A process for the preparation of levalbuterol tartrate

Abstract

The application discloses a preparation method of levalbuterol tartrate, and relates to the technical field of compound synthesis. The preparation method of the levalbuterol tartrate comprises the following steps: 1-{4-(acetyloxy)-3-[(acetyloxy)methyl]phenyl}-2-bromoethanone is subjected to catalysis by a chiral catalyst to obtain a reduction product, then the reduction product is subjected to reaction with t-butylamine to obtain levalbuterol, and finally, the levalbuterol is subjected to salt formation with L-tartaric acid; and the chiral catalyst is aluminum hydride coordinated with a hand type (S)-3,3'-Bis(3,5-diphenylphenyl)-1,1'-binol. The preparation method has the advantages of simple process, high total yield and high optical purity, and the starting material 1-{4-(acetyloxy)-3-[(acetyloxy)methyl]phenyl}-2-bromoethanone is widely available, and the preparation method has obvious industrialization advantages.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic compound preparation, and particularly relates to a preparation method of levalbuterol tartrate. BACKGROUND

[0002] Levalbuterol tartrate is an important medicine for treating and preventing reversible airway obstruction diseases, and can activate beta2 adrenergic receptors on respiratory tract smooth muscle to relax the smooth muscle, thereby relieving asthma symptoms. Pharmacological studies have shown that the efficacy of levalbuterol is 80 times that of dextroalbuterol, and the absorption rate in the body is higher and the side effects are smaller.

[0003] For the synthesis of levalbuterol, there are mainly two types of asymmetric synthesis and resolution method. The method of chiral resolution of racemic albuterol is complicated, the resolution process is long, and the yield of levalbuterol obtained by separation is very low, and the enantiomer cannot be utilized, and the production cost is high.

[0004] The Chinese invention patent application with the publication number CN118108608A discloses a synthesis method of levalbuterol hydrochloride, which takes raw material-1(2-[benzyl(tert-butyl)amino]-1-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)ethanone) as a starting material, and sequentially undergoes reduction, resolution, hydrolysis, hydrogenation debenzylization and salt formation reactions to prepare levalbuterol hydrochloride. The method uses raw materials that are not easy to obtain, the resolution step is long, and the enantiomer cannot be utilized after chiral resolution. SUMMARY

[0005] In view of the deficiencies in the prior art, the purpose of the present application is to provide a preparation method of levalbuterol tartrate.

[0006] To achieve the above-mentioned purpose, the present application realizes the following technical scheme:

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

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

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

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

[0011] The above catalyst is prepared in an anhydrous and anaerobic environment. First, (S)-3,3'-Bis(3,5-diphenylphenyl)-1,1'-binaphthyl (BDPB) reacts with NaH, and the two phenolic hydroxyl groups are completely deprotonated to form a diphenolate anion (BDPB-O - ). Then, a THF solution of aluminum chloride is added dropwise to the system at low temperature. Al 3+ forms a coordination bond with the diphenolate anion through the oxygen lone pair electrons, and the excess NaH provides hydrogen anions (H - ) that gradually replace the chlorine ions (Cl - ) at the Al center, ultimately forming a chiral aluminum hydride complex Na3[Al((S)-BDPB)2H2]. In this complex, Al 3+ is coordinated with two bidentate BDPB ligands (each providing two oxygen atoms) and two H - ions, and the charge is neutralized by three Na + ions, forming a six-coordinated octahedral structure. The (S)-chiral skeleton of the binaphthol is transmitted to the metal center through the coordination bond, endowing the complex with asymmetric catalytic activity.

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

[0013]

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

[0015] S1: Under nitrogen protection, a chiral catalyst, potassium tert-butoxide, and isopropyl alcohol are stirred and mixed uniformly, and 1-{4-(acetyloxy)-3-[(acetyloxy)methyl]phenyl}-2-bromoethanone is added. The mixture is reacted at room temperature for 20-25 h, and the reduced product is obtained after treatment.

[0016] S2: under nitrogen protection, stirring and mixing the 1,4-dioxane, tert-butylamine and the reduction product, refluxing for 6-8h, reducing to room temperature, adding the reaction solvent after concentration under reduced pressure, stirring, adding L-tartaric acid in batches, increasing the temperature to 35-45℃, keeping for 2-3h, and then post-processing to obtain the L-tartaric acid levosalbutamol.

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

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

[0019] By adopting the above technical solutions, the application has the following beneficial effects:

[0020] (1) The application prepares a new type of chiral catalyst Na3[Al((S)-BDPB)2H2], which can be applied to the enantioselective reduction reaction of ketone substrates and has high selectivity.

[0021] (2) The preparation method has simple process, high total yield and optical purity, and the starting material 1-{4-(acetyloxy)-3-[(acetyloxy)methyl]phenyl}-2-bromoethanone is widely available, which has obvious industrialization advantages. DETAILED DESCRIPTION

[0022] The application will be further described below in combination with examples, but the application is not limited to these examples.

