CN116351339A

CN116351339A - Production equipment of liquid composition, preparation method and application thereof

Info

Publication number: CN116351339A
Application number: CN202310204871.4A
Authority: CN
Inventors: 王跃; 张颖; 张爱丽; 徐新盛
Original assignee: Beijing Cotimes Biotech Co Ltd
Current assignee: Beijing Cotimes Biotech Co Ltd
Priority date: 2022-06-07
Filing date: 2022-06-07
Publication date: 2023-06-30
Also published as: CN114700006A; WO2023236978A1; CN114700006B

Abstract

The present application provides for the production of trans-2- [2- (5- [ ¹⁸ F]Fluorotridecyl) cyclopropyl]An apparatus for liquid composition of acetic acid (hereinafter referred to as "compound i") comprising: a pretreatment module for enriching ¹⁸ F, ion; reaction mouldA block for concentrating ¹⁸ F, reacting the ion with a precursor of the compound I to generate a tert-butyl compound I, and performing tert-butyl removal reaction on the tert-butyl compound I to obtain a crude product of the compound I; the purification module is used for purifying the crude product of the compound I to obtain a pure product of the compound I; and (3) a prescription module, wherein the purified compound I pure product is prescribed as a compound I liquid composition. The equipment has simple process flow and high yield, can be used by multiple persons through single preparation, and can be directly used in clinic. The application also provides a method for preparing the compound I liquid composition by using the equipment and application of the equipment in preparing the compound I liquid composition.

Description

Production equipment of liquid composition, preparation method and application thereof

The present application is a divisional application of Chinese patent application with application number 202210635474.8, application date 2022, month 06 and 07, and the invention name of "a production device of liquid composition, preparation method and application".

Technical Field

The application relates to the technical field of radiopharmaceuticals, in particular to production equipment of a liquid composition, a preparation method and application thereof.

Background

According to the data of the research report of the Chinese disease prevention control center, the proportion and absolute number of the coronary heart disease death of Chinese people accounting for the total death are obviously improved, the total number of the coronary heart disease death in 2013 is 139.4 ten thousand, and the number of the coronary heart disease death in 1990 is increased by 90 percent. At present, coronary heart disease becomes the first cause of death in six provinces, direct administration and municipal/provincial administrative areas of China. Along with the aggravation of the aging process, the incidence and death number of coronary heart disease in China are continuously increased.

With the development of clinical cardiology, attention has been paid to the transition from the original diagnosis of coronary artery disease to risk stratification and prognosis. It is currently widely believed that myocardial ischemia, cardiac function, surviving myocardium and other information can provide a main basis for layering the risk of coronary artery disease, prognosis judgment and treatment scheme formulation. Therefore, the identification of viable myocardium is of great clinical interest, which is a hotspot for clinical treatment and related event prediction. Currently, nuclear 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]fluorotricycl) cyclic backbone) acrylic acid. Hereinafter referred to as "Compound I") is a radionuclide ¹⁸ The F-labeled Modified Fatty Acid (MFA), which has a structure very similar to that of Free Fatty Acid (FFA) naturally occurring in human body, can be taken up by myocardial cells for Positron Emission Tomography (PET) and evaluation of myocardial cell viability. The structure of the compound I is shown in the following figure:

the compound I can be developed 5 minutes after intravenous injection, and has high compliance and clinical benefit.

The existing equipment has the disadvantages of more synthetic consumable materials, complex technological operation flow and lower yield, and only 1-2 persons can use the equipment in a single preparation process, and clinical use is limited.

Therefore, it is particularly important to develop an apparatus for producing a liquid composition (e.g., injection) of compound I.

Disclosure of Invention

To solve the problems in the prior art, the present application provides an apparatus for producing a liquid composition (e.g., injection) of compound I and a method for preparing the same. The technical scheme of the application is as follows:

1. an apparatus for producing a liquid composition of compound i comprising:

a pretreatment module for enriching ¹⁸ F, ion;

a reaction module for concentrating ¹⁸ F, reacting the ion with a precursor of the compound I to generate a tert-butyl compound I, and performing tert-butyl removal reaction on the tert-butyl compound I to obtain a crude product of the compound I;

the purification module is used for purifying the crude product of the compound I to obtain a pure product of the compound I;

the prescription module is used for prescribing the purified compound I pure product into a compound I liquid composition;

2. the apparatus of item 1, the preprocessing module comprising:

the first valve to the sixth valve at least comprise a first interface, a second interface and a third interface, and any two interfaces of the three interfaces can be conducted or the three interfaces can be conducted respectively; the first port of the first valve is connected with the first positive pressure pipeline, the second port of the first valve is connected with the first port of the second valve, the second port of the second valve is connected with the first port of the third valve, the second port of the third valve is connected with the first port of the fourth valve, the second port of the fourth valve is connected with the first port of the fifth valve, and the second port of the fifth valve is connected with the first port of the sixth valve;

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

a first reagent container connected to a third port of the second valve;

a first syringe connected to a third port of the third valve;

¹⁸ the F ion enrichment bin is connected between the third interface of the fourth valve and the third interface of the fifth valve;

and the second injector is connected with 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 electrically controlled valves.

3. The apparatus of item 2, the preprocessing module further comprising:

the first linear driving device can drive the piston of the first syringe to move in the hollow cylinder;

and the second linear driving device can drive the piston of the second syringe to move in the hollow cylinder.

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

further preferably, the first linear driving device and the second linear driving device are both lead screws, and the lead screws are driven by a stepping motor.

4. The apparatus of item 2, the preprocessing module further comprising:

the positive pressure negative pressure pipeline and the liquid adding pipeline respectively penetrate through the piston of the second injector and extend into the second injector.

