Refining method of levosalbutamol intermediate

Abstract

The invention discloses a refining method of a levosalbutamol intermediate, and relates to the technical field of organic compound preparation. The refining method of the levosalbutamol intermediate comprises the following steps: catalyzing 1-{4-(acetoxyl)-3-[(acetoxyl) methyl] phenyl}-2-bromoethyl ketone by a chiral catalyst to obtain a reduction product, and performing simple recrystallization to obtain the levosalbutamol intermediate. The asymmetric hydrogenation catalyst is a chiral cobalt complex. The chiral cobalt complex prepared by the invention is used for enantioselective hydrogenation, and then the levosalbutamol intermediate with high yield and high optical purity is obtained through simple recrystallization refining.

Description

Technical Field

[0001] The present invention belongs to the technical field of the preparation of organic compounds, and particularly relates to a method for refining an intermediate of levalbuterol. Background Art

[0002] Levalbuterol is an adrenergic β2 receptor agonist, which has an obvious bronchodilator effect. It is currently the first choice drug for clinically treating airway spasms such as bronchial asthma, asthmatic bronchitis, bronchospasm and acute attacks of patients with emphysema, and acute attacks of chronic obstructive pulmonary disease. Levalbuterol is a single enantiomer separated and purified from racemic salbutamol, removing the dextrorotatory isomer, and is the main active ingredient of racemic salbutamol.

[0003] Levalbuterol is mainly prepared by two methods: asymmetric synthesis and resolution. Among them, the chiral resolution of racemic salbutamol has long operation steps, the yield of levalbuterol obtained by separation is very low, and its enantiomer cannot be utilized, resulting in a high production cost.

[0004] The Chinese patent application with the publication number CN115109026A discloses a method for preparing an intermediate of levalbuterol with high ee value and its hydrochloride. Using salbutamol sulfate as the raw material and D-(+)-dibenzoyl tartrate as the resolving agent, the intermediate of levalbuterol is obtained. This method has a long resolution process, and the enantiomer cannot be utilized after chiral resolution. Summary of the Invention

[0005] Aiming at the deficiencies of the existing technology, the purpose of the present invention is to provide a method for refining an intermediate of levalbuterol.

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

[0007] A method for refining an intermediate of levalbuterol, comprising the following steps:

[0008] S1: Mix the catalyst chiral cobalt complex and tetrahydrofuran evenly, add KOH and 1-{4-(acetoxy)-3-[(acetoxy)methyl]phenyl}-2-bromoacetone, introduce hydrogen into the autoclave, heat up to reflux, and react for 40 - 48 h. After post-treatment, a crude product of the intermediate of levalbuterol (R)-1-[4-acetoxy-3-(acetoxymethyl)phenyl]-2-bromoethanol is obtained. The reaction equation is shown as follows:

[0009]

[0010] S2: Mix the crude product evenly with the solvent, heat up to reflux, keep warm for 1 - 2 h, and obtain the intermediate of levalbuterol after post-treatment.

[0011] In step S1, the mass ratio of 1-{4-(acetoxy)-3-[(acetoxy)methyl]phenyl}-2-bromoethanone, KOH, and the chiral cobalt complex is 10:(2 - 5):(0.05 - 0.2).

[0012] In step S2, the mass ratio of the crude product and the solvent is 1:(5 - 10).

[0013] In step S2, the solvent is one of ethyl acetate and absolute ethanol.

[0014] The preparation method of the chiral cobalt complex is as follows: (3-methoxyphenyl)(diphenyl)phosphine is subjected to chlorine substitution to obtain a substitution product, and then undergoes a condensation reaction with (1S,2S)-2,3-dihydro-1H-inden-1,2-diamine to obtain a chiral tetradentate ligand, and finally forms a chiral cobalt complex with cobalt chloride.

