Preparation method of salbutamol sulfate

Abstract

The invention discloses a preparation method of salbutamol sulfate, and belongs to the technical field of organic synthesis. The method comprises the following steps: (1) Friedel-Crafts acylation reaction: reacting reactants salicylaldehyde and an acylation reagent in the presence of a catalyst to generate a compound 1; (2) phenolic hydroxyl group protection reaction: protecting the phenolic hydroxyl group of the compound 1 under base catalysis to generate a compound 2; (3) substitution reaction: carrying out SN2 substitution reaction on the compound 2 and tert-butylamine to obtain a compound 3; (4) reduction reaction: reducing the compound 3 under the condition of sodium borohydride to obtain a compound 4; (5) hydrolysis deprotection reaction: carrying out hydrolysis reaction on the compound 4 under an alkaline condition to obtain salbutamol; and (6) salifying reaction: directly salifying the salbutamol and sulfuric acid to obtain the high-purity salbutamol sulfate. The synthesis route does not involve a high-temperature and high-pressure dangerous process and a high-risk reagent, the used raw materials are simple and easy to obtain, the operation is simple, the method is environment-friendly, the production cost is low, and the method is more suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical synthesis and more specifically relates to a preparation method of salbutamol sulfate. Background Art

[0002] Salbutamol sulfate was first developed by GlaxoSmithKline in the UK as a powerful and fast-acting β2 receptor agonist. It was first approved for marketing in the UK in 1968 and registered in my country in 1988. It is the first choice for the clinical treatment of bronchial asthma, chronic obstructive pulmonary disease, and asthmatic tracheitis. However, the current synthesis route of salbutamol sulfate has the problems of outdated process, expensive reaction reagents, low yield, difficult to remove impurities or highly toxic, pressurized hydrogenation and other high-risk reactions. Therefore, developing a new synthesis process of salbutamol sulfate or optimizing the old synthesis process is of great significance to enterprises and society.

[0003] At present, the main routes for synthesizing salbutamol sulfate in China are as follows: Synthesis route 1: This route is an original synthetic route with long reaction steps, complicated operation, multiple intermediates involved, and difficult purification, which reduces the overall yield. The route uses a highly toxic bromine process, and the bromination of ketones is difficult to complete, and the products such as monobromination and dibromination are difficult to separate and purify. In addition, the last step of the reaction uses a high-risk hydrogenation process, which not only has high production costs, but also has the risk of excessive heavy metals in the product.

[0004] Synthesis route 2: This route uses p-hydroxybenzaldehyde as a raw material, undergoes chloromethylation, propylidene protection, aldehyde epoxidation, and finally obtains the target product through steps such as aminolysis and ring opening with tert-butylamine and hydrolysis and deprotection. At the same time, the ring opening is selective during the preparation of compound 6, which will introduce new impurities. Similarly, the entire reaction route is relatively long, which reduces the overall yield and has a high production cost, making it unsuitable for industrial production.

[0005] Synthesis route three: Although this route has shortened the process steps, the phenolic hydroxyl group of compound 2 is not protected and directly oxidized when compound 3 is obtained by using dimethyl sulfoxide (DMSO) oxidation, which is easy to produce oxidative impurities. In addition, in the process of synthesizing compound 5, highly toxic and explosive borane dimethyl sulfide is used to reduce salicylate, and safety and toxicity production need to be strictly controlled.

[0006] Synthesis route 4: This route is shorter than the original research route and does not involve high-risk reactions. However, the first step uses bromoacetyl chloride, which is expensive, and the cost of the entire route is high. The second step easily forms multiple substitutions, resulting in a lower yield in this step, an increase in process impurities, and difficulty in subsequent purification. The third step uses borohydride reduction to obtain the product, and the phenolic hydroxyl group easily combines with boron to form a boron-containing complex, resulting in excessive boron content in the product. In addition, domestic and foreign pharmacopoeias have strict indicators for controlling the boron content of salbutamol. To increase the boron content to meet pharmaceutical standards, additional complex process steps need to be added, increasing the difficulty and cost of the process. Summary of the invention

[0007] The invention aims to overcome the defects and shortcomings of the existing method for synthesizing salbutamol sulfate, such as low yield, heavy metal pollution, and a long synthesis route that is not conducive to industrial amplification, and to provide a method for preparing salbutamol sulfate with low cost, high yield, mild conditions, green environmental protection, simple operation, low equipment requirements, and suitable for industrial large-scale production.

