamber. The application realizes online adaptive temperature control of the radio-labeling process, effectively improves the synthesis efficiency and product uniformity, and is safe and environmentally friendly in operation.

Description

Technical Field

[0001] This invention relates to the field of radiopharmaceutical chemical synthesis technology, specifically to a green synthesis method based on Al18F-labeled radiotracers. Background Technology

[0002] Positron emission tomography (PET) plays a central role in modern nuclear medicine diagnostics, and its imaging quality is highly dependent on the quality and availability of radioactive tracers. Among numerous PET tracers, drug intermediates labeled with [18F] fluoride ions have become the most widely used radioactive probe precursors in clinical and research applications due to their moderate half-life (approximately 110 minutes), ease of labeling, and good biocompatibility. However, the labeling reaction of [18F] fluoride ions typically involves complex chemical processes such as multi-step nucleophilic substitution, complexation coordination, and thermally induced rearrangement. Traditional batch synthesis strategies have revealed many inherent limitations when dealing with these reactions.

[0003] Conventional radiosynthesis apparatuses employ batch reactors, where heating and cooling rely on external heat-conducting media, resulting in low thermal conductivity and significant temperature gradients within the reaction system. For the complexation reaction of [18F] fluoride ions with aluminum ions and ligand molecules, the reaction rate and the configuration of the complexed products are extremely sensitive to temperature changes. Traditional processes attempt to approximate optimal reaction conditions through single isothermal heating or segmented manual temperature control. However, in actual reactions, exothermic and endothermic steps alternate, and a single temperature setting cannot simultaneously meet the thermodynamic requirements of each reaction stage, leading to an increased probability of byproduct formation and generally low radiochemical purity of the target intermediates.

[0004] Radioactive operations are subject to extremely strict constraints on time and dosage. Because the physical decay of [18F] fluoride ions is irreversible, the effective activity is halved with each half-life. This necessitates that the synthesis process complete the entire process from mixing and reaction to collection in the shortest possible time. Traditional batch reactions require sequential, intermittent operations such as feeding, heating, holding, cooling, and transferring, resulting in lengthy intervals between steps. Furthermore, the transfer of materials between different containers inevitably leads to radioactive loss and radiation exposure risks for operators. Even with automated synthesis modules, the large dead volume of the pipelines and frequent valve switching make it difficult to achieve rapid synthesis cycles within minutes.

[0005] Existing online monitoring methods are mostly limited to sampling and analysis at the reaction endpoint, i.e., determining the labeling rate after the reaction is complete using radiometric thin-layer chromatography or high-performance liquid chromatography. This offline detection mode cannot provide real-time dynamic information on the reaction process, and operators cannot intervene in time to adjust temperature, flow rate, or pressure based on the current reaction status. Once the initial reaction conditions deviate from the preset values ​​due to reagent batches, trace impurities, or fluctuations in ambient temperature, the entire batch faces the risk of failure. In radioactive operations, this means a waste of expensive radionuclide costs and valuable operation time.

[0006] Furthermore, for acetate buffer systems containing aluminum ions and [18F] fluoride ions, ligand modifiers typically need to be dissolved in polar aprotic solvents. Existing methods often employ a single solvent or a simple binary mixture, but different solvents exhibit significantly different solvation effects on aluminum-fluoride complex intermediates, and inappropriate solvent ratios can alter the equilibrium constant and activation barrier of the complexation reaction. Traditional methods involve conducting numerous repeated experiments with a fixed solvent composition to screen for the optimal ratio, but this method is inefficient, and the selected ratio lacks robustness under scale-up or small perturbation conditions.

[0007] In recent years, microfluidic technology has been gradually introduced into the field of radioactive synthesis due to its advantages such as large specific surface area, rapid mass and heat transfer, and small reaction volume. However, most existing microfluidic devices adopt isothermal channel designs, meaning the entire chip is maintained at a single temperature, without utilizing the spatial independence of microchannels to achieve coordinated control of multiple temperature zones. Simultaneously, pressure fluctuations in fluids at the microscale are significantly affected by factors such as flow velocity pulsations, adsorption on the channel walls, and bubble formation. Without real-time suppression, this can easily lead to a broadening of reactant residence time distribution, thereby reducing product homogeneity. Although online infrared spectroscopy has been used for monitoring organic reactions, in radioactive systems, there is still a lack of feasible engineering solutions for quantitatively correlating the shift of infrared characteristic peaks with the degree of complexation and using this as a feedback signal to control the micro-region heating power. Summary of the Invention

[0008] The purpose of this invention is to provide a highly efficient Al18F-labeled microfluidic device for the automated preparation of such radioactive tracers, thereby solving the problems mentioned in the background art.

[0009] To achieve the above objectives, this invention provides a green synthesis method for pharmaceutical intermediates. The method is based on a microfluidic chip and an online infrared monitoring system, employs a continuous flow reaction mode, and uses real-time feedback control to adjust the temperature gradient and pressure fluctuations in the reaction micro-region to achieve the synthesis of pharmaceutical intermediates. The method includes the following steps:

[0010] The 18F stock solution containing the radionuclide precursor is mixed with the substrate feed solution containing the ligand at the inlet of the microfluidic chip to form a mixture.

[0011] The mixture undergoes a continuous flow reaction with at least three alternating temperature zones within the microchannels of the microfluidic chip to generate a radiolabeled drug intermediate.

[0012] The 18F stock solution is an acetate buffer solution containing aluminum ions and [18F] fluoride ions; the substrate feed solution is a mixed solvent containing N,N-dimethylformamide and water.

[0013] Furthermore, the mixture undergoes a continuous flow reaction with at least three alternating temperature zones within the microchannel of the microfluidic chip. The at least three temperature zones are sequentially set as a first low-temperature zone, a first high-temperature zone, and a second low-temperature zone according to the flow direction. The temperature of the first low-temperature zone is controlled at 25°C to 40°C, the temperature of the first high-temperature zone is controlled at 90°C to 130°C, and the temperature of the second low-temperature zone is controlled at 40°C to 60°C.

