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Method for preparing fluorine-18-labeled fluoromethyl-substituted radiopharmaceuticals using selective azide substitution reaction and precursor scavenging

A technology of azide compound and fluoromethyl group is applied in the field of preparation of fluoromethyl-substituted radiopharmaceuticals marked with fluorine-18 by using selective azide compound substitution reaction and precursor scavenging, which can solve the cumbersome and long-term Labeling time, low labeling yield and other problems, to achieve the effect of cost saving, high labeling yield, high purity

Inactive Publication Date: 2021-05-04
BIK治疗公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The HPLC separation procedure in the preparation process of this radiopharmaceutical becomes cumbersome for the preparation process (needing more than 30 minutes), and requires a long labeling time (also needs more than 30 minutes), resulting in low labeling yield, and then in Reasons for many restriction points in the preparation of radiopharmaceuticals under Good Manufacturing Practice (GMP)

Method used

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  • Method for preparing fluorine-18-labeled fluoromethyl-substituted radiopharmaceuticals using selective azide substitution reaction and precursor scavenging
  • Method for preparing fluorine-18-labeled fluoromethyl-substituted radiopharmaceuticals using selective azide substitution reaction and precursor scavenging
  • Method for preparing fluorine-18-labeled fluoromethyl-substituted radiopharmaceuticals using selective azide substitution reaction and precursor scavenging

Examples

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preparation example Construction

[0038] In order to achieve the above object, the preparation method of the fluorine-18 labeled fluoromethyl-substituted radiopharmaceutical using the selective azide substitution reaction of the present invention comprises: the first step, passing through the cyclotron 18 O(p,n) 18 F reacts to get [ 18 F] fluoride; the second step, using dissolved K 2.2.2 and K 2 CO 3 The acetonitrile reaction solution was separated from the above [ 18 F] Fluoride to get [ 18 F]F - / H 2 18 O solution; the third step, heating the above [ 18 F]F - / H 2 18 O solution to get K 2.2.2 / K 18 F; the fourth step, the above K 2.2.2 / K 18 F and bis(toluenesulfonyloxy)methane compound are put into the reaction vessel together, and the reaction solution is added to react to obtain the first precursor solution; the fifth step is to cool the above-mentioned first precursor solution, add the azide compound, and only Prepare [ 18 F] fluoromethyl tosylate compound; the sixth step, in the above ...

Embodiment 1

[0078] Hereinafter, experiments using F-19 and F-18 in radiopharmaceuticals produced by the method for producing fluoromethyl-substituted radiopharmaceuticals utilizing the selective azide substitution reaction and precursor scavenging of the present invention according to the examples The process is detailed below.

[0079] Experiment 1

[0080] 1 H-NMR and HPLC analysis

[0081] Dissolve the same equivalent (4.9 mmol) of 1a and 2a in DMF-d as NMR solvent 7 Afterwards, with NaN 3 (2.5 eq., 12.3 mmol) work-up followed by reaction at 65°C. Over time, the results were analyzed by NMR and HPLC at 5 min, 10 min, 15 min intervals compared to the 0 min results for untreated azide. The azide anion (N 3 - ) appears to be a competing reaction between 1a and 2a, more relatively bis(tosyloxy)methane, which is electron-rich at the methyl carbon, preferentially undergoes azide substitution. As predicted, it was confirmed that bis(toluenesulfonyloxy)methane was significantly more ...

preparation example 1

[0101] Preparation of bis(toluenesulfonyloxy)methane compound

[0102]

[0103] After dibromomethane (500 uL, 7.12 mmol) and silver p-toluenesulfonate (4.17 g, 14.95 mmol) were dissolved in acetonitrile (8 mL), it was allowed to reflux for 16 hours. After completion of the reaction, extraction was performed with water and dichloromethane, only the organic solvent layer was separated, and water was removed with sodium sulfate, followed by filtration. Removal of the solvent from the filtered solution afforded 2a-b as white solids.

[0104] Anal. Calculated for (C 15 h 16 o 6 S 2 ,2a): C, 50.55; H, 4.53; O, 26.93; S, 17.99%. MS (ESI) m / z 357.24 (M+H + ); m.p.119.9-122.1℃. 1 H NMR (400MHz, CDCl 3 )δ7.59(d, J=8.4Hz, 3H), 7.24(d, J=8.4Hz, 4H), 5.81(s, 2H), 2.45(s, 6H); 13 C NMR (100MHz, CDCl 3 )δ145.2, 133.1, 129.6, 127.8, 87.79, 21.6.

[0105] Anal. Calculated for (C 15 h 14 D. 2 o 6 S 2 ,2b): C, 50.27; H, 5.06; O, 26.78; S, 17.89%. MS (ESI) m / z 359.24 (M+H) + ;...

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Abstract

The present invention relates to a method for preparing a fluorine-18-labeled fluoromethyl-substituted radiopharmaceutical using selective azide substitution reaction, the method comprising: a first step for obtaining [<18>F]fluoride from a cyclotron through a <18>O(p, n)<18>F reaction; a second step for obtaining a [<18>F]F- / H2 18O solution by separating the [<18>F]fluoride using an acetonitrile reaction solution in which K2.2.2 and K2CO3 are dissolved; a third step for obtaining K2.2.2 / K<18>F by heating the [<18>F]F- / H2<18>O solution; a fourth step for obtaining a first precursor solution by adding the K2.2.2 / K<18>F and a bis(toxyloxy)methane compound into a reactor and adding a reaction solvent thereto to cause reaction; a fifth step for obtaining a [<18>F]fluoromethyltosylate compound by cooling the first precursor solution and adding an azide reagent thereto to cause azide substitution reaction.

Description

technical field [0001] The present invention relates to [ 18 F] A method for the preparation of fluoromethyl-substituted radiopharmaceuticals, in more detail relating to the selective azide substitution of unreacted precursor substances, etc. during the synthesis of fluoromethyl-substituted radiopharmaceuticals labeled with fluorine-18 Reaction and precursor scavenger (scavenger) effects reduce preparation time in radiopharmaceutical synthesis, give high labeling yields, and can save costs, even if HPLC (HPLC, High Performance Liquid Chromatography) is almost necessary The separation and purification process can also be used to prepare high-purity and high-quality radiopharmaceuticals using selective azide substitution reactions and precursor scavenging methods for the preparation of fluoromethyl-substituted radiopharmaceuticals labeled with fluorine-18. Background technique [0002] Positron Emission Tomography (PET, Positron Emission Tomography) is an imaging device mainl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07B59/00A61K51/04
CPCC07B59/00A61K51/04A61K51/0406C07B59/001C07B2200/05A61K51/0402
Inventor 李炳喆陆颖清赵炳珉
Owner BIK治疗公司
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