Method for continuously preparing 18F-FDG by using same synthesis equipment

Abstract

A method for continuously preparing 18F-FDG by the same synthesis equipment relates to the technical field of radioactive chemical preparation processes, and adopts the technical scheme that the method comprises the following steps: S1, completing multiple synthesis in sequence, completing cleaning of a reaction tube between two adjacent synthesis until a plurality of purification pipelines complete one-time synthesis, and completing water removal in multiple stages in the synthesis process, reducing the temperature of the reaction tube to be lower than 75 DEG C in a temperature gradient manner, and increasing the air flow in a gradient manner; and S2, replacing the raw material bottle with a cleaning liquid bottle to complete the cleaning of the pipeline, then replacing a new reaction tube and a new raw material bottle, and returning to S1 to repeatedly execute. The dehydration step is improved, the dehydration effect is good, the internal temperature is lower than 75 DEG C, the subsequent nucleophilic reaction is very facilitated, the nucleophilic reaction temperature and the concentration temperature are also reduced, the overheating phenomenon is avoided, and the uncorrected synthesis rate of the product is increased; a cleaning step is added, so that the uncorrected synthesis rate of subsequent synthesis operation is obviously improved.

Description

Technical Field

[0001] The present invention relates to the technical field of radioactive chemical preparation technology, and in particular to a 18 A method for continuously preparing F-FDG using the same synthesis equipment. Background Art

[0002] Radiopharmaceuticals 18 F-FDG is a commonly used radioactive tracer. 18 Fluoride-fluorodeoxyglucose has become an important tool in clinical and scientific research due to its unique physiological characteristics and application in PET imaging. Patent application number CN202110621956.3 discloses a synthesis system for preparing the positron-emitting drug 18F-FDG. The reaction is fully airtight and controllable through various valves and pipeline connections, and the pipeline is cleaned and cooled using a blowing device. Multiple drug synthesis can be achieved continuously without opening the reaction tube and will not affect the quality of drug production.

[0003] In the original process, the QMA column 18 After the F ions are eluted into the reaction tube, water needs to be removed before the nucleophilic reaction. The water removal step is divided into two steps. First, heat the liquid to evaporate until the reaction tube is dry, and then add anhydrous acetonitrile and heat to 140°C to azeotropize until the reaction tube is dry. The steps are relatively cumbersome and time-consuming. The applicant found in further research that overheating is prone to occur in the later stage of water removal, which will have an adverse effect on product synthesis. In addition, multiple syntheses are carried out continuously, and each use will cause pollution to the pipeline, especially the reaction tube is more seriously polluted. The prior art simply washes the reaction tube with water and adds a small amount of acetonitrile to transfer and dry to complete the cleaning of the reaction tube, but it will still cause the uncorrected synthesis rate of the same batch of multiple synthesis products to gradually decrease. Using the original synthesis and cleaning process, the average uncorrected synthesis rate of the same batch of multiple synthesis is only about 48% at most. Summary of the invention

[0004] In view of the problems in the prior art that the water removal step is complicated, overheating occurs, and the pollution of the reaction tube seriously affects the uncorrected synthesis rate of the product, the present invention provides a 18 A method for continuously preparing F-FDG using the same synthesis equipment.

[0005] The present invention provides the following technical solution: 18 A method for continuously preparing F-FDG using the same synthesis equipment, wherein the synthesis equipment comprises a leaching pipeline, a precursor pipeline, an acetonitrile pipeline, a multi-channel purification pipeline, a reaction tube, and a plurality of raw material bottles, wherein the purification pipeline comprises a capture column and a purification column, and comprises the following steps:

[0006] S1, select one of the multiple purification pipelines in turn to complete 18The synthesis of F-FDG. Between two syntheses, the reaction tube is cleaned by using the reagents and pipelines of the synthesis equipment for synthesizing products until all multi-channel purification pipelines have completed one synthesis, and the synthesis operation of one batch ends.

[0007] After each synthesis ends, the selected purification pipeline and the only reaction tube have been contaminated. The applicant's further research finds that whether the reaction tube is cleaned or not and the degree of cleaning have a great impact on the synthesis rate of subsequent synthesis operations. Therefore, between two synthesis operations of the present invention, the reaction tube is cleaned by using the reagents and pipelines of the synthesis equipment for synthesizing products, and then the subsequent synthesis operation is carried out until all multi-channel purification pipelines have completed one synthesis, which significantly improves the uncorrected synthesis rate and reduces the radiation damage suffered by the operator compared with the traditional cleaning method.