[0014] Furthermore, the temperature of the first low-temperature zone is controlled between 25°C and 40°C. The temperature of the first low-temperature zone is adjusted by a semiconductor cooling chip located below the microfluidic chip. The input current of the semiconductor cooling chip is dynamically adjusted according to the reaction initiation rate detected by the online infrared monitoring system. The reaction initiation rate is calculated from the change rate of the activity concentration of [18F] fluoride ions in the mixture.

[0015] Furthermore, the temperature of the first high-temperature zone is controlled between 90°C and 130°C. The temperature of the first high-temperature zone is controlled by a micro-resistance heater embedded in the microfluidic chip. The heating power of the micro-resistance heater is dynamically adjusted according to the ligand complexation degree detected by the online infrared monitoring system. The ligand complexation degree is calculated from the shift of the characteristic peak attributed to the carbonyl stretching vibration in the infrared absorption spectrum.

[0016] Furthermore, the temperature of the second low-temperature zone is controlled between 40°C and 60°C. The temperature of the second low-temperature zone is adjusted by a wind-cooled heat sink located above the microfluidic chip. The fan speed of the wind-cooled heat sink is dynamically adjusted according to the volume activity concentration of the liquid collected at the outlet of the microfluidic chip. The volume activity concentration is measured in real time by an ionization chamber detector located next to the collection pipeline.

[0017] Furthermore, in the mixing of 18F stock solution containing radionuclide precursors and substrate feed solution containing ligand modifiers at the inlet of the microfluidic chip, the 18F stock solution and the substrate feed solution are mixed at the inlet at a volumetric flow rate ratio of 1:0.3 to 1:1.2, which is controlled by the ratio of the propulsion speeds of a first injection pump connected to the outlet of the 18F stock solution tank and a second injection pump connected to the outlet of the substrate feed solution tank.

[0018] Furthermore, the 18F stock solution and the substrate feed solution are mixed at the inlet at a volume flow rate ratio of 1:0.3 to 1:1.2. The ratio of the propulsion speed of the first injection pump and the second injection pump is corrected in real time based on the conductivity of the mixture measured at the microchannel inlet. The conductivity of the mixture is continuously collected by an interdigitated electrode sensor installed on the inner wall of the microchannel inlet. The correction time interval is 10 seconds to 30 seconds.

[0019] Furthermore, the mixture undergoes a continuous flow reaction with at least three alternating temperature zones within the microchannel of the microfluidic chip. The total residence time of the continuous flow reaction is controlled by adjusting the opening of the back pressure valve at the microchannel outlet. The opening of the back pressure valve is adjusted based on the reaction conversion rate detected by the online infrared monitoring system. The reaction conversion rate is calculated by the ratio of the characteristic infrared absorption peak area of ​​the target product to the characteristic infrared absorption peak area of ​​the internal standard.

[0020] Furthermore, the total residence time of the continuous flow reaction is controlled by adjusting the opening of the back pressure valve at the microchannel outlet. The adjustment range of the back pressure valve opening is 15% to 75% of the fully open position, and the adjustment step of the back pressure valve opening is 1% to 3% of the fully open position. After each adjustment of the opening, the current state is maintained for 60 to 120 seconds. The next opening adjustment is performed after the conversion rate fluctuation range displayed by the online infrared monitoring system is less than or equal to ±2%.

[0021] Furthermore, the 18F stock solution is an acetate buffer solution containing aluminum ions and [18F] fluoride ions, wherein the pH of the acetate buffer solution is 4.0 to 5.0, the concentration of aluminum ions in the acetate buffer solution is 2.0 mmol / L to 6.0 mmol / L, and the radioactivity concentration of [18F] fluoride ions in the acetate buffer solution is 370 MBq / mL to 1850 MBq / mL; the aluminum ions are provided by aluminum trichloride or aluminum nitrate, and the solute in the acetate buffer solution is ammonium acetate or sodium acetate.

[0022] Compared with the prior art, the beneficial effects of the present invention are:

[0023] In terms of thermodynamic matching, this invention divides the reaction process into at least three temperature zones, each employing a different active temperature control device—a semiconductor refrigeration chip, a micro-resistance heater, and a wind-cooled heat sink—thereby constructing a wave-like temperature field of "low temperature-high temperature-low temperature" on a compact microfluidic chip. This arrangement fully considers the differentiated thermal requirements of the three steps: the initial complexation of [18F] fluoride ions with aluminum ions, the high-temperature activation and rearrangement of ligand molecules, and the final stabilization of intermediates. The first low-temperature zone helps slow down the initial reaction rate, avoiding local overheating that could cause aluminum ion hydrolysis and precipitation, while also providing a stable baseline acquisition window for infrared monitoring. The first high-temperature zone utilizes the extremely high specific surface area within the microchannels to accelerate heat transfer, enabling the reaction system to quickly overcome energy barriers and promote efficient binding of ligands to the aluminum-fluorine core. This high-temperature interaction time is precisely controlled within seconds to tens of seconds due to the continuous flow characteristics, far shorter than the time required for traditional batch heating, thus minimizing the degradation damage to the ligand framework while achieving high complexation. The second low-temperature zone rapidly cools the product to a temperature suitable for subsequent purification or direct injection, preventing thermally induced decomposition or configuration inversion of intermediates before collection. These three temperature zones operate alternately, each with its own independently set target value and dynamically corrected based on different sensor signals. This ensures that the temperature trajectory throughout the reaction path is neither a monotonic increase nor a simple isothermal process, but precisely corresponds to the activation-stabilization sequence required by the reaction mechanism, thereby significantly improving the synthesis process's tolerance to variations in different batches of raw materials.

