Preparation method of 1-(2-hydroxy-3-methoxyphenyl) ethanone

Abstract

The invention discloses a preparation method of 1-(2-hydroxy-3-methoxyphenyl) ethanone, which sequentially comprises the following steps: carrying out esterification reaction on 5-bromo-2-methoxyphenol serving as a raw material and an acetylation reagent in a solvent to generate an intermediate I; carrying out Fries rearrangement reaction on the intermediate I in a solvent under the catalytic action of a catalyst to generate an intermediate II; and carrying out reductive hydrogenation reaction on the intermediate II in a solvent containing ammonium formate under the catalytic action of a palladium-carbon catalyst to generate 1-(2-hydroxy-3-methoxyphenyl) ethanone. According to the preparation method, raw materials are easy to obtain, dangerous reagents such as methyl lithium and methyl magnesium bromide which are high in price and not easy to store are not used, reaction conditions are mild, side reactions are reduced, operation is simple and easy to control, and the requirement for experimental equipment is not high; the intermediate and the product can be purified through the steps of extraction, reduced-pressure evaporation to dryness, solvent impurity removal, suction filtration, drying and the like, the purity of the target product reaches up to 99% or above, column chromatography and other methods which are inconvenient for industrial operation are not used for post-treatment of the whole route, and the method is simple, convenient and easy to implement.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a method for preparing 1-(2-hydroxy-3-methoxyphenyl)ethyl ketone. Background Technology

[0002] 1-(2-hydroxy-3-methoxyphenyl)ethyl ketone is an important intermediate in fine chemicals, pharmaceuticals, and pesticides, with broad application prospects in organic synthesis and the pharmaceutical industry. In recent years, 1-(2-hydroxy-3-methoxyphenyl)ethyl ketone has been widely used as an intermediate in the synthesis of the coronary vasodilator trimetazidine hydrochloride and the calcium channel blocker lomerizine, the synthesis of amino acid alkylphenol ether inhibitors of influenza A virus, and the synthesis of herbicides such as 4-phenylcoumarin and its thio derivatives. It also serves as a key precursor in the synthesis of the MEK inhibitor PD98059 (2-(2-amino-3-methoxyphenyl)chromone), which can block the ERK1 / 2 signaling pathway and has significant value in cancer research such as melanoma.

[0003] Currently, the main methods for synthesizing 1-(2-hydroxy-3-methoxyphenyl)ethyl ketone are as follows:

[0004] US08093273B2 discloses a route for synthesizing 1-(2-hydroxy-3-methoxyphenyl)ethyl ketone using 3-methoxysalicylic acid as a starting material, which is difficult to obtain and prepare. Furthermore, the synthesis of the target product 1-(2-hydroxy-3-methoxyphenyl)ethyl ketone requires the use of highly hazardous methyllithium, making the operation cumbersome and the post-processing complex.

[0005] Du, Zhen-Ting et al. (Journal of Chemical Research, 2010, #4, pp. 222-227) reported a route for the synthesis of 1-(2-hydroxy-3-methoxyphenyl)ethyl ketone, directly synthesizing the target product 1-(2-hydroxy-3-methoxyphenyl)ethyl ketone from 1-(2,3-dimethoxyphenyl)ethyl ketone. The starting material, 1-(2,3-dimethoxyphenyl)ethyl ketone, is a difficult-to-obtain compound to synthesize in its own samples, and there are no commercially available products.

[0006] The invention patent application with application number CN201610863586 reports a process for preparing 1-(2-hydroxy-3-methoxyphenyl)ethyl ketone. Using o-vanillin as raw material, 1-(2-hydroxy-3-methoxyphenyl)ethyl ketone is obtained through a four-step reaction of adding a protecting group, alkylation, oxidation and deprotection. Among them, the alkylation step uses magnesium methyl bromide, which can spontaneously combust in air when dry and is extremely flammable when exposed to open flame or high heat, posing a certain danger. The oxidation step is also a high-risk process.