[0008] S2. Replace the raw material bottle with a cleaning solution bottle, complete the cleaning of the rinsing pipeline, precursor pipeline, acetonitrile pipeline, and purification pipeline, then replace the new reaction tube and raw material bottle, and return to S1 to repeat the execution.

[0009] After the synthesis operation of one batch is completed, the pipeline continuously contacts reagents containing organic and inorganic substances, and the pollution situation is quite serious. If the synthesis continues, the uncorrected synthesis rate will continue to decrease. Therefore, it is necessary to replace the raw material bottle with a cleaning solution bottle, thoroughly clean the rinsing pipeline, precursor pipeline, acetonitrile pipeline, and purification pipeline, and then carry out another batch of synthesis operations.

[0010] Among them, 18 The synthesis steps of F-FDG are specifically as follows:

[0011] S111. Input F ions into the QMA column to complete capture, and then input the eluent into the QMA column to elute the F ion solution into the reaction tube. 18 F ions are input into the QMA column to complete capture, and then the eluent is input into the QMA column to elute the F ion solution into the reaction tube. 18 The F ion solution is eluted into the reaction tube.

[0012] S112. Input acetonitrile into the reaction tube for azeotropy, and complete water removal in multiple stages. In multiple stages, the temperature of the reaction tube decreases in a gradient manner until it is lower than 75 °C, and the gas flow rate input into the reaction tube increases in a gradient manner.

[0013] The so-called gradient decrease means that the temperature of the latter stage is not higher than that of the previous stage, and the so-called gradient increase means that the gas flow rate of the latter stage is not lower than that of the previous stage; in this way of gradient temperature reduction and gradient increase of gas flow rate, it can be ensured that after water removal ends, there is no excess liquid inside the reaction tube, the water removal effect is good, and the internal temperature is less than 75 °C, which is very conducive to the subsequent nucleophilic reaction. After optimizing the water removal step and combining with the existing synthesis equipment, the present invention can achieve an uncorrected synthesis efficiency of 65% ± 5%.

[0014] S113. After the reaction tube is cooled, heat the reaction tube again, add a precursor to the reaction tube to carry out a nucleophilic reaction to generate an intermediate.

[0015] S114. Continue to raise the temperature of the reaction tube to concentrate the liquid in the reaction tube.

[0016] S115. Select an unused path in the multi-channel purification column, add water to the reaction tube to transfer the liquid in the reaction tube to the capture column to capture the intermediate.

[0017] S116. Add a sodium hydroxide solution to the capture column to carry out solid-phase base hydrolysis to generate 18 F-FDG product.

[0018] S117. Add water to the capture column to bring the 18 F-FDG product into the purification column for purification and then discharge it into the product bottle.

[0019] Preferably, in S112, the water removal is completed in three stages. In the first stage, the temperature of the reaction tube is 90 °C and the gas flow rate is 120 mL / min. In the second stage, the temperature of the reaction tube is 75 °C and the gas flow rate is 140 mL / min. In the third stage, the temperature of the reaction tube is 74 °C and the gas flow rate is 140 mL / min.

[0020] Preferably, in S113, heat the reaction tube to 80 °C for the nucleophilic reaction.

[0021] Preferably, in S114, heat the reaction tube to 105 °C for concentration.

[0022] Preferably, the synthesis equipment has 4 purification pipelines.

[0023] Preferably, in S1, the specific steps for cleaning the reaction tube include:

[0024] S121. Input acetonitrile into the reaction tube and heat it to rinse the pollutants on the inner wall of the reaction tube, then add water and mix them before transferring to the waste liquid bottle;

[0025] S122. Input acetonitrile into the reaction tube again, and introduce nitrogen to make acetonitrile rinse the reaction tube and then transfer it to the waste liquid bottle;

[0026] S123. Add water to the reaction tube for rinsing and then transfer the waste liquid to the waste liquid bottle;

[0027] S124. Add acetonitrile to the reaction tube and heat it for evaporation, then introduce nitrogen to use acetonitrile gas to carry away the residual moisture in the reaction tube to complete the drying of the reaction tube. After the reaction tube is cooled, the cleaning is completed.

[0028] Preferably, in S2, the cleaning liquid in the cleaning liquid bottle includes a mixed liquid of acetonitrile and water, and anhydrous acetonitrile.

