Preparation method of levosalbutamol tartrate

Abstract

The invention discloses a preparation method of levosalbutamol tartrate, and relates to the technical field of compound synthesis. The preparation method of the levosalbutamol tartrate comprises the following steps: catalyzing 1-{4-(acetoxyl)-3-[(acetoxyl) methyl] phenyl}-2-bromoethyl ketone by a chiral catalyst to obtain a reduction product, reacting the reduction product with tert-butylamine to obtain levosalbutamol, and finally salifying the levosalbutamol and L-tartaric acid to prepare the levosalbutamol tartrate. The chiral catalyst is a chiral (S)-3, 3 '-Bis (3, 5-diphenyl phenyl)-1, 1'-binaphthol coordinated aluminum hydride. The preparation method disclosed by the invention is simple in process and relatively high in total yield and optical purity, and the adopted initial raw material 1-{4-(acetoxyl)-3-[(acetoxyl) methyl] phenyl}-2-bromoethyl ketone is wide in source and has obvious industrialization advantages.

Description

Technical Field

[0001] The present invention belongs to the technical field of the preparation of organic compounds, and particularly relates to a preparation method of levosalbutamol tartrate. Background Art

[0002] Levosalbutamol tartrate is an important drug for the treatment and prevention of reversible airway obstructive diseases, which can activate β2-adrenergic receptors on airway smooth muscle, relax the smooth muscle, and thus relieve asthma symptoms. Pharmacological studies have shown that the efficacy of levosalbutamol is 80 times that of dextral salbutamol, and it has a higher absorption rate and fewer side effects in the body.

[0003] For the synthesis of levosalbutamol, there are mainly two categories: asymmetric synthesis and resolution methods. The method of chiral resolution of racemic salbutamol has cumbersome operations, a long resolution process, a very low yield of separated levosalbutamol, and its enantiomer cannot be utilized, resulting in a high production cost.

[0004] The Chinese patent application with the publication number CN118108608A discloses a synthesis method of levosalbutamol hydrochloride, which uses raw material -1 (2 - [benzyl(tert-butyl)amino]-1-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)ethanone) as the starting material, and successively undergoes reduction, resolution, hydrolysis, hydrogenation debenzylation, and salt formation reactions to prepare levosalbutamol hydrochloride. This method uses raw materials that are not easily available, has a long resolution step, and the enantiomer cannot be utilized after chiral resolution. Summary of the Invention

[0005] Aiming at the deficiencies existing in the prior art, the purpose of the present invention is to provide a preparation method of levosalbutamol tartrate.

[0006] To achieve the above purpose, the present invention is realized through the following technical solutions:

[0007] A preparation method of levosalbutamol tartrate, the preparation method is as follows: 1-{4-(acetoxy)-3-[(acetoxy)methyl]phenyl}-2-bromoethanone is catalyzed by a chiral catalyst to obtain a reduction product, then reacts with tert-butylamine to obtain levosalbutamol, and finally forms a salt with L-tartaric acid for preparation; the chiral catalyst is aluminum hydride coordinated with chiral (S)-3,3'-Bis(3,5-diphenylphenyl)-1,1'-binaphthol.

[0008] The chiral catalyst is prepared by the following method:

[0009] Under anhydrous and anaerobic conditions, (S)-3,3'-Bis(3,5-diphenylphenyl)-1,1'-binaphthol is dissolved in THF. Under ice bath conditions, NaH is added and stirred for 2 - 3 h. Then, a THF solution of AlCl3 is slowly added dropwise, and the reaction is stirred at room temperature for 20 - 28 h to obtain the product.

[0010] The molar ratio of the feed of (S)-3,3'-Bis(3,5-diphenylphenyl)-1,1'-binaphthol, NaH, and AlCl3 is 1:(4 - 5):(0.5 - 0.6).