[0023] Example 1: Preparation of a chiral catalyst

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

[0025] Example 2: Preparation of a chiral catalyst

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

[0027] Example 3: Preparation of a chiral catalyst

[0028] Under argon protection, 10 mmol (S)-3,3'-Bis(3,5-diphenylphenyl)-1,1'- binaphthyl 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, and 25 ml of a THF solution of AlCl3(containing 5.5 mmol of AlCl3) was slowly added dropwise while the temperature was controlled at ≤5°C. After the addition was completed, the ice bath was removed, and the mixture was stirred at room temperature for 24 h. The insoluble precipitate was removed by suction filtration under reduced pressure, and the filtrate was concentrated by rotary evaporation. Then, 100 ml of n-hexane was added to precipitate yellow solids, and the yellow solids were recrystallized from 120 ml of a toluene / n-hexane solution (volume ratio 1:5). The recrystallized yellow solids were dried at 60°C under vacuum for 5 h to obtain Na3[Al((S)-BDPB)2H2] catalyst.

[0029] In the preparation of the catalyst of the present application, anhydrous reaction conditions need to be ensured, and the raw material needs to be first treated to remove water.

[0030] Example 4: Preparation of levalbuterol tartrate

[0031] S1: Under nitrogen protection, 0.02 mol of the chiral catalyst (prepared in Example 1), 0.15 mol of potassium tert-butoxide, and 500 ml of isopropyl alcohol were stirred and mixed uniformly, and 1 mol of 1-{4-(acetyloxy)-3-[(acetyloxy)methyl]phenyl}-2-bromoethanone was added. The mixture was reacted at room temperature for 20 h, and then 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 sequentially with 0.1 mol / L HCl (200 ml x 2 times) and 200 ml of saturated brine. The mixture was distilled under reduced pressure at 40°C for 3 h, and then dried under vacuum at 70°C for 6 h to obtain 281.49 g of the reduction product, with a molar yield of 85.0%. The nuclear magnetic resonance hydrogen spectrum data of the reduction product are as follows: 1H 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 bottle, stirred and mixed uniformly, refluxed for 8 h, reduced to room temperature, concentrated at 55°C under reduced pressure for 3 h, 1000 ml of anhydrous methanol was added, stirred, 0.6 mol of L-tartaric acid was added in batches (divided into 5 times, 5 min interval each time), the temperature was raised to 35°C, and the reaction was kept for 3 h, filtered, 300 ml of methanol was slurried for 1 h, filtered, 50 ml of methanol was washed, 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 isopropyl alcohol were stirred and mixed uniformly, 1 mol of 1-{4-(acetyloxy)-3-[(acetyloxy)methyl]phenyl}-2-bromoethanone was added, and the reaction was kept at room temperature for 24 h, the reaction was stopped, filtered, the filtrate was distilled at 50°C under reduced pressure for 3 h, 300 ml of ether was added, and 0.1 mol / L HCl (200 ml x 2 times), 200 ml of saturated brine was used in sequence for washing, distilled at 40°C under reduced pressure for 3 h, and dried at 70°C under vacuum 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 bottle, stirred and mixed uniformly, refluxed for 7 h, reduced to room temperature, concentrated at 55°C under reduced pressure for 3 h, 1000 ml of anhydrous ethanol was added, stirred, 0.7 mol of L-tartaric acid was added in batches (divided into 5 times, 5 min interval each time), the temperature was raised to 40°C, and the reaction was kept for 2.5 h, filtered, 300 ml of anhydrous ethanol was slurried for 1 h, filtered, 50 ml of anhydrous ethanol was washed, 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] Example 6 Preparation of levalbuterol tartrate:

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

[0038] S2: 800 ml of 1,4-dioxane, 6 mol of tert-butylamine and 1 mol of the reduction product were placed in a reaction bottle and stirred and mixed under nitrogen protection. The reaction was carried out at reflux for 6 h, and then the temperature was lowered to room temperature. The mixture was concentrated at 55°C under reduced pressure for 3 h. 1000 ml of anhydrous ethanol was added, and the mixture was stirred. 0.75 mol of L-tartaric acid was added in portions (divided into 5 portions, with an interval of 5 min between each addition). The temperature was raised to 45°C, and the mixture was incubated for 2 h. The mixture was filtered, and the filter cake was washed with 300 ml of anhydrous ethanol. The filter cake was washed with 50 ml of anhydrous ethanol, and then 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 by a chiral catalyst prepared by the following method:

