A process for the preparation of tert-butyl 2-hydroxymethylbenzoate

Abstract

This invention provides a method for preparing tert-butyl 2-hydroxymethylbenzoate, the method comprising the following steps: (1) reacting tert-butyl hydrogen phthalate and isobutyl chloroformate to obtain compound 1, (2) reacting compound 1 to obtain tert-butyl 2-hydroxymethylbenzoate; the preparation method provided by this invention has a high yield and stable process, the post-processing is relatively simple, it can avoid operations such as column chromatography, and the reagents used are all conventional reagents, which reduces the production cost and is applicable to industrial scale-up production, providing technical support for the reduction of carboxylic acid compounds into primary alcohols.

Description

Technical Field

[0001] This invention belongs to the field of mechanical synthesis technology and relates to a method for preparing tert-butyl 2-hydroxymethylbenzoate. Background Technology

[0002] 2-Terbutyl hydroxymethyl benzoate is an important intermediate for the synthesis of pharmaceutical and pesticide raw materials. It has been used in the synthesis of various drugs, such as mast cell degranulation inhibitors, histamine release inhibitors, eicosanoic acid-like synthesis inhibitors, mast cell proliferation and differentiation inhibitors, IL-13 production inhibitors, and other chemically synthesized drugs. It is also used in the synthesis of drugs for the prevention and treatment of immune diseases, inflammatory diseases, allergic diseases, respiratory diseases, urinary system diseases, and cardiovascular diseases.

[0003] However, according to existing literature, the synthesis methods are all based on tert-butyl 2-aldehyde benzoate as a precursor, which is then hydrogenated to obtain tert-butyl 2-hydroxymethyl benzoate. The synthetic methods are relatively simple. For example, a similar method is reported in patent EP1849465A1, where the final step involves reducing the aldehyde group to an alcohol hydroxyl group with sodium borohydride in methanol, with a yield of approximately 76%. The reported overall reaction steps are relatively long, and the yield is relatively low. The reaction process is as follows: Furthermore, if the synthetic approach follows the reduction of an aldehyde group to an alcohol, then tert-butyl 2-aldehyde benzoate is the most crucial intermediate. Several methods for synthesizing tert-butyl 2-aldehyde benzoate have been reported. For example, researchers such as Mirabdolbaghi ​​et al. published in journals like *Organic Letters* and *Tetrahedron*: using 2-aldehyde benzoic acid as a starting material, reacting it with tert-butanol under concentrated sulfuric acid conditions to generate tert-butyl 2-aldehyde benzoate, with a yield maintained at 80%. Another method by Mirabdolbaghi ​​et al. involved replacing tert-butanol with tert-butane iodide, reacting it with a carboxyl group to form tert-butyl 2-aldehyde benzoate. Yet another method, published by Iyori et al. in *Chemical Communications*, synthesized tert-butyl 2-aldehyde benzoate from tert-butyl 2-methylbenzoate via radical bromination and NMO oxidation, but with a yield of only 28%, exhibiting problems of low yield and difficulty in purification. The reaction route is as follows: Regarding the third step of the reaction, Professor He Wei's research group at Tsinghua University published a method for synthesizing 2-aldehyde benzoic acid in the journal Chemistry-A European Journal. This method involves reacting benzolactone with iron triacetylacetone, copper nitrate, and Selectfluor in acetonitrile solvent, yielding a product yield of approximately 60%, which is the highest reported yield for this reaction. Other studies have investigated halogenating the carbonyl group at the α-position with bromine, followed by ring-opening and elimination reactions to obtain the target product, but the yields have all been less than 60%.

[0004] The yields of the first and second steps are relatively good, and the reaction conditions are more well-established. Professors such as Meyer, Ogawa, and Ziyaei Halimehjani have conducted excellent research on the first step, achieving near 100% yields. The second step involves synthesis using methods from the reaction route and electrochemical methods, both with satisfactory results.

[0005] To reduce the number of steps in the overall reaction, we attempted to synthesize compound 3 directly from the starting material SM1, but the results were not ideal. The reaction route is shown below. When using LiAlH4, diisobutylaluminum hydride, and Red-Al as reducing agents, despite optimizing the amount of reducing agent, the experimental system was found to be very mixed. The reaction solution still contained residual SM1, impurities that reduced both carboxyl groups to alcohols, substituents that were one alcohol and one aldehyde, and impurities related to the ring ring, making it difficult to control the reaction so that the two carboxyl groups reacted in the ideal manner.

