Method for preparing F-18 labeled compound
By carrying out a substitution reaction between a compound containing α-fluorotrifluoromethanesulfonate and a radioactive fluorine salt in a nitrile solvent, the problems of long preparation time, high cost, and low yield of F-18 labeled compounds in the prior art have been solved, and an efficient and easy-to-operate preparation method has been realized.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
- Filing Date
- 2025-11-04
- Publication Date
- 2026-05-08
AI Technical Summary
Existing methods for preparing F-18 labeled compounds suffer from problems such as long preparation time, high cost, and low yield, making it difficult to achieve industrial application.
F-18 labeled compounds were prepared by substitution reaction of compounds containing α-fluorotrifluoromethanesulfonate with radioactive fluorine salts in the presence of K222 in nitrile solvents at a reaction temperature of 70–90 °C.
It improves the reaction efficiency and yield of F-18 labeled compounds, making them suitable for industrial applications.
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Figure CN121990871A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to a method for preparing F-18 labeled compounds. Background Technology
[0002] F-18 labeled compounds are a class of compounds whose molecules contain the radioactive isotope fluorine-18 (F-18). Fluorine-18 is a positron-emitting radioactive isotope with nine protons and nine neutrons in its nucleus, exhibiting radioactivity and a half-life of 109.8 minutes. F-18 labeled compounds can be used in medicine and the synthesis of radiopharmaceuticals, for example, in medical imaging using positron emission tomography (PET) to track the distribution and metabolism of these molecules in the body.
[0003] The preparation of F-18-labeled compounds typically requires a medical cyclotron and involves nuclear reactions, such as proton bombardment of O-rich water (deuterated water) to produce F-18. The labeling process can involve nucleophilic substitution or electrophilic substitution reactions to attach F-18 to the target molecule, making the operation complex. Existing methods for synthesizing F-18-labeled compounds suffer from drawbacks such as long preparation time, high cost, and low yield, hindering industrial application.
[0004] Therefore, it is of particular importance to develop a method for preparing F-18 labeled compounds that is efficient, yield-efficient, and easy to operate. Summary of the Invention
[0005] The technical problem this invention aims to solve is to overcome the deficiency of limited methods for preparing radioactive fluorine compounds in existing technologies. Therefore, this invention provides a method for preparing F-18-labeled compounds. The method provided by this invention has high reaction efficiency, high yield, and good application prospects.
[0006] The present invention solves the above-mentioned technical problems through the following technical solution:
[0007] This invention provides a method for preparing an F-18 labeled compound, comprising the following steps: in the presence of a solvent, a compound containing α-fluorotrifluoromethanesulfonate... The compound undergoes a substitution reaction with a radioactive fluoride salt to obtain a product containing... Radiolabeled products;
[0008] The temperature of the substitution reaction is 70~90℃;
[0009] The solvent is a nitrile solvent.
[0010] In some embodiments, the nitrile solvent is acetonitrile.
[0011] In some embodiments, the substitution reaction occurs at K 222 It is performed under the condition that it exists.
[0012] In some embodiments, the α-fluorotrifluoromethanesulfonate ester... The compound is a compound of formula I, or the compound containing... The radiolabeled product is a compound of formula II;
[0013] Where L is C 1-6 Alkylene, A is C 6-10 aryl, 5-6 membered heteroaryl, with one or more R 1 Replacement C 6-10 aryl or aryl with one or more R 2 The substituted 5-6 membered heteroaryl group; wherein the heteroaryl group has 1, 2, or 3 heteroatoms; the heteroatoms are selected from one or more of N, O, and S; R 1 and R 2 C independently 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogen-substituted alkyl, C 1-6 Alkyl-O-CO-, halogen, nitro or cyano;
[0014] , .
[0015] In some embodiments, L is linear ethylidene, linear propyleneide, or linear butylidene; preferably linear ethylidene.
[0016] In some implementations, in A, the "C" 6-10 aryl, "by one or more R 1 Replacement C 6-10 The "C" in "aryl" 6-10 "Aryl" is independently phenyl.