[0008] In order to achieve the above technical objectives, the technical solution adopted by the present invention is: A method for preparing salbutamol sulfate comprises the following steps: (1) Acylation reaction: Add catalyst AlCl3 to organic solvent A, heat and stir, then add acylating agent bromoacetyl bromide dichloromethane solution under nitrogen protection, stir and keep warm for a period of time, then add salicylaldehyde dichloromethane solution, continue to keep warm and react, after the reaction is completed, purify and obtain compound 1, the structural formula of compound 1 is ; (2) Phenol hydroxyl protection reaction: Compound 1 is dissolved in organic solvent B, and a base and a hydroxyl protective agent are added in sequence after adjusting to the reaction temperature. The reaction is kept warm. After the reaction is complete, the filtrate is filtered, dried and purified to obtain compound 2. The structural formula of compound 2 is ; (3) Substitution reaction: Compound 2 was dissolved in organic solvent C, tert-butylamine was added dropwise in an ice-water bath under nitrogen protection, and then stirred and heated to carry out SN2 substitution reaction. After TLC monitoring, the reaction was completed and then purified to obtain compound 3. The structural formula of compound 3 is ; (4) Reduction reaction: Compound 3 is added to an organic solvent D, and the temperature is lowered to 0-5°C, and then a reducing agent is added in portions and the temperature is raised to carry out a reduction reaction. After the reaction is completed, compound 4 is separated and purified to obtain compound 4. The structural formula of compound 4 is ; (5) Hydrolysis deprotection reaction: Compound 4 is dissolved in an organic solvent E and mixed with an alkaline solution and stirred at a specific temperature to perform a hydrolysis reaction. After the hydrolysis is completed, the solvent is evaporated under reduced pressure to obtain salbutamol; (6) Salt-forming reaction: The obtained salbutamol is dissolved in an organic solvent F and heated to 45-50°C, and a 30% sulfuric acid solution is slowly added. After the addition is complete, the temperature is lowered and stirred to crystallize. After the reaction is completed, the salbutamol sulfate is obtained by suction filtration and drying.

[0009] Preferably, in step (1), the molar ratio of the catalyst, salicylaldehyde and bromoacetyl bromide is 4:1:1.2; the concentration of the bromoacetyl bromide dichloromethane solution is 1-3 g / mL; and the concentration of the salicylaldehyde dichloromethane solution is 0.5-1.5 g / mL.

[0010] Preferably, the insulation reaction time in step (1) is 10-80° C. and the reaction temperature is 6-20 hours.

[0011] Preferably, the organic solvent A in step (1) is any one of dichloromethane, 1,2-dichloroethane and nitromethane; the temperature is raised to 35-40°C and the reaction is kept warm, and the reaction is kept warm for 1-2 hours after the acylating agent is added dropwise, and then kept warm for 16-18 hours after the salicylaldehyde is added.

[0012] Furthermore, the purification method of compound 1 is to use one or more mixed solvents of ethyl acetate, acetonitrile, acetone, petroleum ether, n-hexane, and n-heptane for recrystallization or slurry purification, preferably ethyl acetate / n-hexane recrystallization.

[0013] Preferably, the organic solvent B in step (2) is selected from any one of tetrahydrofuran, acetonitrile, acetone, and dichloromethane; the hydroxyl protecting agent is acetyl chloride or acetic anhydride; the base is any one of pyridine, triethylamine, DIPEA, potassium carbonate, sodium carbonate, sodium bicarbonate, and potassium bicarbonate; the molar ratio of the compound 1, the hydroxyl protecting agent, and the base is 1:1-10:1.1-3; the reaction temperature is 10-20°C, and the reaction time is 4-8h.

[0014] Preferably, in step (3), the molar ratio of compound 2 to tert-butylamine is 1:1-10; the stirring and heating to 40-45° C. are performed for 3-5 h; and the organic solvent C is any one of ethanol, isopropanol and tetrahydrofuran.

