Method for preparing a liquid composition containing compound I and its use in myocardial perfusion PET imaging.

Abstract

The present application provides a method for preparing a liquid composition containing Compound I, which comprises a step of purifying a crude product containing Compound I by high performance liquid chromatography, and its use in myocardial perfusion PET imaging, wherein the mobile phase used in the purification step by high performance liquid chromatography contains ethanol and water. By optimizing the process parameters and process flow, it can be applied to large-scale batch activity production and meet the needs of automation. The resulting myocardial perfusion PET contrast agent has high radiochemical purity, high activity concentration, good product stability, and high and stable yield or output.

Description

[Technical Field]

[0001] This application belongs to the field of chemical and pharmaceutical technology, and more particularly to a method for preparing a liquid composition containing compound I and its use in myocardial perfusion PET imaging. [Background technology]

[0002] Myocardial perfusion imaging began to be used in the 1970s as a non-invasive examination of cardiac disease, and its enormous diagnostic value has been widely accepted worldwide, making it one of the most important imaging methods in the diagnosis, evaluation of treatment effectiveness, and prognosis of coronary heart disease. Myocardial perfusion single-photon emission computed tomography (SPECT) imaging technology is currently the primary non-invasive perfusion imaging method used clinically for the detection of coronary heart disease. However, compared to SPECT, positron emission tomography (PET) imaging has higher spatial and temporal resolution, which allows for effective reduction of tissue attenuation, and enables absolute quantification of coronary blood flow using standard tissue attenuation correction methods. Furthermore, the short half-life of the positron nuclide can effectively reduce the radiation dose around the target tissue, and the short half-life also allows for a shorter interval between static and motion imaging. Commonly used myocardial perfusion PET contrast agents include: 15 O-H2O, 13 N-NH3·H2O, 82 This includes Rb, etc. However, the half-lives of the above contrast agents are all short, and their clinical application remains largely limited. Compared to other positron-emitting radionuclides, 18 F has a long half-life (t 1 / 2 Because it has a low positron energy (average energy 249.8 keV) (109.8 minutes), causes little radiation damage to normal tissue, has a van der Waals radius (1.35) similar to that of hydrogen (1.2), and does not affect the biological activity of the labeled compound, the development of a new fluorine-18 labeled myocardial perfusion contrast agent has practical significance.

[0003] Compound I has the chemical name 2-tert-butyl-4-chloro-5-((3-((4-((2-(2-fluoro 18 F]ethoxy)ethoxy)methyl))-1H-1,2,3-triazol-1-yl)methyl)benzyl)oxy)pyridazin-3(2H)-one, contains the radionuclide 18 F, can be used in positron emission tomography (PET) imaging, has the characteristic that the content of the chemical substance is very small and a pure product cannot be isolated, and most of the prepared products exist in a solution state.

Disclosure of the Invention

[0004] In the prior art, in the preparation of Compound I, there is a problem that the concentration of 18 F ions added is high, but the yield of the final product is low. Furthermore, the radiochemical purity of the prepared Compound I is not high, especially when left for a certain period of time, the radiochemical purity significantly decreases, and the stability cannot meet the application requirements.

[0005] The object of the present application is to provide a large batch of a liquid composition of Compound I that meets the quality requirements such as high radiochemical purity, high activity concentration, good product stability, and high and stable yield or quantity.

[0006] The object of the present application is to provide an automatic preparation method for a large batch of a liquid composition of Compound I for meeting the needs of clinical pharmaceuticals and designing a continuous and stable production process. The technical route provided by the present application can meet the needs of a large amount of initial 18 F activity labeling, optimize the usage amount of the reaction precursor, reaction time, and purification HPLC conditions, improve the reaction yield, and improve the radiochemical purity and stability of Compound I.

[0007] The technical solution of the present application is as follows. 1. A method for preparing a liquid composition of Compound I, comprising the following steps: The process includes purifying a crude product containing compound I by high-performance liquid chromatography. The mobile phase used in the purification step by high-performance liquid chromatography comprises ethanol and water. The aforementioned compound I is 2-tert-butyl-4-chloro-5-((3-((4-((2-(2-fluoro[ 18 F]Ethoxy)ethoxy)methyl)-1H-1,2,3-triazole)-1-yl)methyl)benzyl)oxy)pyridazine-3(2H)-one, A preparation method wherein the mobile phase further comprises one or more of the following: sodium vitamin C, vitamin C, and gentisic acid. 2. In the purification step by high-performance liquid chromatography, In the mobile phase, the amount of ethanol is 0.2 to 2 parts by volume per 1 part by volume of water. The preparation method described in item 1. 3. In the mobile phase, the amount of ethanol is 0.4 to 1 part by volume per 1 part by volume of water. The preparation method described in item 2. 4. In the purification step by high-performance liquid chromatography, The amount of sodium vitamin C added is 0 to 20 mg / mL, preferably 0.2 to 10 mg / mL. The preparation method described in item 1. 5. In the purification step by high-performance liquid chromatography, The amount of vitamin C added is 0 to 10 mg / mL, preferably 0.1 to 5 mg / mL. The preparation method described in item 1. 6. In the purification step by high-performance liquid chromatography, The amount of gentisinic acid added is 0 to 10 mg / mL, preferably 0.1 to 5 mg / mL. The preparation method described in item 1. 7. The chromatography column used in the purification step by high-performance liquid chromatography is a silica gel column, preferably a reversed-phase C18 silica gel column, and more preferably an XBridge BEH C18 OBD Prep column. Preferably, isocratic elution is used for purification, and the elution flow rate of the mobile phase is 3-6 mL / min. The preparation method described in item 1. 8. Prior to the purification step by high-performance liquid chromatography, the process further includes a step of carrying out a nucleophilic substitution reaction, In the aforementioned nucleophilic substitution reaction, the activated 18 The F ions are mixed with a precursor-containing solution of compound I to carry out a nucleophilic substitution reaction, producing a crude product containing compound I. The name of the precursor of compound I is 2-(2-((1-(3-(((1-(tert-butyl)))-5-chloro-6-oxo-1,6-dihydropyridazine-4-yl)oxy)methyl)benzyl)-1H-1,2,3-triazole-4-yl)methoxy)ethoxy)ethyl-4-methylbenzenesulfonate methyl ester. The preparation method described in item 1. 9. In the nucleophilic substitution reaction, the reaction solvent is an aprotic polar solvent, and the amount of the precursor of compound I / 18 The ratio of F ion activities is in the range of (0.5-8):1, the reaction temperature is 90-140°C, the reaction time is 5-60 minutes, and it is a closed reaction. The unit of dose of the precursor of compound I is mg. 18 The unit of F ion activity is Ci. The preparation method described in item 8. 10. The aprotic polar solvent is one or more of acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, and 2-methyl-2-butanol. The preparation method described in item 9. 11. Before the step of the nucleophilic substitution reaction, 18 The process further includes a step of preparing F ions, The aforementioned 18 The step of preparing F ions is 18Preparation of F-ion solution, 18 Concentration and elution of F ions, and 18 Further includes activation of F ions, More preferably, The aforementioned 18 In the preparation of F-ion solutions, an accelerator is used 18 Prepare an F ion solution, The aforementioned 18 In the concentration of F ions, the prepared ions were passed through an anion exchange cartridge. 18 Concentrate the F ion solution, The aforementioned 18 For the elution of F ions, a cryptand and alkali metal salt catalyst solution is used. 18 Elute F ions, The aforementioned 18 In the activation of F ions, the temperature is programmed to dry the solvent with nitrogen or other inert gas. 18 Activates the F ion, and the activated 18 To obtain F ions, The preparation method described in item 8. 12. The above 18 In the step of preparing the F-ion solution, 18 Water containing oxygen is transferred to the target position of the accelerator, and the accelerator is started to generate a proton beam. 18 By colliding water containing oxygen, 18 A solution containing F ions is produced, 18 The initial activity of F is 0.045Ci to 11Ci, preferably the above 18 The initial activity of the F ion is 3.15 Ci to 11 Ci. The preparation method described in item 11. 13. The above 18 In the F ion concentration step, The anion exchange cartridge is a tetraalkylammonium salt anion exchange cartridge. The preparation method described in item 11. 14. The above 18 In the F ion elution step, In the catalyst solution of the cryptand and alkali metal salt, the dose of the cryptand is 5 to 40 mg, and the dose of the alkali metal salt is 1.5 to 20 mg. Preferably, the cryptand is 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8,8,8]hexacosane (cryptofix-2.2.2, aminopolyether), and the alkali metal salt is one or more of K2CO3, Na2CO3, Cs2CO3, KHCO3, and NaHCO3. More preferably, the catalyst solution is selected from a mixed solvent system of acetonitrile and water, and the volume ratio of acetonitrile to water is (0.2 to 10):1. The preparation method described in item 11. 15. The above 18 In the F ion activation step, The activation temperature is 80-130°C. The control according to the temperature program follows these steps: 100~120°C, positive pressure 50~200mbar, vacuum pressure -20~-60mbar, evaporation 60~120 seconds; 120~130°C, positive pressure 50~200mbar, vacuum pressure -20~-60mbar, evaporation 150~200 seconds; 120~130°C, positive pressure 50~200mbar, vacuum pressure -60~-100mbar, evaporation 10 seconds ~30 seconds; 100~120℃, positive pressure 800~1200mbar, vacuum pressure -800~-1000mbar, evaporation 80~120 seconds; 80~100℃, positive pressure 400~600mbar, vacuum pressure -800~-1000mbar, evaporation 100~120 seconds; 80~100℃, positive pressure 600~900mbar, vacuum pressure -800~-1000mbar, evaporation 10~20 seconds, including The preparation method described in item 11. 16. Use of a liquid composition of compound I prepared by any one of the methods described in items 1 to 15 in a myocardial perfusion PET contrast agent.

