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A method for synthesizing 5-fluoro-1-azabicyclo[3,2,2]nonane and derivatives thereof

A technology of azabicyclic derivatives, applied in the field of organic chemical synthesis, can solve the problems of 5-fluoro substituted derivatives without literature and patent reports, etc.

Active Publication Date: 2020-12-08
NANCHANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] 1-Azabicyclo[3,2,2]nonane is a tertiary amine with one more carbon than quinuclidine, and it is an important drug intermediate (Guan Shiyou, Chen Xiaojun, Zhao Zhen, Wang Lixia, Zhao Chunhua, Lin Fangqin , Ren Dayong, application for a patent for invention (patent number: CN102584816 A), 2012-07-18); it has a quasi-spherical structure and may also be used in molecular ferroelectric materials (Zhang,H.-Y.; Tang, Y .-Y.; Shi,P.-P.; Xiong, R.-G. Acc. Chem. Res., 2019, 52, 1928) There have been literature and patent reports on the synthesis of 1-azabicyclo[3,2,2]nonane, but there are no literature and patent reports on the 5-fluoro-substituted derivatives of this compound

Method used

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  • A method for synthesizing 5-fluoro-1-azabicyclo[3,2,2]nonane and derivatives thereof
  • A method for synthesizing 5-fluoro-1-azabicyclo[3,2,2]nonane and derivatives thereof
  • A method for synthesizing 5-fluoro-1-azabicyclo[3,2,2]nonane and derivatives thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Example 1: Preparation of 5-fluoro-1-azabicyclo[3.2.2]nonane (2)

[0019]

[0020] at 0 o Under C, compound 1 (2.0 g, 14.1 mmol) was added to a closed 100 mL reaction vessel, and HF (14.1 mmol, 1.00 equiv.), SF 4 (14.1 mmol, 1.00 equiv), the reaction mixture was reacted at 20 °C for 12 hours. The reaction mixture was monitored by HPLC for the formation of new product. The reaction mixture was quenched with aqueous KOH (20%) and washed with NaHCO 3 The pH of the aqueous solution was adjusted to 6-7, and then extracted with ethyl acetate (50 mL*1). Na for water phase 2 CO 3 The pH of the aqueous solution was adjusted to 9-10, and extracted with ethyl acetate (50 mL*4). The organic phases were combined and washed with saturated brine, and the organic phase was washed with Na 2 SO 4 It was dried and filtered, and the obtained filtrate was subjected to rotary evaporator to remove solvent, and the obtained residue was separated by preparative chromatography to fina...

Embodiment 2

[0024] Example 2: Bulk synthesis of 5-fluoro-1-azabicyclo[3.2.2]nonane (2)

[0025]

[0026] at 0 o Under C, compound 1 (130.0 g, 0.92 mol, 1.00 equiv) was added to a closed 2.0 L reaction vessel, and then HF (0.92 mol, 1.00 equiv) was passed into the reaction vessel, SF 4 (0.92 mol, 1.00 equiv), the reaction mixture was reacted at 20 °C for 12 hours. The reaction mixture was monitored by HPLC for the formation of new product. The reaction mixture was quenched with aqueous KOH (20%) and washed with NaHCO 3 The pH of the aqueous solution was adjusted to 6-7, and then extracted with ethyl acetate (1000 mL*1). Na for water phase 2 CO 3 The pH of the aqueous solution was adjusted to 9-10, and extracted with ethyl acetate (1000 mL*3). The organic phases were combined and washed with saturated brine, and the organic phase was washed with Na 2 SO 4 After drying and filtering, the obtained filtrate was removed from the solvent by a rotary evaporator, the obtained residue wa...

Embodiment 3

[0029] Example 3: Preparation of 5-fluoro-1-azabicyclo[3.2.2]nonane (2)

[0030]

[0031] at 0 o At C, compound 1 (1.41 g, 10.0 mmol) was added to a 50 mL three-neck flask, and dichloromethane (DCM) (20.0 mL) was added to the reaction flask. The air environment in the flask was replaced with a nitrogen atmosphere, and diethylaminosulfur trifluoride (DAST) (2.41 g, 15.0 mmol) was added to the flask at 0 °C, and the reaction mixture was stirred at 0 °C for 1 hour, The reaction was carried out at room temperature for 12 hours. The reaction mixture was monitored by HPLC for the formation of new product. The reaction mixture was quenched with aqueous NaOH (20%) and washed with NaHCO 3The pH of the aqueous solution was adjusted to 6-7, and then extracted with ethyl acetate (50 mL*1). Na for water phase 2 CO 3 The pH of the aqueous solution was adjusted to 9-10, and extracted with ethyl acetate (50 mL*3). The organic phases were combined and washed with saturated brine, and...

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Abstract

The invention relates to the technical field of organic chemical synthesis, and relates to a method for synthesizing 5-fluoro-1-azabicyclo[3, 2, 2]nonane and derivatives thereof. The preparation method comprises the following steps: reacting a 4-(hydroxymethyl)quinuclidine derivative with a fluorinating reagent at normal temperature, rearranging one six-membered ring of a quinine ring to obtain afluorine substituted product of a seven-membered ring, carrying out extraction, solvent removal and concentration on a reaction mixture, and carrying out column chromatography separation or sublimation to obtain pure 5-fluoro-1-azabicyclo[3, 2, 2]nonane and derivatives thereof. The 5-fluoro-1-azabicyclo[3, 2, 2]nonane and the derivative thereof are obtained through one-step synthesis by reacting the 4-(hydroxymethyl)quinuclidine derivative with the fluorinating reagent, and the method is discovered for the first time. The synthesis method is simple, has few synthesis steps, is easy to separate, and can realize large-scale synthesis of target products.

Description

technical field [0001] The invention belongs to the technical field of organic chemical synthesis, and relates to a method for synthesizing 5-fluoro-1-azabicyclo[3,2,2]nonane and derivatives thereof. Background technique [0002] Organofluorine compounds have important applications in drugs and molecular functional materials. such as Freon-11 (CFCl 3 ) and Freon-12 (CF 2 Cl 2 ) and other fluorine-containing alkanes can be used as refrigerants or sprays, polytetrafluoroethylene can be used as high-temperature and corrosion-resistant materials, and perfluorocarboxylic acids can be used as surfactants due to the good hydrophobicity of fluorine atoms. These perfluorinated organic compounds, due to the introduction of fluorine, endow these compounds with good stability, surface activity and high temperature resistance. Fluorine-substituted compounds can also adjust the properties of ferroelectric materials. Compared with their corresponding non-fluorine-substituted compounds,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/08
CPCC07D471/08
Inventor 谢永发蔡琥郑晶晶喻雅俊吴纪勇余庆书
Owner NANCHANG UNIV
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