[0015] The chiral cobalt complex is prepared by the following method:

[0016] S1: Under ice bath, dissolve (3-methoxyphenyl)(diphenyl)phosphine in dichloromethane, displace with nitrogen, add azobisisobutyronitrile, stir for 0.5 - 1 h, slowly dropwise add a dichloromethane solution of N-chlorosuccinimide, warm to room temperature, stir in the dark for 15 - 20 h, and perform post-treatment to obtain the substitution product. The reaction equation is shown as follows:

[0017]

[0018] S2: Under ice bath, dissolve the substitution product in THF, sequentially add sodium bicarbonate and (1S,2S)-2,3-dihydro-1H-inden-1,2-diamine, raise the temperature to room temperature, react for 6 - 10 h, and perform post-treatment to obtain the chiral tetradentate ligand. The reaction equation is shown as follows:

[0019]

[0020] S3: Mix acetonitrile, cobalt chloride, and the chiral tetradentate ligand evenly, heat to reflux, react for 20 - 25 h, and perform post-treatment to obtain the chiral cobalt complex. The reaction equation is shown as follows:

[0021]

[0022] In step S1, the molar ratio of (3-methoxyphenyl)(diphenyl)phosphine, azobisisobutyronitrile, and N-chlorosuccinimide is 1:(0.05 - 0.15):(1 - 1.5).

[0023] In step S2, the molar ratio of the substitution product, sodium bicarbonate, and (1S,2S)-2,3-dihydro-1H-inden-1,2-diamine is (2 - 2.5):(2 - 2.5):1.

[0024] In step S3, the molar ratio of the cobalt chloride to the chiral tetradentate ligand fed is (1 - 1.5):1.

[0025] Due to the above technical solutions, the beneficial effects of the present invention include:

[0026] (1) In this application, an asymmetric hydrogenation catalyst - chiral cobalt complex is prepared, which has high selectivity for the enantioselective hydrogenation reduction reaction of 1-{4-(acetoxy)-3-[(acetoxy)methyl]phenyl}-2-bromoacetone.

[0027] (2) The present invention conducts asymmetric catalysis on 1-{4-(acetoxy)-3-[(acetoxy)methyl]phenyl}-2-bromoacetone to obtain a crude product of (R)-1-[4-acetoxy-3-(acetoxymethyl)phenyl]-2-bromoethanol, the intermediate of levosalbutamol, with high yield and high optical purity. After simple recrystallization and purification, a high-purity intermediate of levosalbutamol can be obtained. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 It is the optical purity diagram of the crude product of the intermediate of levosalbutamol prepared in step S1 of Example 4;

[0029] Figure 2 It is the optical purity diagram of the intermediate of levosalbutamol prepared in step S2 of Example 4;

[0030] Figure 3 It is the optical purity diagram of the crude product of the intermediate of levosalbutamol prepared in step S1 of Example 5;

[0031] Figure 4 It is the optical purity diagram of the intermediate of levosalbutamol prepared in step S2 of Example 5;

[0032] Figure 5 It is the optical purity diagram of the crude product of the intermediate of levosalbutamol prepared in step S1 of Comparative Example 1. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0033] The following is further illustrated in conjunction with embodiments, but the present invention is not limited to these embodiments.

[0034] Example 1 Preparation of chiral cobalt complex:

[0035] S1: Under ice bath, add 800 ml of dichloromethane and 1 mol of (3-methoxyphenyl)(diphenyl)phosphine into a reaction flask, stir, displace with nitrogen, add 0.05 mol of azobisisobutyronitrile, stir for 0.5 h, slowly dropwise add 500 ml of a dichloromethane solution of N-chlorosuccinimide (containing 1 mol of N-chlorosuccinimide), finish dropping in 1 h, raise the temperature to room temperature, stir in the dark for 15 h, add 500 ml of saturated sodium bicarbonate solution, stir for 15 min, separate the layers, dry the organic phase with 50 g of anhydrous magnesium sulfate, filter, concentrate under reduced pressure at 30 °C for 4 h to obtain the substituted product; the nuclear magnetic resonance hydrogen spectrum data is as follows: 1 H NMR(500MHz,Chloroform-d)δ7.36(ddt,J=7.6,5.8,1.6Hz,2H),7.33-7.29(m,4H),7.29(d,J=0.8Hz,1H),7.28-7.25(m,4H),7.07(ddd,J=7.8,2.1,1.2Hz,1H),6.90-6.86(m,1H),6.85(dd,J=2.1,1.2Hz,1H),5.58(s,2H).