Preferably, a flowmeter is arranged on the liquid adding pipeline.

5. The apparatus of item 2, the reaction module comprising:

a seventh valve, an eighth valve, a ninth valve, a tenth valve, an eleventh valve, a twelfth valve and a tenth valve, wherein the seventh valve to the thirteenth valve at least comprise a first interface, a second interface and a third interface respectively, and any two interfaces of the three interfaces can be conducted or none of the three interfaces can be conducted by the seventh valve to the tenth valve; the first interface of the seventh valve is connected with the pretreatment module, the second interface of the seventh valve is connected with the first interface of the eighth valve, the second interface of the eighth valve is connected with the first interface of the ninth valve, the second interface of the ninth valve is connected with the first interface of the tenth valve, the second interface of the tenth valve is connected with the first interface of the eleventh valve, the second interface of the eleventh valve is connected with the first interface of the twelfth valve, the second interface of the twelfth valve is connected with the first interface of the tenth valve, and the third interface of the twelfth valve is connected with the purification module;

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

a temperature control assembly for heating and/or cooling the reaction vessel;

a second reagent container connected to a third port of the eighth valve;

a third syringe connected to a third port of the ninth valve;

a third reagent container connected to a third port of the tenth valve;

a fourth reagent container connected to the third port of the eleventh valve;

and a fifth reagent container connected with a third interface of the tenth valve.

Preferably, the seventh valve, the eighth valve, the ninth valve, the tenth valve, the eleventh valve, the twelfth valve and the tenth valve are all electrically controlled valves.

6. The apparatus of item 5, the reaction module further comprising:

and the third linear driving device can drive the piston of the third syringe to move in the hollow cylinder.

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

further preferably, the third linear driving device is a screw, and the screw is driven by a stepping motor.

7. The apparatus of item 5, the purification module comprising:

The fourteenth valve at least comprises a first interface, a second interface, a third interface, a fourth interface, a fifth interface and a sixth interface, wherein the fourteenth valve can be switched between a first mode and a second mode, the first mode is that the first interface is conducted with the second interface, the third interface is conducted with the fourth interface, and the fifth interface is conducted with the sixth interface; the second mode is that the second interface is conducted with the third interface, the fourth interface is conducted with the fifth interface, and the sixth interface is conducted with the first interface; the fourth interface of the fourteenth valve is connected with the reaction module;

one end of the chromatographic column assembly is connected with the second interface of the fourteenth valve;

the two ends of the quantitative ring are respectively connected with the third interface of the fourteenth valve and the sixth interface of the fourteenth valve;

a liquid delivery pump connected to the first port of the fourteenth valve;

the second recovery container is connected with a fifth interface of the fourteenth valve;

the fifteenth valve at least comprises a first interface, a second interface and a third interface, and the fifteenth valve can realize the conduction between the first interface and the second interface or the conduction between the first interface and the third interface; the first interface of the fifteenth valve is connected with the other end of the chromatographic column assembly, the second interface of the fifteenth valve is connected with the prescription module, and the third interface of the fifteenth valve is connected with the second recovery container;

Preferably, the fourteenth valve and the fifteenth valve are electrically controlled valves.

8. The apparatus of item 7, the prescribing module comprising:

the sixteenth valve and the seventeenth valve at least comprise a first interface, a second interface and a third interface respectively, and any two interfaces of the three interfaces can be conducted or none of the three interfaces can be conducted by the sixteenth valve and the seventeenth valve; the first port of the sixteenth valve is connected with the second port of the tenth valve, the second port of the sixteenth valve is connected with the first port of the seventeenth valve, the third port of the sixteenth valve is connected with the purification module, and the second port of the seventeenth valve is connected with a third negative pressure pipeline;

a finished product collection container;

and the transfer container is respectively connected with the third interface of the seventeenth valve, the finished product collecting container and the fourth negative pressure pipeline.

9. A process for producing a liquid composition of compound i, using the apparatus of any one of items 1 to 8, comprising:

enrichment using a pretreatment module ¹⁸ F, ion;

enrichment using a reaction module ¹⁸ F, reacting the ion with a precursor of the compound I to generate a tert-butyl compound I, and performing tert-butyl removal reaction on the tert-butyl compound I to obtain a crude product of the compound I;

Purifying the crude product of the compound I by using a purification module to obtain a pure product of the compound I;

the purified pure compound I is formulated into a liquid compound I composition using a formulation module.

10. Use of the apparatus according to any one of claims 1 to 8 for the production of liquid compositions of compound i.

The equipment for producing the liquid composition of the compound I can be used for preparing the crude product of the compound I, purifying and prescribing the crude product of the compound I to prepare the liquid composition of the compound I for clinical use, and the equipment is simple in technological operation flow and high in yield, and can be used by multiple persons in a single preparation. And, the automation of the equipment can be realized by controlling each valve and the like through a microprocessor control system (such as a PLC and the like). Also, methods of using the above devices are provided.

The foregoing description is only an overview of the technical solutions of the present application, to the extent that it can be implemented according to the content of the specification by those skilled in the art, and to make the above-mentioned and other objects, features and advantages of the present application more obvious, the following description is given by way of example of the specific embodiments of the present application.

