CN113387800A - Preparation method of 3, 5-dimethoxybenzoic acid methyl ester - Google Patents
Preparation method of 3, 5-dimethoxybenzoic acid methyl ester Download PDFInfo
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Abstract
The invention discloses a preparation method of 3, 5-dimethoxybenzoic acid methyl ester, which takes 3, 5-dimethoxybenzoic acid as a raw material to perform methylation reaction with tetramethyl quaternary ammonium salt in the presence of alkali. The method has the advantages of cheap and easily-obtained methylating reagent, no toxicity, simple operation, convenient post-treatment, less three wastes and higher yield.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of 3, 5-dimethoxybenzoic acid methyl ester.
Background
Methyl 3, 5-dimethoxybenzoate is an important pharmaceutical and chemical intermediate. It can be used for preparing 3, 5-dihydroxy acetophenone [ Sanford S, Jenkins. Journal of the American Chemical Society, 1933, 55(7): 2896-; methyl 3, 5-dimethoxybenzoate can also be converted into 3, 5-dimethoxybenzaldehyde, and further the strong antioxidant resveratrol [ Zhu Guang lan et al, J. Med. Chem.2002, 12 (3): 152-154] is synthesized; methyl 3, 5-dimethoxybenzoate can be reduced to form 3, 5-dimethoxybenzyl alcohol, so as to further synthesize chalcone which is a natural antioxidant substance and has chemopreventive and antitumor activities [ McNulty J, McLeod D. Tetrahedron Letters, 2013, 54: 6303-; methyl 3, 5-dimethoxybenzoate is also used for synthesizing 3, 5-dihydroxypentylbenzene, which can be used for inhibiting and treating human immunodeficiency, cancer and other malignant tumors caused by retrovirus [ xuyulun et al fine chemical, 2006, 23: 382 once 385 ]; methyl 3, 5-dimethoxybenzoate can also be used to synthesize cannabinoids which can be used to alleviate pain, calm, resist inflammation, aid digestion and resist hypertension [ Teske J A, Deiters A. Organic Letters, 2008, 10: 2195-.
At present, the synthesis method of methyl 3, 5-dimethoxybenzoate mainly comprises the following two methods:
the compound is prepared by using 3, 5-dihydroxy benzoic acid as raw material and treating with methylating agent. Such as CN 103193625A, CN 105503652A, CN 101648851A, starting from 3, 5-dihydroxybenzoic acid, in an acid-binding agent K2CO3Promoting the reaction of the methyl ester and a methylating agent dimethyl sulfate to obtain the 3, 5-dimethoxybenzoic acid methyl ester. Denmark, S.E. et al tetrahedron, 2010, 66(26): 4745-]Adding methyl 3, 5-dihydroxybenzoate to K2CO3Promoting the reaction with methyl iodide to obtain 3, 5-dimethoxybenzoic acid methyl ester.
The compound is also obtained by treating 3, 5-dihydroxy methyl benzoate serving as a raw material with a methylating agent. Such as CN 109988156A, starting from methyl 3, 5-dihydroxybenzoate, in an acid-binding agent K2CO3Promoting the reaction with dimethyl sulfate to obtain 3, 5-dimethoxy methyl benzoate; also for example, Sharif, E, U, et al [ Heterocycles, 2014, 88(2): 1275-.]And Denmark, S.E. et al tetrahedron, 2010, 66(26): 4745-]Adding methyl 3, 5-dihydroxybenzoate to K2CO3Promoting the reaction with methyl iodide to obtain 3, 5-dimethoxybenzoic acid methyl ester.