[0036] S2: Under ice bath, add 2 L of THF and 2 mol of the substituted product into a reaction flask and stir evenly, successively add 2 mol of sodium bicarbonate and 1 mol of (1S,2S)-2,3-dihydro-1H-inden-1,2-diamine, raise the temperature to room temperature, react for 6 h, add 500 ml of saturated brine, separate the layers, distill under reduced pressure at 40 °C for 2 h to obtain the chiral tetradentate ligand; the nuclear magnetic resonance hydrogen spectrum data is as follows: 11H NMR (500 MHz, Chloroform-d) δ 7.39 - 7.34 (m, 4H), 7.33 - 7.29 (m, 8H), 7.29 (d, J = 1.0 Hz, 2H), 7.28 - 7.25 (m, 8H), 7.24 - 7.21 (m, 2H), 7.20 - 7.14 (m, 2H), 7.07 (ddd, J = 7.7, 2.2, 1.2 Hz, 2H), 6.91 (t, J = 2.2 Hz, 2H), 6.85 (dtd, J = 7.3, 2.1, 1.1 Hz, 2H), 4.92 (dd, J = 11.4, 3.4 Hz, 1H), 4.79 (ddd, J = 11.4, 4.7, 3.2 Hz, 2H), 4.66 (dd, J = 11.2, 3.0 Hz, 1H), 4.55 (ddd, J = 6.1, 4.9, 1.8 Hz, 1H), 4.21 (dt, J = 6.8, 3.4 Hz, 1H), 3.96 - 3.87 (m, 1H), 3.38 (dt, J = 7.3, 3.0 Hz, 1H), 3.06 (ddd, J = 15.3, 3.2, 0.7 Hz, 1H), 2.86 - 2.73 (m, 1H).

[0037] S3: Add 1.5 L of acetonitrile, 1 mol of cobalt chloride, and 1 mol of chiral tetradentate ligand into the reaction flask in sequence, heat up to reflux, react for 20 h, cool to room temperature, let stand for 12 h to precipitate crystals, filter, wash with 500 ml of absolute ethanol, and dry in vacuum at 60 °C for 8 h to obtain the chiral cobalt complex.

[0038] Preparation of chiral cobalt complex in Example 2:

[0039] S1: Under ice bath, add 800 ml of dichloromethane and 1 mol of (3 - methoxyphenyl)(diphenyl)phosphine into the reaction flask, stir, displace with nitrogen, add 0.1 mol of azobisisobutyronitrile, stir for 1 h, slowly dropwise add 500 ml of dichloromethane solution of N - chlorosuccinimide (containing 1.2 mol of N - chlorosuccinimide) dropwise over 1 h, raise the temperature to room temperature, stir in the dark for 18 h, add 500 ml of saturated sodium bicarbonate solution, stir for 15 min, separate the layers, dry the organic phase with 50 g of anhydrous magnesium sulfate, filter, and concentrate under reduced pressure at 30 °C for 4 h to obtain the substituted product;

[0040] S2: Under ice bath, add 2 L of THF and 2.3 mol of the substituted product into the reaction flask and stir evenly, add 2.3 mol of sodium bicarbonate and 1 mol of (1S,2S)-2,3 - dihydro - 1H - indene - 1,2 - diamine in sequence, raise the temperature to room temperature, react for 8 h, add 500 ml of saturated brine, separate the layers, distill under reduced pressure at 40 °C for 2 h to obtain the chiral tetradentate ligand;

[0041] S3: Add 1.5 L of acetonitrile, 1.2 mol of cobalt chloride, and 1 mol of chiral tetradentate ligand into the reaction flask in sequence. Heat up to reflux and react for 24 h. Cool to room temperature and let it stand for 12 h to precipitate crystals. Filter, wash with 500 ml of absolute ethanol, and dry in vacuum at 60 °C for 8 h to obtain the chiral cobalt complex.

[0042] Preparation of chiral cobalt complex in Example 3:

[0043] S1: Under ice bath, add 800 ml of dichloromethane and 1 mol of (3 - methoxyphenyl)(diphenyl)phosphine into the reaction flask, stir, displace with nitrogen, add 0.15 mol of azobisisobutyronitrile, stir for 1 h, slowly dropwise add 500 ml of dichloromethane solution of N - chlorosuccinimide (containing 1.5 mol of N - chlorosuccinimide) over 1 h. After adding, raise the temperature to room temperature and stir in the dark for 20 h. Add 500 ml of saturated sodium bicarbonate solution, stir for 15 min, separate the layers. Dry the organic phase with 50 g of anhydrous magnesium sulfate, filter, and concentrate under reduced pressure at 30 °C for 4 h to obtain the substituted product.