[0008] Furthermore, this application provides a liquid composition containing compound I, and the specific technical proposal is as follows: 1. A liquid composition of compound I comprising one or more selected from vitamin C, sodium vitamin C, and gentisic acid, The aforementioned compound I is 2-tert-butyl-4-chloro-5-((3-((4-((2-(2-fluoro[ 18 A liquid composition containing F]ethoxy(ethoxy)methyl)-1H-1,2,3-triazole)-1-yl)methyl)benzyl)oxy)pyridazine-3(2H)-one. 2. The liquid composition according to item 1, wherein the ratio of the vitamin C concentration (mg / mL) to the compound I activity concentration (mCi / mL) is 0.02 to 0.2. 3. The liquid composition according to item 2, wherein the ratio of the vitamin C concentration (mg / mL) to the compound I activity concentration (mCi / mL) is 0.04 to 0.15. 4. The liquid composition according to item 1, wherein the ratio of the gentisinic acid concentration (mg / mL) to the compound I activity concentration (mCi / mL) is 0.02 to 0.2. 5. The ratio of the gentisinic acid concentration (mg / mL) to the compound I activity concentration (mCi / mL) is 0.04 to 0.15. The liquid composition described in item 4. 6. The ratio of the vitamin C sodium concentration (mg / mL) to the compound I activity concentration (mCi / mL) is 0.04 to 1. The liquid composition described in item 1. 7. The ratio of the vitamin C sodium concentration (mg / mL) to the compound I activity concentration (mCi / mL) is 0.1 to 1. The liquid composition described in item 6. 8. The amount of sodium vitamin C is 2 to 10 parts by weight per 1 part by weight of vitamin C. The liquid composition described in item 1. 9. The amount of sodium vitamin C is 3 to 10 parts by weight per 1 part by weight of vitamin C. The liquid composition described in item 8. 10. The amount of gentisic acid is 0.1 to 5 parts by weight per 1 part by weight of vitamin C. The liquid composition described in item 1. 11. The amount of gentisic acid is 0.1 to 3 parts by weight per 1 part by weight of vitamin C. The liquid composition described in item 10. 12. The liquid composition according to item 1, wherein the formulation of the liquid composition further comprises an aqueous solution of polyethylene glycol and / or ethanol. 13. The concentration of polyethylene glycol is 0.1 to 0.3 g / mL, preferably 0.1 to 0.2 g / mL. The liquid composition described in item 12. 14. The polyethylene glycol is polyethylene glycol 400. The liquid composition described in item 12. 15. The amount of ethanol is 5 to 20 mL per 100 mL of water. The liquid composition described in item 12. 16. Dissolve one or more of vitamin C, vitamin C sodium, and gentisic acid in water, stir, recover compound I, and mix with them to obtain a liquid composition of compound I. A method for preparing a liquid composition as described in any one of items 1 to 15. 17. Dissolve one or more of vitamin C, sodium vitamin C, and gentisic acid, a polyethylene glycol-based substance, and / or ethanol in water, stir, recover compound I, and mix with them to obtain a liquid composition of compound I. The method for the liquid composition described in item 16. 18. Use of a liquid composition of compound I prepared by any one of items 1 to 15, or by the method described in item 16 or 17, in the preparation of a PET contrast agent for myocardial perfusion.

[0009] Furthermore, this application provides a reagent kit for the automated preparation of a liquid composition of compound I, wherein the reagent kit includes a reaction bottle and a formulation bottle. The reaction bottle includes reaction bottle R1, reaction bottle R2, and reaction bottle R3. The reaction bottle R1 is 18 Used to contain the eluent for F-ion elution, The reaction bottle R2 is 18 It is used to contain a solution of compound I precursor for the nucleophilic substitution reaction of F ions. The reaction bottle R3 is used to contain reagents used to dilute the crude product and rinse the reaction system. The aforementioned prescription bottle includes prescription bottle P1 and prescription bottle P2. The aforementioned prescription bottle P1 18 It is used to transport reaction products after nucleophilic substitution reactions of F ions. The aforementioned formulation bottle P2 18 It is used to contain a substance used to stabilize the reaction product after a nucleophilic substitution reaction of F ions.

[0010] Furthermore, the reaction bottle R1 contains an aminopolyether, potassium carbonate, water for injection, and acetonitrile, preferably with a concentration of 5 to 40 mg / mL of aminopolyether, a concentration of 1.5 to 20 mg / mL of potassium carbonate, and a volume ratio of acetonitrile to water of (0.25 to 19):1. Alternatively, the reaction bottle R2 is 18 The solution comprises an acetonitrile solution of a compound I precursor for the nucleophilic substitution reaction of F ions, preferably having a concentration of the compound I precursor in the acetonitrile solution of 1 to 10 mg / mL. Alternatively, the reaction bottle R3 contains anhydrous ethanol.

[0011] Furthermore, the formulation bottle P1 contains polyethylene glycol, preferably with a concentration of 0.05 to 0.3 g / mL. or, The aforementioned formulation bottle P2 18 It contains one or more of vitamin C, sodium vitamin C, and gentisic acid, which are used to stabilize the reaction product after the nucleophilic substitution reaction of the F ion. Preferably, the vitamin C concentration is 2 to 16 mg / mL, the vitamin C sodium concentration is 15 to 40 mg / mL, and the gentisic acid concentration is 2 to 16 mg / mL.

[0012] Compared to existing technologies, the beneficial effects of this application are as follows: (1) This application optimizes the experimental process design, changes the dose of compound I precursor, shortens the reaction time to achieve the same labeling efficiency, and initial 18 The yield is increased by increasing the radioactive activity of F ions and thereby increasing the labeling efficiency. The process parameters and process flow are clear and specific, making it applicable to large-scale batch activity production and meeting automation needs. (2) In the optimized technology of this application, a radiolysis inhibitor is used in the mobile phase of the purification process, thereby avoiding product loss due to radiolysis during the purification and formulation processes, and thereby improving the yield. Furthermore, in the formulation process of this application, product stability can be ensured because a radiolysis inhibitor is used. (3) This application optimizes the purification process by eliminating the C18 cartridge and using an ethanol / water system instead of an acetonitrile / water system as the mobile phase. This reduces the time required and improves the radiochemical purity and stability of the product. (4) The reagent kit of this application provides convenience, cost savings, and precise control for the automated preparation of liquid compositions of compound I. (5) In the prior art, it is common to prepare samples temporarily, and after each preparation is completed, a testing officer must perform testing before shipment, resulting in a heavy workload, low production efficiency, and high production costs. However, this application allows for the direct preparation of the liquid composition of compound I by using an automated device after it has been prepared into a reagent kit. The process is simple, easy to operate, and the quality of the final product is controllable. Furthermore, under conditions that meet GMP, control can be standardized according to the established manufacturing process requirements, enabling the continuous and stable production of reagent kits that meet the expected quality standards. In this way, the overall process flow is simplified, and production costs are significantly reduced. Details of the Invention

[0013] The chemical name of compound I is 2-tert-butyl-4-chloro-5-((3-((4-((2-(2-fluoro[ 18 F]Ethoxy)ethoxy)methyl))-1H-1,2,3-triazol-1-yl)methyl)benzyl)oxy)pyridazine-3(2H)-one. Its chemical structure is as follows.

[0014] [ka]

[0015] Molecular formula:C 23 H 29 Cl 18 FN5O4 Molecular weight: 492.97

[0016] The mechanism of action of compound I as a myocardial perfusion PET contrast agent is as follows: Upon entering cardiomyocytes, compound I immediately interacts with respiratory chain complex I (MC-I) in mitochondria and remains in the myocardium for a long period. Preliminary animal study data showed high cardiac uptake and low hepatic uptake 15 minutes after injection, and maintained a good cardiac-to-liver ratio 60 minutes after injection, indicating good potential for myocardial perfusion imaging.

[0017] In this application, a liquid composition of compound I or compound I is used as a myocardial perfusion PET contrast agent.

[0018] Compound I precursor: Its chemical name is 2-(2-((1-(3-(((1-(tert-butyl))-5-chloro-6-oxo-1,6-dihydropyridazine-4-yl)oxy))methyl)benzyl)-1H-1,2,3-triazole-4-yl)methoxy)ethoxy)ethyl-4-methylbenzenesulfonate methyl ester, and its chemical structure is as follows.

[0019] [ka]

[0020] Molecular formula:C30 H 36 ClN5O7S Molecular weight: 646.16

[0021] Aminopolyether (K 222 Azacryptand is a three-bridged crown ether molecule with a cryptoid cavity, a typical azacryptand, and a type of cryptand. Due to its unique coordination properties, azacryptands can appropriately select cations to complex with transition metals and heavy metals, and the resulting complexes are more stable and possess both lipophilic and hydrophilic properties, making them excellent research prospects.

[0022] Amino polyether (K) in existing technologies 222 A typical synthesis method for aminopolyether (K) is the highly diluted method proposed by Lehn et al., which is one of the representative non-template ion synthesis methods. The specific procedure is as follows: The starting materials 1,8-diamino-3,6-dioxaoctane and 1,8-diasilloride-3,6-dioxaoctane are dissolved in a large amount of benzene solvent and reacted by heating for 8 hours, then reduced with lithium aluminum tetrahydrogen for 24 hours, separated by column chromatography, and recrystallized to obtain aminopolyether (K). 222 ) is obtained. This method requires large amounts of solvents such as benzene, has a long synthesis route, is complicated to operate, has a low yield, and is not economically beneficial. In addition to the highly dilution method, amino polyether (K 222 Another typical synthetic method for ) is the method proposed by Kulstad and Malmsten, in which Na2CO3 etc. is used as a template and amino polyether (K) in acetonitrile. 222 After obtaining a sodium iodide complex of ) and then decomposing this complex with a resin, an amino polyether (K 222) is obtained. The specific procedure involves refluxing the starting materials 1,2-bis(2-iodoethoxy)ethane and benzylamine in acetonitrile solution for 3 days, and then working up to obtain an intermediate. This intermediate is recrystallized with acetone, filtered, and then a NaI complex is obtained. This complex is decomposed under acidic conditions using a cation exchange resin and an anion exchange resin, respectively, to obtain an aminopolyether (K 222 A solution is prepared. This method is simple in terms of equipment, consumes little solvent, and has relatively mild reaction conditions. However, the applicant found through research that in the decomposition method using ion exchange resin, when the sodium ion content is reduced to a certain level, decomposition cannot proceed and the yield decreases.

[0023] In this application, the applicant has found that existing methods for preparing compound I cannot obtain liquid compositions of compound I in large batches that meet quality requirements, nor can they obtain products with high activity concentrations.