The above processes all require the use of the conventional methylating agent dimethyl sulfate or methyl iodide. Both are now government regulated hypertonic poisons. Methyl iodide is expensive and is generally used for laboratory and industrial pilot scale preparation. Dimethyl sulfate is a less expensive methylating agent that is more often used in commercial processes. But dimethyl sulfate is more toxic, has the effect similar to mustard gas, and has the acute toxicity similar to phosgene which is 15 times larger than chlorine. Dimethyl sulfate has strong stimulation effect on eyes and upper respiratory tract; has strong corrosive effect on skin, and can cause conjunctival congestion, edema, corneal epithelial exfoliation, necrosis of epithelial cells of trachea and bronchus, and edema of longitudinal and subcutaneous tissues due to penetration. In addition, dimethyl sulfate can also damage liver, kidney, cardiac muscle, etc.; it is also highly carcinogenic. Dimethyl sulfate is listed in class 2A carcinogens in carcinogenic lists published by international cancer research institute of world health organization, 10 and 27 of 2017. Furthermore, dimethyl sulfate vapor is colorless and tasteless, can be absorbed by respiratory tract and skin, and has a 3-4 hour latent period of poisoning phenomenon.
The current situation of chemical engineering urgently needs a convenient and low-toxicity method for preparing 3, 5-dimethoxybenzoic acid methyl ester.
Disclosure of Invention
The invention aims to solve the problem of the toxicity of a methylating agent adopted in the existing preparation process of the methyl 3, 5-dimethoxybenzoate, and provides a convenient and safe preparation method of the methyl 3, 5-dimethoxybenzoate.
The technical scheme adopted by the invention for solving the technical problems is as follows:
a preparation method of methyl 3, 5-dimethoxybenzoate comprises the steps of taking 3, 5-dihydroxybenzoic acid as a raw material, adding an aprotic polar solvent, a methylation reagent and an acid-binding agent, reacting at 190 ℃ for 6-14h, and carrying out aftertreatment to obtain the methyl 3, 5-dimethoxybenzoate.
The technical route of the invention is as follows:
the method takes 3, 5-dihydroxy benzoic acid as a raw material, and the raw material reacts with a methylating reagent in a high-boiling-point aprotic polar solvent under the promotion of an acid-binding agent to obtain a target product, namely 3, 5-dimethoxybenzoic acid methyl ester. The methylation reagent used in the reaction has low toxicity, safety, low price and high yield.
Preferably, the molar ratio of the 3, 5-dihydroxy benzoic acid, the non-protonized polar solvent, the methylating agent and the acid binding agent is 1: 3-6: 3-5.
Preferably, the methylating agent is tetramethylammonium chloride, tetramethylammonium bromide or tetramethylammonium fluoride. The reaction speed of the tetramethylammonium chloride is relatively slow; tetramethyl ammonium fluoride and tetramethyl ammonium iodide are expensive. Tetramethylammonium bromide has a suitable reaction rate and is inexpensive and is a preferred reagent of the present invention. The methylating agent (tetramethyl ammonium bromide) used in the whole process is a colorless and tasteless solid, and is convenient to transport, store and use; low cost and low toxicity; simple operation of the process and less three wastes.
The conventional application of the methylating agent is commonly used as a phase transfer catalyst for organic reaction to prepare ionic liquid, increase the conductivity of an organic solvent and the like, the conventional application of the methylating agent is changed, and the methylating agent is used for the preparation method of the 3, 5-dimethoxybenzoic acid methyl ester and is used as the methylating agent, so that the methylating agent has low toxicity, safety, low price and high yield. And the non-protonized polar solvent and the adjustment of reaction conditions are matched with the methylating agent, so that the function of the methylating agent can be exerted.
Preferably, the aprotic polar solvent is a high-boiling point aprotic polar solvent, and the high-boiling point aprotic polar solvent is one selected from N-methylpyrrolidone, dimethyl sulfoxide, 1, 3-dimethyl-2-imidazolidinone, and o-dichlorobenzene. N-methylpyrrolidone is preferred. The main reaction temperature involved in the invention is higher, and a solvent with higher boiling point is preferably adopted; and protic solvents such as water, alcohol, etc. are easily reacted with the methylating agent and cannot be selected.
