Preparation method of methyl benzoate containing chiral 1-hydroxyethyl

Abstract

The invention provides a preparation method of methyl benzoate containing chiral 1-hydroxyethyl, and relates to the technical field of organic synthesis. The invention provides a preparation method of methyl benzoate containing chiral 1-ethoxyl, which comprises the following steps: by taking methyl acetylbenzoate as a raw material, carrying out chiral reduction on (R)-1-methyl-3, 3-diphenyl hexahydropyrrolo [1, 2-c] [1, 3, 2] oxazole borane (chiral reduction catalyst) and borane, thereby obtaining the methyl benzoate containing chiral 1-ethoxyl. Carrying out hydrolysis, chiral resolution and neutralization to obtain high-ee-value benzoic acid containing chiral 1-ethoxyl, and then carrying out esterification to obtain methyl benzoate containing chiral 1-ethoxyl. The chiral 1-hydroxyethyl-containing methyl benzoate prepared by the preparation method provided by the invention has a high ee value, ee% gt; 96%.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing methyl benzoate containing chiral 1-hydroxyethyl. Background Technology

[0002] Methyl benzoate containing chiral 1-hydroxyethyl can be used to synthesize β1 selective antagonists and ROS1 kinase inhibitors. β1 selective antagonists are antagonistic drugs targeting the β1-adrenergic receptor, possessing anti-inflammatory activity and commonly used in the treatment of cardiovascular diseases. ROS1 kinase inhibitors are targeted therapies for ROS1-positive non-small cell lung cancer (NSCLC), offering enhanced efficacy and safety.

[0003] Chiral synthesis of methyl benzoate containing (1-hydroxyethyl) has been reported, such as direct reduction with reducing agents like borane, or reduction with borane under the catalysis of a chiral reducing catalyst. However, the products prepared by this method generally have low ee values, failing to meet the usual selling requirements (ee%>95%) for pharmaceutical intermediates. Summary of the Invention

[0004] In view of this, the object of the present invention is to provide a method for preparing methyl benzoate containing chiral 1-hydroxyethyl. The methyl benzoate containing chiral 1-hydroxyethyl obtained by the preparation method provided by the present invention has a high ee value (ee%>96%).

[0005] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a method for preparing methyl benzoate containing chiral 1-hydroxyethyl, comprising the following steps: Methyl acetylbenzoate, a chiral reducing catalyst, borane, and an organic solvent were mixed and subjected to a reduction reaction to obtain a reduction product; the chiral reducing catalyst was (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazolborane. The reduction product, organic solvent, and alkaline compound aqueous solution are mixed and subjected to a hydrolysis reaction to obtain the hydrolysis product; The hydrolysis product, organic solvent, and chiral resolving agent are mixed and subjected to chiral resolution, followed by neutralization reaction with an acid to obtain benzoic acid containing chiral 1-hydroxyethyl; the chiral resolving agent is R(+)-α-phenylethylamine. The chiral 1-hydroxyethyl benzoic acid, iodomethane, an organic solvent, and a basic compound are mixed and subjected to an esterification reaction to obtain methyl benzoate containing chiral 1-hydroxyethyl. The methyl acetylbenzoate has the structure shown in formula A1 or formula A2; Formula A1, Formula A2; When the methyl acetylbenzoate has the structure shown in Formula A1, the chiral 1-hydroxyethyl benzoic acid and the chiral 1-hydroxyethyl methyl benzoate have the structures shown in Formula E1 and Formula F1 respectively. E1, Formula F1; When the methyl acetylbenzoate has the structure shown in Formula A2, the chiral 1-hydroxyethyl benzoic acid and the chiral 1-hydroxyethyl methyl benzoate have the structures shown in Formula E2 and Formula F2, respectively. E2, Formula F2.

[0006] Preferably, the borane is BH3·THF, and the molar ratio of methyl acetylbenzoate, chiral reduction catalyst and borane is 1:(1.1~2):(1.1~2).