[0006] Existing synthetic routes suffer from numerous problems due to their complex reaction steps, low yields, and significant challenges in synthesizing large quantities of intermediate 3. Considering that tert-butyl 2-hydroxymethylbenzoate is an important intermediate, developing a high-yield, low-cost synthetic route is of great significance. Summary of the Invention

[0007] To address the shortcomings of existing technologies, the present invention aims to provide a method for preparing tert-butyl 2-hydroxymethylbenzoate. The preparation method provided by the present invention features high yield and stable process, simple post-processing, avoidance of operations such as column chromatography, and the use of conventional reagents, thus reducing production costs. It is suitable for industrial-scale production and provides technical support for the reduction of carboxyl-like compounds.

[0008] To achieve this objective, the present invention adopts the following technical solution: On one hand, the present invention provides a method for preparing tert-butyl 2-hydroxymethylbenzoate, the preparation method comprising the following steps: (1) Tert-butyl hydrogen phthalate and isobutyl chloroformate react to give compound 1, and the reaction formula is as follows: ; (2) Compound 1 reacts to give tert-butyl 2-hydroxymethylbenzoate; the reaction formula is as follows: .

[0009] In this invention, the starting materials tert-butyl hydrogen phthalate and isobutyl chloroformate first undergo a nucleophilic reaction to obtain compound 1; then compound 1 reacts with a reducing agent to obtain the target product tert-butyl 2-hydroxymethylbenzoate.

[0010] The preparation method provided by this invention has a high yield and stable process, and the post-processing is relatively simple. It avoids operations such as column chromatography, and all reagents used are conventional reagents, which reduces production costs. It is suitable for industrial scale-up production and provides technical support for the reduction of carboxylic acid compounds into primary alcohols.

[0011] Preferably, the molar ratio of tert-butyl hydrogen phthalate and isobutyl chloroformate in step (1) is 1:(1-1.5), for example, it can be 1:1, 1:1.1.05, 1:1.1, 1:1.2, 1:1.4 or 1:1.5, etc., preferably 1:(1.05-1.1).

[0012] Preferably, the reaction in step (1) is carried out in a solvent.

[0013] Preferably, the solvent includes any one or a combination of at least two of tetrahydrofuran, toluene, N,N-dimethylformamide or dichloromethane, with tetrahydrofuran being the most preferred.

[0014] Preferably, the ratio of tert-butyl hydrogen phthalate to solvent is 1 g: (5-15) mL, for example, it can be 1 g: 5 mL, 1 g: 8 mL, 1 g: 10 mL, 1 g: 12 mL, 1 g: 14 mL, 1 g: 15 mL, etc., and preferably 1 g: (8-10) mL.

[0015] Preferably, the reaction in step (1) is carried out in the presence of an organic base.

[0016] Preferably, the organic base includes any one or a combination of at least two of piperidine, triethylamine, N,N-diisopropylethylamine, or N,N-diisopropylamine, with triethylamine being the most preferred.

[0017] Preferably, the molar ratio of tert-butyl hydrogen phthalate to organic base is 1:(1-4), for example, it can be 1:1, 1:1.5, 1:2.0, 1:2.5, 1:3.0, 1:3.5, 1:4.0, etc., and preferably 1:(1.5-2.0).

[0018] Preferably, the reaction temperature in step (1) is 0-50℃, for example, 0℃, 10℃, 20℃, 30℃, 40℃, etc., and the reaction time is 1.0-5.0 h, for example, 1.0 h, 2.0 h, 3.0 h, 4.0 h, 5.0 h, etc.

[0019] Preferably, the reaction temperature in step (1) is 20-30°C and the reaction time is 1.0-2.0 h.

[0020] Preferably, after the reaction in step (1) is completed, separation is performed by filtration and washing to obtain crude compound 1, which is not purified for use in the next step.

[0021] Preferably, the reaction in step (2) is carried out in the presence of a commonly used reducing agent.

[0022] Preferably, the reducing agent includes any one of sodium borohydride, sodium cyanoborohydride, red aluminum, or lithium aluminum hydride, with sodium borohydride being the most preferred.

[0023] Preferably, the molar ratio of compound 1 to reducing agent is 1:(1-4), for example, it can be 1:1, 1:1.5, 1:2.0, 1:2.5, 1:3.0, 1:3.5, 1:4.0, etc., and preferably 1:(2.0-2.5).

[0024] Preferably, the reaction in step (2) is carried out in a solvent.

[0025] Preferably, the solvent includes any one or a combination of at least two of tetrahydrofuran, toluene, N,N-dimethylformamide or dichloromethane, with tetrahydrofuran being the most preferred.

