CN104072362A - Synthesis process for antiviral chemical compound protocatechuic acid - Google Patents
Synthesis process for antiviral chemical compound protocatechuic acid Download PDFInfo
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- CN104072362A CN104072362A CN201410333599.0A CN201410333599A CN104072362A CN 104072362 A CN104072362 A CN 104072362A CN 201410333599 A CN201410333599 A CN 201410333599A CN 104072362 A CN104072362 A CN 104072362A
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
- C07C51/295—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with inorganic bases, e.g. by alkali fusion
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Abstract
The invention relates to a preparation method for an antiviral chemical compound protocatechuic acid. According to the method, vanillin is used as raw material and fused by strong base, acidification is performed, and then demethylation reaction is performed, so that protocatechuic acid is prepared.. The preparation method has the advantages that the less impurity is achieved, the yield is high.
Description
Technical field
The present invention relates to a kind of antiviral compound and synthesis technique thereof.
Background technology
Protocatechuic Acid is white to brown crystalline powder, can variable color in air.Density 1.54g/cm
3.Approximately 200 ℃ of fusing points (decomposition).Be dissolved in 50 parts of water, dissolve in ethanol, ether.The leaf that is present in Lindsaeaceae plant Stenoloma chusana [Stenoloma chusanum Ching], in the plants such as leaf of holly plant Chinese ilex (Ilex chinensis Sims).Protocatechuic Acid has anti-microbial effect, during in vitro tests, Pseudomonas aeruginosa, intestinal bacteria, Corynebacterium diphtheriae, dysentery bacterium, product inspection bacillus and Bacillus subtilus and streptococcus aureus is all had to bacteriostatic action in various degree.At field of medicaments, Protocatechuic Acid have eliminate the phlegm, antiasthmatic effect, the clinical chronic tracheitis that is used for the treatment of.In addition, Protocatechuic Acid is improved endogenous antioxidase activity, reduces the ability of lipid peroxidation, reduces cerebral tissue pathology injury, and then the effect of the oxidated damage of neuroprotective unit, and this is found to be Protocatechuic Acid treatment Parkinson's disease theoretical foundation is provided.There are some researches show that Protocatechuic Acid has certain provide protection for myocardial ischemia and myocardial infarction.Protocatechuic Acid copies and has stronger restraining effect hepatitis B virus (HBV) simultaneously, and this inhibition may be relevant with direct inhibition viral DNA.As antiviral drug, the research in medical medicine field makes great progress visible Protocatechuic Acid, prior synthesizing method is through alkali fusion dissolved oxygen demethylation by vanillin food grade,1000.000000ine mesh, through acidifying, prepare again, this technique needs 240 ℃ of above high temperature, the reaction most of the time is solid state reaction, restive, must use special conversion unit, investment is large, plant factor is low, so product is once without manufacturer production.
Summary of the invention
The present invention relates to a kind of antiviral compound and synthesis technique thereof.
Problem to be solved by this invention is to provide a kind of antiviral compound method of preparing.Prior synthesizing method is through alkali fusion dissolved oxygen demethylation by vanillin food grade,1000.000000ine mesh, through acidifying, prepare again, this technique needs 240 ℃ of above high temperature, the reaction most of the time is solid state reaction, restive, must use special conversion unit, investment is large, plant factor is low, so product is once without manufacturer production.The present invention improves in traditional method, adopts demethylation reagents demethylation, and temperature in whole reaction process is controlled at below 200 ℃, and high-temperature reaction equipment that can be special, more easily realizes suitability for industrialized production, and productive rate is higher, more than 90%.
The invention provides a kind of antiviral compound method of preparing comprises the steps:
The first step: employing Vanillin is raw material, and after alkali fusion, acidization is prepared vanillic acid, the alkali of employing is highly basic, preferred sodium hydroxide and potassium hydroxide, temperature range is 160 ℃-200 ℃, and the reaction times is 1-3 hour, and the acid of employing is hydrochloric acid.
Second step: take vanillic acid as intermediate, be dispersed in methylene dichloride, then add boron tribromide wherein, react 10-17 hour within the scope of-78 ℃-0 ℃.After having reacted, return to room temperature, then be poured in cold water, by extracted with diethyl ether, obtain Protocatechuic Acid after extraction liquid is revolved to steaming.
