Synthesis method of 2-halogen-5-iodobenzoic acid

A technology of iodobenzoic acid and synthesis method, which is applied in the direction of chemical instruments and methods, carboxylate preparation, organic compound preparation, etc., can solve the problems of excessive three wastes, low economic benefit, unfavorable industrialization, etc., and achieve the improvement of product quality, The effect of reducing environmental pollution and cleaning production

Active Publication Date: 2019-08-02
杭州科耀医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] After analyzing the above schemes, it is found that although NIS can obtain products by the above methods, the cost is high and the economic benefit is low, while the nitrification and diazotization reactions are hazardous reactions, which are not easy for industrial production, and the reaction steps are long
Although it is greener when using carbon dioxide, the reaction conditions are relatively harsh. It reacts with butyllithium at -70°C. Butyllithium is prone to exothermic reaction when it meets water and oxygen. High concentration (greater than 1.0M) butyllithium solution meets moisture Air is easy to burn quickly, and the solvent in the packaging container is generally a flammable and explosive liquid with a low boiling point. Once heated, it will easily cause explosion, and the product yield is low, which is not conducive to industrial production.
[0005] Related literature: In CA2735130A1, sodium periodate / potassium iodide / sulfuric acid is used for iodination, and a large amount of sulfuric acid is used in the reaction, resulting in more three wastes, and the yield is low, which is not conducive to industrialization

Method used

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  • Synthesis method of 2-halogen-5-iodobenzoic acid
  • Synthesis method of 2-halogen-5-iodobenzoic acid
  • Synthesis method of 2-halogen-5-iodobenzoic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Embodiment 1 (comparative example 1)

[0032] In a four-neck flask equipped with a thermometer and agitator, add 15.6g of o-chlorobenzoic acid and dissolve it in 320.0g of 90% sulfuric acid, then add 3.8g of sodium periodate and 13.0g of iodine into the reaction solution, start stirring, and control the reaction temperature 25 ~ 30 ℃, heat preservation reaction for 1 hour, the reaction solution turns black, after the reaction of the raw materials is completed, the reaction solution is poured into cold sodium thiosulfate aqueous solution to quench, the reaction solution is spin-dried, filtered, the purity of the crude product is 65%, a Content 18%, b content 10%. Recrystallized with 46.8ml of methanol to obtain 12.6g of crude product. Yield 45%. 98.2% purity.

[0033] When adopting Tetrahedron, 60 (2004), when the reaction condition of 9113-9119 was used o-chlorobenzoic acid, the reaction solution was black, the product quality was poor, and there were many impurities...

Embodiment 2

[0035] In a four-necked flask equipped with a thermometer and an agitator, add 15.6g of o-chlorobenzoic acid to dissolve in 78.0g of sulfuric acid and 62.4g of DCM, then add 3.8g of sodium periodate and 13.0g of iodine into the reaction solution, start stirring, and control The reaction temperature is 25-30°C, and the heat preservation reaction is carried out for 1 hour. A purple solid is precipitated in the reaction solution. After the reaction of the raw materials is completed, the product content in the reaction solution is 88%, and the content of 3-iodo-2-halo-benzoic acid (a) is 8%. 3, 5-diiodo-2-halo-benzoic acid (b) content 2%. Pour the reaction solution into cold sodium thiosulfate aqueous solution to quench, spin the reaction solution to dryness, filter, and recrystallize with 46.8ml of methanol to obtain 19.3g of 2-chloro-5-iodobenzoic acid. Yield 68.6%, purity 99.1%. 1 H NMR (CDCl 3 ,400MHz), δ: 11.26(s,1H); 8.32(d,1H); 7.77(dd,1H); 7.23(d,1H).

Embodiment 3

[0037] In a four-necked flask equipped with a thermometer and agitator, add 15.6g of o-chlorobenzoic acid and dissolve in 78.0g of sulfuric acid and 62.4g of DCM, then add 4.0g of potassium iodate and 13.0g of iodine into the reaction solution, start stirring, and control the reaction The temperature is 25-30°C, heat preservation reaction for 1 hour, a purple solid is precipitated in the reaction solution, after the reaction of the raw materials, the product content in the reaction is 89%, the content of 3-iodo-2-halo-benzoic acid (a) is 9%, and the content of 3,5- The content of diiodo-2-halo-benzoic acid (b) is 0.5%. Pour the reaction solution into cold sodium thiosulfate aqueous solution to quench, spin the reaction solution to dryness, filter, and recrystallize with 46.8ml of methanol to obtain 19.6g of 2-chloro-5-iodobenzoic acid. Yield 69.6%, purity 99.3%.

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Abstract

The invention discloses a synthesis method of 2-halogen-5-iodobenzoic acid. The synthesis method comprises steps as follows: o-halogen benzoic acids are subjected to one-step iodo treatment in an iodio reagent, and 2-halogen-5-iodobenzoic acid is obtained. Aftertreatment comprises steps as follows: a reaction liquid is poured into a cold reductive water solution and quenched, a solvent is evaporated to dryness, recrystallization and filtration are performed, and a product can be obtained. The method is short in reaction route, simple to operate, environmentally friendly, safer and more economical and has broad application prospects.

Description

technical field [0001] The invention relates to a preparation method of a chemical intermediate, in particular to a synthesis method of high-grade 2-halogen-5-iodobenzoic acid. Background technique [0002] 2-Halo-5-iodobenzoic acid is an aromatic functional monomer with two different halogens and one carboxyl group. It can use the activity difference of each group to react with different groups to synthesize compounds substituted by various functional groups. It is widely used in medical metal organic chemistry and so on. For example: 2-chloro-5-iodobenzoic acid is mainly used in the synthesis of the latest hypoglycemic drugs dapagliflozin (BMS-512148), sotagliflozin, Empagliflozin and Ertugliflozin. [0003] There are fewer reports about the preparation method of 2-halogen-5-iodobenzoic acid, and what is known and clearly reported is Journalof Medicinal Chemistry, 5(2006), 1506-1508. Taking o-fluorobenzoic acid as raw material, using NIS / Sulfuric acid is the iodide reag...

Claims

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Application Information

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IPC IPC(8): C07C51/363C07C63/70
CPCC07C51/363C07C63/70
Inventor 任川周军明
Owner 杭州科耀医药科技有限公司
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