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A kind of synthetic method of 2-substituted pyridine drug intermediate compound

A synthetic method and compound technology, which is applied in the synthesis of pharmaceutical intermediate compounds and the synthesis of 2-substituted pyridine drug intermediate compounds, which can solve the problem of unsatisfactory reaction yield and rare synthetic methods of 2-substituted pyridine compounds and other issues, to achieve the effect of good industrial application prospects and value

Inactive Publication Date: 2016-09-07
侯芳霖
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] As mentioned above, although a variety of preparation methods of such compounds, especially pyridines, have been reported in the prior art, there are few synthetic methods for 2-substituted pyridines, and the reaction yield is not ideal.

Method used

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  • A kind of synthetic method of 2-substituted pyridine drug intermediate compound
  • A kind of synthetic method of 2-substituted pyridine drug intermediate compound
  • A kind of synthetic method of 2-substituted pyridine drug intermediate compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Example 1: 2-(3,4-difluorophenyl)pyridine

[0046]

[0047] At room temperature, add 100mmol 3,4-difluorobenzoyl chloride, 100mmol n-butylamine, 5mmol copper(II) ethylacetoacetate, 5mmol ligand L1, 100mmol dimethylamino to an appropriate amount of n-propanol in the reactor Pyridine and 20 mmol of silver acetate were heated up to 60°C with stirring, and the reaction was continued with stirring at this temperature for 12 hours.

[0048] After the reaction, the reaction system was naturally cooled to room temperature, fully washed with deionized water, separated into layers, the upper organic phase was taken, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography. Deliquification is a mixture of n-butanol and ethyl acetate, the volume ratio of the two is 1:3,

[0049] The compound 2-(3,4-difluorophenyl)pyridine of formula (I) was obtained with a yield of 96.2%.

[0050] 1 H...

Embodiment 2

[0052] Example 2: 2-p-nitrophenylpyridine

[0053]

[0054] Add 100mmol p-nitrobenzoyl chloride, 150mmol n-butylamine, 10mmol copper(II) ethylacetoacetate, 8mmol ligand L1, 150mmol dimethylaminopyridine and 40mmol silver acetate to an appropriate amount of toluene in the reactor at room temperature , the temperature was raised to 80°C with stirring, and the stirring reaction was continued at this temperature for 10 hours.

[0055] After the reaction, the reaction system was naturally cooled to room temperature, fully washed with deionized water, separated into layers, the upper organic phase was taken, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography. Deliquoring is a mixture of n-butanol and ethyl acetate, the volume ratio of the two is 1:4, and the compound 2-p-nitrophenylpyridine of formula (I) is obtained with a yield of 95.8%.

[0056] 1 H-NMR (400MHz, CDCl 3 )δ:8.76...

Embodiment 3

[0058] Example 3: 2,2'-bipyridine

[0059]

[0060] At room temperature, add 100 mmol of pyridin-2-ylformyl chloride, 200 mmol of n-butylamine, 15 mmol of copper(II) ethylacetoacetate, 10 mmol of ligand L1, 200 mmol of dichloroethane to an appropriate amount of 1,2-dichloroethane in the reactor. Add aminopyridine and 60 mmol silver acetate, stir and heat up to 90° C., and keep stirring at this temperature for 8 hours.

[0061] After the reaction, the reaction system was naturally cooled to room temperature, fully washed with deionized water, separated into layers, the upper organic phase was taken, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography. The deliquored mixture is a mixture of n-butanol and ethyl acetate, the volume ratio of which is 1:5, and the compound 2,2'-bipyridine of formula (I) is obtained with a yield of 96.7%.

[0062] 1 H-NMR (400MHz, CDCl 3 )δ: 8.69 (...

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Abstract

The invention relates to a synthesis method of a 2-substituted pyridine-class drug intermediate compound shown in the formula (I) (please see the formula in the specification). The method includes the steps that when catalysts, ligand, alkali and additives exist, a compound with the formula (II) and a compound with the formula (III) react in an organic solvent so that the compound shown in the formula (I) (please see the formula in the specification) can be obtained, wherein R1, R2 and R3 are independently selected from H, halogen or C-C6 alkyl groups; the formula (please see the formula in the specification) is a C6-C10 aryl group which is not substituted or has 1-2 substitutent groups or is a C4-C10 heterocyclic radical which is not substituted or has 1-2 substitutent groups, and the substitutent grous are halogen, nitro or C1-C6 alkyl groups; Hal serves as the halogen. According to the method, the catalysts, the ligand, the alkali and the additives are properly selected and combined, and therefore a high yield is achieved, and the method has good industrial prospects and good application potentiality.

Description

technical field [0001] The invention relates to a method for synthesizing a drug intermediate compound, more specifically to a method for synthesizing a 2-substituted pyridine drug intermediate compound, and belongs to the technical field of organic synthesis and medicinal chemistry intermediates. Background technique [0002] In the field of organic chemistry, pyridine structural modules widely exist in synthetic drugs, natural products, and functional materials, especially in pharmaceutical compounds containing heterocyclic or fused rings. Therefore, the development of such compounds plays a very important role in the design and synthesis of drugs and their intermediates. [0003] The traditional synthetic method of pyridines mainly involves the condensation reaction of carbonyl compounds, but this method has some limitations, such as poor substrate expansion. In recent years, in order to improve the limitations of such methods, many researchers have developed a variety o...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/26C07D213/22C07D213/16
CPCC07D213/12C07D213/16C07D213/22C07D213/26
Inventor 侯芳霖李欣方云云张文理
Owner 侯芳霖
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