CN1800131B - 2,3,4,5-tetramethoxyl toluene synthesis method - Google Patents
2,3,4,5-tetramethoxyl toluene synthesis method Download PDFInfo
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- CN1800131B CN1800131B CN 200510037633 CN200510037633A CN1800131B CN 1800131 B CN1800131 B CN 1800131B CN 200510037633 CN200510037633 CN 200510037633 CN 200510037633 A CN200510037633 A CN 200510037633A CN 1800131 B CN1800131 B CN 1800131B
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Abstract
The invention relates to a method for synthesizing 2, 3, 4, 5-four metonym toluene, which comprises the following steps: using 3, 4, 5-three metonym toluene as starting raw material, obtaining the intermediate 2, 3, 4-three metonym-6-methxyl benzaldehyde after 2-bit formylated, obtaining 2, 3, 4-three metonym-6-methxyl benzene after oxidizing and obtaining 2, 3, 4, 5-four metonym toluene after methylamine. The methylamine reagent is cheesed form methyl iodide, methyl sulfate, methyl carbonate, and azimethane; the base is cheesed form caustic soda, caustic potash, potash and sodium hydride; the reagent is cheesed form alcohol, tetrahydropyran, acetone and propylidene chloride; the oxidant is cheesed form hydrogen diode solution and perbenzoic acid and so on. The formylation is N, N-dimethyl formamide solution with the drop phosphorus trichloride temperature below 50 deg. and the reacting temperature 60 deg.-100 deg.
Description
Technical field
The present invention relates to a kind of chemical industry synthesis technique, be specifically related to a kind of pharmaceutical-chemical intermediate 2,3,4, the synthetic method of 5-tetramethoxy toluene.
Background technology
2,3,4,5-tetramethoxy toluene is a very important pharmaceutical-chemical intermediate, is mainly used in synthesizing coenzyme Q series product (Q
0～10) raw material.Bibliographical information 2,3,4, the synthetic method of 5-tetramethoxy toluene has: be raw material with the p-methyl phenol, after the bromine bromination, methoxylation methylates and obtains 2,3,4,5-tetramethoxy toluene, perhaps with 3,4, the 5-trimethoxytoluene is a raw material, after the bromine bromination, methoxylation obtains 2,3,4,5-tetramethoxy toluene.Synthetic route as shown below (J.Org.Chem.1987,52,3872-3875).Should the operation of synthetic preparation route go up that inconvenience, productive rate are not high, product is difficult for purifying, be not suitable for suitability for industrialized production.
Summary of the invention
The objective of the invention is in order to overcome the difficulty of above synthesis technique, reduce cost, make new technology can be fit to suitability for industrialized production.
The technical scheme of finishing the foregoing invention task is: pharmaceutical-chemical intermediate 2,3,4, and the synthetic method of 5-tetramethoxy toluene may further comprise the steps:
By 3,4,5-trimethoxytoluene (structural formula I) is a starting raw material, obtains intermediate 2,3 through 2 formylations, 4-trimethoxy-6-tolyl aldehyde (structural formula II);
Obtain 2,3 through oxidation again, 4-trimethoxy-6-methylphenol (structural formula II I);
After methylating, obtain 2,3,4 again, 5-tetramethoxy toluene (structural formula IV).
This synthetic route is succinct, efficient, and total recovery is fit to suitability for industrialized production more than 73%.
The described phenolic hydroxyl group employed methylating reagent that methylates comprises methyl iodide, methyl-sulfate, methylcarbonate, diazomethane etc.;
Employed alkali comprises sodium hydroxide, potassium hydroxide, salt of wormwood, sodium hydride etc.;
Employed solvent comprises ethanol, tetrahydrofuran (THF), acetone, methylene dichloride etc.;
The employed reagent of described oxidation comprises hydrogen peroxide, metachloroperbenzoic acid, benzoyl hydroperoxide, peroxy trifluoroacetic acid, Peracetic Acid, six hydration monoperphthalic acid magnesium etc.