According to above-mentioned synthetic method, wherein the highly basic in the first step reaction is selected from the mixture of sodium hydroxide and potassium hydroxide.
According to above-mentioned synthetic method, the acid wherein adopting in the first step reaction is hydrochloric acid.
According to above-mentioned synthetic method, wherein the mol ratio of sodium hydroxide and potassium hydroxide is 1: 5-20: 1.
According to above-mentioned synthetic method, the sour concentration of employing is 3mol/L-6mol/L.
According to above-mentioned synthetic method, after the first step reaction, also comprise that suction filtration drying step obtains vanillic acid.
According to above-mentioned synthetic method, the dispersion medium of second step reaction is selected methylene dichloride.
According to above-mentioned synthetic method, the temperature of reaction of second step reaction is-50 ℃-0 ℃.
According to above-mentioned synthetic method, the reaction times of second step reaction is controlled at 8-17 hour.
According to above-mentioned synthetic method, the catalyzer using in second step reaction is selected from aluminum chloride, boron tribromide, aluminium triiodide.
Above-mentioned steps the first step concrete operation step is as follows:
By stoichiometric ratio, take appropriate NaOH and KOH at 2: 5 in stainless steel cauldron, after dissolving by appropriate amount of deionized water, add Vanillin, be heated to 200 ℃, continue stirring and be cooled to room temperature after 1 hour, add 50mL water and be transferred in three mouthfuls of round bottom glass flask, continue to pass into sulfur dioxide gas 2 minutes, add wherein afterwards enough 6N hydrochloric acid, make reaction solution become acidity, now have Precipitation to be intermediate vanillic acid.
Above-mentioned steps second step concrete steps are as follows: take the product vanillic acid of the first step, be dispersed in methylene dichloride, then add boron tribromide wherein, within the scope of-78 ℃-0 ℃, react 10-17 hour.After having reacted, return to room temperature, then be poured in cold water, by extracted with diethyl ether, obtain Protocatechuic Acid after extraction liquid is revolved to steaming.
Accompanying drawing 1 is for preparing the H of Protocatechuic Acid
1nMR.
Specific implementation method
Below in conjunction with embodiment, illustrate the present invention.
Embodiment 1:
The first step: take 28gNaOH and 196gKOH in stainless steel cauldron, with after appropriate 100mL deionized water dissolving, add 15.2g Vanillin, be heated to 160 ℃, continue stirring and be cooled to room temperature after 1 hour, add 50mL water and be transferred in three mouthfuls of round bottom glass flask, continue to pass into sulfur dioxide gas 2 minutes, add wherein afterwards enough 6N hydrochloric acid, make reaction solution become acidity, now there is Precipitation to be intermediate vanillic acid, dried for standby after suction filtration.
Second step: the vanillic acid that the first step reaction is obtained is dispersed in 50mL methylene dichloride, then adds wherein 20g boron tribromide, reacts 17 hours under-20 ℃ of conditions.After having reacted, return to room temperature, then be poured in cold water, be extracted with ethyl acetate, obtain Protocatechuic Acid 15.3g, yield 99.4% after extraction liquid is revolved to steaming.
Embodiment 2:
The first step: take 28gNaOH and 196gKOH in stainless steel cauldron, with after appropriate 100mL deionized water dissolving, add 15.2g Vanillin, be heated to 200 ℃, continue stirring and be cooled to room temperature after 1 hour, add 50mL water and be transferred in three mouthfuls of round bottom glass flask, continue to pass into sulfur dioxide gas 2 minutes, add wherein afterwards enough 6N hydrochloric acid, make reaction solution become acidity, now there is Precipitation to be intermediate vanillic acid, dried for standby after suction filtration.
Second step: the vanillic acid that the first step reaction is obtained is dispersed in 50mL methylene dichloride, then adds wherein 7g boron tribromide, reacts 16 hours under 0 ℃ of condition.After having reacted, return to room temperature, then be poured in cold water, by extracted with diethyl ether, obtain Protocatechuic Acid 13.7g, yield 90.0% after extraction liquid is revolved to steaming.