[0044] S2: Under ice bath, add 2 L of THF and 2.5 mol of the substituted product into the reaction flask and stir evenly. Then add 2.5 mol of sodium bicarbonate and 1 mol of (1S,2S) - 2,3 - dihydro - 1H - indene - 1,2 - diamine in sequence. Raise the temperature to room temperature and react for 10 h. Add 500 ml of saturated brine, separate the layers, and distill under reduced pressure at 40 °C for 2 h to obtain the chiral tetradentate ligand.

[0045] S3: Add 1.5 L of acetonitrile, 1.5 mol of cobalt chloride, and 1 mol of chiral tetradentate ligand into the reaction flask in sequence. Heat up to reflux and react for 25 h. Cool to room temperature and let it stand for 12 h to precipitate crystals. Filter, wash with 500 ml of absolute ethanol, and dry in vacuum at 60 °C for 8 h to obtain the chiral cobalt complex.

[0046] Purification of the intermediate of levosalbutamol in Example 4:

[0047] S1: Put 800 ml of tetrahydrofuran and 5 mmol of chiral cobalt complex (prepared in Example 1) into the reaction flask, stir to mix evenly, add 0.2 mol of KOH and 1 mol of 1 - {4 - (acetoxy) - 3 - [(acetoxy)methyl]phenyl} - 2 - bromoethanone. Introduce hydrogen into the autoclave, heat up to reflux, and react for 40 h. Cool to room temperature and concentrate under reduced pressure at 40 °C for 2 h to obtain 320.2 g of the crude product, with a yield of 96.7% and an optical purity of e.e. 97.6%. The nuclear magnetic resonance hydrogen spectrum 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);

[0048] S2: Add 500 g of ethyl acetate and 100 g of the crude product into the reaction flask, heat up to reflux, keep the temperature for 1 h, cool down to 0 °C to precipitate crystals, keep the temperature for 2 h, filter by suction, wash with 50 g of ethyl acetate, filter by suction again, and dry in vacuum at 60 °C for 6 h to obtain 90.8 g of the intermediate of levosalbutamol, with a yield of 90.8% and an optical purity of 99.8% e.e.

[0049] Example 5 Purification of the intermediate of levosalbutamol:

[0050] S1: Put 800 ml of tetrahydrofuran and 15 mmol of the chiral cobalt complex (prepared in Example 2) into the reaction flask, stir and mix evenly, add 0.4 mol of KOH and 1 mol of 1-{4-(acetoxy)-3-[(acetoxy)methyl]phenyl}-2-bromoacetone, introduce hydrogen into the autoclave, heat up to reflux, react for 45 h, cool down to room temperature, concentrate under reduced pressure at 40 °C for 2 h to obtain 322.2 g of the crude product, with a yield of 97.3% and an optical purity of 98.8% e.e.;

[0051] S2: Add 800 g of ethyl acetate and 100 g of the crude product into the reaction flask, heat up to reflux, keep the temperature for 2 h, cool down to 0 °C to precipitate crystals, keep the temperature for 2 h, filter by suction, wash with 30 g of ethyl acetate, filter by suction again, and dry in vacuum at 60 °C for 6 h to obtain 94.9 g of the intermediate of levosalbutamol, with a yield of 94.9% and an optical purity of 99.8% e.e.

[0052] Example 6 Purification of the intermediate of levosalbutamol:

[0053] S1: Put 800 ml of tetrahydrofuran and 20 mmol of the chiral cobalt complex (prepared in Example 3) into the reaction flask, stir and mix evenly, add 0.5 mol of KOH and 1 mol of 1-{4-(acetoxy)-3-[(acetoxy)methyl]phenyl}-2-bromoacetone, introduce hydrogen into the autoclave, heat up to reflux, react for 48 h, cool down to room temperature, concentrate under reduced pressure at 40 °C for 2 h to obtain 318.9 g of the crude product, with a yield of 96.3% and an optical purity of 98.1% e.e.;

[0054] S2: Add 1000 g of absolute ethanol and 100 g of the crude product into the reaction flask, heat up to reflux, keep the temperature for 2 h, cool down to 0 °C to precipitate crystals, keep the temperature for 2 h, carry out suction filtration, wash with 30 g of absolute ethanol, carry out suction filtration again, and dry in vacuum at 60 °C for 6 h to obtain 92.3 g of the intermediate of levosalbutamol, with a yield of 92.3% and an optical purity of e.e. 99.8%.

