WO2023246830A1 - Procédé de préparation d'une composition liquide de composé i et son utilisation dans l'imagerie tep du métabolisme myocardique - Google Patents

Procédé de préparation d'une composition liquide de composé i et son utilisation dans l'imagerie tep du métabolisme myocardique Download PDF

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WO2023246830A1
WO2023246830A1 PCT/CN2023/101561 CN2023101561W WO2023246830A1 WO 2023246830 A1 WO2023246830 A1 WO 2023246830A1 CN 2023101561 W CN2023101561 W CN 2023101561W WO 2023246830 A1 WO2023246830 A1 WO 2023246830A1
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compound
tert
preparation
mobile phase
butyl ester
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PCT/CN2023/101561
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English (en)
Chinese (zh)
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王跃
张颖
张爱丽
徐新盛
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北京先通国际医药科技股份有限公司
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Publication of WO2023246830A1 publication Critical patent/WO2023246830A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0404—Lipids, e.g. triglycerides; Polycationic carriers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/001—Acyclic or carbocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/47—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • This application belongs to the field of chemical pharmaceutical technology, and in particular relates to a preparation method of a liquid composition of Compound I and its use in PET imaging of myocardial metabolism.
  • molecular medical imaging technology uses imaging methods to conduct qualitative and quantitative research on biological processes in living bodies at the cellular and molecular levels, and to analyze the physiology and pathology of organisms at the molecular level.
  • Multimodal molecular imaging technology can realize the complementary advantages of different imaging equipment, making the imaging results obtained more accurate and reliable.
  • Clinical practice has proven that multi-modal molecular medical imaging equipment plays an important role in early diagnosis and treatment of major diseases, formulation of treatment plans, and verification and evaluation of treatment effects.
  • Positron Emission Tomography (PET) equipment is mainly functional imaging. It consists of a PET imaging device and a radioactive tracer injected into the patient's blood.
  • a frequently used radioactive tracer is Fluoro-deoxy-glucose (FDG), which is a compound synthesized from a simple sugar and a small amount of radioactive fluorine.
  • FDG Fluoro-deoxy-glucose
  • This application provides a preparation method and use of Compound I that can be used for cardiac imaging.
  • the crude product containing compound I is purified by high performance liquid chromatography; wherein, the mobile phase used in the high performance liquid chromatography purification step includes ethanol and water;
  • Compound I is trans-2-(2-(5-fluoro[ 18F ]tridecyl)cyclopropyl)acetic acid.
  • the ethanol is 2-5 parts by volume
  • the ethanol is 3-4 parts by volume relative to 1 part by volume of water.
  • the mobile phase also includes vitamin C.
  • the added amount of vitamin C is 0.1 mg/mL-10 mg/mL; preferably, it is 0.1 mg/mL-5 mg/mL.
  • the mobile phase also includes gentisic acid.
  • the added amount of gentisic acid is 0.1 mg/mL-10 mg/mL; preferably, it is 0.1 mg/mL-5 mg/mL.
  • the chromatographic column is a silica gel column, preferably a reversed-phase C18 silica gel column, and further preferably an XBridge BEH C18 OBD Prep column;
  • isocratic elution is used, and the elution flow rate of the mobile phase is 3 mL/min-6 mL/min.
  • nucleophilic substitution reaction step Before the high-performance liquid chromatography purification step, a nucleophilic substitution reaction step and a de-tert-butyl esterification reaction step are also included:
  • Nucleophilic substitution reaction Mix the activated 18 F ions with a solution containing the precursor of Compound I tert-butyl ester to perform a nucleophilic substitution reaction to obtain an intermediate product solution containing Compound I tert-butyl ester;
  • De-tert-butyl esterification reaction Add an acidic solvent to the intermediate product solution of the above-mentioned compound I tert-butyl ester to perform the de-tert-butyl esterification reaction to obtain a product containing compound I;
  • the precursor of compound I tert-butyl ester is trans-tert-butyl 2-(2-(5-(methanesulfonyloxy)tridecyl)cyclopropyl)acetate;
  • Compound I tert-butyl ester is trans-2-(2-(5-fluoro[ 18F ]tridecyl)cyclopropyl)acetate tert-butyl ester.
  • the starting activity ratio range of compound I tert-butyl ester precursor/ 18 F is (0.2-5):1;
  • the weight unit of the compound I tert-butyl ester precursor is mg, and the unit of initial activity is Ci.
