WO2023246829A1 - 包含化合物ⅰ的液体组合物、制备方法及用途 - Google Patents

包含化合物ⅰ的液体组合物、制备方法及用途 Download PDF

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WO2023246829A1
WO2023246829A1 PCT/CN2023/101560 CN2023101560W WO2023246829A1 WO 2023246829 A1 WO2023246829 A1 WO 2023246829A1 CN 2023101560 W CN2023101560 W CN 2023101560W WO 2023246829 A1 WO2023246829 A1 WO 2023246829A1
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compound
liquid composition
vitamin
concentration
activity
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PCT/CN2023/101560
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English (en)
French (fr)
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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 WO2023246829A1 publication Critical patent/WO2023246829A1/zh

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    • 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
    • A61K51/0402—Organic compounds carboxylic acid carriers, fatty acids
    • 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
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • 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 liquid composition containing Compound I, its preparation method and its use.
  • 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 ratio range of compound I tert-butyl ester precursor (mg)/ 18 F initial activity (Ci) is (0.2-5):1.
  • 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/compound I activity concentration ratio range is (0.009-0.2): 1;
  • the vitamin C concentration unit is mg/mL
  • the compound I activity concentration unit is mCi/mL.
  • the vitamin C concentration/compound I activity concentration ratio range is (0.009-0.1):1;
  • the vitamin C concentration unit is mg/mL
  • the compound I activity concentration unit is mCi/mL.
  • the gentisic acid concentration/compound I activity concentration ratio range is (0.009-0.2): 1;
  • the concentration unit of gentisic acid is mg/mL
  • the activity concentration unit of compound I is mCi/mL.
  • the ratio range of gentisic acid concentration/compound I activity concentration is (0.009-0.1):1;
  • the concentration unit of gentisic acid is mg/mL
  • the activity concentration unit of compound I is mCi/mL.
  • 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.
  • a method for performing cardiac imaging on a subject which comprises administering to the subject a Compound I liquid composition prepared according to any one of Items 1 to 7, or a Compound I liquid prepared by the method described in Item 8 or 9. combination.
  • 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 also lipophilic and hydrophilic. Therefore, it has good research prospects.
  • the specific steps are as follows: the raw materials 1,2-bis(2-iodoethoxy)ethane and benzylamine are refluxed in an acetonitrile solution for 3 days, and then an intermediate is obtained through post-treatment, and the intermediate is recrystallized with acetone. After filtration, a NaI complex is obtained.
  • the complex is decomplexed by cation exchange resin and anion exchange resin respectively under acidic conditions to prepare amino polyether (K 222 ).
  • This method has simple equipment, less solvent consumption, and relatively mild reaction conditions.
  • 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, the ethanol is 2-5 parts by volume relative to 1 part by volume. integral part of water, 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 in the high performance liquid chromatography purification step: the mobile phase further includes gentisic acid.
  • 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;
  • Detert-butyl esterification reaction Add acidic solvent to the intermediate product solution of the above compound I tert-butyl ester. agent, carry out de-tert-butyl esterification reaction to obtain a product containing compound I.
  • Compound I tert-butyl ester precursor / 18 F initial activity (Ci) ratio range is (0.2-5): 1;
  • the compound I tert-butyl ester precursor/ 18 F initial activity (Ci) ratio 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 is trifluoroacetic acid and acetonitrile; relative to 1 volume part 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 (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 comprising Compound I in the liquid composition comprising Compound I, it can be Sometimes it contains vitamin C and gentisic acid, or it can only contain 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, and polysorbate 80 are mixed with an ethanol aqueous solution containing vitamin C and/or gentisic acid and compound I to obtain an aqueous solution containing compound I.
  • Liquid composition In some embodiments of the present application, vitamin C and/or gentisic acid, sodium chloride, and polysorbate 80 are mixed with an ethanol aqueous solution containing vitamin C and/or gentisic acid and compound I to obtain an aqueous solution containing compound I. Liquid composition.
  • This application also provides the application of the above-mentioned Compound I liquid composition and the Compound I liquid composition prepared by the above-mentioned method as a PET imaging agent for myocardial metabolism.
  • 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 18 F and the reaction precursor.
  • the leaving group in the compound is converted into the final labeled product.
  • the labeled product contains 18 F, so the labeling rate is defined as the activity ratio of the labeled product to 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 preparation method of the above-mentioned compound I provided by this application can increase the yield to more than 30% and shorten the production time from about 80 minutes to about 60 minutes.
  • the solvent used in the de-tert-butyl esterification reaction is acetonitrile, the step of nitrogen removal of the solvent can be omitted and the process can be shortened.
  • the use of trifluoroacetic acid/acetonitrile system in the de-tert-butyl esterification reaction reduces the risk of solvent residues in the final product, while increasing the initial activity of compound I tert-butyl ester precursor and 18 F, and improving the conversion of this step.
  • 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), the rest of the 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 (i.e. 1.54:1), the 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 high-performance liquid chromatography purification, 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 high-performance liquid chromatography purification, the mobile phase is a mixed solvent system of ethanol and water, where 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 ⁇ 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 It is thought that 9Ci-11Ci and 1Ci are the starting activity of 18 F of the target.
  • the starting activity can be 0.9Ci-1.1Ci. 4Ci is the starting activity of 18 F of the target. In the actual detection, the starting activity can be 0.9Ci-1.1Ci.
  • the temperature can be 3.6Ci-4.4Ci.
  • 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 components are added to obtain a compound I liquid composition, 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 22 The difference between Example 22 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, 2 mg/mL polysorbate 80, 0.5 mg/mL of 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, 2 mg/mL polysorbate 80, 0.5 mg/mL of 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 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 24 The difference between Example 24 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, 1 mg /mL of vitamin C (wherein, vitamin C concentration (mg/mL)/compound I activity concentration degree (mCi/mL) is 0.018), 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, 1 mg /mL of vitamin C (wherein, vitamin C concentration (mg/mL)/compound I activity concentration degree (mCi/mL) is 0.018), and the other conditions are the same.
  • Example 25 The difference between Example 25 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, 5 mg /mL of vitamin C (wherein, vitamin C concentration (mg/mL)/compound I activity concentration (mCi/mL) is 0.09), 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, 5 mg /mL of vitamin C (wherein, vitamin C concentration (mg/mL)/compound I activity concentration (mCi/mL) is 0.09), 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, 1 mg/mL propylene glycol, 0.5 mg/mL of 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 product radioactivity peak The ratio of the area 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.