[0007] In summary, most existing methods for synthesizing 1-(2-hydroxy-3-methoxyphenyl)ethyl ketone suffer from drawbacks such as the use of non-commercially available raw materials, difficulty in self-synthesis, complex synthesis processes, cumbersome post-processing, high costs, and significant risks, hindering industrial application. Therefore, this invention proposes a method for preparing 1-(2-hydroxy-3-methoxyphenyl)ethyl ketone to address these technical problems. Summary of the Invention

[0008] The purpose of this invention is to overcome the shortcomings of existing technologies and provide a method for preparing 1-(2-hydroxy-3-methoxyphenyl)ethyl ketone. Using 5-bromo-2-methoxyphenol as a raw material, 1-(2-hydroxy-3-methoxyphenyl)ethyl ketone is obtained through a series of esterification, Fres rearrangement, and reductive hydrogenation reactions. The raw materials are readily available, and expensive and difficult-to-store reagents such as lithium methyl bromide and magnesium methyl bromide are not used. The reaction conditions are relatively mild, reducing side reactions. The operation is simple and easy to control, and the requirements for experimental equipment are not high. Intermediates and products can be purified through extraction, vacuum evaporation, solvent removal, filtration, and drying. The purity of the target product is as high as 99% or more. The post-processing of the entire route does not use methods inconvenient for industrial operation, such as column chromatography, making it simple and easy to implement.

[0009] To achieve the above objectives, the technical solution of the present invention is to design a method for preparing 1-(2-hydroxy-3-methoxyphenyl)ethyl ketone, comprising the following steps:

[0010] S1: Using 5-bromo-2-methoxyphenol as a starting material, intermediate I is generated by esterification with an acetylation reagent in a solvent, as shown in Formula 1 below:

[0011]

[0012] Intermediate I

[0013] Formula 1;

[0014] S2: Intermediate I in a solvent, under the catalysis of a catalyst, undergoes a Fresch rearrangement reaction to generate intermediate II, as shown in Equation 2 below:

[0015]

[0016] Intermediate I Intermediate II Impurities

[0017] Formula 2;

[0018] S3: Intermediate II, in a solvent containing ammonium formate, undergoes a reductive hydrogenation reaction under the catalysis of a palladium-on-carbon catalyst to produce 1-(2-hydroxy-3-methoxyphenyl)ethyl ketone, as shown in Equation 3 below:

[0019]

[0020] Intermediate II

[0021] Formula 3.

[0022] The preferred technical solution is that, in step S1, the acetylation reagent used is one of acetyl chloride and acetic anhydride, the molar ratio of the acetylation reagent to 5-bromo-2-methoxyphenol is 1:1~1.2, the reaction time is 2~6h, and the reaction temperature is 50~120℃.

[0023] Another preferred technical solution is that, in step S2, the catalyst used is one of aluminum trichloride, zinc chloride, titanium tetrachloride, trifluoromethanesulfonate, and methanesulfonic acid, the molar ratio of intermediate I to catalyst is 1:3~5, the reaction time is 4~16h, and the reaction temperature is 20~80℃.

[0024] A preferred technical solution is that, in step S3, the molar ratio of intermediate II to ammonium formate is 1:3~6, the mass ratio of intermediate II to palladium-carbon catalyst is 1:0.1~0.2, and the reaction time is 2~4 hours.

[0025] Further preferred technical solutions include: in step S1, the solvent used is toluene; in step S2, the solvent used is dichloroethane; and in step S3, the solvent used is methanol.

[0026] A further preferred technical solution includes refining and purifying the crude intermediate II containing impurities by dissolving it in a poor solvent.

[0027] The advantages and beneficial effects of this invention are as follows:

[0028] 1. This invention provides a method for preparing 1-(2-hydroxy-3-methoxyphenyl)ethyl ketone, using 5-bromo-2-methoxyphenol as a raw material, and obtaining 1-(2-hydroxy-3-methoxyphenyl)ethyl ketone through esterification, Freis rearrangement, and reductive hydrogenation. The raw materials are readily available, and it does not use expensive and difficult-to-store hazardous reagents such as lithium methyl bromide and magnesium methyl bromide. The reaction conditions are relatively mild, reducing the occurrence of side reactions. The operation is simple and easy to control, and the requirements for experimental equipment are not high.

[0029] 2. The present invention provides a method for preparing 1-(2-hydroxy-3-methoxyphenyl)ethyl ketone. The intermediates and products can be purified by extraction, vacuum evaporation, solvent removal, filtration and drying. The purity of the target product is as high as 99% or more. The post-processing of the entire route does not use methods that are inconvenient for industrial operation, such as column chromatography, and is simple and easy to implement. Attached Figure Description

[0030] Figure 1 This is the 1H NMR spectrum of the target product prepared in Example 1;

[0031] Figure 2 This is a high-performance liquid chromatogram of the target product prepared in Example 1. Detailed Implementation

[0032] The specific embodiments of the present invention will be further described below with reference to the accompanying drawings and examples. The following examples are only used to more clearly illustrate the technical solutions of the present invention and should not be construed as limiting the scope of protection of the present invention.