[0015] Furthermore, the specific purification method of the product after the reaction in step (3) is: slowly dropwise add a mixture consisting of equal volumes of concentrated hydrochloric acid and an organic solvent, cool to 20-25°C after the dropwise addition, stir for 6 hours, filter and dry; the molar ratio of concentrated hydrochloric acid to compound 2 is 1-5:1.

[0016] Preferably, in step (4), the organic solvent D is any one of methanol, tetrahydrofuran, anhydrous ethanol and isopropanol; the molar ratio of the compound 3 to the reducing agent is 1:2-5; the reaction temperature is 20-25°C, and the reaction time is 3-4h.

[0017] Preferably, the reducing agent in step (4) is sodium borohydride.

[0018] Preferably, in step (5), the organic solvent E is any one of methanol, anhydrous ethanol, water / methanol, water / ethanol or a mixture of water / isopropanol; the alkaline solution is any one of sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium bicarbonate, potassium carbonate and potassium hydroxide; the amount of the organic solvent E is 4 to 6 times the mass of compound 4; the concentration of the alkaline solution is 2 mol / L, and the ratio of compound 4 to alkali is 10 g:0.01-0.015 mol; the specific temperature is 10-70 ° C, and the reaction time is 2-4 h; more preferably, the specific temperature is 40-50 ° C.

[0019] Preferably, in step (6), the organic solvent F is any one of anhydrous ethanol, isopropanol or a mixture of acetone; the crystallization temperature is -10-20°C, and the reaction is for 2-4 hours. More preferably, the organic solvent F is anhydrous ethanol, and the crystallization temperature is 0-10°C.

[0020] The reaction scheme of the present invention is as follows: Compared with the prior art, the present invention has the following beneficial effects: 1. In the method for preparing salbutamol sulfate of the present invention, acetyl is used to protect the phenolic hydroxyl group in the second step, which can prevent the formation of boron-containing complexes and the generation of oxidative process impurities, avoid complex purification process steps, and reduce process difficulty and production costs.

[0021] 2. The method for preparing salbutamol sulfate of the present invention has shortened reaction steps, no bromination process in the whole reaction process, no high-risk reagents used in the whole process, mild reaction conditions, low equipment requirements, and is suitable for industrial production.

[0022] 3. The method for preparing salbutamol sulfate of the present invention has all raw materials involved in the process which are in sufficient supply in the market, cheap and easily available, which significantly improves the total molar yield, and the purity of the product after purification is as high as 99.7% or more, and the product cost is greatly reduced. The method is an ideal new process for preparing salbutamol sulfate with high scalability. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is the HPLC purity analysis chart of the salbutamol sulfate prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0024] The technical solution of the present invention is further described below in conjunction with specific embodiments, but is not limited thereto.

[0025] Example 1 A method for preparing salbutamol sulfate comprises the following steps: (1) Preparation of Compound 1 Add 26.67 g of anhydrous AlCl3 and 40 ml of dichloromethane to the reaction bottle, heat it to 35-40°C, stir, and under nitrogen protection, add a mixed solution of 12.12 g of bromoacetyl bromide and 5 ml of dichloromethane dropwise. After the addition is complete, keep warm and stir for 1.0 h. Start adding a mixed solution of 6.10 g of salicylaldehyde and 5 ml of dichloromethane dropwise, and keep warm at 35-40°C for 18 h. HPLC and TLC were used to monitor the reaction until it was complete. The reaction solution was slowly added dropwise to a mixture of 150 ml of ice water and 50 ml of dichloromethane with stirring, and concentrated hydrochloric acid was added to adjust the pH value to 1.0-3.0. The mixture was stirred at room temperature for 1 h, and the organic layer was separated. The aqueous layer was extracted with 30 ml of dichloromethane × 2 times, and the combined organic phases were washed with 2 × 60 ml of saturated brine. The organic phases were separated and collected, and anhydrous sodium sulfate was added to dry for 30 min. The filtrate was filtered and dried, and 40 ml of ethyl acetate was added and the temperature was raised until the solution was clear. 60 ml of n-hexane was added and stirred for 15 min, and the temperature was lowered by 0-5 ° C. The mixture was stirred and crystallized by filtration and dried to obtain compound 1 with a yield of 85.7%.

