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CN-121990871-A - Method for preparing F-18 labeled compound

CN121990871ACN 121990871 ACN121990871 ACN 121990871ACN-121990871-A

Abstract

The invention discloses a method for preparing an F-18 labeled compound. Specifically, the invention provides a preparation method of an F-18 labeled compound, which comprises the following steps of containing alpha-fluorotrifluoromethanesulfonate in the presence of a solvent and K 222 The compound of (C) and radioactive fluoride undergo substitution reaction to generate the product containing Wherein the temperature of the substitution reaction is 70-90 ℃, and the solvent is a nitrile solvent.

Inventors

  • ZHANG XINGANG
  • MIN QIAOQIAO
  • Han Yuanzhan
  • ZHAO HAIYANG

Assignees

  • 中国科学院上海有机化学研究所

Dates

Publication Date
20260508
Application Date
20251104
Priority Date
20241105

Claims (10)

  1. 1. A process for the preparation of F-18 labelled compounds comprising the steps of containing alpha-fluorotrifluoromethanesulfonate in the presence of a solvent The compound of (C) and radioactive fluoride undergo substitution reaction to obtain the product containing Is a radiolabeled product of (a); wherein the temperature of the substitution reaction is 70-90 ℃; The solvent is nitrile solvent.
  2. 2. The method of claim 1, wherein the alpha-fluorotrifluoromethanesulfonate is present The compound of (C) is a compound of formula I, Or said contain Is a compound of formula II; Wherein L is C 1-6 alkylene, A is C 6-10 aryl, 5-6 membered heteroaryl, C 6-10 aryl substituted with one or more R 1 or 5-6 membered heteroaryl substituted with one or more R 2 , wherein the number of heteroatoms in the heteroaryl is1, 2 or 3, the type of heteroatom is selected from one or more of N, O and S, R 1 and R 2 are each independently C 1-6 alkyl, C 1-6 alkoxy, C 1-6 halogen substituted alkyl, C 1-6 alkyl-O-CO-, halogen, nitro or cyano; , 。
  3. 3. The method of preparation of claim 2, wherein the method of preparation meets one or more of the following conditions: (1) L is a linear ethylene, linear propylene or linear butylene group, preferably a linear ethylene group; (2) In said a, "C 6-10 aryl" of said "C 6-10 aryl" and "C 6-10 aryl substituted with one or more R 1 " are independently phenyl; (3) In said A, the "5-6 membered heteroaryl" in said "5-6 membered heteroaryl" and "5-6 membered heteroaryl substituted with one or more R 2 " are independently ; (4) In said A, "C 1-6 " in said "C 1-6 alkyl", "C 1-6 alkoxy", "C 1-6 halogen substituted alkyl" and "C 1-6 alkyl-O-CO-" in R 1 and R 2 are independently C 1-4 ; (5) In said A, the "halogen" in said "halogen" and "C 1-6 halogen substituted alkyl" is independently F, cl, br or I; preferably, A is 、 、 、 、 、 、 、 、 Or (b) 。
  4. 4. The process of claim 3, wherein the compound of formula I is 、 、 、 、 、 、 、 、 Or (b) ; Or the compound of formula II 、 、 、 、 、 、 、 、 Or (b) 。
  5. 5. The method of claim 1, wherein the radiofluoride salt is M +18 F - ,M + is an alkali metal ion or (R 3 ） 4 N + ,R 3 is C 1-6 alkyl).
  6. 6. The method of claim 5, wherein one or both of the following conditions are satisfied: (1) The alkali metal ion is K + or Na + , preferably K + ; (2) R 3 is n-ethyl, n-propyl or n-butyl, preferably n-ethyl or n-butyl; Preferably, the radioactive fluoride salt is K 18 F、 n Bu 4 N 18 F or n Et 4 N 18 F, preferably K 18 F.
  7. 7. The process according to any one of claims 2 to 6, wherein the substitution reaction is 。
  8. 8. The preparation method according to claim 1, characterized in that it satisfies one or more of the following conditions: (1) The substitution reaction is carried out in the presence of K 222 , preferably the molar ratio of the radiofluoride salt to K 222 is 1 (0.1-5), for example 1:1; (2) The alpha-fluoro-trifluoro-methanesulfonic acid ester (1-5) 1, E.g., (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, 10min; (5) The reaction material of the substitution reaction consists of the solvent and the alpha-fluoro-trifluoro-methanesulfonate The K 222 and the radiofluoride salt; (6) The nitrile solvent is acetonitrile; (7) The alpha-fluoro-trifluoro-methanesulfonic acid ester The volume ratio of the compound of (2) to the nitrile solvent is (0.1-5): 9, preferably 1:9.
  9. 9. The process according to claim 1, wherein the substitution reaction further comprises the steps of mixing an aqueous potassium salt solution with 18 F - to obtain a mixed solution, adding K 222 , adding a nitrile solvent, concentrating, and mixing with the nitrile solvent and the alpha-fluorotrifluoromethane sulfonate The compound of (C) is reacted at 70-90 ℃ to obtain the product Is a radiolabeled product of (a).
  10. 10. The method of claim 9, wherein one or more of the following conditions are satisfied: (1) The potassium salt aqueous solution is KOTf solution or K 2 CO 3 solution; (2) The concentration of the potassium salt aqueous solution is (8-24) mg/ml, for example 10mg/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 performed under a protective gas atmosphere, for example, under a nitrogen atmosphere; (6) The temperature of the concentration is 100-120 ℃, such as 110 ℃; (7) The mass to volume ratio of the K 222 to the mixture is (0.1-5) 50: 50 mg/. Mu.L, for example 1:50 mg/. Mu.L or 8:150 mg/. Mu.L; (8) The substitution reaction comprises passing water solution containing 18 F - through QMA column, collecting QMA column 18 F - with potassium salt water solution, adding K 222 , adding nitrile solvent, concentrating, mixing with the nitrile solvent and the alpha-fluoro-trifluoromethane sulfonate The compound of (C) is reacted at 70-90 ℃ to obtain the product Preferably, the QMA column is a Sep-PAK light QMA column.