[0033] Example 1

[0034] The preparation of 1-(2-hydroxy-3-methoxyphenyl)ethyl ketone using the method of the present invention includes the following steps:

[0035] S1: Add 20g of 5-bromo-2-methoxyphenol to a 250mL reaction flask, add 100mL of toluene and 7.73g (1.0eq) of acetyl chloride, heat to 50℃ and react for 2h. Monitor the reaction of 5-bromo-2-methoxyphenol by thin-layer chromatography (Ethyl acetate: n-hexane: triethylamine = 3:8:1). Cool to room temperature, transfer the reaction solution to 100mL of water, stir and separate the layers. Concentrate the toluene layer under reduced pressure to dryness to obtain 21g of intermediate I.

[0036] S2: Add 20g of intermediate I prepared in step S1 to a 250mL reaction flask, add 100mL of dichloroethane and 39.2g (5eq) of methanesulfonic acid, heat to 30℃, and keep the reaction at this temperature for 16h. Monitor the reaction of intermediate I by thin-layer chromatography (TLC) (ethyl acetate: n-hexane: triethylamine = 3:8:1). Cool to room temperature, transfer the reaction solution to 100mL of water, stir and separate the layers. Concentrate the dichloroethane layer under reduced pressure to dryness to obtain 19g of crude intermediate II. Add 57mL of methyl tert-butyl ether to the crude intermediate II and reflux for half an hour. Cool to room temperature, filter, and dry the filter cake at 30℃ to obtain 15g of pure intermediate II.

[0037] S3: Add 11g of intermediate II prepared in step S2 to a 100mL reaction flask, add 55mL of methanol and 1.1g of palladium on carbon catalyst, heat to reflux, and slowly add 8.5g (3eq) of ammonium formate under reflux conditions. Keep the reaction at this temperature for 2h. Monitor the reaction of intermediate II by thin-layer chromatography (TLC) (ethyl acetate: n-hexane: triethylamine = 3:8:1). Filter while hot, concentrate the filtrate under reduced pressure to dryness, and obtain 10g of crude product. Add 200mL of n-hexane to the crude product, heat to reflux to dissolve, filter while hot, cool to 10℃ and keep at this temperature for 1h, filter again, and dry the filter cake at 30℃ with forced air to obtain 6g of pure target product, with a yield of 53% (based on 5-bromo-2-methoxyphenol) and a purity of 99.49%.

[0038] Appendix Figure 1The 1H NMR spectrum of the pure target product prepared in Example 1 is shown below, and the corresponding NMR data are as follows: 1 HNMR (400MHz, DMSO-d6) δ: 12.50 (s, 1H), 7.28-7.26 (d, J = 8.0 Hz, 1H), 7.00-6.98 (d, J = 8.0 Hz, 1H), 6.79-6.75 (t, J = 16.0 Hz, 1H), 3.83 (s, 3H), 2.56 (s, 3H), consistent with the theoretical NMR data of 1-(2-hydroxy-3-methoxyphenyl)ethyl ketone, indicating that the target product is indeed 1-(2-hydroxy-3-methoxyphenyl)ethyl ketone.

[0039] Appendix Figure 2 The image shows a high-performance liquid chromatogram of the target product prepared in Example 1, where JD0257 is 5-bromo-2-methoxyphenol and JD0231 is the target product. The data shows that the purity of the target product is 99.49%.

[0040] Example 2

[0041] The preparation of 1-(2-hydroxy-3-methoxyphenyl)ethyl ketone using the method of the present invention includes the following steps:

[0042] S1: Add 20g of 5-bromo-2-methoxyphenol to a 250mL reaction flask, add 100mL of toluene and 12g (1.2eq) of acetic anhydride, heat to 110℃ and react for 4h. Monitor the reaction of 5-bromo-2-methoxyphenol by thin-layer chromatography (Ethyl acetate: n-hexane: triethylamine = 3:8:1). Cool to room temperature, transfer the reaction solution to 100mL of water, stir and separate the layers. Concentrate the toluene layer under reduced pressure to dryness to obtain 23g of intermediate I.