Drawings

Fig. 1: the pretreatment module, the reaction module and the prescription module of the equipment for producing the compound I are assembled in a schematic diagram;

fig. 2 (a) to 2 (b): schematic of the purification module of the plant for producing compound i (purification module is purified by switching between fig. 2 (a) mode and fig. 2 (b) mode);

fig. 3 (a) to 3 (h): the three-way valve structure is schematically shown (fig. 3 (a) is a schematic diagram of three interfaces in the three-way valve being communicated, fig. 3 (b) to 3 (d) are schematic diagrams of two interfaces in the three-way valve being communicated respectively, and fig. 3 (e) to 3 (h) are schematic diagrams of three interfaces in the three-way valve being not communicated each other respectively);

fig. 4 (a) to 4 (d): fig. 3 is a schematic diagram of a three-way valve (fig. 4 (a) is a schematic diagram of a three-way valve corresponding to fig. 3 (b), fig. 4 (b) is a schematic diagram of a three-way valve corresponding to fig. 3 (c), fig. 4 (c) is a schematic diagram of a three-way valve corresponding to fig. 3 (d), and fig. 4 (d) is a schematic diagram of a three-way valve corresponding to fig. 3 (e) to 3 (h);

fig. 5 (a) to 5 (b): the six-way valve is structurally schematic (fig. 5 (a) and fig. 5 (b) are schematic diagrams of the valve core of the six-way valve in different working positions respectively);

fig. 6 (a) to 6 (c): schematic diagram of the working principle of the preprocessing module (the preprocessing module is realized according to the sequence from fig. 6 (a) to fig. 6 (c)) ¹⁸ F, enriching and feeding the ions into a reaction module);

Fig. 7 (a) to 7 (h): schematic diagram of the working principle of the reaction module (the reaction module reacts according to the sequence of fig. 7 (a), 7 (b), 7 (c), 7 (d), 7 (e), 7 (d), 7 (b), 7 (f), 7 (d), 7 (g), 7 (d), 7 (h);

fig. 8 (a) to 8 (b): schematic diagram of the working principle of the prescription module (the prescription module prescriptes and collects the final product according to the sequence of fig. 8 (a) and 8 (b));

fig. 9: the total negative pressure pipeline is connected with a schematic diagram.

Reference numerals illustrate:

1 to 17, a first valve to a seventeenth valve; v1, a three-way valve body; v2, a valve core of the three-way valve; v3, six-way valve body; v4, a six-way valve core;

18. a first recovery vessel; 19. a first reagent container; 20. a first syringe; 21. ¹⁸ f, ion enrichment bin; 22. a second syringe; 23. a positive pressure negative pressure pipeline; 24. a liquid adding pipeline;

25. a reaction vessel; 26. a second reagent container; 27. a third syringe; 28. a third reagent container; 29. a fourth reagent container; 30. a fifth reagent container;

31. a chromatographic column assembly; 32. a dosing ring; 33. a liquid transfer pump; 34. a second recovery vessel;

35. a transfer container; 36. a finished product collection container;

37. a third recovery vessel;

p0, positive pressure pipeline of positive pressure negative pressure pipeline; p1, a first positive pressure pipeline;

N, total negative pressure pipeline; n0, a negative pressure pipeline of the positive pressure negative pressure pipeline; n1, a first negative pressure pipeline; n2, a second negative pressure pipeline; n3, a third negative pressure pipeline; and N4, a fourth negative pressure pipeline.

Detailed Description

The following embodiments of the present application are merely illustrative of specific embodiments for practicing the present application and are not to be construed as limiting the present application. Any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principles of the present application are intended to be equivalent arrangements which are within the scope of the present application.

This example provides a process for the production of trans-2- [2- (5- ] ¹⁸ F]Fluorotridecyl) cyclopropyl]An apparatus for preparing a liquid composition (e.g., injection) of acetic acid (hereinafter referred to as "compound i") comprising:

a pretreatment module for enriching ¹⁸ F, ion;

a reaction module for enriching ¹⁸ F, reacting the ion with a precursor of the compound I to generate a tert-butyl compound I, and performing tert-butyl removal reaction on the tert-butyl compound I to obtain a crude product of the compound I;

and (3) a prescription module, wherein the purified compound I pure product is prescribed as a compound I liquid composition.

As shown in the following figure, compound I is prepared from precursor of Compound I and radioactive fluorine ¹⁸ F]The ion is used as a starting material and is prepared through two steps of reactions. The first step being fluorine [ ¹⁸ F]Nucleophilic substitution of the methanesulfonyloxy (-OMs) group in the precursor of compound i gives the tert-butyl ester of compound i. And secondly, adding trifluoroacetic acid/acetonitrile solution without separation and purification to perform a t-butyl removal reaction to obtain a crude product of the compound I. Under the synthetic route of the crude product of the compound IThe figure shows the figure.

In the figure, K ₂₂₂ Is 4,7,13,16,21, 24-hexaoxy-1, 10-diazabicyclo [8.8.8 ]]And (3) hexacosane, namely aminopolyether.

It will thus be appreciated that the present application differs from the process of preparing crude compounds i of the applicant's alternative application and that the applicant has accordingly modified the production equipment to produce the present application.

This example shows an apparatus for producing a liquid composition of compound I (e.g., injection) which is first enriched by a pretreatment module ¹⁸ F, ion; after enrichment ¹⁸ F ions enter a reaction module, and then the reaction module reacts with a precursor of the compound I to generate the compound I tert-butyl ester, and further the compound I tert-butyl ester is subjected to a tert-butyl removal reaction to obtain a crude product of the compound I; purifying the crude product of the compound I in a purification module to obtain a pure product of the compound I; further, the pure compound I is fed to a prescription module and prescribed as a liquid compound I composition.

By the technical scheme of the embodiment, the crude product of the compound I can be obtained and purified and prescribed for direct clinical use.

In addition, the "crude product" and "pure product" in the present application refer to the products before and after purification, respectively; the "prescription" in this example refers specifically to the preparation of a liquid composition of compound i from pure product of compound i and auxiliary materials.

