A method for preparing high-purity alfasal

Abstract

This invention belongs to the field of organic synthesis and specifically discloses a method for preparing high-purity alfasal. The method includes the following steps: (1)-(3): (1) Using compound A as the starting material, reducing it with red aluminum and then processing it to obtain compound B; (2) Using compound B as the starting material, adding acid and phosphine reagent, reacting it in the presence of azo reagent, removing the phosphide through processing, and purifying it to obtain compound C; (3) Using compound C as the starting material, hydrolyzing it with sodium hydroxide, processing it, and then purifying it twice with a mixed solvent to obtain high-purity compound D, i.e., alfasal. This preparation method has a low raw material cost, high selectivity, high yield, and is easy to separate and purify to obtain high-purity alfasal, which is very suitable for subsequent industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, and specifically discloses a method for preparing high-purity alfasal. Background Technology

[0002] Alfasal, developed and marketed by GSK in the 1970s and 1980s, is a steroidal anesthetic and a GABAAR agonist. In the central nervous system (CNS), γ-aminobutyric acid (GABA) receptors exist in two forms: GABAA receptors (GABAAR) and GABAB receptors (GABABR). GABAAR plays an important role in regulating memory, consciousness, and sleep in the brain. As a GABAAR agonist, alfasal has sedative, anesthetic, anticonvulsant, and neuroprotective effects. It is characterized by rapid onset, quick recovery, and relatively high safety. However, due to the early use of castor oil as an excipient in the preparation of the injectable solution, which easily caused allergic side effects, it was withdrawn from the human market. Currently, it is mainly used as a veterinary drug for the induction of general anesthesia, short surgeries, and surgical procedures, or as an adjunct to other general anesthesias. Until recently, several patents (WO2011088503A1, CN107261152A, CN201180013975, CN202110443005) reported that alfasalone, using cyclodextrin derivatives as excipients, showed in non-clinical studies that this type of formulation could reduce allergic side effects. These findings have once again made alfasalone a hot topic among intravenous anesthetic drugs. Therefore, researching and developing synthetic methods for alfasalone and its key intermediates is of great significance. The A and B rings of the steroidal ring in the alfasalone molecule are in a trans configuration, containing two unique chiral structures, 5αH and 3αOH, which are the key challenges in the entire synthetic process.

[0003] Currently, there are three main methods for synthesizing alfasal:

[0004] One method involves preparing 5α-H using a metal ammonia solution, followed by preparing 3-α-OH using a selective reducing agent, as described in Method 1 (see: Zonglei Zhang, et al. First Synthesis of a C-Homosteroid from Pregn-4-ene-3,11,20-trione[J]. Helvetica Chimica Acta, 2011, 94.).

[0005] Second, 5α-H and 3β-OH are prepared in one step by adding different promoters to Pd catalyst. Then, 3β-OH is esterified with methanesulfonyl chloride, and finally, configuration inversion occurs under the action of DMF and potassium nitrite to generate 3α-OH product, as in method 2 (see: Barbora Slavíkov, et al. Allopregnanolone and Pregnanolone Analogues Modifified in the C Ring: Synthesis and Activity. Journal of Medicinal Chemistry, 2013, 56(6), 2323-2336.).

[0006] Third, a product dominated by 3-α-OH is prepared by selective reduction with rare metals and additives. Finally, a sterically hindered etherifying reagent reacts only with β-OH under certain experimental conditions, and then the pure product is obtained by solvent purification, as reported in patent WO2020006596 (such as method 3).

[0007] The above method has the following drawbacks:

[0008] Method 1: The synthesis of alfasalon uses potassium triisobutylborohydride as a reducing agent, which is expensive and not conducive to industrial production. Moreover, the reaction generates more than 10% isomers, which are difficult to purify and cannot obtain alfasalon with acceptable purity.

[0009] Method 2: Reduction with palladium on carbon produces multiple isomers, which are difficult to separate and purify. Using precious metal catalysis is very costly and not conducive to commercial production.

