A kind of synthetic method of 2-methoxycinnamaldehyde

Abstract

The present invention provides a method for synthesizing 2-methoxycinnamaldehyde, and belongs to the technical field of organic synthesis. The synthesis method provided by the present invention comprises the following steps: (1) under the action of a quaternary ammonium salt catalyst, 2-hydroxybenzaldehyde and a methylating agent undergo a methylation reaction to obtain 2-methoxybenzaldehyde; (2) under alkaline conditions, 2-methoxybenzaldehyde and acetaldehyde undergo a condensation reaction to obtain 2-methoxycinnamaldehyde. The present invention uses 2-hydroxybenzaldehyde as a starting material, and has the advantages of a wide range of sources and low cost; the present invention has a short synthesis route, few side reactions, and the obtained 2-methoxycinnamaldehyde has a high yield and purity, and is suitable for industrial promotion and application. The results of the embodiments show that the yield of 2-methoxycinnamaldehyde obtained by the synthesis method provided by the present invention is ≥90%, and the purity is ≥95%.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing 2-methoxycinnamaldehyde. Background Art

[0002] Cinnamon is widely distributed in southern China, and its bark and branches have long been used as traditional Chinese herbal medicine to relieve fever, inflammation, chronic bronchitis, induce sweat and improve blood circulation. 2-Methoxycinnamaldehyde is one of the active ingredients isolated from cinnamon oil, mainly used as a food flavoring agent, and is also an important intermediate raw material for the synthesis of pharmaceutical products.

[0003] The existing synthesis methods of 2-methoxycinnamaldehyde are as follows:

[0004] 1) Pankaj D et al. (Pankaj D et al., Visible-light mediated facile dithianedeprotection under metal free conditions, 2019, 10.1016) reported that 2-methoxycinnamaldehyde can be synthesized using thioacetal as a raw material. The reaction is as follows:

[0005]

[0006] 2) Chao Guo et al. (Chao Guo et al., Biocatalytic Asymmetric Michael Additions of Nitromethane to α, β-Unsaturated Aldehydes via Enzyme-bound Iminium Ion Intermediates, 2019.10.1021) et al. reported the synthesis of 2-methoxycinnamaldehyde using 2-hydroxycinnamaldehyde and iodomethane as raw materials. The reaction is as follows:

[0007]

[0008] 3) Zhimin Deng et al. (Zhimin Deng et al., Organoselenium-Catalyzed, Hydroxy-Controlled Regio-and Stereoselective Amination of Terminal Alkenes: Efficient Synthesis of 3-Amino Allylic Alcohols, 2015) reported the synthesis of 2-methoxycinnamaldehyde using 3-(2-methoxyphenyl)-3-propene-1-ol as raw material. The reaction is as follows:

[0009]

[0010] Based on the above synthesis methods, it is not difficult to find that the existing methods for synthesizing 2-methoxycinnamaldehyde have the disadvantages of small supply of raw materials in the market, difficulty in obtaining, and high price of raw materials, and are not suitable for industrial production. Summary of the invention

[0011] In view of this, the present invention aims to provide a method for synthesizing 2-methoxycinnamaldehyde. The raw materials used in the method of the present invention are widely available and low in cost.

[0012] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0013] The present invention provides a method for synthesizing 2-methoxycinnamaldehyde, comprising the following steps:

[0014] (1) Under the action of a quaternary ammonium salt catalyst, 2-hydroxybenzaldehyde and a methylating agent undergo a methylation reaction to obtain 2-methoxybenzaldehyde;

[0015] (2) Under alkaline conditions, the 2-methoxybenzaldehyde and acetaldehyde undergo condensation reaction to obtain 2-methoxycinnamaldehyde.

[0016] Preferably, the quaternary ammonium salt catalyst is one or more of benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride and tetrabutylammonium hydrogen sulfate.