In one embodiment, the preprocessing module as described in fig. 1, 3, 4 and 6 includes:

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 comprise at least a first interface, a second interface and a third interface, and any two interfaces of the three interfaces can be conducted or none of the three interfaces can be conducted by the first valve 1 to the sixth valve 6; the first port of the first valve 1 is connected with the first positive pressure pipeline P1, the second port of the first valve 1 is connected with the first port of the second valve 2, the second port of the second valve 2 is connected with the first port of the third valve 3, the second port of the third valve 3 is connected with the first port of the fourth valve 4, the second port of the fourth valve 4 is connected with the first port of the fifth valve 5, and the second port of the fifth valve 5 is connected with the first port of the sixth valve 6;

A first recovery container 18 connected to the first negative pressure line N1 and the third port of the first valve 1, respectively;

a first reagent vessel 19 connected to the third port of the second valve 2, the first reagent vessel 19 for holding ¹⁸ F leacheate (e.g. acetonitrile + water + K) ₂₂₂ +K ₂ CO ₃ Etc.);

a first syringe 20 connected to a third port of the third valve 3;

¹⁸ an F ion enrichment chamber 21 connected between the third port of the fourth valve 4 and the third port of the fifth valve 5, the ¹⁸ The F ion enrichment bin 21 is filled with anion exchange resin;

a second syringe 22 connected to the third port 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 electrically controlled valves (such as solenoid valves).

First, as shown in fig. 3, a three-way valve is provided, which can realize the functions of the first to sixth valves 1 to 6, but can also realize the functions of the seventh to thirteenth valves 7 to 13 and the sixteenth and

seventeenth valves

16 and 17, which will not be described in detail.

As shown in fig. 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, wherein the three-way valve body V1 is provided with a first port (1) on the left side, a second port (2) on the right side, a third port (3) on the upper side, and a T-shaped flow channel is provided in the three-way valve core V2. By rotating the valve core V2, it is possible to realize that the first interface (1) is communicated with the third interface (3) (shown in fig. 3 (b)), that the first interface (1) is communicated with the second interface (2) (shown in fig. 3 (c)), that the second interface (2) is communicated with the third interface (3) (shown in fig. 3 (d)), and that none of the three interfaces is communicated (shown in fig. 3 (e) to 3 (h)). In addition, given the above three-way valve structure, a person skilled in the art knows how to control the rotation of the three-way valve spool V2 by a fixed angle relative to the three-way valve body V1 to achieve electric (electromagnetic) control of the three-way valve (e.g., to provide a stepper motor to control the rotation of the three-way valve spool V2). In addition, in order to enable a simple description of the state of the three-way valve hereinafter, fig. 4 gives a schematic view of the three-way valve in fig. 3, in which fig. 4 (a) is a schematic view corresponding to the three-way valve in fig. 3 (b); FIG. 4 (b) is a schematic diagram of a three-way valve corresponding to FIG. 3 (c); FIG. 4 (c) is a schematic diagram of a three-way valve corresponding to FIG. 3 (d); fig. 4 (d) is a schematic diagram of the three-way valve corresponding to fig. 3 (e) to 3 (h).

In addition, the first negative pressure pipeline N1 is specifically configured to provide negative pressure by vacuumizing, and the negative pressure pipeline N0, the second negative pressure pipeline N2, the third negative pressure pipeline N3, and the fourth negative pressure pipeline N4 of the positive pressure negative pressure pipeline can also provide negative pressure by vacuumizing, which will not be described in detail below. And, negative pressure pipeline N0, first negative pressure pipeline N1, second negative pressure pipeline N2, third negative pressure pipeline N3, fourth negative pressure pipeline N4 of positive pressure negative pressure pipeline can connect a vacuum apparatus alone, also can wherein more than two connect on a vacuum apparatus/pipeline. Specifically, as shown in fig. 9, the third recovery container 37 is connected to the total negative pressure pipeline N, and other negative pressure pipelines (more than one of 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) are also connected to the third recovery container 37 (specifically, the pipeline on the left side of the third recovery container 37 in fig. 9), so that more than one negative pressure pipeline can be driven to work by one vacuumizing device, and the third recovery container 37 can store the liquid flowing from the negative pressure pipeline.

The first positive pressure pipeline P1 is configured to provide positive pressure by blowing inert gas (such as nitrogen, argon, etc.), and in addition, a filter membrane may be installed in the first positive pressure pipeline P1 to ensure the cleaning of the inert gas entering the apparatus. The positive pressure line P0 of the positive pressure negative pressure line can also provide positive pressure in this way, and will not be described in detail.

Moreover, those skilled in the art know that, generally, a control valve (such as an electric control valve, specifically, an electromagnetic valve) may be disposed on the negative pressure pipeline N0, the first negative pressure pipeline N1, the second negative pressure pipeline N2, the third negative pressure pipeline N3, the fourth negative pressure pipeline N4, the positive pressure pipeline P0 of the positive pressure negative pressure pipeline, and the first positive pressure pipeline P1 to control on-off of the pipeline, and/or a flow valve/flowmeter may be disposed to control the positive pressure/negative pressure, which will not be described herein.

Those skilled in the art will appreciate that the hollow barrel, and the piston within the hollow barrel, are the necessary components of the syringe. The piston can be of a strip-shaped structure, and the piston and the hollow cylinder can move relatively by pushing the part of the piston outside the hollow cylinder; the piston can also be just a rubber head which plays a role in sealing and is positioned in the hollow cylinder, and at the moment, the piston is provided with a core rod, and the piston and the hollow cylinder can be driven to move relatively by pushing the core rod. As shown in fig. 1, the structure of the syringe is given by a hollow cylinder, a piston and a core rod.

