CN115368272A

CN115368272A - Preparation method of 4-cyano-2-methoxybenzaldehyde

Info

Publication number: CN115368272A
Application number: CN202211058782.5A
Authority: CN
Inventors: 柴金柱; 陈杨; 李堃; 罗江胜
Original assignee: Hanrui Pharmaceutical Jingmen Co ltd
Current assignee: Hanrui Pharmaceutical Jingmen Co ltd
Priority date: 2022-08-31
Filing date: 2022-08-31
Publication date: 2022-11-22

Abstract

The invention discloses a preparation method of 4-cyano-2-methoxybenzaldehyde, which comprises the steps of reacting 3-methoxy-4-methylbenzoic acid with thionyl chloride, then reacting with ammonia water to obtain 3-methoxy-4-methylbenzamide, enabling the 3-methoxy-4-methylbenzamide to generate 3-methoxy-4-methylbenzonitrile in the presence of trifluoroacetic anhydride and N-methylmorpholine, then brominating the 3-methoxy-4-methylbenzonitrile on NBS to obtain 4-dibromomethyl-3-methoxybenzonitrile, and finally reacting with sodium iodide for hydrolysis to obtain 4-cyano-2-methoxybenzaldehyde; the preparation method of the invention reduces the use of toxic reagents, avoids high-temperature reaction, reduces the use of palladium catalysts, greatly reduces the production cost and improves the operation convenience.

Description

Preparation method of 4-cyano-2-methoxybenzaldehyde

Technical Field

The invention belongs to the technical field of medicine production, and particularly relates to a preparation method of 4-cyano-2-methoxybenzaldehyde.

Background

The molecular formula of the 4-cyano-2-methoxy benzaldehyde is

The synthesis is very difficult, and the following routes are reported in related documents at present:

。

the route starts from a compound 1, and a target compound 4 is obtained through methylation, reduction and coupling.

The first step of the reaction of the route uses a toxic reagent, namely dimethyl sulfate, which is dangerous; the second step of the reaction of the route needs red aluminum which has inflammability; and the third step uses noble metal palladium, so that the production cost is greatly increased.

Disclosure of Invention

The invention aims to provide a preparation method of 4-cyano-2-methoxybenzaldehyde, which solves the problems in the background technology.

The technical scheme adopted by the invention for solving the technical problems is as follows: a preparation method of 4-cyano-2-methoxybenzaldehyde comprises the following steps in sequence:

s1, taking dichloromethane as a solvent, reacting 3-methoxy-4-methylbenzoic acid with thionyl chloride, adding the obtained intermediate into ammonia water, and reacting to obtain 3-methoxy-4-methylbenzamide;

s2, reacting 3-methoxy-4-methylbenzamide with trifluoroacetic anhydride and N-methylmorpholine to generate 3-methoxy-4-methylbenzonitrile by taking dichloromethane as a solvent;

s3, then brominating the 3-methoxy-4-methylbenzonitrile by using NBS to obtain 4-dibromomethyl-3-methoxybenzonitrile, wherein the reaction temperature is 90-95 ℃;

and S4, reacting the 4-dibromomethyl-3-methoxybenzonitrile with sodium iodide, and hydrolyzing to obtain the 4-cyano-2-methoxybenzaldehyde.

The preparation method of the 4-cyano-2-methoxybenzaldehyde comprises the following steps of S1: adding 500mL of dichloromethane into a 1000mL three-mouth reaction bottle, cooling to 0-5 ℃, adding 50g of 3-methoxy-4-methylbenzoic acid, slowly dropwise adding 53.68 g of thionyl chloride, keeping the temperature at 0-5 ℃, stirring for 1 hour, controlling the reaction in TLC, concentrating under reduced pressure to remove the solvent, adding 50mL of dichloromethane solvent into the residue to dissolve, slowly dropwise adding the solution into a mixed solution of 50mL of 7M ammonia water and 500mL of methanol, keeping the temperature at 10-30 ℃, stirring for 12h, controlling the reaction in TLC to remove the solvent, concentrating under reduced pressure to remove the solvent, adding 100mL of water and 200mL of ethyl acetate into the concentrated residue, extracting and separating, extracting the aqueous phase with 50mL of ethyl acetate again, washing the combined organic phase with 50mL of saturated sodium chloride aqueous solution once, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 45g of pale yellow solid 3-methoxy-4-methylbenzamide.

The preparation method of the 4-cyano-2-methoxybenzaldehyde comprises the following steps of S2: adding 20.0 g of 3-methoxy-4-methylbenzamide and 200mL of DCM into a 500mL three-mouth reaction bottle, then adding 18.37g of N-methylmorpholine, cooling to 0-5 ℃, then slowly dropwise adding 38.14g of TFAA, keeping the temperature at 0-10 ℃, after dropwise adding, heating to 40-45 ℃, stirring for 12h, after TLC is finished, pouring 100mL of clear water into the reaction solution, stirring for 30 minutes, drying an organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 13.78 g of light yellow solid 3-methoxy-4-methylbenzonitrile with the purity of 96.5%.