[0007] Preferably, the reduction reaction is carried out at a temperature of -60 to -80°C for 1 to 5 hours.

[0008] Preferably, the alkaline compound in the aqueous solution includes one or more of LiOH, NaOH, and KOH; the molar ratio of the reduction product to the alkaline compound in the aqueous solution is 1:(2~5).

[0009] Preferably, the hydrolysis reaction is carried out at a temperature of 15~30℃ for a time of 2 hours or more.

[0010] Preferably, the molar ratio of the hydrolysis product to the chiral resolving agent is 1:(0.8~1).

[0011] Preferably, the chiral splitting temperature is 15~30℃ and the time is 10~24h.

[0012] Preferably, the acid includes hydrochloric acid, and the neutralization reaction is carried out at a temperature of 15-30°C for a time of 0.5-2 hours.

[0013] Preferably, the basic compound used in the esterification reaction includes one or more of potassium carbonate, cesium carbonate and NaH, and the molar ratio of the chiral 1-hydroxyethyl benzoic acid, iodomethane and the basic compound is 1:(1.1~2):(1.1~2).

[0014] Preferably, the esterification reaction is carried out at a temperature of 15-30°C for 2-24 hours.

[0015] This invention provides a method for preparing chiral 1-hydroxyethyl methyl benzoate. The method uses acetylbenzoate as a raw material, and involves chiral reduction with (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazolylborane (a chiral reduction catalyst) and borane. Following hydrolysis, chiral resolution, and neutralization, a high-ee value chiral 1-hydroxyethyl benzoic acid is obtained. This is then esterified to obtain chiral 1-hydroxyethyl methyl benzoate. The chiral 1-hydroxyethyl methyl benzoate prepared by the method provided by this invention has a high ee value, with ee% > 96%. Attached Figure Description

[0016] Figure 1 The NMR spectrum of methyl benzoate containing chiral 1-hydroxyethyl prepared in Example 1; Figure 2 The NMR spectrum of the chiral 1-hydroxyethyl methyl benzoate prepared in Example 2 is shown. Detailed Implementation

[0017] This invention provides a method for preparing methyl benzoate containing chiral 1-hydroxyethyl, comprising the following steps: Methyl acetylbenzoate, a chiral reducing catalyst, borane, and an organic solvent were mixed and subjected to a reduction reaction to obtain a reduction product; the chiral reducing catalyst was (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazolborane. The reduction product, organic solvent, and alkaline compound aqueous solution are mixed and subjected to a hydrolysis reaction to obtain the hydrolysis product; The hydrolysis product, organic solvent, and chiral resolving agent are mixed and subjected to chiral resolution, followed by neutralization reaction with an acid to obtain benzoic acid containing chiral 1-hydroxyethyl; the chiral resolving agent is R(+)-α-phenylethylamine. The chiral 1-hydroxyethyl benzoic acid, iodomethane, an organic solvent, and a basic compound are mixed and subjected to an esterification reaction to obtain methyl benzoate containing chiral 1-hydroxyethyl. The methyl acetylbenzoate has the structure shown in formula A1 or formula A2; Formula A1, Formula A2; When the methyl acetylbenzoate has the structure shown in Formula A1, the chiral 1-hydroxyethyl benzoic acid and the chiral 1-hydroxyethyl methyl benzoate have the structures shown in Formula E1 and Formula F1 respectively. E1, Formula F1; When the methyl acetylbenzoate has the structure shown in Formula A2, the chiral 1-hydroxyethyl benzoic acid and the chiral 1-hydroxyethyl methyl benzoate have the structures shown in Formula E2 and Formula F2, respectively. E2, Formula F2.

[0018] Unless otherwise specified, all raw materials involved in this invention are commercially available products well known in the art.

[0019] This invention involves mixing methyl acetylbenzoate, a chiral reduction catalyst, borane, and an organic solvent to carry out a reduction reaction, thereby obtaining the reduction product.