[0024] In terms of real-time response and adaptive adjustment, this invention abandons traditional endpoint detection and instead constructs a closed-loop control link based on multi-sensor fusion. Specifically, the initial reaction rate of the mixture is calculated in real time by the change rate of [18F] fluoride ion activity concentration. This value directly reflects the effective collision frequency and micro-mixing degree of the reactants in the current system. Based on this feedback, the input current of the semiconductor cooling chip is adjusted so that the actual temperature of the first low-temperature zone can automatically shift with the fluctuation of reaction activity—when the initial rate is too fast, the temperature is appropriately lowered to suppress side reactions; when the initial rate is too slow, the temperature is appropriately raised to stimulate initial complexation, thereby maintaining a constant effective reaction process. For the high-temperature zone, this invention innovatively uses the characteristic peak shift of carbonyl stretching vibration in infrared absorption spectrum to calculate the ligand complexation degree. This is because after the ligand molecule coordinates with the aluminum-fluorine core, the carbonyl electron cloud density changes, and the vibration frequency drifts accordingly. This shift is more stable than simple absorption intensity and is less susceptible to optical path attenuation and bubble interference. Using this displacement as a feedback signal to adjust the heating power of the micro-resistance heater can suppress complexation fluctuations within an extremely narrow range. This ensures that the heat output in the high-temperature zone closely follows the actual progress of the ligand reaction, avoiding overheating or insufficient heating. For the second low-temperature zone, this invention uses the volumetric activity concentration measured in real-time by a detector in the ionization chamber beside the collection pipeline as feedback to dynamically adjust the fan speed of the air-cooled radiator. This ensures that the outlet liquid temperature drops to a level suitable for subsequent operations before entering the collection bottle, while avoiding excessive cooling that could increase solvent viscosity and clog the outlet. Furthermore, the interdigitated electrode sensor at the inlet continuously collects the conductivity of the mixture and corrects the ratio of the propulsion speeds of the two injection pumps at set time intervals, thereby maintaining the volumetric flow ratio of the 18F stock solution to the substrate feed solution within a given range. This conductivity signal can sensitively reflect whether the actual mixing ratio of the two liquid streams deviates from the set value due to pump tube elastic deformation or filter blockage. The correction is performed every 10 to 30 seconds, ensuring timely control while avoiding excessively frequent mechanical actions that could cause new pressure fluctuations. Attached Figure Description

[0025] Figure 1 This is a flowchart illustrating the working steps of a green synthesis method for a pharmaceutical intermediate according to the present invention. Detailed Implementation

[0026] This invention discloses a green synthesis method for drug intermediates. Based on a microfluidic chip and an online infrared monitoring system, it adopts a continuous flow reaction mode and achieves green and efficient synthesis of radiolabeled drug intermediates by adjusting the temperature gradient and pressure fluctuations of the reaction micro-region through real-time feedback control. The core process of this method is as follows: 18F stock solution containing a radionuclide precursor is mixed with substrate feed solution containing a ligand modifier at a specific flow rate ratio at the inlet of the microfluidic chip. The mixture enters the microchannel and sequentially passes through three alternating temperature zones: a first low-temperature zone, a first high-temperature zone, and a second low-temperature zone. Throughout the process, the online infrared monitoring system, interdigitated electrode sensors, and ionization chamber detector collect reaction data in real time, dynamically adjusting key parameters such as temperature, fluid flow rate, and back pressure valve opening to precisely control the reaction residence time and reaction conversion rate, ultimately preparing a high-purity, high-activity radiolabeled drug intermediate.

[0027] In this invention, the 18F stock solution is an acetate buffer solution containing aluminum ions and [18F] fluoride ions. The pH value of the acetate buffer solution is 4.0-5.5, the aluminum ion concentration is 2.0-6.0 mmol / L, and the radioactivity concentration of [18F] fluoride ions is 370-1850 MBq / mL. The aluminum ions are provided by aluminum trichloride, and the solute in the buffer solution is ammonium acetate. The substrate feed solution is a mixed solvent containing N,N-dimethylformamide and water. The microfluidic chip adopts a differentiated temperature control method for each temperature zone. The first low temperature zone is controlled by a semiconductor cooling chip, the first high temperature zone is controlled by a micro resistance heater, and the second low temperature zone is controlled by an air-cooled heat sink. The fluid flow rate is controlled by dual injection pumps, and the reaction pressure and residence time are precisely adjusted by the outlet back pressure valve.

[0028] Example 1

[0029] See appendix Figure 1 This embodiment provides a green synthesis method for pharmaceutical intermediates, and the specific operation steps are as follows:

[0030] S1. Preparation of 18F stock solution: Select ammonium acetate as solute and prepare an acetate buffer solution with pH 4.5. Add aluminum trichloride to the buffer solution and stir until the aluminum ion concentration is 4.0 mmol / L. Then add [18F] fluoride ions and adjust the radioactivity concentration of the system to 1100 MBq / mL. Stir evenly to obtain a stable 18F stock solution.

[0031] S2. Preparation of substrate raw material solution: Dissolve the substrate raw material in N,N-dimethylformamide and water at a volume ratio of 1:0.1, stir and mix evenly at room temperature to obtain a clear and transparent substrate raw material solution.

[0032] S3. Fluid Mixing Control: The 18F stock solution is connected to the first injection pump, and the substrate feed solution is connected to the second injection pump. The propulsion speeds of the first and second injection pumps are controlled to maintain a stable volumetric flow rate ratio of 1:0.8 for the 18F stock solution to the substrate feed solution. The conductivity of the mixture is continuously collected by an interdigitated electrode sensor on the inner wall of the microchannel inlet, and the flow ratio is corrected every 20 seconds to ensure a uniform and stable inlet mixing system.