[0024] In this application, a large batch refers to a product with a high total activity, and generally may refer to a product with a total activity exceeding 1 Ci, or 37 GBq. High-activity-concentration products generally refer to products with an activity concentration exceeding 50 mCi / mL, or 1850 MBq / mL.

[0025] In this application, labeling efficiency is defined as follows: 18 A labeling reaction occurs between F and the reaction precursor. 18 This refers to the process where F substitutes for a leaving group in the precursor, converting it into the final labeled product, and the labeled product contains 18 Because F is present, the labeling efficiency is the total amount involved in the reaction. 18 It is defined as the ratio of the activity of the labeled product to the activity of the F-activity.

[0026] In this application, yield means initial 18 This refers to the ratio of the activity of the liquid composition of compound I, the final product, to the activity of F.

[0027] For example, in the prior art, high-performance liquid chromatography (HPLC) is used for purification, and the mobile phase used in this purification step is a mixture of acetonitrile and water. The applicant states, 18 Increasing the activity of F increases the amount of crude compound I obtained, and if the existing method is used as is, the difficulty of purification increases, and the initial 18 We found that the labeling efficiency decreases when the F activity is high. At the same time, the yield calculated after purification also decreases, making it impossible to obtain a large batch of liquid composition of compound I that meets the quality requirements. Therefore, using the reaction and purification conditions of existing technologies, the initial 18 It is clear that simply increasing the F-ion activity is not enough to produce the required high-quality, high-volume batch product. From this, it can be seen that purifying the crude product of compound I using a mixture of acetonitrile and water as the mobile phase results in very low labeling efficiency and yield.

[0028] Furthermore, the applicant found that when purifying the crude product of compound I using a mixture of acetonitrile and water as the mobile phase, it is necessary to remove organic solvents such as acetonitrile from the HPLC mobile phase using a C18 cartridge. However, compound I is highly susceptible to radiolysis and decomposes during purification. During purification with the C18 cartridge, the radioactive material is concentrated to a very small volume, causing radiolysis. After radiolysis, the yield decreases. Moreover, the radiochemical purity and stability of the final compound I product cannot meet the requirements, and the preparation time is prolonged. The C18 cartridge is an octadecyl-bonded silica gel cartridge that can be used for the concentration and removal of organic solvents such as acetonitrile.

[0029] To obtain large batches of liquid compositions of compound I that meet quality requirements, increase labeling efficiency, improve the radiochemical purity and stability of the final product, and shorten the overall reaction process time, the applicant has developed a technical solution that solves the problems of low labeling efficiency, low radiochemical purity, and low stability through repeated verification through multiple studies.

[0030] This application provides a method for preparing compound I, the synthesis route being as follows:

[0031] [ka]

[0032] Activated 18 The F ions are mixed with an acetonitrile solution containing a precursor of compound I, and a nucleophilic substitution reaction is carried out under the action of a catalyst to produce a crude product containing compound I.

[0033] The method for preparing compound I provided in this application involves purifying a crude product containing compound I using high-performance liquid chromatography (HPLC), wherein the mobile phase used in the purification step by high-performance liquid chromatography contains ethanol and water instead of the original acetonitrile and water system. When using the acetonitrile and water system, a C18 cartridge is required to remove the organic solvent, which leads to high-activity radiolysis and makes it impossible to meet production needs.

[0034] In the method for preparing compound I provided in this application, sodium vitamin C (VcNa) and / or vitamin C (Vc) and / or gentisic acid, which are radiolysis inhibitors, are added to the mobile phase used in the high-performance liquid chromatography purification step. Sodium vitamin C, vitamin C, and gentisic acid have radiolysis inhibitory effects. During the HPLC purification process, radioactivity 18 To avoid radiolysis due to the concentration of F ions, adding Vc and / or VcNa and / or gentisic acid to the mobile phase can reduce the radiolysis of compound I during the column purification process.

[0035] The above-mentioned method for preparing compound I provided in this application improves the radiochemical purity of the liquid composition of compound I, eliminates the purification step using a C18 cartridge, and reduces radiolysis on the C18 cartridge.

[0036] In the preparation method of this application, the step of removing the solvent after removing the C18 cartridge is omitted, and injectable ethanol can be used as the mobile phase. Furthermore, using ethanol as the mobile phase reduces the risk of high-risk solvents such as acetonitrile remaining in the liquid composition.

[0037] In some specific embodiments of this application, the purification step by high-performance liquid chromatography is performed in which the mobile phase contains 0.2 to 2 parts by volume of ethanol per 1 part by volume of water, preferably 0.4 to 1 part by volume of ethanol per 1 part by volume of water.

[0038] For example, with respect to 1 part by volume of water, the amount of ethanol may be 0.2 parts by volume, 0.3 parts by volume, 0.4 parts by volume, 0.5 parts by volume, 0.6 parts by volume, 0.7 parts by volume, 0.8 parts by volume, 0.9 parts by volume, 1 part by volume, 1.1 parts by volume, 1.2 parts by volume, 1.3 parts by volume, 1.4 parts by volume, 1.5 parts by volume, 1.6 parts by volume, 1.7 parts by volume, 1.8 parts by volume, 1.9 parts by volume, 2 parts by volume, or any range in between.

[0039] In some specific embodiments of this application, in the purification step by high-performance liquid chromatography, the amount of sodium vitamin C added to the mobile phase is 0 to 20 mg / mL, preferably 0.2 to 10 mg / mL. Here, the amount of sodium vitamin C added may be 0, 2, 5, 8, 10, 12, 15, 20 mg / mL, or any range in between.

[0040] In some specific embodiments of the present application, in the purification step by high-performance liquid chromatography, the amount of vitamin C added to the mobile phase is 0 to 10 mg / mL, preferably 0.1 to 5 mg / mL. The amount of vitamin C added may be 0, 0.1, 0.5, 1, 2, 5, 8, 9, 10 mg / mL, or any range in between.

[0041] In some specific embodiments of this application, in the purification step by high-performance liquid chromatography, the amount of gentisic acid added to the mobile phase is 0 to 10 mg / mL, preferably 0.1 to 5 mg / mL. The amount of gentisinic acid added may be 0, 0.1, 0.5, 1, 2, 5, 8, 9, 10 mg / mL, or any range in between.

[0042] In some embodiments of this application, the chromatography column is a silica gel column, preferably a reversed-phase C18 silica gel chromatography column, and more preferably an XBridge BEH C18 OBD Prep column. This chromatography column is selected because it has acid and alkali resistance and good resolution.

[0043] In some embodiments of this application, isocratic (fixed composition) elution is used in the purification step, and the elution rate of the mobile phase is 3 to 6 mL / min, for example, the elution rate of the mobile phase may be 3, 4, 5, 6 mL / min, or any range in between.

[0044] In some embodiments of this application, a step of performing a nucleophilic substitution reaction is also included prior to the purification step by high-performance liquid chromatography, in which activated 18 The F ions are mixed with a precursor solution of compound I to carry out a nucleophilic substitution reaction, producing a crude product containing compound I.

[0045] Activated 18 The nucleophilic substitution reaction between the F ion and the precursor of compound I can be carried out by methods known to those skilled in the art.

[0046] In some embodiments of this application, in the nucleophilic substitution reaction, the reaction solvent is an aprotic polar solvent, and the dose of compound I precursor / 18The ratio of F ion activity is in the range of (0.5-8):1, the reaction temperature is 90-140°C, the reaction time is 5-60 minutes, it is a closed reaction, and the unit of dose of compound I precursor is mg. 18 The unit for F ion activity is Ci.

[0047] Here, the dose of compound I precursor / 18 The ratio of F ion activities can be in the range of 0.5:1, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1 or any range in between, and the unit of dose of compound I precursor is mg. 18 The unit for F ion activity is Ci. The reaction temperature may be 90, 100, 110, 120, 130, 140°C, or any range in between. The reaction time may be 5, 15, 20, 35, 45, 60 minutes, or any range in between.

[0048] In some embodiments of this application, the dose of the reaction solvent is 0.2 to 5 mL, and the dose of compound I precursor is 0.8 to 20 mg, preferably 7 to 20 mg. Here, the dose of compound I precursor may be 0.8, 2, 6, 7, 8, 12, 18, 20 mg, or any range in between. In some embodiments of this application, the aprotic polar solvent is one or more of acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, and 2-methyl-2-butanol.

[0049] In some embodiments of this application, before the nucleophilic substitution reaction step, 18 The F ion preparation step is also included. 18 The F ion preparation step is, 18 Preparation of F-ion solution, 18 Concentration and elution of F ions, and 18 Further includes activation of F ions, Here, 18 In the preparation of F-ion solutions, an accelerator is used 18 Prepare an F ion solution, 18 In the concentration of F ions, the F ion solution prepared above is concentrated through an anion exchange cartridge, 18 and in the elution of F ions, a cryptand and an alkali metal salt catalyst solution are used to elute the F ions, 18 and in the activation of F ions, the temperature is programmed to dry the solvent with nitrogen or other inert gases to activate the F ions and obtain the activated F ions. 18 In some embodiments of the present application, in the step of preparing the F ion solution, 18 water containing O is transferred to the target position of the accelerator, the accelerator is started to generate a proton beam, and the water containing O is collided to generate a solution containing F ions. 18 In some embodiments of the present application, in the concentration step of F ions, the anion exchange cartridge is a Sep-Pak Accell Plus QMA Carbonate Plus Light Cartridge, specifically a tetraalkylammonium salt anion exchange cartridge. 18 In the present application, the initial activity of F, also referred to as the activity of F ions, means that the accelerator is started to generate a proton beam, and the water containing oxygen

[0050] O] is collided to generate a solution containing F ions, and it refers to the activity of F ions measured using an activity meter. 18 In the present application, the initial activity of F means that the accelerator is started to generate a proton beam, and the water containing oxygen 18 O] is collided. 18 18 18 18

[0051] In some embodiments of the present application, 18 in the concentration step of F ions, the anion exchange cartridge is a Sep-Pak Accell Plus QMA Carbonate Plus Light Cartridge, specifically a tetraalkylammonium salt anion exchange cartridge.

