CN111153881A - Preparation method for synthesizing intermediate 3-methylflavone-8-carboxylic acid of flavoxate hydrochloride - Google Patents
Preparation method for synthesizing intermediate 3-methylflavone-8-carboxylic acid of flavoxate hydrochloride Download PDFInfo
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- CN111153881A CN111153881A CN202010029862.2A CN202010029862A CN111153881A CN 111153881 A CN111153881 A CN 111153881A CN 202010029862 A CN202010029862 A CN 202010029862A CN 111153881 A CN111153881 A CN 111153881A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
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Abstract
The invention provides a preparation method for synthesizing a flavoxate hydrochloride intermediate 3-methylflavone-8-carboxylic acid. The invention comprises the following steps: preparing 2-benzoyloxy-3-propionyl methyl benzoate and preparing 3-methylflavone-8-carboxylic acid. The invention has the advantages of high product yield, high purity, short process, low production risk and low production cost.
Description
Technical Field
The invention relates to a preparation method for synthesizing a flavoxate hydrochloride intermediate 3-methylflavone-8-carboxylic acid.
Background
The key intermediate 3-methylflavone-8-carboxylic acid (compound 2) for synthesizing flavoxate hydrochloride is prepared by reacting 2-hydroxy-3-propionyl methyl benzoate with excessive benzoyl chloride and sodium benzoate at 190 ℃, and the method has harsh conditions due to overhigh temperature and is not easy to industrialize; excessive benzoyl chloride and sodium benzoate are used, so that a large amount of raw materials are wasted, the reaction post-treatment is very difficult, the residue of benzoic acid in the intermediate 3-methylflavone-8-carboxylic acid cannot be avoided, and finally the standard exceeding of flavoxate hydrochloride impurities is caused.
Disclosure of Invention
Aiming at the defects existing in the problems, the invention provides the preparation method for synthesizing the intermediate 3-methylflavone-8-carboxylic acid of flavoxate hydrochloride, so that the product has high yield, high purity, short process, low production risk and low production cost.
In order to solve the above problems, the present invention provides a preparation method for synthesizing flavoxate hydrochloride intermediate 3-methylflavone-8-carboxylic acid, wherein the preparation method comprises the following steps:
s1, preparing 2-benzoyloxy-3-propionyl methyl benzoate;
s2 and preparing 3-methylflavone-8-carboxylic acid.
Preferably, in step S1, the method further includes the steps of:
s10, a, bromine and dichloromethane, at 0-15 ℃ for 4 hours;
s11, b is propionyl chloride, alchlor, 60-65 deg.C, 2.5 hours;
s12, c, hydrogen, palladium carbon and ethanol, and the reaction lasts for 1.5 hours at room temperature;
s13, d is benzoyl chloride, sodium hydroxide and dichloromethane at 0-25 deg.c for 2-3 hr.
Preferably, in step S2, the method further includes the steps of:
s20, mixing methyl 2-benzoyloxy-3-propionyl benzoate and dry alkaline alumina, starting stirring, raising the temperature in an oil bath, controlling the temperature to be 165-;
s21, starting vacuum to remove water, stirring and reacting for 4-5 hours, wherein the color of the reaction liquid gradually changes into dark yellow, and the reaction is finished;
s22, cooling to about 80 ℃, adding methanol and 40% sodium hydroxide solution, controlling the temperature to be 75-80 ℃, reacting for 1.5 hours, and cooling to 30 ℃ when the pH is about 11;
s23, filtering and recovering alumina, and drying for recycling;
s24, adjusting the pH value of the filtrate to 3 by hydrochloric acid, crystallizing for 2 hours, filtering, washing with water, drying to obtain a crude product of 3-methylflavone-8-carboxylic acid, recrystallizing by methanol, and then, carrying out mp235-236 ℃.
Compared with the prior art, the invention has the following advantages:
1. the invention avoids using excessive benzoyl chloride and sodium benzoate, has high atom utilization rate, saves raw materials, has simple treatment after the reaction is finished and has less three wastes; the product does not have residual benzoic acid, the purity of the product reaches 99.5 percent, and the quality standard of the flavoxate hydrochloride can be further improved.
2. The reaction temperature is reduced by 10-20 ℃, the conditions are relatively mild, and the industrial production is easy to realize.
3. The invention reduces the reaction steps, combines cyclization reaction and hydrolysis reaction, and greatly improves the reaction efficiency.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following examples, which are not intended to limit the present invention.