[0020] In this invention, the chiral reduction catalyst is (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazolium borane, preferably BH3·THF (borane-tetrahydrofuran); the molar ratio of methyl acetylbenzoate, the chiral reduction catalyst, and borane is preferably 1:(1.1~2):(1.1~2), and can be 1:1.2:(1.1~1.2). In this invention, the organic solvent is preferably tetrahydrofuran (THF). This invention does not have specific requirements for the amount of organic solvent used, as long as the dissolution of the raw materials and the smooth progress of the reaction are ensured.

[0021] In this invention, the preferred method for mixing methyl acetylbenzoate, the chiral reduction catalyst, borane, and the organic solvent is as follows: The organic solvent and chiral reduction catalyst were added to the reaction vessel. Borane was added dropwise under nitrogen protection. The mixture was cooled to below -70°C and stirred to obtain a mixture. The methyl acetylbenzoate was dissolved in the organic solvent to obtain a methyl acetylbenzoate solution. The methyl acetylbenzoate solution is added dropwise to the mixture.

[0022] In this invention, the temperature of the reduction reaction is preferably -60~-80℃, and can be -70℃; the time is preferably 1~5h, and can be 2, 3 or 4h; the time of the reduction reaction is calculated from the time the mixed liquid is added.

[0023] After the reduction reaction is completed, the present invention preferably performs post-treatment on the obtained reduction reaction solution, and the preferred method for post-treatment is as follows: The obtained reduction reaction solution is kept at a temperature below -70℃ (or -70℃). Saturated ammonium chloride solution is added dropwise. After the addition is complete, the temperature is allowed to return to 0℃ to room temperature naturally. The solution is stirred for at least 30 minutes. Then water is added, and the solution is extracted with ethyl acetate (EA). The resulting organic phase is dried, concentrated, and subjected to column chromatography with stirring. The solvent is then removed to obtain the reduction product.

[0024] After obtaining the reduction product, the present invention mixes the reduction product, organic solvent and alkaline compound aqueous solution to carry out a hydrolysis reaction to obtain the hydrolysis product.

[0025] In this invention, the alkaline compound in the aqueous solution preferably includes one or more of LiOH, NaOH, and KOH, and the concentration of the aqueous solution can be 2 mol / L. The molar ratio of the reduction product to the alkaline compound in the aqueous solution is preferably 1:(2~5), or 1:(3~4). In this invention, the organic solvent preferably includes one or more of methanol, ethanol, and tetrahydrofuran. This invention does not have specific requirements on the amount of organic solvent used, as long as the reaction proceeds smoothly. In this invention, the temperature of the hydrolysis reaction is preferably 15~30℃. In the embodiments of this invention, the hydrolysis reaction is carried out at room temperature (i.e., without additional heating or cooling), and the time is preferably more than 2 hours, or 2~18 hours.

[0026] After the hydrolysis reaction is completed, the present invention preferably performs post-treatment on the obtained hydrolysis reaction solution, and the preferred method of post-treatment is as follows: The obtained hydrolysis reaction solution was extracted twice with methyl tert-butyl ether (MTBE). The pH of the resulting aqueous phase was adjusted to below 3 with hydrochloric acid (3 is acceptable), and then extracted with EA. The resulting organic phase was dried and concentrated sequentially to obtain the hydrolysis product.

[0027] After obtaining the hydrolysis product, the present invention mixes the hydrolysis product, organic solvent and chiral resolving agent for chiral resolving, and then performs a neutralization reaction with acid to obtain benzoic acid containing chiral 1-hydroxyethyl.

[0028] In this invention, the chiral resolving agent is R(+)-α-phenylethylamine, and the molar ratio of the hydrolysis product to the chiral resolving agent is preferably 1:(0.8~1), or can be 1:(0.8~0.9); the organic solvent is preferably ethyl acetate. This invention does not have any special requirements on the amount of the organic solvent used, as long as the dissolution of the raw materials and the smooth progress of the reaction are ensured.