[0026] Preferably, the reaction temperature in step (2) is 0-40℃, for example, 0℃, 10℃, 20℃, 25℃, 30℃, 35℃, 40℃, etc., and the reaction time is 1.0-6.0h, for example, 1.0h, 2.0h, 3.0h, 4.0h, 5.0h, 6.0h, etc.

[0027] Preferably, the reaction temperature in step (2) is 20-25°C and the reaction time is 2.0-3.0 h.

[0028] Preferably, the reaction in step (2) further includes a post-processing step.

[0029] Preferably, the post-processing includes: quenching the reaction, extracting with an organic solvent, drying, filtering, and concentrating the obtained filtrate to obtain tert-butyl 2-hydroxymethylbenzoate.

[0030] In this invention, commonly used quenching reagents are used to quench the reaction.

[0031] Preferably, the quenching agent includes water, a saturated ammonium chloride aqueous solution, and a citric acid aqueous solution, and more preferably a saturated ammonium chloride aqueous solution.

[0032] Preferably, the concentration of the citric acid aqueous solution is 0.5-2 mol / L, such as 0.5 mol / L, 0.7 mol / L, 0.9 mol / L, 1.1 mol / L, 1.3 mol / L, 1.5 mol / L, 1.7 mol / L, 1.9 mol / L, or 2 mol / L.

[0033] Preferably, the organic solvent used for extraction includes methyl tert-butyl ether, ethyl acetate, and dichloromethane, with dichloromethane being the preferred solvent.

[0034] Preferably, the drying is performed using anhydrous sodium sulfate.

[0035] As a preferred embodiment of the present invention, the preparation method specifically includes the following steps: (1) Tert-butyl hydrogen phthalate and isobutyl chloroformate are reacted with a solvent in the presence of an organic base at 0-50°C for 1.0-5.0 h to obtain compound 1. The molar ratio of tert-butyl hydrogen phthalate and isobutyl chloroformate is 1:(1-1.5). The solvent includes any one or a combination of at least two of tetrahydrofuran, toluene, N,N-dimethylformamide or dichloromethane. The molar ratio of tert-butyl hydrogen phthalate to solvent is 1 g:(5-15) mL. The organic base includes any one or a combination of at least two of piperidine, triethylamine, N,N-diisopropylethylamine or N,N-diisopropylamine. The molar ratio of tert-butyl hydrogen phthalate to organic base is 1:(1-4). After the reaction in step (1) is completed, separation is performed by filtration and washing to obtain crude compound 1. It is not purified and is directly used in the next step of the reaction. (2) Compound 1 is reacted in a solvent at 0-40°C for 1.0-6.0 h in the presence of a reducing agent to obtain tert-butyl 2-hydroxymethylbenzoate. The reducing agent includes any one of sodium borohydride, sodium cyanoborohydride, red aluminum or lithium aluminum hydride. The molar ratio of compound 1 to the reducing agent is 1:(1-4). The solvent includes any one or a combination of at least two of tetrahydrofuran, toluene, N,N-dimethylformamide or dichloromethane. After the reaction is completed, the reaction is quenched, extracted with an organic solvent, dried, filtered, and the filtrate is concentrated to obtain tert-butyl 2-hydroxymethylbenzoate.

[0036] Compared with the prior art, the present invention has at least the following beneficial effects: The preparation method provided by this invention has a high yield and stable process, and the post-processing is relatively simple. It avoids operations such as column chromatography, and all reagents used are conventional reagents, which reduces production costs. It is suitable for industrial scale-up production and provides technical support for the reduction of carboxylic acid compounds into primary alcohols. Attached Figure Description

[0037] Figure 1 It is the target compound P1 in Example 1. 1 H-NMR spectrum.

[0038] Figure 2 It is the target compound P1 in Example 1. 13 C-NMR spectrum. Detailed Implementation

[0039] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention in any way.

[0040] In the following examples, tert-butyl hydrogen phthalate is represented by SM1, isobutyl chloroformate by SM2, and tert-butyl 2-hydroxymethylbenzoate by P1.

[0041] Example 1 This embodiment provides a method for preparing tert-butyl 2-hydroxymethylbenzoate, specifically including the following steps: (1) Weigh the starting material SM1 (10.0 g, 45 mmol, 1.0 eq.) and add it to tetrahydrofuran (80 mL, 8 V). After stirring until completely dissolved, add triethylamine (9.11 g, 90 mmol, 2.0 eq.). Cool the above reaction to 0-5 °C using an ice-water bath, and then add SM2 (6.45 g, 47.2 mmol, 1.05 eq.) dropwise to the reaction solution. After the addition is complete, remove the ice-water bath and react at 20 °C for 2 hours. A large amount of white solid byproduct is produced in the reaction solution. After the reaction is complete under TLC monitoring, a new compound with low polarity is generated in the reaction. Filter to remove the white solid, and wash the white solid with 10 mL of tetrahydrofuran to obtain a tetrahydrofuran solution of compound 1. Since it is an active ester, this solution is not further processed and is directly used in the next reaction according to the theoretical yield.