Embodiment 3:
The first step: take 28gNaOH and 196gKOH in stainless steel cauldron, with after appropriate 100mL deionized water dissolving, add 15.2g Vanillin, be heated to 180 ℃, continue stirring and be cooled to room temperature after 1 hour, add 50mL water and be transferred in three mouthfuls of round bottom glass flask, continue to pass into sulfur dioxide gas 2 minutes, add wherein afterwards enough 3N hydrochloric acid, make reaction solution become acidity, now there is Precipitation to be intermediate vanillic acid, dried for standby after suction filtration.
Second step: the vanillic acid that the first step reaction is obtained is dispersed in 50mL methylene dichloride, then adds wherein 15g boron tribromide, reacts 10 hours under-30 ℃ of conditions.After having reacted, return to room temperature, then be poured in cold water, be extracted with ethyl acetate, obtain Protocatechuic Acid 14.5g, yield 94.2% after extraction liquid is revolved to steaming.
Embodiment 4:
The first step: take 140gNaOH and 39.2gKOH in stainless steel cauldron, with after appropriate 100mL deionized water dissolving, add 15.2g Vanillin, be heated to 200 ℃, continue stirring and be cooled to room temperature after 1 hour, add 50mL water and be transferred in three mouthfuls of round bottom glass flask, continue to pass into sulfur dioxide gas 2 minutes, add wherein afterwards enough 4N hydrochloric acid, make reaction solution become acidity, now there is Precipitation to be intermediate vanillic acid, dried for standby after suction filtration.
Second step: the vanillic acid that the first step reaction is obtained is dispersed in 50mL methylene dichloride, then adds wherein 10g boron tribromide, reacts 10 hours under-30 ℃ of conditions.After having reacted, return to room temperature, then be poured in cold water, be extracted with ethyl acetate, obtain Protocatechuic Acid 12.9g, yield 83.8% after extraction liquid is revolved to steaming.
Embodiment 5:
The first step: take 140gNaOH and 39.2gKOH in stainless steel cauldron, with after appropriate 100mL deionized water dissolving, add 15.2g Vanillin, be heated to 200 ℃, continue stirring and be cooled to room temperature after 1 hour, add 50mL water and be transferred in three mouthfuls of round bottom glass flask, continue to pass into sulfur dioxide gas 2 minutes, add wherein afterwards enough 4N hydrochloric acid, make reaction solution become acidity, now there is Precipitation to be intermediate vanillic acid, dried for standby after suction filtration.
Second step: the vanillic acid that the first step reaction is obtained is dispersed in 50mL methylene dichloride, then adds wherein 15g boron tribromide, reacts 10 hours under-78 ℃ of conditions.After having reacted, return to room temperature, then be poured in cold water, be extracted with ethyl acetate, obtain Protocatechuic Acid 13.5g, yield 87.7% after extraction liquid is revolved to steaming.
Embodiment 6:
The first step: take 160gNaOH and 11.2gKOH in stainless steel cauldron, with after appropriate 100mL deionized water dissolving, add 15.2g Vanillin, be heated to 200 ℃, continue stirring and be cooled to room temperature after 1 hour, add 50mL water and be transferred in three mouthfuls of round bottom glass flask, continue to pass into sulfur dioxide gas 2 minutes, add wherein afterwards enough 6N hydrochloric acid, make reaction solution become acidity, now there is Precipitation to be intermediate vanillic acid, dried for standby after suction filtration.
Second step: the vanillic acid that the first step reaction is obtained is dispersed in 50mL methylene dichloride, then adds wherein 10g aluminum chloride, reacts 16 hours under 0 ℃ of condition.After having reacted, return to room temperature, then be poured in cold water, be extracted with ethyl acetate, obtain Protocatechuic Acid 12.5g, yield 81.2% after extraction liquid is revolved to steaming.
Embodiment 7:
The first step: take 28gNaOH and 196gKOH in stainless steel cauldron, with after appropriate 100mL deionized water dissolving, add 15.2g Vanillin, be heated to 180 ℃, continue stirring and be cooled to room temperature after 1 hour, add 50mL water and be transferred in three mouthfuls of round bottom glass flask, continue to pass into sulfur dioxide gas 2 minutes, add wherein afterwards enough 6N hydrochloric acid, make reaction solution become acidity, now there is Precipitation to be intermediate vanillic acid, dried for standby after suction filtration.