[0017] In some embodiments, in A, the "5-6 member heteroaryl" is "been to one or more R 2 The "5-6 heteroaryl" in "substituted 5-6 heteroaryl" is independently... .
[0018] In some implementations, in A, R 1 and R 2 In the middle, the "C" mentioned 1-6 Alkyl", C 1-6 Alkoxy, C 1-6 Halogen-substituted alkyl groups and C 1-6 The "C" in "alkyl-O-CO-" 1-6 "Independently for C"1-4 ; preferably methyl, ethyl or tert-butyl.
[0019] In some implementations, in A, the "halogen" and "C" 1-6 The "halogen" in "halogen-substituted alkyl" is independently F, Cl, Br or I; preferably F.
[0020] In some implementation schemes, A is , , , , , , , , or .
[0021] In some embodiments, the compound of formula I is , , , , , , , , or ;
[0022] Alternatively, the compound of formula II is , , , , , , , , or .
[0023] In some embodiments, the radioactive fluoride salt is M. +18 F - M + It is an alkali metal ion or (R 3 )4N + R 3 C 1-6 alkyl.
[0024] In some embodiments, the alkali metal ion is K. + Or Na + K is preferred + .
[0025] In some implementation schemes, R 3 It is n-ethyl, n-propyl, or n-butyl; preferably n-ethyl or n-butyl.
[0026] In some embodiments, the radioactive fluorine salt is K 18 F, n Bu4N 18 F or n Et4N 18 F; K is preferred 18 F.
[0027] In some embodiments, the substitution reaction comprises the step of reacting a compound of formula I with a radioactive fluorine salt M in the nitrile solvent. +18 F - The substitution reaction shown below will proceed;
[0028]
[0029] The temperature of the substitution reaction is 70~90℃;
[0030] A, L, M +18 F - Independently as described in any embodiment of the present invention.
[0031] In some embodiments, the radioactive fluoride salt and the K 222 The molar ratio is 1:(0.1-5), for example, 1:1.
[0032] In some embodiments, the α-fluorotrifluoromethanesulfonate ester... The molar ratio of the compound to the radioactive fluoride salt is (1~5):1; for example (1~3):1, preferably 1:1, 2:1 or 3:1.
[0033] In some embodiments, the α-fluorotrifluoromethanesulfonate ester... The volume ratio of the compound to the nitrile solvent is (0.1-5):9, preferably 1:9.
[0034] In some embodiments, the reaction temperature of the substitution reaction is 70°C, 80°C, or 90°C.
[0035] In some embodiments, the reaction progress of the substitution reaction can be monitored using conventional methods for monitoring such reactions in the art, such as HPLC. 19 F-NMR, etc., generally use α-fluorotrifluoromethanesulfonate esters. The reaction endpoint is defined as the disappearance or cessation of reaction of the compound, and the reaction time of the substitution reaction is 8 to 15 minutes; for example, 10 minutes.
[0036] In some embodiments, the reactants for the substitution reaction consist of: the nitrile solvent, the α-fluorotrifluoromethanesulfonate ester, and the nitrile solvent. The compound, the K 222 and the radioactive fluoride salts.
[0037] In some embodiments, the substitution reaction includes the following steps:
[0038] Potassium salt aqueous solution and 18 F - Mix to obtain a mixture, then add K 222 A nitrile solvent is added, and after concentration, it is reacted with the nitrile solvent and the α-fluorotrifluoromethanesulfonate. The compound was reacted at 70-90°C to obtain the compound containing... Radiolabeled products.
[0039] In some embodiments, the potassium salt aqueous solution is an aqueous solution of KOTf or K2CO3.
[0040] In some embodiments, the concentration of the potassium salt aqueous solution is (8~24) mg / ml; for example, 10 mg / ml, 12 mg / ml or 20 mg / ml.
