Preparation method of 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid

Abstract

The invention relates to the technical field of compound synthesis, and provides a method for preparing 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid. The method comprises: step S1, causing a methylation reaction between the 2-phenolic hydroxyl group of 2,4-dihydroxybenzaldehyde and a methylating agent to generate 4-hydroxy-2-methoxybenzaldehyde; step S2, causing a nucleophilic substitution reaction between 4-hydroxy-2-methoxybenzaldehyde and ethyl bromobutyrate to generate ethyl 4-(4-aldehyde-3-methoxyphenoxy)butyrate; step S3, causing ethyl 4-(4-aldehyde-3-methoxyphenoxy)butyrate to react with a reducing agent to generate ethyl 4-(4-hydroxymethyl-3-methoxyphenoxy)butyrate; and step S4, causing ethyl 4-(4-hydroxymethyl-3-methoxyphenoxy)butyrate to undergo a hydrolysis reaction under alkaline conditions to generate 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid. This application proposes for the first time a method for preparing 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid, and the method is highly safe and suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of compound preparation, and more specifically, relates to a method for preparing 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid. Background Art

[0002] 4-(4-Hydroxymethyl-3-methoxyphenoxy)butyric acid is one of the solid phase synthesis peptide linkers. It has similar effects to 4-hydroxymethyl-3-methoxyphenoxyacetic acid, HMP linker, Fmoc-linker and other linkers. It is very stable in solid phase synthesis and can be quantitatively cut off after peptide synthesis without destroying the peptide chain structure.

[0003] At present, there is no literature report on the preparation method of 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid. In the synthesis method of 4-hydroxymethyl-3-methoxyphenoxyacetic acid with a similar structure, the phenolic hydroxyl group at the 4-position is directly nucleophilically replaced with ethyl bromoacetate, which has poor selectivity and low yield. The hazardous chemicals sodium hydrogen sulfide and methyl iodide used in the methylation reaction of the phenolic hydroxyl group at the 2-position have poor operability and high risk factor. Summary of the invention

[0004] In view of this, the object of the present invention is to provide a method for preparing 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid suitable for industrial production.

[0005] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0006] The method for preparing 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid according to an embodiment of the present invention comprises the following steps:

[0007] Step S1, causing the 2-phenolic hydroxyl group of 2,4-dihydroxybenzaldehyde to undergo a methylation reaction with a methylating agent to generate 4-hydroxy-2-methoxybenzaldehyde;

[0008] Step S2, allowing the 4-hydroxy-2-methoxybenzaldehyde and ethyl bromobutyrate to undergo a nucleophilic substitution reaction to generate ethyl 4-(4-formyl-3-methoxyphenoxy)butyrate;

[0009] Step S3, reacting the ethyl 4-(4-formyl-3-methoxyphenoxy)butyrate with a reducing agent to generate ethyl 4-(4-hydroxymethyl-3-methoxyphenoxy)butyrate;

[0010] Step S4, hydrolyzing ethyl 4-(4-hydroxymethyl-3-methoxyphenoxy)butyrate under alkaline conditions to generate 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid.

[0011] In some embodiments of the present invention, step S1 comprises:

[0012] Step S11, using a phenolic hydroxyl protecting agent to protect the 4-position phenolic hydroxyl group of the 2,4-dihydroxybenzaldehyde to generate an intermediate 1, wherein the intermediate 1 is 4-protected group-2-hydroxybenzaldehyde;

[0013] Step S12, allowing the 2-phenolic hydroxyl group of the intermediate 1 to undergo a methylation reaction with the methylating agent to generate an intermediate 2, wherein the intermediate 2 is 4-protected-2-methoxybenzaldehyde;

[0014] Step S13, removing the protecting group of the phenolic hydroxyl group at the 4-position of the intermediate 2 by acid treatment to generate the 4-hydroxy-2-methoxybenzaldehyde.

[0015] Furthermore, the phenolic hydroxyl protecting agent is one or more of p-methoxybenzyl chloride (PMB-Cl), dihexyl phthalate (DHP), and di-tert-butyl dicarbonate (Boc anhydride), and the step S11 comprises:

[0016] Add 2,4-dihydroxybenzaldehyde and triethylamine to tetrahydrofuran, and then add the phenolic hydroxyl protecting agent for protection to generate the intermediate 1;

[0017] After the reaction is completed, the by-product triethylamine hydrochloride is removed by filtration to obtain a filtrate containing the intermediate 1.