[0042] (2) A tetrahydrofuran solution of compound 1 was added to a three-necked flask, evacuated, and protected with nitrogen. The solution was then cooled to 0-5°C using an ice-water bath. Sodium borohydride (3.4 g, 90 mmol, 2.0 eq.) was slowly added to the reaction solution, and the reaction was carried out at 20°C for 2 hours. TLC monitoring showed that compound 1 had reacted completely and a new compound was formed. The reaction solution was then cooled to 0-5°C again using an ice-water bath, and 20 mL of saturated ammonium chloride aqueous solution was added dropwise to quench the reaction. After the addition was complete, the ice-water bath was removed, and the mixture was stirred at room temperature for another 30 minutes. 100 mL of dichloromethane and 100 mL of water were added to the reaction flask, and the reaction was extracted. After standing and separating the layers, the organic phase was separated, dried with anhydrous sodium sulfate, and concentrated to obtain 8.62 g of colorless oily target compound P1, with a yield of 92%.

[0043] P1 detection data 1 H-NMR and 13 The C-NMR values ​​are as follows: 1 H-NMR(400MHz, CDCl3): δ 7.92-7.94(m, 1H), 7.47-7.51(m, 1H), 7.42-7.44(m, 1H), 7.33-7.35(m, 1H), 4.76(s, 2H), 3.87(brs, 1H), 1.62 (s, 9H).

[0044] 13 C-NMR (126MHz, CDCl3): δ 167.54, 142.56, 132.45, 131.04, 130.89, 130.09, 127.61, 82.13, 64.72, 28.20.

[0045] 1 H-NMR spectra and 13 The C-NMR spectra are as follows: Figure 1 and Figure 2 As shown.

[0046] Example 2 This embodiment provides a method for preparing tert-butyl 2-hydroxymethylbenzoate, specifically including the following steps: (1) Weigh the starting material SM1 (10.0 g, 45 mmol, 1.0 eq.) and add it to tetrahydrofuran (80 mL, 8 V). After stirring until completely dissolved, add triethylamine (6.83 g, 67.5 mmol, 1.5 eq.). Cool the above reaction to 0-5 °C in an ice-water bath, and then add SM2 (7.38 g, 54 mmol, 1.2 eq.) dropwise to the reaction solution. After the addition is complete, remove the ice-water bath and react at 20 °C for 1 hour. A large amount of white solid byproduct is produced in the reaction solution. After the reaction is complete under TLC monitoring, a new compound with low polarity is generated in the reaction. Filter to remove the white solid, and wash the white solid with 10 mL of tetrahydrofuran to obtain a tetrahydrofuran solution of compound 1. Since it is an active ester, this solution is not further processed and is directly used in the next reaction according to the theoretical yield.

[0047] (2) A tetrahydrofuran solution of compound 1 was added to a three-necked flask, evacuated, and protected with nitrogen. The solution was then cooled to 0-5°C using an ice-water bath. Sodium borohydride (3.4 g, 90 mmol, 2.0 eq.) was slowly added to the reaction solution, and the mixture was stirred at 25°C for 3 hours. TLC monitoring showed that compound 1 had reacted completely and a new compound was formed. The reaction solution was then cooled to 0-5°C again using an ice-water bath, and 20 mL of saturated ammonium chloride aqueous solution was added dropwise to quench the reaction. After the addition was complete, the ice-water bath was removed, and the mixture was stirred at room temperature for another 30 minutes. 100 mL of dichloromethane and 100 mL of water were added to the reaction flask, and the reaction was extracted. After standing and separating the layers, the organic phase was separated, dried with anhydrous sodium sulfate, and concentrated to obtain 8.34 g of colorless oily target compound P1, with a yield of 89%.

