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Synthetic method of 2,6-dihalopyridine-3-carboxylic acid

A technology of dihalopyridine and a synthesis method, which is applied in the synthesis of 2,6-dihalopyridine-3-carboxylic acid and the synthesis of pyridine compounds, can solve the problems of low yield and the like, and achieves good operation reproducibility. Effect

Active Publication Date: 2019-03-19
CANGZHOU PURUI DONGFANG SCI & TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method avoids the problem of low yield when the traditional CO2 method is used to enlarge the scale, and the operation reproducibility between batches is good

Method used

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  • Synthetic method of 2,6-dihalopyridine-3-carboxylic acid
  • Synthetic method of 2,6-dihalopyridine-3-carboxylic acid

Examples

Experimental program
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Effect test

Embodiment 1

[0026] Under the protection of nitrogen, 2,6-difluoropyridine (11.5 g, 0.1 mol), Boc2O (26.0 g, 0.12 mol) and 130 mL of tetrahydrofuran were stirred until completely dissolved, and the ice-salt bath was lowered to -15 ° C, and the drop Add a pre-prepared 1M LDA tetrahydrofuran solution (0.13 mol), and control the temperature not to exceed -10°C during the entire dropwise addition. After the dropwise addition, keep stirring for 2-3 hours, then naturally rise to room temperature and stir to react overnight, and TLC detects that there is basically no remaining raw material.

[0027] Lower the reaction solution to 0°C again, add 15% aqueous hydrochloric acid dropwise to pH = 1-2 (note that the acidity adjustment should not be too strong, when the acidic hydrolysis is not controlled, a small amount of 2-hydroxy-6-fluoro-pyridine- 3-carboxylic acid). During the dropwise addition process, heat is obviously released, control the temperature not to exceed 30°C, raise the temperature t...

Embodiment 2

[0029] Under the protection of nitrogen, 2,6-dichloropyridine (14.8 g, 0.1 mol), Boc2O (26.0 g, 0.12 mol) and 130 mL of tetrahydrofuran were stirred until completely dissolved, and the ice-salt bath was lowered to -15 ° C, and the drop Add the isopropylmagnesium chloride-lithium chloride solution dropwise into the diisopropylamine tetrahydrofuran solution in advance, and prepare a 1M diisopropylamine magnesium chloride-lithium chloride tetrahydrofuran solution (0.15 moles). over -10°C. After the dropwise addition, keep stirring for 2-3 hours, then naturally rise to room temperature and stir to react overnight, and TLC detects that there is basically no remaining raw material.

[0030] The reaction solution was lowered to 0°C again, and 36% aqueous hydrochloric acid was added dropwise until pH=1. During the dropwise addition process, the heat is obviously exothermic, and the temperature should not exceed 30°C. After the dropwise addition, the temperature should be raised to 35...

Embodiment 3

[0032] Under the protection of nitrogen, stir 2,6-difluoropyridine (11.5 g, 0.1 mol) and 120 mL of tetrahydrofuran until completely dissolved, then cool down the dry ice / acetone system to -75°C, and start to add the pre-prepared 1M LDA tetrahydrofuran dropwise solution (0.12 moles), the temperature control during the whole dropping process should not exceed -60°C. After the dropwise addition, keep stirring for 1.5 hours, then dissolve the DBU-CO2 complex (0.11mol) in 65mL tetrahydrofuran solution, control the temperature not to exceed -60°C and drop into the reaction solution, keep stirring for 2 hours, and naturally rise to The reaction was stirred at room temperature overnight, and there was almost no remaining raw material as detected by TLC.

[0033] The reaction solution was lowered to 0°C again, and 15% hydrochloric acid aqueous solution was added dropwise to pH=3-5. During the dropwise addition process, the heat is obviously released, and the temperature is controlled ...

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Abstract

The invention discloses a synthetic method of 2,6-dihalopyridine-3-carboxylic acid and belongs to the field of medicine intermediate synthesis. The synthetic method comprises the following steps: dissolving 2,6-dihalopyridine and Boc2O in an organic solvent; dropwise adding LDA or i-Pr2NMgCl-LiCl to react at a low temperature; then adding an acid-water solution to raise the temperature to react; and adding alkali to adjust pH to obtain 2,6-dihalopyridine-3-carboxylic acid. In addition, by adding LDA into 2,6-dihalopyridine at an ultralow temperature to abstract protons, and then adding DBU-CO2to react and quenching the solution, the 2,6-dihalopyridine-3-carboxylic acid is obtained. The two methods solve the problem that the yield is low by adopting a conventional CO2 introducing method for scaled production and the inter-batch operating repeatability is good.

Description

technical field [0001] The invention relates to the synthesis of pyridine compounds, in particular to a synthesis method of 2,6-dihalopyridine-3-carboxylic acid, and belongs to the technical field of pharmaceutical intermediate synthesis. Background technique [0002] 2,6-Dihalopyridine-3-carboxylic acids, including 2,6-difluoropyridine-3-carboxylic acid, 2,6-dichloropyridine-3-carboxylic acid, 2,6-diiodopyridine-3- Carboxylic acids are all pharmaceutical and chemical intermediates, used as raw materials containing amides in pyridine drugs. Taking 2,6-difluoropyridine-3-carboxylic acid and 2,6-dichloropyridine-3-carboxylic acid as examples, the existing published literature is as follows: [0003] Eur. J. Org. Chem., 2004, 5, 1018 - 1024 reported the reaction of 2,6-difluoropyridine and LDA at ultra-low temperature, and reacted with carbon dioxide after lithiation to obtain 2,6-difluoropyridine after treatment -3-carboxylic acid, the reaction yield is 94%. US2009 / 318412, ...

Claims

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Application Information

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IPC IPC(8): C07D213/80C07D213/803
CPCC07D213/80C07D213/803
Inventor 张进王栋召李振宇张兴猛冷延国
Owner CANGZHOU PURUI DONGFANG SCI & TECH
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