WO2023237092A1

WO2023237092A1 - Production device for liquid composition, preparation method therefor and use thereof

Info

Publication number: WO2023237092A1
Application number: PCT/CN2023/099328
Authority: WO
Inventors: 王跃; 张颖; 张爱丽; 徐新盛
Original assignee: 北京先通国际医药科技股份有限公司
Priority date: 2022-06-10
Filing date: 2023-06-09
Publication date: 2023-12-14
Also published as: CN114732918A; CN114732918B

Abstract

Provided are a device for producing a liquid composition of trans-2-[2-(5-[18F]fluorotridecyl)cyclopropyl]acetic acid (compound I), a preparation method therefor and use thereof. In particular, the production device comprises: a pretreatment module, configured to enrich 18F ions; a reaction module, configured to perform a reaction to obtain a crude product of the compound I; a purification module, configured to purify the crude product of the compound I to obtain a pure product of the compound I; and a prescribing module, configured to enrich the pure product of the compound I obtained through purification and prescribe the pure product into a liquid composition of the compound I. Each value is controlled by a microprocessor to achieve the automation of the device, and the prepared liquid composition of the compound I can be directly used for clinical application.

Description

Production equipment for liquid composition and preparation method and use thereof

Technical field

The present application relates to the technical field of radiopharmaceuticals, and specifically to a production equipment for a liquid composition and its preparation method and use.

Background technique

According to data from a research report by the Chinese Center for Disease Control and Prevention, the proportion and absolute number of coronary heart disease deaths in the Chinese population have increased significantly. The total number of coronary heart disease deaths in China in 2013 was 1.394 million, an increase of 90% from the number of coronary heart disease deaths in 1990. %. Currently, coronary heart disease has become the leading cause of death in six provinces, municipalities/provincial administrative regions in my country. As the aging process intensifies, the number of incidences and deaths from coronary heart disease in my country will continue to increase.

With the development of clinical cardiology, the focus has gradually shifted from the original diagnosis of coronary artery disease to risk stratification and prognosis judgment. It is generally believed that information such as myocardial ischemia, cardiac function and viable myocardium can provide the main basis for coronary artery disease risk stratification, prognosis judgment and treatment plan formulation. Therefore, identifying viable myocardium has important clinical significance, and it is a hot topic in clinical treatment and prediction of related events. Currently, radionuclide myocardial imaging remains the gold standard for in vivo assessment of viable myocardium.

Trans-2-[2-(5-[ ¹⁸ F]fluorotridecyl)cyclopropyl]acetic acid (trans-2-[2-(5-[ ¹⁸ F]fluorotridecyl)cyclopropyl)acetic acid; hereinafter referred to as "Compound I") is a radionuclide ^18F- labeled modified fatty acid (MFA), which is very similar in structure to naturally occurring free fatty acids (FFA) in the human body. It can be taken up by cardiomyocytes and used for positron emission computed tomography. Imaging (PET) to evaluate the viability of cardiomyocytes. The structure of compound I is shown below:

Compound I can be imaged 5 minutes after intravenous injection, and has high compliance and clinical benefit.

At present, non-fully automatic production methods cannot provide complete radiation protection, and manual labeling cannot prepare large batches (radioactive activity) of compound I liquid compositions (such as injections). A single preparation can only satisfy 1-2 people. Clinical use is limited.

Therefore, it is particularly important to develop an automated equipment for producing compound I liquid compositions (such as injections).

Contents of the invention

In order to solve the problems in the prior art, this application provides equipment for producing trans-2-[2-(5-[ ^18F ]fluorotridecyl)cyclopropyl]acetic acid liquid composition (such as injection) and Its preparation method and use. The technical solution for this application is as follows:

1. Equipment for producing compound I liquid composition, including:

Pretreatment module for enriching ¹⁸ F ions;

The reaction module is used to react the enriched ¹⁸ F ions with the precursor of compound I to generate compound I tert-butyl ester, and perform the de-tert-butyl esterification reaction of compound I tert-butyl ester to obtain compound I crude product;

Purification module, used to purify crude compound I to obtain pure compound I;

The prescription module enriches the purified Compound I pure product and formulates it into a Compound I liquid composition;

2. The equipment described in item 1, the preprocessing module includes:

A first valve, a second valve, a third valve, a fourth valve, a fifth valve, and a sixth valve, the first valve to the sixth valve respectively include at least a first interface, a second interface, and a third interface, And the first valve to the sixth valve can realize any two of the three interfaces to be connected or all three interfaces to be disconnected; the first interface of the first valve and the first positive pressure pipe The second interface of the first valve is connected to the first interface of the second valve, the second interface of the second valve is connected to the first interface of the third valve, and the third valve The second interface of the fourth valve is connected to the first interface of the fourth valve, the second interface of the fourth valve is connected to the first interface of the fifth valve, and the second interface of the fifth valve is connected to the first interface of the fourth valve. The first interface of the six valves is connected;

The first recovery container is respectively connected to the first negative pressure pipeline and the third interface of the first valve;

The first reagent container is connected to the third interface of the second valve;

A first syringe connected to the third interface of the third valve;

¹⁸ F ion enrichment chamber, connected to the third interface of the fourth valve and the third interface of the fifth valve between mouth;

a second syringe connected to the third interface of the sixth valve;

Preferably, the first valve, the second valve, the third valve, the fourth valve, the fifth valve and the sixth valve are all electric control valves.

3. For the equipment described in item 2, the preprocessing module also includes:

A first linear drive device capable of driving the piston of the first syringe to move within the empty barrel;

a second linear drive device capable of driving the piston of the second syringe to move within the empty barrel;

Preferably, the first linear drive device and the second linear drive device are selected from one of a pneumatic rod, a hydraulic rod, and a screw;

Further preferably, both the first linear drive device and the second linear drive device are screws, and the screws are driven by stepper motors.

4. For the equipment described in item 2, the positive and negative pressure pipelines and the liquid adding pipeline respectively pass through the piston of the second syringe and extend into the second syringe;

Preferably, a flow meter is provided on the liquid adding pipeline.

5. The equipment as described in item 2, the reaction module includes:

The seventh valve, the eighth valve, the ninth valve, the tenth valve, the eleventh valve, and the twelfth valve. The seventh valve to the twelfth valve respectively include at least a first interface, a second interface, and a third valve. Three interfaces, and the seventh valve to the twelfth valve can realize conduction of any two interfaces of the three interfaces or non-conduction of all three interfaces; the first interface of the seventh valve and all the The pretreatment module is connected, the second interface of the seventh valve is connected to the first interface of the eighth valve, the second interface of the eighth valve is connected to the first interface of the ninth valve, the The second interface of the ninth valve is connected to the first interface of the tenth valve, the second interface of the tenth valve is connected to the first interface of the eleventh valve, and the second interface of the eleventh valve is connected to the first interface of the eleventh valve. The interface is connected to the first interface of the twelfth valve, and the third interface of the twelfth valve is connected to the purification module;

The reaction vessel is respectively connected to the second negative pressure pipeline and the third interface of the seventh valve;

A temperature control component for heating and/or cooling the reaction vessel;

A third syringe connected to the third interface of the eighth valve;

a second reagent container connected to the third interface of the ninth valve;

A third reagent container is connected to the third interface of the tenth valve;

a fourth syringe connected to the third interface of the eleventh valve;

Preferably, the seventh valve, eighth valve, ninth valve, tenth valve, eleventh valve and twelfth valve are all electric control valves.