[0018] Further, the methylating agent is one or more of dimethyl sulfate, methyl iodide, and dimethyl carbonate, and the step S12 comprises:

[0019] A sodium hydroxide aqueous solution and the methylation reagent are added dropwise to the filtrate obtained in step S11 to carry out the methylation reaction to generate the intermediate 2.

[0020] Furthermore, the acid used in the acid treatment in step S13 is one or more of hydrochloric acid, sulfuric acid, and trifluoroacetic acid, and step S13 comprises:

[0021] After the reaction in step S12 is completed, the acid is added dropwise to remove the protecting group of the 4-phenol to generate the 4-hydroxy-2-methoxybenzaldehyde.

[0022] Furthermore, the molar ratio of the 2,4-dihydroxybenzaldehyde to triethylamine, phenolic hydroxyl protecting agent, sodium hydroxide and methylating agent is 1:(1-1.2):(1-1.2):(1-1.4):(1-1.2).

[0023] In some embodiments of the present invention, in step S2, the nucleophilic substitution reaction is carried out in the presence of a first inorganic base, the first inorganic base is one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, and sodium hydroxide, and step S2 comprises:

[0024] The 4-hydroxy-2-methoxybenzaldehyde and the inorganic base are added to acetonitrile, and the ethyl bromobutyrate is added dropwise into the reaction system to carry out the nucleophilic substitution reaction to generate the ethyl 4-(4-formyl-3-methoxyphenoxy)butyrate, the molar ratio of the 4-hydroxy-2-methoxybenzaldehyde to the first inorganic base and the ethyl bromobutyrate is 1:(1-1.2):(1-1.2), the reaction temperature is 10-20°C, and the reaction time is 1-4 hours.

[0025] In some embodiments of the present invention, step S2 further includes:

[0026] After the reaction is completed, the reaction solution is concentrated to remove acetonitrile, water and ethyl acetate are added and stirred thoroughly, and then the liquids are separated. The organic phase is washed with water and saturated brine, and the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the 4-(4-formyl-3-methoxyphenoxy)butyric acid ethyl ester.

[0027] In some embodiments of the present invention, the reducing agent is one or more of sodium borohydride, lithium borohydride, sodium cyanoborohydride, and red aluminum. In step S3, the molar ratio of ethyl 4-(4-formyl-3-methoxyphenoxy)butyrate to the reducing agent is 1:(0.2-0.8), the reaction temperature is 10-20°C, and the reaction time is 2-6 hours.

[0028] In some embodiments of the present invention, step S3 may further include: after the reaction is completed, adding a saturated aqueous solution of ammonium chloride to the reaction solution to quench it and then separating the liquids, adding dichloromethane to the aqueous phase for extraction once, combining the organic phases, washing with water and saturated brine, and drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating to obtain ethyl 4-(4-hydroxymethyl-3-methoxyphenoxy)butyrate.

[0029] In some embodiments of the present invention, step S4 includes:

[0030] Ethyl 4-(4-hydroxymethyl-3-methoxyphenoxy)butyrate is added to tetrahydrofuran / water, and a second inorganic base is added in batches. The addition temperature and the reaction temperature are 30-40° C., and the reaction time is 1-4 hours. The second inorganic base is one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, and sodium hydroxide.

[0031] In some embodiments of the present invention, step S4 may further include: after the reaction is completed, ethyl acetate is added to the reaction solution for extraction, the organic phase is washed with water and saturated brine, the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, and the crude product is recrystallized from ethyl acetate to obtain 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid.

[0032] The above technical solution of the present invention has at least one of the following beneficial effects:

[0033] According to the preparation method of the embodiment of the present invention, a preparation method of 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid is proposed for the first time, and the method has high safety and is suitable for industrial production;

[0034] Furthermore, the phenolic hydroxyl group at the 4-position is first protected and then removed using an easily removable protecting agent, and the methylation reaction of the phenolic hydroxyl group at the 2-position is completed in one pot, which can prevent the phenolic hydroxyl group at the 4-position from participating in the methylation reaction, avoid the generation of unnecessary by-products, improve the yield, and the operation is simple and easy to control;

[0035] Furthermore, during the methylation reaction, dimethyl sulfate, a methylation reagent with a relatively low risk factor, is used for methylation under the condition of controlling the pH of the system to 10-12 by sodium hydroxide, and then the protecting group is removed by acid to obtain an intermediate with high yield and good quality, which is beneficial to improve the overall yield;

[0036] Furthermore, the overall synthesis route is short, the total yield is high, less three wastes are generated, the route is more feasible, and it is suitable for industrial production. DETAILED DESCRIPTION

[0037] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution of the present invention will be clearly and completely described in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the described embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field belong to the scope of protection of the present invention.