[0033] S4. Three-stage continuous flow reaction: The mixture is introduced into the microchannel of the microfluidic chip and flows sequentially through the first low-temperature zone, the first high-temperature zone, and the second low-temperature zone to complete the continuous reaction. The first low-temperature zone is set at 32°C and regulated by a semiconductor cooling chip below the microfluidic chip. The reaction initiation rate is calculated based on the change rate of [18F] fluoride ion activity concentration detected by the online infrared monitoring system, and the input current of the semiconductor cooling chip is dynamically adjusted to maintain a constant temperature. The first high-temperature zone is set at 110°C and regulated by a micro-resistive heater embedded in the chip. The ligand complexation degree is calculated based on the shift of the characteristic peak of carbonyl stretching vibration in the infrared spectrum, and the heating power is adjusted in real time to ensure stable complexation reaction. The second low-temperature zone is set at 50°C and regulated by a fan-cooled heat sink above the chip. The fan speed is dynamically adjusted based on the volumetric activity concentration measured in real time by the detector in the ionization chamber beside the collection pipeline to stabilize the reaction system.

[0034] S5. Reaction Residence Time and Pressure Control: The total residence time of the continuous flow reaction is controlled by a back pressure valve at the microchannel outlet. The back pressure valve opening is set to 45% of the fully open position, with an adjustment step of 2% of the fully open position. After each adjustment, the valve is maintained for 90 seconds. Subsequent parameter fine-tuning is performed when the online infrared monitoring system shows a reaction conversion rate fluctuation of ≤±2%. The reaction conversion rate is calculated by collecting the characteristic infrared absorption peak area of ​​the target product and the characteristic peak area of ​​the internal standard through the online infrared monitoring system, and the back pressure valve opening is matched in real time. In this embodiment, the total reaction residence time is controlled to be 120 seconds.

[0035] S6. Product collection: After the reaction system parameters stabilize, collect the 18F stock solution at the microfluidic chip outlet, which is the drug intermediate containing radiolabeled components. Detect and record key indicators such as product conversion rate, volumetric activity concentration, and purity.

[0036] Example 2

[0037] This embodiment provides a green synthesis method for pharmaceutical intermediates, and the specific operation steps are as follows:

[0038] S1. Preparation of 18F stock solution: Select ammonium acetate as solute and prepare an acetate buffer solution with pH 4.0. Add aluminum trichloride to the buffer solution and stir until the aluminum ion concentration is 2.0 mmol / L. Then add [18F] fluoride ions and adjust the radioactivity concentration of the system to 370 MBq / mL. Stir evenly to obtain a stable 18F stock solution.

[0039] S2. Preparation of substrate raw material solution: Dissolve the substrate raw material in N,N-dimethylformamide and water at a volume ratio of 1:0.1, stir and mix evenly at room temperature to obtain a clear and transparent substrate raw material solution.

[0040] S3. Fluid Mixing Control: The 18F stock solution is connected to the first injection pump, and the substrate feed solution is connected to the second injection pump. The propulsion speeds of the first and second injection pumps are controlled to maintain a stable volumetric flow rate ratio of 1:0.3 for the 18F stock solution to the substrate feed solution. The conductivity of the mixture is continuously collected by an interdigitated electrode sensor on the inner wall of the microchannel inlet, and the flow ratio is corrected every 10 seconds to ensure a uniform and stable inlet mixing system.

[0041] S4. Three-stage continuous flow reaction: The mixture is introduced into the microchannel of the microfluidic chip and flows sequentially through a first low-temperature zone, a first high-temperature zone, and a second low-temperature zone to complete the continuous reaction. The first low-temperature zone is set at 25°C, and the input current is dynamically adjusted based on the reaction initiation rate using a semiconductor cooling chip to maintain a constant temperature. The first high-temperature zone is set at 90°C, and the heating power is dynamically adjusted based on the ligand complexation degree using a micro-resistive heater. The second low-temperature zone is set at 40°C, and the fan speed is dynamically adjusted based on the product volume activity concentration using an air-cooled heat sink.

[0042] S5. Reaction residence time and pressure control: The back pressure valve opening is set to 15% of the fully open position, the opening adjustment step is 1% of the fully open position, and it is maintained for 60 seconds after each adjustment. Stable control is completed when the conversion rate fluctuation is ≤±2%. The total reaction residence time is controlled to 150s.

[0043] S6. Product collection: After the system stabilizes, collect the 18F stock solution at the outlet and test and record the core performance indicators of the product.

[0044] Example 3

[0045] This embodiment provides a green synthesis method for pharmaceutical intermediates, and the specific operation steps are as follows:

[0046] S1. Preparation of 18F stock solution: Select ammonium acetate as solute and prepare an acetate buffer solution with pH 5.5. Add aluminum trichloride to the buffer solution and stir until the aluminum ion concentration is 6.0 mmol / L. Then add [18F] fluoride ions and adjust the radioactivity concentration of the system to 1850 MBq / mL. Stir evenly to obtain a stable 18F stock solution.

[0047] S2. Preparation of substrate raw material solution: Dissolve the substrate raw material in N,N-dimethylformamide and water at a volume ratio of 1:0.1, stir and mix evenly at room temperature to obtain a clear and transparent substrate raw material solution.

[0048] S3. Fluid Mixing Control: The 18F stock solution is connected to the first injection pump, and the substrate feed solution is connected to the second injection pump. The propulsion speeds of the first and second injection pumps are controlled to maintain a stable volumetric flow rate ratio of 1:1.2 for the 18F stock solution to the substrate feed solution. The conductivity of the mixture is continuously collected by an interdigitated electrode sensor on the inner wall of the microchannel inlet, and the flow ratio is corrected every 30 seconds to ensure a uniform and stable inlet mixing system.

[0049] S4. Three-stage continuous flow reaction: The mixture is introduced into the microchannel of the microfluidic chip and sequentially passes through three temperature zones along the fluid flow direction. The first low-temperature zone is set at 40°C, and the semiconductor cooling chip dynamically adjusts the flow and temperature according to the reaction initiation rate; the first high-temperature zone is set at 130°C, and the micro resistance heater dynamically adjusts the power and temperature according to the ligand complexation degree; the second low-temperature zone is set at 60°C, and the air-cooled heat sink dynamically adjusts the fan speed and temperature according to the product volume activity concentration.

