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Synthesis of pyrazol [1,5-alpha] pyridine-3-carboxylic acid derivatives

A carboxylic acid derivative, 5-a technology, applied in the direction of organic chemistry, can solve the problems of low safety and limited scope of application, and achieve the effect of reducing production cost and saving synthesis time

Inactive Publication Date: 2019-01-18
CHONGQING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The purpose of the invention is to solve the problems of low safety and limited scope of application existing in the prior art of synthesizing pyrazol[1,5-a]pyridine-3-carboxylic acid derivatives

Method used

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  • Synthesis of pyrazol [1,5-alpha] pyridine-3-carboxylic acid derivatives
  • Synthesis of pyrazol [1,5-alpha] pyridine-3-carboxylic acid derivatives
  • Synthesis of pyrazol [1,5-alpha] pyridine-3-carboxylic acid derivatives

Examples

Experimental program
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Effect test

Embodiment 1

[0043] Example 1 Synthesis of 6-fluoropyrazol[1,5-a]pyridine-3'-carboxylic acid

[0044] The steps of the synthetic method include:

[0045] 1) Synthesis of Compound 3:

[0046] 1.1) 1.20 kg of trimethylsulfonyl chloride, 738.02 g of tert-butoxycarbonyl hydroxylamine were dissolved in 12.5 L of methyl tert-butyl ether, purified with nitrogen and cooled to ~0 °C;

[0047] 1.2) The mixture in step 1.1) was continuously stirred, and 772.27 mL of triethylamine was added dropwise, stirred and reacted for 2 hours, and the obtained reaction solution was filtered and washed with 4 L of methyl tert-butyl ether (MTBE);

[0048]1.3) The filtrate of step 1.2) was concentrated under vacuum at 20°C and 150mm Hg until about 1L of MTBE left;

[0049] 1.4) Add 6L of n-hexane to the concentrated solution of step 1.3) at normal temperature and pressure, stir for 5min and a white solid appears, and filter and wash with 2L of n-hexane to obtain compound 3 as a white solid, yield 1705.85g, 99.57%...

Embodiment 2

[0064] Example 2 Synthesis of pyrazo[1,5-a]pyridine-3-carboxylic acid

[0065] The steps of the synthetic method include:

[0066] 1) Synthesis of compound 3:

[0067] 1.1) 12kg of trimethylsulfonyl chloride, 7.38Kg of tert-butoxycarbonyl hydroxylamine were dissolved in 125L of methyl tert-butyl ether, purified with nitrogen and cooled to 0°C;

[0068] 1.2) The mixed solution of step 1.1) was continuously stirred and 7.723L of triethylamine was added dropwise, and the reaction was stirred for 2h, and the obtained reaction solution was filtered and washed with 40L of methyl tert-butyl ether (MTBE);

[0069] 1.3) The filtrate of step 1.2) was concentrated under vacuum at 20°C and 150mm Hg until about 10L of MTBE left;

[0070] 1.4) Add 60L of n-hexane to the concentrated solution of step 1.3) at normal temperature and pressure, stir for 5min and a white solid appears, and filter and wash with 20L of n-hexane to obtain compound 3 as a white solid with a yield of 17.0585Kg, 99.5...

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Abstract

The invention relates to synthesis of pyrazol [1,5-alpha] pyridine-3-carboxylic acid derivatives, and belongs to the field of organic synthesis. Trimethylsulfonyl chloride is used as a raw material toreact with tert-butoxycarbonyl hydroxylamine to obtain a compound 3; then the compound 3 reacts with trifluoroacetic acid to obtain a mixed solution of a compound 4; the mixed solution directly reacts with pyrazine to obtain a compound 6 without carrying out separation, washing and drying; an ethyl propiolate reaction is continuously performed; a water phase obtained after the reaction is extracted by ethyl acetate; an organic extract obtained after extraction is dried by anhydrous MgSO4 and evaporated; remaining residues are subjected to recrystallization (ethyl acetate, methylbenzene or petroleum ether), separation, washing and drying to obtain a compound 8; the compound 8 further reacts with NaOH to obtain a compound 9. In the route, the second step and the third step are continuouslycarried out, so that not only is the risk of the process reduced, but also yield is over 70%. No matter whether the raw material is of a symmetrical structure, the target product can be accurately obtained. The synthesis is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to the synthesis of pyrazol[1,5-a]pyridine-3-carboxylic acid derivatives. Background technique [0002] Pyrazolopyridine compounds are important intermediates of fused heterocyclic reactions. Pharmacological studies have shown that these compounds often have bactericidal, herbicidal, antifungal, anti-inflammatory, anti-allergic, anti-malarial, anti-anxiety, and anti-thrombotic properties. , Anti-hypotension, antibacterial, analgesic, anti-platelet activity and many other activities, it is a class of compounds with high research value. [0003] There are three main types of pyrazolopyridine compounds: pyrazolo[3,4-b]pyridine, pyrazolo[4,3-c]pyridine, and pyrazolo[1,5-a]pyridine. [1,5-a]pyridine compounds are the most researched and have good development prospects. [0004] At present, there are two main synthetic methods of pyrazol[1,5-a]pyridine compounds. One is to synthesize a p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 张莉梅刘殿卿董立春王引珍谭陆西
Owner CHONGQING UNIV