  • Example 6 and Example 7 changed the three steps in the removal of tert-butyl ester reaction step. As the volume ratio of fluoroacetic acid and acetonitrile increases, the yield and labeling rate increase as the amount of trifluoroacetic acid increases.
  • 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 by 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 clarity (should be clear) and insoluble particles ( ⁇ 10 ⁇ m Should be less than 1200 grains/mL) does 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

一种包含反式-2-(2-(5-(氟[ 18F])十三烷基)环丙基)乙酸的液体组合物、其制备方法及其在制备用于心肌代谢PET显像剂中的应用，该液体组合物还包括维生素C和/或龙胆酸，进一步地可包括聚山梨酯80，其制备方法包括将维生素C和/或龙胆酸、氯化钠、聚山梨酯80与含维生素C和/或龙胆酸、反式-2-(2-(5-(氟[ 18F])十三烷基)环丙基)乙酸的乙醇水溶液混合。

Description

包含化合物Ⅰ的液体组合物、制备方法及用途 技术领域
本申请属于化学制药技术领域，特别是涉及一种包含化合物Ⅰ的液体组合物、制备方法及用途。
背景技术
作为当今生物医学工程领域最先进的成像技术，分子医学影像技术是应用影像学的方法对活体状态下的生物过程进行细胞和分子水平的定性和定量研究，在分子水平上对生物体生理、病理的变化进行实时、动态、在体、无创的成像技术。它是研究靶向性、特异性分子探针及治疗药物的关键、核心技术。多模态分子影像技术可实现不同影像设备的优势互补，使获取的影像结果更精确、更可靠。临床实践已证明，多模态分子医学影像设备在重大疾病的早诊早治、治疗方案的制定、治疗效果的验证与评估中发挥着重要作用。
正电子发射断层成像(Positron Emission Tomography，PET)设备主要是功能成像，它由一个PET成像装置和注射到病人血液中的放射性示踪剂组成。一种经常使用的放射性示踪剂是氟代脱氧葡萄糖(Fluoro-deoxy-glucose，FDG)，它是一种由一个简单的糖和少量的放射性氟合成的化合物，人体注射[18F]FDG后，其会在体内的组织和器官中蓄积，与此同时，18F会进行衰变，发射出一个正电子，正电子发生湮灭反应，产生一对反向运动的光子，其能量为511keV。PET设备能够检测到这些光子，并记录下这一对光子的信息，通过这些信息，还原正电子在体内湮灭的位置，从而得到[18F]FDG在人体内的分布图。
然而18F-FDG在以葡萄糖代谢为能量底物的脑肿瘤显像、肿瘤与炎症的鉴别诊断等方面的临床应用中仍存在一些局限性。
发明内容
本申请提供了一种可用于心脏影像的化合物Ⅰ的制备方法及其用途。
本申请技术方案如下：
1.一种化合物Ⅰ液体组合物的制备方法，
对包含化合物Ⅰ的粗产品利用高效液相色谱进行纯化；其中，高效液相色谱纯化步骤中使用的流动相包括乙醇和水；
化合物Ⅰ为反式-2-(2-(5-氟[18F]十三烷基)环丙基)乙酸。
2.根据项1所述的制备方法，
在高效液相色谱纯化步骤中：
在所述流动相中，
相对于1体积份的水，所述乙醇为2-5体积份；
优选地，相对于1体积份的水，所述乙醇为3-4体积份。
3.根据项1所述的制备方法，
在高效液相色谱纯化步骤中：
所述流动相还包括维生素C。
4.根据项3所述的制备方法，
在高效液相色谱纯化步骤中：
在所述流动相中，所述维生素C添加量为0.1mg/mL-10mg/mL；优选为0.1mg/mL-5mg/mL。
5.根据项1所述的制备方法，
在高效液相色谱纯化步骤中：
所述流动相还包括龙胆酸。
6.根据项5所述的制备方法，
在高效液相色谱纯化步骤中：
在所述流动相中，所述龙胆酸添加量为0.1mg/mL-10mg/mL；优选为0.1mg/mL-5mg/mL。
7.根据项1所述的制备方法，
所述色谱柱为硅胶柱，优选为反相C18硅胶色谱柱，进一步优选为XBridge BEH C18 OBD Prep column；
更优选地，采用等度洗脱，所述流动相的洗脱流速为3mL/min-6mL/min。
8.根据项1所述的制备方法，
在高效液相色谱纯化步骤之前，还包括亲核取代反应步骤和脱叔丁酯基反应步骤：
亲核取代反应：将经活化后的18F离子与含化合物Ⅰ叔丁酯前体的溶液混合，进行亲核取代反应，得到含化合物Ⅰ叔丁酯的中间产品溶液；
脱叔丁酯基反应：向上述化合物Ⅰ叔丁酯的中间产品溶液中加入酸性溶剂，进行脱叔丁酯基反应，得到含有化合物Ⅰ的产品；
化合物Ⅰ叔丁酯前体为反式-2-(2-(5-(甲磺酰氧基)十三烷基)环丙基)乙酸叔丁酯；
化合物Ⅰ叔丁酯为反式-2-(2-(5-氟[18F]十三烷基)环丙基)乙酸叔丁酯。
9.根据项8所述的制备方法，
在亲核取代反应中，
化合物Ⅰ叔丁酯前体(mg)/18F起始活度(Ci)比值范围为(0.2-5):1。
10.根据项9所述的制备方法，
所述18F起始活度为0.09Ci-11Ci，优选为3.6Ci-11Ci。
11.根据项8所述的制备方法，
在脱叔丁酯基反应中，
所述酸性溶剂为三氟乙酸与乙腈混合体系；