[0048] Example 3 This embodiment provides a method for preparing tert-butyl 2-hydroxymethylbenzoate, specifically including the following steps: (1) Weigh the starting material SM1 (10.0 g, 45 mmol, 1.0 eq.) and add it to tetrahydrofuran (100 mL, 10 V). After stirring until completely dissolved, add triethylamine (6.83 g, 67.5 mmol, 1.5 eq.). Cool the above reaction to 0-5 °C in an ice-water bath, and then add SM2 (9.23 g, 67.5 mmol, 1.5 eq.) dropwise to the reaction solution. After the addition is complete, remove the ice-water bath and react at 30 °C for 5 hours. A large amount of white solid byproduct is produced in the reaction solution. After the reaction is complete under TLC monitoring, a new compound with low polarity is generated in the reaction. Filter to remove the white solid, and wash the white solid with 10 mL of tetrahydrofuran to obtain a tetrahydrofuran solution of compound 1. Since it is an active ester, this solution is not further processed and is directly used in the next reaction according to the theoretical yield.

[0049] (2) A tetrahydrofuran solution of compound 1 was added to a three-necked flask, evacuated, and protected with nitrogen. The solution was then cooled to 0-5°C using an ice-water bath. Sodium borohydride (4.28 g, 112.5 mmol, 2.5 eq.) was slowly added to the reaction solution, and the mixture was stirred at 40°C for 1 hour. TLC monitoring showed that compound 1 had reacted completely and a new compound was formed. The reaction solution was then cooled to 0-5°C again using an ice-water bath, and 20 mL of saturated ammonium chloride aqueous solution was added dropwise to quench the reaction. After the addition was complete, the ice-water bath was removed, and the mixture was stirred at room temperature for another 30 minutes. 100 mL of dichloromethane and 100 mL of water were added to the reaction flask, and the reaction was extracted. After standing and separating the layers, the organic phase was separated, dried with anhydrous sodium sulfate, and concentrated to obtain 8.43 g of colorless oily target compound P1, with a yield of 90%.

[0050] Example 4 This embodiment provides a method for preparing tert-butyl 2-hydroxymethylbenzoate, specifically including the following steps: This embodiment provides a method for preparing tert-butyl 2-hydroxymethylbenzoate, specifically including the following steps: (1) Weigh the starting material SM1 (10.0 g, 45 mmol, 1.0 eq.) and add it to tetrahydrofuran (100 mL, 10 V). After stirring until completely dissolved, add triethylamine (6.83 g, 67.5 mmol, 1.5 eq.). Cool the above reaction to 0-5 °C using an ice-water bath, and then add SM2 (9.23 g, 67.5 mmol, 1.5 eq.) dropwise to the reaction solution. After the addition is complete, remove the ice-water bath and react at 40 °C for 2 hours. A large amount of white solid byproduct is produced in the reaction solution. After the reaction is complete under TLC monitoring, a new compound with low polarity is generated in the reaction. Filter to remove the white solid, and wash the white solid with 10 mL of tetrahydrofuran to obtain a tetrahydrofuran solution of compound 1. Since it is an active ester, this solution is not further processed and is directly used in the next reaction according to the theoretical yield.

[0051] (2) A tetrahydrofuran solution of compound 1 was added to a three-necked flask, evacuated, and protected with nitrogen. The solution was then cooled to 0-5°C using an ice-water bath. Sodium borohydride (5.13 g, 135 mmol, 3.0 eq.) was slowly added to the reaction solution, and the mixture was stirred at 20°C for 6 hours. TLC monitoring showed that compound 1 had reacted completely and a new compound was formed. The reaction solution was then cooled to 0-5°C again using an ice-water bath, and 20 mL of saturated ammonium chloride aqueous solution was added dropwise to quench the reaction. After the addition was complete, the ice-water bath was removed, and the mixture was stirred at room temperature for another 30 minutes. 100 mL of dichloromethane and 100 mL of water were added to the reaction flask, and the reaction was extracted. After standing and separating the layers, the organic phase was separated, dried with anhydrous sodium sulfate, and concentrated to obtain 8.24 g of colorless oily target compound P1, with a yield of 88%.

[0052] Example 5 This embodiment provides a method for preparing tert-butyl 2-hydroxymethylbenzoate, specifically including the following steps: (1) Weigh the starting material SM1 (10.0 g, 45 mmol, 1.0 eq.) and add it to dichloromethane (80 mL, 8 V). After stirring until completely dissolved, add triethylamine (9.11 g, 90 mmol, 2.0 eq.). Cool the above reaction to 0-5 °C using an ice-water bath, and then add SM2 (6.45 g, 47.2 mmol, 1.05 eq.) dropwise to the reaction solution. After the addition is complete, remove the ice-water bath and react at 20 °C for 1 hour. A white solid byproduct is produced in the reaction solution. After the reaction is complete under TLC monitoring, a new compound with low polarity is generated in the reaction. Filter to remove the white solid, and wash the white solid with 10 mL of dichloromethane to obtain a dichloromethane solution of compound 1. Since it is an active ester, this solution is not further processed and is directly used in the next reaction according to the theoretical yield.

