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Alcohol compound-based in-situ deoxygenation fluorination synthesis method and alcohol compound-based <18>F radiolabeling method

A technology of radioactive labeling and synthesis method, which is applied in the preparation of organic compounds, steroid compounds, organic chemical methods, etc., to achieve the effects of easy realization, wide substrate applicability, simple and safe operation

Pending Publication Date: 2020-01-24
HEFEI UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] Aiming at the shortcomings of existing deoxyfluorination reagents, the present invention provides an in-situ deoxyfluorination synthesis method based on alcohol compounds and a 18F radioactive labeling method, directly using potassium fluoride to convert trifluoromethylsulfonyl in the same process Fluorine, and in situ formation of trifluoromethanesulfonate with alcohol, and nucleophilic substitution by fluorine to generate deoxyfluoride

Method used

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  • Alcohol compound-based in-situ deoxygenation fluorination synthesis method and alcohol compound-based &lt;18&gt;F radiolabeling method
  • Alcohol compound-based in-situ deoxygenation fluorination synthesis method and alcohol compound-based &lt;18&gt;F radiolabeling method
  • Alcohol compound-based in-situ deoxygenation fluorination synthesis method and alcohol compound-based &lt;18&gt;F radiolabeling method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044]

[0045] Add 4-phenyl-1-butanol (0.5 mmol), MTBD (7-methyl-1,5,7-triazabicyclo[4.4.0 ]dec-5-ene) (0.75mmol), then add 2.5mL tetrahydrofuran; in another reaction tube 2 equipped with a magnetic stirrer 5ml, add N-phenylbis(trifluoromethanesulfonyl)imide (2.5mmol ) and potassium fluoride (3.75mmol), then add 2mL of N,N-dimethylformamide, the two tubes are connected by a catheter, the reaction tubes 1 and 2 are fixed on the oil bath, and stirred. After the reaction system was reacted at 60°C for 60 minutes, the reaction was completed; add an appropriate amount of water to the reaction solution in reaction tube 1, extract with ethyl acetate, dry with anhydrous sodium sulfate, and finally remove the solvent by rotary evaporation, and the crude product was passed through the column layer Analysis (petroleum ether) separation and purification to obtain the target product (2a), with a yield of 95%. The NMR data of this compound are: 1 H NMR (400MHz, CDCl 3 )δ7.30(dd, J=9....

Embodiment 2

[0047]

[0048] Replace 4-phenyl-1-butanol (1a) with 3-(4-bromo-phenyl)propanol (1b), others are the same as Example 1, and column chromatography (petroleum ether) obtains target product (2b), Yield 78%. The NMR data of this compound are: 1 H NMR (600MHz, CDCl 3 )δ7.42(dd, J=8.1,1.3Hz,2H),7.08(d,J=6.9Hz,2H),4.48(td,J=5.7,1.4Hz,1H),4.41(td,J=5.8 ,1.4Hz,1H),2.71(t,J=7.1Hz,2H),2.04–1.90(m,2H). 13 C NMR (101MHz, CDCl 3 )δ140.05(s), 131.53(s), 130.26(s), 119.82(s), 83.67(s), 82.02(s), 31.86(d, J=19.8Hz), 30.78(d, J=5.2 Hz). 19 F NMR (564MHz, CDCl 3 )δ-218.77–-220.57(m).

Embodiment 3

[0050]

[0051] Replace 4-phenyl-1-butanol (1a) with 4-biphenylmethanol (1c), others are the same as Example 1, and column chromatography (petroleum ether: ethyl acetate=100:1) obtains target product (2c ), yield 51%. The NMR data of this compound are: 1 H NMR (600MHz, CDCl 3 )δ7.61(dd, J=16.1,7.6Hz,4H),7.45(t,J=7.7Hz,4H),7.36(t,J=7.4Hz,1H),5.46(s,1H),5.38( s, 1H). 13 C NMR (101MHz, CDCl 3 )δ141.77(d, J=3.2Hz), 140.62(s), 128.84(s), 128.07(d, J=5.7Hz), 127.65–127.27(m), 127.17(s), 85.24(s), 83.59(s). 19 F NMR (564MHz, CDCl 3 )δ-206.07-206.24(t).

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Abstract

The invention discloses an alcohol compound-based in-situ deoxidation fluorination synthesis method and an alcohol compound-based <18>F radiolabeling method. Alkyl alcohols such as 4-phenyl-1-butanol,which are used as raw materials, react with trifluoromethylsulfonyl fluoride gas, generated by N-phenylbis(trifluoromethanesulphonimide) and potassium fluoride in a short time, under the catalysis ofan organic alkali to realize the deoxygenation fluorination reaction of alcoholic hydroxyl groups, and monofluoro-substituted compounds are obtained after separation and purification. The synthesis method has the characteristics of high atom economy, simplicity in preparation, greenness, high efficiency, high selectivity and few elimination byproducts, is suitable for large-scale production, andcan be applied to the radioactive isotope <18>F labeling process to label drug molecules containing alcoholic hydroxyl groups.

Description

technical field [0001] The invention relates to an in-situ deoxyfluorination synthesis method based on alcohol compounds and a 18F radioactive labeling method, based on the in-situ reaction of N-phenylbis(trifluoromethanesulfonyl)imide, potassium fluoride and alcohols , to carry out the deoxyfluorination process, belonging to the field of organic synthesis and radiochemistry. Background technique [0002] In drug design, the construction of carbon-fluorine bonds can significantly improve the stability of metabolism, liposolubility and activity of prodrugs [1] . Deoxyfluorination of alcohols is one of the most attractive approaches to form aliphatic C–F bonds due to the abundance and availability of alcohol-containing precursors. [2] . The deoxyfluorination reagent will generate an activated leaving group and a nucleophilic fluorine source, which react in situ to obtain the target product. In addition, for cancer cells 18 The chemical labeling method of F imaging agent h...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C17/16C07C41/22C07C201/12C07C253/30C07D205/04C07D333/12C07H15/18C07J1/00C07H1/00C07B39/00C07C22/08C07C205/37C07C255/54C07C43/225C07C21/18
CPCC07B39/00C07B2200/05C07C17/16C07C41/22C07C201/12C07C253/30C07D205/04C07D333/12C07H15/18C07J1/0011C07J1/0014C07C22/08C07C205/37C07C255/54C07C43/225C07C21/18
Inventor 徐俊姚博霖戴建军许华建
Owner HEFEI UNIV OF TECH
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