优选地，相对于1体积份的乙腈，三氟乙酸为0.4-2体积份；
进一步优选地，相对于1体积份的乙腈，三氟乙酸为0.6-1.5体积份。
12根据项1-11任一项所述方法制备的化合物Ⅰ液体组合物在制备用于心肌代谢PET显像剂中的应用。
另外，本申请提供了一种包含化合物I的液体组合物，具体方案如下：
1.一种包含化合物Ⅰ的液体组合物，其中，所述液体组合物还包括维生素C和/或龙胆酸；
化合物Ⅰ为反式-2-(2-(5-(氟[18F])十三烷基)环丙基)乙酸。
2.根据项1所述的液体组合物，维生素C浓度/化合物Ⅰ活度浓度比值范围为(0.009-0.2):1；
其中，所述维生素C浓度单位为mg/mL，所述化合物Ⅰ活度浓度单位为mCi/mL。
3.根据项2所述的液体组合物，
维生素C浓度/化合物Ⅰ活度浓度比值范围为(0.009-0.1):1；
其中，所述维生素C浓度单位为mg/mL，所述化合物Ⅰ活度浓度单位为 mCi/mL。
4.根据项1所述的液体组合物，龙胆酸浓度/化合物Ⅰ活度浓度比值范围为(0.009-0.2):1；
其中，所述龙胆酸浓度单位为mg/mL，所述化合物Ⅰ活度浓度单位为mCi/mL。
5.根据项4所述的液体组合物，
龙胆酸浓度/化合物Ⅰ活度浓度比值范围为(0.009-0.1):1；
其中，所述龙胆酸浓度单位为mg/mL，所述化合物Ⅰ活度浓度单位为mCi/mL。
6.根据项1所述的液体组合物，所述组合物还包括聚山梨酯80。
7.根据项6所述的液体组合物，
所述聚山梨酯80浓度为0.5mg/mL-2mg/mL。
8.一种制备项1-7任一项所述的液体组合物的方法，其中，
从纯化步骤中将含维生素C和/或龙胆酸、化合物Ⅰ的乙醇水溶液进行收集，得到包含化合物Ⅰ的液体组合物。
9.根据项8所述的方法，
将维生素C和/或龙胆酸、氯化钠、聚山梨酯80与含维生素C和/或龙胆酸、化合物Ⅰ的乙醇水溶液混合，得到包含化合物Ⅰ的液体组合物。
10.根据项1-7任一项所述的化合物Ⅰ液体组合物、项8或9所述方法制备的化合物Ⅰ液体组合物在制备用于心肌代谢PET显像剂中的应用。
11.一种对受试者进行心脏显影的方法，其包括向受试者基于根据项1-7任一项所述的化合物Ⅰ液体组合物、项8或9所述方法制备的化合物Ⅰ液体组合物。
与现有技术相比，本申请的有益效果为：
(1)本申请通过优化实验工艺方案，通过改变化合物Ⅰ叔丁酯前体用量，缩短达到相同标记率所用的反应时间，提高起始18F离子的放射性活度，提高了标记率，从而提高收率。工艺参数与工艺流程明确具体，可适用于大批量活度生产，满足了自动化需求。
(2)本申请优化技术方案中，纯化过程流动相使用抗辐射分解剂，避免在纯化和处方化过程中由于辐射分解造成的产品损失，从而提高产率。另外，本申请在处方过程中，使用抗辐射分解剂，保证了产品的稳定性。
(3)本申请优化纯化工艺，去除了C18小柱，流动相采用乙醇/水体系代替乙腈/水体系。简化了时间，提高了产品的放射化学纯度和稳定性。
具体实施方式
化合物Ⅰ，化学名称为反式-2-(2-(5-(氟[18F])十三烷基)环丙基)乙酸，化学结构式为：
化学式为：C18H33 18FO2
分子量为：299.46
在本申请中，18F标记心肌代谢PET显像剂指化合物Ⅰ液体组合物。
化合物Ⅰ叔丁酯前体，化学名称为反式-2-(2-(5-(甲磺酰氧基)十三烷基)环丙基)乙酸叔丁酯，化学结构式为：
化学式为：C23H44O5S
分子量为：432.66
化合物Ⅰ叔丁酯，化学名称为反式-2-(2-(5-氟[18F]十三烷基)环丙基)乙酸叔丁酯，化学结构式为：
化学式为：C22H41 18FO2
分子量为：355.57
氨基聚醚(K222)为具有穴状空腔的三桥冠醚分子，是典型的氮杂穴醚，为穴醚的一种。氮杂穴醚由于其独特的配位特性，能很好地选择络合过渡金属和重金属的阳离子，得到的络合物更加稳定，并且还具有亲脂性和亲水性， 因此具有较好的研究前景。
现有技术中，氨基聚醚(K222)的经典合成方法是Lehn等提出的高度稀释法，是典型的非模板离子合成法之一，具体步骤为，将原料1,8-二氨基-3,6-二氧杂辛烷和1,8-二酰氯-3,6-二氧杂辛烷溶于大量的苯溶剂中，并加热反应8h，然后通过四氢铝锂还原反应24h，再通过柱层析分离和重结晶得到氨基聚醚(K222)。该方法需要大量的溶剂，如苯，合成路线长，操作繁杂，收率较低，经济效益不高。除了高度稀释法，氨基聚醚(K222)的另一经典合成方法是Kulstad和Malmsten提出的利用Na2CO3等为模板在乙腈中得到氨基聚醚(K222)的碘化钠配合物，然后通过树脂来进行解络，得到氨基聚醚(K222)的合成方法。其具体步骤为，将原料1,2-二(2-碘乙氧基)乙烷和苄胺在乙腈溶液中回流反应3天，然后通过后处理得到中间体，该中间体用丙酮重结晶，过滤后得到NaI的络合物，该络合物在酸性条件下，分别通过阳离子交换树脂和阴离子交换树脂进行解络合制备得到氨基聚醚(K222)。该方法设备简单，溶剂用量少，反应条件较为温和。但是，申请人经过研究发现，通过离子交换树脂进行解络的方法，当钠离子的含量降低到一定量时，解络合就无法进行下去，产率较低。
本申请提供了一种化合物Ⅰ的制备方法，合成路线如下：
本申请提供了一种化合物Ⅰ的制备方法，`其中，
对包含化合物Ⅰ的粗产品利用高效液相色谱进行纯化；
其中，高效液相色谱纯化步骤中使用的流动相包括乙醇和水。
在本申请的一些实施方式中，在高效液相色谱纯化步骤中：在所述流动相中，相对于1体积份的水，所述乙醇为2-5体积份；优选地，相对于1体 积份的水，所述乙醇为3-4体积份；
例如，相对于1体积份的水，所述乙醇可以为2体积份、3体积份、4体积份、5体积份或其之间的任意范围。
在本申请的一些实施方式中，在高效液相色谱纯化步骤中：所述流动相还包括维生素C。