[0038] The following first describes in detail the preparation method of 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid according to an embodiment of the present invention.

[0039] The method for preparing 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid according to an embodiment of the present invention comprises the following steps:

[0040] Step S1, causing the 2-phenolic hydroxyl group of 2,4-dihydroxybenzaldehyde to undergo a methylation reaction with a methylating agent to generate 4-hydroxy-2-methoxybenzaldehyde;

[0041] Step S2, allowing the 4-hydroxy-2-methoxybenzaldehyde and ethyl bromobutyrate to undergo a nucleophilic substitution reaction to generate ethyl 4-(4-formyl-3-methoxyphenoxy)butyrate;

[0042] Step S3, reacting the ethyl 4-(4-formyl-3-methoxyphenoxy)butyrate with a reducing agent to generate ethyl 4-(4-hydroxymethyl-3-methoxyphenoxy)butyrate;

[0043] Step S4, hydrolyzing ethyl 4-(4-hydroxymethyl-3-methoxyphenoxy)butyrate under alkaline conditions to generate 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid.

[0044] According to the preparation method of the embodiment of the present invention, a preparation method of 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid is proposed for the first time, and the method has high safety and is suitable for industrial production.

[0045] Below, each step is described in detail.

[0046] (i) Step S1, causing the 2-phenolic hydroxyl group of 2,4-dihydroxybenzaldehyde to undergo a methylation reaction with a methylating agent to generate 4-hydroxy-2-methoxybenzaldehyde.

[0047] That is, according to the preparation method of the present application, 2,4-dihydroxybenzaldehyde is first used as a starting material, and its 2-hydroxymethylphenol group is subjected to a methylation reaction to obtain the intermediate 4-hydroxy-2-methoxybenzaldehyde.

[0048] In some embodiments of the present invention, step S1 may include:

[0049] Step S11, using a phenolic hydroxyl protecting agent to protect the 4-position phenolic hydroxyl group of the 2,4-dihydroxybenzaldehyde to generate an intermediate 1, wherein the intermediate 1 is 4-protected group-2-hydroxybenzaldehyde;

[0050] Step S12, allowing the 2-phenolic hydroxyl group of the intermediate 1 to undergo a methylation reaction with the methylating agent to generate an intermediate 2, wherein the intermediate 2 is 4-protected-2-methoxybenzaldehyde;

[0051] Step S13, removing the protecting group of the phenolic hydroxyl group at the 4-position of the intermediate 2 by acid treatment to generate the 4-hydroxy-2-methoxybenzaldehyde.

[0052] That is to say, the phenolic hydroxyl group at the 4-position is first protected using an easily removable protecting agent, and the protecting group is removed after the methylation reaction of the phenolic hydroxyl group at the 2-position is completed. The upper protection, methylation reaction of the phenolic hydroxyl group at the 2-position, and deprotection are completed in one pot, which can prevent the phenolic hydroxyl group at the 4-position from participating in the methylation reaction, avoid the generation of unnecessary by-products, improve the yield, and the operation is simple and easy to control.

[0053] In some embodiments of the present invention, the phenolic hydroxyl protecting agent is one or more of PMB-Cl, DHP, and Boc anhydride, wherein PMB-Cl is preferred. These phenolic hydroxyl protecting agents are not only easy to protect, but can also be simply deprotected by acid treatment, and after deprotection, the phenolic hydroxyl protecting agent can be retained in the inorganic phase by liquid separation, thereby being well separated from the intermediate (present in the organic phase).

[0054] In some embodiments of the present invention, step S11 specifically includes:

[0055] Add 2,4-dihydroxybenzaldehyde and triethylamine to tetrahydrofuran, and then add the phenolic hydroxyl protecting agent for protection to generate the intermediate 1;

[0056] After the reaction is completed, the by-product triethylamine hydrochloride is removed by filtration to obtain a filtrate containing the intermediate 1.