[0010] Method three, obtained through asymmetric reduction with noble metals, contains approximately 20% isomers. It also uses noble metal catalysis, is costly, requires column chromatography for post-processing, has low yield, and is difficult to industrialize. Although these three methods use different raw materials to prepare alfasalone, the difficulty in purifying and removing alfasalone isomers makes the synthesis of alfasalone crucial. Therefore, finding an industrially feasible method to obtain the product with high selectivity and high purity at a lower cost has become key. Existing methods are either expensive or have excessively high isomer content, making separation and purification difficult, and also result in low yields.

[0011] The following are the reaction formulas for methods one through three:

[0012] Method 1:

[0013]

[0014] Method 2:

[0015]

[0016] Method 3:

[0017] Summary of the Invention

[0018] To address the aforementioned problems, this invention discloses a method for preparing alfasalol. This method yields high-purity alfasalol with low raw material costs, high selectivity, high yield, and easy separation and purification, making it highly suitable for subsequent industrial production.

[0019] This invention includes the following technical solutions:

[0020] A method for preparing high-purity alfasalol includes the following steps (1)-(3):

[0021] (1) Compound A was used as the starting material, and compound B was obtained by reduction with red aluminum and post-treatment.

[0022] (2) Using compound B as a raw material, add acid and phosphine reagent, react in the presence of azo reagent, remove phosphide after post-treatment, and purify to obtain compound C;

[0023] (3) Using compound C as raw material, hydrolyze it with sodium hydroxide, then process it and purify it twice with a mixed solvent to obtain high-purity compound D;

[0024]

[0025] Furthermore, in the above-mentioned method for preparing high-purity alfasalol, step (1) includes the following specific steps:

[0026] Compound A was added to a solvent and treated in an anhydrous and oxygen-free environment. Then, 2-3 equivalents of red aluminum were added at low temperature. The reaction temperature was -10 to 0°C and the reaction time was 2-6 hours. TLC showed that PE:EA = 1:1. After the reaction was complete, compound B was purified from the reaction product.

[0027]

[0028] The solvent is selected from one of tetrahydrofuran, methyltetrahydrofuran, diethyl ether, isopropyl ether, ethylene glycol dimethyl ether, and dioxane; more preferably, the solvent is selected from tetrahydrofuran.

[0029] Using red aluminum hydroxide offers higher specificity than sodium borohydride, with a 3-β-OH:3-α-OH ratio of 99:1, effectively preventing the reduction of the carbonyl group at position 20. The optimal reaction weight is 1.2–2.0 equivalents; below 1.2 equivalents, the reaction is incomplete, and above 2.0 equivalents, over-reduction occurs. Suitable solvents include tetrahydrofuran, methyltetrahydrofuran, diethyl ether, isopropyl ether, ethylene glycol dimethyl ether, and dioxane. The product has poor solubility in diethyl ether, isopropyl ether, and ethylene glycol dimethyl ether, resulting in poor reaction performance. Among tetrahydrofuran, methyltetrahydrofuran, and dioxane, tetrahydrofuran is preferred. The temperature should be controlled near 0°C; too low a temperature results in a very slow reaction and makes complete reaction difficult, while too high a temperature easily leads to over-reduction. The reaction time should be controlled between 3 and 5 hours.

[0030] Furthermore, in the above-mentioned method for preparing high-purity alfasalol, step (2) includes the following specific steps:

[0031] At 0°C, acid and phosphine reagent were added to a solvent, and the mixture was treated in an anhydrous and oxygen-free environment. Diisopropyl azodicarbonate was then slowly added dropwise, and the reaction was allowed to proceed for 10 min. Compound B was then added, and the mixture was reacted at room temperature for 8-16 h. A complexing agent was added, and the mixture was stirred for 3 h. The phosphide was removed by filtration, and compound C was then obtained by crystallization from methanol. The reaction formula is as follows:

[0032]

[0033] The solvent is selected from one of diethyl ether, dichloromethane, toluene, ethyl acetate, acetonitrile, DMF, and tetrahydrofuran;

[0034] The acid is selected from one of formic acid, acetic acid, trifluoroacetic acid, benzoic acid, and p-nitrobenzoic acid;

[0035] The phosphine reagent is selected from one of tri-o-methylphenylphosphine, tributylphosphine, and triphenylphosphine;

[0036] The azo reagent is selected from one of DEAD, DIAD, and TMAD;

[0037] The complexing agent is selected from one of zinc dichloride, magnesium chloride, and calcium bromide.