[0043] S2: Add 20g of intermediate I prepared in step S1 to a 250mL reaction flask, add 100mL of dichloroethane and 32.7g (3eq) of aluminum trichloride, heat to 80℃, keep the temperature for 4h, monitor the reaction of intermediate I by thin-layer chromatography (TLC) (ethyl acetate: n-hexane: triethylamine = 3:8:1), cool to room temperature, transfer the reaction solution to 100mL of water, stir and separate the layers, concentrate the dichloroethane layer under reduced pressure to dryness, and obtain 20g of crude intermediate II. Add 60mL of methyl tert-butyl ether to the crude intermediate II and reflux for half an hour, cool to room temperature, filter, and dry the filter cake at 30℃ to obtain 16g of pure intermediate II.

[0044] S3: Add 11g of intermediate II prepared in step S2 to a 100mL reaction flask, add 55mL of methanol and 1.1g of palladium on carbon catalyst, heat to reflux, and slowly add 17g (6eq) of ammonium formate under reflux conditions. Keep the reaction at this temperature for 4h. Monitor the reaction of intermediate II by thin-layer chromatography (TLC) (ethyl acetate: n-hexane: triethylamine = 3:8:1). Filter while hot, concentrate the filtrate under reduced pressure to dryness, and obtain 11g of crude product. Add 200mL of n-hexane to the crude product, heat to reflux to dissolve, filter while hot, cool to 10℃ and keep at this temperature for 1h, filter again, and dry the filter cake at 30℃ with forced air to obtain 6.6g of the target product in pure form, with a yield of 58.3% (based on 5-bromo-2-methoxyphenol) and a purity of 99.5%.

[0045] The NMR and HPLC data of the target product purified in Example 2 are consistent with those of the target product purified in Example 1.

[0046] Example 3

[0047] The preparation of 1-(2-hydroxy-3-methoxyphenyl)ethyl ketone using the method of the present invention includes the following steps:

[0048] S1: Add 20g of 5-bromo-2-methoxyphenol to a 250mL reaction flask, add 100mL of toluene and 8.5g (1.1eq) of acetyl chloride, heat to 80℃ and react for 3h. Monitor the reaction of 5-bromo-2-methoxyphenol by thin-layer chromatography (Ethyl acetate: n-hexane: triethylamine = 3:8:1). Cool to room temperature, transfer the reaction solution to 100mL of water, stir and separate the layers. Concentrate the toluene layer under reduced pressure to dryness to obtain 23g of intermediate I.

[0049] S2: Add 20g of intermediate I prepared in step S1 to a 250mL reaction flask, add 100mL of dichloroethane and 46.4g (3eq) of titanium tetrachloride, heat to 20℃, keep the temperature for 8h, monitor the reaction of intermediate I by thin-layer chromatography (TLC) (ethyl acetate: n-hexane: triethylamine = 3:8:1), cool to room temperature, transfer the reaction solution to 100mL of water, stir and separate the layers, concentrate the dichloroethane layer under reduced pressure to dryness, and obtain 20g of crude intermediate II. Add 60mL of methyl tert-butyl ether to the crude intermediate II and reflux for half an hour, cool to room temperature, filter, and dry the filter cake at 30℃ to obtain 17g of pure intermediate II.

[0050] S3: Add 11g of intermediate II prepared in step S2 to a 100mL reaction flask, along with 55mL of methanol and 2.2g of palladium on carbon catalyst. Heat to reflux, and slowly add 11.3g (4eq) of ammonium formate under reflux conditions. Maintain the reaction temperature for 3h. Monitor the reaction of intermediate II by thin-layer chromatography (TLC) (ethyl acetate: n-hexane: triethylamine = 3:8:1). Filter while hot, concentrate the filtrate under reduced pressure to dryness, and obtain 10.4g of crude product. Add 200mL of n-hexane to the crude product, heat to reflux to dissolve, filter while hot, cool to 10℃ and maintain the temperature for 1h, filter again, and dry the filter cake at 30℃ with forced air to obtain 6.3g of the target product in pure form, with a yield of 56% (based on 5-bromo-2-methoxyphenol) and a purity of 99.51%.

[0051] The NMR and HPLC data of the target product pure product prepared in Example 3 are consistent with those of the target product pure product prepared in Example 1.

[0052] Example 4

[0053] The preparation of 1-(2-hydroxy-3-methoxyphenyl)ethyl ketone using the method of the present invention includes the following steps:

[0054] S1: Add 20g of 5-bromo-2-methoxyphenol to a 250mL reaction flask, add 100mL of toluene and 11g (1.1eq) of acetic anhydride, heat to 60℃ and react for 4h. Monitor the reaction of 5-bromo-2-methoxyphenol by thin-layer chromatography (Ethyl acetate: n-hexane: triethylamine = 3:8:1). Cool to room temperature, transfer the reaction solution to 100mL of water, stir and separate the layers. Concentrate the toluene layer under reduced pressure to dryness to obtain 22g of intermediate I.