在本申请的一些实施方式中，在所述流动相中，所述维生素C添加量为0.1mg/mL-10mg/mL；优选为0.1mg/mL-5mg/mL；
例如，所述维生素C添加量可以为0.1mg/mL、1mg/mL、2mg/mL、3mg/mL、4mg/mL、5mg/mL、6mg/mL、7mg/mL、8mg/mL、9mg/mL、10mg/mL或其之间的任意范围。
在本申请的一些实施方式中，在高效液相色谱纯化步骤中：所述流动相还包括龙胆酸。
在本申请的一些实施方式中，在所述流动相中，所述龙胆酸添加量为0.1mg/mL-10mg/mL；优选为0.1mg/mL-5mg/mL；
例如，所述龙胆酸添加量可以为0.1mg/mL、1mg/mL、2mg/mL、3mg/mL、4mg/mL、5mg/mL、6mg/mL、7mg/mL、8mg/mL、9mg/mL、10mg/mL或其之间的任意范围。
在本申请的一些实施方式中，在所述流动相中，可以同时含有维生素C和龙胆酸，也可以只含有维生素C和龙胆酸之一。
在本申请的一些实施方式中，在高效液相色谱纯化步骤中，所述色谱柱为硅胶柱，优选为反相C18硅胶色谱柱，进一步优选为XBridge BEH C18 OBD Prep column。
在本申请的一些实施方式中，采用等度洗脱，所述流动相的洗脱流速为3mL/min-6mL/min；
例如，所述流动相的洗脱流速可以为3mL/min、4mL/min、5mL/min、6mL/min或其之间的任意范围。
在本申请的一些实施方式中，在高效液相色谱纯化步骤之前，还包括亲核取代反应步骤和脱叔丁酯基反应步骤：
亲核取代反应：将经活化后的18F离子与含化合物Ⅰ叔丁酯前体的溶液混合，进行亲核取代反应，得到含化合物Ⅰ叔丁酯的中间产品溶液；
脱叔丁酯基反应：向上述化合物Ⅰ叔丁酯的中间产品溶液中加入酸性溶 剂，进行脱叔丁酯基反应，得到含有化合物Ⅰ的产品。
在本申请的一些实施方式中，在亲核取代反应中，
化合物Ⅰ叔丁酯前体/18F起始活度(Ci)比值范围为(0.2-5):1；
例如，化合物Ⅰ叔丁酯前体/18F起始活度(Ci)比值可以为0.2:1、0.3:1、0.5:1、0.7:1、1:1、2:1、3:1、4:1、5:1或其之间的任意范围。
在本申请的一些实施方式中，所述18F起始活度为0.09Ci-11Ci，优选为3.6Ci-11Ci；
例如，所述18F起始活度为0.09Ci、0.1Ci、0.5Ci、1Ci、2Ci、3Ci、4Ci、5Ci、6Ci、7Ci、8Ci、9Ci、10Ci、11Ci或其之间的任意范围。
在本申请的一些实施方式中，在脱叔丁酯基反应中，所述酸性溶剂为三氟乙酸与乙腈；相对于1体积份的乙腈，三氟乙酸为0.4-2体积份；进一步优选地，相对于1体积份的乙腈，三氟乙酸为0.6-1.5体积份；
例如，相对于1体积份的乙腈，三氟乙酸为0.4体积份、0.5体积份、0.6体积份、0.7体积份、0.8体积份、0.9体积份、1体积份、1.5体积份、2体积份或其之间的任意范围。
本申请还提供了一种包含化合物Ⅰ的液体组合物，其中，所述液体组合物还包括维生素C和/或龙胆酸。
在本申请的一些实施方式中，维生素C浓度(mg/mL)/化合物Ⅰ活度浓度(mCi/mL)比值范围为(0.009-0.2):1，优选为(0.009-0.1):1；
例如，维生素C浓度(mg/mL)/化合物Ⅰ活度浓度(mCi/mL)比值可以为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或其之间的任意范围。
在本申请的一些实施方式中，龙胆酸浓度(mg/mL)/化合物Ⅰ活度浓度(mCi/mL)比值范围为(0.009-0.2):1，优选为(0.009-0.1):1；
例如，龙胆酸(mg/mL)/化合物Ⅰ活度浓度(mCi/mL)比值可以为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或其之间的任意范围。
在本申请的一些实施方式中，在包含化合物Ⅰ的液体组合物中，可以同 时含有维生素C和龙胆酸，也可以只含有维生素C和龙胆酸之一。
在本申请的一些实施方式中，所述液体组合物还包括聚山梨酯80。
在本申请的一些实施方式中，所述聚山梨酯80浓度为0.5mg/mL-2mg/mL；
例如，所述聚山梨酯80浓度可以为0.5mg/mL、0.8mg/mL、1mg/mL、1.5mg/mL、2mg/mL或其之间的任意范围。
本申请还提供了一种上述液体组合物的制备方法，其中，
从纯化步骤中将含维生素C和/或龙胆酸、化合物Ⅰ的乙醇水溶液进行收集，得到包含化合物Ⅰ的液体组合物。
在本申请的一些实施方式中，将维生素C和/或龙胆酸、氯化钠、聚山梨酯80与含维生素C和/或龙胆酸、化合物Ⅰ的乙醇水溶液混合，得到包含化合物Ⅰ的液体组合物。
本申请还提供了上述化合物Ⅰ液体组合物、上述方法制备的化合物Ⅰ液体组合物在用于心肌代谢PET显像剂中的应用。
在本申请中，18F起始活度又称为18F离子活度，是指启动加速器产生质子束轰击含氧[18O]的水后，生产出含18F离子的溶液，利用活度计测定的18F离子活度。
在本申请中，18F起始活度是指利用启动加速器产生质子束轰击含氧[18O]的水后，生产出含18F离子的溶液之后即可检测的浓度，即可检测是指本领域技术人员可以掌控的合理的检测时间，例如生产之后10分钟之内。此外，本领域技术人员可以理解，随着生产之后放置时间的变化，18F起始活度会有一定的变化，但通常误差范围在±10％的范围即可。
在本申请的一些实施方式中，所述18F起始活度为0.09Ci-11Ci；优选为3.6Ci-11Ci；例如，18F起始活度可以为0.09Ci、0.1Ci、0.5Ci、1Ci、2Ci、3Ci、4Ci、5Ci、6Ci、8Ci、9Ci、10Ci、11Ci或其之间的任意范围。