  • the initial activity of 18 F is 0.09Ci-11Ci, preferably 3.6Ci-11Ci.
  • the acidic solvent is a mixed system of trifluoroacetic acid and acetonitrile
  • trifluoroacetic acid is 0.4-2 parts by volume relative to 1 part by volume of acetonitrile;
  • the amount of trifluoroacetic acid is 0.6-1.5 parts by volume relative to 1 part by volume of acetonitrile.
  • a liquid composition comprising compound I, wherein the liquid composition further includes vitamin C and/or gentisic acid;
  • Compound I is trans-2-(2-(5-(fluoro[ 18F ])tridecyl)cyclopropyl)acetic acid.
  • the vitamin C concentration (mg/mL)/compound I activity concentration (mCi/mL) ratio range is (0.009-0.2):1.
  • the ratio range of vitamin C concentration (mg/mL)/compound I activity concentration (mCi/mL) is (0.009-0.1):1.
  • the ratio range of gentisic acid concentration (mg/mL)/compound I activity concentration (mCi/mL) is (0.009-0.1):1.
  • the polysorbate 80 concentration is 0.5mg/mL-2mg/mL.
  • the ethanol aqueous solution containing vitamin C and/or gentisic acid and compound I is collected from the purification step to obtain a liquid composition containing compound I.
  • This application optimizes the experimental process plan, changes the dosage of the tert-butyl ester precursor of Compound I, shortens the reaction time to achieve the same labeling rate, increases the radioactive activity of the initial 18 F ions, and increases the labeling rate, thereby improving Yield.
  • the process parameters and process flow are clear and specific, which can be applied to large-volume activity production and meet the automation needs.
  • an anti-radiation decomposition agent is used in the mobile phase of the purification process to avoid product loss due to radiation decomposition during the purification and formulation process, thereby increasing the yield.
  • this application uses an anti-radiation decomposition agent during the formulation process to ensure the stability of the product.
  • This application optimizes the purification process, removes the C18 column, and uses ethanol/water system instead of acetonitrile/water system as the mobile phase. This simplifies time and improves the radiochemical purity and stability of the product.
  • 18 F-labeled myocardial metabolism PET imaging agent refers to the compound I liquid composition.
  • Aminopolyether (K 222 ) is a three-bridged crown ether molecule with a cryptoid cavity. It is a typical aza cryptether and a kind of cryptether. Due to its unique coordination characteristics, azacryptoethers can well select cations to complex transition metals and heavy metals. The resulting complexes are more stable and are lipophilic and hydrophilic, so they have good research potential. prospect.
  • the specific steps are as follows: react the raw materials 1,2-bis(2-iodoethoxy)ethane and benzylamine in an acetonitrile solution under reflux for 3 days, and then obtain an intermediate through post-processing. The intermediate is recrystallized with acetone. After filtration, a NaI complex is obtained. The complex is decomplexed through cation exchange resin and anion exchange resin under acidic conditions to prepare amino polyether (K 222 ). This method has simple equipment, less solvent consumption, and relatively mild reaction conditions. However, the applicant found through research that when the content of sodium ions is reduced to a certain amount using the method of decomplexing through ion exchange resin, the decomplexation cannot proceed and the yield is low.
  • This application provides a method for preparing compound I.
  • the synthesis route is as follows:
  • the crude product containing compound I is purified by high performance liquid chromatography;
  • the mobile phase used in the high performance liquid chromatography purification step includes ethanol and water.
  • the ethanol in the high performance liquid chromatography purification step: in the mobile phase, the ethanol is 2-5 parts by volume relative to 1 part by volume of water; preferably, relative to 1 part by volume parts of water, and the ethanol is 3-4 parts by volume;
  • the ethanol may be 2 parts by volume, 3 parts by volume, 4 parts by volume, 5 parts by volume, or any range therebetween.
  • the mobile phase in the high performance liquid chromatography purification step: the mobile phase further includes vitamin C.
  • the added amount of vitamin C is 0.1 mg/mL-10 mg/mL; preferably 0.1 mg/mL-5 mg/mL;
  • the vitamin C addition amount can be 0.1 mg/mL, 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 , 10mg/mL or any range in between.
  • the mobile phase Gentisic acid is also included.
  • the added amount of gentisic acid in the mobile phase, is 0.1 mg/mL-10 mg/mL; preferably 0.1 mg/mL-5 mg/mL;
  • the added amount of gentisic acid can be 0.1 mg/mL, 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. mL, 10 mg/mL, or any range in between.