Description

Method for preparing F-18 labeled compound Technical Field The present invention relates to a process for the preparation of F-18 labelled compounds. Background F-18 labeled compounds refer to a class of compounds that contain the radioisotope fluorine-18 (F-18) in the compound molecule. Fluorine-18 is a positron-emitting radioisotope with 9 protons and 9 neutrons in the nuclear, and has radioactivity and a half-life of 109.8 minutes. F-18 labeled compounds are useful in medicine and radiopharmaceutical synthesis, for example in medical imaging in positron emission tomography (Positron Emission Tomography, PET), for tracking the distribution and metabolism of these molecules in the body. The preparation of F-18 labeled compounds is typically accomplished by a medical cyclotron involving nuclear reactions such as proton bombardment of O-rich water (heavy oxygen water) to produce F-18. The labeling process can connect F-18 to the target molecule through nucleophilic substitution reaction or electrophilic substitution reaction and other modes, and the operation is complex. The existing F-18 labeled compound synthesis method has the defects of long preparation time, high cost and low yield, and is difficult to industrialize and apply. It is seen that it is important to develop a process for preparing F-18 labeled compounds which is efficient, high yield and easy to handle. Disclosure of Invention The technical problem to be solved by the invention is to overcome the defect of few preparation methods of radioactive fluorine compounds in the prior art, so that the invention provides a method for preparing F-18 labeled compounds. The method provided by the invention has the advantages of high reaction efficiency, high yield and good application prospect. The invention solves the technical problems by the following technical scheme: the present invention provides a method for preparing F-18 labeled compound, which comprises the steps of containing alpha-fluorotrifluoromethanesulfonate in the presence of a solvent The compound of (C) and radioactive fluoride undergo substitution reaction to obtain the product containingIs a radiolabeled product of (a); wherein the temperature of the substitution reaction is 70-90 ℃; The solvent is nitrile solvent. In some embodiments, the nitrile solvent is acetonitrile. In some embodiments, the substitution reaction is performed in the presence of K 222. In some embodiments, the alpha-fluorotrifluoromethanesulfonate-containing compound isThe compound of formula I is a compound of formula I, or the said compositionIs a compound of formula II; Wherein L is C 1-6 alkylene, A is C 6-10 aryl, 5-6 membered heteroaryl, C 6-10 aryl substituted with one or more R 1 or 5-6 membered heteroaryl substituted with one or more R 2, wherein the number of heteroatoms in the heteroaryl is1, 2 or 3, the type of heteroatom is selected from one or more of N, O and S, R 1 and R 2 are each independently C 1-6 alkyl, C 1-6 alkoxy, C 1-6 halogen substituted alkyl, C 1-6 alkyl-O-CO-, halogen, nitro or cyano; ,。 in some embodiments, L is a linear ethylene, linear propylene or linear butylene group, preferably a linear ethylene group. In some embodiments, in the a, "C 6-10 aryl" in the "C 6-10 aryl," C 6-10 aryl substituted with one or more R 1 "is independently phenyl. In some embodiments, in the "5-6 membered heteroaryl", "5-6 membered heteroaryl substituted with one or more R 2" are independently。 In some embodiments, in the A, R 1 and R 2, the "C 1-6" in the "C 1-6 alkyl", "C 1-6 alkoxy", "C 1-6 halogen substituted alkyl" and "C 1-6 alkyl-O-CO-" are independently C 1-4, preferably methyl, ethyl or tert-butyl. In some embodiments, in the A, "halogen" in the "halogen" and "C 1-6 halogen substituted alkyl" is independently F, cl, br or I, preferably F. In some embodiments, a is、、、、、、、、Or (b)。 In some embodiments, the compound of formula I is、、、、、、、、Or (b); Or the compound of formula II、、、、、、、、Or (b)。 In some embodiments, the radiofluoride salt is M +18F-,M+ is an alkali metal ion or (R 3）4N+,R3 is C 1-6 alkyl). In some embodiments, the alkali metal ion is K + or Na +, preferably K +. In some embodiments, R 3 is n-ethyl, n-propyl, or n-butyl, preferably n-ethyl or n-butyl. In some embodiments, the radioactive fluoride salt is K 18F、nBu4N18 F or nEt4N18 F, preferably K 18 F. In some embodiments, the substitution reaction comprises the step of subjecting a compound of formula I to a substitution reaction with a radiofluoride salt M +18F- in the nitrile solvent as shown below; wherein the temperature of the substitution reaction is 70-90 ℃; A. l, M +18F- are independently described in any of the embodiments of the present invention. In some embodiments, the molar ratio of the radioactive fluoride salt to the K 222 is 1 (0.1-5), such as 1:1. In some embodiments, the alpha-fluorotrifluoromethanesulfonate-containing compound isThe molar ratio of the compound (1-5) to the radioactive fluoride salt is 1, for example (