[0017] Preferably, the methylating agent is one or more of dimethyl sulfate, dimethyl carbonate, methyl iodide, methyl bromide and methyl p-toluenesulfonate.

[0018] Preferably, the molar ratio of the 2-hydroxybenzaldehyde to the methylating agent is 1:(1-3).

[0019] Preferably, the methylation reaction is carried out at pH = 10-12.

[0020] Preferably, the methylation reaction is carried out at a temperature of 35 to 45° C. and for a time of 1 to 4 hours.

[0021] Preferably, in step (2), the molar ratio of 2-methoxybenzaldehyde to acetaldehyde is 1:(1-3).

[0022] Preferably, the alkaline condition in step (2) is provided by an alkaline reagent, and the alkaline reagent is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, ammonium acetate and sodium methoxide.

[0023] Preferably, the condensation reaction temperature is 10-20° C. and the time is 1-3 hours.

[0024] Preferably, after the condensation reaction, the obtained condensation reaction liquid is subjected to post-treatment, and the post-treatment comprises:

[0025] The condensation reaction liquid is sequentially subjected to acid neutralization and extraction to obtain an organic phase;

[0026] The organic phase is washed, dried and recrystallized in sequence to obtain pure 2-methoxycinnamaldehyde.

[0027] The present invention provides a method for synthesizing 2-methoxycinnamaldehyde, comprising the following steps: (1) methylating 2-hydroxybenzaldehyde and a methylating agent under the action of a quaternary ammonium salt catalyst to obtain 2-methoxybenzaldehyde; (2) condensing 2-methoxybenzaldehyde and acetaldehyde under alkaline conditions to obtain 2-methoxycinnamaldehyde. The present invention uses 2-hydroxybenzaldehyde as a starting material, which has the advantages of wide sources and low cost; the present invention has a short synthesis route, and the obtained 2-methoxycinnamaldehyde has a high yield and purity, which is suitable for industrial promotion and application. The results of the embodiment show that the yield of 2-methoxycinnamaldehyde obtained by the synthesis method provided by the present invention is ≥90%, and the purity is ≥95%. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 This is the gas chromatogram of 2-methoxycinnamaldehyde obtained in Example 1;

[0029] Figure 2 The 2-methoxycinnamaldehyde obtained in Example 1 1 H-NMR spectrum;

[0030] Figure 3 This is the liquid chromatogram of 2-methoxycinnamaldehyde obtained in Example 1. DETAILED DESCRIPTION

[0031] The present invention provides a method for synthesizing 2-methoxycinnamaldehyde, comprising the following steps:

[0032] (1) Under the action of a quaternary ammonium salt catalyst, 2-hydroxybenzaldehyde and a methylating agent undergo a methylation reaction to obtain 2-methoxybenzaldehyde;

[0033] (2) Under alkaline conditions, the 2-methoxybenzaldehyde and acetaldehyde undergo condensation reaction to obtain 2-methoxycinnamaldehyde.

[0034] In the present invention, 2-hydroxybenzaldehyde and a methylating agent are subjected to a methylation reaction under the action of a quaternary ammonium salt catalyst to obtain 2-methoxybenzaldehyde. In the present invention, the quaternary ammonium salt catalyst is preferably one or more of benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride and tetrabutylammonium hydrogen sulfate; in the present invention, the methylating agent is preferably one or more of dimethyl sulfate, dimethyl carbonate, methyl iodide, methyl bromide and methyl p-toluenesulfonate.

[0035] In the present invention, the molar ratio of the 2-hydroxybenzaldehyde to the methylating agent is preferably 1:(1-3), more preferably 1:(1-2).

[0036] In the present invention, the methylation reaction is preferably carried out in an organic solvent, and the organic solvent is preferably one or more of dichloromethane, acetone, chloroform, carbon tetrachloride, acetonitrile and tetrahydrofuran.