[0029] In this invention, the chiral separation temperature is preferably 15~30℃. In the embodiments of this invention, the chiral separation is carried out at room temperature (i.e., without additional heating or cooling), and the time is preferably 10~24h, which can be 12~18h. The chiral separation is preferably carried out under nitrogen protection.

[0030] After the chiral resolution, the present invention preferably filters the resulting reaction solution, washes the resulting filter cake with ethyl acetate, and then recrystallizes it with an alcohol to obtain the resolved product. In the present invention, the alcohol is preferably methanol or ethanol, and the recrystallization is preferably performed twice.

[0031] In this invention, the acid preferably includes hydrochloric acid, and the molar ratio of the acid to the resolution product is preferably 1 or more, and can be 3.4 to 3.6. In this invention, the neutralization reaction is preferably carried out by adding the resolution product, an organic solvent (such as ethyl acetate), and the acid to a reaction vessel, and conducting the neutralization reaction under stirring conditions. In this invention, the temperature of the neutralization reaction is preferably 15 to 30°C. In the embodiments of this invention, the neutralization reaction is carried out at room temperature (i.e., without additional heating or cooling), and the time is preferably 0.5 to 2 hours, and can be 0.5 or 1 hour.

[0032] After the neutralization reaction is completed, the present invention preferably separates the obtained reaction solution to obtain an aqueous phase and an organic phase. The organic phase obtained by EA extraction of the aqueous phase is combined with the above organic phase, dried, concentrated, and the solvent is removed by vacuum extraction. The solution is then vortexed three times with dichloromethane (DCM) to obtain the chiral 1-hydroxyethyl benzoic acid.

[0033] After obtaining chiral 1-hydroxyethyl benzoic acid, the present invention mixes the chiral 1-hydroxyethyl benzoic acid, iodomethane, an organic solvent and a basic compound to carry out an esterification reaction to obtain methyl benzoate containing chiral 1-hydroxyethyl.

[0034] In this invention, the basic compound used in the esterification reaction preferably includes one or more of potassium carbonate, cesium carbonate, and NaH. The molar ratio of the chiral 1-hydroxyethyl benzoic acid, iodomethane, and the basic compound is preferably 1:(1.1~2):(1.1~2), but can be 1:(1.2~1.5):(1.5~2). In this invention, the organic solvent is preferably N,N-dimethylformamide (DMF). This invention does not have specific requirements on the amount of the organic solvent used, as long as it ensures the dissolution of the raw materials and the smooth progress of the reaction.

[0035] In this invention, the preferred method for mixing chiral 1-hydroxyethyl benzoic acid, iodomethane, an organic solvent, and a basic compound is as follows: The chiral 1-hydroxyethyl benzoic acid, organic solvent, and basic compound are added to a reaction vessel, and iodomethane is added dropwise to the resulting mixed solution under ice bath conditions.

[0036] In this invention, the temperature of the esterification reaction is preferably 15~30°C. In the embodiments of this invention, the esterification reaction is carried out at room temperature (i.e., without additional heating or cooling), and the time is preferably 2~24h, which can be 12~18h.

[0037] After the esterification reaction is completed, the present invention preferably pours the obtained reaction solution into hydrochloric acid, extracts it with EA, dries the obtained organic phase, concentrates it, mixes it with column chromatography, and removes the solvent to obtain the methyl benzoate containing chiral 1-hydroxyethyl.

[0038] In this invention, when the methyl acetylbenzoate has the structure shown in Formula A1, the reaction involved in preparing the methyl benzoate containing chiral 1-hydroxyethyl is as follows: , Among them, B1, C1 and D1 are the main chemical structural formulas of the reduction product, hydrolysis product and resolution product, respectively.

[0039] In this invention, when the methyl acetylbenzoate has the structure shown in Formula A2, the reaction involved in preparing the methyl benzoate containing chiral 1-hydroxyethyl is as follows: , Among them, B2, C2 and D2 are the main chemical structural formulas of the reduction product, hydrolysis product and resolution product, respectively.

