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Preparation method for N-tert-butyloxycarboryl-azetidine aromatic ether/aromatic heterocyclic ether compounds

A technology of azetidine aromatic ether and tert-butoxycarbonyl, which is applied in the field of organic synthesis, can solve problems such as harsh conditions and environmental pollution, and achieve the effects of mild reaction conditions, strong reaction specificity, and good substrate applicability

Active Publication Date: 2014-11-12
TYK MEDICINES ZHENGZHOU INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] However, the above three methods still have limitations in some aspects
For example, a nucleophilic substitution reaction usually requires a strong base, and only aryl halogens with electron-withdrawing groups are easy to participate in the reaction, while the Mitsunobu reaction will produce triphenylphosphine oxide, which will pollute the environment. The conditions required for the preparation of certain phenolic compounds relatively harsh

Method used

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  • Preparation method for N-tert-butyloxycarboryl-azetidine aromatic ether/aromatic heterocyclic ether compounds
  • Preparation method for N-tert-butyloxycarboryl-azetidine aromatic ether/aromatic heterocyclic ether compounds
  • Preparation method for N-tert-butyloxycarboryl-azetidine aromatic ether/aromatic heterocyclic ether compounds

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Embodiment 1

[0032]

[0033] The preparation of N-tert-butoxycarbonyl-azetidine phenyl ether comprises the following steps:

[0034] In a dry Schlenk tube, add magneton, 1-tert-butoxycarbonyl-3-iodoazetidine (141.6 mg, 0.5 mmol), phenylboronic acid (121.9 mg, 1.0 mmol), cuprous iodide (9.5 mg, 10mol%), TMEDA (5.8mg, 10mol%), tripotassium phosphate (212.3mg, 2mmol), N,N-dimethylformamide 2mL. Under the condition of oil bath, the reaction solution was heated to 120° C., and the reaction time was 24 hours. Stop the reaction, cool to room temperature, dilute the reaction solution with ethyl acetate, wash the organic phase twice with water, once with saturated brine, and wash with MgSO 4 Dry, filter, concentrate, and evacuate. The crude product was separated by column chromatography using ethyl acetate / petroleum ether=1:100-1:80 as a developing solvent to obtain 37 mg of the target product, with a yield of 30%. The NMR characterization of the compound is as follows 1 H NMR (400MHz, CDCl ...

Embodiment 2

[0036] The preparation of N-tert-butoxycarbonyl-azetidine phenyl ether comprises the following steps:

[0037]In a dry Schlenk tube, add magneton, 1-tert-butoxycarbonyl-3-iodoazetidine (141.6 mg, 0.5 mmol), phenylboronic acid (121.9 mg, 1.0 mmol), cuprous iodide (9.5 mg, 10mol%), TMEDA (5.8mg, 10mol%), potassium carbonate (138.2mg, 2mmol), N,N-dimethylformamide 2mL. Under the condition of oil bath, the reaction solution was heated to 120° C., and the reaction time was 24 hours. Stop the reaction, cool to room temperature, dilute the reaction solution with ethyl acetate, wash the organic phase twice with water, once with saturated brine, and wash with MgSO 4 Dry, filter, concentrate, and evacuate. The crude product was separated by column chromatography using ethyl acetate / petroleum ether=1:100-1:80 as a developing solvent to obtain 22 mg of the target product with a yield of 18%.

Embodiment 3

[0039] The preparation of N-tert-butoxycarbonyl-azetidine phenyl ether comprises the following steps:

[0040] In a dry Schlenk tube, add magneton, 1-tert-butoxycarbonyl-3-iodoazetidine (141.55 mg, 0.5 mmol), phenylboronic acid (121.9 mg, 1.0 mmol), cuprous iodide (9.5 mg, 10mol%), TMEDA (5.8mg, 10mol%), sodium hydroxide (40.0mg, 2mmol), N,N-dimethylformamide 2mL. Under the condition of oil bath, the reaction solution was heated to 120° C., and the reaction time was 24 hours. Stop the reaction, cool to room temperature, dilute the reaction solution with ethyl acetate, wash the organic phase twice with water, once with saturated brine, and wash with MgSO 4 Dry, filter, concentrate, and evacuate. The crude product was separated by column chromatography using ethyl acetate / petroleum ether=1:100-1:80 as a developing solvent to obtain 21mg of the target product with a yield of 17%.

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Abstract

The invention discloses a preparation method for N-tert-butyloxycarbonyl-azetidine aromatic ether / aromatic heterocyclic ether compounds, and belongs to the technical field of organic synthesis. The method is as follows: by taking 1-tert-butyloxycarboryl-3-iodoazetidine and arylboronic acid or nitrogen-containing heterocyclic boric acid as materials, producing the N-tert-butyloxycarboryl-azetidine aromatic ether / aromatic heterocyclic ether compound by virtue of copper-catalyzed carbon-oxygen cross-coupling reaction. The reaction conditions are gentle, the substrate applicability is good, the reaction specificity is strong, and a medium to high yield can be obtained. A catalyst system for the reaction has good stability, efficient catalytic activity and extensive applicability, and can effectively avoid damages of strong-basicity reaction conditions on a certain functional groups; moreover, the materials are cheap and easy to obtain, so that the cost is low.

Description

technical field [0001] The invention specifically relates to a preparation method of N-tert-butoxycarbonyl-azetidine aromatic ether / aromatic heterocyclic ether compounds, belonging to the technical field of organic synthesis. Background technique [0002] N-tert-butoxycarbonyl-azetidine aromatic ether / aromatic heterocyclic ether compound is an important class of pharmaceutical intermediates, especially playing a very important role in the treatment of obesity and metabolic syndrome. At present, there are mainly three methods to synthesize azetidine aromatic ether / aromatic heterocyclic ether compounds. [0003] (1) Nucleophilic substitution reaction between 3-hydroxyazetidine compounds and aryl halogens (the reaction equation is shown in Formula 1), see patents WO2008076562A1, WO2008089580A1, WO2009050522A1, WO2010043052A1 and WO2010059393A1. [0004] [0005] (2) Nucleophilic substitution reaction between 3-iodoazetidine compounds and phenolic compounds (the reaction equ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D205/04C07D401/12
CPCC07D205/04C07D401/12
Inventor 吴豫生吴养洁宋娟娟邹大鹏郭瑞云李敬亚
Owner TYK MEDICINES ZHENGZHOU INC
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