[0037] In the present invention, the condensation reaction is preferably carried out under alkaline conditions, and the pH value of the alkaline conditions is preferably 10 to 12. In the present invention, the alkaline reagent used to provide alkaline conditions is preferably one or more of sodium hydroxide, potassium carbonate, potassium hydroxide, sodium carbonate, ammonium acetate, sodium methoxide, potassium tert-butoxide or triethylamine.

[0038] In the present invention, the methylation reaction preferably comprises:

[0039] Mixing 2-hydroxybenzaldehyde with a first organic solvent to obtain an organic solution of 2-hydroxybenzaldehyde;

[0040] Mixing a first alkaline reagent and a catalyst to obtain an aqueous solution;

[0041] The organic solution of 2-hydroxybenzaldehyde is mixed with the aqueous solution to perform a pre-reaction to obtain a pre-reaction solution;

[0042] The pre-reaction liquid, the second alkaline reagent, the methylating reagent and the second organic solvent are mixed to carry out a methylation reaction to obtain 2-methoxybenzaldehyde.

[0043] In the present invention, the first organic solvent is preferably dichloromethane; the first alkaline agent is preferably NaOH.

[0044] In the present invention, the temperature of the pre-reaction is preferably the reflux temperature, and the time is preferably 2 hours. The present invention converts -OH into -ONa (or -OK, -ONH4) through the pre-reaction, which can promote the reaction, wherein the first alkaline reagent acts as a catalyst.

[0045] In the present invention, the second alkaline agent is preferably potassium carbonate, and the second organic solvent is preferably acetone.

[0046] In the present invention, the temperature of the methylation reaction is preferably the reflux temperature, specifically preferably 35 to 45° C., more preferably 40° C.; the time is preferably 1 to 4 hours, more preferably 2 to 3 hours.

[0047] After obtaining the 2-methoxybenzaldehyde, the present invention performs a condensation reaction between the 2-methoxybenzaldehyde and acetaldehyde under alkaline conditions to obtain 2-methoxycinnamaldehyde. In the present invention, the alkaline reagent providing alkaline conditions is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, ammonium acetate and sodium methoxide. In the present invention, the molar ratio of the 2-methoxybenzaldehyde to the alkaline reagent is preferably 1: (1 to 3). In the present invention, the alkaline reagent is preferably added in the form of an aqueous solution.

[0048] In the present invention, the molar ratio of 2-methoxybenzaldehyde to acetaldehyde is preferably 1:(1-3), more preferably 1:(1-2).

[0049] In the present invention, 2-methoxybenzaldehyde is preferably dissolved in an organic solvent to carry out the condensation reaction. The organic solvent is preferably one or more of ethanol, methanol, n-butanol, n-propanol and tert-butanol.

[0050] In the present invention, the temperature of the condensation reaction is preferably 10 to 20° C., more preferably 15 to 20° C.; the time is preferably 1 to 3 hours, more preferably 1 to 2 hours.

[0051] After the condensation reaction, the present invention preferably performs post-treatment on the obtained condensation reaction solution; in the present invention, the post-treatment preferably comprises the following steps:

[0052] The obtained condensation reaction liquid is sequentially subjected to acid neutralization and extraction to obtain an organic phase;

[0053] The organic phase is washed, dried and recrystallized in sequence to obtain pure 2-methoxycinnamaldehyde.

[0054] In the present invention, the acidic agent used in the acid neutralization is preferably hydrochloric acid. The present invention quenches the reaction by the acid neutralization.

[0055] In the present invention, the reagent used in the extraction is preferably ethyl acetate. In the present invention, the detergent used in the washing is preferably water.

[0056] In the present invention, the desiccant used for the drying is preferably sodium sulfate. The present invention has no special requirements for the recrystallization method, and a recrystallization method well known to those skilled in the art can be used.

[0057] In the present invention, the synthesis route of 2-methoxycinnamaldehyde is shown in Formula 1.