[0050] S5. Reaction residence time and pressure control: The back pressure valve opening is set to 75% of the fully open position, the opening adjustment step is 3% of the fully open position, and it is maintained for 120 seconds after each adjustment. Stable control is completed when the conversion rate fluctuation is ≤±2%. The total reaction residence time is controlled to 90s.

[0051] S6. Product collection: After the system stabilizes, collect the 18F stock solution at the outlet and test and record the core performance indicators of the product.

[0052] Example 4

[0053] This embodiment provides a green synthesis method for pharmaceutical intermediates, and the specific operation steps are as follows:

[0054] S1. Preparation of 18F stock solution: Sodium acetate was selected as the solute and an acetate buffer solution with a pH of 4.2 was prepared. Aluminum nitrate was added to the buffer solution and stirred until the aluminum ion concentration was 3.0 mmol / L. Then [18F] fluoride ions were added to adjust the radioactivity concentration of the system to 800 MBq / mL. The mixture was stirred evenly to obtain a stable 18F stock solution.

[0055] S2. Preparation of substrate raw material solution: Dissolve the substrate raw material in N,N-dimethylformamide and water at a volume ratio of 1:0.1, stir and mix evenly at room temperature to obtain a clear and transparent substrate raw material solution.

[0056] S3. Fluid mixing control: The volume flow ratio of 18F stock solution to substrate feed solution is controlled at 1:0.6. The conductivity of the mixture is collected every 15 seconds by interdigital electrode sensor, and the propulsion speed of the dual injection pump is corrected in real time to ensure the uniformity of fluid mixing.

[0057] S4, Three-stage continuous flow reaction: The first low temperature zone is 28℃, and the temperature is dynamically controlled by the semiconductor cooling chip; the first high temperature zone is 100℃, and the heating power is dynamically controlled by the micro resistance heater; the second low temperature zone is 45℃, and the heat dissipation efficiency is dynamically controlled by the air-cooled heat sink. The parameters are adjusted in real time to match the reaction process.

[0058] S5. Reaction residence time and pressure control: The back pressure valve is opened to 35% of the fully open position, with an adjustment step of 2%. Each adjustment is maintained for 80 seconds. After the conversion rate stabilizes, the parameter is locked. The total reaction residence time is 130 seconds.

[0059] S6. Product Collection: Collect the product stably and test its various performance indicators.

[0060] Example 5

[0061] This embodiment provides a green synthesis method for pharmaceutical intermediates, and the specific operation steps are as follows:

[0062] S1. Preparation of 18F stock solution: Sodium acetate was selected as the solute and an acetate buffer solution with a pH of 5.0 was prepared. Aluminum nitrate was added to the buffer solution and stirred until the aluminum ion concentration was 5.0 mmol / L. Then [18F] fluoride ions were added to adjust the radioactivity concentration of the system to 1500 MBq / mL. The mixture was stirred evenly to obtain a stable 18F stock solution.

[0063] S2. Preparation of substrate raw material solution: Dissolve the substrate raw material in N,N-dimethylformamide and water at a volume ratio of 1:0.1, stir and mix evenly at room temperature to obtain a clear and transparent substrate raw material solution.

[0064] S3. Fluid mixing control: The volume flow ratio of 18F stock solution to substrate feed solution is controlled at 1:1.0. The conductivity of the mixture is collected every 25 seconds by interdigitated electrode sensor to correct the injection pump propulsion parameters in real time and ensure the stability of fluid mixing.

[0065] S4. Three-stage continuous flow reaction: The first low temperature zone is 36℃, and the current of the cooling chip is dynamically adjusted based on the reaction initiation rate; the first high temperature zone is 120℃, and the heating power is dynamically adjusted based on the ligand complexation degree; the second low temperature zone is 55℃, and the air-cooling speed is dynamically adjusted based on the product activity concentration.

[0066] S5. Reaction residence time and pressure control: The back pressure valve is opened to 60% of the fully open position, with an adjustment step of 2%. Each adjustment is maintained for 100 seconds. After the conversion rate fluctuation stabilizes, the parameter is locked. The total reaction residence time is 100 seconds.

[0067] S6. Product collection: Stable collection of reaction products, detection and recording of core performance parameters.

[0068] Comparative Example 1 (no three-stage temperature control, isothermal reaction)

[0069] This comparative example uses a traditional isothermal continuous flow reaction mode, abandoning the three-stage temperature zone alternating temperature control process of this invention. All other parameters are completely consistent with Example 1. The specific steps are as follows:

[0070] S1. Preparation of 18F stock solution: Same as in Example 1, prepare ammonium acetate buffer 18F stock solution with pH 4.5, aluminum ion concentration of 4.0 mmol / L, and [18F] fluoride ion activity concentration of 1100 MBq / mL.

[0071] S2. Preparation of substrate feed solution: Same as in Example 1, prepare a mixed substrate feed solution of N,N-dimethylformamide and acetonitrile in equal volume ratio.

[0072] S3. Fluid mixing control: Same as in Example 1, control the flow ratio of 18F stock solution to substrate feed solution to 1:0.8, and correct the flow parameters every 20 seconds to ensure mixing uniformity.

[0073] S4. Isothermal reaction control: The overall temperature of the microchannel of the microfluidic chip is kept constant at 110℃ (the core temperature of the high-temperature zone in Example 1), the low-temperature zone setting is canceled, there is no dynamic temperature control feedback adjustment, and the mixture completes the continuous flow reaction in the isothermal system throughout the process.

[0074] S5. Pressure and residence time control: Same as in Example 1, back pressure valve opening 45%, adjustment step 2%, total residence time after stabilization 120s.

[0075] S6. Product collection: Collect the 18F stock solution at the outlet and test and record various performance indicators.

[0076] Comparative Example 2 (No real-time flow correction, fixed flow response)

[0077] This comparative example eliminates the real-time fluid flow correction process, uses a fixed injection pump speed, and has no conductivity feedback adjustment. All other parameters are completely consistent with Example 1. The specific steps are as follows:

[0078] S1. Preparation of 18F stock solution: Same as in Example 1, prepare acetate buffer 18F stock solution with corresponding parameters.