[0011] During the preparation of the above catalyst, it is necessary to ensure an anhydrous and anaerobic environment. (S)-3,3'-Bis(3,5-diphenylphenyl)-1,1'-binaphthol (BDPB) first reacts with NaH, and its two phenolic hydroxyl groups are completely deprotonated to form bisphenolate anion (BDPB - O - ); Subsequently, the THF solution of aluminum trichloride is added dropwise to the system at low temperature. Al 3+ forms a coordination bond with the bisphenolate anion through the lone pair electrons of the oxygen atom. At the same time, the hydride ion (H - ) provided by the excessive NaH gradually replaces the chloride ion (Cl - ) at the Al center, and finally forms a chiral aluminum hydride complex Na3[Al((S)-BDPB)2H2]. Among them, Al 3+ coordinates with two bidentate BDPB ligands (each providing two oxygen atoms) and two H - , and the charge is neutralized by three Na + to form an octahedral configuration with six coordination. The (S)-chiral skeleton of binaphthol is transferred to the metal center through the coordination bond, endowing the complex with asymmetric catalytic activity.

[0012] A preparation method of levosalbutamol tartrate is schematically shown by the following reaction equation:

[0013]

[0014] A preparation method of levosalbutamol tartrate specifically includes the following steps:

[0015] S1: Under nitrogen protection, the chiral catalyst, potassium tert-butoxide, and isopropanol are stirred and mixed evenly. Then, 1-{4-(acetoxy)-3-[(acetoxy)methyl]phenyl}-2-bromoethanone is added, and the reaction is carried out at room temperature for 20 - 25 h. After post-treatment, the reduction product is obtained;

[0016] S2: Under nitrogen protection, 1,4-dioxane, tert-butylamine and the reduction product are stirred and mixed evenly, and refluxed for 6 - 8 h. After cooling to room temperature, the mixture is concentrated under reduced pressure, then a reaction solvent is added, and stirred. L-tartaric acid is added in batches, and the temperature is raised to 35 - 45 °C and kept warm for 2 - 3 h. After post-treatment, levosalbutamol tartrate is obtained.

[0017] In step S1, the molar ratio of the chiral catalyst, potassium tert-butoxide and 1-{4-(acetoxy)-3-[(acetoxy)methyl]phenyl}-2-bromoethanone is (0.2 - 0.5):(1.5 - 3):10.

[0018] In step S2, the molar ratio of tert-butylamine, the reduction product and L-tartaric acid is (4 - 6):1:(0.6 - 0.75); the reaction solvent is one of methanol and absolute ethanol.

[0019] Due to the above technical solutions, the beneficial effects of the present invention include:

[0020] (1) A novel chiral catalyst Na3[Al((S)-BDPB)2H2] is prepared in this application, which can be applied to the enantioselective reduction reaction of ketone substrates and has high selectivity.

[0021] (2) The preparation method of the present invention has simple process, high total yield and optical purity, and the starting material 1-{4-(acetoxy)-3-[(acetoxy)methyl]phenyl}-2-bromoethanone used has a wide source, showing obvious industrialization advantages. Specific Embodiments

[0022] The following is further illustrated with reference to embodiments, but the present invention is not limited to these embodiments.

[0023] Example 1 Preparation of chiral catalyst:

[0024] Under argon protection, 10 mmol of (S)-3,3'-Bis(3,5-diphenylphenyl)-1,1'-binaphthol is dissolved in 70 ml of anhydrous THF, cooled to 0 °C in an ice bath, and 40 mmol of NaH is slowly added and stirred for 2 h; 25 ml of a THF solution of AlCl3 (containing 5 mmol of AlCl3) is slowly added dropwise, and the temperature is controlled ≤ 5 °C during the dropping process. After the dropping is completed, the ice bath is removed, and the reaction is stirred at room temperature for 20 h; the insoluble precipitate is removed by suction filtration under reduced pressure, the filtrate is concentrated by rotary evaporation, then 100 ml of n-hexane is added to precipitate a yellow solid, and then recrystallized with 120 ml of a toluene / n-hexane solution (volume ratio 1:5), and vacuum dried at 60 °C for 5 h to obtain the Na3[Al((S)-BDPB)2H2] catalyst.

