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6-azabicyclo (3.2.1) nonane-3-substituted derivative and preparation method thereof

An azabicyclo and derivative technology, which is applied in the field of 6-azabicyclo[3.2.1]octane-3-substituted derivatives and preparation, can solve the problems of poor water solubility of compounds, limitation of spatial structure extension, etc. Physiological activity, the effect of improving diversity

Inactive Publication Date: 2009-11-18
无锡药明康德新药开发股份有限公司 +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 bridged ring compound of 6-azabicyclo[3.2.1]octane structure is limited in spatial structure extension and the compound has poor water solubility

Method used

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  • 6-azabicyclo (3.2.1) nonane-3-substituted derivative and preparation method thereof
  • 6-azabicyclo (3.2.1) nonane-3-substituted derivative and preparation method thereof
  • 6-azabicyclo (3.2.1) nonane-3-substituted derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1: the preparation of 3-hydroxyl-5-(methylbenzylamine) cyclohexene

[0042]

[0043] Steps:

[0044] Under the protection of nitrogen, in a dry three-necked flask, add lithium aluminum hydride (1.75g, 43.75mmol) and tetrahydrofuran (170mL), add 3-hydroxyl-5-formylbenzylamide cyclohexene (5g , 0.0216mol). The reaction solution was stirred at 0°C for 0.5 hours, slowly raised to 65°C and stirred overnight, quenched with saturated ammonium chloride aqueous solution, adjusted to pH 7 with 3N aqueous sodium hydroxide solution, filtered, concentrated filtrate, added water, extracted with ethyl acetate , the organic phase was dried and concentrated to obtain 8.5 g of the product, with a yield of 90%.

[0045] HNMR (DMSO) δ: 7.277-7.338 (m, 5H), 5.597 (s, 2H), 4.982 (s, 2H), 2.900 (s, 2H), 1.734-2.148 (m, 3H), 1.497-1.734 (m , 3H), 1.113-1.142(m, 2H).

Embodiment 2

[0046] Embodiment 2: Preparation of 3-carbonyl-6-benzyl-6-azabicyclo[3.2.1]octane

[0047]

[0048] Steps:

[0049] 3-Hydroxy-5-(methylbenzylamine)cyclohexene (20g, 92mmol) was dissolved in 800mL of anhydrous dichloromethane, and activated manganese dioxide (16.0g, 183.9mmol) was added in one go under nitrogen protection. The reaction system was vigorously stirred for 2 hours. A yellow solid was filtered and washed with dichloromethane (2*50 mL). The filtrates were combined and concentrated to obtain an orange oily crude product, which was solidified and recrystallized in a hot n-hexane / ether system to obtain 13.4 g of the product, with a yield of 68%.

[0050] HNMR (MeOD) δ: 7.216-7.335 (m, 5H), 3.716-3.797 (m, 2H), 3.352 (t, J 1 = 4Hz,J 2 =4.8Hz, 1H), 2.832-2.869(m, 1H), 2.742(d, J=10Hz, 1H), 2.626(s, 1H), 2.566(t, J 1 = 1.6Hz,J 2 =2.4Hz, 2H), 2.403(d, J=2Hz, 1H), 2.102-2.122(m, 1H), 1.912(d, J=12Hz, 1H).

Embodiment 3

[0051] Example 3: Preparation of 3-carbonyl-6-tert-butoxycarbonyl-6-azabicyclo[3.2.1]octane

[0052]

[0053] Steps:

[0054] In a dry three-necked flask, add 3-carbonyl-6-benzyl-6-azabicyclo[3.2.1]octane (4g, 18.6mmol), 100mL of anhydrous dichloromethane, then cool to 0°C, Chloroethyl α-chloroformate (2 mL, 22.5 mmol) was added dropwise under nitrogen protection. The reaction solution was stirred at 0°C for 10 minutes, then warmed to room temperature and stirred for 1.5 hours. The reaction solution was concentrated, anhydrous methanol (37.5 mL) was added, and the reaction was refluxed for 2 hours. The reaction solution was concentrated, anhydrous dichloromethane (100 mL) was added to form a suspension, triethylamine (20 mL, 150 mmol) and di-tert-butyl carbonate (5 g, 24 mmol) were added sequentially under ice cooling, warmed to room temperature, and reacted for 64 hours. The reaction solution was diluted with dichloromethane, washed successively with water (100 mL), 1N ...

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Abstract

The invention relates to a 6-azabicyclo (3.2.1) nonane-3-substituted derivative and a preparation method thereof, which mainly solve the technical problems that the extension of the prior endocyclic compound with 6-azabicyclo (3.23.1) nonane structure in a space structure is limited and the water solubility of the compound is poor. The reaction formula of the 6-azabicyclo (3.2.1) nonane-3-substituted derivative is shown as above. 3-nitrile-6-azabicyclo (3.2.1) nonane compound IV is obtained by adopting 6-azabicyclo (3.2.1) nonane-3-ketone III as raw materials through nitrile addition, and then the compound IV is reacted with ethanol under acid condition to generate ester compound I; or the compound III is reacted with oxyammonia, aminos, hydrazines, amides, sulfonamides, hydrazides or sulfonyl hydrazides to generate compound V, and the compound V is reduced to generate compound II.

Description

Technical field: [0001] The present invention relates to 6-azabicyclo[3.2.1]octane-3-substituted derivatives and a preparation method thereof, especially 6-azabicyclo[3.2.1]octane-3-amine derivatives and 6-nitrogen Heterobicyclo[3.2.1]octane-3-carboxylic acid derivatives and methods for their preparation. Background technique: [0002] Bridged ring compounds are a class of molecules with a special structure, which can effectively link and integrate key pharmacophore units into their rigid structures to form molecules with special spatial configurations and conformations, which can match the biological macromolecules in the body. Spatial structure produces different biological activities or effects. 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 a 6-azabicyclic structure have been proved by many experiments to have vario...

Claims

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Application Information

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IPC IPC(8): C07D209/02
Inventor 胡利红彭宣嘉毕晨光董径超吴颢马汝建陈曙辉
Owner 无锡药明康德新药开发股份有限公司
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