1,3-disubstituted-3-diazabicyclo[3,3,1] nonane derivative and preparation method thereof

A technology of azabicyclo and derivatives, which is applied in the field of 1,3-disubstituted-3-azabicyclo[3,3,1]nonane derivatives and its preparation, which can solve the limitations of unfavorable rapid screening and spatial structure extension and other issues to achieve the effect of increasing diversity and improving polarity

Active Publication Date: 2013-01-16
WUXI BIOLOGICS CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It mainly solves the technical problems that the current azabicyclo[3,3,1]nonane-structure bridged ring compounds are limited in spatial structure extension, which is not conducive to rapid screening of compound activity and structure-activity analysis

Method used

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  • 1,3-disubstituted-3-diazabicyclo[3,3,1] nonane derivative and preparation method thereof
  • 1,3-disubstituted-3-diazabicyclo[3,3,1] nonane derivative and preparation method thereof
  • 1,3-disubstituted-3-diazabicyclo[3,3,1] nonane derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1 : 1-ethoxycarbonyl-3-benzyl-9-carbonyl-3-azabicyclo[3,3,1]nonane

[0048]

[0049] Steps:

[0050] Add ethyl cyclohexanone-2-carboxylate in a 500 ml three-necked flask 1 (8 g, 0.058 mol), N,N-diethoxymethyl-benzylamine (25 g, 0.116 mol) and anhydrous acetonitrile (300 ml), trichlorophenylsilane (11.75 g, 0.116 mol), and the mixture was stirred at room temperature for 16 hours under nitrogen protection. The reaction solution was adjusted to pH 7 with saturated sodium bicarbonate solution at zero degrees Celsius, extracted with ethyl acetate, and the organic phase was concentrated to obtain 10 grams of 1-ethoxycarbonyl-3-benzyl-9-carbonyl-3-azabicyclo[3 ,3,1] nonane 2 , directly used in the next reaction with a yield of 71%.

[0051] HNMR (CDCl 3 ) d: 7.28-7.36 (m, 5H), 4.18-4.20 (m, 2H), 3.52 (s, 2H), 3.12-3.18 (m, 2H), 2.97-3.00 (m, 1H), 2.61-2.64 ( m, 2H), 2.51-2.57 (m, 1H), 2.21-2.26 (m, 3H), 1.63-1.64 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H).

Embodiment 2

[0052] Example 2 : Preparation of 1-ethoxycarbonyl-3-benzyl-9-p-toluenesulfonylhydrazone-3-azabicyclo[3,3,1]nonane

[0053]

[0054] Steps:

[0055] In a 500 ml three-necked flask, add 1-ethoxycarbonyl-3-benzyl-9-carbonyl-3-azabicyclo[3,3,1]nonane 2 (10 g, 0.033 mol) and anhydrous methanol (200 ml), add p-toluenesulfonyl hydrazide (30 g, 0.16 mol) dropwise at zero degrees Celsius, and stir at room temperature for 36 hours under nitrogen protection. The reaction solution was directly concentrated at a temperature of 40°C to 50°C, and purified through a column with an eluent system of petroleum ether and ethyl acetate to obtain 4 grams of 1-ethoxycarbonyl-3-benzyl-9-p-toluenesulfonylhydrazone -3-Azabicyclo[3,3,1]nonane 3 , directly used in the next reaction with a yield of 27%.

[0056] HNMR (CDCl 3 ) d: 7.74-7.77 (m, 2H), 7.26-7.35 (m, 8H), 4.08-4.16 (m, 2H), 3.48 (s, 2H), 2.75-2.95 (m, 5H), 2.43 (s, 3H), 2.23-2.37(m, 2H), 1.89-1.98(m, 2H), 1.69-1.70(m, 1H), 1.51-1.58...

Embodiment 3

[0057] Example 3 : Preparation of 1-ethoxycarbonyl-3-benzyl-3-azabicyclo[3,3,1]nonane

[0058]

[0059] Steps:

[0060] In a 500 ml three-necked flask, add 1-ethoxycarbonyl-3-benzyl-9-p-toluenesulfonylhydrazone-3-azabicyclo[3,3,1]nonane 3 (5 g, 0.01 mol), methanol (100 ml) and tetrahydrofuran (100 ml), add sodium cyanoborohydride (1.34 g, 0.021 mol) at zero degrees Celsius, and use 1N dilute hydrochloric acid to adjust the pH value of the reaction system at 4, stirred at room temperature for 2 hours under nitrogen protection. The reaction solution was quenched and diluted with water, extracted with ethyl acetate (3×100 ml), the organic phase was concentrated and dissolved in ethanol (100 ml), and sodium acetate monohydrate (20 g, 0.20 mol) was added. Under the protection of nitrogen, the reaction was stirred at 80° C. for 2 hours. The reaction solution was diluted with water, extracted with ethyl acetate (3×100 ml), the organic phase was concentrated, and the eluent sy...

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Abstract

The invention relates to a 1,3-disubstituted-3-diazabicyclo[3,3,1] nonane derivative and a preparation method thereof, mainly solving the technical problems that bridge-ring compounds with 3-diazabicyclo[3,3,1] nonane structure are limited in space structural extension, which is not good for rapid screening of compound activity and SAR analysis. The derivative disclosed herein is represented by the following formula, wherein R1 represents a protecting group of a substituted functional group or an amino group, and is selected form H, C1-C10 straight chain or one of alkyl, alkanoyl and alkylsulphonyl which contain substituent side chains; and G is one of hydroxymethyl, hydroxyl, ester, and formamido.

Description

technical field [0001] The present invention relates to 1,3-disubstituted-3-azabicyclo[3,3,1]nonane derivatives and their preparation methods, especially 1-formic acid-3-substituted-3-azabicyclo[3,3, 1] Nonane derivatives and 1-ethoxycarbonyl-3-substituted-3-azabicyclo[3,3,1]nonane derivatives and their preparation methods. Background technique [0002] Bridged ring compounds are a class of molecules with special structures, which can effectively link and integrate key pharmacophore units into their rigid structures to form molecules with special spatial configurations / conformations, which can match different biological macromolecules in vivo Many bridged ring 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 3-azabicyclic structures have been proved by many experiments to have various biological activities. The following are some examples ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D221/22C07D401/06A61P35/00A61P11/00
CPCY02P20/55
Inventor 王丽萍彭宣嘉胡利红俞钦洋蔡兰兰沈余红董径超吴颢马汝建陈曙辉
Owner WUXI BIOLOGICS CO LTD
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