CN114276321A

CN114276321A - Method for preparing 7, 8-dihydroxyflavone

Info

Publication number: CN114276321A
Application number: CN202111577334.1A
Authority: CN
Inventors: 张明亮; 帅红梅
Original assignee: Jinan Mingwei Pharmaceutical Technology Co ltd
Current assignee: Jinan Mingwei Pharmaceutical Technology Co ltd
Priority date: 2021-12-21
Filing date: 2021-12-21
Publication date: 2022-04-05

Abstract

A method for preparing 7, 8-dihydroxyflavone relates to the preparation technology of (3-pentylphenyl) acetic acid, take pyrogallol as raw materials, carry on the friedel-crafts reaction with acetyl chloride and prepare 2, 3, 4-trihydroxy acetophenone, utilize benzyl chloride to selectively protect 3-position and 4-position hydroxy group, unprotected 2-position hydroxy group and benzoyl chloride carry on esterification reaction, esterification product get 8-dihydroxyflavone through Baker-Venkataraman rearrangement, ring closure and debenzylation.

Description

Method for preparing 7, 8-dihydroxyflavone

Technical Field

The invention belongs to the field of medicine and health care, and particularly relates to a natural product 7, 8-dihydroxyflavone and a preparation method thereof.

Background

Flavone is an important natural product, and is widely present in various plants such as vegetables, fruits and the like. Researches show that the flavonoid compounds show a plurality of biological activities, such as whitening, antioxidation, antivirus, antitumor, antiphlogosis, neuron protection, cardiovascular protection and the like. Flavone is an important lead compound because of having various pharmacological activities, provides valuable design basis for researchers to develop therapeutic drugs for various diseases, and many natural flavonoid products are already used as therapeutic drugs in clinic, such as ginkgetin, hawthorn flavone, puerarin, quercetin and the like.

7, 8-dihydroxy flavone is an important member of flavone family, and because it has the action of brain-derived neurotrophic factor and is also TrkB receptor agonist, 7, 8-dihydroxy flavone has very good pharmacological activity in the aspects of protecting cranial nerve, improving memory capacity and improving Alzheimer's disease, Huntington's chorea, Parkinson's disease, Rett syndrome and the like. Therefore, the development of the production process of the 7, 8-dihydroxyflavone is of great significance.

Disclosure of Invention

The technical problem to be solved by the invention is as follows: the method comprises the steps of taking pyrogallol as a raw material, carrying out friedel-crafts reaction with acetyl chloride to prepare 2, 34-trihydroxyacetophenone, selectively protecting 3-position hydroxyl and 4-position hydroxyl by using a benzyl protective reagent, carrying out esterification reaction on unprotected 2-position hydroxyl and benzoyl chloride, and carrying out Baker-Venkataraman rearrangement, ring closure and debenzylation on an esterification product to obtain 8-dihydroxyflavone. The process route provides a reliable solution for the large-scale production of the 7, 8-dihydroxyflavone.

In order to realize the process, the invention provides the following specific technical scheme:

wherein, X ═ chlorine, bromine, iodine, trifluoromethanesulfonyloxy, methanesulfonyloxy, benzenesulfonate group, p-toluenesulfonate group;

1. in the preparation process of the compound 1, as pyrogallol has poor solubility in organic solvents such as dichloromethane, carbon disulfide, chlorobenzene, nitrobenzene, 1, 4-dioxane and the like, acetic acid which has high solubility to the pyrogallol and does not interfere with the reaction is selected as a solvent, so that the reaction liquid is always homogeneous in the reaction process.

Acetyl chloride or acetic anhydride is used as an acetylation reagent, anhydrous aluminum trichloride, anhydrous stannic chloride, anhydrous zinc chloride, anhydrous ferric chloride, sulfuric acid, hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and benzenesulfonic acid are used as catalysts, wherein when protonic acid is used as a catalyst, the compound 1 is difficult to separate and purify, and when Lewis acid is used as a catalyst, the compound 1 is easy to separate out from a reaction system, so that the purification of the compound 1 is facilitated.

When anhydrous aluminium trichloride is used as the catalyst, the activity is strong, the reaction temperature is controlled below-20 ℃, so that a good reaction result can be obtained, and the reaction temperature can be carried out at normal temperature by using the catalyst with weak catalytic activity, such as anhydrous stannic chloride.