[0057] That is to say, in the presence of an organic base such as triethylamine, the protection is carried out in an organic solvent of tetrahydrofuran, and the by-product solid triethylamine hydrochloride obtained by the protective group can be removed by filtering, and the filtrate can directly participate in the next methylation reaction process without the need for complicated intermediate processing steps.

[0058] In some embodiments of the present invention, the methylating agent used in step S12 is one or more of dimethyl sulfate, methyl iodide, and dimethyl carbonate, among which dimethyl sulfate is particularly preferred due to its high efficiency and safety.

[0059] Specifically, in the filtrate obtained in the above step S11, sodium hydroxide is used to control the pH of the reaction system to 10-12, and dimethyl sulfate is added as a methylating agent to carry out a methylation reaction to generate intermediate 2. Compared with the use of commonly used dangerous chemical reagents such as sodium hydrogen, it can improve safety and efficiency.

[0060] In some embodiments of the present invention, the acid used for the acid treatment in step S13 is one or more of hydrochloric acid, sulfuric acid, and trifluoroacetic acid. These inorganic acids can be well separated from 4-hydroxy-2-methoxybenzaldehyde by liquid separation. Among them, hydrochloric acid is preferably used, which further forms PMB-Cl with the deprotected PMB group, which can be recycled to reduce the three wastes and production costs.

[0061] Furthermore, the molar ratio of 2,4-dihydroxybenzaldehyde to triethylamine, phenolic hydroxyl protective agent, sodium hydroxide, and methylating agent is 1:(1-1.2):(1-1.2):(1-1.4):(1-1.2), preferably 1:1.1:1.1:1.2:1.1. That is, using a slightly excess of triethylamine, phenolic hydroxyl protective agent, sodium hydroxide, and methylating agent relative to 2,4-dihydroxybenzaldehyde helps to improve the reaction efficiency and yield while taking into account the cost.

[0062] In addition, the PMB group protection reaction in step S11 can be carried out at room temperature for 2 hours; the reaction temperature of the methylation reaction in step S12 can be set to 20-30°C for 4 hours; the reaction temperature of the removal of the PMB group in step S13 is room temperature for 1 hour. In other words, the one-pot reaction in step S1 of the present application has high reaction efficiency, simple and easy-to-control conditions, and low cost.

[0063] Specifically, the phenolic hydroxyl protecting agent is PMB-Cl, the methylating agent is dimethyl sulfate, and the deprotection is carried out using hydrochloric acid as an example. The reaction route is shown in the following formula (1):

[0064] (1)

[0065] (ii) Step S2, allowing the 4-hydroxy-2-methoxybenzaldehyde and ethyl bromobutyrate to undergo a nucleophilic substitution reaction to generate ethyl 4-(4-formyl-3-methoxyphenoxy)butyrate.

[0066] That is, the intermediate 4-hydroxy-2-methoxybenzaldehyde obtained after the 2-position phenolic hydroxyl group is methylated undergoes a nucleophilic substitution reaction with ethyl bromobutyrate to generate ethyl 4-(4-formyl-3-methoxyphenoxy)butyrate.

[0067] In some embodiments of the present invention, the nucleophilic substitution reaction is carried out in the presence of the first inorganic base, and the first inorganic base is one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, and sodium hydroxide, preferably potassium carbonate. As an acid binding agent, the inorganic base can remove the hydrogen on the hydroxyl group of 4-hydroxy-2-methoxybenzaldehyde, and promote the progress of the nucleophilic reaction. In addition, potassium carbonate is alkaline as compared with sodium bicarbonate and sodium hydroxide, and is suitable for this nucleophilic substitution reaction. In addition, potassium carbonate has better solubility in organic solvents and water, and its alkalinity is slightly stronger than sodium carbonate, which has great benefits for the forward progress and post-processing of the reaction.

[0068] In some embodiments of the present invention, step S2 includes:

[0069] The 4-hydroxy-2-methoxybenzaldehyde and the first inorganic base are added to acetonitrile, and the ethyl bromobutyrate is added dropwise into the reaction system to carry out the nucleophilic substitution reaction to generate the ethyl 4-(4-formyl-3-methoxyphenoxy)butyrate.