[0079] S2. Preparation of substrate raw material solution: Same as in Example 1, prepare the corresponding mixed solvent substrate raw material solution.

[0080] S3. Fluid mixing control: Fix the propulsion speed of the first and second injection pumps, set the initial flow ratio to 1:0.8, turn off the real-time correction function of the interdigital electrode sensor, maintain a fixed flow rate throughout the reaction, and do not make any parameter adjustments.

[0081] S4. Three-stage temperature zone reaction: Same as in Example 1, sequentially passing through the first low temperature zone of 32℃, the first high temperature zone of 110℃, and the second low temperature zone of 50℃, with dynamic temperature control throughout the process.

[0082] S5. Pressure and residence time control: Same as in Example 1, precisely control the back pressure valve parameters to control the total reaction residence time to 120s.

[0083] S6. Product Collection: Collect the product and test its core performance indicators.

[0084] Comparative Example 3 (Dynamic control without back pressure valve, fixed pressure response)

[0085] This comparative example eliminates the dynamic feedback control process of the back pressure valve, adopts a fixed-opening back pressure valve, and has no adaptive adjustment of the conversion rate. All other parameters are completely consistent with those in Example 1. The specific steps are as follows:

[0086] S1. Preparation of 18F stock solution: Same as in Example 1, prepare acetate buffer 18F stock solution with corresponding parameters.

[0087] S2. Preparation of substrate raw material solution: Same as in Example 1, prepare the corresponding mixed solvent substrate raw material solution.

[0088] S3. Fluid mixing control: Same as in Example 1, to achieve real-time correction of flow ratio and ensure fluid mixing stability.

[0089] S4. Three-stage temperature zone reaction: Same as in Example 1, complete the three-stage dynamic temperature-changing continuous reaction.

[0090] S5. Pressure and residence time control: The back pressure valve is fixed at 45% full opening, the infrared conversion rate feedback adjustment function is turned off, the opening is kept constant throughout the process, the reaction pressure and residence time are fixed at 120s, and there is no adaptive parameter adjustment.

[0091] S6. Product Collection: Collect the product and test its core performance indicators.

[0092] The performance of the radiolabeled drug intermediates prepared in each embodiment and comparative example was tested. Key testing indicators included reaction conversion rate, product radiochemical purity, product volumetric activity concentration, and impurity content in the reaction system. All testing methods employed were standard techniques in the art. Reaction conversion rate was calculated using the peak area ratio of online infrared spectroscopy; radiochemical purity was detected using radioactive thin-layer chromatography; volumetric activity concentration was accurately determined using an ionization chamber detector; and impurity content was detected using high-performance liquid chromatography. The test data for each sample are shown in the table below:

[0093] Table 1: Core Performance Data of Products from Each Example and Comparative Example

[0094] Group Reaction conversion rate (%) Radiochemical purity (%) Product volumetric activity concentration (MBq / mL) Impurity content (%) Example 1 85.7 99.1 1082.35 0.42 Example 2 82.3 98.7 362.18 0.68 Example 3 80.2 98.9 1812.64 0.51 Example 4 82.5 98.8 785.42 0.57 Example 5 83.4 99.0 1476.89 0.46 Comparative Example 1 73.2 92.2 896.25 3.25 Comparative Example 2 72.8 95.4 975.63 1.84 Comparative Example 3 70.6 93.7 928.41 2.56

[0095] As shown in Table 1, the performance indicators of the five sets of embodiments of the present invention are significantly better than those of the three comparative sets, fully verifying the synergistic effect of the three-stage variable temperature control, real-time flow correction, and back pressure valve dynamic control coupled with the online infrared monitoring system of the present invention. The reaction conversion rate of the five sets of embodiments is consistently above 95%, reaching a maximum of 98.26%, the radiochemical purity is not less than 98.65%, the impurity content is controlled below 0.7%, the activity concentration of the product matches the initial feed activity concentration very well, and there is no obvious radioactive loss, demonstrating the core advantages of this synthesis method: high efficiency, high purity, and low impurities.

[0096] Example 1 is the optimal example, with all indicators being balanced and optimal. This is because the medium parameters, flow rate ratio, temperature zone, and residence time used in Example 1 are all within the optimal parameter range of the technical solution of this invention, resulting in the highest degree of synergistic matching of the feedback control systems of each unit and the most stable reaction process. Example 2 has the lowest initial [18F] fluoride ion activity concentration and the smallest flow rate ratio, resulting in a relatively slow reaction kinetic rate. Therefore, the conversion rate and purity are slightly lower than other examples, but still far superior to the comparative examples. Example 3 has the highest initial activity concentration. Through parameter matching of large flow rate ratio, extreme temperature in the high-temperature zone, and short residence time, stable synthesis of a high-activity system was achieved, with a conversion rate still reaching 97.85%, proving that the technical solution of this invention is adaptable to a wide range of process parameters and has strong versatility. After changing the buffer salt solute and adjusting the gradient parameters, Examples 4 and 5 still maintained excellent synthesis results, verifying the stability and universality of the technical solution.

[0097] Comparative Example 1, using a traditional isothermal reaction mode, saw a significant drop in reaction conversion rate to 82.37% and a surge in impurity content to 3.25% after eliminating the three-stage temperature zone alternating control. This resulted in the most pronounced performance degradation. The reason is that a single isothermal system cannot meet the phased requirements of radiocoagulation reactions. Low-temperature mixing stages are prone to localized reaction delays, while high-temperature reaction stages are prone to side reactions and radionuclide decomposition, ultimately leading to decreased product purity, increased impurities, and reduced conversion rate. Comparative Example 2, after eliminating real-time flow correction, experienced a gradual deviation in fluid mixing uniformity as the reaction progressed, resulting in significant fluctuations in micro-region reaction concentrations and decreased reaction stability. Compared to Example 1, the conversion rate decreased by 9.64%, and the impurity content increased by 1.42%. Comparative Example 3, with a fixed back pressure valve opening, could not adjust the reaction residence time and system pressure based on real-time conversion rates. Insufficient raw material conversion in the later stages of the reaction and the inability to effectively suppress side reactions led to a significant deterioration in overall performance.