2. In the preparation process of the compound 2, the 3-position phenolic hydroxyl group and the 4-position phenolic hydroxyl group can be selectively protected by using a steric hindrance effect, for the process, acetone is used as a solvent, anhydrous potassium carbonate is used as an acid-binding agent, and after the reaction is finished, a reaction solution is poured into water to obtain the compound 2. When a solvent such as N, N-dimethylformamide or acetonitrile is used, the product becomes complicated and it is difficult to isolate and purify compound 2.

3. In the preparation process of the compound 3, pyridine is generally used as a solvent, benzoyl chloride is dropwise added into a pyridine solution of the compound 2 at a low temperature, and after the reaction is finished, the reaction solution is poured into low-temperature acidic water, so that the compound 3 is precipitated.

4. Under the condition of strong alkalinity, the compound 3 is rearranged by Baker-Venkataraman to generate a compound 4, the common strong base comprises sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium hydrogen, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and the like, the reaction solvent is usually an aprotic polar solvent such as pyridine, N-dimethylformamide, N-dimethylacetamide, acetonitrile, N-methylpyrrolidone and the like, and a potassium hydroxide/pyridine system is preferred, and the compound 3 can be converted into the compound 4 in high yield under the system, wherein the pyridine must ensure the absence of water, otherwise, the rearrangement yield is influenced. The compound 3 is reacted in a potassium hydroxide/pyridine system, and the reaction liquid becomes very viscous along with the reaction and is not beneficial to stirring, so that mechanical stirring is selected to be more suitable.

5. In the preparation process of the compound 5, acetic acid is generally used as a reaction solvent, protonic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, perchloric acid and the like are used as catalysts to catalyze the ring closure of the compound 4, and the ring closure reaction yield is generally more than 80%.

6. The debenzylation process of the compound 5 is usually performed by using palladium-carbon hydrogenation debenzylation, the hydrogenation pressure is 3-5MPa, and the reaction temperature is about 60 ℃. The solubility of the compound 5 in methanol or ethanol is poor, so that ethyl acetate/ethanol or ethyl acetate/ethanol mixed solvent is selected as a reaction solvent, and the whole reaction process is homogeneous.

The invention provides a specific preparation method of a compound 1, a compound 2, a compound 3, a compound 4, a compound 5 and 7, 8-dihydroxyflavone, which comprises the following steps:

detailed description of the preferred embodiments

Example 1: preparation of Compound 1

Acetic acid (1000mL) and pyrogallol (200g, 1.59mol) were added to a reaction flask, stirred, added with anhydrous tin chloride (98.26g, 0.48mol), slowly added dropwise with acetyl chloride (136.94g, 1.74mol), the temperature was controlled to 35 ℃ or lower, and after completion of the addition, the reaction was stirred for further 12 hours. The reaction solution was cooled to 0 ℃, ice water (1000mL) was added dropwise at a temperature below 10 ℃, after the addition was completed, the mixture was stirred at 0 ℃ for 1 hour with heat preservation, filtered, the filter cake was washed with ice water (500mL), and the filter cake was dried at 50 ℃ under reduced pressure to obtain 173.45g of compound 1 as a dark yellow solid.

Example 2: preparation of Compound 2

Adding acetone (750mL) and benzyl bromide (305.08g, 1.78mol) into a reaction bottle, stirring, adding compound 1(150g, 0.89mol), potassium iodide (7.40g, 0.045mol) and anhydrous potassium carbonate (369.88g, 2.68mol), refluxing for 10 hours, cooling to normal temperature, filtering, washing with acetone (200mL), concentrating under reduced pressure to obtain a crude product, adding the crude product into ethanol (1200mL), heating to reflux for dissolving, continuing stirring for 10 minutes, cooling to 0-5 ℃ with cold water, stirring for crystallizing for 2 hours, filtering, washing a filter cake with ethanol, and drying the filter cake under reduced pressure at 40 ℃ to obtain 238.62g of compound 2, namely a white-like solid.