[0025] Example 2 Preparation of chiral catalyst:

[0026] Under argon protection, 10 mmol of (S)-3,3'-Bis(3,5-diphenylphenyl)-1,1'-binaphthol was dissolved in 70 ml of anhydrous THF, cooled to 0 °C in an ice bath, and 45 mmol of NaH was slowly added. The mixture was stirred for 2.5 h. Then, 25 ml of a THF solution of AlCl3 (containing 5.5 mmol of AlCl3) was slowly added dropwise, and the temperature was controlled at ≤5 °C during the addition. After the addition was completed, the ice bath was removed, and the reaction was stirred at room temperature for 24 h. The insoluble precipitate was removed by suction filtration under reduced pressure. The filtrate was concentrated by rotary evaporation and then 100 ml of n-hexane was added to precipitate a yellow solid. The solid was recrystallized from 120 ml of a toluene / n-hexane solution (volume ratio 1:5) and dried in vacuo at 60 °C for 5 h to obtain the catalyst Na3[Al((S)-BDPB)2H2].

[0027] Example 3 Preparation of chiral catalyst:

[0028] Under argon protection, 10 mmol of (S)-3,3'-Bis(3,5-diphenylphenyl)-1,1'-binaphthol was dissolved in 70 ml of anhydrous THF, cooled to 0 °C in an ice bath, and 50 mmol of NaH was slowly added. The mixture was stirred for 3 h. Then, 25 ml of a THF solution of AlCl3 (containing 6 mmol of AlCl3) was slowly added dropwise, and the temperature was controlled at ≤5 °C during the addition. After the addition was completed, the ice bath was removed, and the reaction was stirred at room temperature for 28 h. The insoluble precipitate was removed by suction filtration under reduced pressure. The filtrate was concentrated by rotary evaporation and then 100 ml of n-hexane was added to precipitate a yellow solid. The solid was recrystallized from 120 ml of a toluene / n-hexane solution (volume ratio 1:5) and dried in vacuo at 60 °C for 5 h to obtain the catalyst Na3[Al((S)-BDPB)2H2].

[0029] During the preparation of the catalyst of the present application, an anhydrous reaction condition needs to be ensured, and the raw materials need to be dehydrated first.

[0030] Example 4 Preparation of Levosalbutamol Tartrate:

[0031] S1: Under nitrogen protection, 0.02 mol of chiral catalyst (prepared in Example 1), 0.15 mol of potassium tert-butoxide and 500 ml of isopropanol were stirred and mixed evenly, and 1 mol of 1-{4-(acetoxy)-3-[(acetoxy)methyl]phenyl}-2-bromoethanone was added. The reaction was carried out at room temperature for 20 h, then the reaction was stopped and filtered. The filtrate was distilled under reduced pressure at 50 °C for 3 h, 300 ml of ether was added, and the mixture was washed successively with 0.1 mol / L HCl (200 ml × 2 times) and 200 ml of saturated brine, and then distilled under reduced pressure at 40 °C for 3 h and dried in vacuo at 70 °C for 6 h to obtain 281.49 g of the reduction product, with a molar yield of 85.0%. The 1H NMR data are as follows: 11H NMR (500 MHz, Chloroform-d) δ 7.42 (p, J = 0.8 Hz, 1H), 7.19 (dt, J = 8.4, 0.9 Hz, 1H), 7.06 (s, 1H), 5.20 (t, J = 0.7 Hz, 2H), 4.95 - 4.89 (m, 1H), 3.75 (dd, J = 11.5, 3.5 Hz, 1H), 3.63 (d, J = 4.8 Hz, 1H), 3.49 (dd, J = 11.4, 3.6 Hz, 1H), 2.36 (s, 3H), 2.09 (s, 3H).;

[0032] S2: Under nitrogen protection, 800 ml of 1,4-dioxane, 4 mol of tert-butylamine and 1 mol of the reduction product were put into a reaction flask, stirred and mixed evenly, refluxed for 8 h, cooled to room temperature, concentrated under reduced pressure at 55 °C for 3 h, 1000 ml of anhydrous methanol was added, stirred, and 0.6 mol of L-tartaric acid was added in batches (divided into 5 times, with an interval of 5 min each time). The temperature was raised to 35 °C and kept for reaction for 3 h. Filtration was carried out, slurried with 300 ml of methanol for 1 h, filtered, washed with 50 ml of methanol, and dried at 50 °C for 10 h to obtain 287.1 g of levosalbutamol tartrate, with a molar yield of 91.3% and an optical purity of 99.2%.