[0038] Preferably, the solvent is selected from tetrahydrofuran, the phosphine reagent is selected from triphenylphosphine, the azo reagent is selected from DIAD, and the complexing agent is selected from calcium bromide.

[0039] After this reaction and purification step, isomers of compound B can be easily removed, yielding a high-purity single product.

[0040] Furthermore, the equivalent of nitrobenzoic acid, triphenylphosphine, and DIAD to compound B is 1.0–2.0 eq; and the equivalent of calcium bromide to compound B is 1.0–4.0 eq.

[0041] Preferably, the equivalent of nitrobenzene, triphenylphosphine, and DIAD to compound B is 1.5 eq; and the equivalent of calcium bromide to compound B is 3.0 eq.

[0042] Furthermore, in the above-mentioned method for preparing high-purity alfasalol, step (3) includes the following specific steps:

[0043] Compound C was added to a solvent at 10–20°C, followed by the addition of alkali and reaction at room temperature for 2–4 hours. The pH was adjusted to 7 with glacial acetic acid, and the mixture was extracted and concentrated. The resulting product was then slurried in a mixed solvent of methyl tert-butyl ether:n-heptane and recrystallized from tetrahydrofuran:n-heptane to obtain high-purity compound D. The reaction formula is as follows:

[0044]

[0045] The solvent is selected from one of methanol, ethanol, isopropanol, methanol-water, tetrahydrofuran-water, ethanol-water, isopropanol-water, methanol-tetrahydrofuran-water, ethanol-tetrahydrofuran-water, and isopropanol-tetrahydrofuran-water.

[0046] The alkali is selected from one of sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, and potassium hydroxide.

[0047] Preferably, the solvent is selected from methanol-tetrahydrofuran-water, and the base is selected from sodium hydroxide.

[0048] On the other hand, the present invention discloses an alfasal, which is prepared by the above method.

[0049] Compared with the prior art, the present invention has the following beneficial effects:

[0050] This invention offers a simple, highly selective, and high-yield preparation process. It utilizes conventional operations and reagents, and the three-step reaction effectively removes the 3-β-OH isomer, yielding a high-purity product. This process is suitable for large-scale industrial production, promoting technological innovation in the preparation of alfasal and its derivatives, providing stable and reliable raw material support for the preparation of alfasal-related drugs, and also offering insights for the preparation of other steroidal compounds. Attached Figure Description

[0051] Figure 1 The chromatogram of the product of Example 7;

[0052] Figure 2 The chromatogram of the product of Example 8;

[0053] Figure 3 The chromatogram of the product of Example 9;

[0054] Figure 4 The NMR spectrum of the product of Example 9 is shown. Detailed Implementation

[0055] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions in the embodiments of this invention will be clearly and completely described below in conjunction with the embodiments of this invention. Obviously, the described embodiments are only some embodiments of this invention, not all embodiments. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0056] All materials used in the following examples can be purchased through conventional means;

[0057] The substrate in the examples is compound A;

[0058] TLC, thin-layer chromatography;

[0059] Equivalent is defined as the molar ratio to the main raw material;

[0060] The term "weight yield" is defined as follows:

[0061] Weight yield = (weight of target product / weight of reactants) × 100%;

[0062] Wherein: the weight of the reactant is the weight of compound A.