[0053] (2) A dichloromethane solution of compound 1 was added to a three-necked flask, evacuated, and protected with nitrogen. The solution was then cooled to 0-5°C using an ice-water bath. Sodium borohydride (3.4 g, 90 mmol, 2.0 eq.) was slowly added to the reaction solution, and the mixture was stirred at 20°C for 2 hours. TLC monitoring showed that compound 1 had reacted completely and a new compound was formed. The reaction solution was then cooled to 0-5°C again using an ice-water bath, and 20 mL of saturated ammonium chloride aqueous solution was added dropwise to quench the reaction. After the addition was complete, the ice-water bath was removed, and the mixture was stirred at room temperature for another 30 minutes. 100 mL of dichloromethane and 100 mL of water were added to the reaction flask, and the reaction was extracted. After standing and separating the layers, the organic phase was separated, dried with anhydrous sodium sulfate, and concentrated. TLC showed that the crude product contained a relatively large number of impurities. After purification by column chromatography, 6.1 g of a colorless oily compound was obtained, with a yield of 65%.

[0054] Example 6 This embodiment provides a method for preparing tert-butyl 2-hydroxymethylbenzoate, specifically including the following steps: (1) Weigh the starting material SM1 (10.0 g, 45 mmol, 1.0 eq.) and add it to tetrahydrofuran (60 mL, 6 V). After stirring until completely dissolved, add triethylamine (9.11 g, 90 mmol, 2.0 eq.). Cool the above reaction to 0-5 °C using an ice-water bath, and then add SM2 (6.45 g, 47.2 mmol, 1.05 eq.) dropwise to the reaction solution. After the addition is complete, remove the ice-water bath and react at 20 °C for 2 hours. A large amount of white solid byproduct is produced in the reaction solution. After the reaction is complete under TLC monitoring, a new compound with low polarity is generated in the reaction. Filter to remove the white solid, and wash the white solid with 10 mL of tetrahydrofuran to obtain a tetrahydrofuran solution of compound 1. Since it is an active ester, this solution is not further processed and is directly used in the next reaction according to the theoretical yield.

[0055] (2) A tetrahydrofuran solution of compound 1 was added to a three-necked flask, evacuated, and protected with nitrogen. The solution was then cooled to 0-5°C using an ice-water bath. Lithium aluminum hydride (3.42 g, 90 mmol, 2.0 eq.) was slowly added to the reaction solution, and the mixture was stirred at 20°C for 2 hours. TLC monitoring showed that compound 1 had reacted completely and a new compound had been formed, but several impurities were present in the reaction system. The reaction solution was cooled to 0-5°C again using an ice-water bath, and 20 mL of saturated ammonium chloride aqueous solution was added dropwise to quench the reaction. After the addition was complete, the ice-water bath was removed, and the mixture was stirred at room temperature for another 30 minutes. 100 mL of dichloromethane and 100 mL of water were added to the reaction flask to extract the reaction mixture. After standing and separating the layers, the organic phase was separated, dried with anhydrous sodium sulfate, concentrated, and then purified by column chromatography to obtain 7.31 g of colorless oily target compound P1, with a yield of 78%.

[0056] Example 7 This embodiment provides a method for preparing tert-butyl 2-hydroxymethylbenzoate, specifically including the following steps: (1) Weigh the starting material SM1 (10.0 g, 45 mmol, 1.0 eq.) and add it to tetrahydrofuran (120 mL, 12 V). After stirring until completely dissolved, add piperidine (5.75 g, 67.5 mmol, 1.5 eq.). Cool the above reaction to 0-5 °C in an ice-water bath, and then add SM2 (7.38 g, 54 mmol, 1.2 eq.) dropwise to the reaction solution. After the addition is complete, remove the ice-water bath and react at 20 °C for 1 hour. A white solid byproduct is produced in the reaction solution. TLC monitoring of the reaction showed that some starting material had not reacted completely, the target product was generated in the reaction, and SM2 remained in the reaction solution. Wash the white solid with 10 mL of tetrahydrofuran to obtain a tetrahydrofuran solution of compound 1. Since it is an active ester, this solution is not further processed and is directly used in the next reaction according to the theoretical yield.