The reaction conditions of above each step of scheme is:
Described formylated condition is: at N, in the dinethylformamide solution, controlled temperature is dripping phosphorus oxychloride below 50 ℃, and temperature of reaction is at 60 ℃～100 ℃;
The condition of described oxidation is: in methyl alcohol or alcohol solvent, add oxygenant, controlled temperature drips 2,3 below 20 ℃, the methyl alcohol or the ethanolic soln of 4-trimethoxy-6-tolyl aldehyde (structural formula II), after dropwising, it is complete until raw material reaction to continue reaction, obtains 2,3,4-trimethoxy-6-methylphenol;
Described methylated condition is: 2,3, and 4-trimethoxy-6-methylphenol (structural formula II I) is dissolved in the solvent, and under the effect of alkali and methylating reagent, 0～100 ℃ of reaction obtains 2,3,4,5-tetramethoxy toluene.
Repeatedly saying, also is more specifically more optimally to say, each step of above technical scheme is:
With 3,4,5-trimethoxytoluene (structural formula I) is a starting raw material, at N, in the dinethylformamide solvent, controlled temperature drips phosphorus oxychloride below 50 ℃, be warmed up to 60 ℃～100 ℃ reactions then, complete until raw material reaction, obtain 2,3,4-trimethoxy-6-tolyl aldehyde (structural formula II), yield is more than 85%.In methyl alcohol or alcohol solvent, add oxygenant, controlled temperature drips 2 below 20 ℃, 3, the methyl alcohol or the ethanolic soln of 4-trimethoxy-6-tolyl aldehyde (structural formula II), after dropwising, it is complete until raw material reaction to continue reaction, obtain 2,3,4-trimethoxy-6-methylphenol (structural formula II I), yield is more than 95%.Then 2,3,4-trimethoxy-6-methylphenol (structural formula II I) is dissolved in the solvent, and under the effect of alkali and methylating reagent, 0～100 ℃ of reaction obtains 2,3,4,5-tetramethoxy toluene (structural formula IV), and yield is more than 90% after the rectification under vacuum.
The present invention is with 3,4, and 5-trimethoxytoluene (structural formula I) is a starting raw material, at N, in the dinethylformamide solvent, controlled temperature drips phosphorus oxychloride below 50 ℃, be warmed up to 60 ℃～100 ℃ reactions then, complete until raw material reaction, obtain 2,3,4-trimethoxy-6-tolyl aldehyde (structural formula II), yield is more than 85%.In methyl alcohol or alcohol solvent, add oxygenant as claimed in claim 5, controlled temperature drips 2 below 20 ℃, 3, the methyl alcohol or the ethanolic soln of 4-trimethoxy-6-tolyl aldehyde (structural formula II), after dropwising, it is complete until raw material reaction to continue reaction, obtain 2,3,4-trimethoxy-6-methylphenol (structural formula II I), yield is more than 95%.Then 2,3,4-trimethoxy-6-methylphenol (structural formula II I) is dissolved in the solvent as claimed in claim 3, under the effect of alkali as claimed in claim 3 and methylating reagent, 0～100 ℃ of reaction obtains 2,3,4,5-tetramethoxy toluene (structural formula IV), yield is more than 90% after the rectification under vacuum.This synthetic route is succinct, efficient, and total recovery is fit to suitability for industrialized production more than 73%.
Embodiment
Embodiment 1
With 91 grams 3,4, the 5-trimethoxytoluene is dissolved among 300 milliliters of DMF, and the water-bath cooling drips 250 gram phosphorus oxychloride down, and temperature, is warming up to 90 ℃ and reacts complete to raw material reaction after dropwising below 50 ℃ in the control reactor.After being cooled to room temperature, in reactor, add mixture of ice and water, be neutralized to neutrality, be cooled to room temperature again, separate out crystallization, filter, washing with sodium hydroxide solution.Vacuum-drying gets 2,3,4-trimethoxy-6-tolyl aldehyde 90.5 grams, and yield is 86.2%.
Embodiment 2
In reactor, add 500 milliliters of ethanol and 200 gram metachloroperbenzoic acids, 90.5 grams 2,3,4-trimethoxy-6-tolyl aldehyde is dissolved in the ethanol, drops in the reactor, and after dropwising, it is complete until raw material reaction to continue reaction.Add hypo solution, the water ethyl acetate extraction, dry back concentrates and obtains 2,3,4-trimethoxy-6-methylphenol 81.3 grams, yield 95.3%.