[0052] In the present application, 18 the initial activity of F refers to 18 the activity of F ions, that is, the accelerator is started to generate a proton beam, and the water containing oxygen 18 O] is collided, 18 a solution containing F ions is generated, and it refers to the activity of F ions measured using an activity meter. 18 In the present application,

[0053] the initial activity of F means that the accelerator is started to generate a proton beam, and the water containing oxygen 18 O] is collided, 18 18This refers to a concentration that can be detected immediately after the preparation of a solution containing F ions. Immediate detection refers to a reasonable detection time that can be controlled by a person skilled in the art, such as within 10 minutes after preparation. Furthermore, if the standing time after preparation changes, 18 Those skilled in the art will understand that while the initial activity of F may vary to some extent, the error is usually within ±10%.

[0054] In some embodiments of this application, the 18 The F ion activity is 0.045 Ci to 11 Ci, preferably 3.15 Ci to 11 Ci, for example, 18 The F ion activity can be 0.045Ci, 0.05Ci, 1Ci, 3Ci, 3.15Ci, 5Ci, 6Ci, 8Ci, 9Ci, 10Ci, 11Ci, or any range in between.

[0055] In some embodiments of this application, the 18 In the F-ion elution step, the dose of cryptand in the catalyst solution of cryptand and alkali metal salt is 5 to 40 mg, and the dose of alkali metal salt is 1.5 to 20 mg. The dose of cryptand in the solution may be 5, 8, 10, 15, 20, 40 mg, or any range between these, and the dose of alkali metal salt in the solution may be 1.5, 3, 5, 10, 20 mg, or any range between these.

[0056] In some embodiments of this application, the cryptotande is 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8,8,8]hexacosane (cryptofix-2.2.2, aminopolyether), and the alkali metal salt is one or more of K2CO3, Na2CO3, Cs2CO3, KHCO3, and NaHCO3.

[0057] In some embodiments of this application, the catalyst solution is selected from a mixed solvent system of acetonitrile and water, where the volume ratio of acetonitrile to water is (0.2 to 10):1, for example, the volume ratio of acetonitrile to water may be in the range of 0.2:1, 1:1, 2:1, 4:1, 7:1, 10:1, or in between. The volume of the mixed solvent of acetonitrile and water is 0.3 to 2 mL.

[0058] In some embodiments of this application, 18 In the F ion activation step, the activation temperature is 80-130°C. Here, the programmed temperature is as follows: 100~120°C, positive pressure 50~200mbar, vacuum pressure -20~-60mbar, evaporation 60~120 seconds; 120~130°C, positive pressure 50~200mbar, vacuum pressure -20~-60mbar, evaporation 150~200 seconds; 120~130°C, positive pressure 50~200mbar, vacuum pressure -60~-100mbar, evaporation 10 Includes: ~30 seconds; 100~120℃, positive pressure 800~1200mbar, vacuum pressure -800~-1000mbar, evaporation 80~120 seconds; 80~100℃, positive pressure 400~600mbar, vacuum pressure -800~-1000mbar, evaporation 100~120 seconds; 80~100℃, positive pressure 600~900mbar, vacuum pressure -800~-1000mbar, evaporation 10~20 seconds.

[0059] The method for preparing compound I provided in this application allows for the modification of the compound I precursor, shortening the reaction time to achieve the same labeling efficiency, increasing the labeling efficiency, thereby increasing the yield and obtaining the compound I product. The process parameters and process flow are clear and specific, applicable to large-scale batch activity production, and can meet the needs of automation. Furthermore, a radiolysis inhibitor is used in the mobile phase of the purification process to avoid product loss due to radiolysis during the purification and formulation processes, thereby improving the yield. In addition, the formulation process of this application uses a radiolysis inhibitor, thus ensuring product stability.

[0060] The increase in reaction solvent is based on the fact that compound I, which is required after the reaction is complete, is a lipid-soluble substance. When the proportion of the organic phase increases after dilution with water, the residue of compound I in the reaction bottle decreases, and the yield increases.

[0061] In some embodiments of this application, the preparation of compound I includes the following steps: 1) 18 Preparation of F-ion solution oxygen[ 18 Transfer 2-3g of water containing [O] to the target position of the accelerator, start the accelerator to generate a proton beam and then use oxygen [ 18 By colliding water containing O, 18 It is generated in a solution containing F ions. 2) 18 Concentration of F ions Prepared as described above 18 After passing the F-ion solution through an anion exchange solid-phase extraction cartridge (Waters brand QMA cartridge; preferably the QMA cartridge is activated with 1 mol / L NaHCO3), 18 F ions are concentrated on the QMA cartridge. 3) 18 Elution of F ions Using a cryptand and alkali metal salt catalyst solution 18 The F ions are eluted into the reaction bottle. Specifically, K 222 Mix 5-40 mg with 1.5-20 mg of K2CO3 to prepare a mixed solvent system of acetonitrile and water (volume ratio of acetonitrile to water is (0.2-10):1, volume of acetonitrile and water mixed solvent is 0.3-2 mL), and elute the above QMA cartridge, K 18 F / K 222 The complex is eluted into the reaction bottle. 4) 18 Activation of F ions Step 3) Eluted 18 The F ions are heated to 80-130°C under a flow of nitrogen or inert gas, and the solvent is dried to activate them. 18 F ions are obtained. 5) 18 Nucleophilic substitution reaction of F ions Add 0.2-5 mL of acetonitrile solution of compound I precursor to the reaction bottle. The dose of compound I precursor is 7-20 mg. Heat under sealed conditions at 90-140°C and react for 5-60 minutes. Compound I precursor and K 18 F / K 222 The nucleophilic substitution reaction proceeds, yielding a crude product containing compound I. 6) Purification by high-performance liquid chromatography The crude product containing compound I is loaded into the sample loop, a certain amount of water is extracted to rinse the reaction bottle, and then loaded into the sample loop and purified according to the following chromatographic conditions. Column: Reverse-phase C18 silica gel column Mobile phase: A mixture of ethanol and water. Here, the volume ratio of ethanol to water is (0.2-2):1, and the mobile phase contains 0-20 mg / mL of sodium vitamin C and / or 0-10 mg / mL of vitamin C and / or 0-10 mg / mL of gentisic acid; Flow rate: 3~6mL / min Detector: Radioactivity detector The radioactive signal is monitored and tracked, and the main radioactive peak of compound I is collected in a transfer bottle. After purification, a purified product of compound I is obtained.

[0062] In some embodiments of this application, the mobile phase may contain 0 to 20 mg / mL of sodium vitamin C and / or 0 to 10 mg / mL of vitamin C.

[0063] In some embodiments of this application, the mobile phase may contain 0 to 20 mg / mL of sodium vitamin C and / or 0 to 10 mg / mL of gentisic acid.

[0064] In some embodiments of this application, the mobile phase may contain both vitamin C and gentisic acid, or it may contain only one of vitamin C and gentisic acid.

[0065] This application also provides a liquid composition of compound I as described above, wherein compound I is collected in a transfer bottle to which a formulation has been pre-added, and the liquid composition of compound I is mixed with the HPLC main peak mobile phase to obtain a liquid composition of compound I. The liquid composition of compound I comprises one or more of vitamin C, sodium vitamin C, and gentisic acid.

[0066] In some embodiments of the present application, the ratio of vitamin C concentration (mg / mL) to compound I activity concentration (mCi / mL) is 0.02 to 0.2, and preferably, the ratio of vitamin C concentration (mg / mL) to compound I activity concentration (mCi / mL) is 0.04 to 0.15. For example, the ratio of vitamin C concentration (mg / mL) to compound I activity concentration (mCi / mL) may be 0.02, 0.04, 0.06, 0.08, 0.1, 0.12, 0.14, 0.16, 0.18, 0.2, or any range in between.

[0067] In some embodiments of this application, the ratio of gentisinic acid concentration (mg / mL) to compound I activity concentration (mCi / mL) is 0.02 to 0.2, preferably 0.04 to 0.15. For example, the ratio of gentisinic acid concentration (mg / mL) to compound I activity concentration (mCi / mL) may be 0.02, 0.04, 0.06, 0.08, 0.1, 0.12, 0.14, 0.16, 0.18, 0.2, or any range in between.

[0068] In some embodiments of this application, the ratio of vitamin C sodium concentration (mg / mL) to compound I activity concentration (mCi / mL) is 0.04 to 1, preferably 0.1 to 1. For example, the ratio of vitamin C sodium concentration (mg / mL) to compound I activity concentration (mCi / mL) is 0.04, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, or any range in between.

[0069] In some embodiments of this application, the amount of sodium vitamin C is 2 to 10 parts by weight per 1 part by weight of vitamin C. Preferably, the amount of sodium vitamin C is 3 to 10 parts by weight per 1 part by weight of vitamin C. For example, the amount of sodium vitamin C may be 2, 3, 4, 5, 6, 7, 8, 9, 10 parts by weight, or any range in between, per 1 part by weight of vitamin C.

[0070] In some embodiments of this application, the gentisic acid is 0.1 to 5 parts by weight per 1 part by weight of vitamin C, preferably 0.1 to 3 parts by weight per 1 part by weight of vitamin C. For example, with respect to 1 part by weight of vitamin C, the amount of gentisic acid may be 0.1 parts by weight, 0.5 parts by weight, 1 part by weight, 1.5 parts by weight, 2 parts by weight, 2.5 parts by weight, 3 parts by weight, 3.5 parts by weight, 4 parts by weight, 4.5 parts by weight, 5 parts by weight, or any range in between.

[0071] In some embodiments of this application, the liquid composition of compound I may contain both vitamin C and gentisic acid, or it may contain only one of vitamin C and gentisic acid.

[0072] In some embodiments of this application, the liquid composition of compound I also includes an aqueous solution of polyethylene glycol and / or ethanol, wherein the polyethylene glycol concentration is 0.1 to 0.3 g / mL, preferably 0.1 to 0.2 g / mL. For example, the polyethylene glycol concentration is 0.1, 0.2, 0.3 g / mL, or any range in between.

[0073] In some embodiments of this application, the ethanol concentration in the aqueous ethanol solution is 0.05 to 0.20 mL / mL, and preferably, the ethanol concentration in the aqueous ethanol solution is 0.05 to 0.15 mL / mL. The ethanol concentration in the aqueous ethanol solution is 0.05, 0.10, 10.15, 0.20 mL / mL, or any range in between.