[0063] Example 1

[0064] Preparation Example (Step 1)

[0065] (1): Add 700 ml of tetrahydrofuran and 35 g (1.00 eq) of compound A to a 2 L reaction flask. Purge with nitrogen (the entire subsequent operation is under nitrogen protection), cool to -5 °C, maintain the temperature between -10 and 0 °C, and add 36.7 g (1.2 eq) of a toluene solution of red aluminum dropwise. Stir the reaction at -10 to -0 °C for 4 h, then add 40 ml of methanol dropwise at -10 °C and stir for 10 minutes. Control the temperature to -20 °C, add 200 ml of 10% hydrochloric acid dropwise, and stir at 0 °C for 30 minutes. Raise the temperature to 15 °C, add 130 ml of dichloromethane, stir, filter, wash the filter cake with 30 ml of dichloromethane, and concentrate under reduced pressure to obtain the crude product. Add 130 ml of dichloromethane, stir, add 100 ml of 0.5 N hydrochloric acid, stir, separate the liquid and concentrate the organic phase under reduced pressure, add 500 ml of methyl tert-butyl ether, reflux for 1 hour; slowly cool to 20 °C, stir for 2 hours, filter, and wash the filter cake with a small amount of methyl tert-butyl ether. Dry the filter cake to obtain 31 g of white product compound B, purity 94.57%, weight yield: 88%.

[0066] Example 2

[0067] Preparation Example (Step 1)

[0068] (1) Add 700 ml of tetrahydrofuran to a 2 L reaction flask, then add 35 g (1.00 eq) of compound A. Purge with nitrogen (the entire subsequent operation is under nitrogen protection), cool to -15 °C, maintain the temperature between -20 and -10 °C, and add 45.9 g (1.5 eq) of toluene solution of red aluminum dropwise. Stir the reaction at -20 to -10 °C for 4 h, then add 40 ml of methanol dropwise at -10 °C and stir for 10 minutes. Control the temperature to -20 °C, add 200 ml of 10% hydrochloric acid dropwise, and stir at -20 °C for 30 minutes. Raise the temperature to 15 °C, add 130 ml of dichloromethane, stir, filter, and rinse the filter cake with 30 ml of dichloromethane. The crude product was concentrated under reduced pressure. 130 ml of dichloromethane was added, and the mixture was stirred. Then, 100 ml of 0.5 N hydrochloric acid was added, and the mixture was stirred again. The mixture was separated, and the organic phase was concentrated under reduced pressure. 500 ml of methyl tert-butyl ether was added, and the mixture was refluxed for 1 hour. The temperature was slowly lowered to 20°C, and the mixture was stirred for 2 hours. The mixture was filtered, and the filter cake was washed with a small amount of methyl tert-butyl ether. The filter cake was dried to give 20.4 g of white product compound B, with a purity of 90.53% and a yield of 68% by weight.

[0069] Example 3

[0070] Preparation Example (Step 1)

[0071] Add 700 ml of tetrahydrofuran to a 2 L reaction flask, then add 35 g (1.00 eq) of compound A. Purge with nitrogen (subsequent operations under nitrogen protection), cool to 5 °C, maintain temperature between 0 and 10 °C, and add dropwise 36.7 g (1.2 eq) of a toluene solution of red aluminum. Stir the reaction at 0–10 °C for 4 h, then add 40 ml of methanol at -10 °C and stir for 10 minutes. Control the temperature to -20 °C, add 200 ml of 10% hydrochloric acid, and stir at -20 °C for 30 minutes. Raise the temperature to 15 °C, add 130 ml of dichloromethane, stir, filter, and rinse the filter cake with 30 ml of dichloromethane. The crude product was concentrated under reduced pressure. 130 ml of dichloromethane was added, and the mixture was stirred. Then, 100 ml of 0.5 N hydrochloric acid was added, and the mixture was stirred again. The mixture was separated, and the organic phase was concentrated under reduced pressure. 500 ml of methyl tert-butyl ether was added, and the mixture was refluxed for 1 hour. The temperature was slowly lowered to 20°C, and the mixture was stirred for 2 hours. The mixture was filtered, and the filter cake was washed with a small amount of methyl tert-butyl ether. The filter cake was dried to give 31.5 g of white product compound B, with a purity of 94.42% and a yield of 90% by weight.