[0033] Example 5 Preparation of Levosalbutamol Tartrate:

[0034] S1: Under nitrogen protection, 0.04 mol of chiral catalyst (prepared in Example 2), 0.2 mol of potassium tert-butoxide and 500 ml of isopropanol were stirred and mixed evenly, 1 mol of 1-{4-(acetoxy)-3-[(acetoxy)methyl]phenyl}-2-bromoethanone was added, and the reaction was carried out at room temperature for 24 h. The reaction was stopped and filtered. The filtrate was distilled under reduced pressure at 50 °C for 3 h, 300 ml of ether was added, and it was washed successively with 0.1 mol / L HCl (200 ml × 2 times) and 200 ml of saturated brine, and distilled under reduced pressure at 40 °C for 3 h and dried in vacuum at 70 °C for 6 h to obtain 286.1 g of the reduction product, with a molar yield of 86.4%;

[0035] S2: Under nitrogen protection, 800 ml of 1,4-dioxane, 5 mol of tert-butylamine and 1 mol of the reduction product were put into a reaction flask, stirred and mixed evenly, refluxed for 7 h, cooled to room temperature, concentrated under reduced pressure at 55 °C for 3 h, 1000 ml of anhydrous ethanol was added, stirred, and 0.7 mol of L-tartaric acid was added in batches (divided into 5 times, with an interval of 5 min each time). The temperature was raised to 40 °C and kept for reaction for 2.5 h. Filtration was carried out, slurried with 300 ml of anhydrous ethanol for 1 h, filtered, washed with 50 ml of anhydrous ethanol, and dried at 50 °C for 10 h to obtain 290.6 g of levosalbutamol tartrate, with a molar yield of 92.4% and an optical purity of 99.5%.

[0036] Preparation of Levalbuterol Tartrate: Example 6

[0037] S1: Under nitrogen protection, 0.05 mol of chiral catalyst (prepared in Example 3), 0.3 mol of potassium tert-butoxide and 500 ml of isopropanol were stirred and mixed evenly. Then 1 mol of 1-{4-(acetoxy)-3-[(acetoxy)methyl]phenyl}-2-bromoethanone was added. The reaction was carried out at room temperature for 25 h. After stopping the reaction, filtration was carried out. The filtrate was distilled under reduced pressure at 50 °C for 3 h. Then 300 ml of ether was added, and it was washed successively with 0.1 mol / L HCl (200 ml × 2 times) and 200 ml of saturated brine, and then distilled under reduced pressure at 40 °C for 3 h and dried in vacuum at 70 °C for 6 h to obtain 280.2 g of the reduction product with a molar yield of 84.6%;

[0038] S2: Under nitrogen protection, 800 ml of 1,4-dioxane, 6 mol of tert-butylamine and 1 mol of the reduction product were put into a reaction flask, stirred and mixed evenly, and refluxed for 6 h. After cooling to room temperature, it was concentrated under reduced pressure at 55 °C for 3 h. Then 1000 ml of absolute ethanol was added and stirred. 0.75 mol of L-tartaric acid was added in batches (divided into 5 times, with an interval of 5 min each time). The temperature was raised to 45 °C and kept warm for 2 h. Then filtration was carried out, and it was slurried with 300 ml of absolute ethanol for 1 h, filtered, washed with 50 ml of absolute ethanol, and dried at 50 °C for 10 h to obtain 285.3 g of levalbuterol tartrate with a molar yield of 90.8% and an optical purity of 99.3%.