6. The equipment as described in item 5, the reaction module further includes:

a third linear drive device capable of driving the piston of the third syringe to move within the empty barrel;

A fourth linear drive device, the fourth linear drive device can drive the piston of the fourth syringe to move within the empty barrel;

Preferably, the third linear drive device and the fourth linear drive device are selected from one of a pneumatic rod, a hydraulic rod, and a screw;

Further preferably, both the third linear drive device and the fourth linear drive device are screws, and the screws are driven by stepper motors.

7. The equipment as described in item 5, the purification module includes:

A seventeenth valve, the seventeenth valve includes at least a first interface, a second interface, a third interface, a fourth interface, a fifth interface, and a sixth interface, wherein the seventeenth valve can operate in the first mode and second mode, the first mode is that the first interface is connected to the second interface, the third interface is connected to the fourth interface, and the fifth interface is connected to the sixth interface; the second mode is The second interface is connected to the third interface, the fourth interface is connected to the fifth interface, and the sixth interface is connected to the first interface; the fourth interface of the seventeenth valve is connected to the reaction module;

Chromatography column assembly, one end of the chromatography column assembly is connected to the second interface of the seventeenth valve;

A quantitative loop, both ends of which are respectively connected to the third interface of the seventeenth valve and the sixth interface of the seventeenth valve;

a liquid transfer pump, connected to the first interface of the seventeenth valve;

The second recovery container is connected to the fifth interface of the seventeenth valve;

The eighteenth valve includes at least a first interface, a second interface, and a third interface. The eighteenth valve can realize communication between the first interface and the second interface or the first interface and the third interface. conduction; the first interface of the eighteenth valve is connected to the other end of the chromatography column assembly, the second interface of the eighteenth valve is connected to the prescription module, and the first interface of the eighteenth valve is connected to the other end of the chromatography column assembly. Three interfaces are connected to the second recycling container;

Preferably, the seventeenth valve and the eighteenth valve are both electric control valves.

8. The device as described in item 7, the prescription module includes:

The thirteenth valve, the fourteenth valve, the fifteenth valve, the sixteenth valve, the nineteenth valve, the twentieth valve, the twenty-first valve, the twenty-second valve, the twenty-third valve, as described The thirteenth valve to the sixteenth valve and the nineteenth valve to the twenty-third valve respectively include at least a first interface, a second interface, and a third interface, and the thirteenth valve to the The sixteenth valve, the nineteenth valve to the twenty-third valve can realize conduction of any two interfaces among the three interfaces or non-conduction of all three interfaces; wherein, the thirteenth valve The first interface of the valve is connected to the second interface of the twelfth valve, the second interface of the thirteenth valve is connected to the first interface of the fourteenth valve, and the second interface of the fourteenth valve The interface is connected to the first interface of the fifteenth valve, the second interface of the fifteenth valve is connected to the first interface of the sixteenth valve, and the second interface of the sixteenth valve is connected to the The first interface of the nineteenth valve is connected to the first interface of the twentieth valve, the second interface of the twentieth valve is connected to the twenty-first The first interface of the valve is connected, the second interface of the twenty-first valve is connected with the first interface of the twenty-second valve, and the second interface of the twenty-second valve is connected with the twenty-third valve. The first interface of the valve is connected, the second interface of the twenty-third valve is connected to the fourth negative pressure pipeline, and the third interface of the twenty-third valve is connected to the purification module;

The fifth syringe is connected to the third interface of the thirteenth valve;

a fourth reagent container connected to the third interface of the fourteenth valve;

The fifth reagent container is connected to the third interface of the fifteenth valve;

The sixth reagent container is connected to the third interface of the sixteenth valve;

The first transfer container is connected to the third interface of the nineteenth valve;

The second transfer container is connected to the third interface and the third negative pressure pipeline of the twenty-second valve respectively;

Compound I enrichment warehouse, connected between the third interface of the twentieth valve and the third interface of the twenty-first valve;

The finished product collection container is connected with the second transfer container.

9. The device as described in item 8, the prescription module further includes:

A fifth linear drive device, the fifth linear drive device can drive the piston of the fifth syringe to move within the empty barrel;

Preferably, the fifth linear drive device is selected from one of a pneumatic rod, a hydraulic rod, and a screw;

Further preferably, the fifth linear driving device is a screw, and the screw is driven by a stepper motor.

10. A method for producing a liquid composition of Compound I, using the equipment described in any one of the above items 1 to 9, including:

Use the preprocessing module to enrich ¹⁸ F ions;

Use the reaction module to react the enriched ¹⁸ F ions with the precursor of compound I to generate compound I tert-butyl ester, and perform a de-tert-butyl esterification reaction on compound I tert-butyl ester to obtain compound I crude product;

Use the purification module to purify the crude compound I to obtain the pure compound I;

Use the prescription module to enrich the purified compound I pure product and formulate it into a compound I liquid composition.

11. Use of the equipment described in any one of items 1 to 9 in producing compound I liquid composition.

This application provides equipment for producing trans-2-[2-(5-[ ¹⁸ F]fluorotridecyl) cyclopropyl]acetic acid (referred to as "Compound I") liquid composition, which can prepare Compound I The crude product of Compound I was purified, enriched, and formulated to prepare a liquid composition of Compound I for direct clinical use. Moreover, each valve can be controlled by a microprocessor system (such as PLC, etc.) to realize equipment automation. At the same time, this application provides methods and uses for using the above equipment.

The above description is only an overview of the technical solutions of the present application. In order to make the technical means of the present application more clear and understandable to the extent that those skilled in the art can implement them according to the contents of the description, and in order to achieve the above and other purposes of the present application, The features and advantages can be more clearly understood and are illustrated below with specific embodiments of the present application.

Description of drawings

Figure 1: Schematic assembly diagram of the pretreatment module, reaction module, and prescription module of the production equipment;

Figure 2(a) ~ Figure 2(b): Schematic diagram of the purification module of the production equipment (the purification module performs purification by switching between the mode in Figure 2(a) and the mode in Figure 2(b));

Figure 3(a) ~ Figure 3(h): Schematic diagram of the three-way valve structure (Figure 3(a) is a schematic diagram of the three interfaces in the three-way valve being connected, Figure 3(b) ~ Figure 3(d) are the three Schematic diagram of the two interfaces in the one-way valve being connected; Figure 3(e) to Figure 3(h) are respectively schematic diagrams of the three interfaces of the three-way valve being disconnected);

Figure 4(a) ~ Figure 4(d): A schematic diagram of the three-way valve in Figure 3(a) ~ Figure 3(h) (Figure 4(a) is a schematic diagram corresponding to the three-way valve in Figure 3(b) ; Figure 4(b) is a simplified diagram corresponding to the three-way valve in Figure 3(c); Figure 4(c) is a simplified diagram corresponding to the three-way valve in Figure 3(d); Figure 4(d) is corresponding to Figure 3(e) )~Figure 3(h) Simplified diagram of three-way valve);

Figure 5(a) ~ Figure 5(b): Schematic diagram of the six-way valve structure (Figure 5(a) and Figure 5(b) are schematic diagrams of the six-way valve core in different working positions respectively);

Figure 6(a) ~ Figure 6(c): Schematic diagram of the working principle of the pretreatment module (the pretreatment module implements ¹⁸ F ion enrichment and sends it to the reaction module in the order of Figure 6(a) ~ Figure 6(c));

Figure 7(a) ~ Figure 7(g): Schematic diagram of the working principle of the reaction module (the reaction module is in accordance with Figures 7(a), 7(b), 7(c), 7(b), 7(d), 7(c ), 7(b), 7(e), 7(f), 7(g) are reacted in sequence);

Figure 8(a)~Figure 8(h): Schematic diagram of the working principle of the prescription module (the prescription module is in accordance with Figures 8(a), 8(b), 8(c), 8(d), 8(b), 8 (d), 8(e), 8(f), 8(g), 8(f), 8(h) are enriched and formulated sequentially);

Figure 9: Schematic diagram of total negative pressure pipeline connection.