[0055] Comparative Example 1

[0056] The refining method of the intermediate of levosalbutamol is basically the same as that in Example 5, the difference is that the chiral cobalt complex (prepared in Example 2) in step S1 is replaced with a chiral catalyst prepared by the following method:

[0057] S1: Under ice bath, add 2 L of THF and 2.3 mol of 2-(chloromethyl)phenyl diphenylphosphine into the reaction flask and stir evenly. Then add 2.3 mol of sodium bicarbonate and 1 mol of (1S,2S)-2,3-dihydro-1H-inden-1,2-diamine in sequence, raise the temperature to room temperature, react for 8 h, add 500 ml of saturated brine, separate the layers, and carry out reduced pressure distillation at 40 °C for 2 h to obtain the chiral tetradentate ligand;

[0058] S2: Add 1.5 L of acetonitrile, 1.2 mol of cobalt chloride and 1 mol of the chiral tetradentate ligand into the reaction flask in sequence, heat up to reflux, react for 24 h, cool down to room temperature, let stand for 12 h, filter, wash with 500 ml of absolute ethanol, and dry in vacuum at 60 °C for 8 h to obtain the chiral cobalt complex.

[0059] The yield of step S1 of the intermediate of levosalbutamol is 97.0%, and the optical purity is e.e. 94.0%.

[0060] This comparative example uses different chiral cobalt complexes for the preparation of the intermediate of levosalbutamol. The difference from the present application lies in the different organic ligands used. The reason for the low yield in Comparative Example 1 may be that: the chiral cobalt complex in the example contains an ether bond, which can serve as a directing group, cooperate with the chiral organic ligand, and guide the metal center to selectively activate a specific C=O bond, thereby improving the selectivity and efficiency of the reaction; while the chiral cobalt complex used in Comparative Example 1 only has a phosphine ligand to provide a rigid structure, weakening the catalytic activity and enantioselectivity of the metal.

[0061] Comparative Example 2

[0062] The refining method of the intermediate of levosalbutamol is basically the same as that in Example 5, the difference is that the chiral cobalt complex (prepared in Example 2) in step S1 is replaced with a chiral catalyst prepared by the following method:

[0063] S1: Under ice bath, add 2 L of THF and 2.3 mol of 2-chloroethyl(diphenyl)phosphine into a reaction flask and stir evenly. Then add 2.3 mol of sodium bicarbonate and 1 mol of (1S,2S)-2,3-dihydro-1H-inden-1,2-diamine in sequence. Raise the temperature to room temperature and react for 8 h. Add 500 ml of saturated brine, separate the layers, and distill under reduced pressure at 40 °C for 2 h to obtain a chiral tetradentate ligand.

[0064] S2: Add 1.5 L of acetonitrile, 1.2 mol of cobalt chloride and 1 mol of chiral tetradentate ligand into a reaction flask in sequence. Heat up to reflux and react for 24 h. Cool to room temperature, let stand for 12 h, filter, wash with 500 ml of absolute ethanol, and dry in vacuum at 60 °C for 8 h to obtain a chiral cobalt complex.

[0065] The yield of the intermediate of levosalbutamol in step S1 is 93.3%, and the optical purity is e.e. 65.7%.

[0066] This comparative example uses different chiral cobalt complexes to prepare the intermediate of levosalbutamol. The difference from this application lies in the different organic ligands used. The reasons for its low yield and optical purity may be: in the example, the triphenyl substitution of the chiral cobalt complex forms a rigid structure through steric hindrance, which not only locks the chiral conformation but also completely wraps the metal center, forcing the ligand to arrange in a specific orientation to ensure efficient chiral transfer; while the steric hindrance of the 2-phenyl substitution is reduced, resulting in the loosening of the chiral cavity and the decrease of enantioselectivity.

[0067] Comparative Example 3

[0068] The purification method of the intermediate of levosalbutamol is basically the same as that of Example 5, except that the chiral cobalt complex in step S1 (prepared in Example 2) is replaced with a chiral catalyst prepared by the following method:

[0069] Add 1.5 L of acetonitrile, 1.1 mol of cobalt chloride and 1 mol of (1S,2S)-N,N'-bis(2-diphenylphosphino-1-naphthoyl)-1,2-cyclohexanediamine into a reaction flask in sequence. Heat up to reflux and react for 24 h. Cool to room temperature, let stand for 12 h, filter, wash with 500 ml of ethanol, and dry in vacuum at 60 °C for 8 h to obtain a chiral cobalt complex.

