WO2019100786A1

WO2019100786A1 - Method for synthesizing 3-ethoxy-4-methoxybenzaldehyde

Info

Publication number: WO2019100786A1
Application number: PCT/CN2018/102292
Authority: WO
Inventors: 李彦雄; 徐亮; 毛波
Original assignee: 中山奕安泰医药科技有限公司
Priority date: 2017-11-23
Filing date: 2018-08-24
Publication date: 2019-05-31
Also published as: CN107827722A; CN107827722B

Abstract

Provided is a method for synthesizing 3-ethoxy-4-methoxybenzaldehyde, comprising the following steps: by using isovanillin and a halogenated ethane as raw materials, stirring the reaction in a solvent under the action of a base and a catalyst and filtering to obtain 3-ethoxy-4-methoxybenzaldehyde. The reaction of the method is simple to operate and safe, the equipment is simple, the product can be easily separated, and the management of the three wastes is simple and easy.

Description

Method for synthesizing 3-ethoxy-4-methoxybenzaldehyde

Technical field

The invention belongs to the field of synthesis of pharmaceutical chemical intermediates, and mainly relates to a method for synthesizing 3-ethoxy-4-methoxybenzaldehyde.

Background technique

Psoriasis is a chronic inflammation type of skin disease that has a long course of disease and is prone to recurrence. It is estimated that there are 2%-3% of patients in the world. The clinical manifestations are erythema and scaling of the skin; it can be divided into pustular, arthritic, common, and erythrodermic. The cause of psoriasis is still unclear. It is generally considered to be related to genetic, immune abnormalities, endocrine and other factors. Drug therapy is mainly divided into traditional drugs and biological agents.

Celgene Corporation has successfully developed a phosphodiesterase-4 (PDE-4) inhibitor, Apster, by modifying the traditional drug thalidomide, which is passed through adenosine monophosphate ( cAMP) is specific, increases cellular cAMP levels, inhibits the activity of multiple inflammations involved in the pathogenesis of psoriasis, and is effective in treating psoriasis.

Apster is an oral small molecule PDE-4 inhibitor that is less expensive and more convenient than the biological agents used for injection; in the central nervous system, Alpst has fewer side effects than other PDE-4 inhibitors.

3-Ethoxy-4-methoxybenzaldehyde as a material intermediate for the synthesis of Apost, its ease of synthesis directly affects the market prospects of Apost. At present, the main synthetic routes of 3-ethoxy-4-methoxybenzaldehyde are as follows:

Method one: using isovanillin as a raw material and ethylating with diethyl sulfate under basic conditions to obtain the target product a, the yield is about 80%.

Method 2: using vanilloid as a raw material, and substituting with an alkyl halide to obtain the target product a, the yield is about 70%.

Method 3: The method is similar to the method (1). The ethyl vanillin is used as a raw material, and methylated with dimethyl sulfate or methyl iodide to obtain the target product a, and the yield thereof is 83-85%.

However, all of the above methods have defects. In the first method, DMF is used as a solvent to make the product inconvenient to be distilled or extracted, resulting in a low yield (80%); in both methods 2 and 3, dimethyl sulfate or inevitably is used. Diethyl sulfate These highly toxic substances are highly harmful to the human body or the environment and are not suitable for industrial production.

Summary of the invention

In view of the deficiencies of the prior art, it is an object of the present invention to provide a process for the synthesis of 3-ethoxy-4-methoxybenzaldehyde. The use of water as a reflection medium avoids the use of an organic solvent. The method of the invention is simple and safe in reaction, the obtained product is easy to separate, the three wastes are easy to handle, the equipment used in the reaction process is simple, no special equipment is needed, and no high pressure is required. It can be implemented under conditions such as high vacuum, and is an environmentally friendly green synthetic process.

In order to achieve the above object, the present invention adopts the following technical solutions:

A method for synthesizing 3-ethoxy-4-methoxybenzaldehyde, comprising the steps of: using isoamyl lanolin and halogenated ethane as raw materials, stirring the reaction in a solvent under the action of a base and a catalyst; Filtration to give 3-ethoxy-4-methoxybenzaldehyde, the reaction formula is as follows:

Wherein the equivalent ratio of the iso-vanillin to the base is 1: (1.1-1.5);

The equivalent ratio of the isovanelin to the catalyst is 1: (0.1-0.5);

The equivalent ratio of the isovanillin to the haloethane is 1: (1.1-1.5).

Preferably, the haloethane is ethyl bromide.

Preferably, the solvent is water.

Preferably, the base is at least one selected from the group consisting of cesium carbonate, N,N-diisopropylethylamine, sodium hydroxide, potassium carbonate, triethylamine, and pyridine.

Further preferably, the base is sodium hydroxide.

Preferably, the catalyst is a phase transfer catalyst.

Further preferably, the catalyst is selected from at least one of polyethylene glycol, tetrabutylammonium bromide, benzyltriethylammonium chloride, and tetrabutylammonium fluoride.