Example 1
Preparation of compound 1:
a: bromine and dichloromethane at 0-15 ℃ for 4 hours; b: propionyl chloride and aluminum trichloride at 60-65 ℃ for 2.5 hours; c: hydrogen, palladium on carbon, ethanol, room temperature, 1.5 hours. d: benzoyl chloride, sodium hydroxide and dichloromethane at 0-25 ℃ for 2-3 hours, extracting and layering, and recovering dichloromethane to obtain a compound 1.1H NMR(600MHz,CDCl3)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＝7.74 Hz),3.73(3H,s),2.89(2H,q,J＝6.96Hz),1.11(3H,t,J＝7.20Hz)；13C NMR(150 MHz,CDCl3)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+)。
Preparation of compound 2:
mixing 320 g of 2-benzoyloxy-3-propionyl methyl benzoate and 110 g of dry alkaline alumina, starting stirring, heating in an oil bath, controlling the temperature to be 165 ℃, starting vacuum to remove water, stirring and reacting for 4 hours, gradually changing the color of a reaction solution into dark yellow, finishing the reaction, cooling to about 80 ℃, adding 800ml of methanol and 115ml of 40% sodium hydroxide solution, controlling the temperature to be 75 ℃ and reacting for 1.5 hours, controlling the pH to be about 11, cooling to 30 ℃, filtering and recovering the alumina, and drying and recycling. Adjusting the pH value of the filtrate to 3 by hydrochloric acid, crystallizing for 2 hours, filtering, washing with water, and drying to obtain 245 g of crude 3-methylflavone-8-carboxylic acid with yield of 88%, and after methanol recrystallization, controlling the temperature to mp235-236 ℃.
Synthesizing a route type:
example 2
Preparation of compound 1:
a: bromine and dichloromethane at 0-15 ℃ for 4 hours; b: propionyl chloride and aluminum trichloride at 60-65 ℃ for 2.5 hours; c: hydrogen, palladium on carbon, ethanol, room temperature, 1.5 hours. d: benzoyl chloride, sodium hydroxide and dichloromethane at 0-25 ℃ for 2-3 hours.
Preparation of compound 2:
mixing 320 g of 2-benzoyloxy-3-propionyl methyl benzoate and 110 g of dry alkaline alumina, starting stirring, heating in an oil bath, controlling the temperature to be 175 ℃, starting vacuum to remove water, stirring and reacting for 4.5 hours, gradually changing the color of a reaction solution into dark yellow, finishing the reaction, cooling to about 80 ℃, adding 800ml of methanol and 115ml of 40% sodium hydroxide solution, controlling the temperature to be 78 ℃ and reacting for 1.5 hours, controlling the pH to be about 11, cooling to 30 ℃, filtering and recovering the alumina, and drying and recycling. Adjusting the pH value of the filtrate to 3 by hydrochloric acid, crystallizing for 2 hours, filtering, washing with water, and drying to obtain 220 g of crude 3-methylflavone-8-carboxylic acid with yield of 79 percent, and after methanol recrystallization, controlling the temperature to be mp235-236 ℃.
Synthesizing a route type:
example 3
Preparation of compound 1:
a: bromine and dichloromethane at 0-15 ℃ for 4 hours; b: propionyl chloride and aluminum trichloride at 60-65 ℃ for 2.5 hours; c: hydrogen, palladium on carbon, ethanol, room temperature, 1.5 hours. d: benzoyl chloride, sodium hydroxide and dichloromethane at 0-25 ℃ for 2-3 hours.
Preparation of compound 2:
mixing 320 g of 2-benzoyloxy-3-propionyl methyl benzoate and 60 g of dry alkaline alumina, starting stirring, heating in an oil bath, controlling the temperature to be 175 ℃, starting vacuum to remove water, stirring and reacting for 5 hours, gradually changing the color of a reaction solution into dark yellow, finishing the reaction, cooling to about 80 ℃, adding 800ml of methanol and 115ml of 40% sodium hydroxide solution, controlling the temperature to be 80 ℃ and reacting for 1.5 hours, controlling the pH to be about 11, cooling to 30 ℃, filtering and recovering the alumina, and drying and recycling. Adjusting the pH value of the filtrate to 3 by hydrochloric acid, crystallizing for 2 hours, filtering, washing with water, and drying to obtain 235 g of crude 3-methylflavone-8-carboxylic acid with yield of 84%, and after methanol recrystallization, controlling the temperature to be mp235-236 ℃.
Synthesizing a route type:
the previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (3)
1. A preparation method for synthesizing a flavoxate hydrochloride intermediate 3-methylflavone-8-carboxylic acid is characterized by comprising the following steps:
s1, preparing 2-benzoyloxy-3-propionyl methyl benzoate;
s2 and preparing 3-methylflavone-8-carboxylic acid.