在本申请中，大批量是指高的总活度产品，一般可指超过1Ci即37GBq的总活度产品；
高活度浓度产品，一般可指超过50mCi/mL，即1850MBq/mL活度浓度产品。
在本申请中，标记率是指18F与反应前体之间进行标记反应，18F取代前 体中的离去基团，转化为最终标记产物，标记产物含18F，因此标记率定义为标记产物的活度比上参加反应的总18F活度。
在本申请中，产率是指最终产品化合物Ⅰ液体组合物活度与18F起始活度的比值。
在本申请的一些实施方式中，在亲核取代反应步骤之前，还包括18F离子制备步骤；18F离子制备步骤还包括18F离子溶液制备、18F离子富集与洗脱、18F离子活化；
其中，18F离子溶液制备：加速器制备18F离子溶液；
18F离子富集：将上述制备的18F离子溶液通过阴离子交换小柱富集；
18F离子洗脱：采用穴醚和碱金属盐催化剂溶液淋洗，洗脱18F离子；
18F离子活化：通过程序控制温度、氮气或其他惰性气体吹干溶剂，活化18F离子，得到活化后的18F离子。
在本申请的一些实施方式中，在18F离子溶液制备步骤中，将含18O的水传输至加速器靶位，启动加速器产生质子束轰击含18O的水，生产出含18F离子的溶液。
在本申请的一些实施方式中，在18F离子富集步骤中，阴离子交换小柱为Sep-Pak Accell Plus QMA Carbonate Plus Light Cartridge，具体为四烷基铵盐阴离子交换小柱。
在本申请的一些实施方式中，所述18F离子洗脱步骤中，在穴醚和碱金属盐催化剂溶液中，穴醚用量为5mg-40mg，碱金属盐用量为1.5mg-20mg；溶液中穴醚用量可以为5mg、8mg、10mg、15mg、20mg、40mg或其之间的任意范围；溶液中碱金属盐用量可以为1.5mg、3mg、5mg、10mg、20mg或其之间的任意范围。
在本申请的一些实施方式中，所述穴醚为4,7,13,16,21,24-六氧杂-1,10-二氮杂双环[8,8,8]二十六烷(Kryptofix-2.2.2，氨基聚醚)；所述碱金属盐为K2CO3、Na2CO3、Cs2CO3、KHCO3、NaHCO3中的一种或两种以上。
在本申请的一些实施方式中，所述催化剂溶液选自乙腈与水的混合溶剂体系，其中乙腈与水的体积比为(0.2～10):1；例如，乙腈与水的体积比可以为0.2:1、1:1、2:1、4:1、7:1、10:1或其之间的任意范围；乙腈和水混合溶剂的体积为0.3mL-2mL。
在本申请的一些实施方式中，在18F离子活化步骤中，活化温度为 80℃-130℃；
其中，程序控制温度包括如下步骤：100-120℃，正压50-200mbar，真空压力-20～-60mbar，蒸发60-120s；120-130℃，正压50-200mbar，真空压力-20～-60mbar，蒸发150-200s；120-130℃，正压50-200mbar，真空压力-60～-100mbar，蒸发10-30s；100-120℃，正压800-1200mbar，真空压力-800～-1000mbar，蒸发80-120s；80-100℃，正压400-600mbar，真空压力-800～-1000mbar，蒸发100-120s；80-100℃，正压600-900mbar，真空压力-800～-1000mbar，蒸发10-20s。
有保护基团(如叔丁酯基保护羧基、叔丁氧羰基保护氨基等)的反应，均采用两步法进行。
本申请中氟[18F]离子的用量由4Ci级别提高至10Ci级别。本申请制备方法可适用于更高的18F离子起标量。
本申请提供的上述化合物Ⅰ的制备方法，该方法使得产率提高至30％以上，生产时间由80min左右缩短至了60min左右。在本制备方法中，由于在脱叔丁酯基反应中使用的溶剂为乙腈，可以省略氮气除溶剂的步骤，缩短流程。在脱叔丁酯基反应中使用三氟乙酸/乙腈体系，降低了终产品中溶剂残留的风险，同时提高了化合物Ⅰ叔丁酯前体和18F起始活度，提高了该步骤的转化率；高效液相色谱纯化步骤中使用的流动相乙醇/水混合溶剂体系，省略了后续的C18小柱富集纯化以及无水乙醇洗脱的步骤，避免了产品在高活度下发生的辐射分解，同时缩短制备流程。另外，在流动相又加入了抗辐射分解剂维生素C，避免了在柱纯化过程中发生的辐射分解。
本申请对试验中所用到的材料以及试验方法进行一般性和/或具体的描述，在下面的实施例中，如果无其他特别的说明，％表示wt％，即重量百分数。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规试剂产品，其中，表1为实施例中所用到的原料来源。
本实施例所设参数为本申请的优选实施例，本领域技术人员可以预测到其他参数范围也会取得本申请所述技术效果。
表1实施例中所用到的原料来源

实施例
自动化设备选用Trasis公司的型号为AllinOne的设备。设备动力单元为高纯氮气与注射器电动转子，可提供真空系统，并且配置有HPLC纯化系统。由于本工艺使用了自动化设备，自动化设备置于射线屏蔽箱中，可以保护操作人员避免辐射伤害，加大操作剂量，同时由于计算机的控制，可使工艺步骤控制更加精确，可重复性更高，减少人为偏差。
实施例1化合物Ⅰ的制备
1)18F离子溶液制备
将含氧[18O]的水2g传输至加速器靶位，启动加速器产生质子束轰击含氧[18O]的水，生产出含18F离子的溶液，18F起始活度4Ci。
2)18F离子富集
将上述制得的18F离子的溶液通过阴离子交换固相萃取小柱(Waters品牌的QMA小柱，QMA小柱优选先用5mL 0.5mol/L的K2CO3淋洗，再用10mL水淋洗，完成活化后，18F离子富集至QMA小柱上。
3)18F离子洗脱