[0058]

[0059] The synthesis method of 2-methoxycinnamaldehyde provided by the present invention is described in detail below in conjunction with the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0060] Example 1

[0061] (1) Synthesis of 2-methoxybenzaldehyde

[0062]

[0063] 3.3 g of 2-hydroxybenzaldehyde was dissolved in 20 mL of dimethylformamide, 1.2 g of NaOH and 0.2 g of TEBA were dissolved in 20 mL of water, the two solutions were mixed, and refluxed for 1 h; 2.0 g of potassium carbonate was added to the solution, and then 5 g of dimethyl carbonate was added, and refluxed with 30 mL of dimethylformamide to obtain 2-methoxybenzaldehyde with a yield of 98.9% and a purity of 99.7% as shown by GC detection.

[0064] The GC chart of the obtained 2-methoxybenzaldehyde is as follows: Figure 1 shown.

[0065] (2) Synthesis of 2-methoxycinnamaldehyde

[0066]

[0067] 1.16g of 2-methoxybenzaldehyde was dissolved in 20mL of ethanol, 1.5g of NaOH was dissolved in 50mL of a mixed solution of ethanol / water, the solution was cooled to 10°C, 5mL of acetaldehyde was dropped into the solution, and the reaction was carried out at 20°C for 1h. The reaction mixture was neutralized with 20mL of HCl, the reaction was interrupted, and the organic phase was extracted twice with ether, and washed with water. Finally, the product was dried with sodium sulfate, filtered, and crystals were obtained, which were then purified by recrystallization, with a yield of 90%, and a purity of 95% as shown by GC detection.

[0068] The obtained 2-methoxycinnamaldehyde 1 H-NMR images Figure 2 shown.

[0069] Example 2

[0070] (1) Synthesis of 2-methoxybenzaldehyde

[0071]

[0072] 6 g of 2-hydroxybenzaldehyde was dissolved in 30 mL of ethanol, 2 g of NaOH and 0.22 g of TBAB were dissolved in 30 mL of water, the two solutions were mixed, and refluxed for 1 h; 2.5 g of potassium carbonate was added to the solution, and then 5.3 g of dimethyl carbonate was added, and refluxed with 50 mL of DMF to obtain 2-methoxybenzaldehyde with a yield of 99% and a purity of 99.5% as shown by GC detection.

[0073] (2) Synthesis of 2-methoxycinnamaldehyde

[0074]

[0075] 1.3g of 2-methoxybenzaldehyde was dissolved in 20mL of ethanol, 2g of KOH was dissolved in 50mL of a mixed solution of ethanol / water, the solution was cooled to 10°C, 5.6mL of acetaldehyde was dropped into the solution, and the reaction was carried out at 15°C for 1h. The reaction mixture was neutralized with 20mL of HCl, the reaction was interrupted, and the organic phase was extracted twice with ether, and washed with water. Finally, the product was dried with sodium sulfate, filtered, and crystals were obtained, which were then purified by recrystallization, with a yield of 92% and a purity of 96% as shown by GC detection.

[0076] Example 3

[0077] (1) Synthesis of 2-methoxybenzaldehyde

[0078]

[0079] 5.3 g of 2-hydroxybenzaldehyde was dissolved in 50 mL of dichloromethane, 1.3 g of NaOH and 0.4 g of tetrabutylammonium chloride were dissolved in 50 mL of water, the two solutions were mixed, and refluxed for 2 h; 3.0 g of potassium carbonate was added to the solution, and then 6 g of iodomethane was added, and refluxed with 50 mL of acetone to obtain 2-methoxybenzaldehyde with a yield of 99.3% and a purity of 99.1% as shown by GC detection.

[0080] (2) Synthesis of 2-methoxycinnamaldehyde

[0081]

[0082] Dissolve 1.4g of 2-methoxybenzaldehyde in 20mL of ethanol, dissolve 1.7g of NaOH in 50mL of water, cool the solution to 10°C, drop 5.7mL of acetaldehyde into the solution, and react at 20°C for 1h. Neutralize the reaction mixture with 20mL of HCl, interrupt the reaction, extract twice with petroleum ether, and wash the organic phase with water. Finally, dry with sodium sulfate, filter to obtain crystals, and then recrystallize for purification, with a yield of 94%, and GC detection shows a purity of 96%.