[0072] Example 4

[0073] Preparation Example (Step 2)

[0074] Add 300 mL of tetrahydrofuran, 28.4 g (1.2 eq) of triphenylphosphine, and 18.2 g (1.2 eq) of p-nitrobenzoic acid to a 500 mL reaction flask; purge with nitrogen (subsequent operations under nitrogen protection); add 21.9 g (1.2 eq) of DIAD dropwise at 5 °C, stir for 10 minutes, then add 30 g (1.0 eq) of compound B in portions, react at 20 °C for 16 hours. Add 100 mL of tetrahydrofuran and 43.2 g of calcium bromide to the reaction flask; stir at 25 °C for 3 hours, filter, and wash the filter cake with 60 mL of tetrahydrofuran. Concentrate the filtrate under reduced pressure, add 300 mL of methanol, cool to 5 °C, and stir for 2 hours. Filter, wash the filter cake with 30 mL of methanol, and dry to obtain 30.39 g of white product compound C, HPLC purity 94.4%, weight yield: 101.3%.

[0075] Example 5

[0076] Preparation Example (Step 2)

[0077] Add 300 mL of tetrahydrofuran, 35.5 g (1.5 eq) of triphenylphosphine, and 22.7 g (1.5 eq) of p-nitrobenzoic acid to a 500 mL reaction flask; purge with nitrogen (subsequent operations under nitrogen protection); add 27.4 g (1.5 eq) of DIAD dropwise at 5 °C, stir for 10 minutes, add 30 g (1.0 eq) of compound B in portions, and react at 20 °C for 16 hours. Add 100 mL of tetrahydrofuran and 43.2 g of calcium bromide to the reaction flask; stir at 25 °C for 3 hours, filter, and wash the filter cake with 60 mL of tetrahydrofuran. Concentrate the filtrate under reduced pressure, add 300 mL of methanol, cool to 5 °C, and stir for 2 hours. Filter, wash the filter cake with 30 mL of methanol, and dry to obtain 38.5 g of white product compound C, HPLC purity 95.52%, weight yield: 128.3%.

[0078] Example 6

[0079] Preparation Example (Step 2)

[0080] Add 300 mL of tetrahydrofuran, 42.5 g (1.8 eq) of triphenylphosphine, and 27.3 g (1.8 eq) of p-nitrobenzoic acid to a 500 mL reaction flask; purge with nitrogen (subsequent operations under nitrogen protection); add 32.8 g (1.8 eq) of DIAD dropwise at 5 °C, stir for 10 minutes, then add 30 g (1.0 eq) of compound B in portions, and react at 20 °C for 16 hours. Add 100 mL of tetrahydrofuran and 43.2 g of calcium bromide to the reaction flask, stir at 25 °C for 3 hours, filter, and wash the filter cake with 60 mL of tetrahydrofuran. Concentrate the filtrate under reduced pressure, add 300 mL of methanol, cool to 5 °C, and stir for 2 hours. Filter, wash the filter cake with 30 mL of methanol, and dry to obtain 37.8 g of white product compound C, HPLC purity 91.09%, weight yield: 126%.

[0081] Example 7

[0082] Preparation Example (Step 3)

[0083] Add 150 mL of tetrahydrofuran and 30 g of compound C to a 500 mL reaction flask, and stir until dissolved. Add 90 mL of methanol, heat to 35 °C, add 30 mL of an aqueous solution of sodium hydroxide (5.1 g), maintain the temperature at 35 °C, and stir for 3 hours. Add 30 mL of water, cool to 10 °C, adjust the pH to 7 with glacial acetic acid, concentrate, add 300 mL of dichloromethane and 150 mL of water, stir for 20 minutes, separate the liquid and liquid phases, wash the organic phase with sodium carbonate solution, concentrate, add 150 mL of methyl tert-butyl ether, reflux for 1 hour, add 150 mL of n-heptane, cool to 20 °C, and stir for 2 hours. Filter, and wash the filter cake with 30 mL of a 1:1 mixture of methyl tert-butyl ether and n-heptane. The filter cake was added to a 250 ml reaction flask, followed by 40 ml of tetrahydrofuran. The mixture was heated to 50 °C and stirred until dissolved. Then, 40 ml of n-heptane was slowly added dropwise. The mixture was cooled to 5 °C and stirred for 1 hour. The mixture was filtered, and the filter cake was dried to obtain 10.1 g of a white solid with a purity of 100% and a yield of 33.7% by weight. The chromatogram is shown below. Figure 1 As shown.