[0029] Preferably, in S2, the specific cleaning steps for the elution pipeline, precursor pipeline, and acetonitrile pipeline are as follows: Use the input pump to drain the cleaning solution along the pipeline into the reaction tube, and then use nitrogen to purge the pipeline to send the residual liquid into the reaction tube; after repeating the above steps multiple times, drain the waste liquid in the reaction tube.

[0030] Preferably, in S2, the specific cleaning steps for the purification pipeline are as follows: Select one of the multiple purification pipelines, and use the input pump to rinse the cleaning solution along the pipeline and drain it into the waste liquid bottle, and repeat multiple times.

[0031] Preferably, the raw material bottles include an eluent bottle, an acetonitrile bottle, a precursor bottle, a water bottle, and an alkali solution bottle. The eluent bottle contains a mixed solution of 0.58 ml of K2CO3 aqueous solution and 6.38 ml of cryptand acetonitrile solution. The acetonitrile bottle contains 50 ml of anhydrous acetonitrile. The precursor bottle contains 100 mg of trifluoromannose acetonitrile solution. The water bottle contains injection water. The alkali solution bottle contains 7 ml of NaOH solution; the cleaning solution bottles include a first cleaning solution bottle and a second cleaning solution bottle. The first cleaning solution bottle contains a mixed solution of 28 ml of anhydrous acetonitrile and water, where the volume ratio of anhydrous acetonitrile to water is 11:1. The second cleaning solution bottle contains 50 ml of anhydrous acetonitrile for cleaning.

[0032] The beneficial effects of the present invention are: The water removal step in 18 the synthesis of F-FDG is improved. 18 After the F ions are eluted into the reaction tube, acetonitrile is directly added for azeotropic water removal. The water removal process is divided into multiple stages, the temperature of the reaction tube decreases in a gradient manner, and the gas flow rate input into the reaction tube increases in a gradient manner. The water removal effect is good, and the internal temperature is less than 75°C, which is very beneficial for subsequent nucleophilic reactions. The nucleophilic reaction temperature and concentration temperature are also reduced, avoiding overheating phenomena, and effectively improving the uncorrected synthesis rate of the product; A step of cleaning the reaction tube is added between multiple synthesis operations in the same batch, significantly improving the uncorrected synthesis rate of subsequent synthesis operations, and using the reagents and pipelines of the synthesis equipment itself for cleaning will not increase the radiation damage received by the operator; Cleaning the pipeline and replacing a new reaction tube between multiple batches of synthesis also helps to eliminate the adverse effects of pipeline contamination and ensure the stability of the uncorrected synthesis rate of the product. Brief Description of the Drawings

[0033] Figure 1 It is a schematic diagram of the existing synthesis equipment.

[0034] Reference numerals: 1 - QMA column, 2 - recovery bottle, 3 - transfer bottle, 4 - recovery bottle, 5 - capture column, 6 - purification column, 7 - waste liquid bottle, 8 - product bottle, 9 - flow controller, 10 - nitrogen source, 11 - air source, A1 - eluent bottle, A2 - acetonitrile bottle, A3 - precursor bottle, A4 - water bottle, A5 - alkali solution bottle, C1 - reaction tube, L1 - first input pump, L2 - second input pump, L3 - third input pump, L4 - fourth input pump, L5 - fifth input pump, V1 - first multi - way valve, V2 - second multi - way valve, V3 - third multi - way valve, V4 - fourth multi - way valve, V5 - fifth multi - way valve, V6 - sixth multi - way valve, V7 - seventh multi - way valve, V8 - eighth multi - way valve, V9 - stop valve, V10 - first solenoid valve, V11 - second solenoid valve, V12 - third solenoid valve, V13 - fourth solenoid valve, V14 - fifth solenoid valve. Detailed implementation mode

[0035] The following further elaborates on the implementation mode of the present invention in combination with the attached drawings and reference numerals, enabling those skilled in the art to implement it after studying this specification. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0036] The present invention is prepared using existing synthesis equipment. The existing synthesis equipment includes an elution pipeline, an acetonitrile pipeline, a precursor pipeline, four purification pipelines, a reaction tube C1, multiple raw material bottles, a product bottle, and a positive pressure pipeline. Among them, the raw material bottles include an eluent bottle A1, an acetonitrile bottle A2, a precursor bottle A3, a water bottle A4, and an alkali solution bottle A5. The reaction tube C1 is provided with a heating device. The above components are connected through pipelines in accordance with Figure 1 the manner shown.