Second step: the vanillic acid that the first step reaction is obtained is dispersed in 50mL methylene dichloride, then adds wherein 15g aluminium triiodide, reacts 12 hours under 0 ℃ of condition.After having reacted, return to room temperature, then be poured in cold water, be extracted with ethyl acetate, obtain Protocatechuic Acid 15.1g, yield 98.1% after extraction liquid is revolved to steaming.
Claims (10)
1. a synthetic method for antiviral compound Protocatechuic Acid, its feature is as follows:
The first step: employing Vanillin is raw material, and after alkali fusion, acidization is prepared vanillic acid, the alkali wherein adopting is highly basic, and temperature range is 120 ℃-200 ℃, and the reaction times is 1-3 hour, obtains vanillic acid.
Second step: take vanillic acid as intermediate, be dispersed in organic solvent, then add wherein catalyzer boron tribromide, react 10-17 hour within the scope of-78 ℃-0 ℃.After having reacted, return to room temperature, then be poured in cold water, be extracted with ethyl acetate, obtain Protocatechuic Acid after extraction liquid is revolved to steaming.
2. synthetic method according to claim 1, is characterized in that the highly basic in the first step reaction is selected from sodium hydroxide, potassium hydroxide or its mixture.
3. synthetic method according to claim 1 and 2, is characterized in that the acid adopting in the first step reaction acidization is hydrochloric acid.
4. synthetic method according to claim 2, the mol ratio that it is characterized in that sodium hydroxide and potassium hydroxide is 1: 5-20: 1.
5. synthetic method according to claim 1, is characterized in that the sour concentration adopting in acidization is 3mol/L-6mol/L.
6. synthetic method according to claim 1, is characterized in that also comprising that suction filtration drying step obtains vanillic acid after the first step reaction.
7. synthetic method according to claim 1, is characterized in that the dispersion medium of second step reaction is selected methylene dichloride.
8. synthetic method according to claim 1, is characterized in that the temperature of reaction of second step reaction is-50 ℃-0 ℃.
9. synthetic method according to claim 1, is characterized in that the reaction times of second step reaction is controlled at 8-17 hour.
10. synthetic method according to claim 1, is characterized in that the catalyzer using in second step reaction is selected from aluminum chloride, boron tribromide, aluminium triiodide.
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| CN201410333599.0A CN104072362A (en) | 2014-07-15 | 2014-07-15 | Synthesis process for antiviral chemical compound protocatechuic acid |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108129298A (en) * | 2018-01-06 | 2018-06-08 | 诚达药业股份有限公司 | A kind of vanillic acid continuous production device and production method |
| US20190000786A1 (en) * | 2013-05-01 | 2019-01-03 | Lanny Leo Johnson | Methods of diagnosing and treating infected implants |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2441839A (en) * | 1947-09-16 | 1948-05-18 | Paper Chemistry Inst | Production of vanillic acid |
| US3256336A (en) * | 1961-06-21 | 1966-06-14 | Monsanto Co | Cleavage of alkyl o-hydroxyphenyl ethers |
| CN100396657C (en) * | 2001-05-11 | 2008-06-25 | 罗狄亚化学公司 | Method for oxidising aromatic aldehyde into corresponding carboxylic acid |
-
2014
- 2014-07-15 CN CN201410333599.0A patent/CN104072362A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2441839A (en) * | 1947-09-16 | 1948-05-18 | Paper Chemistry Inst | Production of vanillic acid |
| US3256336A (en) * | 1961-06-21 | 1966-06-14 | Monsanto Co | Cleavage of alkyl o-hydroxyphenyl ethers |
| CN100396657C (en) * | 2001-05-11 | 2008-06-25 | 罗狄亚化学公司 | Method for oxidising aromatic aldehyde into corresponding carboxylic acid |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20190000786A1 (en) * | 2013-05-01 | 2019-01-03 | Lanny Leo Johnson | Methods of diagnosing and treating infected implants |
| US10398664B2 (en) * | 2013-05-01 | 2019-09-03 | Lanny Leo Johnson | Methods of diagnosing and treating infected implants |
| CN108129298A (en) * | 2018-01-06 | 2018-06-08 | 诚达药业股份有限公司 | A kind of vanillic acid continuous production device and production method |
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Application publication date: 20141001 |