Fluorodithiophosphoric ester compounds and their preparation methods and applications

The technology of fluorodithiophosphate and substituted dithiophosphate is applied in the application field in the preparation of positron emission imaging agents, and can solve the problems of poor stability, defluorination, large molecular weight, etc., and achieve high stability The effect of stability, short labeling time and low molecular weight

Active Publication Date: 2021-03-26
XIAMEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, such non-carbon 18 The F labeling method has the following disadvantages: 1) it needs to be labeled in a specific pH environment; 2) the molecular weight of the labeling precursor is large; 3) there is defluorination in vivo, etc.
In 2005, it was reported that at room temperature through phosphorus oxychloride and [ 18 F]F - Through halogen metathesis reaction to construct with P- 18 F, the radiochemical yield is as high as 96%, unfortunately the P -18 F showed poor stability

Method used

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  • Fluorodithiophosphoric ester compounds and their preparation methods and applications
  • Fluorodithiophosphoric ester compounds and their preparation methods and applications
  • Fluorodithiophosphoric ester compounds and their preparation methods and applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] This embodiment provides a 19 F-labeled fluorodithiophosphate compounds, the preparation process and specific steps are as follows:

[0081]

[0082] Synthetic steps of compound 1:

[0083] Put 10mmol of dichloro(diethylamino)phosphine in the reaction flask, add 40mL of anhydrous benzene under the protection of argon, then add 10mmol of 1,2-ethanedithiol dropwise into the reaction flask under ice-water bath conditions After reacting for 30 minutes, react at room temperature for 2 hours, filter, and spin dry under reduced pressure.

[0084] NMR data of compound 1:

[0085] 31 P NMR (162MHz, CDCl 3 ):δ106.98.

[0086] Synthetic steps of compound 2:

[0087] Put 5mol of compound 1 and 6mmol of 5-ethylthiotetrazole in a reaction flask, add 40mL of anhydrous dichloromethane, add 5mmol of 3-butyn-1-ol, react at room temperature for 3 hours and then filter. Spin dry under reduced pressure.

[0088]NMR data of compound 2:

[0089] 31 P NMR (162MHz, CDCl 3 ): δ148....

Embodiment 2

[0099] This embodiment provides a positron emission imaging 18 F-labeled fluorodithiophosphoric ester compounds, the synthesis steps of compound 3 are the same as in Example 1, and the specific steps of its labeling are as follows:

[0100]

[0101] Method 1: Use 8mg K2.2.2 and 1mg K 2 CO 3 Acetonitrile water rinse [ 18 F]F - Enriched QMA-Sep-Pak column, after acetonitrile azeotropic water removal, use K 2 CO 3 , K2.2.2, [ 18 F]F - The mixture and 0.5 mg of compound 3 were dissolved in 100 μL of acetonitrile solvent, and reacted at 20° C. for 30 seconds. Stop the reaction, add about 10mL water to dilute the reaction system, then pass through the Sep-Pak C18 column, and collect the filtrate in No. 1 bottle (mainly the [ 18 F]F - ), and then wash the column with 10mL of water, and collect the filtrate into bottle No. 2 (make sure that [ 18 F]F - Thoroughly rinsing clean), dry the Sep-Pak C18 column with nitrogen, wash the C18 column with 2mL of acetonitrile, collec...

Embodiment 3

[0102] Embodiment 3 (product structure is with embodiment 2)

[0103] Method 2: with [ 18 F]F - The fluoride ion aqueous solution and 0.5 mg of compound 3 were dissolved in 100 μL of acetonitrile solvent, and reacted at 20° C. for 30 seconds. Stop the reaction, add about 10mL water to dilute the reaction system, then pass through the Sep-Pak C18 column, and collect the filtrate in No. 1 bottle (mainly the [ 18 F]F - ), and then wash the column with 10ml of water, and collect the filtrate into bottle No. 2 (make sure that the [ 18 F]F - Thoroughly rinsing), dry the Sep-Pak C18 column with nitrogen, wash the Sep-Pak C18 column with 2mL of acetonitrile, collect the filtrate into No. Acetonitrile was dried to obtain 18 F-labeled fluorodithiophosphate compounds [ 18 F] 4, the radiochemical purity of the marker is greater than 99%.

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Abstract

The invention relates to a fluoro dithio phosphate compound and a preparation method and application thereof. The fluoro dithio phosphate compound is of a structure shown in a formula (I). 1,3,2-Dioxathion heterocyclic pentane is a 18 / 19F mark precursor for the first time, and through a nucleophilic substitution-elimination low-reaction-energy barrier mark strategy, the fluoro dithio phosphate compound is established through one step at an ultra high speed. The fluoro dithio phosphate compound can be prepared in a water-containing solution, the mark condition is mild, the reaction time is short, the reaction is conducted for 30 seconds at 20 DEG C so that the yield of 97% can be achieved, and F- does not need to be dried; the specific activity is high, purification is conveniently conducted, the in-vitro-and-vivo stability of a mark product is good, and the compound has wide application prospects in the field of preparation of positive electron medicines of biomolecules such as phosphoric acid analogue molecule probes and thermal-sensitive and solvent-sensitive polypeptide or protein.

Description

Technical field: [0001] The invention relates to the synthesis and labeling of a novel fluorodithiophosphoric ester compound, in particular to the application of the compound in the preparation of a positive electron emission imaging agent. Background technique: [0002] Positron emission tomography (PET) is an imaging technique that can display biomolecular metabolism, various receptors and neurotransmitter activities in vivo. It has been widely used in tumors, nervous system and cardiovascular system, etc. Disease diagnosis and differential diagnosis, condition judgment, curative effect evaluation, organ function research and new drug development, etc. [0003] Among the nuclides commonly used in PET imaging, 18 F is the most widely used positron nuclide, with excellent chemical properties and nuclide characteristics: the van der Waals radius of the fluorine atom is similar to that of the hydrogen atom, and has little effect on the biological properties of the labeled com...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/20C07H1/00C07F9/20C07B59/00A61K51/08A61K51/04A61K51/02
CPCA61K51/02A61K51/0489A61K51/08C07B59/001C07B59/005C07B2200/05C07F9/20C07F9/2003C07F9/2006C07H1/00C07H19/20
Inventor 李子婧杨鸿章刘欢欢牟钊彪王潮
Owner XIAMEN UNIV
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