[0070] That is, the nucleophilic substitution reaction is carried out in the organic solvent acetonitrile, which can well dissolve 4-hydroxy-2-methoxybenzaldehyde, ethyl bromobutyrate, and ethyl 4-(4-formyl-3-methoxyphenoxy)butyrate, thereby promoting the reaction.

[0071] In some embodiments of the present invention, the molar ratio of 4-hydroxy-2-methoxybenzaldehyde to the first inorganic base and ethyl bromobutyrate is 1:(1-1.2):(1-1.2), preferably 1:1.1:1.1. A slightly excess of potassium carbonate and ethyl bromobutyrate helps to promote the reaction and improve the yield.

[0072] In addition, the reaction temperature of the nucleophilic reaction is, for example, 10-20° C., and the reaction time is 1-4 hours. The reaction conditions are simple, easy to control, and easy to operate, and the reaction efficiency is high.

[0073] Specifically, the reaction formula is shown in the following formula (2):

[0074] (2)

[0075] In some embodiments of the present invention, step S2 may further include:

[0076] After the reaction is completed, the reaction solution is concentrated to remove acetonitrile, water and ethyl acetate are added and stirred thoroughly, and then the liquids are separated. The organic phase is washed with water and saturated brine, and the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the 4-(4-formyl-3-methoxyphenoxy)butyric acid ethyl ester.

[0077] In other words, the post-treatment after the nucleophilic reaction is simple and easy to operate, with less waste, less waste and higher safety.

[0078] (iii) Step S3, reacting the ethyl 4-(4-formyl-3-methoxyphenoxy)butyrate with a reducing agent to generate ethyl 4-(4-hydroxymethyl-3-methoxyphenoxy)butyrate.

[0079] That is, after ethyl 4-(4-formyl-3-methoxyphenoxy)butyrate is generated in step S2, the aldehyde group is reduced to a hydroxymethyl group by a reducing agent.

[0080] Specifically, the reducing agent can be one or more of sodium borohydride, lithium borohydride, sodium cyanoborohydride, and red aluminum. Among them, sodium borohydride is preferred because it is not only highly safe, but also can completely reduce the aldehyde group without affecting the ester group.

[0081] Specifically, its chemical formula is shown in the following formula (3):

[0082] (3)

[0083] In some embodiments of the present invention, the molar ratio of ethyl 4-(4-formyl-3-methoxyphenoxy)butyrate to the reducing agent is 1:(0.2-0.8), preferably 1:0.4. In this reaction, the theoretical amount of the reducing agent is 0.33, and a slightly excessive amount of the reducing agent can promote the rapid progress of the reaction and also reduce the interference of a small amount of water that may exist in the organic solvent.

[0084] The reaction temperature may be 10-20°C, and the reaction time may be 2-6 hours.

[0085] In some embodiments of the present invention, ethyl 4-(4-formyl-3-methoxyphenoxy)butyrate is added to dichloromethane, sodium borohydride is added in batches at a temperature of 10-20°C, and the reaction is kept warm for 3 hours.

[0086] In some embodiments of the present invention, step S3 may further include: after the reaction is completed, adding a saturated aqueous solution of ammonium chloride to the reaction solution to quench it and then separating the liquids, adding dichloromethane to the aqueous phase for extraction once, combining the organic phases, washing with water and saturated brine, and drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating to obtain ethyl 4-(4-hydroxymethyl-3-methoxyphenoxy)butyrate.

[0087] It can be seen that the post-processing of this step is also simple and easy to operate.

[0088] (iv) Step S4, hydrolyzing ethyl 4-(4-hydroxymethyl-3-methoxyphenoxy)butyrate under alkaline conditions to generate 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid.

[0089] That is, after obtaining ethyl 4-(4-hydroxymethyl-3-methoxyphenoxy)butyrate through step S3, it is only necessary to hydrolyze the terminal ester group to obtain the target product 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid.

[0090] In some embodiments of the present invention, step S4 includes:

[0091] Ethyl 4-(4-hydroxymethyl-3-methoxyphenoxy)butyrate is added to tetrahydrofuran / water, and a second inorganic base is added in batches. The second inorganic base is one or more of sodium carbonate, potassium carbonate, sodium bicarbonate and sodium hydroxide.

