Preparation method of 3-methyl flavone-8-carboxylic acid

A technology of methyl flavonoid and carboxylic acid, applied in the field of pharmaceutical synthesis, can solve the problems of high toxicity, high risk, long synthesis route and the like, and achieves the effects of avoiding expensive price, reducing the generation of isomer impurities, and efficient synthesis process

Pending Publication Date: 2022-07-12
迪嘉药业集团股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] In the patent EP107804, methyl salicylate is used as the starting material, and after bromination reaction, the product is reacted with propionyl chloride and rearranged under the catalysis of aluminum trichloride, and then ring-closed under the catalysis of sodium benzoate, then undergoes hydrogenolysis, 3-Methylflavone-8 carboxylic acid is obtained by hydrolysis. The advantage of the route is that it avoids the formation of rearranged isomers. The disadvantage is that the synthesis route is long and bromine is used in the route, which has high toxicity and risk.

Method used

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  • Preparation method of 3-methyl flavone-8-carboxylic acid
  • Preparation method of 3-methyl flavone-8-carboxylic acid
  • Preparation method of 3-methyl flavone-8-carboxylic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] The first step, the preparation of methyl 3-propionyl salicylate

[0034] Add 30.4g (0.2mol) methyl salicylate and 200ml carbon disulfide to a 500ml four-necked flask, turn on stirring, slowly drop in 20.4g (0.24mol) of propionyl chloride after the solids are all dissolved, heat up to 40°C, and keep the reaction 4h, add 38.0g (0.2mol) of titanium tetrachloride and stir for 0.5h, evaporate the solvent under reduced pressure, heat up to 120 °C for 4h reaction, add ice water to quench the reaction, and distill the oily substance under reduced pressure to obtain 3-propionylsalicylic acid Methyl ester 33.6g, yield 81%.

[0035] The second step, the preparation of methyl 3-methylflavonoid-8-carboxylate

[0036] Add 33.0g (0.16mol) methyl 3-propionyl salicylate, 63.9g (0.45mol) benzoyl chloride in turn to the 1000ml reaction flask, turn on stirring, add 64.8g (0.45mol) sodium benzoate, heat up to 170°C The reaction was carried out for 4 hours. Using a solution with a volume...

Embodiment 2

[0040] The first step, the preparation of methyl 3-propionyl salicylate

[0041] Add 30.4g (0.2mol) methyl salicylate and 300ml dichloromethane to a 500ml four-necked flask, turn on stirring, slowly drop in 20.4g (0.24mol) of propionyl chloride after all the solids are dissolved, heat up to 40°C, Incubate the reaction for 4 h, add 38.0 g (0.2 mol) of titanium tetrachloride, stir for 0.5 h, evaporate the solvent under reduced pressure, heat up to 150 °C for 4 h, add ice water to quench the reaction, and distill the oil under reduced pressure to obtain 3-propionyl water 31.1 g of methyl succinate, yield 75%.

[0042] The second step, the preparation of methyl 3-methylflavonoid-8-carboxylate

[0043] Add 30.0g (0.15mol) methyl 3-propionyl salicylate, 59.9g (0.42mol) benzoyl chloride to the 1000ml reaction flask in turn, turn on stirring, add 60.8g (0.42mol) sodium benzoate, heat up to 180°C The reaction was carried out for 4 hours, and a solution with a volume ratio of dichloro...

Embodiment 3

[0047] The first step, the preparation of methyl 3-propionyl salicylate

[0048] Add 30.4g (0.2mol) methyl salicylate and 200ml tetrahydrofuran to a 500ml four-necked flask, turn on stirring, slowly drop in 20.4g (0.24mol) of propionyl chloride after all the solids are dissolved, heat up to 40°C, and heat the reaction 4h, add 26.6g (0.2mol) aluminum trichloride, stir for 0.5h, evaporate the solvent under reduced pressure, heat up to 180 °C for 4h, add ice water to quench the reaction, and distill the oily substance under reduced pressure to obtain 3-propionylsalicylic acid Methyl ester 26.9g, yield 65%.

[0049] The second step, the preparation of methyl 3-methylflavonoid-8-carboxylate

[0050] Add 30.0g (0.15mol) methyl 3-propionyl salicylate and 59.9g (0.42mol) benzoyl chloride to the 1000ml reaction flask in turn, turn on stirring, add 60.8g (0.42mol) sodium benzoate, heat up to 170°C The reaction was carried out for 4 hours, and a solution with a volume ratio of dichloro...

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Abstract

The invention discloses a preparation method of 3-methyl flavone-8-carboxylic acid, which comprises the following steps of: rearranging methyl salicylate serving as an initial raw material under the action of Lewis acid to generate propionyl methyl salicylate, and finally cyclizing and hydrolyzing to generate the 3-methyl flavone-8-carboxylic acid. According to the technology, methyl salicylate is adopted for acylation rearrangement reaction, generation of dimer impurities and isomer impurities in the rearrangement process is reduced, the purity is 99.9% or above, and the preparation method is short in technological process, small in production risk, low in technological cost and suitable for large-scale preparation of 3-methyl flavone-8 carboxylic acid.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, and in particular relates to a preparation method of a flavonoid ester intermediate 3-methylflavonoid-8-carboxylic acid. Background technique [0002] 3-Methylflavonoid-8-carboxylic acid is a key intermediate for the preparation of smooth muscle relaxant "flavonoid hydrochloride". [0003] The research on the synthesis of 3-methylflavonoid-8-carboxylic acid has been continuously improved and improved in the past ten years. The current main production methods are as follows: [0004] Patent US2921070 discloses that salicylic acid is used as the starting material, reacts with propionic anhydride to generate esterification, rearranges under the catalysis of aluminum trichloride, and finally closes the ring with benzoic anhydride to generate 3-methyl flavonoid 8-carboxylic acid , the main disadvantage of the route is that the salicylic acid itself forms a dimer, and the content of t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/30
CPCC07D311/30Y02P20/584
Inventor 葛执信王冠苗华明孙龙张寿吉
Owner 迪嘉药业集团股份有限公司
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