Embodiment 3
2,3,4-trimethoxy-6-methylphenol 81.3 restrains in the tetrahydrofuran solvent that is dissolved in 500 milliliters, adds the sodium hydride of 35 grams 60%, drips tetrahydrofuran (THF) (200 milliliters) solution of 150 gram methyl iodide.After dropwising, back flow reaction is complete until raw material reaction, adds 500 milliliters of ethyl acetate, washing, and drying concentrates and obtains 2,3,4,5-tetramethoxy toluene crude product.The cut under 113～115 ℃/3mmHg is collected in underpressure distillation, obtains 2,3,4, pure product 79 grams of 5-tetramethoxy toluene, yield 90.7%.
Claims (3)
1. one kind 2,3,4, the synthetic method of 5-tetramethoxy toluene may further comprise the steps:
By 3,4, the 5-trimethoxytoluene is a starting raw material, obtains intermediate 2,3 through 2 formylations, 4-trimethoxy-6-tolyl aldehyde;
Obtain 2,3 through oxidation again, 4-trimethoxy-6-methylphenol;
After methylating, obtain 2,3,4 again, 5-tetramethoxy toluene.
2. described 2,3,4 according to claim 1, the synthetic method of 5-tetramethoxy toluene is characterized in that,
The described phenolic hydroxyl group employed methylating reagent that methylates is selected from methyl iodide, methyl-sulfate, methylcarbonate, diazomethane;
The employed reagent of described oxidation is selected from hydrogen peroxide, metachloroperbenzoic acid, benzoyl hydroperoxide, peroxy trifluoroacetic acid, Peracetic Acid, six hydration monoperphthalic acid magnesium;
Described formylated condition is at N, and in the dinethylformamide solution, controlled temperature is dripping phosphorus oxychloride below 50 ℃, and temperature of reaction is at 60 ℃～100 ℃.
3. according to claim 1 or 2 described 2,3,4, the synthetic method of 5-tetramethoxy toluene is characterized in that,
The reaction conditions of described each step is:
Formylated condition is: at N, in the dinethylformamide solution, controlled temperature is dripping phosphorus oxychloride below 50 ℃, and temperature of reaction is at 60 ℃～100 ℃;
The condition of oxidation is: in methyl alcohol or alcohol solvent, add oxygenant, controlled temperature drips 2 below 20 ℃, 3, the methyl alcohol or the ethanolic soln of 4-trimethoxy-6-tolyl aldehyde, after dropwising, it is complete until raw material reaction to continue reaction, obtain 2,3,4-trimethoxy-6-methylphenol;
Methylated condition is: 2,3, and 4-trimethoxy-6-methylphenol is dissolved in the solvent, and under the effect of alkali and methylating reagent, 0～100 ℃ of reaction obtains 2,3,4,5-tetramethoxy toluene.
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| CN 200510037633 CN1800131B (en) | 2005-01-07 | 2005-01-07 | 2,3,4,5-tetramethoxyl toluene synthesis method |
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| CN 200510037633 CN1800131B (en) | 2005-01-07 | 2005-01-07 | 2,3,4,5-tetramethoxyl toluene synthesis method |
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| CN1800131B true CN1800131B (en) | 2011-01-05 |
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| CN113563163A (en) * | 2021-07-07 | 2021-10-29 | 南京伊派森化学科技有限公司 | Synthetic method of 5-bromo-1, 2, 3-trimethoxybenzene |
| CN115368217B (en) * | 2022-09-02 | 2024-03-15 | 寿光永康化学工业有限公司 | Synthesis method of 3,4, 5-trimethoxytoluene |
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Non-Patent Citations (2)
| Title |
|---|
| Ehud Keinan,ect.Total Synthhesis of Linear Polyprenoids.2. ImprovedPreparation of the Aromatic Nucleus of Ubiquinone.J.ORG.CHEM.52 17.1987,52(17),3872-3875. |
| Ehud Keinan,ect.Total Synthhesis of Linear Polyprenoids.2. ImprovedPreparation of the Aromatic Nucleus of Ubiquinone.J.ORG.CHEM.52 17.1987,52(17),3872-3875. * |
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