[0039] Comparative Example 1

[0040] The preparation method of levalbuterol tartrate was basically the same as that in Example 5, except that the chiral catalyst (prepared in Example 2) in step S1 was replaced with a chiral catalyst prepared by the following method:

[0041] Under argon protection, 10 mmol of (S)-3,3'-Bis(3,5-diphenylphenyl)-1,1'-binaphthol was dissolved in 70 ml of anhydrous THF, cooled to 0 °C in an ice bath, and 30 mmol of NaH was slowly added and stirred for 2.5 h; 25 ml of a THF solution of AlCl3 (containing 5.5 mmol of AlCl3) was slowly added dropwise, and the temperature was controlled ≤ 5 °C during the dropping process. After the dropping was completed, the ice bath was removed, and the reaction was stirred at room temperature for 24 h; the insoluble precipitate was removed by vacuum filtration. After the filtrate was concentrated by rotary evaporation, 100 ml of n-hexane was added to precipitate a yellow solid, and then recrystallized with 120 ml of a toluene / n-hexane solution (volume ratio 1:5) and dried in vacuum at 60 °C for 5 h to obtain the chiral catalyst.

[0042] The molar yield of step S1 was 65.2%, the molar yield of step S2 was 89.5%, the optical purity was 98.1%, and the total yield of the two steps was 58.4%.

[0043] The reasons for the low yield and optical purity of levosalbutamol tartrate prepared in this comparative example may be as follows: When the amount of NaH was reduced from 45 mmol to 30 mmol, after the phenolic hydroxyl group of BDPB was deprotonated, only 10 mmol of NaH remained in the system, with a relatively low concentration. The insufficient supply of H - resulted in the incomplete substitution of Cl - in AlCl3, and the remaining Cl - occupied the Al central coordination site, not only weakening the reduction ability of active hydrogen but also disrupting the symmetry transfer of the rigid chiral framework of BDPB, leading to a decrease in enantioselectivity. In addition, the lack of H - might force Al 3+ to be unable to completely transform the tetracoordinate tetrahedral structure into the thermodynamically stable hexacoordinate octahedral structure. The tetrahedral structure was less stable due to the steric repulsion between the phenyl substituents of BDPB and H - , resulting in coordination dissociation or structural reorganization during the catalytic process, further exacerbating product racemization, and ultimately leading to a decrease in the number of catalyst active sites and distortion of the chiral microenvironment, finally manifested as a double reduction in reaction yield and optical purity.

[0044] Comparative Example 2

[0045] The preparation method of levosalbutamol tartrate was basically the same as that in Example 5, except that the chiral catalyst prepared in Step S1 (prepared in Example 2) was replaced with a chiral catalyst prepared by the following method:

[0046] Under argon protection, 10 mmol of (S)-3,3'-Bis(3,5-diphenylphenyl)-1,1'-binaphthol was dissolved in 70 ml of anhydrous THF, cooled to 0 °C in an ice bath, and 45 mmol of NaH was slowly added, followed by stirring for 2.5 h. Then, 25 ml of a THF solution of AlCl3 (containing 5.5 mmol of AlCl3) was slowly added dropwise, with the temperature controlled at ≤5 °C during the addition. After the addition was completed, the ice bath was removed, and the reaction was stirred at room temperature for 10 h. The insoluble precipitate was removed by vacuum filtration. The filtrate was concentrated by rotary evaporation and then 100 ml of n-hexane was added to precipitate a yellow solid, which was then recrystallized from 120 ml of a toluene / n-hexane solution (volume ratio 1:5) and vacuum dried at 60 °C for 5 h to obtain the chiral catalyst.

[0047] The molar yield of Step S1 was 78.1%, the molar yield of Step S2 was 90.9%, and the optical purity was 89.6%.