  • the mobile phase may contain both vitamin C and gentisic acid, or may contain only one of vitamin C and gentisic acid.
  • the chromatographic column is a silica gel column, preferably a reverse-phase C18 silica gel chromatographic column, and further preferably an XBridge BEH C18 OBD Prep column.
  • isocratic elution is used, and the elution flow rate of the mobile phase is 3mL/min-6mL/min;
  • the elution flow rate of the mobile phase may be 3 mL/min, 4 mL/min, 5 mL/min, 6 mL/min or any range therebetween.
  • a nucleophilic substitution reaction step and a de-tert-butyl esterification reaction step are also included:
  • Nucleophilic substitution reaction Mix the activated 18 F ions with a solution containing the precursor of Compound I tert-butyl ester to perform a nucleophilic substitution reaction to obtain an intermediate product solution containing Compound I tert-butyl ester;
  • De-tert-butyl esterification reaction Add an acidic solvent to the intermediate product solution of the above compound I tert-butyl ester to perform the de-tert-butyl esterification reaction to obtain a product containing compound I.
  • the starting activity ratio range of compound I tert-butyl ester precursor/ 18 F is (0.2-5):1;
  • the weight unit of the compound I tert-butyl ester precursor is mg, and the unit of initial activity is Ci;
  • the starting activity ratio of Compound I tert-butyl ester precursor/ 18F can be 0.2:1, 0.3:1, 0.5:1, 0.7:1, 1:1, 2:1, 3:1, 4:1 , 5:1 or any range in between.
  • the initial activity of 18 F is 0.09Ci-11Ci, preferably 3.6Ci-11Ci;
  • the 18 F initial activity is 0.09Ci, 0.1Ci, 0.5Ci, 1Ci, 2Ci, 3Ci, 4Ci, 5Ci, 6Ci, 7Ci, 8Ci, 9Ci, 10Ci, 11Ci or any range therebetween.
  • the acidic solvent in the de-tert-butyl esterification reaction, is tris Fluoroacetic acid and acetonitrile; relative to 1 part by volume of acetonitrile, trifluoroacetic acid is 0.4-2 parts by volume; further preferably, relative to 1 part by volume of acetonitrile, trifluoroacetic acid is 0.6-1.5 parts by volume;
  • trifluoroacetic acid is 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, 1.5 parts by volume, 2 parts by volume, or any range in between.
  • the present application also provides a liquid composition containing compound I, wherein the liquid composition further includes vitamin C and/or gentisic acid.
  • the ratio range of vitamin C concentration (mg/mL)/compound I activity concentration (mCi/mL) is (0.009-0.2):1, preferably (0.009-0.1):1;
  • the ratio of vitamin C concentration (mg/mL)/compound I activity concentration (mCi/mL) can be 0.009:1, 0.01:1, 0.02:1, 0.03:1, 0.04:1, 0.05:1, 0.06: 1. 0.07:1, 0.08:1, 0.09:1, 0.1:1, 0.11:1, 0.12:1, 0.13:1, 0.14:1, 0.15:1, 0.16:1, 0.17:1, 0.18:1, 0.19:1, 0.2:1, or any range in between.
  • the ratio range of gentisic acid concentration (mg/mL)/compound I activity concentration (mCi/mL) is (0.009-0.2):1, preferably (0.009-0.1):1;
  • the ratio of gentisic acid concentration (mg/mL)/compound I activity concentration (mCi/mL) can be 0.009:1, 0.01:1, 0.02:1, 0.03:1, 0.04:1, 0.05:1, 0.06 :1, 0.07:1, 0.08:1, 0.09:1, 0.1:1, 0.11:1, 0.12:1, 0.13:1, 0.14:1, 0.15:1, 0.16:1, 0.17:1, 0.18:1 , 0.19:1, 0.2:1 or any range in between.
  • the liquid composition containing compound I may contain both vitamin C and gentisic acid, or may contain only one of vitamin C and gentisic acid.
  • the liquid composition further includes polysorbate 80.
  • the polysorbate 80 concentration is 0.5 mg/mL-2 mg/mL;
  • the polysorbate 80 concentration may be 0.5 mg/mL, 0.8 mg/mL, 1 mg/mL, 1.5 mg/mL, 2 mg/mL or any range therebetween.
  • the present application also provides a method for preparing the above liquid composition, wherein:
  • the ethanol aqueous solution containing vitamin C and/or gentisic acid and compound I is collected from the purification step to obtain a liquid composition containing compound I.