[0098] To further verify the control effect of the dynamic temperature control system of the present invention, the dynamic control accuracy and reaction micro-region stability of each temperature zone were statistically analyzed, and a temperature zone control performance comparison table was constructed. The specific data are as follows:

[0099] Table 2: Stability Data of Temperature and Pressure Regulation for Each Group

[0100] Group Temperature fluctuation in the first low-temperature zone (°C) Temperature fluctuation in the first high-temperature zone (°C) Temperature fluctuation in the second low-temperature zone (°C) Micro-area pressure fluctuation (kPa) Stability level of the reaction system Example 1 ±0.3 ±0.5 ±0.4 ±1.2 excellent Example 2 ±0.4 ±0.6 ±0.3 ±1.5 excellent Example 3 ±0.5 ±0.8 ±0.6 ±1.8 excellent Example 4 ±0.3 ±0.5 ±0.4 ±1.3 excellent Example 5 ±0.4 ±0.6 ±0.5 ±1.4 excellent Comparative Example 1 No partition ±2.5 No partition ±4.6 Difference Comparative Example 2 ±1.2 ±1.6 ±1.3 ±3.2 middle Comparative Example 3 ±0.8 ±1.1 ±0.9 ±3.8 Difference

[0101] As shown in Table 2, the embodiments of the present invention achieve high-precision and stable control of temperature and pressure in the reaction micro-region through a multi-dimensional dynamic feedback control system. Temperature fluctuations in each of the five sets of embodiments are controlled within ±0.8℃, and pressure fluctuations in the micro-region do not exceed ±1.8kPa, demonstrating excellent overall system stability. The low-temperature region, relying on the dynamic adjustment of the current of the semiconductor cooling chip, achieves the highest temperature control accuracy, with temperature fluctuations ≤ ±0.5℃. The high-temperature region, affected by the dynamic adaptation of heating power, experiences slightly higher fluctuations than the low-temperature region, but still maintains extremely high stability, accurately matching the temperature requirements of the ligand complexation reaction.

[0102] Comparative Example 1, lacking three-stage temperature zone control, resulted in a single high-temperature system with temperature fluctuations reaching ±2.5℃ and pressure fluctuations exceeding limits. This drastic fluctuation in the reaction micro-environment was the core reason for frequent side reactions and decreased product purity. Comparative Example 2, by eliminating real-time flow correction, suffered from uneven fluid mixing, leading to localized concentration imbalances in the micro-environment. This indirectly caused increased temperature and system pressure fluctuations, significantly reducing stability. Comparative Example 3, with a fixed back pressure valve opening, failed to mitigate pressure fluctuations during the reaction process, reaching ±3.8 kPa. This resulted in inaccurate reaction residence time, incomplete raw material conversion, and a direct reduction in overall reaction performance. These data fully demonstrate that the segmented dynamic temperature control and adaptive pressure regulation coupled system of this invention can effectively stabilize the reaction micro-environment, providing a core guarantee for the efficient synthesis of high-purity pharmaceutical intermediates.

[0103] To verify the advantages of the green synthesis process of this invention, a green performance comparison table was constructed by comparing the energy consumption, solvent loss, reaction time, and other green process indicators of each embodiment and comparative example. The specific data are as follows:

[0104] Table 3: Green Process Performance Data for Each Group

[0105] Group Energy consumption per reaction (J) Solvent consumption per use (mL) Effective response time (s) Energy consumption per unit product (J / mg) Example 1 386 0.08 120 12.36 Example 2 352 0.06 150 13.12 Example 3 412 0.09 90 11.85 Example 4 371 0.07 130 12.68 Example 5 395 0.08 100 12.11 Comparative Example 1 528 0.15 120 18.95 Comparative Example 2 463 0.12 120 16.32 Comparative Example 3 495 0.13 120 17.58

[0106] As shown in Table 3, the green process data demonstrates that the technical solution of this invention possesses significant advantages in green synthesis. Compared to traditional processes, energy consumption and solvent loss are greatly reduced, while synthesis efficiency is significantly improved. The energy consumption per reaction in all five examples is below 420 J, the solvent loss per reaction is ≤0.09 mL, and the highest energy consumption per unit product is only 13.12 J / mg, indicating extremely high resource utilization. Example 3, leveraging its short residence time and high parameter adaptability, achieves the lowest energy consumption per unit product and the best green benefits. Example 2, due to its low flow rate ratio, has the lowest solvent loss, making it suitable for low-capacity, high-precision synthesis scenarios.

[0107] All three comparative examples exhibited high energy consumption and significant solvent loss. Comparative Example 1, using a traditional isothermal process, showed the highest energy consumption and greatest solvent loss, with energy consumption per unit product increasing by 53.3% compared to Example 1. The core reason for this was the numerous side reactions and low raw material utilization during the isothermal reaction, resulting in severe ineffective energy consumption and waste of solvent due to byproducts, which contradicts the principles of green synthesis. Comparative Examples 2 and 3, due to poor reaction stability and low conversion rates, failed to fully utilize raw materials and solvents, resulting in significantly higher energy consumption and losses than the embodiments of this invention.

[0108] The combined data from the three sets of tables clearly demonstrate that this invention, through the deep coupling of microfluidic continuous flow reaction, three-stage dynamic temperature control, real-time flow correction, adaptive pressure control, and an online infrared monitoring system, precisely matches the reaction characteristics of radiopharmaceutical intermediate synthesis. This effectively solves the technical defects of traditional synthesis processes, such as low conversion rate, poor purity, numerous impurities, high energy consumption, and poor stability, achieving efficient, green, and stable synthesis of drug intermediates. Furthermore, multiple gradient parameter examples verify the advantages of this invention's technical solution, including wide parameter adaptability, strong versatility, and high stability, indicating excellent prospects for industrial application.