[0037] The elution pipeline includes an input pipe, a first multi - way valve V1, a first input pump L1 connected to the eluent bottle A1, and a QMA column 1 for capturing 18 fluoride ions. The input pipe is connected to an interface of the first multi - way valve V1 for inputting 18 fluoride ions; both ends of the QMA column 1 are connected to two interfaces of the first multi - way valve V1; the output pipe of the first input pump L1 is connected to an interface of the first multi - way valve V1; the first multi - way valve V1 also has two interfaces respectively connected to the recovery bottle 2 and the reaction tube C1.

[0038] The acetonitrile pipeline includes a second input pump L2 connected to the acetonitrile bottle A2, and the second input pump L2 is connected to a second multi-way valve V2; the precursor pipeline includes a third input pump L3 connected to the precursor bottle, and the third input pump L3 is connected to the second multi-way valve V2; the second multi-way valve V2 is connected to the reaction tube C1, and the acetonitrile pipeline and the precursor pipeline share the pipeline between the second multi-way valve V2 and the reaction tube C1. In addition, the water bottle A4 is connected to a fourth input pump L4, and the fourth input pump L4 is sequentially connected to the transfer bottle 3, the third multi-way valve V3, and the reaction tube C1. The reaction tube C1 is also sequentially connected to a stop valve V9 and a recovery bottle 4, and the stop valve V9 can be a pinch valve.

[0039] All four purification pipelines include a capture column 5 and a purification column 6. Among them, the capture column 5 can be a C18 column, and the purification column 6 can be an IC-H column, an alumina column, and a C18 column connected in sequence. Specifically, the reaction tube C1 is connected to a fourth multi-way valve V4 through a liquid outlet pipe, and the liquid outlet pipe extends to the bottom of the reaction tube C1 to facilitate the discharge of the liquid in the reaction tube C1. The third multi-way valve V3 is also connected to the fourth multi-way valve V4. The fourth multi-way valve V4 is connected to a fifth multi-way valve V5. Multiple interfaces of the fifth multi-way valve V5 are respectively connected to a capture column 5, and the outlets of multiple capture columns 5 are connected to different interfaces of a sixth multi-way valve V6. The sixth multi-way valve V6 is connected to a seventh multi-way valve V7. Two interfaces of the seventh multi-way valve V7 are respectively connected to a waste liquid bottle 7 and an eighth multi-way valve V8. Multiple interfaces of the eighth multi-way valve V8 are respectively connected to a purification column 6, and the outlet of the purification column 6 is connected to a product bottle 8. The lye bottle A5 is connected to a fifth input pump L5, and the fifth input pump L5 is connected to the fourth multi-way valve V4.

[0040] The positive pressure pipeline includes a nitrogen source 10 and an air source 11. The nitrogen source 10 is connected to the output pipe of the first input pump L1 and is provided with a first solenoid valve V10; the nitrogen source 10 is connected to the liquid outlet pipe and is provided with a second solenoid valve V11 and a flow controller 9; the nitrogen source 10 is connected to the second multi-way valve V2 and is provided with a third solenoid valve V12; the nitrogen source 10 is also connected to the transfer bottle 3 and is provided with a fourth solenoid valve V13. The air source 11 is connected to the air inlet of the heating device to generate convection near the reaction tube to accelerate cooling, and is provided with a fifth solenoid valve V14.

[0041] Example 1

[0042] The present invention provides a 18 Continuous preparation method of F-FDG in the same synthesis equipment, including the following steps:

[0043] S1, sequentially select one of the four purification pipelines to complete 18 The synthesis of F-FDG. The specific synthesis steps are as follows:

[0044] S111, generated by a cyclotron 18F ions enter the first multi-way valve V1 through the input pipe and then flow into the QMA column 1. 18 The F ions are captured by the QMA column; the first input pump L1 is started to pump the cryptand acetonitrile solution containing potassium carbonate in the eluent bottle A1 into the QMA column 1 for elution, and the 18 F ions are eluted into the reaction tube C1; then the first solenoid valve V10 and the stop valve V9 are opened, and the residual liquid in the pipeline is purged into the reaction tube C1 by positive-pressure nitrogen, and the stop valve V9 is used to exhaust and relieve pressure.