Pretreatment module enrichment ¹⁸ The specific process of F ions can be as shown in FIGS. 6 (a) to 6 (c),

initially, as shown in fig. 6 (a), the first to sixth valves 1 to 6 are in a state in which the first negative pressure line N1 is evacuated. The second syringe 22 will contain ¹⁸ F ion oxygen [ ¹⁸ O]Equipped by the eighteen water ¹⁸ F ion oxygen [ ¹⁸ O]Eighteen water flows through ¹⁸ In the case of the F ion enrichment bin 21, ¹⁸ f ion at ¹⁸ The F ion enrichment bin 21 is enriched, and the rest liquid flows into the first recovery container 18;

thereafter, as shown in FIG. 6 (b), the second to third valves 2 to 3 are set so that the first syringe 20 is drawn into the first reagent container 19 ¹⁸ F, leaching liquid;

finally, as shown in FIG. 6 (c), the states of the third to sixth valves 3 to 6 are shown, and the first syringe 20 will ¹⁸ F, pushing out the leaching solution ¹⁸ F, the leacheate is concentrated in ¹⁸ F ion enrichment binIn the inner part ¹⁸ F ions are sent to the reaction module.

The embodiment provides a specific preprocessing module which can simply and conveniently process ¹⁸ Enriching F ions and concentrating ¹⁸ The F ions are leached and sent to a subsequent reaction module. Especially when the valves, positive pressure pipeline, negative pressure pipeline and injector are automatically controlled ¹⁸ F, automatic treatment of enrichment, leaching and feeding of F ions into a reaction module.

In one embodiment, the preprocessing module further comprises:

a first linear drive (not shown in the figures) capable of moving the piston of the first syringe 20 inside the hollow cylinder;

a second linear drive (not shown in the figures) capable of moving the piston of the second syringe 22 inside the hollow cylinder;

The present embodiment controls the first syringe 20 and the second syringe 22 by providing the first linear driving device and the second linear driving device.

When the pneumatic rod and the hydraulic rod are matched with controllers such as a PLC, the automatic control of the first injector 20 and the second injector 22 is conveniently realized.

By using the screw rod, the strokes of the pistons in the first injector 20 and the second injector 22 can be accurately controlled, and especially when the screw rod is driven by a stepping motor, the automatic and accurate control of the first injector 20 and the second injector 22 can be conveniently realized by matching with a microprocessor control system (PLC and the like). The screw rod driven by the stepping motor can be assembled by itself, and the finished product of the electric push rod (a screw rod system) can also be purchased directly.

In one embodiment, as shown in fig. 1, the pretreatment module further includes a positive pressure negative pressure pipeline 23 and a liquid adding pipeline 24, where the positive pressure negative pressure pipeline 23 and the liquid adding pipeline 24 respectively penetrate through the piston of the second syringe 22 and extend into the closed space formed by the piston of the second syringe 22 and the hollow cylinder;

Preferably, the liquid feeding pipe 24 is provided with a flow meter, so as to control the liquid feeding amount, and/or the liquid feeding pipe 24 is provided with a control valve (such as an electric control valve, particularly a solenoid valve) which can control the on-off state of the pipe, so as to control whether liquid feeding is performed.

In the present application, the positive pressure negative pressure pipeline 23 is a positive pressure pipeline P0 of a positive pressure negative pressure pipeline, and the negative pressure pipeline N0 of the positive pressure negative pressure pipeline is connected to one pipeline, and the one pipeline passes through the piston (as shown in fig. 1); or the positive pressure pipeline P0 of the positive pressure negative pressure pipeline and the negative pressure pipeline N0 of the positive pressure negative pressure pipeline respectively penetrate through the pistons.

The present application provides a method of adding liquid (including ¹⁸ F ion oxygen [ ¹⁸ O]Eighteen), specifically, liquid is supplied through the liquid supply line, while vacuum is drawn through the negative pressure line N0 of the positive pressure negative pressure line in order to prevent excessive pressure in the second syringe 22, thereby realizing liquid supply. After filling, the liquid in the second syringe 22 can be discharged for subsequent processing by pushing the piston down/pushing out inert gas (pressurization) through the positive pressure line P0 of the positive pressure negative pressure line.

This embodiment shows a solution for filling the second syringe 22. Thereby providing more contents ¹⁸ F ion oxygen [ ¹⁸ O]Eighteen water to perform ¹⁸ F ion enrichment, provide more and more for subsequent reaction ¹⁸ F, ion. And may provide positive pressure to the subsequent flow Cheng Jiaye by positive pressure line P0 of the positive pressure negative pressure line or more precisely to the subsequent flow Cheng Jiaye by pushing the piston.

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

a seventh valve 7, an eighth valve 8, a ninth valve 9, a tenth valve 10, an eleventh valve 11, a twelfth valve 12 and a thirteenth valve 13, wherein the seventh valve 7 to the tenth valve 13 respectively at least comprise a first interface, a second interface and a third interface, and any two interfaces of the three interfaces can be conducted or none of the three interfaces can be conducted by the seventh valve 7 to the tenth valve 13; the first port of the seventh valve 7 is connected to the pretreatment module (the second port of the sixth valve 6), the second port of the seventh valve 7 is connected to the first port of the eighth valve 8, the second port of the eighth valve 8 is connected to the first port of the ninth valve 9, the second port of the ninth valve 9 is connected to the first port of the tenth valve 10, the second port of the tenth valve 10 is connected to the first port of the eleventh valve 11, the second port of the eleventh valve 11 is connected to the first port of the twelfth valve 12, the second port of the twelfth valve 12 is connected to the first port of the thirteenth valve 13, and the third port of the twelfth valve 12 is connected to the purification module (the fourth port of the fourteenth valve 14);