采用穴醚和碱金属盐催化剂溶液淋洗，洗脱18F离子至反应瓶中，具体地，将K222 8mg(溶于0.3mL乙腈)与K2CO3 4mg(溶于0.3mL水)混合配制成乙腈与水混合溶液，洗脱上述QMA小柱，K18F/K222复合物洗脱至反应瓶中。
4)18F离子活化
将步骤3)中经洗脱的18F离子在氮气流下程序加热100℃-125℃吹干溶剂后得到活化后的18F离子。
5)18F离子亲核取代反应
向反应瓶中加入1mL含化合物Ⅰ叔丁酯前体的乙腈溶液，化合物Ⅰ叔丁酯前体用量为3mg，化合物Ⅰ叔丁酯前体用量(mg)/18F起始活度(Ci)为3mg/4Ci(即0.75:1)，密闭条件下加热至120℃，反应10min，化合物Ⅰ叔丁酯前体与K18F/K222进行亲核取代反应，得到含化合物Ⅰ叔丁酯的中间产品。
6)脱叔丁酯基反应
向上述含化合物Ⅰ叔丁酯的中间产品中加三氟乙酸和乙腈混合体系1mL(其中，三氟乙酸和乙腈的体积比为1:1)，反应温度为70℃，反应时间为2min，脱去叔丁酯保护基团，得到含化合物Ⅰ的粗产品，反应完成后氮气流下加热100℃去除溶剂。
7)高效液相色谱进行纯化
将含化合物Ⅰ的粗产品上样至进样环，按下列色谱条件进行纯化：得到HPLC洗脱液
色谱柱：XBridge BEH C18 OBD Prep column，130A，5μm，10×250mm
流动相：乙醇与水的混合溶剂体系，其中乙醇与水的体积比为3:1，流动相还包括维生素C，维生素C的浓度为0.5mg/mL；
流速：5mL/min
检测器：放射性检测器
监测跟踪放射性信号，收集化合物I放射性主峰至中转瓶。
经纯化后得到化合物Ⅰ纯品。
实施例2
实施例2与实施例1的区别在于：化合物Ⅰ叔丁酯前体用量为6mg，化合物Ⅰ叔丁酯前体用量(mg)/18F起始活度(Ci)为6mg/4Ci(即1.5:1)，其余条件相同。
实施例3
实施例3与实施例1的区别在于：化合物Ⅰ叔丁酯前体用量为10mg，化合物Ⅰ叔丁酯前体用量(mg)/18F起始活度(Ci)为10mg/4Ci(即2.5:1)，其余条件相同。
实施例4
实施例4与实施例3的区别在于：18F离子溶液制备中，18F起始活度6.5Ci，化合物Ⅰ叔丁酯前体用量(mg)/18F起始活度(Ci)为10mg/6.5Ci(即1.54:1)，其余条件相同。
实施例5
实施例5与实施例3的区别在于：18F离子溶液制备中，18F起始活度10Ci，化合物Ⅰ叔丁酯前体用量(mg)/18F起始活度(Ci)为10mg/10Ci(即1:1)，其余条件相同。
实施例6
实施例6与实施例5的区别在于，脱叔丁酯基反应中，三氟乙酸和乙腈的体积比为0.67:1，其余条件相同。
实施例7
实施例7与实施例5的区别在于，脱叔丁酯基反应中，三氟乙酸和乙腈的体积比为0.43:1，其余条件相同。
实施例8
实施例8与实施例5的区别在于，高效液相色谱进行纯化中，流动相：乙醇与水的混合溶剂体系，其中乙醇与水的体积比为4:1，其余条件相同。
实施例9
实施例9与实施例5的区别在于，高效液相色谱进行纯化中，流动相：乙醇与水的混合溶剂体系，其中乙醇与水的体积比为2:1，其余条件相同。
实施例10
实施例10与实施例5的区别在于，高效液相色谱进行纯化中，流动相中维生素C的浓度为1mg/mL，其余条件相同。
实施例11
实施例11与实施例5的区别在于，高效液相色谱进行纯化中，流动相中维生素C的浓度为5mg/mL，其余条件相同。
实施例12
实施例12与实施例5的区别在于，高效液相色谱进行纯化中，流动相中维生素C的浓度为10mg/mL，其余条件相同。
实施例13
实施例13与实施例5的区别在于，高效液相色谱进行纯化中，流动相中不含有维生素C，其余条件相同。
实施例14
实施例14与实施例5的区别在于，高效液相色谱进行纯化中，流动相还包括L-谷胱甘肽，不含有维生素C，L-谷胱甘肽的浓度为0.5mg/mL，其余条件相同。
实施例15
实施例15与实施例5的区别在于，高效液相色谱进行纯化中，流动相还包括硫脲，不含有维生素C，硫脲的浓度为0.5mg/mL，其余条件相同。
实施例16
实施例16与实施例5的区别在于，脱叔丁酯基反应中，三氟乙酸和二氯甲烷的体积比为0.18:1，其余条件相同。
实施例17
实施例17与实施例5的区别在于，高效液相色谱进行纯化中，流动相还包括龙胆酸，不含有维生素C，龙胆酸的浓度为0.5mg/mL，其余条件相同。
实施例18
实施例18与实施例5的区别在于，高效液相色谱进行纯化中，流动相还包括维生素C和龙胆酸，维生素C的浓度为0.25mg/mL，龙胆酸的浓度为0.25mg/mL，其余条件相同。
对比例1
对比例1与实施例5的区别在于，高效液相色谱进行纯化中，流动相：乙腈与水的混合溶剂体系，其中乙腈与水的体积比为3:1，且流动相中不含有维生素C，其余条件相同。
表2实施例1-18及对比例1的参数


表2中，其中色谱柱1为XBridge BEH C18 OBD Prep column，130A，5μm，10×250mm，此外，表2中的显示的18F起始活度数据是指生产之后即可检测的数据，但本领域技术人员可以理解，通常18F起始活度会随放置时间和使用条件有所变化，因此实施例1-18以及对比例1中的18F起始活度的数据通常为该目标的18F起始活度数据±10％的范围内，均属于本领域技术人员所认可的范围，例如10Ci是目标的18F起始活度，在实际检测中起始活度可 以为9Ci-11Ci，1Ci是目标的18F起始活度，在实际检测中起始活度可以为0.9Ci-1.1Ci，4Ci是目标的18F起始活度，在实际检测中起始活度可以为3.6Ci-4.4Ci。
实施例21化合物Ⅰ液体组合物