  • vitamin C and/or gentisic acid, sodium chloride, polysan Pear ester 80 is mixed with an ethanol aqueous solution containing vitamin C and/or gentisic acid and compound I to obtain a liquid composition containing compound I.
  • This application also provides the use of the above-mentioned Compound I liquid composition and the Compound I liquid composition prepared by the above-mentioned method as a myocardial metabolism PET imaging agent.
  • the 18 F initial activity also known as the 18 F ion activity, refers to the production of a solution containing 18 F ions after starting the accelerator to produce a proton beam that bombards oxygen-containing [ 18 O] water.
  • the 18 F ion activity measured by a meter.
  • the 18 F initial activity refers to the concentration that can be detected after producing a solution containing 18 F ions after bombarding oxygen-containing [ 18 O] water with a proton beam generated by a startup accelerator.
  • Detectable refers to A reasonable detection time can be controlled by those skilled in the art, such as within 10 minutes after production.
  • those skilled in the art can understand that as the storage time after production changes, the initial activity of 18 F will change to a certain extent, but usually the error range is within the range of ⁇ 10%.
  • the initial activity of 18 F is 0.09Ci-11Ci; preferably 3.6Ci-11Ci; for example, the initial activity of 18F can be 0.09Ci, 0.1Ci, 0.5Ci, 1Ci , 2Ci, 3Ci, 4Ci, 5Ci, 6Ci, 8Ci, 9Ci, 10Ci, 11Ci or any range in between.
  • large batch refers to products with high total activity, which generally refers to products with total activity exceeding 1 Ci or 37GBq;
  • High activity concentration products generally refer to products with an activity concentration exceeding 50mCi/mL, that is, 1850MBq/mL.
  • the labeling rate refers to the labeling reaction between 18F and the reaction precursor.
  • 18F replaces the leaving group in the precursor and converts it into the final labeled product.
  • the labeled product contains 18F , so the labeling rate is defined as The activity of the labeled product is higher than the total 18 F activity participating in the reaction.
  • the yield refers to the ratio of the activity of the final product Compound I liquid composition to the starting activity of 18 F.
  • a 18 F ion preparation step is also included; the 18 F ion preparation step also includes 18 F ion solution preparation, 18 F ion enrichment and elution, 18 F ion activation;
  • 18 F ion solution preparation the accelerator prepares 18 F ion solution;
  • 18 F ion enrichment The 18 F ion solution prepared above is enriched through an anion exchange column;
  • 18 F ion elution use cryptether and alkali metal salt catalyst solution to elute 18 F ions;
  • 18 F ion activation The solvent is blown dry by programmed control of temperature, nitrogen or other inert gas, and the 18 F ions are activated to obtain activated 18 F ions.
  • water containing 18 O is transported to the accelerator target position, and the accelerator is started to generate a proton beam to bombard the water containing 18 O to produce a solution containing 18 F ions. .
  • the anion exchange cartridge in the 18 F ion enrichment step, is a Sep-Pak Accell Plus QMA Carbonate Plus Light Cartridge, specifically a tetraalkylammonium salt anion exchange cartridge.
  • the dosage of cryptether in the 18 F ion elution step, in the cryptether and alkali metal salt catalyst solution, the dosage of cryptether is 5 mg-40 mg, and the dosage of alkali metal salt is 1.5 mg-20 mg; in the solution
  • the dosage of cryptether can be 5mg, 8mg, 10mg, 15mg, 20mg, 40mg or any range between them; the dosage of alkali metal salt in the solution can be 1.5mg, 3mg, 5mg, 10mg, 20mg or any range between them.
  • the cryptether is 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8,8,8]hexadecane ( Kryptofix-2.2.2, aminopolyether);
  • the alkali metal salt is one or more of K 2 CO 3 , Na 2 CO 3 , Cs 2 CO 3 , KHCO 3 and NaHCO 3 .
  • the catalyst solution is selected from a mixed solvent system of acetonitrile and water, wherein the volume ratio of acetonitrile to water is (0.2-10):1; for example, the volume ratio of acetonitrile to water can be 0.2 :1, 1:1, 2:1, 4:1, 7:1, 10:1 or any range in between; the volume of acetonitrile and water mixed solvent is 0.3mL-2mL.