Explanation of reference symbols:

1～23, the first valve to the twenty-third valve; V1, three-way valve body; V2, three-way valve core; V3, six-way valve body; V4, six-way valve core;

24. First recovery container; 25. First reagent container; 26. First syringe; 27. ¹⁸ F ion enrichment chamber; 28. Second syringe; 29. Positive pressure and negative pressure pipeline; 30. Liquid addition pipeline ;

31. Reaction container; 32. Third syringe; 33. Second reagent container; 34. Third reagent container; 35. Fourth syringe;

36. Chromatographic column assembly; 37. Quantitative loop; 38. Liquid transfer pump; 39. Second recovery container;

40. The fifth syringe; 41. The fourth reagent container; 42. The fifth reagent container; 43. The sixth reagent container; 44. The first transfer container; 45. The second transfer container; 46. Compound I enrichment warehouse; 47 , finished product collection container;

48. The third recycling container;

P0, the positive pressure pipeline of the positive pressure and negative pressure pipeline; P1, the first positive pressure pipeline;

N, total negative pressure pipeline; N0, negative pressure pipeline of positive pressure and negative pressure pipeline; N1, first negative pressure pipeline; N2, second negative pressure pipeline; N3, third negative pressure pipeline; N4 , the fourth negative pressure pipeline.

Detailed ways

The following embodiments of the present application are only used to illustrate specific implementation methods for implementing the present application, and these embodiments cannot be understood as limitations of the present application. Anything else that does not depart from the spirit of this application Changes, modifications, substitutions, combinations, and simplifications made based on the essence and principle are all regarded as equivalent substitutions and fall within the protection scope of this application.

This embodiment provides a method for producing trans-2-[2-(5-[ ^18F ]fluorotridecyl)cyclopropyl]acetic acid (hereinafter referred to as "Compound I") liquid composition (such as injection) equipment, including:

Pretreatment module for enriching ¹⁸ F ions;

Purification module, used to purify crude compound I to obtain pure compound I;

The prescription module enriches the purified Compound I pure product and formulates it into a Compound I liquid composition.

As shown in the figure below, compound I is prepared through a two-step reaction using compound I precursor and radioactive fluorine [ ^18F ] ions as starting materials. The first step is to nucleophilically substitute the methanesulfonyloxy group in the precursor of compound I with fluorine [ ¹⁸ F] to obtain the tert-butyl ester of compound I. In the second step, a dichloromethane solution containing trifluoroacetic acid is added without separation and purification to perform a de-tert-butyl esterification reaction to obtain a crude compound I. The synthetic route of crude compound I is shown in the figure below.

In the figure, K ₂₂₂ is 4,7,13,16,21,24-hexoxo-1,10-diazabicyclo[8.8.8]hexadecane, referred to as aminopolyether.

This embodiment provides a device for producing compound I liquid composition (such as injection), which first enriches ¹⁸ F ions through the pretreatment module; the enriched ¹⁸ F ions enter the reaction module, and then in the reaction module React with the precursor of Compound I to generate Compound I tert-butyl ester, and further perform a de-tert-butyl esterification reaction on Compound I tert-butyl ester to obtain Compound I crude product; Compound I crude product enters the purification module for purification, thereby obtaining Compound I pure product; Further, the pure product of Compound I enters the prescription module, is enriched, and is further formulated into a liquid composition of Compound I.

Through the technical solution of this embodiment, the crude compound I can be obtained, and the crude compound I is purified, enriched, and formulated for direct clinical use.

In addition, it should be noted that the "crude product" and "pure product" in this application refer to the products before and after purification respectively; the "formulation" in this example specifically refers to formulating the pure product of Compound I with auxiliary materials into Compound I Liquid composition.

In one embodiment, the preprocessing module shown in Figure 1, Figure 3(a)-Figure 3(h), Figure 4(a)-Figure 4(d), and Figure 6(a)-Figure 6(c) include:

The first valve 1 , the second valve 2 , the third valve 3 , the fourth valve 4 , the fifth valve 5 , and the sixth valve 6 respectively include at least a first interface, a second interface, and a second valve 6 . interface, the third interface, and the first valve 1 to the sixth valve 6 can realize conduction of any two interfaces of the three interfaces or non-conduction of all three interfaces; the first valve of the first valve 1 The interface is connected to the first positive pressure pipeline P1, the second interface of the first valve 1 is connected to the first interface of the second valve 2, and the second interface of the second valve 2 is connected to the third valve 3 is connected to the first interface, the second interface of the third valve 3 is connected to the first interface of the fourth valve 4, the second interface of the fourth valve 4 is connected to the first interface of the fifth valve 5 The interfaces are connected, and the second interface of the fifth valve 5 is connected to the first interface of the sixth valve 6;

The first recovery container 24 is respectively connected to the first negative pressure pipeline N1 and the third interface of the first valve 1;

The first reagent container 25 is connected to the third interface of the second valve 2. The first reagent container 25 is used to hold ¹⁸ F eluent (such as: acetonitrile + water + K ₂₂₂ + K ₂ CO ₃ , etc. );

The first syringe 26 is connected to the third interface of the third valve 3;

¹⁸ F ion enrichment chamber 27 is connected between the third interface of the fourth valve 4 and the third interface of the fifth valve 5, and the ¹⁸ F ion enrichment chamber 27 is filled with anion exchange resin;

The second syringe 28 is connected to the third interface of the sixth valve 6;

Preferably, the first valve 1, the second valve 2, the third valve 3, the fourth valve 4, the fifth valve 5 and the sixth valve 6 are all electric control valves.

First, as shown in Figure 3 (a) to Figure 3 (h), a three-way valve is provided, which can realize the functions of the first valve 1 to the sixth valve 6 mentioned above. Of course, it can also realize the seventh valve below. The functions of the valves 7 to 16 and the 19th to 23rd valves 19 to 23 will not be described again below.