[0041] In some embodiments, the substitution reaction comprises the following specific steps: [The text abruptly ends here, so the translation stops.] 18 F - An aqueous solution was passed through a QMA column, and the potassium salt aqueous solution was collected from the QMA column. 18 F - Join K 222 A nitrile solvent is added, and after concentration, it is reacted with the nitrile solvent and the α-fluorotrifluoromethanesulfonate. The compound was reacted at 70-90°C to obtain the compound containing... The radiolabeled product. Preferably, the QMA column is a Sep-PAK®light QMA column.
[0042] In some implementations, the K 222 The amount added is conventional in the art, such as the K mentioned above. 222 The mass of the potassium salt aqueous solution and 18 F - The volume ratio of the mixed liquid is (0.1-5):50 mg / μL, for example 1:50 mg / μL or 8:150 mg / μL.
[0043] In some embodiments, the volume ratio of the potassium salt aqueous solution to the nitrile solvent is 1:(1~12); for example, 1:5.
[0044] In some embodiments, the concentration is performed under a protective gas atmosphere; for example, under a nitrogen atmosphere.
[0045] In some embodiments, the concentration temperature is 100-120°C; for example, 110°C.
[0046] Unless otherwise specified, the terms used in this invention have the following meanings:
[0047] When listing numerical ranges, each value and subranges within that range are included. For example, "C1~C6" includes C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl groups.
[0048] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.
[0049] The term "alkyl" refers to a straight-chain or branched alkyl group having a specified number of carbon atoms (e.g., C1 to C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc.
[0050] The term "aryl" refers to an aryl group having a specified number of carbon atoms (e.g., C6~C5). 10 An aryl group is a cyclic group consisting solely of carbon atoms, which can be monocyclic or polycyclic, and at least one ring is aromatic (following Hückel's rule). The aryl group is linked to other segments of the molecule via an aromatic or non-aromatic ring. Aryl groups include, but are not limited to, phenyl and naphthyl groups.
[0051] The term "heteroaryl" refers to a cyclic group having a specified number of ring atoms (e.g., 5 to 10), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). It can be monocyclic or polycyclic, and at least one ring is aromatic (conforming to Hückel's rule). Heteroaryl groups are linked to other segments of a molecule via aromatic or non-aromatic rings. Heteroaryl groups include, but are not limited to, furanyl, pyrroleyl, thiopheneyl, pyrazolyl, imidazoyl, oxazolyl, thiazoyl, pyridinyl, pyrimidinyl, and indoleyl.
[0052] The term "multiple" refers to 2, 3, 4, or 5.
[0053] "Alkoxy" refers to the group -OR, where R is an alkyl group.
[0054] When any variable (e.g., group R) 1 When these terms appear multiple times in the definition of a compound, their definitions are independent and do not affect each other. For example, a compound defined by three R's... 1 Replacement of C6~C 10 Aryl refers to C6~C 10 Aromatic compounds will be 3 R 1 Replace, 3 Rs1 The definitions are independent of each other and do not affect each other.
[0055] The positive and progressive effects of this invention are: the method for preparing radiolabeled compounds provided by this invention has high reaction efficiency and high yield. Detailed Implementation
[0056] The present invention will be further illustrated by way of embodiments below, but the present invention is not limited to the scope of the embodiments described herein.
[0057] Reagent and instrument preparation:
[0058] KOTf solution (282 mg / 3 mL H2O).
[0059] KOTf solution (10 mg / 1 mL H2O),
[0060] K2CO3 solution (10 mg / 1 mL H2O),
[0061] n Bu4NClO4 solution (20 mg / 1 mL H2O) (dissolved with a small amount of acetonitrile).
[0062] n Et4NClO4 solution (12 mg / 1 mL H2O),
[0063] 100 mg / mL precursor solution (acetonitrile solution of α-fluorotrifluoromethanesulfonate compound, as in Examples 1-4) Before using the QMA column, prepare it with 5 mL of anhydrous ethanol, 5 mL of ultrapure water, 3 mL of KOTf solution (282 mg / 3 mL H2O), and 5 mL of ultrapure water.