[0045] S112, the second input pump L2 pumps anhydrous acetonitrile in the acetonitrile bottle A2 into the reaction tube C1 through the second multi-way valve V2. Then the third solenoid valve V12 and the stop valve V9 are opened, and nitrogen is input into the reaction tube C1 through the second multi-way valve V2 to purge the residual liquid in the pipeline into the reaction tube C1. After purging, the reaction tube C1 is heated, and the second solenoid valve V11 is opened to blow nitrogen into the reaction tube C1 for direct water removal. In this embodiment, the water removal is divided into three stages. In the first stage, the reaction tube temperature is 90 °C and the gas flow rate is 120 mL / min. In the second stage, the reaction tube temperature is 75 °C and the gas flow rate is 140 mL / min. In the third stage, the reaction tube temperature is 74 °C and the gas flow rate is 140 mL / min. Each stage lasts for a certain period of time.

[0046] S113, the fifth solenoid valve V14, the second solenoid valve V11 and the stop valve V9 are opened to quickly cool the reaction tube C1. The third input pump L3 inputs the precursor in the precursor bottle A3 into the reaction tube C1 through the second multi-way valve V2 to purge the remaining liquid in the pipeline. The second solenoid valve V11 and the stop valve V9 are opened to input nitrogen into the reaction tube C1 to fully mix the liquid, and the reaction tube C1 is heated to 80 °C for nucleophilic reaction to generate an intermediate. The precursor can be a trifluoromannose acetonitrile solution.

[0047] S114, the reaction tube continues to heat up to 105 °C to concentrate the liquid in the reaction tube. The second solenoid valve V11 and the stop valve V9 are opened, and the waste gas is discharged by positive-pressure nitrogen.

[0048] S115, the reaction tube stops heating; the fourth input pump L4 inputs the injection water from the water bottle A4 into the transfer bottle 3, and then the fourth solenoid valve V13 is opened to press the injection water in the transfer bottle 3 into the reaction tube C1 by nitrogen through the third multi-way valve V3. Then, the liquid in the reaction tube C1 is input into the capture column 5 of the selected purification pipeline through the fourth multi-way valve V4 and the fifth multi-way valve V5 by positive-pressure nitrogen to capture the intermediate, and the waste liquid enters the waste liquid bottle 7 through the sixth multi-way valve V6 and the seventh multi-way valve V7.

[0049] Continue to input injection water into the reaction tube C1 to clean the reaction tube C1, and then input the liquid into the selected capture column 5. The waste liquid enters the waste liquid bottle 7. The fourth input pump L4 inputs the injection water into the transfer bottle 3. Open the fourth electromagnetic valve V13 to allow the injection water to enter the selected capture column 5 through the third, fourth, and fifth multi-way valves for cleaning, and the waste liquid enters the waste liquid bottle 7. This cleaning process can be repeated multiple times.

[0050] S116. The fifth input pump L5 inputs sodium hydroxide solution from the alkali solution bottle A5 into the selected capture column 5 for solid-phase alkali hydrolysis to generate 18 F-FDG product, and the waste liquid is discharged into the waste liquid bottle 7.

[0051] S117. Add injection water to the capture column multiple times to 18 elute the F-FDG product to the purification column for purification and then discharge it to the product bottle 8, and one synthesis is completed.

[0052] After the first synthesis is completed, clean the reaction tube. The specific cleaning steps are as follows:

[0053] S121. The second input pump L2 inputs anhydrous acetonitrile from the acetonitrile bottle A2 into the reaction tube C1, and uses nitrogen to purge the residual liquid in the pipeline into the reaction tube C1. Heat the reaction tube C1 to 85 °C to rinse the pollutants on the inner wall of the reaction tube and then cool it. The fourth input pump L4 extracts injection water into the transfer bottle 3, and then uses nitrogen to transfer the injection water in the transfer bottle 3 to the reaction tube C1 to mix with the anhydrous acetonitrile, and then transfer the liquid in the reaction tube C1 to the waste liquid bottle 7.

[0054] S122. The second input pump L2 inputs anhydrous acetonitrile from the acetonitrile bottle A2 into the reaction tube C1, and uses nitrogen to purge the residual liquid in the pipeline into the reaction tube C1. Then open the second electromagnetic valve V11 and the stop valve V9, introduce nitrogen into the reaction tube C1 to disturb the acetonitrile to rinse the reaction tube, and then open the fourth electromagnetic valve V13 and the third multi-way valve V3 to introduce nitrogen to send the liquid in the reaction tube C1 into the waste liquid bottle 7.