As shown specifically in Figures 3(a) to 3(h), the three-way valve includes a three-way valve core V2 with a circular cross-section, and a three-way valve body V1 outside the three-way valve core V2. The one-way valve body V1 is provided with a first interface ① on the left side, a second interface ② on the right side, and a third interface ③ on the upper side. A T-shaped flow channel is provided in the three-way valve core V2. By rotating the valve core V2, the first interface ① and the third interface ③ can be connected (as shown in Figure 3(b)), the first interface ① can be connected with the second interface ② (as shown in Figure 3(c)), and the first interface ① can be connected with the second interface ② (as shown in Figure 3(c)). The second interface ② is connected to the third interface ③ (as shown in Figure 3(d)). Three None of the interfaces are connected (as shown in Figure 3(e) to Figure 3(h)). In addition, based on the above three-way valve structure, those skilled in the art know based on the existing technology how to control the three-way valve core V2 to rotate at a fixed angle relative to the three-way valve body V1 to realize the electric operation of the three-way valve ( Electromagnetic) control (for example, setting a stepper motor to control the rotation of the three-way valve spool V2). In addition, in order to simply describe the state of the three-way valve in the following, Figures 4(a) to 4(d) provide schematic diagrams of the three-way valve in Figures 3(a) to 3(h), where, Figure 4(a) is a simplified diagram corresponding to the three-way valve in Figure 3(b); Figure 4(b) is a simplified diagram corresponding to the three-way valve in Figure 3(c); Figure 4(c) is corresponding to Figure 3(d) A schematic diagram of a three-way valve; Figure 4(d) is a schematic diagram of the three-way valve corresponding to Figures 3(e) to 3(h).

In addition, the first negative pressure pipeline N1 specifically provides negative pressure through vacuuming. The negative pressure pipeline N0, the second negative pressure pipeline N2, and the third negative pressure pipeline N3 of the positive pressure and negative pressure pipelines below are The fourth negative pressure pipeline N4 can also provide negative pressure through vacuuming, which will not be described again below. Moreover, the negative pressure pipeline N0, the first negative pressure pipeline N1, the second negative pressure pipeline N2, the third negative pressure pipeline N3, and the fourth negative pressure pipeline N4 of the positive pressure and negative pressure pipeline can be connected individually. Vacuuming equipment, two or more of them can also be connected to one vacuuming equipment/pipeline. Specifically, as shown in FIG. 9 , the third recovery container 48 is connected to the total negative pressure pipeline N, and the other negative pressure pipelines (negative pressure pipeline N0 of the positive pressure and negative pressure pipeline, and the first negative pressure pipeline N1 , more than one of the second negative pressure pipeline N2, the third negative pressure pipeline N3, and the fourth negative pressure pipeline N4) is also connected to the third recovery container 48 (specifically, the left side of the third recovery container 48 in Figure 9 pipeline connection), so that more than one negative pressure pipeline can be driven to work through a vacuum device, and the third recovery container 48 can store the liquid flowing in from the negative pressure pipeline.

The first positive pressure pipeline P1 provides positive pressure by blowing out inert gases (such as nitrogen, argon, etc.). In addition, a filter membrane can be installed in the first positive pressure pipeline P1 to ensure the cleanliness of the inert gas entering the equipment. The positive pressure pipeline P0 of the positive pressure and negative pressure pipeline below can also provide positive pressure in this way, which will not be described again below.

Moreover, those skilled in the art know that generally, the negative pressure pipeline N0 of the positive pressure and negative pressure pipeline, the first negative pressure pipeline N1, the second negative pressure pipeline N2, the third negative pressure pipeline N3, A control valve (such as an electric control valve, specifically a solenoid valve) is provided on the fourth negative pressure pipeline N4, the positive pressure pipeline P0 of the positive pressure and negative pressure pipeline, and the first positive pressure pipeline P1 to control the opening and closing of the pipelines. , and/or set up a flow valve/flow meter to control the positive pressure/negative pressure, etc., which will not be described again in this article.

Those skilled in the art know that an empty cylinder and a piston within the empty cylinder are necessary components of a syringe. The piston can be a long strip structure, and the piston can move relative to the empty cylinder by pushing the part of the piston outside the empty cylinder; the piston can also be just a rubber head that has a sealing function and is located inside the empty cylinder. At this time, the piston is A core rod will be installed, and the core rod can be pushed to drive the relative movement of the piston and the empty cylinder. As shown in Figure 1, the structure of the syringe is composed of a hollow cylinder, a piston and a core rod.

The specific process of enriching ¹⁸ F ions by the pretreatment module can be shown in Figure 6(a) to Figure 6(c).

Initially, the states of the first to sixth valves 1 to 6 are as shown in Figure 6(a). At this time, the first negative pressure pipeline N1 is evacuated. Then the second syringe 28 discharges the oxygen [ ¹⁸ O] eighteen water containing ¹⁸ F ions. When the oxygen [ ¹⁸ O] eighteen water containing ¹⁸ F ions flows through the ¹⁸ F ion enrichment chamber 27, ^{the 18} F ions in ¹⁸ F Enrichment is carried out in the ion enrichment chamber 27, and the remaining liquid flows into the first recovery container 24;

After that, the states of the second valve 2 to the third valve 3 are as shown in Figure 6(b), and the first syringe 26 draws in the ¹⁸ F eluent in the first reagent container 25;

Finally, the states of the third to sixth valves 3 to 6 are as shown in Figure 6(c). The first syringe 26 pushes out the ^18F eluent, and the ^18F eluent will be enriched in the ^18F ion enrichment chamber. The ¹⁸ F ions in the reaction module are fed into the reaction module.

This embodiment provides a specific pretreatment module that can simply and conveniently enrich ¹⁸ F ions and send the enriched ¹⁸ F ions to the subsequent reaction module. Especially when each valve, positive pressure pipeline, negative pressure pipeline, and injector are automatically controlled, automatic processing of ¹⁸ F ion enrichment and delivery to the reaction module can be realized.

In one embodiment, the preprocessing module also includes:

A first linear drive device (not shown in the drawings), the first linear drive device can drive the piston of the first syringe 26 to move within the empty barrel;

a second linear drive device (not shown in the drawings), the second linear drive device can drive the piston of the second syringe 28 to move within the empty barrel;

In this embodiment, the first linear drive device and the second linear drive device are provided to control the first syringe 26 and the second syringe 28 .

When using a pneumatic rod or a hydraulic rod in conjunction with a controller such as a PLC, it is convenient to realize automatic control of the first syringe 26 and the second syringe 28.

Using the screw, the stroke of the pistons in the first syringe 26 and the second syringe 28 can be accurately controlled. Especially when the screw is driven by a stepper motor, it is convenient to cooperate with a controller such as a PLC to realize the stroke of the first syringe 26 and the second syringe 28. Automatic and precise control. The screw driven by the stepper motor can be assembled by yourself, or you can directly purchase the finished electric actuator (a screw system).

In one embodiment, as shown in Figure 1, the positive and negative pressure pipelines 29 and the liquid adding pipeline 30 respectively pass through the piston of the second syringe 28 and extend into the closed space formed by the piston and the empty cylinder of the second syringe 28. Inside;

Preferably, the liquid adding pipeline 30 is provided with a flow meter, so that the amount of liquid added can be controlled, and/or the liquid adding pipeline 30 is provided with a control valve (such as an electric control valve, specifically a solenoid valve), The control valve can control the opening and closing of the pipeline, thereby controlling whether to add liquid.

In this application, the positive pressure and negative pressure pipeline 29 is a positive pressure pipeline P0 of the positive pressure and negative pressure pipeline, and a negative pressure pipeline N0 of the positive pressure and negative pressure pipeline connected to one pipeline. Pass through the piston (as shown in Figure 1); or, the positive pressure pipeline P0 of the positive pressure and negative pressure pipeline, and the negative pressure pipeline N0 of the positive pressure and negative pressure pipeline pass through the piston respectively.