[0064] In this invention, fluorobenzene is used as an internal standard. 19 F-NMR ( 19 Fiber spectroscopy (F NMR) was performed using a Bruker AM400 NMR spectrometer (CFCl3 as an internal standard, with a negative low field) to measure product yield; the radioactivity... 18 The yield of product F was determined using radiometric detection equipment (radiochemically labeled yield data were detected and collected using the Chromatography Data System (ThermoFishei Scientific, USA)). 18[F] The radiodoscopy of the radiolabeled samples was determined using a radioisotope dose calibrator CRC-55tR (Capintec Inc.). (The data were recorded and processed by the Chromatography Data System (ThermoFisheiScientific, USA) for determination of radiochemical conversion. The activities of flgpl radiolabeled samples were determined using a radioisotope calibrator CRC-55tR (Capintec Inc.).) and the yield was calculated.
[0065] Example 1 K 18 Preparation and reaction of F:
[0066] The cyclotron produces a mixture of... 18 F - The aqueous solution was enriched by passing it through a Sep-PAK® light QMA column. 18 F - Then, the QMA column was cleaned with KOTf solution (10 mg / 1 mL H2O). 18 F - The solution was released into a labeled tube to obtain 200 μL of eluent. 4 mg of K was added to the 200 μL eluent. 222 Add 1 mL of anhydrous acetonitrile, concentrate under a nitrogen stream at 110 °C, and repeat three times. K is then obtained. 18 F and K 222 The mixture was prepared by mixing the above mixture (1.0 eq) with the precursor solution (50 μL) and 450 μL of acetonitrile, and reacting at 80 °C for 10 min, with a yield of 84.56%.
[0067] Example 2 K 18 Preparation and reaction of F:
[0068] The cyclotron produces a mixture of... 18 F - The aqueous solution was enriched by passing it through a Sep-PAK® light QMA column. 18 F - Then, the QMA column was cleaned with K2CO3 solution (10 mg / 1 mL H2O). 18 F -The solution was released into a labeled tube to obtain 150 μL of eluent. 8 mg of potassium was added to the 150 μL eluent. 222 Add 1 mL of anhydrous acetonitrile, concentrate under a nitrogen stream at 110 °C, and repeat three times. K is then obtained. 18 F and K 222 The mixture was prepared by mixing the above mixture (1.0 eq) with the precursor solution (50 μL) and 450 μL of acetonitrile, and reacting at 80 °C for 10 min, with a yield of 85.9%.
[0069] Example 3 n Bu4N 18 Preparation and reaction of F:
[0070] The cyclotron produces a mixture of... 18 F - The aqueous solution was enriched by passing it through a Sep-PAK® light QMA column. 18 F - Then use n Bu4NClO4 solution (20 mg / 1 mL H2O) was used to clean the QMA column. 18 F - The solution was released into a labeled tube to obtain 400 μL of eluent. 1 mL of anhydrous acetonitrile was added to the 400 μL eluent, and the mixture was concentrated under a nitrogen stream at 90 °C, repeated three times. The desired product was obtained. n Bu4N 18 F and K 222 The mixture was prepared by mixing the above mixture (1.0 eq) with the precursor solution (50 μL) and 450 μL of acetonitrile, and reacting at 80 °C for 10 min, with a yield of 19.5%.
[0071] Example 4 n Et4N 18 Preparation and reaction of F:
[0072] The cyclotron produces a mixture of... 18 F - The aqueous solution was enriched by passing it through a Sep-PAK® light QMA column. 18 F - Then use n Et4NClO4 solution (10 mg / 1 mL H2O) was used to clean the QMA column. 18 F - The eluent was released into a labeled tube to obtain 400–500 μL. 1 mL of anhydrous acetonitrile was added, and the mixture was concentrated under a nitrogen stream at 90 °C, repeated three times. The desired product was obtained. n Et4N 18 F and K 222The mixture was prepared by mixing the above mixture (1.0 eq) with the precursor solution (50 μL) and 450 μL of acetonitrile, and reacting at 80 °C for 10 min, with a yield of 32.4%.
