1,3,7-tri-substituted-diazabicyclo[3,3,1] nonane derivative and preparation method thereof

Abstract

The invention relates to a 1,3,7-tri-substituted-diazabicyclo[3,3,1] nonane derivative and a preparation method thereof, mainly solving the technical problems that bridge-ring compounds with 1,3,7-tri-substituted-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 or benzyl; R2 represents a protecting group for substituting a functional group or an amino group, and is selected form H or carbobenzoxy; and G is one of hydroxymethyl, hydroxyl, ester, and formamido.

Description

technical field

[0001] The present invention relates to 1,3,7-trisubstituted-3,7-diazabicyclo[3,3,1]nonane derivatives and their preparation methods, especially 1-substituted-3-benzyloxycarbonyl-7-benzyl Base-3,7-diazabicyclo[3,3,1]nonane derivatives and 1-ethoxycarbonyl-3,7-disubstituted-3,7-diazabicyclo[3,3,1 ] Nonane derivatives and preparation method thereof. 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. Molecules containing the bicyclic structure of bispiperidine are widely distributed in lupine alkaloids and some biologically ...

Examples

Embodiment 1

[0044] Example 1 : Preparation of 1-ethoxycarbonyl-3-benzyloxycarbonyl-7-benzyl-9-oxo-3,7-diazabicyclo[3,3,1]nonane

[0045]

[0046] Steps:

[0047] Add 1-benzyloxycarbonyl-3-ethyl carboxylate-4-piperidone 1 (5.0 g, 16 mmol), N,N-diethoxymethyl-benzylamine (7.3 g, 32 mmol) and anhydrous acetonitrile (30 ml), trichloromethylsilane (4.9 g, 32 mmol) was added dropwise at 0°C, 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 zero degrees Celsius, extracted with ethyl acetate, and after the organic phase was concentrated, the petroleum ether / ethyl acetate (6 / 1) eluent was passed through the column to obtain 3.2 grams of the product. The yield was 45%.

[0048] HNMR (CDCl 3 ) d: 7.18-7.14 (m, 5H), 7.13-7.10 (m, 5H), 5.15-5.11 (m, 1H), 5.02-4.97 (m, 1H), 4.64-4.51 (m, 1H), 4.42- 4.34 (m, 1H), 4.07-4.02 (m, 2H), 3.64-3.51 (m, 1H), 3.35-2.92 (m, 6H), 2.60-2.52 (m, 1...

Embodiment 2

[0049] Example 2 : Preparation of 1-ethoxycarbonyl-3-benzyloxycarbonyl-7-benzyl-9-p-toluenesulfonylhydrazone-3,7-diazabicyclo[3,3,1]nonane

[0050]

[0051] Steps:

[0052] In a 100 ml three-necked flask, add 1-ethoxycarbonyl-3-benzyloxycarbonyl-7-benzyl-9-oxo-3,7-diazabicyclo[3,3,1]nonane 2 (1.6 g, 3.7 mmol) and anhydrous methanol (25 ml), a methanol solution of p-toluenesulfonyl hydrazide (1.7 g, 9.2 mmol) was added dropwise at zero degrees Celsius, and stirred at room temperature for 36 hours under nitrogen protection. The reaction solution was directly concentrated at a temperature of forty degrees Celsius to fifty degrees Celsius, and purified by column purification with petroleum ether / ethyl acetate (6 / 1) eluent to obtain 0.8 g of 1-ethoxycarbonyl-3-benzyloxycarbonyl-7 -Benzyl-9-p-toluenesulfonylhydrazone-3,7-diazabicyclo[3,3,1]nonane 5 , directly used in the next reaction with a yield of 36%.

[0053] HNMR (CDCl 3 ) d: 7.80-7.71 (m, 2H), 7.34-7.30 (m, 6H), 7.25...

Embodiment 3

[0054] Example 3 : Preparation of 1-ethoxycarbonyl-3-benzyloxycarbonyl-7-benzyl-3,7-diazabicyclo[3,3,1]nonane

[0055]

[0056] Steps:

[0057] In a 100 ml three-necked flask, add 1-ethoxycarbonyl-3-benzyloxycarbonyl-7-benzyl-9-p-toluenesulfonylhydrazone-3,7-diazabicyclo[3,3,1]nonane alkyl 3 (0.8 g, 1.32 mmol), methanol (10 ml) and tetrahydrofuran (10 ml), add sodium cyanoborohydride (57 mg, 0.9 mmol) at zero degrees Celsius, and adjust with 1 mole per liter of dilute hydrochloric acid The pH value of the reaction system was about 4, and it was stirred at room temperature for 2 hours under the protection of nitrogen. The reaction solution was quenched and diluted with water, extracted with ethyl acetate (3×20 ml), the organic phase was concentrated and dissolved in ethanol (30 ml), and sodium acetate monohydrate (4.94 g, 49.3 mmol) was added. Under the protection of nitrogen, the stirring reaction was continued at 75° C. for 2 hours. After the reaction was completed, ...