More preferably, the catalyst is tetrabutylammonium bromide.

Preferably, the reaction temperature is from 0 to 60 ° C for a period of from 3 to 6 hours.

The beneficial effects of the invention:

(1) The synthesis method of the invention is simple in operation, the reaction condition selected is mild (0-60 ° C), the selected reagent is easy to obtain, the three wastes are small, and the highly toxic substance dimethyl sulfate or diethyl sulfate is avoided, and the environment is friendly. , the damage to the human body is small;

(2) The synthesis method of the present invention uses water as a solvent, and does not require complicated post-treatment. After the reaction is completely filtered, the high-purity (HPLC 99.0% or more) and high yield (molar yield of 95% or more) are obtained. product;

(3) The synthesis method of the present invention has low production cost and is suitable for industrial production.

Detailed ways

For a better explanation of the present invention, the following specific embodiments are further illustrated, but the invention is not limited to the specific embodiments.

Example 1

In a 3 L dry reaction flask, 157 g of sodium hydroxide was dissolved in 1500 ml of water, 500 g of isovanillin, 120 g of tetrabutylammonium fluoride and 537 g of ethyl bromide were added, and the reaction was stirred at 25 ° C for 4 h. Filtration was carried out to give 3-ethyloxy-4-methoxybenzaldehyde as a white solid powder, which had a purity of 99.9% and a yield of 96.1%.

Example 2

In a 3 L dry reaction flask, 542 g of potassium carbonate was dissolved in 1500 ml of water, 500 g of isovanillin, 120 g of tetrabutylammonium fluoride and 537 g of ethyl bromide were added, and the reaction was stirred at 25 ° C for 4 h. Filtration gave the white solid powder 3-ethoxy-4-methoxybenzaldehyde with a purity of 99.8% and a yield of 95.1%.

Example 3

In a 3 L dry reaction flask, 157 g of sodium hydroxide was dissolved in 1500 ml of water, 500 g of isovanillin, 104 g of benzyltriethylammonium chloride and 537 g of ethyl bromide were added, and the reaction was stirred at 25 ° C. After 4 h, suction filtration gave 3-ethyloxy-4-methoxybenzaldehyde as a white solid, which had a purity of 99.9% and a yield of 94.8%.

Example 4

In a 3 L dry reaction flask, 198 g of sodium hydroxide was dissolved in 1500 ml of water, 500 g of isovanillin, 120 g of tetrabutylammonium fluoride, and 537 g of ethyl bromide were added, and the reaction was stirred at 25 ° C for 4 h. Filtration was carried out to obtain 3-white ethoxy-4-methoxybenzaldehyde as a white solid, which had a purity of 99.8% and a yield of 95.3%.

The above is only the specific embodiment of the present invention, and is not intended to limit the scope of the invention, and equivalent transformations made by the present invention, or directly or indirectly applied to other related technical fields, are equally included in the present invention. Within the scope of patent protection.

Claims

A method for synthesizing 3-ethoxy-4-methoxybenzaldehyde, comprising the steps of: using isovanillin and halogenated ethane as raw materials, under the action of a base and a catalyst, in a solvent After stirring the reaction, it was filtered to give 3-ethoxy-4-methoxybenzaldehyde, and the reaction was as follows:

Wherein the equivalent ratio of the iso-vanillin to the base is 1: (1.1-1.5);

The equivalent ratio of the isovanelin to the catalyst is 1: (0.1-0.5);

The equivalent ratio of the isovanillin to the haloethane is 1: (1.1-1.5).
The method for synthesizing 3-ethoxy-4-methoxybenzaldehyde according to claim 1, wherein the halogenated ethane is ethyl bromide.
The method for synthesizing 3-ethoxy-4-methoxybenzaldehyde according to claim 1, wherein the solvent is water.
The method for synthesizing 3-ethoxy-4-methoxybenzaldehyde according to claim 1, wherein the base is selected from the group consisting of cesium carbonate, N,N-diisopropylethylamine, and sodium hydroxide. At least one of potassium carbonate, triethylamine, and pyridine.
The method for synthesizing 3-ethoxy-4-methoxybenzaldehyde according to claim 1, wherein the base is sodium hydroxide.
The method for synthesizing 3-ethoxy-4-methoxybenzaldehyde according to claim 1, wherein the catalyst is a phase transfer catalyst.
The method for synthesizing 3-ethoxy-4-methoxybenzaldehyde according to claim 1 or 6, wherein the catalyst is selected from the group consisting of polyethylene glycol, tetrabutylammonium bromide, and benzyltriazole At least one of ethyl ammonium chloride and tetrabutyl ammonium fluoride.
The method for synthesizing 3-ethoxy-4-methoxybenzaldehyde according to claim 1 or 6, wherein the catalyst is tetrabutylammonium bromide.
The method for synthesizing 3-ethoxy-4-methoxybenzaldehyde according to claim 1, wherein the reaction temperature is 0-60 ° C and the time is 3-6 h.