[0092] Here, it should be noted that the first inorganic base and the second inorganic base may be the same or different. The second inorganic base is preferably sodium hydroxide.

[0093] Specifically, its chemical formula is shown in the following formula (4):

[0094] (4)

[0095] The feeding temperature and the reaction temperature can be set at 30-40° C., and the reaction time is 1-4 hours.

[0096] In some embodiments of the present invention, step S4 may further include: after the reaction is completed, ethyl acetate is added to the reaction solution for extraction, the organic phase is washed with water and saturated brine, the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, and the crude product is recrystallized from ethyl acetate to obtain 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid.

[0097] That is to say, according to the preparation method of the present invention, the post-treatment of all intermediates is simple and easy to operate, and only the post-treatment of the target product in the last step needs to be processed by recrystallization. However, its cost and efficiency are much higher than that of complex processes such as column separation.

[0098] In other words, according to the preparation method of the present invention, an intermediate with high yield and good quality can be obtained, and overall, the reaction efficiency is high, the safety is good, the cost is low, and the three wastes are less, which is suitable for industrial large-scale production.

[0099] The following is a detailed description of the method for preparing 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid according to the present invention through specific examples. Embodiment 1:

[0100] (1) Add 2,4-dihydroxybenzaldehyde (56g, 0.41mol, 1.0eq) and triethylamine (45.13g, 0.45mol, 1.1eq) to tetrahydrofuran (280mL, 5P), then add PMB-Cl (76.08g, 0.45mol, 1.1eq) and react at room temperature for 2 hours. Filter the reaction solution to remove triethylamine hydrochloride, and simultaneously add 20% sodium hydroxide (19.46g, 0.49mol, 1.2eq) aqueous solution and dimethyl sulfate (56.25g, 0.45mol, 1.1eq) to the filtrate. Control the temperature at 20-30℃, and control the pH of the system to 10-12 by controlling the rate of sodium hydroxide aqueous solution addition. After the addition is complete, keep the temperature for 4 hours. Add concentrated hydrochloric acid (85mL, 2.5eq) to the reaction solution and stir at room temperature for 1 hour. Water (85 mL) and ethyl acetate (170 mL) were added to the reaction solution and stirred thoroughly, and then the organic phase was separated. The organic phase was washed with water (85 mL) and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 68 g of a crude product. After slurrying with n-heptane (150 mL), 54.0 g of 4-hydroxy-2-methoxybenzaldehyde was obtained, with a yield of 87.5%.

[0101] (2) 4-Hydroxy-2-methoxybenzaldehyde (54.0 g, 0.35 mol, 1.0 eq) and potassium carbonate (53.94 g, 0.39 mol, 1.1 eq) were added to acetonitrile (270 mL, 5P), cooled to 10°C in an ice-water bath, and ethyl bromobutyrate (76.12 g, 0.39 mol, 1.1 eq) was added dropwise. The temperature was controlled at 10-20°C until the addition was completed, and the reaction was kept warm for 2 hours. The reaction solution was concentrated to remove the acetonitrile, and water (100 mL) and ethyl acetate (250 mL) were added and stirred thoroughly before separation. The organic phase was washed with water (100 mL) and saturated brine (70 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 86.9 g of ethyl 4-(4-formyl-3-methoxyphenoxy)butyrate, with a yield of 92.0%.

[0102] (3) Add 4-(4-formyl-3-methoxyphenoxy)butyric acid ethyl ester (86.9 g, 0.33 mol, 1.0 eq) to dichloromethane (430 mL, 5P), and add sodium borohydride (4.94 g, 0.13 mol, 0.4 eq) in batches at a temperature of 10-20°C. After addition, keep warm and react for 3 hours. Add saturated aqueous ammonium chloride solution (100 mL) to the reaction solution to quench, and then separate the liquids. Add dichloromethane (200 mL) to the aqueous phase and extract it once. Combine the organic phases and wash with water (200 mL) and saturated brine (150 mL). Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to obtain 78.11 g of 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid ethyl ester with a yield of 89.2%.