[0084] Example 8

[0085] Preparation Example (Step 3)

[0086] Add 150 mL of tetrahydrofuran and 30 g of compound C to a 500 mL reaction flask, and stir until dissolved. Add 90 mL of methanol, cool to 15 °C, and add 30 mL of an aqueous solution of sodium carbonate (13.6 g) dropwise. Maintain the temperature at 15 °C and stir for 3 hours. Add 30 mL of water, cool to 10 °C, adjust the pH to 7 with glacial acetic acid, concentrate, add 300 mL of dichloromethane and 150 mL of water, stir for 20 minutes, separate the liquid and liquid phases, wash the organic phase with sodium carbonate solution, concentrate, add 150 mL of methyl tert-butyl ether, reflux for 1 hour; reflux for 1 hour, add 150 mL of n-heptane, cool to 20 °C, and stir for 2 hours. Filter, and wash the filter cake with a 1:1 mixture of methyl tert-butyl ether and n-heptane. The filter cake was added to a 250 ml reaction flask, along with 40 ml of tetrahydrofuran. The mixture was heated to 50 °C and stirred until dissolved. Then, 40 ml of n-heptane was slowly added dropwise. The mixture was cooled to 5 °C and stirred for 1 hour. The mixture was then filtered. The filter cake was dried to obtain 12.5 g of a white product with a purity of 100% and a yield of 41.7% by weight. The chromatogram is shown below. Figure 2 As shown.

[0087] Example 9

[0088] Preparation Example (Step 3)

[0089] Add 150 mL of tetrahydrofuran and 30 g of compound C to a 500 mL reaction flask, and stir until dissolved. Add 90 mL of methanol, cool to 15 °C, add 30 mL of an aqueous solution of sodium hydroxide (5.1 g), maintain the temperature at 15 °C, and stir for 3 hours. Add 30 mL of water, cool to 10 °C, adjust the pH to 7 with 0% glacial acetic acid, concentrate, add 300 mL of dichloromethane and 150 mL of water, stir, separate the liquid and liquid phases, wash the organic phase with sodium carbonate solution, concentrate, add 150 mL of methyl tert-butyl ether, reflux for 1 hour, add 150 mL of n-heptane, cool to 20 °C, and stir for 2 hours. Filter, and wash the filter cake with a 1:1 mixture of methyl tert-butyl ether and n-heptane. The filter cake was added to a 250 ml reaction flask, along with 50 ml of tetrahydrofuran. The mixture was heated to 50 °C and stirred until dissolved. Then, 50 ml of n-heptane was slowly added dropwise. The mixture was cooled to 5 °C and stirred for 1 hour. The mixture was then filtered, and the filter cake was washed with n-heptane. The filter cake was dried to obtain 13.7 g of a white product with a purity of 99.9%. The yield was 45.5% by weight. The chromatogram is shown below. Figure 3As shown. ¹H-NMR (400MHz, CDCl₃(TMS), δ(ppm): 0.56(s, 3H), 0.99(s, 3H), 1.14–1.30(m, 5H), 1.34–1.43(m, 1H), 1.46–1.57(m, 4H), 1.71–1.81(m, 7H), 2.01(s, 3H), 2.12–2.24(m, 2H), 2.25–2.56(m, 2H), 2.72(t, 1H), 4.04(brs, 1H); NMR spectrum as shown. Figure 4 As shown.

[0090] As demonstrated in Examples 1-9 above, the preparation process of this invention is simple, highly selective, and yields a high rate. It utilizes conventional operations and reagents, and the three-step reaction effectively removes the 3-β-OH isomer, yielding a high-purity product. This process is suitable for large-scale industrial production, promoting technological innovation in the preparation of alfasalol and its derivatives, providing stable and reliable raw material support for the preparation of alfasalol-related drugs, and also offering insights for the preparation of other steroidal compounds.

