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Fluoro or difluoro-2-azabicyclo [2.2.1] heptane-3-carboxyl acid derivatives, and preparation thereof

A technology of carboxylic acid derivatives and azabicyclo, which is applied in the field of fluorinated or difluoro-2-azabicyclo[2.2.1]heptane-3-carboxylic acid derivatives and its preparation, and can solve the problem of poor metabolic stability And other issues

Inactive Publication Date: 2009-06-24
上海药明康德新药开发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It mainly solves the technical problem that 2-azabicyclo[2.2.1]heptane-3-carboxylic acid derivatives only have hydrophobic groups such as carbon atoms and hydrogen atoms, resulting in poor metabolic stability

Method used

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  • Fluoro or difluoro-2-azabicyclo [2.2.1] heptane-3-carboxyl acid derivatives, and preparation thereof
  • Fluoro or difluoro-2-azabicyclo [2.2.1] heptane-3-carboxyl acid derivatives, and preparation thereof
  • Fluoro or difluoro-2-azabicyclo [2.2.1] heptane-3-carboxyl acid derivatives, and preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] (1R,3S,4S,5S)-5-fluoro-2-tert-butoxycarbonyl-2-azabicyclo[2.2.1]heptane-3-carboxylic acid ethyl ester

[0057] Reaction formula:

[0058]

[0059] Operation steps: -78℃, add (1R,3S,4S,5R)-5-hydroxy-2-tert-butoxycarbonyl-2-azabicyclo[2.2.1]heptane-3-carboxylic acid ethyl ester (1.42 g, 5mmol) was dissolved in 10mL of dichloromethane and added dropwise to 1mL of diethylaminosulfur trifluoride (DAST) in dichloromethane, stirred at -78°C for 6 hours, and warmed to room temperature overnight. After the reaction, the saturated sodium bicarbonate solution was added to the reaction solution, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and passed through the column to obtain the product (1R, 3S, 4S, 5S)-5-fluoro -2-tert-butoxycarbonyl-2-azabicyclo[2.2.1]heptane-3-carboxylic acid ethyl ester was 0.7 g, and the yield was 48.9%.

[0060] HNMRCDCl 3 )δ: 5.29-5.08 (m, 1H); 4.32 (d, 1H, J=7.2 Hz); 4.18 (m, 2H); 2.97 (s, 1H); 2.08...

Embodiment 2

[0063] Preparation of ((1R,3S,4S,5S)-5-fluoro-2-benzyloxycarbonyl-2-azabicyclo[2.2.1]heptane-3-carboxylic acid ethyl ester

[0064] Reaction formula:

[0065]

[0066] Procedure: At -78℃, (1R, 3S, 4S, 5R)-5-hydroxy-2-benzyloxycarbonyl-2-azabicyclo[2.2.1]heptane-3-carboxylic acid ethyl ester (1.6 g, 5mmol) dissolved in 10mL of dichloromethane and added dropwise to 1g of bis(methoxyethyl)aminosulfur trifluoride (Deoxofluor) in dichloromethane solution, stirred at -78°C for 6 hours, and warmed to room temperature overnight . After the reaction, the saturated sodium bicarbonate solution was added to the reaction solution, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and passed through the column to obtain the product (1R, 3S, 4S, 5S)-5-fluoro -2-Benzyloxycarbonyl-2-azabicyclo[2.2.1]heptane-3-carboxylic acid ethyl ester was 0.88 g, and the yield was 55.3%.

[0067] MASS: 322.2(M+1)

Embodiment 3

[0069] ((1R,3S,4S,5S)-5-fluoro-2-benzyloxycarbonyl-2-azabicyclo[2.2.1]heptane-3-carboxylic acid benzyl ester

[0070] Reaction formula:

[0071]

[0072] Specifically referring to Example 1, the reaction solvent was ethyl ether, and the fluorination reagent was diethylaminosulfur trifluoride (DAST), and the yield was 45.3%.

[0073] MASS: 384.2(M+1)

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Abstract

The invention relates to a fluoro or difluoro-2-diazabicyclo (2.2.1) heptane-3-carboxylic acid derivative and a preparing method thereof. A chemical structural formula is shown in the right formula. 5-hydroxyl group-2-diazabicyclo (2.2.1) heptane-3-carboxylic ester or 5-carbonyl-2-diazabicyclo (2.2.1) heptane-3-carboxylic ester is adopted for obtaining 5-fluorine-2-diazabicyclo (2.2.1) heptane-3-carboxylic ester or 5, 5-difluoro-2-diazabicyclo (2.2.1) heptane-3-carboxylic ester after the fluorination. And then carboxylic acid is obtained after hydrolysis. When the protection is drawn off, free amino compounds are obtained. By the transformation of changing protecting groups or ester groups, a target product is obtained. The derivative of the invention is mainly used as an intermediate or a structural fragment during the drug synthesis.

Description

Technical field: [0001] The present invention relates to fluorinated or difluoro-2-azabicyclo[2.2.1]heptane-3-carboxylic acid derivatives and preparation methods, especially 5-fluoro-2-azabicyclo[2.2.1]heptan Alkane-3-carboxylic acid derivatives and 5,5-difluoro-2-azabicyclo[2.2.1]heptane-3-carboxylic acid derivatives and preparation methods thereof. Background technique: [0002] The bridged ring structure connects or integrates the key pharmacophore units into its rigid structure to form a molecule with a special spatial configuration and conformation, which can match the spatial structure of different biological macromolecules in the organism, and produce different biological activities or effects Many compounds have different biological activities, so they have broad application value, especially as template compounds in the process of drug research. Bridged ring compounds containing 2-azabicyclic structures have been proved by many experiments to have various biological acti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/52
CPCY02P20/55
Inventor 蒋富勇刘庆生杜峰胡斌吴颢董径超马汝建陈曙辉李革
Owner 上海药明康德新药开发有限公司