[0026] (2) Preparation of Compound 2 Add 60 ml of tetrahydrofuran to the reaction bottle, add 10.0 g of compound 1, stir and cool to 10-20 ° C, add 5.0 g of acetic anhydride and 4.8 g of triethylamine in sequence, keep warm at 10-20 ° C and stir to react for 5 h, monitor by TLC until the reaction is complete, filter the filtrate and spin dry, add 25 ml of dichloromethane, heat to 35-40 ° C, add 40 ml of n-hexane and stir for 20 min, cool to 0-5 ° C, keep warm and stir, crystallize, filter and dry to obtain compound 2 with a yield of 92.8%.

[0027] (3) Preparation of Compound 3 10.00g of compound 2 was added to 50ml of isopropanol, and 10.24g of tert-butylamine was added dropwise under nitrogen protection in an ice-water bath. After the addition was complete, the mixture was heated in an oil bath and stirred to 40-45°C. The mixture was stirred for 3h at this temperature. After TLC monitoring, the reaction was completed. A mixture of 10ml of concentrated hydrochloric acid and 10ml of isopropanol was slowly added dropwise. After the addition was complete, the mixture was cooled to 20-25°C and stirred for 6h. The mixture was filtered and dried to obtain compound 3 with a yield of 86.7%.

[0028] (4) Preparation of Compound 4 Add 150 ml of anhydrous methanol to a three-necked flask, add 10.0 g of compound 3, cool to 0-5 °C, add 3.0 g of sodium borohydride in batches, raise the temperature to 20-25 °C, react for 3 hours, filter, add anhydrous sodium sulfate to dry, filter, add 150 ml of ethyl acetate dropwise, stir, filter, and dry to obtain 11.8 g of compound 4, with a yield of 91.3%.

[0029] (5) Preparation of salbutamol Add 50 ml of methanol, 10.0 g of compound 4, and 6 ml of 2 mol / L NaOH solution to the reaction flask in sequence, stir and heat to 40-50 °C for 3 h, monitor by TLC until the reaction is complete, and evaporate the solvent under reduced pressure to obtain salbutamol; (6) Preparation of salbutamol sulfate To the salbutamol product obtained in step (5), add 80 ml of anhydrous ethanol, heat to 45-50° C. to dissolve, slowly dropwise add a sulfuric acid aqueous solution (2.1 g of concentrated sulfuric acid and 5 g of deionized water are evenly mixed), cool to 0-10° C. and stir for 3 h, filter and vacuum dry to obtain a crude salbutamol sulfate with a yield of 92.6%.

[0030] Refining of salbutamol sulfate: Add 10g of crude salbutamol sulfate, 200mL of anhydrous ethanol and 50ml of purified water to a reaction flask, stir and heat to 70°C, stir for 15min, start cooling to 0°C, keep stirring and crystallize for 4h, and filter. Wash the filter cake with 30mL of ethyl acetate, and dry under reduced pressure to obtain refined salbutamol sulfate, with a yield of 95.2% and a purity of 99.7%.

[0031] Example 2 A method for preparing salbutamol sulfate comprises the following steps: (1) Preparation of Compound 1 Add 78.60 g of anhydrous AlCl3 and 120 ml of dichloromethane to the reaction bottle, heat it to 35-40°C, stir, and under nitrogen protection, add a mixed solution of 35.70 g of bromoacetyl bromide and 30 ml of dichloromethane dropwise. After the addition is complete, keep warm and stir for 1.0 h. Start adding a mixed solution of 18.0 g of salicylaldehyde and 30 ml of dichloromethane dropwise, and keep warm at 35-40°C for 18 h.

[0032] HPLC and TLC were used to monitor the reaction until it was complete. The reaction solution was slowly added dropwise to a mixture of 450 ml of ice water and 150 ml of dichloromethane with stirring, and concentrated hydrochloric acid was added to adjust the pH value to 1.0-3.0. The mixture was stirred at room temperature for 1 h, and the organic layer was separated. The aqueous layer was extracted with 90 ml of dichloromethane × 2, and the combined organic phases were washed with 2 × 180 ml of saturated brine. The organic phases were separated and collected, and anhydrous sodium sulfate was added to dry for 30 min. The filtrate was filtered and dried, and 120 ml of ethyl acetate was added and the temperature was raised until the solution was clear. 180 ml of n-hexane was added and stirred for 15 min, and the temperature was lowered by 0-5 ° C. The mixture was stirred and crystallized by filtration and dried to obtain compound 1 with a yield of 83.1%.