technical field

[0001] The present invention relates to 1,3,7-trisubstituted-3,7-diazabicyclo[3,3,1]nonane derivatives and their preparation methods, especially 1-substituted-3-benzyloxycarbonyl-7-benzyl Base-3,7-diazabicyclo[3,3,1]nonane derivatives and 1-ethoxycarbonyl-3,7-disubstituted-3,7-diazabicyclo[3,3,1 ] Nonane derivatives and preparation method thereof. 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. Molecules containing the bicyclic structure of bispiperidine are widely distributed in lupine alkaloids and some biologically ...

Examples

Embodiment 1

[0044] Example 1 : Preparation of 1-ethoxycarbonyl-3-benzyloxycarbonyl-7-benzyl-9-oxo-3,7-diazabicyclo[3,3,1]nonane

[0045]

[0046] Steps:

[0047] Add 1-benzyloxycarbonyl-3-ethyl carboxylate-4-piperidone 1 (5.0 g, 16 mmol), N,N-diethoxymethyl-benzylamine (7.3 g, 32 mmol) and anhydrous acetonitrile (30 ml), trichloromethylsilane (4.9 g, 32 mmol) was added dropwise at 0°C, 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 zero degrees Celsius, extracted with ethyl acetate, and after the organic phase was concentrated, the petroleum ether / ethyl acetate (6 / 1) eluent was passed through the column to obtain 3.2 grams of the product. The yield was 45%.

[0048] HNMR (CDCl 3 ) d: 7.18-7.14 (m, 5H), 7.13-7.10 (m, 5H), 5.15-5.11 (m, 1H), 5.02-4.97 (m, 1H), 4.64-4.51 (m, 1H), 4.42- 4.34 (m, 1H), 4.07-4.02 (m, 2H), 3.64-3.51 (m, 1H), 3.35-2.92 (m, 6H), 2.60-2.52 (m, 1...

Embodiment 2

[0049] Example 2 : Preparation of 1-ethoxycarbonyl-3-benzyloxycarbonyl-7-benzyl-9-p-toluenesulfonylhydrazone-3,7-diazabicyclo[3,3,1]nonane

[0050]

[0051] Steps:

[0052] In a 100 ml three-necked flask, add 1-ethoxycarbonyl-3-benzyloxycarbonyl-7-benzyl-9-oxo-3,7-diazabicyclo[3,3,1]nonane 2 (1.6 g, 3.7 mmol) and anhydrous methanol (25 ml), a methanol solution of p-toluenesulfonyl hydrazide (1.7 g, 9.2 mmol) was added dropwise at zero degrees Celsius, and stirred at room temperature for 36 hours under nitrogen protection. The reaction solution was directly concentrated at a temperature of forty degrees Celsius to fifty degrees Celsius, and purified by column purification with petroleum ether / ethyl acetate (6 / 1) eluent to obtain 0.8 g of 1-ethoxycarbonyl-3-benzyloxycarbonyl-7 -Benzyl-9-p-toluenesulfonylhydrazone-3,7-diazabicyclo[3,3,1]nonane 5 , directly used in the next reaction with a yield of 36%.

[0053] HNMR (CDCl 3 ) d: 7.80-7.71 (m, 2H), 7.34-7.30 (m, 6H), 7.25...

Embodiment 3

[0054] Example 3 : Preparation of 1-ethoxycarbonyl-3-benzyloxycarbonyl-7-benzyl-3,7-diazabicyclo[3,3,1]nonane

[0055]

[0056] Steps:

[0057] In a 100 ml three-necked flask, add 1-ethoxycarbonyl-3-benzyloxycarbonyl-7-benzyl-9-p-toluenesulfonylhydrazone-3,7-diazabicyclo[3,3,1]nonane alkyl 3 (0.8 g, 1.32 mmol), methanol (10 ml) and tetrahydrofuran (10 ml), add sodium cyanoborohydride (57 mg, 0.9 mmol) at zero degrees Celsius, and adjust with 1 mole per liter of dilute hydrochloric acid The pH value of the reaction system was about 4, and it was stirred at room temperature for 2 hours under the protection of nitrogen. The reaction solution was quenched and diluted with water, extracted with ethyl acetate (3×20 ml), the organic phase was concentrated and dissolved in ethanol (30 ml), and sodium acetate monohydrate (4.94 g, 49.3 mmol) was added. Under the protection of nitrogen, the stirring reaction was continued at 75° C. for 2 hours. After the reaction was completed, ...

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