The preparation method of the 4-cyano-2-methoxybenzaldehyde comprises the following steps of S3: adding 10.00g of 3-methoxy-4-methylbenzonitrile and 100mL of DCE into a 250mL three-mouth reaction bottle in sequence, then adding 25.39 g of NBS into the mixed solution, finally adding 1g of AIBN, then replacing with nitrogen for three times, heating to 90-95 ℃, stirring for 12 hours, after the TLC controlled reaction is finished, adding clear water into the reaction solution, separating, washing the organic phase with 50mL of 1N sodium hydroxide aqueous solution, drying with anhydrous sodium sulfate, and concentrating to obtain 17.75 g of yellow solid 4-dibromomethyl-3-methoxybenzonitrile.

The preparation method of the 4-cyano-2-methoxybenzaldehyde comprises the following steps of S4: 17.75 g of 4-dibromomethyl-3-methoxybenzonitrile is added into a 500mL three-mouth reaction bottle, 150mL of acetonitrile and 30 mL of clear water are added, 872.39 mg of sodium iodide is added, the temperature is finally raised to 75-85 ℃, stirring is carried out for 1699 h, TLC detection is carried out to detect that the reaction is finished, 450mL of clear water is added into the reaction liquid, stirring is carried out for 30 minutes, filtering is carried out, a filter cake is stirred for 30 minutes at about 0 ℃ by using 40 mL of ethanol, filtering is carried out, and the filter cake is dried to obtain 7.05 g of 4-cyano-2-methoxybenzaldehyde as a light yellow solid.

The invention has the technical effects and advantages that: at present, toxic reagents, flammable reagents and noble metals or oxidizing agents are used in the synthesis method of 4-cyano-2-methoxybenzaldehyde, so that the safety risk of the production process is high, and the production cost is high; the invention reduces the use of toxic reagents and avoids flammable and explosive reagents; the potential safety hazard of the oxidant in production avoids the use of noble metals such as palladium and the like, reduces the production cost, greatly simplifies the post-treatment operation, and provides a brand-new reliable high-yield process synthesis method for synthesizing the compound.

Detailed Description

The following will clearly and completely describe the technical solutions in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Example 1

The synthetic route of the 4-cyano-2-methoxybenzaldehyde disclosed by the invention is as follows:

。

the method comprises the following specific steps:

S1，has a structural formula of

The 3-methoxy-4-methyl benzoic acid is reacted with thionyl chloride to obtain a compound with the structure of

The intermediate B reacts with ammonia water to obtain the intermediate B with the structural formula

3-methoxy-4-methylbenzamide.

The preparation method comprises the following specific steps: adding 500mL of dichloromethane into a 1000mL three-mouth reaction bottle, cooling to 0-5 ℃, then adding 50g of 3-methoxy-4-methylbenzoic acid, slowly dropwise adding 53.68 g of thionyl chloride, keeping the temperature at 0-5 ℃, stirring for 1 hour, controlling the reaction in TLC, and removing the solvent by concentration under reduced pressure. After 50mL of a dichloromethane solvent was added to the residue, the mixture was slowly added dropwise to a mixed solution of 50mL of 7M aqueous ammonia and 500mL of methanol, and the mixture was stirred for 12 hours while maintaining the temperature at 10 to 30 ℃. After the TLC reaction was completed, the solvent was removed by concentration under reduced pressure, 100ml of water and 200ml of ethyl acetate were added to the concentrated residue, the mixture was separated by extraction, the aqueous phase was extracted again with 50ml of ethyl acetate, and the combined organic phases were washed once with 50ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 45g of pale yellow solid 3-methoxy-4-methylbenzamide.

S2, generating the 3-methoxy-4-methylbenzamide obtained in the step in the presence of NMO and TFAA to obtain a compound with a structural formula

The reaction solvent is DCM.

The preparation method comprises the following specific steps: in a 500mL three-necked reaction flask, 20.0 g of 3-methoxy-4-methylbenzamide and 200mL of DCM are charged, and then 18.37g of N-methylmorpholine are added and the temperature is reduced to 0-5 ℃. Then, 38.14g of TFAA is slowly dripped, the temperature is kept between 0 and 10 ℃, and after the dripping is finished, the temperature is increased to 40 to 45 ℃ and the mixture is stirred for 12 hours. After the TLC medium-control reaction is finished, the reaction solution is poured into 100mL of clear water and stirred for 30 minutes, and after an organic phase is dried by anhydrous sodium sulfate, the organic phase is concentrated under reduced pressure to obtain 13.78 g of light yellow solid 3-methoxy-4-methylbenzonitrile with the purity of 96.5 percent.