Example 3: preparation of Compound 2

Adding acetone (500mL) and benzyl chloride (150.56g, 1.19mol) into a reaction bottle, stirring, adding compound 1(100g, 0.59mol), potassium iodide (9.87g, 0.059mol) and anhydrous potassium carbonate (246.58g, 1.78mol), refluxing for reaction for 24 hours, cooling to normal temperature, filtering, washing with acetone (150mL), concentrating under reduced pressure to obtain a crude product, adding the crude product into ethanol (900mL), heating to reflux for dissolving, continuing stirring for 10 minutes, cooling to 0-5 ℃ with cold water, stirring for crystallization for 2 hours, filtering, washing a filter cake with ethanol, and drying the filter cake under reduced pressure at 40 ℃ to obtain 187.74g of compound 2, namely a white-like solid.

Example 4: preparation of Compound 3

Adding pyridine (800mL) into a reaction bottle, stirring, adding a compound 2(200g, 0.57mol), cooling to 0 ℃, slowly dropwise adding benzoyl chloride (88.76g, 0.63mol), controlling the temperature to be below 10 ℃, continuing stirring for 30 minutes after dropwise adding, slowly pouring the reaction liquid into 2mol/L diluted hydrochloric acid (700mL), stirring for 30 minutes, filtering, washing a filter cake with water, and drying the filter cake at 50 ℃ under reduced pressure to obtain 259.76g of a compound 3 white-like solid.

Example 5: preparation of Compound 4

Adding pyridine (1000mL) into a reaction bottle, stirring, adding 85% potassium hydroxide (72.94g, 1.10mol), adding compound 4(250g, 0.55mol), heating to 100 ℃, keeping the temperature for reaction for 2 hours, detecting and controlling by TLC to show that the raw materials disappear, cooling to normal temperature, slowly pouring the reaction liquid into 1mol/L diluted hydrochloric acid (1000mL), quickly stirring, filtering, washing a filter cake with water, and drying the filter cake under reduced pressure at 50 ℃ to obtain 204.34g of compound 4, namely an off-white solid.

Example 6: preparation of Compound 5

Adding acetic acid (1200mL) into a reaction bottle, stirring, adding sulfuric acid (25.99g, 0.265mol), adding compound 4(200g, 0.44mol), heating to 80-90 ℃, keeping the temperature for reaction for 5 hours, cooling to normal temperature, slowly adding cold water, continuing stirring for 2 hours, filtering, and drying a filter cake at 50 ℃ under reduced pressure to obtain 185.54g of compound 5, namely a yellowish solid.

Example 7: preparation of Compound 5

Adding acetic acid (100mL) into a reaction bottle, stirring, adding trifluoroacetic acid (2.52g, 0.022mol), adding compound 4(10g, 0.022mol), heating to 80-90 ℃, keeping the temperature for reaction for 5 hours, cooling to normal temperature, slowly adding cold water, continuing stirring for 2 hours, filtering, and drying a filter cake at 50 ℃ under reduced pressure to obtain 6.54g of compound 5 which is a yellowish solid.

Example 8: preparation of 7, 8-dihydroxyflavone

Adding ethyl acetate (500mL) and ethanol (1000mL) into a hydrogenation kettle, stirring, adding a compound 5(150g, 0.345mol) and 10% palladium-charcoal (20g), replacing hydrogen, increasing the pressure of the hydrogen to 5MPa, increasing the reaction temperature to 60 ℃, reacting for 9 hours, filtering, and concentrating under reduced pressure to obtain a yellow-green solid crude product, and recrystallizing the crude product with an ethanol aqueous solution to obtain 83.38g of 7, 8-dihydroxyflavone.

Claims

1. A method for preparing 7, 8-dihydroxyflavone is characterized in that pyrogallol reacts with an acetylation reagent to generate a compound 1, the compound 1 reacts with a benzyl protection reagent to generate a compound 2, the compound 2 reacts with benzoyl chloride to generate a compound 3, the compound 3 undergoes Baker-Venkataraman rearrangement to generate a compound 4, the compound 4 undergoes ring closure under an acidic condition to generate a compound 5, and the compound 5 undergoes debenzylation to obtain the 7, 8-dihydroxyflavone.

。

2. The process of claim 1, wherein X is chloro, bromo, iodo, trifluoromethanesulfonyloxy, methylsulfonyloxy, benzenesulfonate, p-toluenesulfonate; x is chloro, bromo, iodo, acetoxy.