[0074] In some embodiments of this application, the polyethylene glycol is polyethylene glycol 400.

[0075] This application also provides a method for preparing a liquid composition of compound I, in which one or more of vitamin C, sodium vitamin C, and gentisic acid, a polyethylene glycol-based substance, and / or ethanol are dissolved in water and stirred to obtain a liquid composition formulation of compound I.

[0076] In some embodiments of this application, purified compound I is collected in a formulation bottle, which is pre-filled with the above-mentioned liquid composition, and the purification is completed when the liquid composition is mixed with the main peak mobile phase in high-performance liquid chromatography.

[0077] This application also provides the use of a liquid composition of compound I in a myocardial perfusion PET contrast agent.

[0078] This application provides a reagent kit for the automated preparation of a liquid composition of compound I, the reagent kit comprising a reaction bottle and a formulation bottle, the reaction bottle comprising reaction bottle R1, reaction bottle R2, and reaction bottle R3, and reaction bottle R1 is 18 The reaction bottle R2 is used to contain the eluent for F-ion elution. 18 Reaction bottle R3 is used to contain a solution of compound I precursor for the nucleophilic substitution reaction of F ions, and is used to contain reagents used to dilute the crude product and rinse the reaction system. The formulation bottles include formulation bottle P1 and formulation bottle P2, and formulation bottle P1 is 18 Used to transfer reaction products after nucleophilic substitution reactions of F ions, formulation bottle P2 is, 18 It is used to contain a substance used to stabilize the reaction product after a nucleophilic substitution reaction of F ions.

[0079] In some embodiments of this application, the reaction bottle R1 comprises an aminopolyether, potassium carbonate, water for injection, and acetonitrile, preferably with a concentration of 5 to 40 mg / mL of aminopolyether, a concentration of 1.5 to 20 mg / mL of potassium carbonate, and a volume ratio of acetonitrile to water of (0.25 to 19):1. For example, the concentration of the aminopolyether may be 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 21 mg / mL, 22 mg / mL, 23 mg / mL, 24 mg / mL, 25 mg / mL, 26 mg / mL, 27 mg / mL, 28 mg / mL, 29 mg / mL, 30 mg / mL, 31 mg / mL, 32 mg / mL, 33 mg / mL, 34 mg / mL, 35 mg / mL, 36 mg / mL, 37 mg / mL, 38 mg / mL, 39 mg / mL, 40 mg / mL, or any range in between. The concentration of potassium carbonate may be 1.5 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, or any range in between. The volume ratio of acetonitrile to water may be 0.25:1, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, or any range in between.

[0080] In some embodiments of the present application, the reaction bottle R2 is 18The solution comprises an acetonitrile solution of a compound I precursor for the F-ion nucleophilic substitution reaction, preferably with a concentration of compound I precursor in the acetonitrile solution of 1 to 10 mg / mL. For example, the concentration of compound I precursor in the acetonitrile solution may be 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, or any range in between.

[0081] In some embodiments of this application, the reaction bottle R3 contains anhydrous ethanol.

[0082] In some embodiments of this application, the formulation bottle P1 contains polyethylene glycol, preferably with a concentration of 0.05 to 0.3 g / mL, for example, the concentration of polyethylene glycol may be 0.05 g / mL, 0.1 g / mL, 0.15 g / mL, 0.2 g / mL, 0.25 g / mL, 0.3 g / mL, or any range in between.

[0083] In some embodiments of this application, the formulation bottle P2 is 18The solution contains one or more of vitamin C, sodium vitamin C, and gentisic acid, used to stabilize the reaction product after the nucleophilic substitution reaction of the F ion, wherein vitamin C, sodium vitamin C, and gentisic acid are dissolved in water before use, and preferably the concentration of vitamin C is 2 to 16 mg / mL, the concentration of sodium vitamin C is 15 to 40 mg / mL, and the concentration of gentisic acid is 2 to 16 mg / mL. For example, the concentration of vitamin C may be 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, or any range in between. The sodium vitamin C may be 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 21 mg / mL, 22 mg / mL, 23 mg / mL, 24 mg / mL, 25 mg / mL, 26 mg / mL, 27 mg / mL, 28 mg / mL, 29 mg / mL, 30 mg / mL, 31 mg / mL, 32 mg / mL, 33 mg / mL, 34 mg / mL, 35 mg / mL, 36 mg / mL, 37 mg / mL, 38 mg / mL, 39 mg / mL, 40 mg / mL, or any range in between. The gentisinic acid concentration may be 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, or any range in between.

[0084] Reaction bottles R1, R2, R3, formulation bottles P1, and P2 can be configured according to actual needs, as long as their concentration ranges meet the requirements.

[0085] This application provides a general and / or specific description of the materials and test methods used in the tests. In the following examples, unless otherwise specified, % represents weight percent. Unless the manufacturer of the reagents or equipment used is not indicated, they are all commercially available conventional reagent products. Table 1 shows the sources of the raw materials used in the examples.

[0086] [Table 1] [Examples]

[0087] The automated system used is the Trasis AllinOne model. This system's power unit consists of high-purity nitrogen and an electric syringe rotor, providing a vacuum system and equipped with an HPLC purification system. Because the automated system is installed within a radiation shielding box, operators are protected from radiation exposure, allowing for increased working doses. Furthermore, computer control ensures more precise control of process steps, improved reproducibility, and reduced human error.

[0088] Example 1: Preparation of Compound I 1) 18 Preparation of F-ion solution oxygen[ 18 2g of water containing [O] is transferred to the target position of the accelerator, the accelerator is started to generate a proton beam and oxygen [ 18 By colliding water containing O, 18 A solution containing F ions was prepared. In this example, a large amount of starting material was used. 18 F was used, 18 The initial activity of F was 3.5 Ci. 2) 18 Concentration of F ions Prepared as described above 18 After passing the F-ion solution through an anion exchange solid-phase extraction cartridge (Waters brand QMA cartridge, preferably one activated with 1 mol / L NaHCO3), 18F ions were concentrated on the QMA cartridge. 3) 18 Elution of F ions Using a cryptand and alkali metal salt catalyst solution 18 F ions were eluted into the reaction bottle. Specifically, K 222 Mix 15 mg (dissolved in 0.9 mL of acetonitrile) with 1.5 mg of K2CO3 (dissolved in 0.1 mL of water) to prepare a mixed solvent system of acetonitrile and water (the volume ratio of acetonitrile to water is 9:1) (i.e., reaction bottle R1; for its components and preparation, please refer to Preparation of Reaction Bottle R1), and elute the above QMA cartridge, K 18 F / K 222 The complex was eluted into the reaction bottle. 4) 18 Activation of F ions Step 3) Eluted 18 The F ions were activated by programmed heating to 80-130°C under a flow of nitrogen gas, and the solvent was dried by forced air. 18 F ions were obtained. 5) 18 Nucleophilic substitution reaction of F ions 3 mL of acetonitrile solution containing compound I precursor (i.e., reaction bottle R2; see Preparation of Reaction Bottle R2 for its composition and preparation) was added to the reaction bottle, the dose of compound I precursor being 12 mg, and the mixture was heated to 100°C under sealed conditions and reacted for 10 minutes. Compound I precursor and K 18 F / K 222 The compound underwent a nucleophilic substitution reaction, yielding a crude product containing compound I. 6) Purification by high-performance liquid chromatography The crude product containing compound I was loaded into the sample loop, 2.5 mL of water was extracted to rinse the reaction bottle, and then loaded back into the sample loop for purification under the following chromatographic conditions. Column: XBridge BEH C18 OBD Prep column, 130A, 5μm, 10×250mm Mobile phase: A mixture of ethanol and water. Here, the volume ratio of ethanol to water was 0.6:1, and the mobile phase contained 5 mg / mL of sodium vitamin C and 1 mg / mL of vitamin C (the mobile phase can be obtained via formulation bottle P2; for its composition and preparation, see Preparation of Formulation Bottle P2). Flow rate: 4mL / min Detector: Radioactivity detector The radioactive signal was monitored and tracked, and the main radioactive peak of compound I was collected in a transfer bottle. After purification, a purified product of compound I was obtained.

[0089] Example 2 The difference between Example 2 and Example 1 is 5) 18 The only difference is that the dose of compound I precursor is 20 mg in the nucleophilic substitution reaction of the F ion.

[0090] Example 3 The difference between Example 3 and Example 2 is 1) 18 In the preparation of F-ion solutions, 18 The only difference is that the initial activity of F is 6Ci.

[0091] Example 4 The difference between Example 4 and Example 2 is 1) 18 In the preparation of F-ion solutions, 18 The only difference is that the initial activity of F is 10Ci.

[0092] Example 5 The only difference between Example 5 and Example 4 is that in 6) purification by high-performance liquid chromatography, the mobile phase is a mixture of ethanol and water, with a volume ratio of ethanol to water of 2:1, and the mobile phase further contains 5 mg / mL of sodium vitamin C and 1 mg / mL of vitamin C.

[0093] Example 6 The only difference between Example 6 and Example 4 is that, in 6) purification by high-performance liquid chromatography, the mobile phase is a mixture of ethanol and water, with a volume ratio of ethanol to water of 1:1, and the mobile phase further contains 5 mg / mL of sodium vitamin C and 1 mg / mL of vitamin C.

[0094] Example 7 The only difference between Example 7 and Example 4 is that, in 6) purification by high-performance liquid chromatography, the mobile phase is a mixture of ethanol and water, the volume ratio of ethanol to water is 0.6:1, and the mobile phase further contains 5 mg / mL of sodium vitamin C.

[0095] Example 8 The only difference between Example 8 and Example 4 is that, in 6) purification by high-performance liquid chromatography, the mobile phase is a mixture of ethanol and water, with a volume ratio of ethanol to water of 0.6:1, and the mobile phase further contains 5 mg / mL of sodium vitamin C and 5 mg / mL of vitamin C.

[0096] Example 9 The only difference between Example 9 and Example 4 is that, in 6) purification by high-performance liquid chromatography, the mobile phase is a mixture of ethanol and water, the volume ratio of ethanol to water is 0.6:1, and the mobile phase further contains 1 mg / mL of vitamin C.