[0040] The methyl benzoate containing chiral 1-hydroxyethyl prepared by the preparation method provided by the present invention has a high ee value (ee%>96%).

[0041] To further illustrate the present invention, the preparation method of methyl benzoate containing chiral 1-hydroxyethyl provided by the present invention will be described in detail below with reference to examples, but these should not be construed as limiting the scope of protection of the present invention.

[0042] Example 1 The preparation of methyl benzoate containing chiral 1-hydroxyethyl (compound F1) follows the reaction route as follows: .

[0043] The specific steps are as follows: (1) Add 400 mL of THF and 93.4 g of (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazolborane (CBS) (0.34 mol, 1.2 eq) to a 1 L three-necked flask. Under nitrogen protection, add 320 mL of BH3·THF (1 M, 0.32 mol, 1.14 eq) dropwise. Cool to -70 °C and stir for 15 min. Add 50 g of compound A1 (0.28 mol, 1.0 eq) dissolved in 200 mL of THF dropwise. React at -70 °C for 2 h. The reaction is complete by TLC. Control the temperature at -70 °C and add 300 mL of saturated ammonium chloride solution dropwise. After the addition is complete, allow the temperature to return to 0 °C naturally and stir for 30 min. Add 1 L of water and use 1 L of TLC solution to further process the reaction. Extracted once with EA, the organic phase was dried, concentrated, and then subjected to column chromatography (300-400 mesh silica gel column, petroleum ether and ethyl acetate as elution solvents, collecting the product with a volume ratio of petroleum ether to ethyl acetate of 20:1-10:1). The solvent was removed by vacuum to obtain 30g of colorless liquid B1 (ee%=90.89%). Y1 (i.e., the yield of step (1)) = 59.33%.

[0044] (2) Add 30g B1 (0.17mol, 1.0eq), 60mL methanol, and 250mL 2M LiOH aqueous solution (0.5mol, 3.0eq) to a 100mL single-necked flask. React overnight at room temperature. Add 85mL 2M LiOH solution (0.17mol, 1.0eq) and continue the reaction for 1h. The reaction is complete by TLC. Extract impurities twice with MTBE. Adjust the pH of the aqueous phase to 3 with 2M HCl solution. Extract with EA. Dry the organic phase and concentrate to obtain 18g white solid Cl. Y2 (i.e., the yield of step (2)) = 65.07%.

[0045] (3) Add 18g C1 (0.11mol, 1.0eq), 200mL EA, and 10.45g R(+)-α-phenylethylamine (0.09mol, 0.8eq) to a 250mL single-necked flask. Under nitrogen protection, react overnight at room temperature. Filter, wash the filter cake with EA, and recrystallize twice with methanol to obtain 18g of white solid D1. Y3 (i.e., the yield of step (3)) = 57.83%.

[0046] (4) Add 18g D1 (0.06mol, 1.0eq), 200mL EA, and 215mL 1M HCl solution (0.215mol, 3.4eq) to a 200mL single-necked flask. Stir until dissolved (stirring at room temperature for 30min). Separate the liquid and extract the aqueous phase once with 200mL EA. Combine the organic phases, dry, concentrate, remove the solvent, and vortex three times with DCM to obtain 9.3g of white solid E1 (ee%=97.12%). Y4 (i.e., the yield of step (4)) = 89.34%.

[0047] (5) Add 9.3g E1 (0.056mol, 1.0eq), 100mL DMF, and 15.4g K2CO3 (0.112mol, 2.0eq) to a 250mL single-necked flask. Add 9.5g iodomethane (0.067mol) dropwise under ice bath. After the addition is complete, react at room temperature overnight. When the reaction is complete by TLC, pour the solution into 50mL 2M HCl solution, extract with EA, dry the organic phase, concentrate, and combine the samples for small-scale column chromatography (300~400 mesh silica gel column, petroleum ether and ethyl acetate as elution solvents, collect products with a volume ratio of petroleum ether to ethyl acetate of 20:1~10:1). Remove the solvent and obtain 6.4g orange liquid F1 (ee%=96.80%). Y5 (i.e., the yield of step (5)) = 63.46%, Ytotal (i.e., the total yield) = 12.66%.