[0057] (2) A tetrahydrofuran solution of compound 1 was added to a three-necked flask, evacuated, and protected with nitrogen. The solution was then cooled to 0-5°C using an ice-water bath. Sodium borohydride (3.4 g, 90 mmol, 2.0 eq.) was slowly added to the reaction solution, and the mixture was stirred at 25°C for 3 hours. TLC monitoring showed that compound 1 had reacted completely and several new compounds were formed. The reaction solution was then cooled to 0-5°C again using an ice-water bath, and 20 mL of water was added dropwise to quench the reaction. After the addition was complete, the ice-water bath was removed, and the mixture was stirred at room temperature for another 30 minutes. 100 mL of ethyl acetate and 100 mL of water were added to the reaction flask to extract the reaction mixture. After standing and separating the layers, the organic phase was separated, dried with anhydrous sodium sulfate, and concentrated to obtain 3.0 g of colorless oily target compound P1, with a yield of 32%.

[0058] Example 8 This embodiment provides a method for preparing tert-butyl 2-hydroxymethylbenzoate, specifically including the following steps: (1) Weigh the starting material SM1 (10.0 g, 45 mmol, 1.0 eq.) and add it to tetrahydrofuran (80 mL, 8 V). After stirring until completely dissolved, add N,N-diisopropylamine (6.83 g, 67.5 mmol, 1.5 eq.). Cool the above reaction to 0-5 °C using an ice-water bath, and then add SM2 (7.38 g, 54 mmol, 1.2 eq.) dropwise to the reaction solution. After the addition is complete, remove the ice-water bath and react at 20 °C for 1 hour. A large amount of white solid byproduct is generated in the reaction solution. After the reaction is complete under TLC monitoring, the target product is generated in the reaction. Filter to remove the white solid, and wash the white solid with 10 mL of toluene to obtain a toluene solution of compound 1. Since it is an active ester, this solution is not further processed and is directly used in the next reaction according to the theoretical yield.

[0059] (2) A toluene solution of compound 1 was added to a three-necked flask, evacuated, and protected with nitrogen. The solution was then cooled to 0°C using an ice-water bath. Sodium borohydride (3.4 g, 90 mmol, 2.0 eq.) was slowly added to the reaction solution, and the reaction was carried out at 25°C for 3 hours. TLC monitoring showed that compound 1 had reacted completely and the target compound had been formed, but several impurities were present. 20 mL of saturated ammonium chloride aqueous solution was added dropwise to quench the reaction. After the addition was complete, the mixture was stirred at room temperature for another 30 minutes. 100 mL of methyl tert-butyl ether and 100 mL of water were added to the reaction flask to extract the reaction. After standing and separating the layers, the organic phase was separated, dried with anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 4.5 g of colorless oily target compound P1, with a yield of 48%.

[0060] Example 9 The only difference between this embodiment and Example 1 is that the solvent tetrahydrofuran in step (1) is replaced with an equal volume of N,N-dimethylformamide; all other aspects are the same as in Example 1. 7.03 g of the colorless oily target compound P1 was obtained, with a yield of 75%.

[0061] Example 10 The only difference between this embodiment and Example 1 is that the organic base triethylamine in step (1) is replaced with an equimolar amount of N,N-diisopropylethylamine; all other aspects are the same as in Example 1. 8.53 g of the colorless oily target compound P1 was obtained, with a yield of 91%.

[0062] Example 11 The only difference between this embodiment and Example 1 is that the reducing agent sodium borohydride in step (2) is replaced with an equimolar amount of sodium cyanoborohydride; all other aspects are the same as in Example 1. 7.40 g of the colorless oily target compound P1 was obtained, with a yield of 79%.

[0063] Example 12 The only difference between this embodiment and Example 1 is that the reducing agent sodium borohydride in step (2) is replaced with an equal volume of red aluminum; all other aspects are the same as in Example 1. 6.75 g of the colorless oily target compound P1 was obtained, with a yield of 72%.

[0064] The applicant declares that the present invention is illustrated by the above embodiments, but the present invention is not limited to the above process steps, that is, it does not mean that the present invention must rely on the above process steps to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of the raw materials used in the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing tert-butyl 2-hydroxymethylbenzoate, characterized in that, The preparation method includes the following steps: (1) Tert-butyl hydrogen phthalate and isobutyl chloroformate react to give compound 1, and the reaction formula is as follows: ； (2) Compound 1 reacts to give tert-butyl 2-hydroxymethylbenzoate; the reaction formula is as follows: 。 2. The preparation method according to claim 1, characterized in that, The molar ratio of tert-butyl hydrogen phthalate and isobutyl chloroformate in step (1) is 1:(1-1.5), preferably 1:(1.05-1.1).

3. The preparation method according to claim 1, characterized in that, The reaction described in step (1) is carried out in a solvent; Preferably, the solvent comprises any one or a combination of at least two of tetrahydrofuran, toluene, N,N-dimethylformamide or dichloromethane, preferably tetrahydrofuran; Preferably, the ratio of tert-butyl hydrogen phthalate to solvent is 1 g: (5-15) mL, more preferably 1 g: (8-10) mL.