[0055] S123. The fourth input pump L4 extracts injection water into the transfer bottle 3, and then uses nitrogen to transfer the injection water in the transfer bottle 3 to the reaction tube C1 for rinsing, and then open the fourth electromagnetic valve V13 and the third multi-way valve V3 to introduce nitrogen to send the liquid in the reaction tube C1 into the waste liquid bottle 7.

[0056] S124. Heat the reaction tube; the second input pump L2 inputs anhydrous acetonitrile into the reaction tube C1, and the added amount is 1 / 3 of the acetonitrile added amount in S121, and uses nitrogen to purge the residual liquid in the pipeline into the reaction tube C1. Then, open the second electromagnetic valve V11 and the stop valve V9, input nitrogen into the reaction tube C1 to discharge the waste gas until the reaction tube is completely dry. Finally, cool the reaction tube. The cleaning of the reaction tube is completed.

[0057] After cleaning the reaction tube, select another unused purification line for the second synthesis. Repeat the process in the above manner until each of the four purification lines has completed one synthesis. Then, replace the eluent bottle A1 with the first cleaning solution bottle, containing a mixture of acetonitrile and water with no content; replace both the acetonitrile bottle A2 and the precursor bottle A3 with the second cleaning solution bottle, containing anhydrous acetonitrile. Prepare to clean the lines.

[0058] The specific cleaning steps for the eluent line are as follows: The first input pump L1 discharges the mixture of acetonitrile and water along the eluent passage into the reaction tube C1. Then, open the first solenoid valve V10 and the stop valve V9, and use positive-pressure nitrogen to purge the residual liquid in the line into the reaction tube C1; repeat the above steps multiple times. Then, open the fourth solenoid valve V13, and positive-pressure nitrogen enters the reaction tube C1 through the third multi-way valve V3 to transfer the liquid to the waste liquid bottle. The eluent line can be cleaned repeatedly several times.

[0059] The specific cleaning steps for the precursor line are as follows: The third input pump L3 sends anhydrous acetonitrile into the reaction tube C1 through the second multi-way valve V2. Then, open the third solenoid valve V12 and the stop valve V9, and use positive-pressure nitrogen to purge the residual liquid in the line into the reaction tube C1; repeat the above steps multiple times. Then, open the fourth solenoid valve V13, and positive-pressure nitrogen enters the reaction tube C1 through the third multi-way valve V3 to transfer the liquid to the waste liquid bottle. The precursor line can be cleaned repeatedly several times.

[0060] The specific cleaning steps for the acetonitrile line are as follows: The second input pump L2 sends anhydrous acetonitrile into the reaction tube C1 through the second multi-way valve V2. Then, open the third solenoid valve V12 and the stop valve V9, and use positive-pressure nitrogen to purge the residual liquid in the line into the reaction tube C1; after repeating the above steps multiple times, open the fourth solenoid valve V13, and positive-pressure nitrogen enters the reaction tube C1 through the third multi-way valve V3 to transfer the liquid to the waste liquid bottle.

[0061] The specific cleaning steps for the purification line are as follows: Select one of the four purification lines. The fourth input pump L4 extracts injection water into the transfer bottle 3. Then, open the fourth solenoid valve V13, and the injection water in the transfer bottle 3 flushes the selected capture column, and the waste liquid is discharged into the waste liquid bottle 7. The purification line can be cleaned repeatedly several times.

[0062] After cleaning, replace the cleaning solution bottle with the raw material bottle and replace the reaction tube with a new one, and return to S1 for another batch of synthesis.

[0063] During each gas or liquid transfer in the above synthesis and cleaning steps, only open the valves on the corresponding lines and close the other valves.

[0064] Comparative Example 1

[0065] Same as Example 1, but there is no reaction tube cleaning step between two synthesis operations in S1, and multiple syntheses are carried out continuously.

[0066] Comparative Example 2

[0067] Same as Example 1, but without step S2, and replace the reaction tube after the fourth synthesis in each batch.

[0068] Comparative Example 3

[0069] Adopt the synthesis method provided in a synthesis system for preparing the positron drug 18F-FDG with the application number CN202110621956.3, and clean the reaction tube in the original manner after each synthesis. There is no step S2, and only replace the reaction tube after the fourth synthesis in each batch.

[0070] Conduct experiments according to the methods provided in Example 1, Comparative Example 1, Comparative Example 2, and Comparative Example 3. Use the same raw materials and continuously complete the synthesis operations for 3 batches. In each batch, select one of the 4 purification pipelines in sequence for synthesis, calculate and count the uncorrected synthesis rate of each synthesis, as shown in Tables 1, 2, 3, and 4 respectively.