[0091] The above are merely a few preferred embodiments of the present invention, described in a relatively specific and detailed manner, but they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention.

Claims

1. A method for preparing high-purity alfasalol, characterized in that, Includes the following steps (1)-(3): (1) Compound A was used as the starting material, and compound B was obtained by reduction with red aluminum and post-treatment. (2) Using compound B as a raw material, p-nitrobenzoic acid and phosphine reagent were added and reacted in the presence of azo reagent. After post-treatment to remove phosphide, compound C was obtained by purification. (3) Using compound C as raw material, hydrolyze it with sodium hydroxide, then process it and purify it twice with a mixed solvent to obtain high-purity compound D; 2. The method for preparing high-purity alfasalol according to claim 1, characterized in that, Step (1) includes the following specific steps: Compound A was added to a solvent and treated in an anhydrous and oxygen-free environment. Then, 2-3 equivalents of red aluminum were added at low temperature. The reaction temperature was -10 to 0°C and the reaction time was 2-6 hours. TLC showed that PE:EA = 1:

1. After the reaction was complete, compound B was purified from the reaction product. The solvent is selected from one of tetrahydrofuran, methyltetrahydrofuran, diethyl ether, isopropyl ether, ethylene glycol dimethyl ether, and dioxane.

3. The method for preparing high-purity alfasalol according to claim 2, characterized in that, The solvent is selected from tetrahydrofuran.

4. The method for preparing high-purity alfasalol according to claim 1, characterized in that, Step (2) includes the following specific steps: p-Nitrobenzoic acid and phosphine reagent were added to the solvent at 0℃, and the mixture was treated in anhydrous and oxygen-free conditions. Azo reagent was added dropwise, and the reaction was carried out for 10 min. Compound B was added and the mixture was reacted at room temperature for 8-16 h. A complexing agent was added, and the mixture was stirred for 3 h. The phosphide was removed by filtration, and then compound C was obtained by crystallization from methanol. The solvent is selected from one of diethyl ether, dichloromethane, toluene, ethyl acetate, acetonitrile, DMF, and tetrahydrofuran; The phosphine reagent is selected from one of tri-o-methylphenylphosphine, tributylphosphine, and triphenylphosphine; The azo reagent is selected from one of DEAD, DIAD, and TMAD; The complexing agent is selected from one of zinc dichloride, magnesium chloride, and calcium bromide.

5. The method for preparing high-purity alfasalol according to claim 4, characterized in that, The solvent is selected from tetrahydrofuran, the phosphine reagent is selected from triphenylphosphine, the azo reagent is selected from DIAD, and the complexing agent is selected from calcium bromide.

6. The method for preparing high-purity alfasalol according to claim 5, characterized in that, The equivalent of p-nitrobenzoic acid, triphenylphosphine, and DIAD to compound B is 1.0–2.0 eq; the equivalent of calcium bromide to compound B is 1.0–4.0 eq.

7. The method for preparing high-purity alfasalol according to claim 6, characterized in that, The equivalent of p-nitrobenzoic acid, triphenylphosphine, and DIAD to compound B is 1.5 eq; the equivalent of calcium bromide to compound B is 3.0 eq.

8. The method for preparing high-purity alfasalol according to claim 1, characterized in that, Step (3) includes the following specific steps: Compound C was added to a solvent at 10–20 °C, followed by the addition of sodium hydroxide and reaction at room temperature for 2–4 h. The pH was adjusted to 7 with glacial acetic acid, and the mixture was extracted and concentrated. The mixture was then slurried in a mixed solvent of methyl tert-butyl ether: n-heptane and recrystallized in tetrahydrofuran: n-heptane to obtain high-purity compound D. The solvent is selected from one of methanol, ethanol, isopropanol, methanol-water, tetrahydrofuran-water, ethanol-water, isopropanol-water, methanol-tetrahydrofuran-water, ethanol-tetrahydrofuran-water, and isopropanol-tetrahydrofuran-water.

9. The method for preparing high-purity alfasalol according to claim 8, characterized in that, The solvent is selected from methanol-tetrahydrofuran-water.

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