[0033] (2) Preparation of Compound 2 Add 120 ml of tetrahydrofuran to the reaction bottle, add 20.0 g of compound 1, stir and cool to 0-5 ° C, add 10.0 g of acetic anhydride and 12 g of potassium carbonate in sequence, keep warm at 0-5 ° C and stir to react for 5 h, monitor by TLC until the reaction is complete, filter the filtrate and spin dry, add 50 ml of dichloromethane, heat to 35-40 ° C, add 80 ml of n-hexane and stir for 20 min, cool to 0-5 ° C, keep warm and stir to crystallize, filter and dry to obtain compound 2 with a yield of 91.8%.

[0034] (3) Preparation of Compound 3 10.00g of compound 2 was added to 60ml of isopropanol, and 12.0g of tert-butylamine was added dropwise under nitrogen protection in an ice-water bath. After the addition was complete, the mixture was heated in an oil bath and stirred to 40-45°C. The mixture was stirred for 3h at this temperature. After TLC monitoring, the reaction was completed. A mixture of 12ml of concentrated hydrochloric acid and 12ml of isopropanol was slowly added dropwise. After the addition was complete, the mixture was cooled to 20-25°C and stirred for 6h. The mixture was filtered and dried to obtain compound 3 with a yield of 84.3%.

[0035] (4) Preparation of Compound 4 Add 150 ml of anhydrous ethanol to a three-necked flask, add 10.0 g of compound 3, cool to 0-5 °C, add 3.0 g of sodium borohydride in batches, raise the temperature to 20-25 °C, react for 3 hours, filter, add anhydrous sodium sulfate to dry, filter, add 150 ml of ethyl acetate dropwise, stir, filter, and dry to obtain 11.8 g of compound 4, with a yield of 90.6%.

[0036] (5) Preparation of salbutamol To the reaction flask, 75 ml of anhydrous ethanol, 10.0 g of compound 5, and 5 ml of 2 mol / L KOH solution were added in sequence. The mixture was stirred and heated to 40-50° C. for 3 h. The solvent was evaporated under reduced pressure after TLC monitoring until the reaction was complete to obtain salbutamol.

[0037] (6) Preparation of salbutamol sulfate Add 100 ml of anhydrous ethanol to the product obtained in step (5), heat to 45-50 °C to dissolve, slowly dropwise add sulfuric acid aqueous solution (2.1 g of concentrated sulfuric acid and 5 g of deionized water are evenly mixed), cool to 0-10 °C and stir for 3 h, filter and vacuum dry to obtain crude salbutamol sulfate with a yield of 89.6%.

[0038] Refining of salbutamol sulfate: Add 10g of crude salbutamol sulfate, 200mL of acetone and 50ml of purified water to a reaction flask, stir and heat to 60°C, stir for 15min, start cooling to 10°C, keep stirring and crystallize for 4h, and filter. Wash the filter cake with 30mL of ethyl acetate, and dry under reduced pressure to obtain refined salbutamol sulfate, with a yield of 93.5% and a purity of 99.8%.

[0039] It should be noted that the above embodiments are only some embodiments of the preferred methods of implementing the present invention, rather than all embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing salbutamol sulfate, characterized in that: The following steps are involved: (1) Acylation reaction: Add catalyst AlCl3 to organic solvent A, heat and stir, then add acylating agent bromoacetyl bromide dichloromethane solution under nitrogen protection, stir and keep warm for a period of time, then add salicylaldehyde dichloromethane solution, continue to keep warm and react, after the reaction is completed, purify and obtain compound 1, the structural formula of compound 1 is ; (2) Phenol hydroxyl protection reaction: Compound 1 is dissolved in organic solvent B, and a base and a hydroxyl protective agent are added in sequence after adjusting to the reaction temperature. The reaction is kept warm. After the reaction is complete, the filtrate is filtered, dried and purified to obtain compound 2. The structural formula of compound 2 is ; (3) Substitution reaction: Compound 2 was dissolved in organic solvent C, tert-butylamine was added dropwise in an ice-water bath under nitrogen protection, and then stirred and heated to carry out SN2 substitution reaction. After TLC monitoring, the reaction was completed and then purified to obtain compound 3. The structural formula of compound 3 is ; (4) Reduction reaction: Compound 3 is added to an organic solvent D, the temperature is lowered to 0-5°C, a reducing agent is added in portions, and the temperature is raised to the reaction temperature for reduction reaction. After the reaction is completed, compound 4 is separated and purified to obtain compound 4. The structural formula of compound 4 is ; (5) Hydrolysis deprotection reaction: Compound 4 is dissolved in an organic solvent E and mixed with an alkaline solution and stirred at a specific temperature to perform a hydrolysis reaction. After the hydrolysis is completed, the solvent is evaporated under reduced pressure to obtain salbutamol; (6) Salt-forming reaction: The obtained salbutamol is dissolved in an organic solvent F and heated to 45-50°C, and a 30% sulfuric acid solution is slowly added. After the addition is complete, the temperature is lowered and stirred for reaction. After the reaction is completed, the mixture is filtered and dried to obtain salbutamol sulfate.

