1,3-disubstituted-3-azabicyclo[3.2.1]octane derivative and preparation method

An azabicyclo and disubstituted technology, applied in the field of 1,3-disubstituted-3-azabicyclo[3.2.1]octane derivatives and preparation, can solve the problems of unfavorable rapid screening, limitation of spatial structure and the like , to achieve the effect of changing lipid solubility and metabolic properties, improving polarity, and changing physiological activity

Active Publication Date: 2015-08-19
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 problems that the current azabicyclo[3.2.1]octane-structure bridged ring compounds are restricted in spatial structure extension, which is not conducive to rapid screening of compound activity and SAR analysis

Method used

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  • 1,3-disubstituted-3-azabicyclo[3.2.1]octane derivative and preparation method
  • 1,3-disubstituted-3-azabicyclo[3.2.1]octane derivative and preparation method
  • 1,3-disubstituted-3-azabicyclo[3.2.1]octane derivative and preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Example 1 : Preparation of 1-ethoxycarbonyl-3-benzyl-8-carbonyl-3-azabicyclo[3.2.1]octane

[0052]

[0053] Steps:

[0054] Add ethyl cyclopentanone-2-carboxylate to a 1-liter three-necked flask 1 (20 g, 0.13 mol), N,N-diethoxymethyl-benzylamine (58 g, 0.26 mol) and anhydrous acetonitrile (400 ml), trichloromethylsilane (39 g, 0.26 mol), and stirred at room temperature for 20 hours under nitrogen protection. The reaction solution was adjusted to pH 7 with saturated sodium bicarbonate solution at 0°C, extracted with ethyl acetate, and the organic phase was concentrated to obtain 22 g of 1-ethoxycarbonyl-3-benzyl-8-carbonyl-3-azabicyclo[3.2 .1] Octane 2 , directly used in the next reaction with a yield of 58%.

[0055] HNMR (CDCl 3 ) d: 7.28-7.19 (m, 5H), 4.14-4.09 (m, 2H), 3.62-3.56 (m, 2H), 3.06 (d, J = 10.8 Hz, 1H), 2.90 (d, J = 10.8 Hz, 1H), 2.70 (d, J = 11.2 Hz, 1H), 2.50 (d, J = 10.4 Hz, 1H), 2.38-2.21(m, 3H), 1.98-1.88(m, 2H), 1.24(t, J = 7.2 Hz...

Embodiment 2

[0056] Example 2 : Preparation of 1-ethoxycarbonyl-3-benzyl-8-p-toluenesulfonylhydrazone-3-azabicyclo[3.2.1]octane

[0057]

[0058] Steps:

[0059] In a 500 ml three-necked flask, add 1-ethoxycarbonyl-3-benzyl-8-carbonyl-3-azabicyclo[3.2.1]octane 2 (22 g, 0.08 mol) and anhydrous methanol (200 ml), add p-toluenesulfonylhydrazide (37 g, 0.2 mol) dropwise at 0°C, 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 10 grams of 1-ethoxycarbonyl-3-benzyl-8-p-toluenesulfonylhydrazone -3-Azabicyclo[3.2.1]octane 3 , directly used in the next reaction with a yield of 31%.

[0060] HNMR (CDCl 3 ) d: 7.79-7.75 (m, 2H), 7.36-7.23 (m, 8H), 4.18-4.11 (m, 2H), 3.54-3.46 (m, 2H), 2.97 (d, J = 10.4 Hz, 1H), 2.90 (d, J = 10.8 Hz, 1H), 2.76 (d, J = 11.2 Hz, 1H), 2.52 (d, J = 10.4 Hz, ...

Embodiment 3

[0061] Example 3 : Preparation of 1-ethoxycarbonyl-3-benzyl-3-azabicyclo[3.2.1]octane

[0062]

[0063] Steps:

[0064] Add 1-ethoxycarbonyl-3-benzyl-8-p-toluenesulfonylhydrazone-3-azabicyclo[3.2.1]octane in a 500 ml three-necked flask 3 (10 grams, 0.022 moles), methanol (100 milliliters) and tetrahydrofuran (100 milliliters), add sodium cyanoborohydride (1.6 grams, 0.026 moles) at 0 ° C, 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 (28 g, 0.22 mol) was added. Under the protection of nitrogen, the stirring reaction was continued for 2 hours. The reaction solution was diluted with water, extracted with ethyl acetate (3×100 ml), the organic phase was concentrated, a...

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Abstract

The invention relates to 1,3-disubstituted-3-azabicyclo [3,2,1] octane substituted derivates and a preparation method thereof. The invention mainly solves the technical problems that the extension of the existing bicyclic compound with a 3-azabicyclo [3,2,1] octane structure is limited in a spatial structure, thereby being not favorable for quickly screening compound activity and carrying out SAR (structure-activity relationship) analysis. The chemical structural formula of the derivates is as shown in the specification, wherein R1 is a substituted functional group or amino protecting group and is selected from H, C1-C10 linear chains or one of alkyl, benzyl, tertbutyloxycarbonyl, alkanoyl, sulfonyl, carbamide and thiocarbamide containing substituent lateral chains; and G is selected from hydroxyl, C1-C10 linear chains or one of alkoxyl, methylamino and dimethylamino containing substituent lateral chains.

Description

technical field [0001] The present invention relates to 1,3-disubstituted-3-azabicyclo[3.2.1]octane derivatives and a preparation method thereof, especially 1-carboxy-3-substituted-3-azabicyclo[3,2,1] Octane derivatives and 1-substituted-3-azabicyclo[3.2.1]octane 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 that have been disc...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D221/22A61P35/00
CPCY02P20/55
Inventor 叶俊涛彭宣嘉汪秀胡利红陈莉沈余红董径超吴颢吕强马汝建陈曙辉
Owner 上海药明康德新药开发有限公司
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