  • the activation temperature is 80°C-130°C;
  • the program control temperature includes the following steps: 100-120°C, positive pressure 50-200mbar, vacuum pressure -20 ⁇ -60mbar, evaporation 60-120s; 120-130°C, positive pressure 50-200mbar, vacuum pressure -20 ⁇ - 60mbar, evaporation 150-200s; 120-130°C, positive pressure 50-200mbar, vacuum pressure -60 ⁇ -100mbar, evaporation 10-30s; 100-120°C, positive pressure 800-1200mbar, vacuum pressure -800 ⁇ -1000mbar, Evaporation 80-120s; 80-100°C, positive pressure 400-600mbar, vacuum pressure -800 ⁇ -1000mbar, evaporation 100-120s; 80-100°C, positive pressure 600-900mbar, vacuum pressure -800 ⁇ -1000mbar, evaporation 10 -20s.
  • Reactions with protective groups are all carried out using a two-step method.
  • the dosage of fluorine [ 18 F] ions is increased from 4Ci level to 10Ci level.
  • the preparation method of the present application can be applied to higher 18 F ion starting amounts.
  • the mobile phase ethanol/water mixed solvent system used in the high-performance liquid chromatography purification step omits the subsequent C18 column enrichment purification and absolute ethanol elution steps, avoiding the radiation of the product under high activity Decompose and shorten the preparation process.
  • the anti-radiation decomposition agent vitamin C is added to the mobile phase to avoid radiation decomposition during the column purification process.
  • % means wt%, that is, weight percentage. If the manufacturer of the reagents or instruments used is not indicated, they are all conventional reagent products that are commercially available. Table 1 shows the sources of raw materials used in the examples.
  • the automation equipment is AllinOne equipment from Trasis Company.
  • the power unit of the equipment is high-purity nitrogen and an electric syringe rotor, which can provide a vacuum system and is equipped with an HPLC purification system. Since this process uses automated equipment, which is placed in a radiation shielding box, it can protect operators from radiation damage and increase the operating dose. At the same time, due to computer control, the process steps can be controlled more accurately and with higher repeatability. Reduce human bias.
  • the 18 F ions eluted in step 3) are programmed to heat at 100°C to 125°C under nitrogen flow to dry the solvent to obtain activated 18 F ions.
  • Mobile phase a mixed solvent system of ethanol and water, where the volume ratio of ethanol to water is 3:1.
  • the mobile phase also includes vitamin C, and the concentration of vitamin C is 0.5mg/mL;
  • Radioactivity Detector Radioactivity Detector
  • Example 2 The difference between Example 2 and Example 1 is that: the dosage of Compound I tert-butyl ester precursor is 6 mg, and the dosage of Compound I tert-butyl ester precursor (mg)/ 18 F initial activity (Ci) is 6 mg/4Ci (i.e. 1.5 :1)Other conditions are the same.
  • Example 3 The difference between Example 3 and Example 1 is that: the dosage of Compound I tert-butyl ester precursor is 10 mg, and the dosage of Compound I tert-butyl ester precursor (mg)/ 18 F initial activity (Ci) is 10 mg/4Ci (i.e. 2.5 :1), the rest of the conditions are the same.
  • Example 4 in the preparation of 18 F ion solution, the initial activity of 18 F is 6.5Ci, and the dosage of compound I tert-butyl ester precursor (mg) / 18 F initial activity (Ci) is 10 mg /6.5Ci (ie 1.54:1), other conditions are the same.
  • Example 5 The difference between Example 5 and Example 3 is that: in the preparation of 18 F ion solution, the initial activity of 18 F is 10Ci, and the dosage of compound I tert-butyl ester precursor (mg) / 18 F initial activity (Ci) is 10mg/ 10Ci (i.e. 1:1), other conditions are the same.
  • Example 6 The difference between Example 6 and Example 5 is that in the de-tert-butyl esterification reaction, the volume ratio of trifluoroacetic acid and acetonitrile is 0.67:1, and the other conditions are the same.
  • Example 7 The difference between Example 7 and Example 5 is that in the de-tert-butyl esterification reaction, the volume ratio of trifluoroacetic acid and acetonitrile is 0.43:1, and the other conditions are the same.
  • Example 8 The difference between Example 8 and Example 5 is that during purification by high-performance liquid chromatography, the mobile phase is a mixed solvent system of ethanol and water, where the volume ratio of ethanol to water is 4:1, and the other conditions are the same.
  • Example 9 The difference between Example 9 and Example 5 is that during purification by high performance liquid chromatography, the mobile phase is a mixed solvent system of ethanol and water, in which the volume ratio of ethanol to water is 2:1, and the other conditions are the same.