Then, the present application provides a solution for adding liquid (oxygen [ ¹⁸ O]octahydrate containing ¹⁸ F ions) to the second syringe 28. Specifically, the liquid is added through the liquid adding line. At the same time, in order to prevent the second The pressure in the syringe 28 is too high, and the negative pressure pipeline N0 of the positive pressure and negative pressure pipeline is evacuated to achieve liquid addition. After adding liquid, the liquid in the second syringe 28 can be discharged for subsequent reactions by pushing the piston downward/passing the positive pressure pipeline P0 of the positive pressure and negative pressure pipeline.

This embodiment provides a solution for adding liquid to the second syringe 28 . This can provide more oxygen [ ^18O ]octahydrate containing ^18F ions for ^18F ion enrichment, and provide more ^18F ions continuously for subsequent reactions. And it can provide positive pressure through the positive pressure pipeline P0 of the positive pressure and negative pressure pipeline to add liquid to the subsequent process, or push the piston to more accurately add liquid to the subsequent process.

In one embodiment, as shown in Figure 1, the reaction module includes:

The seventh valve 7, the eighth valve 8, the ninth valve 9, the tenth valve 10, the eleventh valve 11, and the twelfth valve 12. The seventh valve 7 to the twelfth valve 12 respectively include at least a third valve. An interface, a second interface, and a third interface, and the seventh valve 7 to the twelfth valve 12 can realize any of the three interfaces. Two interfaces are connected or all three interfaces are not connected; the first interface of the seventh valve 7 is connected to the pretreatment module (the second interface of the sixth valve 6), and the seventh valve The second interface of 7 is connected to the first interface of the eighth valve 8, the second interface of the eighth valve 8 is connected to the first interface of the ninth valve 9, and the second interface of the ninth valve 9 The interface is connected to the first interface of the tenth valve 10, the second interface of the tenth valve 10 is connected to the first interface of the eleventh valve 11, and the second interface of the eleventh valve 11 is connected to The first interface of the twelfth valve 12 is connected, and the third interface of the twelfth valve 12 is connected to the purification module (the fourth interface of the seventeenth valve 17);

The reaction vessel 31 is connected to the second negative pressure pipeline N2 and the third interface of the seventh valve 7 respectively. Preferably, the second negative pressure pipeline N2, the reaction vessel 31 and the seventh valve 7 are connected to each other. A control valve (such as an electric control valve, specifically an electromagnetic valve) is provided on the pipeline between the third interfaces of 7

valve), the control valve can control the opening and closing of the pipeline, thereby ensuring that the reaction proceeds in the reaction vessel 31;

A temperature control component (not shown in the drawings) is used to heat and/or cool the reaction vessel. The heating can be done by electric heating, and the cooling can be done by air cooling. Specifically, it can be done with reference to the existing technology. I won’t go into details here;

The third syringe 32 is connected to the third interface of the eighth valve 8, and the third syringe 32 is filled with the compound I precursor solution;

The second reagent container 33 is connected to the third interface of the ninth valve 9. The second reagent container 33 is used to hold TFA/DCM (trifluoroacetic acid/dichloromethane) solution;

The third reagent container 34 is connected to the third interface of the tenth valve 10, and the third reagent container 34 is used to hold acetonitrile solution;

The fourth syringe 35 is connected to the third interface of the eleventh valve 11;

Preferably, the seventh valve 7 , the eighth valve 8 , the ninth valve 9 , the tenth valve 10 , the eleventh valve 11 , and the twelfth valve 12 are all electric control valves (such as solenoid valves).

The structures of the seventh valve 7 to the twelfth valve 12, the third syringe 32, the fourth syringe 35, etc. in this embodiment have been introduced above and will not be described again here.

The specific reaction process of the reaction module is shown in Figure 7(a) to Figure 7(g).

Initially, the states of the seventh valve 7 and the eighth valve 8 are as shown in Figure 7(a). At this time, the enriched ¹⁸ F ions are passed by the pretreatment module into the reaction vessel 31 through the seventh valve 7 (specifically, reaction flask).

After that, the states of the first valve 1 to the eighth valve 8 are as shown in Figure 7(b). At this time, the first positive pressure The pipeline P1 outputs positive pressure (inputting inert gas) into the reaction vessel 31, the second negative pressure pipeline N2 performs vacuuming, and the temperature control component heats the reaction vessel 31 (for convenience of subsequent description, this step is collectively referred to as the "solvent removal step" ”), thereby removing the solvent. The heating temperature at this time is 80 to 130°C, so that activated ¹⁸ F ions can be obtained.

After that, the states of the seventh valve 7 and the eighth valve 8 are as shown in Figure 7(c). The third syringe 32 adds 0.2-2.0 ml of compound I precursor solution (0.2-2.0 ml of acetonitrile solution containing 1 to 10 mg of compound I precursor). ) is pushed into the reaction vessel 31, heated to 90-140°C for 2-20 minutes under closed conditions, and the precursor of Compound I undergoes nucleophilic substitution reaction with K ¹⁸ F/K ₂₂₂ to generate Compound I tert-butyl ester, and then the "solvent removal step" is performed ".

Afterwards, the states of the seventh to ninth valves 7 to 9 are as shown in FIG. 7(d) , and the third syringe 32 inhales the TFA/DCM solution in the second reagent container 33 .

After that, the states of the seventh valve 7 and the eighth valve 8 are as shown in Figure 7(c). The third syringe 32 pushes the TFA/DCM solution (0.2-2.0 ml of 10-50% TFA/DCM solution) into the reaction Container 31 reacts at 30-100°C for 1-30 minutes to remove the tert-butyl ester protecting group to obtain the crude compound I. After the reaction is completed, the "solvent removal step" is performed.

After that, the states of the tenth to eleventh valves 10 to 11 are as shown in FIG. 7(e) , and the fourth syringe 35 inhales the acetonitrile solution in the third reagent container 34 .

After that, the states of the seventh valve 7 to the eleventh valve 11 are as shown in Figure 7(f). The fourth syringe 35 pushes the acetonitrile solution into the reaction vessel 31 for dissolving the crude compound I. After that, the fourth syringe 35 Four syringes 35 then draw in the dissolved crude compound I solution.

Finally, the states of the eleventh to twelfth valves 11 to 12 are as shown in Figure 7(g) , and the fourth syringe 35 pushes the dissolved crude compound I solution into the purification module.

This embodiment provides a specific reaction module, by changing the changes of the seventh valve 7 to the twelfth valve 12 in different working states, as well as the first positive pressure pipeline P1, the second negative pressure pipeline N2 and the reaction module. Through the cooperation of the container 31 and the temperature control component, this simple device cleverly realizes the de-tert-butyl esterification of the ^{methanesulfonyloxy} group in the precursor of compound I and the tert-butyl ester of compound I by nucleophilic substitution of fluorine [ 18 F] reaction. Especially when each valve, positive pressure pipeline, negative pressure pipeline, and syringe are automatically controlled, the automation of the above two-step reaction can be realized.

In one embodiment, the reaction module further includes:

A third linear drive device (not shown in the drawings), the third linear drive device is capable of bringing The piston of the third syringe 32 moves within the empty barrel;

A fourth linear drive device (not shown in the drawings), the fourth linear drive device can drive the piston of the fourth syringe 35 to move within the empty barrel;

Further preferably, the third linear drive device and the fourth linear drive device are screws, and the screws are driven by stepper motors.

In this embodiment, the third linear drive device and the fourth linear drive device are provided to control the third syringe 32 and the fourth syringe 35 .

When a pneumatic rod or a hydraulic rod is used in conjunction with a PLC or other controller, automatic control of the third syringe 32 and the fourth syringe 35 can be easily realized.