The reaction vessel 25 is respectively connected with the second negative pressure pipeline N2 and the third port of the seventh valve 7, wherein preferably, control valves (such as electric control valves, specifically, electromagnetic valves) are arranged on the pipelines between the second negative pressure pipeline N2, the reaction vessel 25 and the third port of the seventh valve 7, and the control valves can control the on-off of the pipelines, so that the reaction can be ensured to be carried out in the reaction vessel 25;

a temperature control assembly (not shown in the drawings) for heating and/or cooling the reaction vessel 25, wherein the heating can be performed by an electric heating manner, the cooling can be performed by an air cooling manner, and the details can be performed with reference to the prior art, and the details are not repeated here;

a second reagent vessel 26 connected to the third port of the eighth valve 8, the second reagent vessel 26 being for holding a compound i precursor acetonitrile solution;

a third syringe 27 connected to a third port of the ninth valve 9;

a third reagent container 28 connected to the third port of the tenth valve 10, the third reagent container 28 for holding a TFA/ACN (trifluoroacetic acid/acetonitrile) solution;

a fourth reagent container 29 connected to the third port of the eleventh valve 11, the fourth reagent container 29 being for containing water (sterilized water for injection);

A fifth reagent container 30 connected to the third port of the thirteenth valve 13, the fifth reagent container 30 being used for containing absolute ethanol;

preferably, the seventh valve 7, the eighth valve 8, the ninth valve 9, the tenth valve 10, the eleventh valve 11, the twelfth valve 12, and the tenth valve 13 are all electrically controlled valves (e.g., solenoid valves).

The structures of the seventh to thirteenth valves 7 to 13, the third syringe 27, etc. in the present embodiment have been described above, and will not be described here.

The specific process of the reaction performed by the reaction module is shown in figures 7 (a) to 7 (h),

initially, the seventh valve 7 is in a state as shown in fig. 7 (a), at which time the pretreatment module enriches ¹⁸ The F ions and the like enter the reaction vessel 25 (specifically, may be a reaction bottle) through the seventh valve 7.

Thereafter, as shown in fig. 7 b, the first to seventh valves 1 to 7 are set in a state in which the first positive pressure line P1 outputs positive pressure (inert gas is introduced) to the reaction vessel 25 and the second negative pressure line N2 is evacuated, and the temperature control means heats the reaction vessel 25 to remove the solvent, and the heating temperature at this time is 80 to 130 ℃, whereby activated reaction vessel 25 can be obtained ¹⁸ F, ion.

Thereafter, as shown in fig. 7 (c), the third syringe 27 draws the acetonitrile solution of the precursor of compound i in the second reagent vessel 26 in the state of the eighth valve 8 to the ninth valve 9;

Thereafter, as shown in FIG. 7 (d), the third syringe 27 extracts acetonitrile solution of the precursor of Compound I (acetonitrile solution containing 1 to 10mg of the precursor of Compound I)

0.2-2.0 ml) into the reaction vessel 25; heating the temperature control assembly, heating to 90-140 ℃ under a closed condition, and reacting for 2-20 min, wherein the precursor of the compound I and K ¹⁸ F/K ₂₂₂ Nucleophilic substitution reaction is carried out to generate the compound I tertiary butyl ester;

thereafter, as shown in FIG. 7 (e), the third syringe 27 draws the TFA/ACN solution contained in the third reagent vessel 28 from the state of the ninth to tenth valves 9 to 10;

thereafter, as shown in FIG. 7 (d), the third syringe 27 pushes the withdrawn TFA/ACN solution (10 to 50% TFA/ACN solution, 0.2 to 2.0 ml) into the reaction vessel 25 in the state of the seventh to ninth valves 7 to 9; heating the temperature control assembly, and reacting substances in the reaction container 25 at 30-100 ℃ for 1-30 min to remove tert-butyl ester protecting groups;

after the reaction is cooled, the states of the first valve 1 to the seventh valve 7 are as shown in fig. 7 (b), the first positive pressure pipeline P1 outputs positive pressure into the reaction container 25, the second negative pressure pipeline N2 is vacuumized, and the temperature control component heats the reaction container 25, so that TFA/ACN is removed;

Thereafter, as shown in fig. 7 (f), the third syringe 27 pumps the water contained in the fourth reagent container 29 in the state of the ninth to eleventh valves 9 to 11;

after that, as shown in fig. 7 (d), the third syringe 27 pushes the extracted water into the reaction vessel 25 in the state of the seventh to ninth valves 7 to 9;

then, as shown in fig. 7 (g), the third syringe 27 pumps the absolute ethanol contained in the fifth reagent container 30 in the state of the ninth to eleventh valves 9 to 13;

after that, as shown in fig. 7 (d), the third syringe 27 pushes the extracted absolute ethyl alcohol into the reaction vessel 25 in the state of the seventh to ninth valves 7 to 9;

thereafter, as shown in fig. 7 (d), the seventh to ninth valves 7 to 9 are still in the state of being in fluid in the reaction vessel 25 drawn by the third syringe 27;

finally, as shown in fig. 7 (h), the ninth to twelfth valves 9 to 12 are set, and the third syringe 27 pushes the liquid in the extracted reaction vessel 25 into the purification module.

The embodiment provides a specific reaction module, through changing the seventh valve 7 to the thirteenth valve 13 in different working states and the cooperation of the first positive pressure pipeline P1, the second negative pressure pipeline N2, the reaction container 25 and the temperature control component, the compound I precursor and the K are skillfully realized through simple equipment ¹⁸ F/K ₂₂₂ Nucleophilic substitution reaction is carried out to generate compoundT-butyl ester removal reaction of the compound I and t-butyl ester. Especially when each valve, positive pressure pipeline, negative pressure pipeline, syringe are automatic control, can realize the automation of above-mentioned two step reaction.

