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Preparation method for synthesizing flavoxate hydrochloride intermediate (3-methylflavone-8-carboxylic acid)

A technology of flavoxate hydrochloride and methylflavone, which is applied in the field of preparation of flavoxate hydrochloride intermediate 3-methylflavone-8-carboxylic acid, can solve the problems of difficult industrialization, waste of raw material processing, high conditions, etc. , to achieve the effect of reducing reaction steps, less waste, and improving reaction efficiency

Inactive Publication Date: 2020-05-15
CHEDOM PHARMA
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Problems solved by technology

[0002] The key intermediate 3-methylflavone-8-carboxylic acid (compound 2) for the synthesis of flavoxate hydrochloride is reacted with 2-hydroxy-3-propionylbenzoic acid methyl ester and excess benzoyl chloride and sodium benzoate at a high temperature of 190°C , the method temperature is too high and the conditions are harsh, so it is not easy for industrialization; using excessive benzoyl chloride and sodium benzoate not only wastes a large amount of raw materials but also makes post-reaction treatment very difficult, and cannot avoid the intermediate 3-methylflavone-8-carboxylic acid Residues of benzoic acid eventually lead to excessive flavoxate hydrochloride impurities

Method used

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  • Preparation method for synthesizing flavoxate hydrochloride intermediate (3-methylflavone-8-carboxylic acid)
  • Preparation method for synthesizing flavoxate hydrochloride intermediate (3-methylflavone-8-carboxylic acid)
  • Preparation method for synthesizing flavoxate hydrochloride intermediate (3-methylflavone-8-carboxylic acid)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Preparation of compound 1:

[0025] a: bromine, dichloromethane, 0-15°C, 4 hours; b: propionyl chloride, aluminum trichloride, 60-65°C, 2.5 hours; c: hydrogen, palladium carbon, ethanol, room temperature, 1.5 hours. d: Benzoyl chloride, sodium hydroxide, dichloromethane, 0-25°C, 2-3 hours, extraction and separation, recovery of dichloromethane to give compound 1. 1 H NMR (600MHz, CDCl 3 )δ8.21 (2H, d, J = 7.32Hz), 8.18 (1H, d, J = 6.72Hz), 7.92 (1H, d, J = 7.74Hz), 7.65 (1H, t, J = 7.50Hz) ,7.53(2H,t,J=7.62Hz),7.42(1H,t,J=7.74Hz),3.73(3H,s),2.89(2H,q,J=6.96Hz),1.11(3H,t, J=7.20Hz); 13 C NMR (150 MHz, CDCl 3 )δ200.90,165.14,164.65,148.77,134.89,134.03,133.82,133.62,130.35, 129.18,128.75,126.03,124.79,52.44,35.72,8.22; MS m / z313.09(M+H + ).

[0026] Preparation of Compound 2:

[0027] Mix 320 grams of 2-benzoyloxy-3-propionylbenzoic acid methyl ester with 110 grams of dry basic alumina, start stirring, heat up the oil bath, control the temperature to 165°C, and tur...

Embodiment 2

[0031] Preparation of compound 1:

[0032] a: bromine, dichloromethane, 0-15°C, 4 hours; b: propionyl chloride, aluminum trichloride, 60-65°C, 2.5 hours; c: hydrogen, palladium carbon, ethanol, room temperature, 1.5 hours. d: Benzoyl chloride, sodium hydroxide, dichloromethane, 0-25°C, 2-3 hours.

[0033] Preparation of compound 2:

[0034] Mix 320 grams of 2-benzoyloxy-3-propionylbenzoic acid methyl ester with 110 grams of dry basic alumina, start stirring, heat up the oil bath, control the temperature to 175°C, and turn on the vacuum to remove water, and stir the reaction After 4.5 hours, the color of the reaction solution gradually changed to dark yellow, and the reaction was completed. Cool down to about 80°C, add 800ml of methanol, 115ml of 40% sodium hydroxide solution, control the reaction at 78°C for 1.5 hours, pH=11, cool down to 30°C, and filter Alumina is recovered and recycled after drying. The filtrate was adjusted to pH=3 with hydrochloric acid, crystallized f...

Embodiment 3

[0038] Preparation of Compound 1:

[0039] a: bromine, dichloromethane, 0-15°C, 4 hours; b: propionyl chloride, aluminum trichloride, 60-65°C, 2.5 hours; c: hydrogen, palladium carbon, ethanol, room temperature, 1.5 hours. d: Benzoyl chloride, sodium hydroxide, dichloromethane, 0-25°C, 2-3 hours.

[0040] Preparation of Compound 2:

[0041] Mix 320 grams of methyl 2-benzoyloxy-3-propionylbenzoate with 60 grams of dry basic alumina, start stirring, heat up the oil bath, control the temperature to 175°C, and turn on the vacuum to remove moisture, and stir the reaction After 5 hours, the color of the reaction solution gradually changed to dark yellow, and the reaction was completed. Cool down to about 80°C, add 800ml of methanol, 115ml of 40% sodium hydroxide solution, control the reaction at 80°C for 1.5 hours, pH = about 11, cool down to 30°C, and filter Alumina is recovered and recycled after drying. The filtrate was adjusted to pH=3 with hydrochloric acid, crystallized for...

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Abstract

The invention provides a preparation method for synthesizing a flavoxate hydrochloride intermediate (3-methyl flavone-8-carboxylic acid). The preparation method comprises the following steps: preparing 2-benzoyloxy-3-methyl propionyl benzoate, and preparing 3-methyl flavone-8-carboxylic acid. The method has the advantages of high product yield, high purity, short technological process, low production risk and low production cost.

Description

technical field [0001] The invention relates to a preparation method for synthesizing flavoxate hydrochloride intermediate 3-methylflavone-8-carboxylic acid. Background technique [0002] The key intermediate 3-methylflavone-8-carboxylic acid (compound 2) for the synthesis of flavoxate hydrochloride is reacted with 2-hydroxy-3-propionylbenzoic acid methyl ester and excess benzoyl chloride and sodium benzoate at a high temperature of 190°C , the method temperature is too high and the conditions are harsh, so it is not easy for industrialization; using excessive benzoyl chloride and sodium benzoate not only wastes a large amount of raw materials but also makes post-reaction treatment very difficult, and cannot avoid the intermediate 3-methylflavone-8-carboxylic acid The residue of benzoic acid eventually causes the flavoxate hydrochloride impurity to exceed the standard. Contents of the invention [0003] In view of the deficiencies in the above-mentioned problems, the inve...

Claims

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Application Information

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IPC IPC(8): C07D311/30
CPCC07D311/30
Inventor 李英铁林桂清张春青戈彬
Owner CHEDOM PHARMA
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