  • Example 10 The difference between Example 10 and Example 5 is that during purification by high-performance liquid chromatography, the concentration of vitamin C in the mobile phase is 1 mg/mL, and the other conditions are the same.
  • Example 11 The difference between Example 11 and Example 5 is that during purification by high-performance liquid chromatography, the concentration of vitamin C in the mobile phase is 5 mg/mL, and the other conditions are the same.
  • Example 12 The difference between Example 12 and Example 5 is that during purification by high-performance liquid chromatography, the concentration of vitamin C in the mobile phase is 10 mg/mL, and the other conditions are the same.
  • Example 13 The difference between Example 13 and Example 5 is that during purification by high performance liquid chromatography, the mobile phase does not contain vitamin C, and the other conditions are the same.
  • Example 14 The difference between Example 14 and Example 5 is that during purification by high-performance liquid chromatography, the mobile phase also includes L-glutathione and does not contain vitamin C.
  • the concentration of L-glutathione is 0.5 mg/mL, and the remaining Conditions are the same.
  • Example 15 The difference between Example 15 and Example 5 is that during high-performance liquid chromatography purification, the mobile phase also includes thiourea and does not contain vitamin C.
  • the concentration of thiourea is 0.5 mg/mL, and the other conditions are the same.
  • Example 16 The difference between Example 16 and Example 5 is that in the de-tert-butyl esterification reaction, the volume ratio of trifluoroacetic acid and dichloromethane is 0.18:1, and the other conditions are the same.
  • Example 17 The difference between Example 17 and Example 5 is that during high-performance liquid chromatography purification, the mobile phase also includes gentisic acid and does not contain vitamin C.
  • concentration of gentisic acid is 0.5 mg/mL, and the other conditions are the same.
  • Example 18 The difference between Example 18 and Example 5 is that during purification by high-performance liquid chromatography, the mobile phase also includes vitamin C and gentisic acid.
  • the concentration of vitamin C is 0.25 mg/mL
  • the concentration of gentisic acid is 0.25 mg/mL. , other conditions are the same.
  • Comparative Example 1 The difference between Comparative Example 1 and Example 5 is that during high-performance liquid chromatography purification, the mobile phase is a mixed solvent system of acetonitrile and water, where the volume ratio of acetonitrile and water is 3:1, and the mobile phase does not contain vitamin C. , other conditions are the same.
  • column 1 is XBridge BEH C18 OBD Prep column, 130A, 5 ⁇ m, 10 ⁇ 250mm.
  • the 18F initial activity data shown in Table 2 refers to the data that can be detected after production, but Those skilled in the art can understand that usually the initial activity of 18 F will change with the storage time and use conditions. Therefore, the data of the initial activity of 18 F in Examples 1-18 and Comparative Example 1 are usually the target.
  • the range of 18 F initial activity data within ⁇ 10% is within the range recognized by those skilled in the art.
  • 10Ci is the target 18 F initial activity. In actual detection, the initial activity can be 9Ci-11Ci.
  • 1Ci is the starting activity of 18 F of the target, in actual detection the starting activity can be 0.9Ci-1.1Ci
  • 4Ci is the starting activity of 18 F of the target, in actual detection the starting activity can be 3.6 Ci-4.4 Ci.
  • the compound I liquid composition includes 6.2 mg/mL sodium chloride, 0.88 mL/mL water, 0.12 mL/mL ethanol, 1 mg/mL polysorbate 80, and 0.5 mg/mL vitamin C (wherein , Vitamin C concentration (mg/mL)/Compound I activity concentration (mCi/mL) is 0.009).
  • the above prescription component Compound I liquid composition is added to an ethanol aqueous solution containing a small amount of vitamin C and Compound I, so that the concentration of the above components meets the above conditions.
  • absolute ethanol and polysorbate 80 serve as co-solvents to help dissolve compound I, and vitamin C, as an anti-radiation decomposition agent, can prevent compound I from decomposing due to radiation and improve its stability.
  • Example 23 The difference between Example 23 and Example 21 is that the compound I liquid composition includes 6.2 mg/mL sodium chloride, 0.88 mL/mL water, 0.12 mL/mL ethanol, and 0.5 mg/mL polysorbate 80, 0.5 mg/mL vitamin C (wherein, vitamin C concentration (mg/mL)/compound I activity concentration (mCi/mL) is 0.009), and the other conditions are the same.