In one embodiment, the reaction module further comprises:

a third linear drive (not shown in the figures) capable of moving the piston of the third syringe 27 inside the hollow cylinder;

The present embodiment controls the third syringe 27 by providing a third linear drive.

When the pneumatic rod and the hydraulic rod are matched with a PLC and other controllers, the automatic control of the third injector 27 is conveniently realized.

By using the screw, the stroke of the piston in the third syringe 27 can be accurately controlled, and especially when the screw is driven by a stepping motor, the automatic and accurate control of the third syringe 27 can be conveniently realized by matching with a microprocessor control system (PLC and the like). The screw rod driven by the stepping motor can be assembled by itself, and the finished product of the electric push rod (a screw rod system) can also be purchased directly.

In one embodiment, as shown in fig. 2, the purification module comprises:

a fourteenth valve 14, where the fourteenth valve 14 includes at least a first interface, a second interface, a third interface, a fourth interface, a fifth interface, and a sixth interface (corresponding to (1) to (6) in fig. 5, respectively), and the fourteenth valve 14 is capable of switching between a first mode and a second mode, where the first mode is that the first interface is conducted with the second interface, the third interface is conducted with the fourth interface, and the fifth interface is conducted with the sixth interface; the second mode is that the second interface is conducted with the third interface, the fourth interface is conducted with the fifth interface, and the sixth interface is conducted with the first interface; the fourth port of the fourteenth valve 14 is connected to the reaction module (the third port of the twelfth valve 12) (the line a is connected to the line a');

a chromatographic column assembly 31, wherein one end of the chromatographic column assembly 31 is connected with the second interface of the fourteenth valve 14;

a dosing ring 32 (also called a sample injection ring), wherein two ends of the dosing ring 32 are respectively connected with the third interface of the fourteenth valve 14 and the sixth interface of the fourteenth valve 14;

a liquid transfer pump 33 connected to the first port of the fourteenth valve 14 for transferring a fluid (a solution of ethanol and water in a ratio of ethanol/water=5/1 to 2/1);

A second recovery tank 34 connected to a fifth port of the fourteenth valve 14;

a fifteenth valve 15, where the fifteenth valve 15 includes at least a first interface, a second interface, and a third interface, and the fifteenth valve 15 is capable of implementing conduction between the first interface and the second interface or between the first interface and the third interface; a first port of the fifteenth valve 15 is connected to the other end of the column assembly 31, a second port of the fifteenth valve 15 is connected to the prescription module (a third port of the sixteenth valve 16), and a third port of the fifteenth valve 15 is connected to the second recovery vessel 34;

preferably, the fourteenth valve 14 and the fifteenth valve 15 are electrically controlled valves.

First, as shown in fig. 5, a six-way valve is provided, which can realize the function of the fourteenth valve 14 described above.

As shown in fig. 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, where the six-way valve body V3 is provided with a first port (1), a second port (2), a third port (3), a fourth port (4), a fifth port (5), and a sixth port (6) in a counterclockwise direction, respectively. Through the rotary valve core V4, the first interface (1) is communicated with the second interface (2), the third interface (3) is communicated with the fourth interface (4), the fifth interface (5) is communicated with the sixth interface (6) (as shown in fig. 5 (a)), or the second interface (2) is communicated with the third interface (3), the fourth interface (4) is communicated with the fifth interface (5), and the sixth interface (6) is communicated with the first interface (1) (as shown in fig. 5 (b)). In addition, given the above six-way valve structure, those skilled in the art know how to control the rotation of the six-way valve spool V4 by a fixed angle relative to the six-way valve body V3 to achieve the electric (electromagnetic) control of the six-way valve (e.g., to provide a stepper motor to control the rotation of the spool V4).

In addition, as shown in fig. 2 (a) and 2 (b), the fifteenth valve 15 is a three-way valve, and the three-way valve can realize the conduction between the first interface (1) and the second interface (2) or the conduction between the first interface (1) and the third interface (3), which is the prior art, and can directly purchase corresponding electric control valves (such as electromagnetic valves) in the market.

The chromatographic column is prior art and will not be described in detail herein. The chromatographic column assembly 31 of the present application is an existing chromatographic column or a combination of multiple chromatographic columns (e.g., multiple columns in series and/or parallel).

The purification module can perform the purification process as shown in fig. 2 (a) and 2 (b),

initially, as shown in fig. 2 (a), the fourteenth valve 14 is in a state in which the solution of the crude dissolved compound i flowing from the reaction module enters the dosing ring 32 through the fourth port (4) and the third port (3), and a small amount of the surplus solution flows into the second recovery vessel 34 through the sixth port (6) and the fifth port (5), and the solution of the crude dissolved compound i remains in the dosing ring 32.

Then, as shown in fig. 2 (b), the fourteenth valve 14 is in a state in which the fifteenth valve 15 opens the first port (1) and the third port (3), and the liquid transfer pump 33 starts to operate. The liquid delivery pump 33 pushes out the fluid (ethanol and water), and the fluid flows through the first interface (1) and the sixth interface (6), then brings out the solution of the crude product of the dissolved compound I in the dosing ring 32, and flows into the chromatographic column assembly 31 through the third interface (3) and the second interface (2), so as to purify.

Finally, the fifteenth valve 15 opens the first port (1) and the second port (2), and the fluid pushed out by the liquid delivery pump 33 pushes the purified compound i product solution into the prescription module.

The embodiment provides a specific purification module, and the purification of the crude product of the compound I to obtain a pure product of the compound I is realized through changing the fourteenth valve 14 and the fifteenth valve 15 in different working states and matching with the liquid delivery pump 33. In particular, when the valves and the liquid transfer pump 33 are automatically controlled, the purification can be automated.

