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Synthetic method for imidazole[1,2-a]pyridine and 2-butyl-5-chloro-1H-imidazole-4-carboxaldehyde compounds

A synthesis method, 2-a technology, applied in the field of synthesis of known drug molecules, can solve problems such as the difficulty in effectively synthesizing 4-formylimidazoles, and achieve the effects of mild conditions, simple catalytic system, and high tolerance

Inactive Publication Date: 2013-02-20
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, for 1,2-disubstituted imidazoles, the deprotonation reaction generally occurs only at the 5-position, and it is difficult to efficiently synthesize 4-formyl-substituted imidazoles

Method used

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  • Synthetic method for imidazole[1,2-a]pyridine and 2-butyl-5-chloro-1H-imidazole-4-carboxaldehyde compounds
  • Synthetic method for imidazole[1,2-a]pyridine and 2-butyl-5-chloro-1H-imidazole-4-carboxaldehyde compounds
  • Synthetic method for imidazole[1,2-a]pyridine and 2-butyl-5-chloro-1H-imidazole-4-carboxaldehyde compounds

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Experimental program
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Effect test

Embodiment 1

[0045] 1. Synthesis of imidazo[1,2-a]pyridine compounds

[0046] Raw materials can be synthesized in two ways:

[0047] The first way:

[0048] For simple N-allyl-2-aminopyridine, it can be prepared by reacting 2-aminopyridine with allyl bromide under basic conditions.

[0049]

[0050] The substituents on the pyridine ring are methyl and chlorine, using n-butyllithium or potassium tert-butoxide as the base and tetrahydrofuran as the solvent, a total of 6 raw materials are obtained with a yield between 24% and 77%.

[0051] The specific operation steps are as follows:

[0052] With n-butyllithium as base:

[0053] To a solution of 2-aminopyridine (3.0 mmol) in tetrahydrofuran (10 mL) was added dropwise n-butyllithium (1.8 mL, 2.5M in n-hexane, 1.5 equiv.) at -78°C. After the reaction was placed at -78°C for half an hour, allyl bromide solution (3.6 mmol, 1.2 equiv., diluted in 2 mL of THF) was slowly added dropwise to the reaction liquid. The reaction was kept at -78°C...

Embodiment 2

[0121] Embodiment 2: the synthetic method of necopiridan and saripiridan

[0122] The synthetic method of necopidem comprises the following steps:

[0123]

[0124] The first step, the synthesis of N-(1-(4-ethylphenyl)allyl)-5-methylpyridin-2-amine: 2-amino-5-methylpyridine (1.081g, 10.0 mmol), 4-ethylbenzaldehyde (1.610g, 12mmol, 1.2equiv), p-toluenesulfonic acid (30mg), Molecular sieves (10.0 g) were placed in dry tetrahydrofuran and refluxed for 18 hours. The reaction was cooled to -78°C, and then vinyl Grignard reagent (6 mL, 1.0M in THF, 2.0 equiv) was slowly added dropwise to the reaction system. The reaction was maintained at -78°C for 0.5 hours and then warmed to room temperature. Add saturated ammonium chloride (1 mL) and water to the reaction system successively, and extract with ethyl acetate (30 mL). The aqueous phase was further extracted with ethyl acetate once. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodiu...

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Abstract

The invention discloses a novel synthetic method for 3-formyl-imidazole[1,2-a]pyridine and 2-butyl-5-chloro-1H-imidazole-4-carboxaldehyde, and effective application of the method into synthesis of Necopidem and Saripidem. According to the invention, a 3-formyl-imidazole[1,2-a]pyridine system is established by using a cheap and low toxic Cu-catalyed O2 activated intramolecular olefin under dehydrogenation ammoxidation; conditions for the method are mild, reaction substrates are easily available, a catalytic system is simple, operation is simple, tolerance of functional groups is good, and the method is economical and effective and has very important scientific values and realistic significance.

Description

technical field [0001] The present invention relates to a new synthesis method of 3-formyl-imidazo[1,2-a]pyridine and imidazolaldehyde, and the application of the method to the synthesis of known drug molecules. Background technique [0002] Imidazol[1,2-a]pyridine is an important class of heterocyclic ring system, which widely exists in biologically active compounds. Drugs such as alpitant, necopidem, and saripidem all contain this structural unit. At present, there are not many synthetic methods for this heterocyclic system, especially for 3-alkylimidazol[1,2-a]pyridine. Moreover, most of the existing methods have shortcomings such as narrow scope of substrate application, long synthetic route of raw materials, low yield, and difficult derivatives of products. Therefore, the development of a simpler, more efficient and green method for the synthesis of multi-substituted imidazol[1,2-a]pyridine heterocycles is of great importance for the continued exploration of the possi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04C07D233/64
Inventor 朱强王洪根王勇梁冬冬刘兰英张健存
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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