  • the compound I liquid composition includes 6.2 mg/mL sodium chloride, 0.88 mL/mL water, 0.12 mL/mL ethanol, and 0.5 mg/mL polysorbate 80, 0.5 mg/mL vitamin C (wherein, vitamin C concentration (mg/mL)/compound I activity concentration (mCi/mL) is 0.009), and the other conditions are the same.
  • Example 26 The difference between Example 26 and Example 21 is that the compound I liquid composition includes 6.2 mg/mL sodium chloride, 0.88 mL/mL water, 0.12 mL/mL ethanol, 1 mg/mL polysorbate 80, 10 mg /mL of vitamin C (wherein, vitamin C concentration (mg/mL)/compound I activity concentration (mCi/mL) is 0.18), and the other conditions are the same.
  • the compound I liquid composition includes 6.2 mg/mL sodium chloride, 0.88 mL/mL water, 0.12 mL/mL ethanol, 1 mg/mL polysorbate 80, 10 mg /mL of vitamin C (wherein, vitamin C concentration (mg/mL)/compound I activity concentration (mCi/mL) is 0.18), and the other conditions are the same.
  • Example 27 The difference between Example 27 and Example 21 is that the compound I liquid composition includes 6.2 mg/mL sodium chloride, 0.88 mL/mL water, 0.12 mL/mL ethanol, 1 mg/mL polysorbate 80, 0.5 mg/mL of gentisic acid (wherein, gentisic acid concentration (mg/mL)/compound I activity concentration (mCi/mL) is 0.009).
  • the above prescription components are added to obtain a Compound I liquid composition, so that the concentration of the above components meets the above conditions.
  • the compound I liquid composition includes 6.2 mg/mL sodium chloride, 0.88 mL/mL water, 0.12 mL/mL ethanol, and 0.5 mg/mL vitamin C (wherein, Vitamin C concentration (mg/mL)/compound I activity concentration (mCi/mL) is 0.009).
  • the compound I liquid composition includes 6.2 mg/mL sodium chloride, 0.88 mL/mL water, 0.12 mL/mL ethanol, 1 mg/mL polyethylene glycol 400, 0.5 mg/mL vitamin C (wherein, vitamin C concentration (mg/mL)/compound I activity concentration (mCi/mL) is 0.009).
  • the compound I liquid composition includes 6.2 mg/mL sodium chloride, 0.88 mL/mL water, 0.12 mL/mL ethanol, and 1 mg/mL polysorbate 80.
  • the compound I liquid composition includes 6.2 mg/mL sodium chloride, 0.88 mL/mL water, 0.12 mL/mL ethanol, 1 mg/mL polysorbate 80, 0.5 mg/mL of L-glutathione (where L-glutathione concentration (mg/mL)/compound I activity concentration (mCi/mL) is 0.009).
  • the compound I liquid composition includes 6.2 mg/mL sodium chloride, 0.88 mL/mL water, 0.12 mL/mL ethanol, 1 mg/mL polysorbate 80, 0.5 mg/mL of thiourea (wherein, thiourea concentration (mg/mL)/compound I activity concentration (mCi/mL) is 0.009).
  • the compound I liquid composition includes 6.2 mg/mL sodium chloride, 0.88 mL/mL water, 0.12 mL/mL ethanol, 1 mg/mL polysorbate 80, 0.5 mg/mL sodium metabisulfite (wherein, sodium metabisulfite concentration (mg/mL)/compound I activity concentration (mCi/mL) is 0.009).
  • the measurement method of labeling rate is: after the labeling reaction is completed, use high-performance liquid chromatography (HPLC) to inject and analyze the sample.
  • HPLC high-performance liquid chromatography
  • Undecay-corrected yield is determined as the ratio of the activity of the final liquid composition product measured using an activity meter to the 18 F starting activity.
  • the method of measuring clarity is as follows: observe the solution to be tested under a clarity detector and compare it with a standard turbidity solution to determine the clarity of the solution.
  • the method for measuring insoluble particles is as follows: use the photoresist method to measure the insoluble particles content of the solution under an insoluble particle detector, and the unit is particles/mL.
  • the determination method of radiochemical purity 0h is: using HPLC sample injection analysis, the ratio of the radioactive peak area of the product to the peak area of all radioactive peaks.
  • the measurement method of 6-hour stability is: after the final product is placed at room temperature for 6 hours, HPLC is used for sample injection analysis, and the ratio of the radioactive peak area of the product to the peak area of all radioactive peaks.