[0097] Example 10 The only difference between Example 10 and Example 4 is that, in 6) purification by high-performance liquid chromatography, the mobile phase is a mixture of ethanol and water, with a volume ratio of ethanol to water of 0.6:1, and the mobile phase further contains 10 mg / mL of sodium vitamin C and 1 mg / mL of vitamin C.

[0098] Example 11 The only difference between Example 11 and Example 4 is that in 6) purification by high-performance liquid chromatography, the mobile phase is a mixture of ethanol and water, and the volume ratio of ethanol to water is 0.6:1.

[0099] Example 12 The only difference between Example 12 and Example 4 is that, in 6) purification by high-performance liquid chromatography, the mobile phase is a mixture of ethanol and water, with a volume ratio of ethanol to water of 0.6:1, and the mobile phase further contains 5 mg / mL of sodium vitamin C and 1 mg / mL of gentisic acid.

[0100] Example 13 The only difference between Example 13 and Example 4 is that in 6) purification by high-performance liquid chromatography, the mobile phase is a mixture of ethanol and water, with a volume ratio of ethanol to water of 0.6:1, and the mobile phase further contains 1 mg / mL of gentisic acid.

[0101] Example 14 The only difference between Example 14 and Example 4 is that, in 6) purification by high-performance liquid chromatography, the mobile phase is a mixture of ethanol and water, with a volume ratio of ethanol to water of 0.6:1, and the mobile phase further contains 5 mg / mL of sodium vitamin C and 1 mg / mL of L-glutathione.

[0102] Example 15 The only difference between Example 15 and Example 4 is that in 6) purification by high-performance liquid chromatography, the mobile phase is a mixture of ethanol and water, with a volume ratio of ethanol to water of 0.6:1, and the mobile phase further contains 1 mg / mL of thiourea and 5 mg / mL of sodium vitamin C.

[0103] Example 16 The only difference between Example 16 and Example 4 is that in 6) purification by high-performance liquid chromatography, the mobile phase is a mixture of ethanol and water, with a volume ratio of ethanol to water of 1:9, and the mobile phase further contains 5 mg / mL of sodium vitamin C and 1 mg / mL of vitamin C.

[0104] Comparative Example 1 The only difference between Comparative Example 1 and Example 4 is that, in 6) purification by high-performance liquid chromatography, the mobile phase is a mixture of acetonitrile and water, the volume ratio of acetonitrile to water is 0.6:1, and the mobile phase further contains 5 mg / mL of sodium vitamin C and 1 mg / mL of vitamin C.

[0105] Comparative Example 2 The only difference between Comparative Example 2 and Example 4 is that, in 6) purification by high-performance liquid chromatography, the mobile phase is pure ethanol and does not contain vitamin C, sodium vitamin C, or gentisic acid.

[0106] Please refer to Table 2 for the parameters of Examples 1-16 and Comparative Examples 1-2.

[0107] [Table 2-1]

[0108] [Table 2-2]

[0109] Table 2 shows 18 Initial activity data for F refers to data that can be detected immediately after manufacturing, but usually, 18 Those skilled in the art will understand that the initial activity of F changes depending on the standing time and usage conditions. 18 Initial activity data for F is usually relevant to the target. 18 The initial activity data for F is within ±10% of the range recognized by those skilled in the art. For example, 10Ci is the target 18 If F is the initial activity, in actual detection, the initial activity can be 9Ci~11Ci, and 6Ci is the target. 18 If F is the initial activity, in actual detection, the initial activity can be 5.4Ci~6.6Ci, and 3.5Ci is the target. 18 If F is the initial activity, the actual detection may show an initial activity of 3.15Ci to 3.85Ci.

[0110] Example 17 Liquid composition of compound I A liquid composition of Compound I was prepared using the Compound I product from Example 1. Compound I was collected in a transfer bottle (i.e., Formulation Bottle P1; for the components and preparation of Formulation Bottle P1, see Preparation of Formulation Bottle P1. Here, the Formulation Bottle P1 is as follows: Formulation Bottle P2 is dissolved in water to a predetermined volume, a portion of the reagent is taken from the pre-treated Formulation Bottle P2, and this portion of the reagent in Formulation Bottle P2 is mixed with the reagent in Formulation Bottle P1 to make the Formulation Bottle P1) and then the vitamin C and sodium vitamin C remaining in Formulation Bottle P2 (i.e., Formulation Bottle P2; for the components and preparation of Formulation Bottle P2, see Preparation of Formulation Bottle P2) were added to Formulation Bottle P1. The activity concentration of the purified Compound I after mixing was 2000 MBq / mL, or 54 mCi / mL. The liquid composition was mixed with the HPLC main peak mobile phase to complete the formulation. Specifically, the formulation contains polyethylene glycol 400 0.1 g / mL, vitamin C 2 mg / mL (where the vitamin C concentration (mg / mL) / compound I activity concentration (mCi / mL) is 0.04), vitamin C sodium 20 mg / mL (where the vitamin C sodium concentration (mg / mL) / compound I activity concentration (mCi / mL) is 0.37) (the mass ratio of vitamin C to vitamin C sodium is 1:10), water 0.816 mL / mL, and ethanol 0.094 mL / mL.

[0111] Example 18 The difference between Example 18 and Example 17 is that the formulation contains polyethylene glycol 400 0.1 g / mL, vitamin C 6 mg / mL (where the vitamin C concentration (mg / mL) / compound I activity concentration (mCi / mL) is 0.11), vitamin C sodium 15 mg / mL (where the vitamin C sodium concentration (mg / mL) / compound I activity concentration (mCi / mL) is 0.28) (the mass ratio of vitamin C to vitamin C sodium is 2:5), water 0.816 mL / mL, and ethanol 0.094 mL / mL.

[0112] Example 19 The difference between Example 19 and Example 17 is that the formulation contains polyethylene glycol 400 0.1 g / mL, vitamin C 2 mg / mL (where the vitamin C concentration (mg / mL) / compound I activity concentration (mCi / mL) is 0.04), vitamin C sodium 40 mg / mL (where the vitamin C sodium concentration (mg / mL) / compound I activity concentration (mCi / mL) is 0.74) (the mass ratio of vitamin C to vitamin C sodium is 1:20), water 0.816 mL / mL, and ethanol 0.094 mL / mL.

[0113] Example 20 The difference between Example 20 and Example 17 is that the formulation contains polyethylene glycol 400 0.1 g / mL, vitamin C 8 mg / mL (where the vitamin C concentration (mg / mL) / compound I activity concentration (mCi / mL) is 0.15), vitamin C sodium 20 mg / mL (where the vitamin C sodium concentration (mg / mL) / compound I activity concentration (mCi / mL) is 0.37) (the mass ratio of vitamin C to vitamin C sodium is 2:5), water 0.816 mL / mL, and ethanol 0.094 mL / mL.

[0114] Example 21 The difference between Example 21 and Example 17 is that the formulation contains polyethylene glycol 400 0.1 g / mL, vitamin C 16 mg / mL (where the vitamin C concentration (mg / mL) / compound I activity concentration (mCi / mL) is 0.3), vitamin C sodium 40 mg / mL (where the vitamin C sodium concentration (mg / mL) / compound I activity concentration (mCi / mL) is 0.74) (the mass ratio of vitamin C to vitamin C sodium is 2:5), water 0.816 mL / mL, and ethanol 0.094 mL / mL.

[0115] Example 22 The difference between Example 22 and Example 17 is that the formulation contains polyethylene glycol 400 0.1 g / mL, gentisic acid 2 mg / mL (where the gentisic acid concentration (mg / mL) / compound I activity concentration (mCi / mL) is 0.04), vitamin C sodium 20 mg / mL (where the vitamin C sodium concentration (mg / mL) / compound I activity concentration (mCi / mL) is 0.37) (the mass ratio of gentisic acid to vitamin C sodium is 1:10), water 0.816 mL / mL, and ethanol 0.094 mL / mL.

[0116] Comparative Example 3 The difference between Comparative Example 3 and Example 17 is that the formulation contains polyethylene glycol 400 0.1 g / mL, water 0.816 mL / mL, and ethanol 0.094 mL / mL.

[0117] Comparative Example 4 The difference between Comparative Example 4 and Example 17 is that the formulation contains polyethylene glycol 400 0.1 g / mL, vitamin C sodium 20 mg / mL (where the vitamin C sodium concentration (mg / mL) / activity concentration of compound I (mCi / mL) is 0.37), water 0.816 mL / mL, and ethanol 0.094 mL / mL.

[0118] Comparative Example 5 The difference between Comparative Example 5 and Example 17 is that the formulation contains polyethylene glycol 400 0.1 g / mL, vitamin C 2 mg / mL (where the vitamin C concentration (mg / mL) / compound I activity concentration (mCi / mL) is 0.04), water 0.816 mL / mL, and ethanol 0.094 mL / mL.

[0119] Comparative Example 6 The difference between Comparative Example 6 and Example 17 is that the formulation contains polyethylene glycol 400 0.1 g / mL, L-glutathione 2 mg / mL (where the L-glutathione concentration (mg / mL) / compound I activity concentration (mCi / mL) is 0.04), vitamin C sodium 20 mg / mL (where the vitamin C sodium concentration (mg / mL) / compound I activity concentration (mCi / mL) is 0.37) (the mass ratio of L-glutathione to vitamin C sodium is 1:10), water 0.816 mL / mL, and ethanol 0.094 mL / mL.

[0120] Comparative Example 7 The difference between Comparative Example 7 and Example 17 is that the formulation contains polyethylene glycol 400 0.1 g / mL, thiourea 2 mg / mL (where the thiourea concentration (mg / mL) / compound I activity concentration (mCi / mL) is 0.04), vitamin C sodium 20 mg / mL (where the vitamin C sodium concentration (mg / mL) / compound I activity concentration (mCi / mL) is 0.37) (the mass ratio of thiourea to vitamin C sodium is 1:10), water 0.816 mL / mL, and ethanol 0.094 mL / mL.

