Fluoro or difluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative and preparation

A technology of carboxylic acid derivatives and azabicyclo, applied in the field of 5-fluoro-2-azabicyclo[2.2.2]octane-3-carboxylic acid derivatives, which can solve the problems of poor metabolic stability

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

Mainly solve the technical problem of poor metabolic stability existing in the existing azabicyclic structure

Method used

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  • Fluoro or difluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative and preparation
  • Fluoro or difluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative and preparation
  • Fluoro or difluoro-2-azabicyclo [2.2.2] octane-3-carboxyl acid derivative and preparation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Preparation of (1R, 3S, 4S, 5S)-5-fluoro-2-tert-butoxycarbonyl-2-azabicyclo[2.2.2]octane-3-carboxylic acid ethyl ester

[0057] Reaction formula:

[0058]

[0059] Operation steps: -78°C, (1R, 3S, 4S, 5R)-5-hydroxy-2-tert-butoxycarbonyl-2-azabicyclo[2.2.2]octane-3-carboxylic acid ethyl ester (1.49 g, 5 mmol) was dissolved in 10 mL of dichloromethane and added dropwise to 1 mL of diethylaminosulfur trifluoride (DAST) in dichloromethane, stirred at -78°C for 6 hours, then raised to room temperature overnight. After the reaction, add saturated sodium bicarbonate solution to the reaction solution, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate, and pass through the column to obtain the product (1R, 3S, 4S, 5S)-5-fluoro - 0.78 g of ethyl 2-tert-butoxycarbonyl-2-azabicyclo[2.2.2]octane-3-carboxylate, with a yield of 52.0%.

[0060] HNMR (CDCl3) δ: 5.02-4.81 (m, 1H); 4.46 (m, 1H); 4.30-4.18 (m, 3H); 2.55 (m, 1H); 2.07-1.85 (m3H...

Embodiment 2

[0063] Preparation of ((1R, 3S, 4S, 5S)-5-fluoro-2-benzyloxycarbonyl-2-azabicyclo[2.2.2]octane-3-carboxylic acid ethyl ester

[0064] Reaction formula:

[0065]

[0066] Operating procedure: at -78°C, (1R, 3S, 4S, 5R)-5-hydroxy-2-benzyloxycarbonyl-2-azabicyclo[2.2.2]octane-3-carboxylic acid ethyl ester (1.68 g, 5mmol) was dissolved in 10mL of dichloromethane and added dropwise to 1.2g of di(methoxyethyl)aminosulfur trifluoride (Deoxofluor) in dichloromethane solution, stirred at -78°C for 6 hours, and warmed to room temperature overnight. After the reaction, add saturated sodium bicarbonate solution to the reaction solution, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate, and pass through the column to obtain the product (1R, 3S, 4S, 5S)-5-fluoro - 0.91 g of ethyl 2-benzyloxycarbonyl-2-azabicyclo[2.2.2]octane-3-carboxylate, the yield was 54.5%.

[0067] MASS: 336.2(M+1)

Embodiment 3

[0069] Preparation of ((1R, 3S, 4S, 5S)-5-fluoro-2-benzyloxycarbonyl-2-azabicyclo[2.2.2]octane-3-carboxylic acid benzyl ester

[0070] Reaction formula:

[0071]

[0072] Specifically referring to Example 1, diethyl ether was used as the reaction solvent, and diethylaminosulfur trifluoride (DAST) was used as the fluorinating reagent, and the yield was 47.3%.

[0073] MASS: 398.2 (M+1)

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Abstract

The invention relates to a fluoro or difluoro-2-diazabicyclo (2.2.2) octane-3-carboxylic acid derivative and a preparing method thereof. The derivative is mainly used as an intermediate or a structural fragment during the drug synthesis. A chemical structural formula is as shown in the right formula. 5-hydroxyl group-2-diazabicyclo (2.2.2) octane-3-carboxylic ester or 5-carbonyl-2-diazabicyclo (2.2.2) octane-3-carboxylic ester is adopted for obtaining 5-fluorine-2-diazabicyclo (2.2.2) octane-3-carboxylic ester or 5, 5-difluoro-2-diazabicyclo (2.2.2) octane-3-carboxylic ester by fluorination. And then carboxylic acid is obtained by hydrolysis. When the protection is removed, free amino compound is obtained. By the transformation of changing protecting groups or ester groups, an object product is obtained.

Description

Technical field: [0001] The present invention relates to fluorinated or difluoro-2-azabicyclo[2.2.2]octane-3-carboxylic acid derivatives and their preparation methods, especially 5-fluoro-2-azabicyclo[2.2.2]octane Alkane-3-carboxylic acid derivatives and 5,5-difluoro-2-azabicyclo[2.2.2]octane-3-carboxylic acid derivatives and processes for their preparation. Background technique: [0002] The bridge ring structure connects or integrates the key pharmacophore units into its rigid structure to form molecules with special spatial configuration and conformation, which can match the spatial structure of different biomacromolecules 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 a...

Claims

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Application Information

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Patent Type & AuthorityApplications(China)
IPC IPC(8): C07D221/22
CPCY02P20/55
Inventor曹茉莉郑明伟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