[0041] Under argon protection, 10 mmol of (S)-3,3'-Bis(3,5-diphenylphenyl)-1,1'-binol was dissolved in 70 ml of anhydrous THF, and the mixture was cooled to 0°C in an ice bath. 30 mmol of NaH was slowly added, and the mixture was stirred for 2.5 h. A THF solution of AlCl3 (25 ml, 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 mixture was stirred at room temperature for 24 h. The insoluble precipitate was removed by filtration under reduced pressure. The filtrate was concentrated by rotary evaporation, and then 100 ml of n-hexane was added to precipitate yellow solids. The mixture was recrystallized from 120 ml of a toluene / n-hexane solution (volume ratio 1:5), and then vacuum dried 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 reason for the low yield and optical purity of the levalbuterol tartrate prepared in the comparative example is that when the amount of NaH is reduced from 45 mmol to 30 mmol, after the phenolic hydroxyl group of BDPB is deprotonated, the NaH in the system is only 10 mmol, and the concentration is low, and the H - Insufficient supply makes the Cl - in AlCl3 not be completely replaced by H - , which not only weakens the reducing ability of active hydrogen, but also destroys the symmetry transmission of the rigid chiral backbone of BDPB, leading to a decrease in enantioselectivity; in addition, the lack of H - may force Al 3+ to change from a complete tetrahedral structure to a thermodynamically stable octahedral structure, and the tetrahedral structure is stabilized by the steric repulsion between the phenyl substituent of BDPB and H - , resulting in coordination dissociation or structural reorganization during the catalytic process, further increasing the racemization of the product, and ultimately leading to a decrease in the number of active sites of the catalyst, distortion of the chiral microenvironment, and a decrease in both the yield and optical purity of the reaction.

[0044] Comparative Example 2

[0045] The preparation method of levalbuterol tartrate is basically the same as that of Example 5, except that the chiral catalyst prepared in Example 2 is replaced by the chiral catalyst prepared by the following method:

[0046] Under argon protection, 10 mmol (S)-3,3'-Bis(3,5-diphenylphenyl)-1,1'-binol is dissolved in 70 ml of anhydrous THF, cooled to 0°C in an ice bath, and 45 mmol of NaH is slowly added. Stir for 2.5 h; slowly add 25 ml of an AlCl3 THF solution (containing 5.5 mmol of AlCl3), control the temperature ≤5°C during the dropwise addition, remove the ice bath after the dropwise addition is completed, and stir at room temperature for 10 h; remove the insoluble precipitate by vacuum filtration, and then concentrate the filtrate by rotary evaporation. Add 100 ml of n-hexane to precipitate yellow solids, and then recrystallize from 120 ml of a toluene / n-hexane solution (volume ratio 1:5). Vacuum dry at 60°C for 5 h to obtain the chiral catalyst.

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

[0048] When the stirring time at room temperature is shortened from 20 h to 10 h, the core reason for the decrease in yield and optical purity is that the residual Cl - in AlCl3 is not completely replaced by H - , and the residual Cl -occupying the Al active site, weakening the reduction ability of the catalyst, while Cl - random coordination of Cl destroys the symmetry transmission of BDPB chiral ligand, leading to the decrease of enantioselectivity; due to the influence of BDPB steric hindrance, the tetrahedral coordination formed at the beginning is the kinetic initial product, and 10h is insufficient to complete the conversion from tetrahedral coordination to the optimal spatial orientation of hexagonal octahedron (thermodynamic stable configuration), and the tetrahedron is poor in stability due to the steric hindrance of BDPB phenyl substituent and H - , and is easy to dissociate to generate achiral Al-based compounds during the catalytic process, leading to the racemization of the product.

[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 (prepared in Example 2) in step S1 is replaced by a chiral catalyst prepared by the following method:

[0051] Under the protection of argon, 10 mmol of (S)-3,3'-dimethyl-1,1'-binaphthyl was dissolved in 70 ml of anhydrous THF, cooled to 0°C in an ice bath, and 45 mmol of NaH was slowly added, and stirred for 2.5 h; 25 ml of THF solution of AlCl3 (containing 5.5 mmol of AlCl3) was slowly added dropwise, and the temperature was controlled ≤5°C during the dropwise addition; after the dropwise 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 vacuum filtration, and the filtrate was concentrated by rotary evaporation, then 100 ml of n-hexane was added to precipitate yellow solids, and then recrystallized from 120 ml of toluene / n-hexane solution (volume ratio 1:5), and dried at 60°C under vacuum 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 (prepared in Example 2) in step S1 is replaced by a chiral catalyst prepared by the following method:

[0055] Under argon protection, 10 mmol (S)-3,3'-di(4-methylphenyl)-1,1'-binaphthyl was dissolved in 70 ml of anhydrous THF, cooled to 0°C in an ice bath, and 45 mmol of NaH was slowly added, and stirred for 2.5 h; 25 ml of an AlCl3 THF solution (containing 5.5 mmol of AlCl3) was slowly added dropwise, and the temperature was controlled ≤5°C during the dropwise addition; after the dropwise 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 vacuum filtration, and the filtrate was concentrated by rotary evaporation, then 100 ml of n-hexane was added to precipitate yellow solids, and then recrystallized from 120 ml of a toluene / n-hexane solution (volume ratio 1:5), and dried at 60°C under vacuum for 5 h to obtain a chiral catalyst.