[0048] Figure 1 The NMR spectrum of methyl benzoate containing chiral 1-hydroxyethyl prepared in Example 1 is shown. 1 H-NMR (300MHz, CDCl3): δ 8.03 (1H, t), 7.93 (1H, dt), 7.58 (1H,d), 7.42 (1H, t), 4.98-4.92 (1H,q), 3.91 (3H,s), 2.09 (1H, br) 1.51 (3H, d).

[0049] Example 2 The preparation of methyl benzoate containing chiral 1-hydroxyethyl (compound F2) follows the reaction route as follows: .

[0050] The specific steps are as follows: (1) Add 300 mL of THF and 74.7 g of (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazolborane (CBS) (0.27 mol, 1.2 eq) to a 2 L three-necked flask. Under nitrogen protection, add 270 mL of BH3·THF (1 M, 0.27 mol, 1.2 eq) dropwise. Cool to -70 °C and stir for 15 min. Add 40 g of compound A2 (0.22 mol, 1.0 eq) dissolved in 200 mL of THF dropwise. React at -70 °C for 2 h. The reaction is complete by TLC. Control the temperature at -70 °C and add 500 mL of saturated ammonium chloride solution dropwise. After the addition is complete, allow the temperature to return to 0 °C naturally and stir for 30 min. Add 1 L of water and use 1 L of TLC solution to further cool the mixture. Extract once with EA, dry the organic phase, concentrate, mix and precipitate by column chromatography (300-400 mesh silica gel column, petroleum ether and ethyl acetate as elution solvents, collect the product with a volume ratio of petroleum ether to ethyl acetate of 20:1 to 10:1), remove the solvent and give 34.7 g of colorless liquid B2 (Y1=85.78%, ee%=90.96%).

[0051] (2) 34.7 g B2 (0.19 mol, 1.0 eq), 70 mL methanol, and 380 mL 2 M LiOH aqueous solution (0.76 mol, 4.0 eq) were added to a 100 mL single-necked flask. The reaction was carried out at room temperature for 2 h. The reaction was completed by TLC. Impurities were extracted twice with MTBE. The pH of the aqueous phase was adjusted to 3 with 2 M HCl solution. The phase was extracted with EA, dried, and concentrated to obtain 23 g of white solid C2. Y2 = 71.88%.

[0052] (3) Add 23g C2 (0.14mol, 1.0eq), 250mL EA, and 13.5g R(+)-α-phenylethylamine (0.11mol, 0.8eq) to a 500mL three-necked flask. Under nitrogen protection, react overnight at room temperature. Filter, wash the filter cake with EA, and recrystallize twice with methanol to obtain 28g of white solid D2. Y3=70.40%.

[0053] (4) Add 28g D2 (0.097mol, 1.0eq), 200mL EA, and 331mL 1M HCl solution (0.33mol, 3.4eq) to a 200mL single-necked flask. Stir until dissolved (stirring at room temperature for 30min). Separate the liquid and extract the aqueous phase once with 200mL EA. Combine the organic phases, dry, concentrate, remove the solvent under vacuum, and vortex three times with DCM to obtain 14.4g of white solid E2 (ee%=96.12%). Y4=88.93%.

[0054] (5) Add 14.4g E2 (0.087mol, 1.0eq), 140mL DMF, and 23.8g K2CO3 (0.172mol, 2.0eq) to a 250mL single-necked flask. Add 14.87g iodomethane (0.1mol, 1.2eq) dropwise under ice bath. After the addition is complete, react overnight at room temperature. When the reaction is complete by TLC, pour the solution into 100mL of 2M HCl solution, extract with EA, dry the organic phase, concentrate, and perform column chromatography (300~400 mesh silica gel column, petroleum ether and ethyl acetate as elution solvents, collect the product with a volume ratio of petroleum ether to ethyl acetate of 20:1~10:1). Remove the solvent and obtain 10.2g of orange liquid F2 (ee%=96.03%). Y5=65.32%, Ytotal=25.22%.