[0083] Example 4

[0084] (1) Synthesis of 2-methoxybenzaldehyde

[0085]

[0086] 5.5 g of 2-hydroxybenzaldehyde was dissolved in 50 mL of dichloromethane, and 1.5 g of NaOH and 0.5 g of TBAB were dissolved in 50 mL of water. The two solutions were mixed and refluxed for 2 h. 3.5 g of potassium carbonate and 6.3 g of iodomethane were added to the solution, and refluxed with 50 mL of acetone to obtain 2-methoxybenzaldehyde with a yield of 99.2% and a purity of 98.1% as shown by GC detection.

[0087] (2) Synthesis of 2-methoxycinnamaldehyde

[0088]

[0089] Dissolve 1.7g of 2-methoxybenzaldehyde in 20mL of ethanol, dissolve 2.3g of NaOH in 50mL of water, cool the solution to 10°C, drop 5.4mL of acetaldehyde into the solution, and react at 20°C for 1h. Neutralize the reaction mixture with 20mL of HCl, interrupt the reaction, extract twice with petroleum ether, and wash the organic phase with water. Finally, dry with sodium sulfate, filter to obtain crystals, and then recrystallize for purification, with a yield of 96%, and GC detection shows a purity of 97%.

[0090] Example 5

[0091] (1) Synthesis of 2-methoxybenzaldehyde

[0092]

[0093] 10 g of 2-hydroxybenzaldehyde was dissolved in 70 mL of dichloromethane, 3 g of NaOH and 0.7 g of tetrabutylammonium hydrogen sulfate were dissolved in 70 mL of water, the two solutions were mixed, and refluxed for 2.5 h; 10 g of dimethyl sulfate was added, and refluxed with 100 mL of ethanol to obtain 2-methoxybenzaldehyde with a yield of 98.2% and a purity of 98.17% as shown by GC detection.

[0094] (2) Synthesis of 2-methoxycinnamaldehyde

[0095]

[0096] Dissolve 4g of 2-methoxybenzaldehyde in 20mL of ethanol, dissolve 6.4g of NaOH in 50mL of ethanol solution, cool the solution to 5°C, drop 10mL of acetaldehyde into the solution, and react for 2h at 20°C. Neutralize the reaction mixture with 20mL of HCl, interrupt the reaction, extract twice with petroleum ether, and wash the organic phase with water. Finally, dry with sodium sulfate, filter to obtain crystals, and then recrystallize for purification, with a yield of 93%, and GC detection shows a purity of 98.2%.

[0097] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for synthesizing 2-methoxycinnamaldehyde, comprising the following steps: (1) Dissolve 10 g of 2-hydroxybenzaldehyde in 70 mL of dichloromethane, dissolve 3 g of NaOH and 0.7 g of tetrabutylammonium hydrogen sulfate in 70 mL of water, mix the two solutions, and reflux for 2.5 h; add 10 g of dimethyl sulfate, and reflux with 100 mL of ethanol to obtain 2-methoxybenzaldehyde; (2) 4 g of 2-methoxybenzaldehyde was dissolved in 20 mL of ethanol, and 6.4 g of NaOH was dissolved in 50 mL of ethanol solution. The solution was cooled to 5° C., 10 mL of acetaldehyde was dropped into the solution, and the reaction was carried out at 20° C. for 2 h. The reaction mixture was neutralized with 20 mL of HCl, the reaction was interrupted, and the organic phase was extracted twice with petroleum ether, and the organic phase was washed with water. Finally, the product was dried with sodium sulfate, filtered, and crystals were obtained, which were then purified by recrystallization.

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