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Method for converting halogenopyridinecarboxylic acid into cyanopyridinecarboxylic acid

A technology of halogenated pyridinecarboxylic acid and substituting pyridinecarboxylic acid, which is applied in the field of compound synthesis, can solve problems such as no reports in the literature, and achieve the effects of short process, simplified synthesis steps and broad application prospects

Active Publication Date: 2019-06-04
JINAN SHAOYUAN MEDICAL TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Another example: the synthesis of 5-cyano-6-chloronicotinic acid, which is not reported in the literature

Method used

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  • Method for converting halogenopyridinecarboxylic acid into cyanopyridinecarboxylic acid
  • Method for converting halogenopyridinecarboxylic acid into cyanopyridinecarboxylic acid
  • Method for converting halogenopyridinecarboxylic acid into cyanopyridinecarboxylic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] In this example, 5-cyano-6-hydroxynicotinic acid is synthesized from 5-iodo-6-hydroxynicotinic acid, and the reaction formula is as follows:

[0033]

[0034] Add 50.0g of 5-iodo-6-hydroxynicotinic acid (0.19mol, 1.0eq) and 25g of CuCN (0.28mol, 1.5eq) into 300mL of DMF, heat to an external temperature of 125°C under the protection of nitrogen, keep it for about 5 hours, and the raw materials disappear , stop heating. Remove DMF by rotary steaming, stop the rotary steaming until the viscous porridge in the system does not flow, pour about 500mL MeOH into the bottle, stir well, stir in a low-temperature ice-water bath for about 1 hour, filter, and rinse the filter cake with acetone and PE. The crude product 1B was obtained after drying, and 1B was recrystallized from methanol to obtain 29.1 g of off-white solid 5-cyano-6-hydroxynicotinic acid, with a yield of 93.3%. [M-1] - =163.0, 1 H NMR (400MHz, DMSO) δ 13.16 (brs, 1H), 8.43 (d, J=2.2Hz, 1H), 8.29 (d, J=2.2Hz, 1...

Embodiment 2

[0036] In this example, 5-cyano-6-hydroxynicotinic acid is synthesized from 5-bromo-6-hydroxynicotinic acid, and the reaction formula is as follows:

[0037]

[0038] Take 5.0g of 5-bromo-6-hydroxynicotinic acid (22.9mmol, 1.0eq) and 4.14g of CuCN (45.9mmol, 2.0eq) into a single-necked bottle containing 40mL of NMP, heat to 155°C under nitrogen protection, and keep warm for 5h , click the plate, the raw material disappears, stop heating. Most of the NMP was removed by rotary evaporation, poured into water, extracted three times with 200 mL of EA, and the organic phase was washed twice with 50 mL of water and 20 mL of saturated sodium chloride respectively. The organic phase was dried and spin-dried to obtain crude product 1B, which was recrystallized from methanol to obtain 3.4 g of off-white solid, yield: 90.5%. [M-1] - =163.0, 1 H NMR (400MHz, DMSO) δ13.16 (br s, 1H), 8.43 (d, J=2.2Hz, 1H), 8.29 (d, J=2.2Hz, 1H).

Embodiment 3

[0040] In this example, 5-cyano-6-hydroxynicotinic acid is synthesized from 5-chloro-6-hydroxynicotinic acid, and the reaction formula is as follows:

[0041]

[0042] Take 4.0g of 5-chloro-6-hydroxynicotinic acid (22.9mmol, 1.0eq) and 5.38g of zinc cyanide (45.9mmol, 2.0eq) into a single-necked bottle containing 40mL of NMP, and heat to 180°C under nitrogen protection. Keep warm for 20 hours, touch the plate, the raw material disappears, stop heating. Most of the NMP was removed by rotary evaporation, poured into water, extracted three times with 200 mL of EA, and the organic phase was washed twice with 50 mL of water and 20 mL of saturated sodium chloride respectively. The organic phase was dried and spin-dried to obtain crude product 1B, which was recrystallized from methanol to obtain 3.1 g of off-white solid, yield: 82.5%. [M-1] - =163.0, 1 H NMR (400MHz, DMSO) δ13.16 (br s, 1H), 8.43 (d, J=2.2Hz, 1H), 8.29 (d, J=2.2Hz, 1H).

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PUM

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Abstract

The invention provides a method for converting halogenopyridinecarboxylic acid into cyanopyridinecarboxylic acid. The method is characterized in that the halogenopyridinecarboxylic acid reacts with acyanidation reagent to form the cyanopyridinecarboxylic acid. The preparation method makes the halogenopyridinecarboxylic acid directly converted into the cyanopyridinecarboxylic acid in one step, sothe method has the advantages of omission of esterification and hydrolysis steps, simplification of synthesis steps, shortening of the reaction process, manpower saving, productivity increase, reduction of three wastes, suitableness for industrial production, and broad application prospect.

Description

technical field [0001] The invention belongs to the technical field of compound synthesis, and relates to a method for converting halogenated pyridine carboxylic acid into cyano-substituted pyridine carboxylic acid. Background technique [0002] The method for the synthesis of cyano-substituted pyridinecarboxylic acids from halogenated pyridinecarboxylic acids reported in the literature is generally: first esterification converts halogenated pyridinecarboxylic acids into halogenated pyridinecarboxylic acid esters, and then halogenated pyridinecarboxylic acid esters and A cyaniding agent (such as cuprous cyanide, etc.) converts a halogen atom into a cyano group to obtain a cyano-substituted pyridine carboxylate, and finally hydrolyzes the cyano-substituted pyridine carboxylate to obtain a cyano-substituted pyridine carboxylic acid. For example: the preparation route of 5-cyanonicotinic acid disclosed in EP2533783B1 is as follows: [0003] [0004] Another example: the syn...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/85C07D213/84
Inventor 王海波泮廷廷郑燕
Owner JINAN SHAOYUAN MEDICAL TECH
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