取实施例1的化合物Ⅰ产品，进行化合物Ⅰ液体组合物的处方化，收集化合物Ⅰ至预先加入处方的中转瓶中。混合后，化合物Ⅰ纯品的活度浓度为2000MBq/mL，即54mCi/mL。所述中转瓶中的处方与HPLC主峰流动相混合，即完成处方化。具体地，所述化合物Ⅰ液体组合物包括6.2mg/mL的氯化钠，0.88mL/mL水，0.12mL/mL乙醇，1mg/mL的聚山梨酯80，0.5mg/mL的维生素C(其中，维生素C浓度(mg/mL)/化合物Ⅰ活度浓度(mCi/mL)为0.009)。
具体地，在含少量的维生素C、化合物Ⅰ的乙醇水溶液中，加入上述处方组分得到化合物Ⅰ液体组合物，使上述组分的浓度满足上述条件。
在所述化合物Ⅰ液体组合物中，无水乙醇和聚山梨酯80作为助溶剂，有助于化合物Ⅰ的溶解，维生素C作为抗辐射分解剂，可以防止化合物Ⅰ因辐射作用而分解，提高其稳定性。
实施例22
实施例22与实施例21的区别在于，所述化合物Ⅰ液体组合物包括6.2mg/mL的氯化钠，0.88mL/mL水，0.12mL/mL乙醇，2mg/mL的聚山梨酯80，0.5mg/mL的维生素C(其中，维生素C浓度(mg/mL)/化合物Ⅰ活度浓度(mCi/mL)为0.009)，其余条件相同。
实施例23
实施例23与实施例21的区别在于，所述化合物Ⅰ液体组合物包括6.2mg/mL的氯化钠，0.88mL/mL水，0.12mL/mL乙醇，0.5mg/mL的聚山梨酯80，0.5mg/mL的维生素C(其中，维生素C浓度(mg/mL)/化合物Ⅰ活度浓度(mCi/mL)为0.009)，其余条件相同。
实施例24
实施例24与实施例21的区别在于，所述化合物Ⅰ液体组合物包括6.2mg/mL的氯化钠，0.88mL/mL水，0.12mL/mL乙醇，1mg/mL的聚山梨酯80，1mg/mL的维生素C(其中，维生素C浓度(mg/mL)/化合物Ⅰ活度浓 度(mCi/mL)为0.018)，其余条件相同。
实施例25
实施例25与实施例21的区别在于，所述化合物Ⅰ液体组合物包括6.2mg/mL的氯化钠，0.88mL/mL水，0.12mL/mL乙醇，1mg/mL的聚山梨酯80，5mg/mL的维生素C(其中，维生素C浓度(mg/mL)/化合物Ⅰ活度浓度(mCi/mL)为0.09)，其余条件相同。
实施例26
实施例26与实施例21的区别在于，所述化合物Ⅰ液体组合物包括6.2mg/mL的氯化钠，0.88mL/mL水，0.12mL/mL乙醇，1mg/mL的聚山梨酯80，10mg/mL的维生素C(其中，维生素C浓度(mg/mL)/化合物Ⅰ活度浓度(mCi/mL)为0.18)，其余条件相同。
实施例27
实施例27与实施例21的区别在于，所述化合物Ⅰ液体组合物包括6.2mg/mL的氯化钠，0.88mL/mL水，0.12mL/mL乙醇，1mg/mL的聚山梨酯80，0.5mg/mL的龙胆酸(其中，龙胆酸浓度(mg/mL)/化合物Ⅰ活度浓度(mCi/mL)为0.009)。
具体地，在含少量的龙胆酸、化合物Ⅰ的乙醇水溶液中，加入上述处方组分得到化合物Ⅰ液体组合物，使上述组分的浓度满足上述条件。
对比例2
对比例2与实施例21的区别在于，所述化合物Ⅰ液体组合物包括6.2mg/mL的氯化钠，0.88mL/mL水，0.12mL/mL乙醇，0.5mg/mL的维生素C(其中，维生素C浓度(mg/mL)/化合物Ⅰ活度浓度(mCi/mL)为0.009)。
对比例3
对比例3与实施例21的区别在于，所述化合物Ⅰ液体组合物包括6.2mg/mL的氯化钠，0.88mL/mL水，0.12mL/mL乙醇，1mg/mL的聚乙二醇400，0.5mg/mL的维生素C(其中，维生素C浓度(mg/mL)/化合物Ⅰ活度浓度(mCi/mL)为0.009)。
对比例4
对比例4与实施例21的区别在于，所述化合物Ⅰ液体组合物包括6.2mg/mL的氯化钠，0.88mL/mL水，0.12mL/mL乙醇，1mg/mL的丙二醇，0.5mg/mL的维生素C(其中，维生素C浓度(mg/mL)/化合物Ⅰ活度浓度 (mCi/mL)为0.009)。
对比例5
对比例5与实施例21的区别在于，所述化合物Ⅰ液体组合物包括6.2mg/mL的氯化钠，0.88mL/mL水，0.12mL/mL乙醇，1mg/mL的聚山梨酯80。
对比例6
对比例6与实施例21的区别在于，所述化合物Ⅰ液体组合物包括6.2mg/mL的氯化钠，0.88mL/mL水，0.12mL/mL乙醇，1mg/mL的聚山梨酯80，0.5mg/mL的L-谷胱甘肽(其中，L-谷胱甘肽浓度(mg/mL)/化合物Ⅰ活度浓度(mCi/mL)为0.009)。
对比例7
对比例7与实施例21的区别在于，所述化合物Ⅰ液体组合物包括6.2mg/mL的氯化钠，0.88mL/mL水，0.12mL/mL乙醇，1mg/mL的聚山梨酯80，0.5mg/mL的硫脲(其中，硫脲浓度(mg/mL)/化合物Ⅰ活度浓度(mCi/mL)为0.009)。
对比例8
对比例8与实施例21的区别在于，所述化合物Ⅰ液体组合物包括6.2mg/mL的氯化钠，0.88mL/mL水，0.12mL/mL乙醇，1mg/mL的聚山梨酯80，0.5mg/mL的焦亚硫酸钠(其中，焦亚硫酸钠浓度(mg/mL)/化合物Ⅰ活度浓度(mCi/mL)为0.009)。
表3实施例21-27及对比例2-8的参数

实验例
标记率的测定方法为：标记反应完成后，利用高效液相色谱法(HPLC)进样分析，液相色谱图中目标产物放射性峰面积与所有放射性峰的峰面积的比值。
未衰变校正的收率的测定方法为：利用活度计测定的最终液体组合物产品的活度与18F起始活度的比值。
澄明度的测定方法为：将待测溶液在澄明度检测仪下进行观察，与标准浊度溶液进行对比，判断溶液的澄明度。
不溶性微粒的测定方法为：将待测溶液在不溶性微粒检测仪下用光阻法测定溶液的不溶性微粒含量，单位为粒/mL。
放射化学纯度0h的测定方法为：利用HPLC进样分析，产品放射性峰 面积与所有放射性峰的峰面积的比值。