  • Example 2-3 increases the dosage of compound I tert-butyl ester precursor, and its yield and labeling rate increase, but the radiochemical purity does not change much.
  • Example 4 Compared with Example 3, in Examples 4 and 5, when the dosage of compound I tert-butyl ester precursor is constant and the 18 F ion starting activity is increased, the yield and labeling rate change little, and the radiochemical purity changes. Not big.
  • Examples 6 and 7 changed the volume ratio of trifluoroacetic acid and acetonitrile in the reaction step of removing tert-butyl ester. As the amount of trifluoroacetic acid increases, the yield and labeling rate increase.
  • Example 8 and Example 9 changed the ratio of mobile phase ethanol and water.
  • the yield and labeling rate of Example 8 were both better than those of Example 5.
  • the yield and labeling rate of Example 9 were The yield and labeling rate are both worse than those of Example 5.
  • Examples 10-12 changed the content of vitamin C in the mobile phase, increased the yield and labeling rate, and improved the radiochemical purity.
  • Example 13-15 when vitamin C is not included in the mobile phase or vitamin C is replaced with other substances, such as L-glutathione or thiourea, the yield and labeling rate decrease. Radiochemistry Purity is reduced.
  • Example 16 in the reaction step of removing tert-butyl ester, a mixed system of trifluoroacetic acid and methylene chloride was used. The yield and labeling rate were low, and the radiochemical purity was not high.
  • Example 5 Compared with Example 5, in Examples 17-18, vitamin C was replaced with gentisic acid in the mobile phase, or a mixture of vitamin C and gentisic acid, the yield and labeling rate were equivalent, and the radiochemical purity was equivalent. Gentisic acid It has the same effect as vitamin C in the mobile phase.
  • Comparative Example 1 a mixed system of acetonitrile and water was used as the mobile phase, which required an additional C18 column purification step, increased the total preparation time, low yield and labeling rate, and low radiochemical purity.
  • Examples 24-26 change the dosage of vitamin C. As the dosage of vitamin C increases, the stability and radiochemical purity are improved to a certain extent. When the concentration of vitamin C is between 1mg/mL-10mg/ mL, there is not much change. When the amount of vitamin C increases, the pH value of the solution will decrease, making it too acidic, which is not good for human health.
  • liquid composition containing compound I that is, a liquid composition of trans-2-(2-(5-(fluoro[ 18F ])tridecyl)cyclopropyl)acetic acid
  • the liquid is required to be clear and transparent.
  • the number of insoluble particles with a particle size of ⁇ 10 ⁇ m should be less than 1,200 particles/mL.
  • the poly After sorbate 80 is replaced with polyethylene glycol 400 or propylene glycol, or when polysorbate 80 is not used, the clarity (should be clear) and insoluble particles ( ⁇ 10 ⁇ m should be less than 1200 particles/mL) do not meet the requirements.
  • Example 21 Compared with Example 21, in Comparative Examples 5-8, when vitamin C is not used or vitamin C is replaced by L-glutathione, thiourea or sodium metabisulfite, the stability and radiochemical purity are reduced.
  • Example 27 when vitamin C is replaced by gentisic acid, the stability and radiochemical purity are comparable to Example 21, and the ability of gentisic acid to stabilize Compound I in liquid compositions is comparable. .

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Abstract

La présente demande concerne un procédé de préparation d'un agent d'imagerie PET du métabolisme myocardique, une composition liquide d'acide trans-2-(2-(5-fluoro[18F]tridécyl)cyclopropyl)acétique (composé I, en abrégé), et son utilisation, un produit brut contenant le composé I étant purifié par chromatographie liquide haute performance ; la phase mobile utilisée dans l'étape de purification par chromatographie liquide haute performance comprenant de l'éthanol et de l'eau. La présente demande optimise le procédé expérimental et ajuste la quantité de précurseur d'ester tert-butylique de composé pour raccourcir le temps de réaction requis pour obtenir le même taux de marquage, et augmente la radioactivité des ions 18F initiaux pour augmenter le taux de marquage, ce qui permet d'augmenter le rendement.
PCT/CN2023/101561 2022-06-23 2023-06-21 Procédé de préparation d'une composition liquide de composé i et son utilisation dans l'imagerie tep du métabolisme myocardique WO2023246830A1 (fr)

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CN114796534B (zh) * 2022-06-23 2022-09-16 北京先通国际医药科技股份有限公司 包含化合物ⅰ的液体组合物、制备方法及用途
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