[0048] When the stirring time at room temperature was shortened from 20 h to 10 h, the core reason for the decrease in its yield and optical purity was that short-time stirring during the catalyst coordination process led to the incomplete substitution of Cl - in AlCl3 by H - , and the remaining Cl -Occupying the Al active site weakens the reduction ability of the catalyst. Meanwhile, the random coordination of Cl - destroys the symmetry transfer of the BDPB chiral ligand, leading to a decrease in enantioselectivity. Due to the steric hindrance of BDPB, the initially coordinated structure is a four-coordinate tetrahedron (kinetic initial product). 10 h is not sufficient to complete the transformation from the four-coordinate tetrahedron to the six-coordinate octahedron with the optimal spatial orientation (thermodynamic stable configuration). The tetrahedron is unstable due to the steric repulsion between the phenyl substituents of BDPB and H - , and it is easily dissociated during the catalytic process to form achiral Al-based compounds, resulting in product racemization.

[0049] Comparative Example 3

[0050] The preparation method of levosalbutamol tartrate is basically the same as that of Example 5, except that the chiral catalyst in step S1 (prepared in Example 2) is replaced by a chiral catalyst prepared by the following method:

[0051] Under argon protection, 10 mmol of (S)-3,3'-dimethyl-1,1'-binaphthol was dissolved in 70 ml of anhydrous THF, cooled to 0 °C in an ice bath, and 45 mmol of NaH was slowly added. The mixture was stirred for 2.5 h. Then, 25 ml of a THF solution of AlCl3 (containing 5.5 mmol of AlCl3) was slowly added dropwise, and the temperature was controlled at ≤5 °C during the addition. After the addition, the ice bath was removed, and the reaction was stirred at room temperature for 24 h. The insoluble precipitate was removed by vacuum filtration. The filtrate was concentrated by rotary evaporation and then 100 ml of n-hexane was added to precipitate a yellow solid. The solid was recrystallized from 120 ml of a toluene / n-hexane solution (volume ratio 1:5) and vacuum dried at 60 °C for 5 h to obtain the chiral catalyst.

[0052] The molar yield of the reduction reaction in step S1 was 82.3%, the molar yield of step S2 was 91.5%, and the optical purity was 83.9%.

[0053] Comparative Example 4

[0054] The preparation method of levosalbutamol tartrate is basically the same as that of Example 5, except that the chiral catalyst in step S1 (prepared in Example 2) is replaced by a chiral catalyst prepared by the following method:

[0055] Under argon protection, 10 mmol of (S)-3,3'-bis(4-methylphenyl)-1,1'-binaphthol was dissolved in 70 ml of anhydrous THF, cooled to 0 °C in an ice bath, and 45 mmol of NaH was slowly added. The mixture was stirred for 2.5 h. Then, 25 ml of a THF solution of AlCl3 (containing 5.5 mmol of AlCl3) was slowly added dropwise, and the temperature was controlled at ≤5 °C during the addition. After the addition was completed, the ice bath was removed, and the reaction mixture was stirred at room temperature for 24 h. The insoluble precipitate was removed by suction filtration under reduced pressure. The filtrate was concentrated by rotary evaporation and then 100 ml of n-hexane was added to precipitate a yellow solid. The solid was recrystallized from 120 ml of a toluene / n-hexane solution (volume ratio 1:5) and dried in vacuo at 60 °C for 5 h to obtain the chiral catalyst.

[0056] The molar yield of the reduction reaction in step S1 was 80.3%, the molar yield in step S2 was 91.2%, and the optical purity was 87.1%.