[0070] The yield of the intermediate of levosalbutamol in step S1 is 79.7%, and the optical purity is e.e. 98.1%.

[0071] This comparative example uses different chiral cobalt complexes to prepare the intermediate of levosalbutamol. The difference from this application lies in the different organic ligands used. The reason for its low yield may be: the substituent steric hindrance in the organic ligand used in Comparative Example 3 is large, which hinders the contact between the reactant and the active center of the catalyst, thereby reducing the rate of the catalytic reaction and resulting in a decrease in its yield.

[0072] As described above, it is only the preferred embodiment of the present invention and is not used to limit the present invention. However, for those of ordinary skill in the art, within the scope of the technical solution of the present invention, any slight changes, modifications and equivalent changes made by using the technical content disclosed above are all equivalent embodiments of the present invention. At the same time, any changes, modifications and evolutions made to the above embodiments based on the substantial technology of the present invention are still within the protection scope of the technical solution of the present invention.

Claims

1. A refining method for a levalbuterol intermediate, characterized in that, It includes the following steps: S1: Mix the catalyst chiral cobalt complex and tetrahydrofuran evenly, add KOH and 1-{4-(acetoxy)-3-[(acetoxy)methyl]phenyl}-2-bromoacetophenone, introduce hydrogen into the autoclave, heat up to reflux, react for 40 - 48 h, and obtain the crude product through post-treatment; S2: Mix the crude product and the solvent evenly, heat up to reflux, keep warm for 1 - 2 h, and obtain the intermediate of levosalbutamol through post-treatment; The preparation method of the chiral cobalt complex is as follows: (3-Methoxyphenyl)(diphenyl)phosphine is subjected to chlorine substitution to obtain a substitution product, which is then subjected to a condensation reaction with (1S,2S)-2,3-dihydro-1H-inden-1,2-diamine to obtain a chiral tetradentate ligand, and finally forms a chiral cobalt complex with cobalt chloride.

2. The refining method of a levalbuterol intermediate according to claim 1, characterized in that, In step S1, the molar ratio of 1-{4-(acetoxy)-3-[(acetoxy)methyl]phenyl}-2-bromoacetophenone, KOH, and chiral cobalt complex in the feed is 10:(2 - 5):(0.05 - 0.2).

3. The refining method of a levalbuterol intermediate according to claim 1, characterized in that, In step S2, the mass ratio of the crude product and the solvent in the feed is 1:(5 - 10).

4. The refining method of a levalbuterol intermediate according to claim 1, wherein, In step S2, the solvent is one of ethyl acetate and ethanol.

5. The refining method of a levalbuterol intermediate according to claim 4, characterized in that, The chiral cobalt complex is prepared by the following method: S1: Under ice bath, dissolve (3-Methoxyphenyl)(diphenyl)phosphine in dichloromethane, displace with nitrogen, add azobisisobutyronitrile, stir for 0.5 - 1 h, slowly dropwise add a dichloromethane solution of N-chlorosuccinimide, warm up to room temperature, stir in the dark for 15 - 20 h, and obtain the substitution product through post-treatment; S2: Under ice bath, mix the substitution product and THF evenly, sequentially add sodium bicarbonate and (1S,2S)-2,3-dihydro-1H-inden-1,2-diamine, raise the temperature to room temperature, react for 6 - 10 h, and obtain the chiral tetradentate ligand through post-treatment; S3: Mix acetonitrile, cobalt chloride, and chiral tetradentate ligand evenly, reflux and react for 20 - 25 h, and obtain the chiral cobalt complex through post-treatment.

6. The refining method of a levalbuterol intermediate according to claim 5, characterized in that, In step S1, the molar ratio of (3-Methoxyphenyl)(diphenyl)phosphine, azobisisobutyronitrile, and N-chlorosuccinimide in the feed is 1:(0.05 - 0.15):(1 - 1.5).

7. A purification method of a levalbuterol intermediate according to claim 5, characterized in that, In step S2, the molar ratio of the substitution product, sodium bicarbonate, and (1S,2S)-2,3-dihydro-1H-inden-1,2-diamine in the feed is (2 - 2.5):(2 - 2.5):

1.

8. The refining method of a levalbuterol intermediate according to claim 5, characterized in that, In step S3, the molar ratio of cobalt chloride and chiral tetradentate ligand in the feed is (1 - 1.5):1.

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