Using the screw, the stroke of the pistons in the third syringe 32 and the fourth syringe 35 can be accurately controlled. Especially when the screw is driven by a stepper motor, it is convenient to cooperate with a controller such as a PLC to realize the stroke of the third syringe 32 and the fourth syringe 35. Automatic and precise control. The screw driven by the stepper motor can be assembled by yourself, or you can directly purchase the finished electric actuator (a screw system).

In one embodiment, as shown in Figure 2(a) to Figure 2(b), the purification module includes:

The seventeenth valve 17. The seventeenth valve 17 at least includes a first interface, a second interface, a third interface, a fourth interface, a fifth interface, and a sixth interface (corresponding to Figures 5(a) to 5( respectively). ①～⑥) in b), wherein the seventeenth valve 17 can switch between the first mode and the second mode. The first mode is for the first interface to be connected to the second interface and the third interface to be connected. The fourth interface is connected to the fourth interface, and the fifth interface is connected to the sixth interface. The second mode is that the second interface is connected to the third interface, the fourth interface is connected to the fifth interface, and the sixth interface is connected to the first interface. Conductive; the fourth interface of the seventeenth valve 17 is connected to the reaction module (the third interface of the twelfth valve 12) (pipe A is connected to pipe A');

Chromatography column assembly 36, one end of the chromatography column assembly 36 is connected to the second interface of the seventeenth valve 17;

The two ends of the quantitative loop 37 (also called the sampling loop) are respectively connected to the third interface of the seventeenth valve 17 and the sixth interface of the seventeenth valve 17;

The liquid delivery pump 38 is connected to the first interface of the seventeenth valve 17 and is used to deliver fluid (acetonitrile and water, the ratio in this embodiment is: acetonitrile/water = 6/1 to 3/1);

The second recovery container 39 is connected to the fifth interface of the seventeenth valve 17;

The eighteenth valve 18 includes at least a first interface, a second interface, and a third interface. The eighteenth valve 18 can realize communication between the first interface and the second interface or between the first interface and the second interface. The third interface is conductive; the first interface of the eighteenth valve 18 is connected to the other end of the chromatography column assembly 36, and the second interface of the eighteenth valve 18 is connected to the prescription module (twentieth The third interface of the three valves 23) is connected, and the third interface of the eighteenth valve 18 is connected to the second recovery container 39;

Preferably, the seventeenth valve 17 and the eighteenth valve 18 are both electric control valves.

First, as shown in Figures 5(a) to 5(b), a six-way valve is provided, which can realize the function of the seventeenth valve 17 mentioned above.

As specifically shown in Figures 5(a) to 5(b), the six-way valve includes a six-way valve core V4 with a circular cross-section, and a six-way valve body V3 outside the six-way valve core V4. The valve body V3 is respectively provided with a first interface ①, a second interface ②, a third interface ③, a fourth interface ④, a fifth interface ⑤, and a sixth interface ⑥ in the counterclockwise direction. By rotating the valve core V4, the first interface ① is connected to the second interface ②, the third interface ③ is connected to the fourth interface ④, and the fifth interface ⑤ is connected to the sixth interface ⑥ (as shown in Figure 5(a)), or The second interface ② is connected to the third interface ③, the fourth interface ④ is connected to the fifth interface ⑤, and the sixth interface ⑥ is connected to the first interface ① (as shown in Figure 5(b)). In addition, based on the above-mentioned six-way valve structure, those skilled in the art know based on the existing technology how to control the six-way valve core V4 to rotate at a fixed angle relative to the six-way valve body V3 to realize the electric operation of the six-way valve ( Electromagnetic) control (for example, setting a stepper motor to control the rotation of the spool V4).

In addition, as shown in Figure 2(a) and Figure 2(b), the eighteenth valve 18 is a three-way valve, which can realize the connection between the first interface ① and the second interface ② or the first interface ① It is connected to the third interface ③, which is an existing technology, and the corresponding electric control valve (such as a solenoid valve) can be purchased directly on the market.

The chromatographic column is an existing technology and will not be described in detail here. The chromatography column assembly 36 of the present application is an existing chromatography column or a combination of multiple chromatography columns (such as a series and/or parallel connection of multiple chromatography columns).

The specific process of purification by the purification module can be shown in Figure 2(a) and Figure 2(b).

Initially, the state of the seventeenth valve 17 is as shown in Figure 2(a). At this time, the solution flowing in from the reaction module to dissolve the crude compound I enters the quantitative loop 37 through the fourth interface ④ and the third interface ③, and a small amount is excess. The solution flows into the second recovery container 39 through the sixth interface ⑥ and the fifth interface ⑤. At this time, the solution in which the crude compound I is dissolved will remain in the quantitative loop 37.

After that, the state of the seventeenth valve 17 is as shown in Figure 2(b). The eighteenth valve 18 connects the first interface ① and the third interface ③. At this time, the liquid delivery pump 38 starts to work. The liquid transfer pump 38 pushes out the fluid (acetonitrile and water). After the fluid flows through the first interface ① and the sixth interface ⑥, the solution of the crude compound I dissolved in the quantitative loop 37 is taken out and passes through the third interface ③ and the sixth interface. The second interface ② flows into the chromatographic column assembly 36 for purification.

Finally, the eighteenth valve 18 connects the first interface ① and the second interface ②, and the fluid pushed out by the liquid transfer pump 38 pushes the purified compound I pure solution into the prescription module.

This embodiment provides a specific purification module. By changing the changes of the seventeenth valve 17 and the eighteenth valve 18 in different working states and cooperating with the liquid transfer pump 38, the crude compound I can be purified to obtain Compound Ⅰ pure product. Especially when each valve, positive pressure pipeline, and liquid transfer pump 38 are automatically controlled, the automation of the above purification can be realized.

In one embodiment, the prescription module includes:

The thirteenth valve 13, the fourteenth valve 14, the fifteenth valve 15, the sixteenth valve 16, the nineteenth valve 19, the twentieth valve 20, the twenty-first valve 21, the twenty-second valve 22, The twenty-third valve 23, the thirteenth valve 13 to the sixteenth valve 16 and the nineteenth valve 19 to the twenty-third valve 23 respectively include at least a first interface, a second interface, The third interface, and the thirteenth valve 13 to the sixteenth valve 16 and the nineteenth valve 19 to the twenty-third valve 23 can realize the conduction of any two interfaces among the three interfaces. Or make all three interfaces non-conductive; wherein, the first interface of the thirteenth valve 13 is connected to the second interface of the twelfth valve 12, and the second interface of the thirteenth valve 13 is connected to the second interface of the thirteenth valve 13. The first interface of the fourteenth valve 14 is connected, the second interface of the fourteenth valve 14 is connected with the first interface of the fifteenth valve 15, the second interface of the fifteenth valve 15 is connected with the The first interface of the sixteenth valve 16 is connected, the second interface of the sixteenth valve 16 is connected with the first interface of the nineteenth valve 19, the second interface of the nineteenth valve 19 is connected with the The first interface of the twentieth valve 20 is connected, the second interface of the twentieth valve 20 is connected to the first interface of the twenty-first valve 21, and the second interface of the twenty-first valve 21 The second interface of the twenty-second valve 22 is connected with the first interface of the twenty-third valve 23 . The twenty-third valve 23 The second interface is connected to the fourth negative pressure pipeline N4, and the third interface of the twenty-third valve 23 is connected to the purification module (the second interface of the eighteenth valve 18) (pipe B and pipeline B B' is connected);