3. Process conditions according to claims 1-2 for the reaction of pyrogallol with an acetylating agent, characterized in that the catalyst used is anhydrous aluminum trichloride, anhydrous ferric bromide, anhydrous ferric chloride, anhydrous ferrous chloride, anhydrous stannic chloride, anhydrous zinc chloride, boron trifluoride, boron trichloride, anhydrous titanium tetrachloride, preferably anhydrous stannic chloride.

4. Process conditions according to claims 1-3, compound 2 being condensed with a benzylating agent, characterised in that the base used is lithium hydroxide, sodium hydroxide, potassium hydroxide, caesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, caesium carbonate, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, caesium phosphate, lithium phosphate, sodium phosphate, potassium phosphate, caesium phosphate, lithium acetate, sodium acetate, potassium acetate, caesium acetate, sodium ethoxide, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, ammonia, aqueous ammonia, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, pyridine, picoline, lutidine, collidine, N-dimethylaminophenyl, 1, 8-diazabicycloundecen-7-ene, preferably potassium carbonate.

5. Process conditions according to claims 1-4, compound 2 being condensed with a benzylating agent, characterised in that the solvent used is water, methanol, ethanol, propanol, butanol, acetonitrile, propionitrile, butyronitrile, acetone, butanone, pentanone, ethyl acetate, propyl acetate, phase butyl acetate, methyl tert-butyl ether, phenylmethyl ether, tetrahydrofuran, 1, 4-dioxane, water, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, toluene, xylene, trimethylbenzene, dimethyl sulphoxide, sulfolane or a mixture thereof, preferably acetone.

6. The process conditions of claims 1-5, esterification of compound 2 with benzoyl chloride, the solvent is water, methanol, ethanol, propanol, butanol, acetonitrile, propionitrile, butyronitrile, acetone, butanone, pentanone, ethyl acetate, propyl acetate, butyl acetate, methyl tert-butyl ether, phenyl methyl ether, tetrahydrofuran, 1, 4-dioxane, water, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, toluene, xylene, trimethylbenzene, dimethyl sulfoxide, pyridine, picoline, lutidine, collidine, N-dimethylaminophenyl, 1, 8-diazabicycloundecene-7-ene, triethylamine, diisopropylethylamine, sulfolane or a mixture thereof, preferably pyridine.

7. Process conditions according to claims 1-6, in which compound 3 rearranges to compound 4, characterized in that the solvent used is methanol, ethanol, propanol, butanol, acetonitrile, propionitrile, butyronitrile, acetone, butanone, pentanone, ethyl acetate, propyl acetate, butyl acetate, methyl tert-butyl ether, phenylmethyl ether, tetrahydrofuran, 1, 4-dioxane, water, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, toluene, xylene, trimethylbenzene, dimethyl sulfoxide, pyridine, picoline, lutidine, collidine, N-dimethylaminobenzene, 1, 8-diazabicycloundecene-7-ene, triethylamine, diisopropylethylamine, sulfolane or a mixture thereof, preferably pyridine.

8. Process conditions according to claims 1-7, in which compound 3 rearranges to compound 4, characterized in that the base used is lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide, zinc hydroxide, sodium methoxide, lithium methoxide, potassium methoxide, magnesium methoxide, calcium methoxide, sodium ethoxide, lithium ethoxide, potassium ethoxide, magnesium ethoxide, calcium ethoxide, sodium isopropoxide, lithium isopropoxide, potassium isopropoxide, magnesium isopropoxide, calcium isopropoxide, sodium tert-butoxide, lithium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, calcium tert-butoxide, sodium hydride, calcium hydride, lithium hydride, potassium hydride, preferably potassium hydroxide.

9. Process conditions according to claims 1-8, compound 4 being a ring-closing compound 5, characterized in that the acid used is formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, benzoic acid, nitrobenzoic acid, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, hydrobromic acid, hydroiodic acid or mixtures thereof, preferably a sulfuric acid/acetic acid mixed system.

10. Process conditions according to claims 1-9, compound 5 being hydrodebenzylated, characterized in that the catalyst used is a salt or complex containing copper, iron, nickel, cobalt, ruthenium, rhodium, palladium, iridium, platinum, gold, preferably palladium on carbon.