Preferably, the acid-binding agent is KOH, NaOH or K2CO3、Na2CO3Or K3PO4. The invention relates to deprotonation of hydroxyl groups to form O-The stronger the alkalinity of the acid-binding agent added, the stronger the ability of the acid-binding agent to capture H on hydroxyl groups, and the formation of O-The greater the assistance. The acid scavenger is preferably KOH.
Preferably, the reaction is carried out at 160-190 ℃ for 8-12 h.
Preferably, the post-treatment is cooling the reaction product to room temperature, filtering with suction, and distilling under reduced pressure.
The invention has the beneficial effects that: the used methylating agent is cheap, easy to obtain and nontoxic; the product is solid, the operation is simple, the post-treatment is convenient, and the three wastes are light; the yield is high (47% -88%).
Drawings
FIG. 1 shows the preparation of methyl 3, 5-dimethoxybenzoate according to the invention1H NMR spectrum.
Detailed Description
The technical solution of the present invention will be further specifically described below by way of specific examples.
In the present invention, the raw materials and equipment used are commercially available or commonly used in the art, unless otherwise specified. The methods in the following examples are conventional in the art unless otherwise specified.
The mechanism of the reaction of the present invention may be: removing proton from phenolic hydroxyl under the action of acid-binding agent alkali to generate O-It attacks the methyl group of tetramethylammonium bromide (methylating agent) and removes trimethylamine and Br at high temperature-Finally, O is generated-Alkylated product (see figure below).
General implementation:
a preparation method of methyl 3, 5-dimethoxybenzoate comprises the steps of taking 3, 5-dihydroxybenzoic acid as a raw material, adding an aprotic polar solvent, a methylation reagent and an acid-binding agent, reacting at 190 ℃ for 6-14h, and carrying out aftertreatment to obtain the methyl 3, 5-dimethoxybenzoate. The mol ratio of the 3, 5-dihydroxy benzoic acid, the non-protonized polar solvent, the methylating agent and the acid-binding agent is 1: 3-6: 3-5. The methylating agent is tetramethylammonium chloride, tetramethylammonium bromide or tetramethylammonium fluoride. The non-protonized polar solvent is a high-boiling point non-protonized polar solvent, and the high-boiling point non-protonized polar solvent is one selected from N-methylpyrrolidone, dimethyl sulfoxide, 1, 3-dimethyl-2-imidazolidinone and o-dichlorobenzene. The acid-binding agentIs KOH, NaOH, K2CO3、Na2CO3Or K3PO4. The post-treatment comprises cooling the reaction product to room temperature, filtering to remove salt, and distilling under reduced pressure.
Example 1
A1L three-necked flask was charged with 3, 5-dihydroxybenzoic acid (77g, 0.5mol), N-methylpyrrolidone (400 mL, 4.15 mol), KOH (92.4 g, 1.65mol), tetramethylammonium bromide (254 g, 1.65mol), and heated to 180 ℃ for reaction for 8 hours. The reaction was monitored by Thin Layer Chromatography (TLC) and the starting material was completely reacted. Cooling to room temperature, performing suction filtration, distilling the mother liquor under reduced pressure by using a water pump to recover N-methylpyrrolidone, then distilling under reduced pressure by using an oil pump, collecting 125-135 ℃/2-3mmHg fractions to obtain 86.5 g of methyl 3, 5-dimethoxybenzoate with the yield of 88 percent, m.p.41.5-42.6 ℃,1H NMR (CDCl3, 400 MHz) δ: 7.23(d, J = 4.0 Hz, 2H), 6.69(t, J= 4.0 Hz, 1H), 3.95(s, 3H), 3.87(s, 6H) (fig. 1).