The fifth syringe 40 is connected to the third interface of the thirteenth valve 13;

The fourth reagent container 41 is connected to the third interface of the fourteenth valve 14, and the fourth reagent container 41 is used to hold absolute ethanol;

The fifth reagent container 42 is connected to the third interface of the fifteenth valve 15, and the fifth reagent container 42 is used to hold sodium chloride solution;

The sixth reagent container 43 is connected to the third interface of the sixteenth valve 16, and the sixth reagent container 43 is used to hold water;

The first transfer container 44 is connected to the third interface of the nineteenth valve 19;

The second transfer container 45 is connected to the third interface of the twenty-second valve 22 and the third negative pressure pipeline N3 respectively. The second transfer container 45 is used to hold auxiliary materials (polysorbate 80 (II) ), vitamin C, sodium chloride injection, sterile water for injection);

The compound I enrichment chamber 46 is connected between the third interface of the twentieth valve 20 and the third interface of the twenty-first valve 21. The compound I enrichment chamber 46 is filled with octadecane. Base bonded silica gel;

The finished product collection container 47 is connected to the second transfer container 45 .

The structures of the thirteenth to sixteenth valves 13 to 16, the nineteenth to twenty-third valves 19 to 23, the fifth syringe 40, etc. in this embodiment have been introduced above. , which will not be described in detail here.

The specific process of enrichment and prescription by the prescription module is shown in Figure 8(a) to Figure 8(g).

Initially, the states of the nineteenth to twenty-third valves 19 to 23 are as shown in Figure 8(a). At this time, the compound I product solution flowing out of the purification module enters the first transfer container 44.

After that, the states of the thirteenth to sixteenth valves 13 to 16 are as shown in FIG. 8(b) . At this time, the fifth syringe 40 draws out the sterile water for injection contained in the sixth reagent container 43 .

After that, the states of the thirteenth to sixteenth valves 13 to 16 and the nineteenth valve 19 are as shown in Figure 8(c). At this time, the fifth syringe 40 pushes the sterile water for injection into the first transfer container 44. The compound I product solution is diluted, and then the fifth syringe 40 draws the compound I product solution into the fifth syringe 40 .

After that, the states of the thirteenth to sixteenth valves 13 to 16 and the nineteenth to twenty-third valves 23 are as shown in Figure 8(d). At this time, the fifth syringe 40 pushes out the compound I product solution. , thus starting to enrich the compound I in the enrichment bin 46.

After that, the states of the thirteenth valve 13 to the sixteenth valve 16 are as shown in Fig. 8(b). At this time, the fifth The syringe 40 draws out the sterile water for injection contained in the sixth reagent container 43 .

After that, the states of the thirteenth to sixteenth valves 13 to 16 and the nineteenth to twenty-third valves 19 to 23 are as shown in Figure 8(d). At this time, the fifth syringe 40 pushes the sterile water for injection The compound I enrichment chamber 46 is flushed in to further enrich it.

Afterwards, the states of the thirteenth to fourteenth valves 13 to 14 are as shown in FIG. 8(e) , and the fifth syringe 40 draws out the absolute ethanol contained in the fourth reagent container 41 .

Afterwards, the states of the thirteenth to sixteenth valves 13 to 16 and the nineteenth to twenty-third valves 23 are as shown in Figure 8(f). At this time, the fifth syringe 40 pushes out absolute ethanol, and the fifth syringe 40 pushes out the absolute ethanol. The triple negative pressure pipeline N3 is evacuated, so that the pure compound I enriched in the enrichment chamber 46 is eluted to the second transfer container 45 .

After that, the states of the thirteenth to fifteenth valves 13 to 15 are as shown in FIG. 8(g) , and the fifth syringe 40 draws out the sodium chloride solution contained in the fifth reagent container 42 .

After that, the states of the thirteenth to sixteenth valves 13 to 16 and the nineteenth to twenty-third valves 23 are as shown in Figure 8(f). At this time, the fifth syringe 40 pushes out the sodium chloride solution. , the third negative pressure pipeline N3 is evacuated, so that the pure compound I enriched in the enrichment warehouse 46 is eluted to the second transfer container 45 again.

Finally, referring to Figure 8(h), the first valve 1 to the sixteenth valve 16, the nineteenth valve 19 to the twenty-first valve 21 are all connected with the first interface and the second interface, and the twenty-second valve 22 is The first interface is connected to the third interface, and the first positive pressure pipeline P1 provides positive pressure (and the third negative pressure pipeline N3 is closed), thereby pushing the mixed solution in the second transfer container 45 into the finished product collection container 47, and collecting Final Compound I liquid composition. Preferably, a filter (such as a needle filter) is provided between the second transfer container 45 and the finished product collection container 47, so that the compound I solution flowing out from the second transfer container 45 can be filtered and sterilized. The final product is collected in the finished product collection container 47 .

In one embodiment, the prescription module further includes:

A fifth linear drive device (not shown in the drawings), the fifth linear drive device can drive the piston of the fifth syringe 40 to move within the empty barrel;

When using a pneumatic rod or a hydraulic rod in conjunction with a controller such as a PLC, it is convenient to realize automatic control of the fifth syringe 40 .

Using the screw, the stroke of the piston in the fifth syringe 40 can be accurately controlled. Especially when the screw is driven by a stepper motor, it is convenient to cooperate with a controller such as a PLC to achieve automatic and precise control of the fifth syringe 40 . The screw driven by the stepper motor can be assembled by yourself, or you can directly purchase the finished electric actuator (a screw system).

In addition, in the above technical solution, detection/monitoring equipment is set up to detect the operation of the equipment. Specifically, it can be at one or both positions in the ¹⁸ F ion enrichment chamber 27, the third reagent container 34, the pipeline between the twelfth valve 12 and the seventeenth valve 17, and the compound I enrichment chamber 46. Radioactivity detectors are installed at the above locations to detect radioactivity. UV detectors and radioactive detectors can be set on the column assembly to determine whether the control starts to collect the purification mobile phase.

This embodiment provides a method for producing a liquid composition of Compound I using the above equipment, including:

Use the preprocessing module to enrich ¹⁸ F ions;

Use the reaction module to react the enriched ¹⁸ F ions with the precursor of compound I to generate compound I tert-butyl ester, and perform a de-tert-butyl esterification reaction on the tert-butyl ester of compound I to obtain crude compound I;

Use the prescription module to formulate a prescription for the pure compound I obtained after purification, to obtain a liquid composition of compound I. More specific operation steps have been introduced above and will not be described again.

Although the embodiments of the present application have been described above, the present application is not limited to the above-mentioned specific embodiments and application fields. The above-mentioned specific embodiments are only illustrative and instructive, rather than restrictive. Under the inspiration of this description and without departing from the scope of protection of the claims of this application, those of ordinary skill in the art can also make many forms, which all fall within the scope of protection claimed by this application.