[0055] Figure 2 The NMR spectrum of the chiral 1-hydroxyethyl methyl benzoate prepared in Example 2 is shown. 1 H-NMR (300MHz, CDCl3): δ 8.01 (2H, d), 7.44(2H,d), 4.98-4.93 (1H,q), 3.91 (3H,s), 1.50 (3H,d).

[0056] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. It should be noted that those skilled in the art can make various improvements and modifications without departing from the 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 methyl chiral 1-hydroxyethyl benzoate, characterized in that, The method comprises the following steps: mixing methyl acetylbenzoate, a chiral reduction catalyst, borane and an organic solvent to perform a reduction reaction to obtain a reduction product; the chiral reduction catalyst is (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole; mixing the reduction product, an organic solvent and an aqueous alkali compound to perform a hydrolysis reaction to obtain a hydrolysis product; mixing the hydrolysis product, an organic solvent and a chiral resolution agent to perform chiral resolution, and then performing a neutralization reaction with an acid to obtain a chiral 1-hydroxyethyl-containing benzoic acid; the chiral resolution agent is R(+)-a-phenylethylamine; mixing the chiral 1-hydroxyethyl-containing benzoic acid, methyl iodide, an organic solvent and an alkali compound to perform an esterification reaction to obtain a chiral 1-hydroxyethyl-containing methyl benzoate; the methyl acetylbenzoate has a structure shown in formula A1 or formula A2; Formula A1, Formula A2; when the methyl acetylbenzoate has a structure shown in formula A1, the chiral 1-hydroxyethyl-containing benzoic acid and the chiral 1-hydroxyethyl-containing methyl benzoate have structures shown in formula E1 and formula F1, respectively; Formula E1, Formula F1; when the methyl acetylbenzoate has a structure shown in formula A2, the chiral 1-hydroxyethyl-containing benzoic acid and the chiral 1-hydroxyethyl-containing methyl benzoate have structures shown in formula E2 and formula F2, respectively; Formula E2, Formula F2.

2. The production method according to claim 1, characterized by, the borane is BH3·THF, and the molar ratio of the methyl acetylbenzoate, the chiral reduction catalyst and the borane is 1:(1.1-2):(1.1-2).

3. The production method according to claim 1 or 2, characterized by, The temperature of the reduction reaction is -60 to -80°C, and the time is 1-5 hours.

4. The preparation method according to claim 1, characterized in that, The alkali compound in the aqueous alkali compound includes one or more of LiOH, NaOH and KOH; and the molar ratio of the reduction product to the alkali compound in the aqueous alkali compound is 1:(2-5).

5. The production method according to claim 1 or 4, characterized by, The temperature of the hydrolysis reaction is 15-30°C, and the time is more than 2 hours.

6. The method of claim 1, wherein, The molar ratio of the hydrolysis product to the chiral resolution agent is 1:(0.8-1).

7. The production method according to claim 1 or 6, characterized by, The temperature of the chiral resolution is 15-30°C, and the time is 10-24 hours.

8. The method of claim 1, wherein, The acid includes hydrochloric acid, the temperature of the neutralization reaction is 15-30°C, and the time is 0.5-2 hours.

9. The method of claim 1, wherein, The alkali compound used in the esterification reaction includes one or more of potassium carbonate, cesium carbonate and NaH, and the molar ratio of the chiral 1-hydroxyethyl-containing benzoic acid, methyl iodide to the alkali compound is 1:(1.1-2):(1.1-2).

10. The production method according to claim 1 or 9, characterized by, The temperature of the esterification reaction is 15-30°C, and the time is 2-24 hours.

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