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2-(n-arylmethylpiperidine-4-amino)-4-(substituted phenol)benzene ring derivatives and their preparation methods and applications

An arylmethylpiperidine and derivative technology, applied in the fields of organic synthesis and pharmaceutical applications, can solve the problems of low oral bioavailability, and achieve the effects of low cytotoxicity and strong HIV-1 inhibitory activity

Active Publication Date: 2016-04-13
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, most DAPY compounds have low oral bioavailability due to water solubility. Therefore, it is necessary to use DAPYs as the structural skeleton to conduct further research to improve their bioavailability and expand their antibacterial spectrum.

Method used

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  • 2-(n-arylmethylpiperidine-4-amino)-4-(substituted phenol)benzene ring derivatives and their preparation methods and applications
  • 2-(n-arylmethylpiperidine-4-amino)-4-(substituted phenol)benzene ring derivatives and their preparation methods and applications
  • 2-(n-arylmethylpiperidine-4-amino)-4-(substituted phenol)benzene ring derivatives and their preparation methods and applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Embodiment 1: Preparation of intermediate tert-butyl 4-(5-chloro-2-nitroanilino)piperidine-1-carboxylate (2)

[0069] Dissolve 0.09g (0.5mmol) 4-chloro-2-fluoro-1-nitrobenzene (1), 0.1g (0.5mmol) N-Boc piperidinamine, 0.15g (1.4mmol) sodium carbonate in 5mlN,N -Dimethylformamide (N,N-dimethylformamide), stirred and reacted at 80°C for 1 hour. Distill N,N-dimethylformamide under reduced pressure, dissolve the obtained solid in 10ml of dichloromethane (dichloromethane), wash with saturated brine, collect the organic phase, dry over anhydrous sodium sulfate, filter, concentrate, dry 0.18 g of tert-butyl 4-(5-chloro-2-nitroanilino)piperidine-1-carboxylate (2) was obtained by separation and purification on a column using the method. Yellow solid, yield: 100%, melting point: 93-95°C.

[0070] Product spectral analysis data:

[0071] ESI-MS: m / z373.3(M+18),375.4(M+2+18),378.4(M+23).C 16 h 22 ClN 3 o 4 [355.13].;

Embodiment 2

[0072] Example 2: Intermediate tert-butyl 4-(5-(4-cyano-2,6-dimethylphenoxy)-2-nitroanilino)piperidine-1-carboxylate (3a) preparation of

[0073]0.1g (0.28mmol) tert-butyl 4-(5-chloro-2-nitroanilino)piperidine-1-carboxylate (2), 0.04g (0.27mmol) 4-cyano-3,5 -Dimethylphenol, 0.08g (0.58mmol) potassium carbonate, 0.02g (0.062mmol) tetrabutylammonium bromide, 0.01g (0.060mmol) potassium iodide dissolved in 5ml N,N-dimethylformamide, heated to 120 React at -130°C for 12 hours. Evaporate N,N-dimethylformamide under reduced pressure, dissolve the residue in 10ml of dichloromethane, wash with saturated brine, collect the organic phase, dry over anhydrous sodium sulfate, filter, concentrate, and apply to the column by dry method Separation and purification gave 0.11 g of tert-butyl 4-(5-(4-cyano-2,6-dimethylphenol)-2-nitroanilino)piperidine-1-carboxylate (3a). Yellow solid, yield: 84.62%, melting point: 125-127°C.

[0074] Product spectral analysis data:

[0075] ESI-MS: m / z467.5...

Embodiment 3

[0076] Example 3: Preparation of intermediate tert-butyl 4-(5-(2,4,6-trimethylphenoxy)-2-nitroanilino)piperidine-1-carboxylate (3b)

[0077] 0.05g (0.14mmol) tert-butyl 4-(5-chloro-2-nitroanilino) piperidine-1-carboxylate (2), 0.04g (0.29mmol) 2,4,6-trimethyl Base phenol, 0.08g (0.58mmol) potassium carbonate, 0.01g (0.03mmol) tetrabutylammonium bromide and 0.005g (0.03mmol) potassium iodide were dissolved in N,N-dimethylformamide and heated to 120-130 The reaction was stirred at ℃ for 6h. The reactant was poured into water, the aqueous solution was extracted with ethyl acetate, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, separated and purified by dry loading column to obtain 63.5 mg tert-butyl 4-(5-(2,4 ,6-trimethylphenoxy)-2-nitroanilino)piperidine-1-carboxylate (3b). Yellow solid, yield: 99.22%.

[0078] Product spectral analysis data:

[0079] ESI-MS: m / z 456.5(M+1), 473.3(M+18), 478.4(M+23).C25H33N3O5[455.24].

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Abstract

The invention relates to a 2-(N-alkyl piperidinol-4-amino)-4-(substituent phenol) benzene ring derivative and pharmaceutically acceptable salts thereof. The series of compounds have a general structure formula (I); the invention also relates to a pharmaceutical composition containing the compound with a structure shown in the formula (I), and pharmaceutical application thereof.

Description

technical field [0001] The present invention relates to a derivative and its preparation method and application, in particular to 2-(N-arylmethylpiperidine-4-amino)-4-(substituted phenol) benzene ring derivatives and its preparation method and application, belonging to Organic synthesis and medical application technology field. Background technique [0002] AIDS (AIDS) is one of the world's top ten fatal diseases caused by the human immunodeficiency virus (HIV), which seriously threatens human life and health. In the past two decades, although the number of HIV infections is still increasing sharply, with the clinical popularization of highly active antiretroviral therapy (HAART), the mortality rate caused by HIV infection has been effectively reduced. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have become an essential part of HAART therapy because of their high efficiency and low toxicity. However, since the amino acids at the binding sites of NNRTIs are pro...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/58C07D401/04A61K31/4468A61K31/4545A61P31/18
CPCC07D211/58C07D401/06
Inventor 刘新泳张凌子
Owner SHANDONG UNIV