[0121] Comparative Example 8 The difference between Comparative Example 8 and Example 17 is that the formulation contains polyethylene glycol 400 0.1 g / mL, sodium metabisulfite 2 mg / mL (where the sodium metabisulfite concentration (mg / mL) / compound I activity concentration (mCi / mL) is 0.04), sodium vitamin C 20 mg / mL (where the sodium vitamin C concentration (mg / mL) / compound I activity concentration (mCi / mL) is 0.37) (the mass ratio of sodium metabisulfite to sodium vitamin C is 1:10), water 0.816 mL / mL, and ethanol 0.094 mL / mL.

[0122] The parameters for Examples 17-22 and Comparative Examples 3-8 are shown in Table 3.

[0123] [Table 3-1]

[0124] [Table 3-2]

[0125] The activity concentrations of the products in Table 3 refer to the activity concentrations of the purified compound I product, where 1 mCi = 37 MBq. The activity concentration of the purified compound I product is calculated by dividing the activity of the compound I product by the total volume of the compound I liquid composition.

[0126] In Example 17, the activity concentration of the product was calculated as 2000 MBq / mL, or 54 mCi / mL. The ratio of vitamin C dose (mg / mL) to compound I activity concentration (mCi / mL) was 2 to 54, or 0.04, and the ratio of vitamin C sodium dose (mg / mL) to compound I activity concentration (mCi / mL) was 20 to 54, or 0.37.

[0127] Experimental example The labeling efficiency is measured by injecting the sample after the labeling reaction is complete and analyzing it by high-performance liquid chromatography (HPLC). The ratio of the radioactive peak area of ​​the target product to the peak area of ​​all radioactive peaks in the liquid chromatogram is then calculated.

[0128] The unattenuated corrected yield is the activity of the final liquid composition product measured using an activity meter, 18 It is determined as the ratio of F to its initial activity.

[0129] The radiochemical purity 0h is determined by injecting a sample and analyzing it by HPLC, and then determining it as the ratio of the radioactive peak area of ​​the product to the peak area of ​​all radioactive peaks.

[0130] The 6-hour stability (an indicator of radiochemical purity) is determined by leaving the final product at room temperature for 6 hours, then injecting a sample and analyzing it by HPLC. The stability is then calculated as the ratio of the radioactive peak area of ​​the product to the total peak area of ​​all radioactive peaks.

[0131] Table 4 shows the experimental effect data for Examples 1-16 and Comparative Examples 1-2.

[0132] [Table 4]

[0133] As can be seen from Table 4, in Examples 1-4, after optimizing the purification process by high-performance liquid chromatography, the amount of crude product containing compound I that could be processed increased, and therefore the compound I precursor and 18 This allows for an increase in the initial activity of F, making it possible to provide high-quality liquid compositions of compound I in large batches.

[0134] Compared to Example 1, 18 When the initial activity of F is constant, the dose of compound I precursor increases in Example 2. 18 The conversion of F is facilitated, increasing the yield and labeling efficiency.

[0135] In Examples 2-4, when the dose of the precursor of compound I is constant, 18 Even if the initial activity of F increases, the yield and labeling efficiency remain largely unchanged, and the radiochemical purity also remains largely unchanged.

[0136] Generally, when the dose of compound I precursor is constant, 18 The yield decreases as the initial activity of F increases within a certain range, but once the amount of compound I precursor reaches a certain level, 18 The yield no longer changes as the initial activity of F changes.

[0137] In Examples 4-6, the effect of the volume ratio of ethanol to water in the mobile phase on the final efficiency was investigated. The higher the amount of ethanol in the mobile phase, the faster the final product is obtained, resulting in a shorter total preparation time and a higher yield. Therefore, the yields in Examples 5 and 6 are slightly higher than those in Example 4. However, excessive ethanol content reduces the radiochemical purity of the final product, so the radiochemical purity of Example 5 is lower than that of Examples 4 and 6.

[0138] In Examples 4, 7, and 8, the yield and radiochemical purity of Example 7 are lower than those of Examples 4 and 8 because vitamin C is not present in the mobile phase of Example 7. The yield of Example 8 is better than that of Example 4 because the vitamin C content of Example 8 is increased compared to that of Example 4.

[0139] Of Examples 4 and 9-11, the mobile phase of Example 9 does not contain sodium vitamin C, therefore the yield and radiochemical purity of Example 9 are lower than those of Example 4. Example 10 has a higher sodium vitamin C content than Example 4, therefore the yield of Example 10 is better than that of Example 4. Example 11 does not contain sodium vitamin C or vitamin C, so the yield, labeling efficiency, and radiochemical purity are all lower.

[0140] In Examples 12 and 13, compared to Example 4, Example 12 replaced vitamin C with gentisic acid, and the labeling efficiency, yield, and radiochemical purity were equivalent, indicating that the effect of gentisic acid in the mobile phase is equivalent to that of vitamin C. Compared to Example 12, the mobile phase of Example 13 did not contain sodium vitamin C, so the yield, labeling efficiency, and radiochemical purity of Example 13 were all lower than those of Example 12.

[0141] In Examples 14 and 15, vitamin C was replaced with another substance, resulting in decreased labeling efficiency, yield, and radiochemical purity compared to Example 4. This indicates that vitamin C is more suitable for use in the mobile phase than L-glutathione and thiourea.

[0142] In Example 16, the ratio of ethanol to water in the mobile phase was 1:9, which resulted in a longer peak elution time and a decrease in yield.

[0143] In Comparative Example 1, the mobile phase was a mixture of acetonitrile and water, and the subsequent purification step required the use of a C18 cartridge, which resulted in severe radiolysis, a longer reaction time, and a decrease in final yield and radiochemical purity.

[0144] In Comparative Example 2, since only ethanol is used as the mobile phase, impurities and the final product come out together. Sodium vitamin C and vitamin C are insoluble in ethanol, and it is not possible to include sodium vitamin C and vitamin C in the mobile phase. As a result, the final compound I product has low purity and is unstable.

[0145] Table 5 shows the experimental effect data for Examples 17-22 and Comparative Examples 3-8.

[0146] [Table 5]

[0147] In Examples 17-22, the activity concentration of the product was 2000 MBq / mL, or 54 mCi / mL. Examples 17 and 18 showed high radiochemical purity and good stability for 6 hours.

[0148] In Example 19, the mass ratio of vitamin C to sodium vitamin C was 1:20, resulting in high radiochemical purity, good stability over 6 hours, and a relatively high sodium content.

[0149] In Examples 20 and 21, the ratio of vitamin C to sodium vitamin C was 2:5, resulting in high radiochemical purity and good stability over 6 hours. In Example 21, the vitamin C content was higher, and as a result, the pH of the liquid composition of compound I was lower.

[0150] In Example 22, when vitamin C was replaced with gentisic acid, the radiochemical purity was high and the 6-hour stability effect was also good, indicating that gentisic acid in the composition can play a role equivalent to that of vitamin C.

[0151] Comparative Examples 3-8 show that when the liquid composition of compound I does not contain vitamin C or sodium vitamin C, or when vitamin C is replaced with L-glutathione, thiourea, or sodium metabisulfite, the radiochemical purity at 0 hours is low, and after 6 hours, the stability effect further deteriorates, with a radiochemical purity of less than 90%, making it unsuitable as a myocardial perfusion PET contrast agent.

[0152] This application provides a reagent kit for the automated preparation of a liquid composition of compound I.

[0153] In some embodiments of this application, the configuration of the reaction bottle R1 is as shown in Table 6.

[0154] [Table 6]

[0155] Preparation of potassium carbonate solution: Measure an appropriate amount of sterile water for injection into a glass beaker, add the prescribed amount of potassium carbonate, rinse the container 2-3 times with a small amount of water, add it to the beaker, stir, and dissolve. Preparation of the eluent: Add an appropriate amount of acetonitrile to an Erlenmeyer flask, add the prescribed amount of aminopolyether, wash the container 2-3 times with a small amount of acetonitrile, add it to the Erlenmeyer flask and stir to dissolve. Add the potassium carbonate solution prepared above, wash the beaker 2-3 times with the remaining prescribed amount of water, add it to the Erlenmeyer flask and stir uniformly. Finally, make up with acetonitrile (add to the prescribed amount) and stir uniformly. Filtration: The eluent described above is filtered through two 0.22 μm sterile-grade hydrophobic polytetrafluoroethylene capsule filters. Filling, sealing, and capping: Dispense the filtered solution into 1 mL / bottle, stopper, and cap. Minimally Inspected and Packaging: After passing the minimally inspected product, labels are applied, and the product is packaged one unit per box using cartons, with labels applied and sealed.

[0156] In some embodiments of the present application, the configuration of the reaction bottle R2 is as shown in Table 7.

[0157]

Table 7

[0158] Preparation of the Compound I precursor solution: Weigh the prescription amount of the Compound I precursor acetonitrile solution into a beaker, add it to a wide-mouth bottle with a blue cap, wash the beaker 2-3 times with a small amount of acetonitrile, combine them and put them into the wide-mouth bottle with a blue cap, add acetonitrile to the prescribed amount (make it up), and stir evenly. Filtration: Filter the above Compound I precursor liquid through two 0.22 μm sterile-grade hydrophobic polytetrafluoroethylene capsule filters. Filling, Sealing, Capping: Dispense the filtered solution into 2 mL / bottles, plug and cap. Visual Inspection and Packaging: After passing the visual inspection, label it, and at the same time, use a carton to package it at 1 piece / box, label it, seal and package it.

[0159] In some embodiments of the present application, the configuration of the reaction bottle R3 is as shown in Table 8.

[0160]

Table 8

[0161] Preparation of the liquid: Weigh the prescription amount of absolute ethanol, add it to the liquid preparation tank, turn on the intermediate layer cooling water, make the temperature in the tank less than 20°C, and stir evenly. Filtration: Pre-filter the solution in the preparation tank with a single-stage 5-inch 0.45 μm hydrophobic PTFE filter element, filter it with a two-stage 5-inch 0.22 μm sterile-grade hydrophobic PTFE filter element, and then push it into the receiving tank. Filling, Sealing, Capping: Dispense the filtered solution into 10 mL / bottles, press the plug and cap. Minimally Inspected and Packaging: After passing the minimally inspected product, labels are applied, and the product is packaged one unit per box using cartons, with labels applied and sealed.

[0162] In some embodiments of this application, the configuration of the formulation bottle P1 is as shown in Table 9.