[0073] Example 5
[0074] Precursor:
[0075]
[0076] K2CO3 solution (10 mg / 1 mL H2O)
[0077] 100 mg / mL precursor solution
[0078] QMA column pretreatment: Rinse the QMA column with 5 mL of anhydrous ethanol and 5 mL of ultrapure water.
[0079] K 18 Preparation and reaction of F: The cyclotron-generated fuel containing... 18 F - The aqueous solution was enriched by passing it through a Sep-PAK® light QMA column. 18 F - Then, the QMA column was cleaned with K2CO3 solution (10 mg / 1 mL H2O). 18 F - The solution was released into a labeled tube to obtain 150 μL of eluent. 8 mg of potassium was added to the 150 μL eluent. 222 Add 1 mL of anhydrous acetonitrile, concentrate under a nitrogen stream at 110 °C, and repeat three times. K is then obtained. 18 F and K 222 The mixture was prepared by mixing the above mixture (1.0 eq) with the precursor solution (50 μL) and 450 μL of acetonitrile, and reacting at 80 °C for 10 min. The yield was 75% when the substrate was H3 and 82% when the substrate was H4.
[0080] Example 6
[0081] Using the same method as in Example 2, the substrate was replaced with one of the following compounds, and the yields and number of experiments were as follows:
[0082]
[0083] Comparative Example 1
[0084] Using the same method as in reaction 1 of Example 5, except that the solvent was replaced with DMSO instead of MeCN, the yield was 11%.
[0085] Comparative Example 2
[0086] Using the same method as in reaction 1 of Example 5, except that the temperature was increased to 100°C, the yield was 49%.
[0087] Comparative Example 3
[0088] Using the same method as in reaction 1 of Example 5, except that the temperature was increased to 110°C, the yield was 35%.
[0089] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and the scope of protection of the present invention is defined by the appended claims. Those skilled in the art can make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, but all such changes and modifications fall within the scope of protection of the present invention.
Claims
1. A method for preparing an F-18 labeled compound, comprising the following steps: In the presence of a solvent, α-fluorotrifluoromethanesulfonate esters The compound undergoes a substitution reaction with a radioactive fluoride salt to obtain a product containing... Radiolabeled products; The temperature of the substitution reaction is 70~90℃; The solvent is a nitrile solvent.
2. The preparation method according to claim 1, characterized in that, The α-fluorotrifluoromethanesulfonate The compound is a compound of formula I. Or, the containing The radiolabeled product is a compound of formula II; Where L is C 1-6 Alkylene, A is C 6-10 aryl, 5-6 membered heteroaryl, with one or more R 1 Replacement C 6-10 aryl or aryl with one or more R 2 The substituted 5-6 membered heteroaryl group; wherein the heteroaryl group has 1, 2, or 3 heteroatoms; the heteroatoms are selected from one or more of N, O, and S; R 1 and R 2 C independently 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogen-substituted alkyl, C 1-6 Alkyl-O-CO-, halogen, nitro or cyano; ， 。 3. The preparation method according to claim 2, characterized in that, The preparation method satisfies one or more of the following conditions: (1) L is a linear ethylene, a linear propylene, or a linear butylene; preferably a linear ethylene; (2) In A, the "C" 6-10 "Aryl" and "by one or more R 1 Replacement C 6-10 The "C" in "aryl" 6-10 "Aryl" is independently a phenyl group; (3) In A, the "5-6 member heteroaryl" and "been with one or more R 2 The "5-6 heteroaryl" in "substituted 5-6 heteroaryl" is independently... ; (4) In A, R 1 and R 2 In the middle, the "C" 1-6 Alkyl group, C 1-6 "alkoxy" and "C" 1-6 Halogen-substituted alkyl groups and C 1-6 The "C" in "alkyl-O-CO-" 1-6 "Independently for C" 1-4 ; Preferably methyl, ethyl or tert-butyl; (5) In A, the "halogen" and "C" 1-6 In the halogen-substituted alkyl group, the halogen is independently F, Cl, Br or I; preferably F; Preferably, A is , , , , , , , , or .