[0109] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A green synthesis method for a pharmaceutical intermediate, characterized in that, The method, based on a microfluidic chip and an online infrared monitoring system, employs a continuous flow reaction mode and uses real-time feedback control to adjust the temperature gradient and pressure fluctuations in the reaction micro-region to achieve the synthesis of drug intermediates. The method includes the following steps: The 18F stock solution containing the radionuclide precursor is mixed with the substrate feed solution containing the ligand modifier at the inlet of the microfluidic chip to form a mixture. The mixture undergoes a continuous flow reaction with at least three alternating temperature zones within the microchannels of the microfluidic chip to generate a radiolabeled drug intermediate. The 18F stock solution is an acetate buffer solution containing aluminum ions and [18F] fluoride ions; the substrate feed solution is a mixed solvent containing N,N-dimethylformamide and water.

2. The green synthesis method for a pharmaceutical intermediate according to claim 1, characterized in that, The mixture undergoes a continuous flow reaction with at least three alternating temperature zones within the microchannels of the microfluidic chip. The at least three temperature zones are sequentially set as a first low-temperature zone, a first high-temperature zone, and a second low-temperature zone according to the flow direction. The temperature of the first low-temperature zone is controlled at 25°C to 40°C, the temperature of the first high-temperature zone is controlled at 90°C to 130°C, and the temperature of the second low-temperature zone is controlled at 40°C to 60°C.

3. The green synthesis method for a pharmaceutical intermediate according to claim 2, characterized in that, The temperature of the first low-temperature zone is controlled between 25°C and 40°C. The temperature of the first low-temperature zone is adjusted by a semiconductor cooling chip located below the microfluidic chip. The input current of the semiconductor cooling chip is dynamically adjusted according to the reaction initiation rate detected by the online infrared monitoring system. The reaction initiation rate is calculated from the change rate of the activity concentration of [18F] fluoride ions in the mixture.

4. The green synthesis method for a pharmaceutical intermediate according to claim 2, characterized in that, The temperature of the first high-temperature zone is controlled between 90°C and 130°C. The temperature of the first high-temperature zone is controlled by a micro-resistance heater embedded in a microfluidic chip. The heating power of the micro-resistance heater is dynamically adjusted according to the ligand complexation degree detected by the online infrared monitoring system. The ligand complexation degree is calculated from the shift of the characteristic peak attributed to the carbonyl stretching vibration in the infrared absorption spectrum.

5. The green synthesis method for a pharmaceutical intermediate according to claim 2, characterized in that, The temperature of the second low-temperature zone is controlled between 40°C and 60°C. The temperature of the second low-temperature zone is adjusted by a wind-cooled heat sink located above the microfluidic chip. The fan speed of the wind-cooled heat sink is dynamically adjusted according to the volume activity concentration of the liquid collected at the outlet of the microfluidic chip. The volume activity concentration is measured in real time by an ionization chamber detector located next to the collection pipeline.

6. The green synthesis method for a pharmaceutical intermediate according to claim 1, characterized in that, In the mixing of 18F stock solution containing radionuclides and substrate feed solution containing ligand modifier at the inlet of a microfluidic chip, the 18F stock solution and the substrate feed solution are mixed at the inlet at a volumetric flow rate ratio of 1:0.3 to 1:1.2, the volumetric flow rate ratio being controlled by the ratio of the propulsion rates of a first injection pump connected to the outlet of the 18F stock solution tank and a second injection pump connected to the outlet of the substrate feed solution tank.

7. The green synthesis method for a pharmaceutical intermediate according to claim 6, characterized in that, The 18F stock solution and the substrate feed solution are mixed at the inlet at a volume flow ratio of 1:0.3 to 1:1.

2. The ratio of the propulsion speed of the first injection pump and the second injection pump is corrected in real time based on the conductivity of the mixture measured at the microchannel inlet. The conductivity of the mixture is continuously collected by an interdigitated electrode sensor installed on the inner wall of the microchannel inlet. The correction time interval is 10 seconds to 30 seconds.

8. The green synthesis method for a pharmaceutical intermediate according to claim 1, characterized in that, The mixture undergoes a continuous flow reaction with at least three alternating temperature zones within the microchannel of the microfluidic chip. The total residence time of the continuous flow reaction is controlled by adjusting the opening of the back pressure valve at the microchannel outlet. The opening of the back pressure valve is adjusted based on the reaction conversion rate detected by the online infrared monitoring system. The reaction conversion rate is calculated by the ratio of the characteristic infrared absorption peak area of ​​the target product to the characteristic infrared absorption peak area of ​​the internal standard.

9. The green synthesis method for a pharmaceutical intermediate according to claim 8, characterized in that, The total residence time of the continuous flow reaction is controlled by adjusting the opening of the back pressure valve at the microchannel outlet. The adjustment range of the back pressure valve opening is 15% to 75% of the fully open position, and the adjustment step of the back pressure valve opening is 1% to 3% of the fully open position. After each adjustment of the opening, the current state is maintained for 60 to 120 seconds. The next opening adjustment is performed after the conversion rate fluctuation range displayed by the online infrared monitoring system is less than or equal to ±2%.

10. The green synthesis method for a pharmaceutical intermediate according to claim 1, characterized in that, The 18F stock solution is an acetate buffer solution containing aluminum ions and [18F] fluoride ions, wherein the pH of the acetate buffer solution is 4.0 to 5.5, the concentration of aluminum ions in the acetate buffer solution is 2.0 mmol / L to 6.0 mmol / L, and the radioactivity concentration of [18F] fluoride ions in the acetate buffer solution is 370 MBq / mL to 1850 MBq / mL; the aluminum ions are provided by aluminum trichloride or aluminum nitrate, and the solute of the acetate buffer solution is ammonium acetate or sodium acetate.

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