[0071] Table 1: Statistical Table of Continuous Multiple Syntheses in Example 1

[0072]

[0073]

[0074] Table 2: Statistical Table of Continuous Multiple Syntheses in Comparative Example 1

[0075]

[0076] Table 3: Statistical Table of Continuous Multiple Syntheses in Comparative Example 2

[0077]

[0078]

[0079] Table 4: Statistical Table of Continuous Multiple Syntheses in Comparative Example 3

[0080]

[0081] As can be seen from Table 1, by adopting the synthesis method provided by the present invention, the uncorrected synthesis rate of each synthesis operation in multiple batches is above 60%, and the average uncorrected synthesis rate of each batch is higher than 62%. While the highest uncorrected synthesis rate in the prior art in Table 4 is only 53.7%, and the highest average uncorrected synthesis rate in multiple batches is only about 48%. This shows that the improvement of the synthesis method and the increase in pipeline cleaning can effectively improve the uncorrected synthesis rate; there is no obvious decreasing trend in the uncorrected synthesis rate of multiple synthesis operations in the same batch in Example 1, nor is there an obvious decreasing trend in the average uncorrected synthesis rate of multiple batches.

[0082] As can be seen from Table 2, since the pipeline was cleaned and the reaction tube was replaced between two adjacent batches of Comparative Example 1, the first synthesis of the first, second, and third batches had the highest uncorrected synthesis rate, all above 60%, but the subsequent synthesis rate decreased sharply, and the influence of reaction tube contamination on the synthesis rate was particularly serious. Comparing the data in Tables 1 and 2, it shows that thoroughly cleaning the reaction tube according to the method provided by the present invention after each synthesis helps to improve the synthesis rate of the next synthesis and ensure the stability of the synthesis rate.

[0083] As can be seen from Table 3, since the reaction tube was cleaned after each synthesis in Comparative Example 2, there was no obvious trend of decrease in the uncorrected synthesis rate for multiple synthesis operations in the same batch; the average uncorrected synthesis rate of multiple batches gradually decreased. Comparing with Example 1, it shows that pipeline contamination has a greater impact and needs to be cleaned.

[0084] As can be seen from Table 4, since the synthesis process of Comparative Example 3 was imperfect, the overall synthesis rate was lower than that of Example 1, and also lower than the first synthesis of Comparative Example 1 and the first batch synthesis of Comparative Example 2; although the reaction tube was cleaned after each synthesis in Comparative Example 3, the uncorrected synthesis rate still decreased gradually for multiple syntheses in the same batch, and the decrease amplitude was relatively large. Comparing with Comparative Example 2, it shows that the cleaning effect of the original cleaning method is far less than that of the present invention; at the same time, because the pipeline was not cleaned after 4 syntheses in each batch, the influence of impurity accumulation still exists, and the average uncorrected synthesis rate of multiple batches is still decreasing.

[0085] The above are one or more embodiments of the present invention, and the description is relatively specific and detailed, but it should not be construed as a limitation to the scope of the patent of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several deformations and improvements can still be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention should be subject to the appended claims.

Claims

1. A 18 A method for continuously preparing F-FDG using the same synthesis equipment, wherein the synthesis equipment comprises a leaching pipeline, a precursor pipeline, an acetonitrile pipeline, a multi-channel purification pipeline, a reaction tube, and a plurality of raw material bottles, wherein the purification pipeline comprises a capture column and a purification column, and wherein: The following steps are involved: S1, select one of the multiple purification pipelines in turn to complete 18 F-FDG synthesis, between two syntheses, the reagents and pipelines used in the synthesis equipment for synthesizing the product are used to clean the reaction tubes until all the multiple purification pipelines have completed one synthesis; S2, replace the raw material bottle with a cleaning liquid bottle, complete the cleaning of the elution pipeline, precursor pipeline, acetonitrile pipeline, and purification pipeline, then replace the new reaction tube and raw material bottle, and return to S1 to repeat; in, 18 The specific steps of the synthesis of F-FDG are: S111, 18 The F ions are captured by the QMA column, and then the eluent is input into the QMA column to 18 F ion liquid is eluted into the reaction tube; S112, inputting acetonitrile into the reaction tube for azeotropy, and removing water in multiple stages, wherein the temperature of the reaction tube is gradually reduced until it is lower than 75° C., and the flow rate of the airflow input into the reaction tube is gradually increased; S113, after the reaction tube is cooled, the reaction tube is heated again, and a precursor is added to the reaction tube to perform a nucleophilic reaction to generate an intermediate; S114, the temperature of the reaction tube continues to rise to concentrate the liquid in the reaction tube; S115, selecting an unused channel in the multi-channel purification column, adding water to the reaction tube to transfer the liquid in the reaction tube to the capture column to capture the intermediate; S116, adding sodium hydroxide solution to the capture column for solid phase alkaline hydrolysis to generate 18 F-FDG products; S117, add water to the capture column, 18 The F-FDG product is carried into the purification column for purification and then discharged into the product bottle.