4. The preparation method according to claim 3, characterized in that, The compound of formula I is , , , , , , , , or ; Alternatively, the compound of formula II is , , , , , , , , or .
5. The preparation method according to claim 1, characterized in that, The radioactive fluoride salt is M. +18 F - M + It is an alkali metal ion or (R 3 )4N + R 3 C 1-6 alkyl.
6. The preparation method according to claim 5, characterized in that, It meets one or two of the following conditions: (1) The alkali metal ion is K + Or Na + K is preferred + ; (2) R 3 It is n-ethyl, n-propyl, or n-butyl; preferably n-ethyl or n-butyl; Preferably, the radioactive fluorine salt is K. 18 F, n Bu4N 18 F or n Et4N 18 F; K is preferred 18 F.
7. The preparation method according to any one of claims 2-6, characterized in that, The substitution reaction is as follows: .
8. The preparation method according to claim 1, characterized in that, It meets one or more of the following conditions: (1) The substitution reaction at K 222 The process is carried out in the presence of, preferably, the radioactive fluorine salt and the K 222 The molar ratio is 1:(0.1-5), for example, 1:1; (2) The α-fluorotrifluoromethanesulfonate ester The ratio of the compound to the radioactive fluoride salt is (1-5):1; for example (1-3):1; preferably 1:1, 2:1 or 3:1; (3) The reaction temperature of the substitution reaction is 70℃, 80℃ or 90℃; (4) The reaction time of the substitution reaction is 8-15 min; for example, 10 min; (5) The reactants for the substitution reaction consist of the following: the solvent, the α-fluorotrifluoromethanesulfonate ester. The compound, the K 222 and the radioactive fluoride salt; (6) The nitrile solvent is acetonitrile; (7) The α-fluorotrifluoromethanesulfonate ester The volume ratio of the compound to the nitrile solvent is (0.1-5):9, preferably 1:
9.
9. The preparation method according to claim 1, characterized in that, The substitution reaction further includes the following specific steps: potassium salt aqueous solution and... 18 F - Mix to obtain a mixture, then add K 222 A nitrile solvent is added, and after concentration, it is reacted with the nitrile solvent and the α-fluorotrifluoromethanesulfonate. The compound was reacted at 70-90°C to obtain the compound containing... Radiolabeled products.
10. The preparation method according to claim 9, characterized in that, It meets one or more of the following conditions: (1) The potassium salt aqueous solution is a KOTf solution or a K2CO3 solution; (2) The concentration of the potassium salt aqueous solution is (8~24) mg / ml; for example, 10 mg / ml, 12 mg / ml or 20 mg / ml; (3) The nitrile solvent is acetonitrile; (4) The volume ratio of the potassium salt aqueous solution to the nitrile solvent before concentration is 1:(1~12); for example, 1:5; (5) The concentration is carried out under a protective atmosphere; for example, under a nitrogen atmosphere; (6) The concentration temperature is 100~120℃; for example, 110℃; (7) K 222 The mass ratio of the mixture to the volume of the liquid is (0.1-5):50 mg / μL, for example 1:50 mg / μL or 8:150 mg / μL; (8) The substitution reaction comprises the following specific steps: [The text abruptly ends here, likely due to an incomplete sentence or a formatting error.] 18 F - An aqueous solution was passed through a QMA column, and the potassium salt aqueous solution was collected from the QMA column. 18 F - Join K 222 A nitrile solvent is added, and after concentration, it is reacted with the nitrile solvent and the α-fluorotrifluoromethanesulfonate. The compound was reacted at 70-90°C to obtain the compound containing... The radiolabeled product; preferably, the QMA column is a Sep-PAK®light QMA column.