[0103] (4) Add ethyl 4-(4-hydroxymethyl-3-methoxyphenoxy)butyrate (78.11 g, 0.29 mol, 1.0 eq) to tetrahydrofuran / water (230 mL / 160 mL, 3P / 2P), add sodium hydroxide (17.47 g, 0.44 mol, 1.5 eq) in batches, and heat to 30-40°C for 2 hours. Ethyl acetate (230 mL) was added to the reaction solution for extraction, and the organic phase was washed with water (150 mL) and saturated brine (150 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 75.3 g of crude product. The crude product was recrystallized from ethyl acetate (220 mL) to obtain 64.07 g of 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid, with a yield of 91.6%.

[0104] The product obtained by recrystallization was subjected to nuclear magnetic resonance experiment to confirm the product structure, and the data are as follows:

[0105] 1H NMR (model: AVANCE III HD 400M, CDCl3, 400MHz): δ 12.33 (br, 1H), 7.19-7.21 (d, 1H), 6.46-6.51 (m, 2H), 4.82 (s, 1H), 4.39 (s, 2H), 3.94-4.01 (t, 2H), 3.74 (s, 3H), 2.36-2.38 (t, 2H), 1.89-1.93 (m, 2H). The detection results were consistent with the structure of the target product 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid. Embodiment 2:

[0106] (1) Add 2,4-dihydroxybenzaldehyde (210 g, 1.52 mol, 1.0 eq) and triethylamine (169.24 g, 1.67 mol, 1.1 eq) to tetrahydrofuran (1050 mL, 5P), then add PMB-Cl (285.3 g, 1.67 mol, 1.1 eq) and react at room temperature for 2 hours. Filter the reaction solution to remove triethylamine hydrochloride, and simultaneously drop 20% sodium hydroxide (72.98 g, 1.82 mol, 1.2 eq) aqueous solution and dimethyl sulfate (210.95 g, 1.67 mol, 1.1 eq) into the filtrate, control the temperature at 20-30°C, and control the pH of the system to 10-12 by controlling the rate of sodium hydroxide aqueous solution addition. After the dripping is completed, keep the temperature and react for 4 hours. Add concentrated hydrochloric acid (316 mL, 2.5 eq) to the reaction solution and stir at room temperature for 1 hour. Water (320 mL) and ethyl acetate (640 mL) were added to the reaction solution and the mixture was stirred thoroughly, and then the organic phase was separated. The organic phase was washed with water (320 mL) and saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 258.3 g of a crude product. After slurrying with n-heptane (520 mL), 203.8 g of 4-hydroxy-2-methoxybenzaldehyde was obtained, with a yield of 88.1%.

[0107] (2) Add 4-hydroxy-2-methoxybenzaldehyde (203.8 g, 1.34 mol, 1.0 eq) and potassium carbonate (203.64 g, 1.47 mol, 1.1 eq) to acetonitrile (1 L, 5 P), cool to 10 ° C in an ice-water bath, add ethyl bromobutyrate (287.4 g, 1.47 mol, 1.1 eq) dropwise, control the temperature at 10-20 ° C until the dripping is complete, and keep the temperature to react for 2 hours. The reaction solution is concentrated to remove the acetonitrile, and water (400 mL) and ethyl acetate (1 L) are added and stirred thoroughly, and then the liquid is separated. The organic phase is washed with water (400 mL) and saturated brine (300 mL). The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 327.44 g of ethyl 4-(4-formyl-3-methoxyphenoxy)butyrate, with a yield of 91.8%.

[0108] (3) Add 4-(4-formyl-3-methoxyphenoxy)butyric acid ethyl ester (327.44 g, 1.23 mol, 1.0 eq) to dichloromethane (1.6 L, 5P), and add sodium borohydride (18.61 g, 0.49 mol, 0.4 eq) in batches at a temperature of 10-20°C. After addition, keep warm and react for 3 hours. Add saturated aqueous ammonium chloride solution (450 mL) to the reaction solution to quench, then separate the liquids. Add dichloromethane (900 mL) to the aqueous phase for extraction once. Combine the organic phases and wash with water (900 mL) and saturated brine (700 mL). Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to obtain 297.6 g of 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid ethyl ester with a yield of 90.2%.

[0109] (4) Add 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid ethyl ester (297.6 g, 1.11 mol, 1.0 eq) to tetrahydrofuran / water (900 mL / 600 mL, 3P / 2P), add sodium hydroxide (66.55 g, 1.66 mol, 1.5 eq) in batches, and heat to 30-40°C for 2 hours. Ethyl acetate (600 mL) was added to the reaction solution for extraction, and the organic phase was washed with water (400 mL) and saturated brine (400 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 286.5 g of crude product. The crude product was recrystallized from ethyl acetate (860 mL) to obtain 243.3 g of 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid, with a yield of 91.3%.