2. The method of claim 1, wherein said step S1 further comprises the steps of:
s10, a, bromine and dichloromethane, at 0-15 ℃ for 4 hours;
s11, b is propionyl chloride, alchlor, 60-65 deg.C, 2.5 hours;
s12, c, hydrogen, palladium carbon and ethanol, and the reaction lasts for 1.5 hours at room temperature;
s13, d is benzoyl chloride, sodium hydroxide and dichloromethane at 0-25 deg.c for 2-3 hr.
3. The method of claim 1, wherein said step S2 further comprises the steps of:
s20, mixing methyl 2-benzoyloxy-3-propionyl benzoate and dry alkaline alumina, starting stirring, raising the temperature in an oil bath, controlling the temperature to be 165-;
s21, starting vacuum to remove water, stirring and reacting for 4-5 hours, wherein the color of the reaction liquid gradually changes into dark yellow, and the reaction is finished;
s22, cooling to about 80 ℃, adding methanol and 40% sodium hydroxide solution, controlling the temperature to be 75-80 ℃, reacting for 1.5 hours, and cooling to 30 ℃ when the pH is about 11;
s23, filtering and recovering alumina, and drying for recycling;
s24, adjusting the pH value of the filtrate to 3 by hydrochloric acid, crystallizing for 2 hours, filtering, washing with water, drying to obtain a crude product of 3-methylflavone-8-carboxylic acid, recrystallizing by methanol, and then, carrying out mp235-236 ℃.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114736183A (en) * | 2022-04-14 | 2022-07-12 | 迪嘉药业集团有限公司 | Preparation method of 3-methylflavone-8-carboxylic acid |
| CN115960065A (en) * | 2023-01-06 | 2023-04-14 | 山东鲁西药业有限公司 | Preparation method of flavoxate hydrochloride |
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| US4594345A (en) * | 1982-06-23 | 1986-06-10 | Nippon Shinyaku Co. Ltd. | Methylflavone-8-carboxylates |
| US4634768A (en) * | 1982-09-30 | 1987-01-06 | Yamamoto Chemical Industrial Co., Ltd. | Halo-containing 3-methylflavone-8-carboxylic acid derivatives |
| CN103408525A (en) * | 2013-08-13 | 2013-11-27 | 商洛学院 | Synthetic method and application of flavonoid |
| CN104031015A (en) * | 2014-06-10 | 2014-09-10 | 金坛德培化工有限公司 | Preparation method for 3-methyl flavone-8-carboxylic acid |
| CN105936635A (en) * | 2015-03-06 | 2016-09-14 | 南京圣和药业股份有限公司 | Compound as phosphatidylinositol 3-kinase delta inhibitor and application thereof |
| CN107118191A (en) * | 2017-06-29 | 2017-09-01 | 威海迪素制药有限公司 | Flavoxate hydrochloride is coupled the preparation method of impurity |
-
2020
- 2020-01-13 CN CN202010029862.2A patent/CN111153881A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4594345A (en) * | 1982-06-23 | 1986-06-10 | Nippon Shinyaku Co. Ltd. | Methylflavone-8-carboxylates |
| US4634768A (en) * | 1982-09-30 | 1987-01-06 | Yamamoto Chemical Industrial Co., Ltd. | Halo-containing 3-methylflavone-8-carboxylic acid derivatives |
| CN103408525A (en) * | 2013-08-13 | 2013-11-27 | 商洛学院 | Synthetic method and application of flavonoid |
| CN104031015A (en) * | 2014-06-10 | 2014-09-10 | 金坛德培化工有限公司 | Preparation method for 3-methyl flavone-8-carboxylic acid |
| CN105936635A (en) * | 2015-03-06 | 2016-09-14 | 南京圣和药业股份有限公司 | Compound as phosphatidylinositol 3-kinase delta inhibitor and application thereof |
| CN107118191A (en) * | 2017-06-29 | 2017-09-01 | 威海迪素制药有限公司 | Flavoxate hydrochloride is coupled the preparation method of impurity |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114736183A (en) * | 2022-04-14 | 2022-07-12 | 迪嘉药业集团有限公司 | Preparation method of 3-methylflavone-8-carboxylic acid |
| CN114736183B (en) * | 2022-04-14 | 2023-10-17 | 迪嘉药业集团股份有限公司 | Preparation method of 3-methyl flavone-8-carboxylic acid |
| CN115960065A (en) * | 2023-01-06 | 2023-04-14 | 山东鲁西药业有限公司 | Preparation method of flavoxate hydrochloride |
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Application publication date: 20200515 |