2. A method according to claim 1 18 The method for continuously preparing F-FDG using the same synthesis equipment is characterized in that: In S112, water removal is completed in three stages. In the first stage, the reaction tube temperature is 90°C and the air flow rate is 120 mL / min. In the second stage, the reaction tube temperature is 75°C and the air flow rate is 140 mL / min. In the third stage, the reaction tube temperature is 74°C and the air flow rate is 140 mL / min.

3. A method according to claim 1 18 The method for continuously preparing F-FDG using the same synthesis equipment is characterized in that: In S113, the reaction tube is heated to 80°C to perform a nucleophilic reaction.

4. A method according to claim 1 18 The method for continuously preparing F-FDG using the same synthesis equipment is characterized in that: In S114, the reaction tube is heated to 105°C for concentration.

5. A method according to claim 1 18 The method for continuously preparing F-FDG using the same synthesis equipment is characterized in that: The synthesis equipment has 4 purification lines.

6. A method according to claim 1 18 The method for continuously preparing F-FDG using the same synthesis equipment is characterized in that: In S1, the specific steps of cleaning the reaction tube include: S121, input acetonitrile into the reaction tube and heat it to rinse the pollutants on the inner wall of the reaction tube, then add water and mix it, and then transfer it to a waste liquid bottle; S122, input acetonitrile into the reaction tube again, introduce nitrogen gas to rinse the reaction tube with acetonitrile, and then transfer the mixture to a waste liquid bottle; S123, adding water to the reaction tube for rinsing and transferring the waste liquid to a waste liquid bottle; S124, acetonitrile is added to the reaction tube and heated to evaporate, and then nitrogen is introduced to use the acetonitrile gas to remove the residual water in the reaction tube to complete the drying of the reaction tube. The reaction tube is cooled and cleaned.

7. A method according to claim 1 18 The method for continuously preparing F-FDG using the same synthesis equipment is characterized in that: In S2, the cleaning solution in the cleaning solution bottle includes a mixture of acetonitrile and water and anhydrous acetonitrile.

8. A method according to claim 7 18 The method for continuously preparing F-FDG using the same synthesis equipment is characterized in that: In S2, the specific steps for cleaning the elution pipeline, the precursor pipeline, and the acetonitrile pipeline are: use the input pump to discharge the cleaning liquid along the pipeline into the reaction tube, and then use nitrogen to purge the pipeline to send the residual liquid into the reaction tube; repeat the above steps for multiple times and then discharge the waste liquid in the reaction tube.

9. A method according to claim 7 18 The method for continuously preparing F-FDG using the same synthesis equipment is characterized in that: In S2, the specific steps of cleaning the purification pipeline are: selecting one of the multiple purification pipelines, using an input pump to rinse the cleaning liquid along the pipeline and discharge it into a waste liquid bottle, and repeating the process multiple times.

10. A method according to claim 1 18 The method for continuously preparing F-FDG using the same synthesis equipment is characterized in that: The raw material bottle includes an eluent bottle, an acetonitrile bottle, a precursor bottle, a water bottle and an alkali solution bottle, the eluent bottle contains a mixed solution of 0.58 ml of K2CO3 aqueous solution and 6.38 ml of cryptand acetonitrile solution, the acetonitrile bottle contains 50 ml of anhydrous acetonitrile, the precursor bottle contains 100 mg of trifluoromannose acetonitrile solution, the water bottle contains water for injection, and the alkali solution bottle contains 7 ml of NaOH solution; the cleaning liquid bottle includes a first cleaning liquid bottle and a second cleaning liquid bottle, the first cleaning liquid bottle contains 28 ml of a mixed solution of anhydrous acetonitrile and water, wherein the volume ratio of anhydrous acetonitrile to water is 11:1, and the second cleaning liquid bottle contains 50 ml of anhydrous acetonitrile for cleaning.

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