4. The preparation method according to any one of claims 1-3, characterized in that, The reaction described in step (1) is carried out in the presence of an organic base; Preferably, the organic base includes any one or a combination of at least two of piperidine, triethylamine, N,N-diisopropylethylamine, or N,N-diisopropylamine, with triethylamine being the most preferred. Preferably, the molar ratio of tert-butyl hydrogen phthalate to organic base is 1:(1-4), more preferably 1:(1.5-2.0).

5. The preparation method according to any one of claims 1-4, characterized in that, The reaction temperature in step (1) is 0-50℃, and the reaction time is 1.0-5.0 h; Preferably, the reaction temperature in step (1) is 20-30°C and the reaction time is 1.0-2.0 h.

6. The preparation method according to any one of claims 1-5, characterized in that, After the reaction in step (1) is completed, separation is performed by filtration and washing to obtain crude compound 1, which is not purified and is directly used in step (2).

7. The preparation method according to any one of claims 1-6, characterized in that, The reaction described in step (2) is carried out in the presence of a reducing agent; Preferably, the reducing agent includes any one of sodium borohydride, sodium cyanoborohydride, red aluminum or lithium aluminum hydride, and is preferably sodium borohydride; Preferably, the molar ratio of tert-butyl hydrogen phthalate to reducing agent is 1:(1-4), more preferably 1:(2.0-2.5).

8. The preparation method according to any one of claims 1-7, characterized in that, The reaction described in step (2) is carried out in a solvent; Preferably, the solvent comprises any one or a combination of at least two of tetrahydrofuran, toluene, N,N-dimethylformamide or dichloromethane, preferably tetrahydrofuran; Preferably, the temperature of the reaction in step (2) is 0-40℃ and the reaction time is 1.0-6.0h.

9. The preparation method according to any one of claims 1-8, characterized in that, The reaction temperature in step (2) is 20-25℃, and the reaction time is 2.0-3.0 h; Preferably, the reaction in step (2) further includes a post-processing step; Preferably, the post-processing includes: quenching the reaction, extracting with an organic solvent, drying, filtering, and concentrating the obtained filtrate to obtain tert-butyl 2-hydroxymethylbenzoate; In this invention, commonly used quenching reagents are used to quench the reaction; Preferably, the quenching agent includes water, a saturated ammonium chloride aqueous solution, and a citric acid aqueous solution, and is more preferably a saturated ammonium chloride aqueous solution; Preferably, the concentration of the citric acid aqueous solution is 0.5-2 mol / L; Preferably, the organic solvent used for extraction includes methyl tert-butyl ether, ethyl acetate, and dichloromethane, with dichloromethane being the preferred solvent; Preferably, the drying is performed using anhydrous sodium sulfate.

10. The preparation method according to any one of claims 1-9, characterized in that, The preparation method includes the following steps: (1) Tert-butyl hydrogen phthalate and isobutyl chloroformate are reacted with a solvent in the presence of an organic base at 0-50°C for 1.0-5.0 h to obtain compound 1. The molar ratio of tert-butyl hydrogen phthalate and isobutyl chloroformate is 1:(1-1.5). The solvent includes any one or a combination of at least two of tetrahydrofuran, toluene, N,N-dimethylformamide or dichloromethane. The molar ratio of tert-butyl hydrogen phthalate to solvent is 1 g:(5-15) mL. The organic base includes any one or a combination of at least two of piperidine, triethylamine, N,N-diisopropylethylamine or N,N-diisopropylamine. The molar ratio of tert-butyl hydrogen phthalate to organic base is 1:(1-4). After the reaction in step (1) is completed, separation is performed by filtration and washing to obtain crude compound 1. It is not purified and is directly used in the next step of the reaction. (2) Compound 1 is reacted in a solvent at 0-40°C for 1.0-6.0 h in the presence of a reducing agent to obtain tert-butyl 2-hydroxymethylbenzoate. The reducing agent includes any one of sodium borohydride, sodium cyanoborohydride, red aluminum or lithium aluminum hydride. The molar ratio of compound 1 to the reducing agent is 1:(1-4). The organic solvent includes any one or a combination of at least two of tetrahydrofuran, toluene, N,N-dimethylformamide or dichloromethane. After the reaction is completed, the reaction is quenched, extracted with an organic solvent, dried, filtered, and the filtrate is concentrated to obtain tert-butyl 2-hydroxymethylbenzoate.

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