[0110] The product obtained by recrystallization was subjected to nuclear magnetic resonance experiment to confirm the product structure, and the data are as follows:

[0111] 1H NMR (model: AVANCE III HD 400M, CDCl3, 400MHz): δ 12.12 (br, 1H), 7.19-7.21(d, 1H), 6.46-6.51(m, 2H), 4.83 (s, 1H), 4.39 (s, 2H), 3.95-3.96 (t, 2H), 3.74(s, 3H), 2.36-2.40 (t, 2H), 1.89-1.96 (m, 2H). The detection results were consistent with the structure of the target product 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid.

[0112] The above is 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 principles 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 preparing 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid, characterized in that: The steps include: Step S11, adding 2,4-dihydroxybenzaldehyde and triethylamine to tetrahydrofuran, and then adding p-methoxybenzyl chloride as a phenolic hydroxyl protecting agent to generate intermediate 1, wherein intermediate 1 is 4-protected group-2-hydroxybenzaldehyde; After the reaction is completed, filtering is performed to remove the by-product triethylamine hydrochloride to obtain a filtrate containing the intermediate 1; Step S12, adding a sodium hydroxide aqueous solution and dimethyl sulfate as a methylating agent to the filtrate to carry out a methylation reaction to generate the intermediate 2, wherein the intermediate 2 is 4-protected-2-methoxybenzaldehyde; Step S13, after the reaction of step S12 is completed, adding an acid dropwise to remove the protecting group of the phenolic hydroxyl group at the 4-position to generate the 4-hydroxy-2-methoxybenzaldehyde, wherein the acid used is one or more of hydrochloric acid, sulfuric acid, and trifluoroacetic acid; The molar ratio of the 2,4-dihydroxybenzaldehyde to triethylamine, phenolic hydroxyl protecting agent, sodium hydroxide and methylating agent is 1:(1-1.2):(1-1.2):(1-1.4):(1-1.2); Step S2, adding the 4-hydroxy-2-methoxybenzaldehyde and the first inorganic base to acetonitrile, and dropping ethyl bromobutyrate into the reaction system to perform a nucleophilic substitution reaction to generate ethyl 4-(4-formyl-3-methoxyphenoxy)butyrate, wherein the molar ratio of the 4-hydroxy-2-methoxybenzaldehyde to the first inorganic base and ethyl bromobutyrate is 1:(1-1.2):(1-1.2), the reaction temperature is 10-20° C., the reaction time is 1-4 hours, and the first inorganic base is one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, and sodium hydroxide; Step S3, reacting the ethyl 4-(4-formyl-3-methoxyphenoxy)butyrate with a reducing agent to generate ethyl 4-(4-hydroxymethyl-3-methoxyphenoxy)butyrate; Step S4, hydrolyzing ethyl 4-(4-hydroxymethyl-3-methoxyphenoxy)butyrate under alkaline conditions to generate 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid.

2. The preparation method according to claim 1, characterized in that: The step S2 further comprises: After the reaction is completed, the reaction solution is concentrated to remove acetonitrile, water and ethyl acetate are added and stirred thoroughly, and then the liquids are separated. The organic phase is washed with water and saturated brine, and the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the 4-(4-formyl-3-methoxyphenoxy)butyric acid ethyl ester.

3. The preparation method according to claim 1, characterized in that: The reducing agent is one or more of sodium borohydride, lithium borohydride, sodium cyanoborohydride, and red aluminum. In the step S3, the molar ratio of ethyl 4-(4-formyl-3-methoxyphenoxy)butyrate to the reducing agent is 1:(0.2-0.8), the reaction temperature is 10-20° C., and the reaction time is 2-6 hours.

4. The preparation method according to claim 1, characterized in that: The step S4 comprises: Ethyl 4-(4-hydroxymethyl-3-methoxyphenoxy)butyrate is added to tetrahydrofuran / water, and a second inorganic base is added in batches. The addition temperature and the reaction temperature are 30-40° C., and the reaction time is 1-4 hours. The second inorganic base is one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, and sodium hydroxide.