Example 2
A1L three-necked flask was charged with 3, 5-dihydroxybenzoic acid (77g, 0.5mol), dimethyl sulfoxide (400 mL, 5.63 mol), KOH (92.4 g, 1.65mol), and tetramethylammonium bromide (254 g, 1.65mol), and the mixture was heated to 180 ℃ to react for 10 hours. The reaction was monitored by TLC and the starting material was completely reacted. Cooling to room temperature, carrying out suction filtration, distilling the mother liquor by a water pump under reduced pressure to recover dimethyl sulfoxide, then distilling by an oil pump under reduced pressure, and collecting 125-135 ℃/2-3mmHg fractions to obtain 82.6 g of methyl 3, 5-dimethoxybenzoate with the yield of 84%.
Example 3
3, 5-dihydroxybenzoic acid (77g, 0.5mol), N-methylpyrrolidone (400 mL, 4.15 mol), NaOH (66 g, 1.65mol), tetramethylammonium bromide (254 g, 1.65mol) were added to a 1L three-necked flask, and after the addition, the temperature was raised to 180 ℃ to react for 10 hours. The reaction was monitored by TLC and the starting material was completely reacted. Cooling to room temperature, carrying out suction filtration, distilling the mother liquor by a water pump under reduced pressure to recover N-methylpyrrolidone, then distilling the mother liquor by an oil pump under reduced pressure, and collecting 125-135 ℃/2-3mmHg fractions to obtain 81.6 g of methyl 3, 5-dimethoxybenzoate with the yield of 83%.
Example 4
1L three-mouth bottleTo this mixture were added 3, 5-dihydroxybenzoic acid (77g, 0.5mol), N-methylpyrrolidone (400 mL, 4.15 mol), and K2CO3(227.7 g, 1.65mol), tetramethylammonium bromide (254 g, 1.65mol), after the addition, the temperature was raised to 180 ℃ for reaction for 8 hours. The reaction was monitored by TLC and the starting material was completely reacted. Cooling to room temperature, carrying out suction filtration, distilling the mother liquor under reduced pressure by a water pump to recover N-methylpyrrolidone, then distilling under reduced pressure by an oil pump, and collecting 125-135 ℃/2-3mmHg fractions to obtain 60.0g of methyl 3, 5-dimethoxybenzoate with the yield of 61%.
Example 5
A1L three-necked flask was charged with 3, 5-dihydroxybenzoic acid (77g, 0.5mol), N-methylpyrrolidone (400 mL, 4.15 mol), and K3PO4(349.8 g, 1.65mol), tetramethylammonium bromide (254 g, 1.65mol), and after the addition, the temperature was raised to 180 ℃ to react for 10 hours. The reaction was monitored by TLC and the starting material was completely reacted. Cooling to room temperature, carrying out suction filtration, distilling the mother liquor by a water pump under reduced pressure to recover N-methylpyrrolidone, then distilling the mother liquor by an oil pump under reduced pressure, and collecting 125-135 ℃/2-3mmHg fractions to obtain 63.9 g of methyl 3, 5-dimethoxybenzoate with the yield of 65%.
Example 6
3, 5-dihydroxybenzoic acid (77g, 0.5mol), N-methylpyrrolidone (400 mL, 4.15 mol), KOH (112 g, 2mol), tetramethylammonium chloride (181.5 g, 1.65mol) were added to a 1L three-necked flask, and after the addition, the temperature was raised to 180 ℃ to react for 8 hours. The reaction was monitored by TLC and the starting material was completely reacted. Cooling to room temperature, carrying out suction filtration, distilling the mother liquor by a water pump under reduced pressure to recover N-methylpyrrolidone, then distilling the mother liquor by an oil pump under reduced pressure, and collecting 125-135 ℃/2-3mmHg fractions to obtain 46.2 g of methyl 3, 5-dimethoxybenzoate with the yield of 47%.