S3, then bromine is added to the 3-methoxy-4-methyl benzonitrile by NBS to obtain the compound with the structural formula

4-dibromomethyl-3-methoxybenzonitrile.

The preparation method comprises the following specific steps: 10.00g of 3-methoxy-4-methylbenzonitrile and 100mL of DCE were sequentially charged into a 250mL three-necked reaction flask, and then 25.39 g of NBS and finally 1g of AIBN were added to the mixed solution. Then replacing with nitrogen for three times, heating to 90-95 ℃, stirring for 12 hours, after the TLC controlled reaction is finished, adding clear water into the reaction solution, separating, washing the organic phase with 50mL of 1N sodium hydroxide aqueous solution, drying with anhydrous sodium sulfate, and concentrating to obtain 17.75 g of yellow solid 4-dibromomethyl-3-methoxybenzonitrile.

S4, hydrolyzing the 4-dibromomethyl-3-methoxy benzonitrile obtained in the step by sodium iodide to obtain a compound with a structural formula shown in the specification

4-cyano-2-methoxybenzaldehyde.

The preparation method comprises the following specific steps: 17.75 g of 4-dibromomethyl-3-methoxybenzonitrile is added into a 500mL three-mouth reaction flask to 150mL of acetonitrile and 30 mL of clear water, 872.39 mg of sodium iodide is added, the temperature is finally raised to 75-85 ℃, stirring is carried out for 1693 h, and the TLC detection reaction is finished. 450mL of clear water was added to the reaction mixture, and the mixture was stirred for 30 minutes. After filtration, the filter cake was stirred with 40 ml of ethanol at about 0 ℃ for 30 minutes and then filtered, and the filter cake was dried to obtain 7.05 g of 4-cyano-2-methoxybenzaldehyde as a pale yellow solid.

Although the present invention has been described with reference to a preferred embodiment, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims

1. A preparation method of 4-cyano-2-methoxybenzaldehyde is characterized by comprising the following steps: comprises the following steps

s3, brominating the 3-methoxy-4-methylbenzonitrile by using NBS to obtain 4-dibromomethyl-3-methoxybenzonitrile, wherein the reaction temperature is 90-95 ℃;

2. The preparation method of 4-cyano-2-methoxybenzaldehyde according to claim 1, wherein the step S1 specifically comprises: adding dichloromethane and 3-methoxy-4-methylbenzoic acid into a three-mouth reaction bottle, cooling to 0-5 ℃, adding thionyl chloride, keeping the temperature at 0-5 ℃, stirring for 1 hour, performing TLC (thin layer chromatography) controlled reaction, concentrating and drying reaction liquid, dissolving the reaction liquid with dichloromethane, slowly dropwise adding the reaction liquid into a mixed solution of ammonia water and methanol, keeping the temperature at 10-30 ℃, stirring for 12h, performing TLC controlled reaction, performing reduced pressure concentration to remove a solvent, adding dichloromethane, extracting, and drying to obtain a light yellow solid 3-methoxy-4-methylbenzonitrile.

3. The preparation method of 4-cyano-2-methoxybenzaldehyde according to claim 2, wherein the step S2 specifically comprises: adding 3-methoxy-4-methylbenzamide and dichloromethane into a three-mouth reaction bottle, cooling to 0-5 ℃, adding N-methylmorpholine, dropwise adding trifluoroacetic anhydride slowly in batches, keeping the temperature at 0-5 ℃, stirring for 1 hour, heating to 40-45 ℃, stirring for 12h, after TLC (thin layer chromatography) controlled reaction is finished, adding the reaction solution into cold clear water, stirring for 30 minutes, extracting, and drying organically to obtain a light yellow solid 3-methoxy-4-methylbenzonitrile.

4. The preparation method of 4-cyano-2-methoxybenzaldehyde according to claim 3, wherein the step S3 specifically comprises: adding 3-methoxy-4-methylbenzonitrile, DCE and NBS into a three-mouth reaction bottle, adding AIBN, replacing the mixture with nitrogen for three times, heating to 90 ℃, stirring for 12 hours, pouring clear water into TLC after the reaction is finished, stirring for 30 minutes, separating liquid, washing an organic phase with 1N sodium hydroxide aqueous solution, drying anhydrous sodium sulfate, and concentrating under reduced pressure to obtain yellow solid 4-dibromomethyl-3-methoxybenzonitrile.

5. The preparation method of 4-cyano-2-methoxybenzaldehyde according to claim 4, wherein the step S4 specifically comprises: adding 4-dibromomethyl-3-methoxybenzonitrile, acetonitrile, water and sodium iodide into a three-mouth reaction flask, heating to 90 ℃, stirring for 12 hours, pouring into clear water after TLC (thin layer chromatography) neutral control reaction is finished, stirring for 30 minutes, filtering, pulping a filter cake by using ethanol, filtering, and drying to obtain light yellow solid 4-cyano-2-methoxybenzaldehyde.