Claims

Equipment for producing liquid compositions of Compound I, including:

Pretreatment module for enriching 18 F ions;

The reaction module is used to react the enriched 18 F ions with the precursor of compound I to generate compound I tert-butyl ester, and perform the de-tert-butyl esterification reaction of compound I tert-butyl ester to obtain compound I crude product;

Purification module, used to purify crude compound I to obtain pure compound I;

The prescription module enriches the purified Compound I pure product and formulates it into a Compound I liquid composition;
The device of claim 1, wherein,

The preprocessing module includes:

A first valve, a second valve, a third valve, a fourth valve, a fifth valve, and a sixth valve, the first valve to the sixth valve respectively include at least a first interface, a second interface, and a third interface, And the first valve to the sixth valve can realize any two of the three interfaces to be connected or all three interfaces to be disconnected; the first interface of the first valve and the first positive pressure pipe The second interface of the first valve is connected to the first interface of the second valve, the second interface of the second valve is connected to the first interface of the third valve, and the third valve The second interface of the fourth valve is connected to the first interface of the fourth valve, the second interface of the fourth valve is connected to the first interface of the fifth valve, and the second interface of the fifth valve is connected to the first interface of the fourth valve. The first interface of the six valves is connected;

The first recovery container is respectively connected to the first negative pressure pipeline and the third interface of the first valve;

The first reagent container is connected to the third interface of the second valve;

A first syringe connected to the third interface of the third valve;

18 F ion enrichment chamber, connected between the third interface of the fourth valve and the third interface of the fifth valve;

The second syringe is connected to the third interface of the sixth valve.
The device of claim 2, wherein,

The preprocessing module also includes:

A first linear drive device capable of driving the piston of the first syringe to move within the empty barrel;

A second linear drive device capable of driving the piston of the second syringe to move within the empty barrel.
The device of claim 2, wherein,

The preprocessing module also includes:

Positive pressure and negative pressure pipelines and liquid adding pipelines respectively pass through the piston of the second syringe and extend into the second syringe.
The device of claim 2, wherein,

The reaction module includes:

The seventh valve, the eighth valve, the ninth valve, the tenth valve, the eleventh valve, and the twelfth valve. The seventh valve to the twelfth valve respectively include at least a first interface, a second interface, and a third valve. Three interfaces, and the seventh valve to the twelfth valve can realize conduction of any two interfaces of the three interfaces or non-conduction of all three interfaces; the first interface of the seventh valve and all the The pretreatment module is connected, the second interface of the seventh valve is connected to the first interface of the eighth valve, the second interface of the eighth valve is connected to the first interface of the ninth valve, the The second interface of the ninth valve is connected to the first interface of the tenth valve, the second interface of the tenth valve is connected to the first interface of the eleventh valve, and the second interface of the eleventh valve is connected to the first interface of the eleventh valve. The interface is connected to the first interface of the twelfth valve, and the third interface of the twelfth valve is connected to the purification module;

The reaction vessel is respectively connected to the second negative pressure pipeline and the third interface of the seventh valve;

A temperature control component for heating and/or cooling the reaction vessel;

A third syringe connected to the third interface of the eighth valve;

a second reagent container connected to the third interface of the ninth valve;

A third reagent container is connected to the third interface of the tenth valve;

The fourth syringe is connected to the third interface of the eleventh valve.
The device of claim 5, wherein,

The reaction module also includes:

a third linear drive device capable of driving the piston of the third syringe to move within the empty barrel;

A fourth linear drive device, the fourth linear drive device can drive the piston of the fourth syringe to move within the empty barrel.
The device of claim 5, wherein,

The purification module includes:

A seventeenth valve, the seventeenth valve includes at least a first interface, a second interface, a third interface, a fourth interface, a fifth interface, and a sixth interface, wherein the seventeenth valve can operate in the first mode and second mode, the first mode is that the first interface is connected to the second interface, the third interface is connected to the fourth interface, and the fifth interface is connected to the sixth interface; the second mode is The second interface is connected to the third interface, the fourth interface is connected to the fifth interface, and the sixth interface is connected to the first interface; the fourth interface of the seventeenth valve is connected to the reaction module;

Chromatography column assembly, one end of the chromatography column assembly is connected to the second interface of the seventeenth valve;

A quantitative loop, both ends of which are respectively connected to the third interface of the seventeenth valve and the sixth interface of the seventeenth valve;

a liquid transfer pump, connected to the first interface of the seventeenth valve;

The second recovery container is connected to the fifth interface of the seventeenth valve;

The eighteenth valve includes at least a first interface, a second interface, and a third interface. The eighteenth valve can realize communication between the first interface and the second interface or the first interface and the third interface. conduction; the first interface of the eighteenth valve is connected to the other end of the chromatography column assembly, the second interface of the eighteenth valve is connected to the prescription module, and the first interface of the eighteenth valve is connected to the other end of the chromatography column assembly. Three interfaces are connected to the second recovery container.
The device of claim 7, wherein

The prescription module includes:

The thirteenth valve, the fourteenth valve, the fifteenth valve, the sixteenth valve, the nineteenth valve, the twentieth valve, the twenty-first valve, the twenty-second valve, the twenty-third valve, as described The thirteenth valve to the sixteenth valve and the nineteenth valve to the twenty-third valve respectively include at least a first interface, a second interface, and a third interface, and the thirteenth valve to the The sixteenth valve, the nineteenth valve to the twenty-third valve can all realize conduction of any two interfaces among the three interfaces or non-conduction of all three interfaces; wherein, The first interface of the thirteenth valve is connected to the second interface of the twelfth valve, the second interface of the thirteenth valve is connected to the first interface of the fourteenth valve, and the tenth valve The second interface of the four valves is connected to the first interface of the fifteenth valve, the second interface of the fifteenth valve is connected to the first interface of the sixteenth valve, and the first interface of the sixteenth valve The second interface is connected to the first interface of the nineteenth valve, the second interface of the nineteenth valve is connected to the first interface of the twentieth valve, and the second interface of the twentieth valve is connected to the first interface of the twentieth valve. The first interface of the twenty-first valve is connected to the first interface of the twenty-second valve, and the second interface of the twenty-second valve is connected to the first interface of the twenty-second valve. The first interface of the twenty-third valve is connected, the second interface of the twenty-third valve is connected to the fourth negative pressure pipeline, and the third interface of the twenty-third valve is connected to the purification module;

The fifth syringe is connected to the third interface of the thirteenth valve;

a fourth reagent container connected to the third interface of the fourteenth valve;

The fifth reagent container is connected to the third interface of the fifteenth valve;

The sixth reagent container is connected to the third interface of the sixteenth valve;

The first transfer container is connected to the third interface of the nineteenth valve;

The second transfer container is connected to the third interface and the third negative pressure pipeline of the twenty-second valve respectively;

Compound I enrichment warehouse, connected between the third interface of the twentieth valve and the third interface of the twenty-first valve;

The finished product collection container is connected with the second transfer container.
The device of claim 8, wherein,

The prescription module also includes:

A fifth linear drive device, the fifth linear drive device can drive the piston of the fifth syringe to move within the empty barrel.
A method for producing a liquid composition of Compound I, using the equipment according to any one of claims 1 to 9, including:

Use the preprocessing module to enrich 18 F ions;

Use the reaction module to react the enriched 18 F ions with the precursor of compound I to generate compound I tert-butyl ester, and perform a de-tert-butyl esterification reaction on compound I tert-butyl ester to obtain compound I crude product;

Use the purification module to purify the crude compound I to obtain the pure compound I;

Use the prescription module to enrich the purified compound I pure product and formulate it into a compound I liquid composition.
Use of the equipment according to any one of claims 1 to 9 in producing a liquid composition of Compound I.