2. The method for preparing salbutamol sulfate according to claim 1, characterized in that: In the step (1), the molar ratio of the catalyst, salicylaldehyde and bromoacetyl bromide is 4:1:1.2; the concentration of the bromoacetyl bromide dichloromethane solution is 1-3 g / mL; and the concentration of the salicylaldehyde dichloromethane solution is 0.5-1.5 g / mL.

3. The method for preparing salbutamol sulfate according to claim 1, characterized in that: In the step (1), the organic solvent A is any one of dichloromethane, 1,2-dichloroethane, and nitromethane; the temperature is raised to 35-40° C. and the reaction is carried out by heat preservation, wherein the reaction is carried out by heat preservation for 1-2 hours after the acylating agent is added dropwise, and then the reaction is continued for 16-18 hours after the salicylaldehyde is added. Compound 1 is recrystallized or purified by pulping using one or more mixed solvents selected from ethyl acetate, acetonitrile, acetone, petroleum ether, n-hexane, and n-heptane.

4. The method for preparing salbutamol sulfate according to claim 1, characterized in that: The organic solvent B in the step (2) is selected from any one of tetrahydrofuran, acetonitrile, acetone, and dichloromethane; the hydroxyl protecting agent is acetyl chloride or acetic anhydride; the base is any one of pyridine, triethylamine, DIPEA, potassium carbonate, sodium carbonate, sodium bicarbonate, and potassium bicarbonate; the molar ratio of the compound 1, the hydroxyl protecting agent, and the base is 1:1-10:1.1-3; the reaction temperature is 10-20°C, and the reaction time is 4-8h.

5. The method for preparing salbutamol sulfate according to claim 1, characterized in that: In the step (3), the molar ratio of compound 2 to tert-butylamine is 1:1-10; the stirring and heating to 40-45° C. are performed for 3-5 hours; and the organic solvent C is any one of ethanol, isopropanol, and tetrahydrofuran.

6. The method for preparing salbutamol sulfate according to claim 1, characterized in that: In step (4), the organic solvent D is selected from any one of methanol, tetrahydrofuran, anhydrous ethanol and isopropanol; the molar ratio of the compound 3 to the reducing agent is 1:2-5; the reaction temperature is 20-25°C, and the reaction time is 3-4h.

7. The method for preparing salbutamol sulfate according to claim 1, characterized in that: The reducing agent in step (4) is sodium borohydride.

8. The method for preparing salbutamol sulfate according to claim 1, characterized in that: In the step (5), the organic solvent E is any one of methanol, anhydrous ethanol, water / methanol, water / ethanol or a mixture of water / isopropanol; the alkaline solution is any one of sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium bicarbonate, potassium carbonate and potassium hydroxide; the amount of the organic solvent E is 4 to 6 times the mass of compound 4; the concentration of the alkaline solution is 2 mol / L, and the ratio of compound 4 to alkali is 10 g:0.01-0.015 mol; the specific temperature is 40-50° C., and the reaction time is 2-4 h.

9. The method for preparing salbutamol sulfate according to claim 1, characterized in that: In the step (6), the organic solvent F is any one of anhydrous ethanol, isopropanol or a mixture of acetone; the cooling is to cool to 0-10° C. and react for 2-4 hours.

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