[0057] Comparative Examples 3 and 4 used different chiral catalysts for the preparation of levosalbutamol tartrate. The difference from this application was that the organic ligands of the aluminum hydride coordination compounds used were different. The possible reasons for the low optical purity in Comparative Examples 3-4 were as follows: In this application, the 3,5-diphenylphenyl substituent of BDPB formed a rigid structure through multi-level steric hindrance (phenyl-phenyl-naphthalene ring three-level stacking), which not only locked the (S)-chiral conformation of binaphthol but also completely wrapped the Al center, forcing the ligands to arrange in a specific orientation to ensure efficient chiral transfer. However, the steric hindrance of the 4-methylphenyl or dimethyl substituent was reduced, resulting in an increased rotational freedom of the C1-C1' axis of binaphthol, the loosening of the chiral cavity, the generation of diastereoisomers, and the decrease in enantioselectivity. In addition, the 3,5-diphenylphenyl of BDPB stabilized the Al-O bond through an electron-withdrawing effect and moderately activated the Al-H bond, while the electron-donating property of the methyl substituent increased the electron density of the phenoxide anion, decreased the stability of the Al-H bond, and prone to premature release or protonation of H- during the catalytic cycle, reducing the reduction efficiency.

[0058] The above are only the preferred embodiments of the present invention and are not used to limit the present invention. However, for those of ordinary skill in the art, without departing from the scope of the technical solution of the present invention, some equivalent changes such as slight modifications, evolutions, and modifications made using the technical content disclosed above are all equivalent embodiments of the present invention. At the same time, any equivalent changes, modifications, and evolutions made to the above embodiments based on the essential technology of the present invention still fall within the protection scope of the technical solution of the present invention.

Claims

1. A preparation method of levosalbutamol tartrate, characterized in that, The preparation method is as follows: 1-{4-(acetoxy)-3-[(acetoxy)methyl]phenyl}-2-bromoacetophenone is catalyzed by a chiral catalyst to obtain a reduction product, which is then reacted with tert-butylamine to obtain levalbuterol, and finally salted with L-tartaric acid for preparation; the chiral catalyst is aluminum hydride coordinated with chiral (S)-3,3'-Bis(3,5-diphenylphenyl)-1,1'-binaphthol.

2. The preparation method of levosalbutamol tartrate according to claim 1, wherein, The chiral catalyst is prepared by the following method: Under anhydrous and anaerobic conditions, (S)-3,3'-Bis(3,5-diphenylphenyl)-1,1'-binaphthol is dissolved in THF. Under ice bath conditions, NaH is added and stirred for 2-3 h. Then, a THF solution of AlCl3 is slowly added dropwise, and the reaction is stirred at room temperature for 20-28 h to obtain the product.

3. The preparation method of levosalbutamol tartrate according to claim 2, wherein The molar ratio of (S)-3,3'-Bis(3,5-diphenylphenyl)-1,1'-binaphthol, NaH and AlCl3 in the feed is 1:(4-5):(0.5-0.6).

4. The preparation method of levosalbutamol tartrate according to claim 1, characterized in that, The preparation method includes the following steps: S1: Under nitrogen protection, the chiral catalyst, potassium tert-butoxide and isopropanol are stirred and mixed evenly, 1-{4-(acetoxy)-3-[(acetoxy)methyl]phenyl}-2-bromoacetophenone is added, and the reaction is carried out at room temperature for 20-25 h, and then post-treated to obtain a reduction product. S2: Under nitrogen protection, 1,4-dioxane, tert-butylamine and the reduction product are stirred and mixed evenly, and the reaction is refluxed for 6-8 h. After cooling to room temperature, the reaction mixture is concentrated under reduced pressure, and then a reaction solvent is added. Stir, add L-tartaric acid in batches, heat up to 35-45 °C, keep warm for 2-3 h, and then post-treat to obtain levalbuterol tartrate.

5. The preparation method of levosalbutamol tartrate according to claim 4, characterized in that, In step S1, the molar ratio of the chiral catalyst, potassium tert-butoxide and 1-{4-(acetoxy)-3-[(acetoxy)methyl]phenyl}-2-bromoacetophenone in the feed is (0.2-0.5):(1.5-3):

10.

6. The preparation method of levosalbutamol tartrate according to claim 4, characterized in that, In step S2, the molar ratio of tert-butylamine, the reduction product and L-tartaric acid in the feed is (4-6):1:(0.6-0.75).

7. The preparation method of levosalbutamol tartrate according to claim 4, wherein In step S2, the reaction solvent is one of methanol and absolute ethanol.

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