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3-azabicyclo (3.3.1) nonane-9-substituted derivative and preparation method thereof

An azabicyclo and derivative technology, which is applied in the field of 3-azabicyclo[3.3.1]nonane-9-substituted derivatives and preparation, can solve the problems of poor water solubility of compounds, limitation of spatial structure extension, etc. Physiological activity, improving selectivity, improving water solubility

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

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Problems solved by technology

It aims to solve the technical problems that the current azabicyclo[3.3.1]nonane-structure bridged ring compounds are limited in spatial structure extension and the compound's poor water solubility

Method used

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  • 3-azabicyclo (3.3.1) nonane-9-substituted derivative and preparation method thereof
  • 3-azabicyclo (3.3.1) nonane-9-substituted derivative and preparation method thereof
  • 3-azabicyclo (3.3.1) nonane-9-substituted derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Example 1: Preparation of 3-benzyl-3-azabicyclo[3.3.1]-9-nonanone

[0059]

[0060] Operation steps: add 210mL (1.6mmol) of benzylamine in a 2L round bottom flask, then add 160mL of concentrated hydrochloric acid under nitrogen protection, add 163mL (1.6mmol) of cyclohexanone, 376mL of 37% formaldehyde to the mixture aqueous solution and 2190 mL of acetic acid. The mixed solution was heated and stirred at 80° C. for two hours, and then concentrated. Diethyl ether and water were added to the residue, the layers were separated, and the aqueous phase was washed with diethyl ether, washed with Na 2 CO 3 The pH of the solid was adjusted to 8, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was dissolved with 450 mL of ethanol, and 150 mL of acetic anhydride was added. The resulting mixture was stirred for two hours, and 160 mL of concentrated hydrochloric acid was added to the...

Embodiment 2

[0062] Example 2: Preparation of 3-benzyl-9-cyano-3-azabicyclo[3.3.1]nonane

[0063]

[0064] Operation steps: At 0°C, potassium tert-butoxide (81.23g, 725.1mmol) was added to 3-benzyl-3-azabicyclo[3.3.1]-9-nonanone (37.5g, 207.15 mmol), p-toluenesulfonylmethyl isocyanide (72.75 g, 372.9 mmol) and 278 mL of 1,2-dichloroethane were added simultaneously. The mixture was heated at 50°C for 10 hours, and then poured into saturated brine. The mixture was extracted with ethyl acetate and concentrated to give crude product. Crude product is used column chromatography, obtains the 3-benzyl-9-cyano group-3-azabicyclo[3.3.1]nonane (yield 38.1%) of 18.954 grams (wherein petroleum ether / ethyl acetate is used as washing remover).

[0065] HNMR (CDCl3) δ: 7.34 (m, 5H), 3.47 (s, 1H), 3.42 (s, 1H), 3.05 (d, 1H), 2.95 (d, 1H), 2.73 (m, 3H), 2.32 ( dd, J=10.8Hz, J=37.6Hz, 1H), 2.11(m, 3H), 1.85-1.98(m, 1H), 1.52-1.72(m, 3H). MS: 241 (M+1).

Embodiment 3

[0066] Embodiment 3: Preparation of ethyl 3-benzyl-3-azabicyclo[3.3.1]nonane-9-carboxylate

[0067]

[0068] Operation steps: 9-cyano-3-benzyl-3-azabicyclo[3.3.1]nonane (23.954g, 99.8mmol) and 1500mL of HCl gas-saturated ethanol mixture was heated to reflux, and then 12mL of water was added , and the mixture was heated to reflux for 14 hours under nitrogen protection. The reaction mixture was concentrated and washed with saturated NaHCO 3 The solution was adjusted to pH 8. Then dichloromethane and water were added, the layers were separated, and the organic phase was concentrated to obtain a crude product. Column chromatography of the crude product yielded 8.56 g of ethyl 3-benzyl-3-azabicyclo[3.3.1]nonane-9-carboxylate. (Yield 29.9%) (where petroleum ether / ethyl acetate is the eluent).

[0069] HNMR (CDCl3) δ: 7.25 (m, 5H), 3.93-4.19 (m, 2H), 3.28 (d, 2H), 2.90 (d, 1H), 2.66 (m, 2H), 2.04-2.37 (m, 4H) ), 1.31-1.91 (m, 6H), 1.20 (m, 3H). MS: 288 (M+1).

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Abstract

The invention relates to a 3-azabicyclo (3.3.1) nonane-9-substituted derivative and a preparation method thereof, which mainly solve the technical problems that the extension of the prior endocyclic compound with 3-azabicyclo (3.3.1) nonane structure in a space structure is limited and the water solubility of the compound is poor. The chemical structural formula of the 3-azabicyclo (3.3.1) nonane-9-substituted derivative is shown as above, and the optimal compound structure in the formula (1) is I, II, III, and IV. The invention is mainly used as a template compound in medicine research.

Description

Technical field: [0001] The present invention relates to 3-azabicyclo[3.3.1]nonane-9-substituted derivatives and a preparation method thereof, especially 3-azabicyclo[3.3.1]nonane-9-amine derivatives and 3-nitrogen Heterobicyclo[3.3.1]nonane-9-carboxylic acid derivatives and their preparation methods. 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. The spatial structure produces different biological activities or effects. Many bridged ring compounds have different biological activities and 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 bio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D221/22
Inventor 张鹏彭宣嘉徐芳荣李鹏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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