[0055] S2: Add 20g of intermediate I prepared in step S1 to a 250mL reaction flask, add 100mL of dichloroethane and 33.4g (3eq) of zinc chloride, heat to 60℃, keep the temperature for 12h, monitor the reaction of intermediate I by thin-layer chromatography (TLC) (ethyl acetate: n-hexane: triethylamine = 3:8:1), cool to room temperature, transfer the reaction solution to 100mL of water, stir and separate the layers, concentrate the dichloroethane layer under reduced pressure to dryness, and obtain 21g of crude intermediate II. Add 60mL of methyl tert-butyl ether to the crude intermediate II and reflux for half an hour, cool to room temperature, filter, and dry the filter cake at 30℃ to obtain 14.5g of pure intermediate II.

[0056] S3: Add 11g of intermediate II prepared in step S2 to a 100mL reaction flask, add 55mL of methanol and 1.1g of palladium on carbon catalyst, heat to reflux, and slowly add 14.1g (5eq) of ammonium formate under reflux conditions. Keep the reaction at this temperature for 4h. Monitor the reaction of intermediate II by thin-layer chromatography (TLC) (ethyl acetate: n-hexane: triethylamine = 3:8:1). Filter while hot, concentrate the filtrate under reduced pressure to dryness, and obtain 10.8g of crude product. Add 200mL of n-hexane to the crude product, heat to reflux to dissolve, filter while hot, cool to 10℃ and keep at this temperature for 1h, filter, and dry the filter cake at 30℃ with forced air to obtain 6.5g of the target product in pure form, with a yield of 57.4% (based on 5-bromo-2-methoxyphenol) and a purity of 99.31%.

[0057] The NMR and HPLC data of the target product purified in Example 4 are consistent with those of the target product purified in Example 1.

[0058] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the technical principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A process for the preparation of l-(2-hydroxy-3-methoxyphenyl)ethanone, characterized in that, The method comprises the following steps: S1: using 5-bromo-2-methoxyphenol as raw material, esterification reaction with acetylating agent in a solvent to generate intermediate I, the reaction is shown in the following formula 1: Formula 1; S2: intermediate I is subjected to Fries rearrangement reaction in a solvent under the catalysis of a catalyst to generate intermediate II, the reaction is shown in the following formula 2: Formula 2; S3: intermediate II is subjected to reduction hydrogenation reaction in a solvent containing ammonium formate under the catalysis of a palladium-carbon catalyst to generate 1-(2-hydroxy-3-methoxyphenyl) ethanone, the reaction is shown in the following formula 3: Formula 3.

2. The process for the preparation of l-(2-hydroxy-3-methoxyphenyl)ethanone according to claim 1, characterized in that, In the step S1, the acetylating agent used is one of acetyl chloride and acetic anhydride, the molar feeding ratio of the acetylating agent to 5-bromo-2-methoxyphenol is 1:1-1.2, the reaction time is 2-6 hours, and the reaction temperature is 50-120 DEG C.

3. The process for the preparation of l-(2-hydroxy-3-methoxyphenyl)ethanone as claimed in claim 1, wherein, In the step S2, the catalyst used is one of aluminum chloride, zinc chloride, titanium tetrachloride, triflate and methanesulfonic acid, the molar feeding ratio of intermediate I to the catalyst is 1:3-5, the reaction time is 4-16 hours, and the reaction temperature is 20-80 DEG C.

4. The process for the preparation of l-(2-hydroxy-3-methoxyphenyl)ethanone according to claim 1, characterized in that, In the step S3, the molar feeding ratio of intermediate II to ammonium formate is 1:3-6, and the mass feeding ratio of intermediate II to the palladium-carbon catalyst is 1:0.1-0.2, and the reaction time is 2-4 hours.

5. The process for the preparation of l-(2-hydroxy-3-methoxyphenyl)ethanone according to any one of claims 1 to 4, characterized in that, In the step S1, the solvent used is toluene; in the step S2, the solvent used is dichloroethane; and in the step S3, the solvent used is methanol.

6. The process for the preparation of l-(2-hydroxy-3-methoxyphenyl)ethanone according to claim 5, characterized in that, In the step S2, the crude intermediate II containing impurities is dissolved in a poor solvent of intermediate II for purification.

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