[0163] [Table 9]

[0164] Preparation of polyethylene glycol 400 solution: Weigh out the prescribed amount of polyethylene glycol 400 (for injection), add an appropriate amount of sterile water for injection (<30°C) to the polyethylene glycol 400 solution preparation barrel, stir to dissolve, and store for later use. Preparation of the formulation substrate solution: Add an appropriate amount of water to the preparation tank, transfer the polyethylene glycol 400 solution to the preparation tank, wash the preparation barrel three times with an appropriate amount of sterile water for injection (<30°C), combine them and add them to the preparation tank, stir uniformly, then add sterile water for injection (<30°C) to the specified amount and stir uniformly. Filtration: The solution is filtered through a single 5-inch 0.45 μm hydrophilic polyethersulfone filter element, then filtered through a second 5-inch 0.22 μm sterile-grade hydrophilic polyethersulfone filter element, and then pushed into the receiving tank. Filling, sealing, and capping: Dispense the filtered solution into 13.8 mL bottles and press the stopper to seal. Sterilization: After sealing, the intermediate product is sterilized. Sterilization conditions are: sterilization temperature 121°C, sterilization time 15 minutes, F0 ≥ 12. Minimally Inspected and Packaging: After passing the minimally inspected product, labels are applied, and the bottled product and plastic inner holder are placed in a carton, packaged one per box, labeled, and sealed.

[0165] In this application, formulation bottle P1 is used as a transfer bottle, and the reagent in formulation bottle P1 is combined with a portion of the reagent dissolved in water in another formulation bottle P2 to form a formulation substrate solution.

[0166] In some embodiments of this application, the configuration of the formulation bottle P2 is as shown in Table 10.

[0167] [Table 10]

[0168] The composition of prescription bottle P2 is as follows: Weighing: Weigh out the prescribed amounts of vitamin C and sodium vitamin C. Powder filling, sealing, and capping: A high-precision packaging machine is used for powder filling and sealing. The amount of vitamin C filled is 1.6g, and the amount of sodium vitamin C filled is 8.8g. The cap is then pressed to seal. Minimally Inspected and Packaging: After passing the minimally inspected product, labels are applied, and the bottled product and plastic inner holder are placed in a carton, packaged one per box, labeled, and sealed.

[0169] In this application, there are two formulation bottles P2, one of which is used for the mobile phase. The other formulation bottle P2 is used for storing the purified reagent.

[0170] Taking Example 1 as an example, before starting the reaction, the previously prepared reaction bottles R1, R2, R3, and formulation bottle P1 are placed in their corresponding positions and the reaction is initiated. 18 After the nucleophilic substitution reaction of the F ion is complete, the mixture is purified by high-performance liquid chromatography, and the vitamin C and sodium vitamin C in the mobile phase are from formulation bottle P2. Here, the other formulation bottle P2 is pre-dissolved in a predetermined volume with water, some reagent is taken from the processed other formulation bottle P2, and some of the reagent in this other formulation bottle P2 is mixed with the reagent in formulation bottle P1 to form a formulation substrate solution. After purification, compound I is recovered into formulation bottle P1 to which the formulation substrate solution has been pre-added, and a liquid composition of compound I is obtained.

[0171] Although this application is disclosed through embodiments as described above, these embodiments are not intended to limit this application, and any person with ordinary skill in the relevant art may make any changes and modifications without departing from the spirit and scope of this application. Therefore, the scope of protection of this application shall be determined by the scope of the appended patent application.

Claims

1. A method for preparing a liquid composition of compound I, comprising the following steps: The process includes purifying a crude product containing compound I by high-performance liquid chromatography. The mobile phase used in the purification step by high-performance liquid chromatography comprises ethanol and water. The aforementioned compound I is 2-tert-butyl-4-chloro-5-((3-((4-((2-(2-fluoro[ １８ F) is ethoxy)ethoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)benzyl)oxy)pyridazine-3(2H)-one, and in the purification step by high-performance liquid chromatography, A preparation method wherein the mobile phase contains 0.2 to 2 parts by volume of ethanol per 1 part by volume of water.

2. The preparation method according to claim 1, wherein the mobile phase further comprises one or more of vitamin C sodium, vitamin C, and gentisic acid.

3. In the mobile phase, the amount of ethanol is 0.4 to 1 part by volume per 1 part by volume of water. The preparation method according to claim 1.

4. In the purification step using high-performance liquid chromatography, The amount of sodium vitamin C added is 0 to 20 mg / mL. The preparation method according to claim 2.

5. In the purification step using high-performance liquid chromatography, The amount of gentisinic acid added is 0 to 10 mg / mL. The preparation method according to claim 2.

6. Prior to the purification step by high-performance liquid chromatography, the process further includes a step of carrying out a nucleophilic substitution reaction. In the aforementioned nucleophilic substitution reaction, the activated １８ The F ions are mixed with a precursor-containing solution of compound I to carry out a nucleophilic substitution reaction, producing a crude product containing compound I. The name of the precursor of compound I is 2-(2-((1-(3-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazine-4-yl)oxy)methyl)benzyl)-1H-1,2,3-triazole-4-yl)methoxy)ethoxy)ethyl-4-methylbenzenesulfonic acid methyl ester. The preparation method according to claim 1.

7. Before the nucleophilic substitution reaction step, １８ The process further includes a step of preparing F ions, The aforementioned １８ The step of preparing F ions is, １８ Preparation of F-ion solution, １８ Concentration and elution of F ions, and １８ Further includes activation of F ions, In the above-mentioned １８ In the step of preparing the F-ion solution, the １８ F-ion solution is prepared by an accelerator, The aforementioned １８ In the F ion concentration step, the above-prepared ions were passed through an anion exchange cartridge. １８ Concentrate the F ion solution, The aforementioned １８ In the F-ion elution step, a cryptand and alkali metal salt catalyst solution is used. １８ Elute F ions, The aforementioned １８ In the F ion activation step, the temperature is programmed to dry the solvent with nitrogen or other inert gas. １８ Activates the F ions, and the activated １８ Obtain F ions. The preparation method according to claim 6.

8. The aforementioned １８ In the F ion concentration step, The anion exchange cartridge is a tetraalkylammonium salt anion exchange cartridge. The preparation method according to claim 7.

9. The aforementioned １８ In the F ion elution step, In a catalyst solution of cryptand and alkali metal salt, the dose of cryptand is 5 to 40 mg, and the dose of alkali metal salt is 1.5 to 20 mg. The preparation method according to claim 7.

10. The aforementioned １８ In the F ion activation step, The activation temperature is 80 to 130°C. The programmable temperature control is as follows: 100-120°C, positive pressure 50-200 mbar, vacuum pressure -20 to -60 mbar, evaporation 60-120 seconds; 120-130°C, positive pressure 50-200 mbar, vacuum pressure -20 to -60 mbar, evaporation 150-200 seconds; 120-130°C, positive pressure 50-200 mbar, vacuum pressure -60 to -100 mbar, evaporation 10-3 0 seconds; 100-120°C, positive pressure 800-1200 mbar, vacuum pressure -800 to -1000 mbar, evaporation 80-120 seconds; 80-100°C, positive pressure 400-600 mbar, vacuum pressure -800 to -1000 mbar, evaporation 100-120 seconds; 80-100°C, positive pressure 600-900 mbar, vacuum pressure -800 to -1000 mbar, evaporation 10-20 seconds, including The preparation method according to claim 7.

11. Use of a liquid composition of compound I prepared by the method of any one of claims 1 to 10 in the preparation of a myocardial perfusion PET contrast agent.

12. A reagent kit for the automated preparation of a liquid composition of compound I, comprising a reaction bottle and a formulation bottle, The reaction bottle includes reaction bottle R1, reaction bottle R2, and reaction bottle R3. The reaction bottle R1 is １８ Used to contain the eluent for F-ion elution, The reaction bottle R2 is １８ Used to contain a solution of compound I precursor for the nucleophilic substitution reaction of F ions, The reaction bottle R3 is used to contain reagents used to dilute the crude product and rinse the reaction system. The aforementioned formulation bottle includes formulation bottle P1 and formulation bottle P2. The aforementioned formulation bottle P1 １８ It is used to transfer the reaction product after the nucleophilic substitution reaction of F ions. The aforementioned formulation bottle P2 １８ It is used to contain a substance used to stabilize the reaction product after the nucleophilic substitution reaction of F ions. The reaction bottle R1 contains amino polyether, potassium carbonate, water for injection, and acetonitrile. The reaction bottle R2 is １８ The solution comprises an acetonitrile solution of compound I precursor for the nucleophilic substitution reaction of F ions, The reaction bottle R3 contains anhydrous ethanol. The formulation bottle P1 contains polyethylene glycol, The aforementioned formulation bottle P2 １８ It contains one or more of vitamin C, sodium vitamin C, and gentisic acid, which are used to stabilize the reaction product after the nucleophilic substitution reaction of the F ion. The aforementioned compound I is 2-tert-butyl-4-chloro-5-((3-((4-((2-(2-fluoro[ １８ F) is ethoxy)ethoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)benzyl)oxy)pyridazine-3(2H)-one, The name of the precursor of compound I is 2-(2-((1-(3-(((1-(tert-butyl)-5-chloro-6-oxo-1,6-dihydropyridazine-4-yl)oxy)methyl)benzyl)-1H-1,2,3-triazole-4-yl)methoxy)ethoxy)ethyl-4-methylbenzenesulfonic acid methyl ester, The amino polyether is an azacryptand, which is a tri-crosslinked crown ether molecule having a cryptoid cavity. Reagent kit.

13. The concentration of the aminopolyether is 5 to 40 mg / mL, the concentration of the potassium carbonate is 1.5 to 20 mg / mL, and the volume ratio of acetonitrile to water is (0.25 to 19):

1. Alternatively, the reagent kit according to claim 12, wherein the concentration of the compound I precursor in the acetonitrile solution is 1 to 10 mg / mL.

14. The concentration of the polyethylene glycol is 0.05 to 0.3 g / mL. or, The reagent kit according to claim 12, wherein the vitamin C concentration is 2 to 16 mg / mL, the vitamin C sodium concentration is 15 to 40 mg / mL, and the gentisic acid concentration is 2 to 16 mg / mL.

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