[0056] The molar yield of the reduction reaction of step S1 was 80.3%, the molar yield of 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, which differed from the present application in that the organic ligand of the aluminum hydride complex used was different; the reason for the low optical purity of Comparative Examples 3-4 may be that the 3,5-diphenylphenyl substituent of BDPB in the present application forms a rigid structure through multi-level steric hindrance (three-level stacking of phenyl-phenyl-naphthalene ring), which not only locks the (S)-chiral conformation of binaphthol, but also completely wraps the Al center, forcing the ligand to arrange in a specific orientation, ensuring efficient transmission of chirality; while the steric hindrance of the 4-methylphenyl or dimethyl substituent is reduced, resulting in an increase in the rotational freedom of the C1-C1' axis of binaphthol, a loosening of the chiral cavity, and the generation of diastereoisomers, reducing the enantioselectivity. In addition, the 3,5-diphenylphenyl group of BDPB stabilizes the Al-O bond through an electron-withdrawing effect and moderately activates the Al-H bond, while the electron-donating property of the methyl substituent increases the electron density of the phenolic oxygen anion, reducing the stability of the Al-H bond, and making it prone to premature release or protonation of H during the catalytic cycle, reducing the reduction efficiency.

[0058] The above description is only a preferred embodiment of the present application and is not intended to limit the present application; however, for those of ordinary skill in the art, some minor changes, modifications and equivalent changes made to the above disclosed technical content without departing from the scope of the technical solutions of the present application are equivalent embodiments of the present application; at the same time, any equivalent changes, modifications and evolution of the above embodiments made in accordance with the essential technology of the present application are still within the protection scope of the technical solutions of the present application.

Claims

1. A process for the preparation of levalbuterol tartrate, characterized in that, The preparation method comprises the following steps: 1-{4-(acetyloxy)-3-[(acetyloxy)methyl]phenyl}-2-bromoethanone is subjected to catalysis by a chiral catalyst to obtain a reduction product, the reduction product is reacted with tert-butylamine to obtain levosalbutamol, and finally, the levosalbutamol is subjected to salt formation with L-tartaric acid to obtain the levosalbutamol tartrate. The chiral catalyst is aluminum hydride coordinated with (S)-3,3'-Bis(3,5-diphenylphenyl)-1,1'-binol, and the structural formula is Na3[Al((S)-BDPB)2H2], which is prepared by the following method: Under anhydrous and anaerobic conditions, (S)-3,3'-Bis(3,5-diphenylphenyl)-1,1'-binol is dissolved in THF, NaH is added under ice bath conditions, and the mixture is stirred for 2-3 hours, and then an AlCl3 THF solution is slowly added dropwise, and the mixture is stirred at room temperature for 20-28 hours to obtain the product; wherein the molar ratio of (S)-3,3'-Bis(3,5-diphenylphenyl)-1,1'-binol, NaH and AlCl3 is 1:(4-5):(0.5-0.6).

2. The process for preparing levalbuterol according to claim 1, wherein, The preparation method comprises the following steps: S1: under nitrogen protection, the chiral catalyst, potassium tert-butoxide and isopropyl alcohol are stirred and uniformly mixed, 1-{4-(acetyloxy)-3-[(acetyloxy)methyl]phenyl}-2-bromoethanone is added, and the mixture is reacted at room temperature for 20-25 hours, and then the reduction product is obtained after post-treatment; S2: under nitrogen protection, 1,4-dioxane, tert-butylamine and the reduction product are stirred and uniformly mixed, and the mixture is refluxed for 6-8 hours, and then the mixture is cooled to room temperature, concentrated under reduced pressure, and then a reaction solvent is added, stirred, and L-tartaric acid is added in batches, and the mixture is heated to 35-45 DEG C and kept for 2-3 hours, and then the levosalbutamol tartrate is obtained after post-treatment.

3. The process for preparing levalbuterol according to claim 2, wherein, In step S1, the molar ratio of the chiral catalyst, potassium tert-butoxide and 1-{4-(acetyloxy)-3-[(acetyloxy)methyl]phenyl}-2-bromoethanone is (0.2-0.5):(1.5-3):

10.

4. The process for preparing levalbuterol according to claim 2, wherein, In step S2, the molar ratio of tert-butylamine, the reduction product and L-tartaric acid is (4-6):1:(0.6-0.75).

5. The process for preparing levalbuterol according to claim 2, wherein, In step S2, the reaction solvent is one of methanol and anhydrous ethanol.

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