6h稳定性(放化纯指标)的测定方法为：最终产品在室温下放置6h后，利用HPLC进样分析，产品放射性峰面积与所有放射性峰的峰面积的比值。
表4实施例1-18及对比例1的实验效果数据
与实施例1相比，实施例2-3增大化合物Ⅰ叔丁酯前体用量，其收率和标记率都增大，放射化学纯度变化不大。
与实施例3相比，实施例4和实施例5中，当化合物Ⅰ叔丁酯前体用量一定，增大18F离子起标活度，收率和标记率变化不大，放射化学纯度变化不大。
与实施例5相比，实施例6和实施例7改变了脱叔丁酯反应步骤中，三 氟乙酸和乙腈的体积比，随着三氟乙酸用量增加，收率和标记率增大。
与实施例5相比，实施例8和实施例9改变了流动相乙醇和水的比例，实施例8的收率和标记率均比实施例5的收率和标记率好，实施例9的收率和标记率均比实施例5的收率和标记率均差，当流动相中乙醇含量越大时，出峰时间越快，制备时间越短，收率会有所增加，但放射化学纯度会降低。
与实施例5相比，实施例10-12改变了流动相中维生素C的含量，收率和标记率都增大，放射化学纯度提高。
与实施例5相比，实施例13-15中，流动相中不含维生素C或将维生素C换成其他物质，如L谷胱甘肽或硫脲时，收率和标记率下降，放射化学纯度降低。
实施例16中，在脱叔丁酯反应步骤中，使用三氟乙酸和二氯甲烷混合体系，收率和标记率低，放射化学纯度不高。
与实施例5相比，实施例17-18中，流动相中将维生素C换成龙胆酸，或维生素C与龙胆酸混合物，收率和标记率相当，放射化学纯度相当，龙胆酸在流动相中作用与维生素C相当。
对比例1中，流动相使用乙腈与水的混合体系，使得后续需要增加C18小柱纯化步骤，增加总制备时间，收率和标记率低，放射化学纯度不高。
表5实施例21-27及对比例2-8的实验效果数据

实施例21-23中，考察了聚山梨酯80的用量对稳定性和放射化学纯度的影响，其中随着聚山梨酯80的增大，化合物Ⅰ液体组合物的稳定性和放射化学纯度变化不大。
与实施例21相比，实施例24-26改变了维生素C的用量，随着维生素C用量的增大，稳定性和放射化学纯度有一定提高，当维生素C的浓度在1mg/mL-10mg/mL时，变化不大。当维C量增加还会导致溶液pH值减少，酸性过大，不利于人体健康。
作为包含化合物Ⅰ的液体组合物，即反式-2-(2-(5-(氟[18F])十三烷基)环丙基)乙酸的液体组合物，要求液体澄清透明，另外，要求不溶性微粒粒径在≥10μm的微粒数应小于1200粒/mL。与实施例21相比，对比例2-4中将聚山梨酯80用聚乙二醇400或丙二醇替代后，或不使用聚山梨酯80时，澄明度(应澄明)及不溶性微粒(≥10μm应小于1200粒/mL)不满足要求。
与实施例21相比，对比例5-8中，当不使用维生素C或将维生素C替换为L-谷胱甘肽、硫脲或焦亚硫酸钠时，稳定性和放射化学纯度均有所下降。
与实施例21相比，实施例27中，当将维生素C替换为龙胆酸，稳定性和放射化学纯度与实施例21相当，龙胆酸在液体组合物中用于稳定化合物I的能力相当。
另一方面，化合物Ⅰ，放射化学纯度需要≥90％，<90％是不合适的，不能使用。
虽然本案已以实施例揭露如上然其并非用以限定本案，任何所属技术领域中具有通常知识者，在不脱离本案的精神和范围内，当可作些许的更动与润饰，故本案的保护范围当视后附的专利申请范围所界定者为准。

Claims (11)

  1. 一种包含化合物Ⅰ的液体组合物，其中，所述液体组合物还包括维生素C和/或龙胆酸；
    化合物Ⅰ为反式-2-(2-(5-(氟[18F])十三烷基)环丙基)乙酸。
  2. 根据权利要求1所述的液体组合物，其中，
    维生素C浓度/化合物Ⅰ活度浓度比值范围为(0.009-0.2):1；
    其中，所述维生素C浓度单位为mg/mL，所述化合物Ⅰ活度浓度单位为mCi/mL。
  3. 根据权利要求2所述的液体组合物，其中，
    维生素C浓度(mg/mL)/化合物Ⅰ活度浓度(mCi/mL)比值范围为(0.009-0.1):1；
    其中，所述维生素C浓度单位为mg/mL，所述化合物Ⅰ活度浓度单位为mCi/mL。
  4. 根据权利要求1所述的液体组合物，其中，
    龙胆酸浓度/化合物Ⅰ活度浓度比值范围为(0.009-0.2):1；
    其中，所述龙胆酸浓度单位为mg/mL，所述化合物Ⅰ活度浓度单位为mCi/mL。
  5. 根据权利要求4所述的液体组合物，其中，
    龙胆酸浓度(mg/mL)/化合物Ⅰ活度浓度(mCi/mL)比值范围为(0.009-0.1):1；
    其中，所述龙胆酸浓度单位为mg/mL，所述化合物Ⅰ活度浓度单位为mCi/mL。
  6. 根据权利要求1所述的液体组合物，其中，
    所述液体组合物还包括聚山梨酯80。
  7. 根据权利要求6所述的液体组合物，其中，
    所述聚山梨酯80浓度为0.5mg/mL-2mg/mL。
  8. 一种制备权利要求1-7任一项所述的液体组合物的方法，其中，
    从纯化步骤中将含维生素C和/或龙胆酸、化合物Ⅰ的乙醇水溶液进行收集，得到包含化合物Ⅰ的液体组合物。
  9. 根据权利要求8所述的方法，其中，
    将维生素C和/或龙胆酸、氯化钠、聚山梨酯80与含维生素C和/或龙胆酸、化合物Ⅰ的乙醇水溶液混合，得到包含化合物Ⅰ的液体组合物。
  10. 根据权利要求1-7任一项所述的化合物Ⅰ液体组合物、权利要求8或9所述方法制备的化合物Ⅰ液体组合物在制备用于心肌代谢PET显像剂中的应用。
  11. 一种对受试者进行心脏显影的方法，其包括向受试者基于根据权利要求1-7任一项所述的化合物Ⅰ液体组合物、权利要求8或9所述方法制备的化合物Ⅰ液体组合物。
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