Example 7
A1L three-necked flask was charged with 3, 5-dihydroxybenzoic acid (77g, 0.5mol), o-dichlorobenzene (400 mL, 3.54 mol), KOH (92.4 g, 1.65mol), tetramethylammonium bromide (254 g, 1.65mol), and heated to 180 ℃ for reaction for 8 hours. The reaction was monitored by TLC and the starting material was completely reacted. Cooling to room temperature, carrying out suction filtration, distilling the mother liquor by a water pump under reduced pressure to recover N-methylpyrrolidone, then distilling the mother liquor by an oil pump under reduced pressure, and collecting 125-135 ℃/2-3mmHg fractions to obtain 54.1 g of methyl 3, 5-dimethoxybenzoate with the yield of 55%.
Example 8
A1L three-necked flask was charged with 3, 5-dihydroxybenzoic acid (77g, 0.5mol), N-dimethylacetamide (400 mL, 4.30 mol), KOH (92.4 g, 1.65mol), tetramethylammonium bromide (254 g, 1.65mol), and heated to 180 ℃ for reaction for 8 hours. The reaction was monitored by TLC and the starting material was completely reacted. Cooling to room temperature, carrying out suction filtration, distilling the mother liquor by a water pump under reduced pressure to recover dimethyl sulfoxide, then distilling the mother liquor by an oil pump under reduced pressure, and collecting 125-135 ℃/2-3mmHg fractions to obtain 48.2 g of methyl 3, 5-dimethoxybenzoate with the yield of 49%.
Example 9
A1L three-necked flask was charged with 3, 5-dihydroxybenzoic acid (77g, 0.5mol), DMF (400 mL, 5.17 mol), KOH (92.4 g, 1.65mol), and tetramethylammonium bromide (254 g, 1.65mol), and heated to 180 ℃ for reaction for 8 hours. The reaction was monitored by TLC and the starting material was completely reacted. Cooling to room temperature, carrying out suction filtration, distilling the mother liquor by a water pump under reduced pressure to recover N-methylpyrrolidone, then distilling the mother liquor by an oil pump under reduced pressure, and collecting 125-135 ℃/2-3mmHg fractions to obtain 47.2g of methyl 3, 5-dimethoxybenzoate with the yield of 48%.
The above-described embodiments are only preferred embodiments of the present invention, and are not intended to limit the present invention in any way, and other variations and modifications may be made without departing from the spirit of the invention as set forth in the claims.
Claims (7)
1. A preparation method of 3, 5-dimethoxybenzoic acid methyl ester is characterized in that 3, 5-dihydroxybenzoic acid is taken as a raw material, an aprotic polar solvent, a methylation reagent and an acid-binding agent are added, the mixture reacts for 6 to 14 hours at the temperature of 190 ℃ with 160-.
2. The method according to claim 1, wherein the molar ratio of the 3, 5-dihydroxybenzoic acid, the aprotic polar solvent, the methylating agent and the acid-binding agent is 1: 3-6: 3-5.
3. The method of claim 1, wherein the methylating agent is tetramethylammonium chloride, tetramethylammonium bromide or tetramethylammonium fluoride.
4. The method according to claim 1, wherein the aprotic polar solvent is a high-boiling-point aprotic polar solvent selected from the group consisting of N-methylpyrrolidone, dimethylsulfoxide, 1, 3-dimethyl-2-imidazolidinone and o-dichlorobenzene.
5. The method of claim 1, wherein the acid scavenger is KOH, NaOH, K2CO3、Na2CO3Or K3PO4。
6. The method as claimed in claim 1, wherein the reaction is carried out at 160-190 ℃ for 8-12 h.
7. The method according to claim 1, wherein the post-treatment comprises cooling the reaction product to room temperature, filtering to remove salts, and distilling under reduced pressure.
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| CN114487237A (en) * | 2022-01-26 | 2022-05-13 | 中山奕安泰医药科技有限公司 | Detection method of 3, 5-dimethoxybenzoic acid methyl ester |
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Application publication date: 20210914 |