In one embodiment, the prescribing module includes:

a sixteenth valve 16 and a seventeenth valve 17, wherein the sixteenth valve 16 and the seventeenth valve 17 at least comprise a first interface, a second interface and a third interface respectively, and the sixteenth valve and the seventeenth valve can realize the conduction of any two interfaces or the non-conduction of any three interfaces; wherein the first port of the sixteenth valve 16 is connected to the second port of the tenth valve 13, the second port of the sixteenth valve 16 is connected to the first port of the seventeenth valve 17, the third port of the sixteenth valve 16 is connected to the purification module (the second port of the fifteenth valve 15) and the second port of the seventeenth valve 17 is connected to the third negative pressure line N3;

A finished product collection container 36 connected to the transfer container 35;

and a transfer container 35 connected with the third port of the seventeenth valve 17, the finished product collecting container 36 and the fourth negative pressure pipeline N4, wherein the transfer container 35 contains polysorbate 80 (ii), sodium chloride, vitamin C and sterilized water for injection for prescription.

The structure of the sixteenth valve 16, seventeenth valve 17, etc. in the present embodiment is described above and will not be described here.

The specific process of enrichment and prescription by the prescription module is shown in figures 8 (a) to 8 (b),

initially, the sixteenth valve 16 and the seventeenth valve 17 are in the state shown in fig. 8 (a), and at this time, the product solution of compound i flowing out from the purification module is introduced into the transfer vessel 35 to be prescribed;

thereafter, as shown in FIG. 8 (b), the first to seventeenth valves 1 to 17 are set to a positive pressure in the first positive pressure line P1, and the prescribed compound I solution is pushed into the final product collection container 36, whereby the compound I liquid composition is collected. Preferably, a filter (e.g., a needle filter) is provided between the transfer vessel 35 and the finished product collection vessel 36, so that the solution of compound i flowing out of the transfer vessel 35 is filter-sterilized to obtain the final product.

The present example shows a specific prescription module, by controlling the sixteenth valve 16 and seventeenth valve 17 to work in cooperation with the purification module, the prescription of the purified compound i is achieved, and the compound i liquid composition is further collected. In particular, when the sixteenth valve 16, the seventeenth valve 17, and the like are automatically controlled, automation of prescription and collection can be achieved.

In addition, in the above technical solution, a detection/monitoring device is provided to detect the operation of the device. In particular, it can be used in a pair of ¹⁸ A radioactivity detector is provided at one or more positions in the line between the F-ion enrichment bin 21, the fifth reagent container 30, the twelfth valve 12 and the fourteenth valve 14 to detect radioactivity. An ultraviolet detector and a radioactivity detector can be provided on the chromatographic column assembly to determine if control begins to collect the purified mobile phase.

This example provides a method of producing a liquid composition of compound i using the apparatus described above, comprising:

enrichment using a pretreatment module ¹⁸ F, ion;

More specific operation steps have been described above and will not be described in detail.

Although embodiments of the present application have been described above, the present application is not limited to the specific embodiments and fields of application described above, which are merely illustrative, instructive, and not restrictive. Those skilled in the art, having the benefit of this disclosure, may make numerous forms of the invention without departing from the scope of the invention as claimed.

Claims

1. An apparatus for producing a liquid composition of compound i, comprising:

a pretreatment module for enriching ¹⁸ F, ion;

the preprocessing module comprises:

a second syringe for introducing a liquid composition containing a compound I into the apparatus for producing a liquid composition containing a compound I ¹⁸ F ion oxygen [ ¹⁸ O]Eighteen water;

the positive pressure negative pressure pipeline and the liquid adding pipeline respectively penetrate through the piston of the second injector and extend into the second injector; a core bar which drives the piston and the hollow cylinder to move relatively is arranged in the piston of the second injector;

the reaction module includes:

The reaction container is respectively connected with the second negative pressure pipeline and the third interface of the seventh valve; a pipeline for connecting the reaction vessel and the third port of the seventh valve extends into the bottom of the reaction vessel; control valves for controlling the on-off of the pipelines are arranged on the pipelines among the second negative pressure pipeline, the reaction container and the third interface of the seventh valve;

a temperature control assembly for heating and/or cooling the reaction vessel;

a second reagent container connected to a third port of the eighth valve;

a third syringe connected to a third port of the ninth valve;

a third reagent container connected to a third port of the tenth valve;

a fourth reagent container connected to the third port of the eleventh valve;

a fifth reagent container connected to a third port of the tenth valve;

the pretreatment module further includes a first positive pressure line capable of providing positive pressure to a first port of the seventh valve.

2. The apparatus of claim 1, wherein,

the preprocessing module further comprises:

3. The apparatus of claim 1, wherein,

the reaction module further comprises:

4. The apparatus of claim 1, wherein,

the purification module comprises:

A liquid delivery pump connected to the first port of the fourteenth valve;

the fifteenth valve at least comprises a first interface, a second interface and a third interface, and the fifteenth valve can realize the conduction between the first interface and the second interface or the conduction between the first interface and the third interface; the first interface of the fifteenth valve is connected with the other end of the chromatographic column assembly, the second interface of the fifteenth valve is connected with the prescription module, and the third interface of the fifteenth valve is connected with the second recovery container.

5. The apparatus of claim 4, wherein,

the prescribing module includes:

A finished product collection container;

6. A process for the production of a liquid composition of compound i using an apparatus according to any one of claims 1 to 5, comprising:

enrichment using a pretreatment module ¹⁸ F, ion;

7. Use of the apparatus according to any one of claims 1 to 5 for the production of liquid compositions of compound i.