A process for the preparation of salbutamol sulfate

Abstract

The application discloses a preparation method of salbutamol sulfate and belongs to the technical field of organic synthesis. The method comprises the following steps: (1) a Friedel-Crafts acylation reaction: reactants salicylaldehyde and an acylating agent are reacted to generate compound 1 under the condition of a catalyst; (2) a phenolic hydroxyl protection reaction: the phenolic hydroxyl of compound 1 is protected to generate compound 2 under the catalysis of an alkali; (3) a substitution reaction: compound 2 and t-butylamine are subjected to an SN2 substitution reaction to obtain compound 3; (4) a reduction reaction: compound 3 is subjected to reduction under the condition of sodium borohydride to obtain compound 4; (5) a hydrolysis deprotection reaction: compound 4 is subjected to a hydrolysis reaction under the condition of an alkali to obtain salbutamol; and (6) a salt formation reaction: salbutamol is directly subjected to salt formation with sulfuric acid to obtain salbutamol sulfate with high purity. The synthesis route of the application does not involve a dangerous process of high temperature and high pressure and high-risk reagents, raw materials used are simple and easy to obtain, operation is simple, the method is environment-friendly, production cost is low, and the method is more suitable for industrialized production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic chemical synthesis. More particularly, it relates to a preparation method of salbutamol sulfate. BACKGROUND

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 However, the current synthesis route of salbutamol sulfate has the problems of outdated process, expensive reagents, low yield, difficult impurity removal, or high-risk reactions such as pressurized hydrogenation.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

[0003] Currently, there are several main routes for the synthesis of salbutamol sulfate in China:

[0004] Synthesis route one:

[0005]

[0006] This route is the original research synthesis route. It has long reaction steps, complicated operation, involves multiple intermediates, is difficult to purify, and reduces the overall yield. In this route, toxic bromine is used, and the reaction of ketone bromination is difficult to complete. Mono-brominated and di-brominated products 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 cost, but also has the risk of exceeding the standard of heavy metals in the product.

[0007] Synthesis route two:

[0008]

[0009] This route uses p-hydroxybenzaldehyde as the raw material, and goes through chloromethylation, propylidene protection, aldehyde epoxidation, and finally amine cleavage of tert-butylamine, hydrolysis deprotection, etc. to obtain the target product. In the preparation process of compound 6, there is selectivity in the ring opening, which will introduce new impurities. Similarly, the entire reaction route is long, which reduces the total yield and production cost, and is not suitable for industrial production.

[0010] Synthesis route three:

[0011]

[0012] The process steps of this route are shortened, but the use of dimethyl sulfoxide (DMSO) oxidation method is used to obtain compound 3, and the phenolic hydroxyl group of compound 2 is not protected and is directly oxidized, which is easy to produce oxidation impurities. Moreover, in the process of synthesizing compound 5, borane dimethyl sulfide, which is toxic and explosive, is used to reduce salicylate, and safety and toxicity production need to be strictly controlled.

[0013] Synthetic route four:

[0014]

[0015] Compared with the original research route, this route is shortened and does not involve high-risk reactions, but the first step reaction uses expensive bromoacetyl chloride, and the whole route cost is high; the second step is easy to form polysubstituted compounds, which reduces the yield of this step, increases the process impurities, and is not easy to purify in the later period; the third step reaction uses borohydride to reduce the product, and the phenolic hydroxyl group is easy to combine with boron to form a complex containing boron, which leads to the boron content exceeding the standard in the product, and the pharmacopoeia at home and abroad has strict control on the boron content of salbutamol. To process the boron content to meet the drug standard, additional complex process steps need to be added, which increases the process difficulty and cost. SUMMARY

[0016] The purpose of the present application is to overcome the defects and deficiencies of the existing synthetic salbutamol sulfate method, such as low yield, heavy metal pollution, long synthesis route, and not conducive to industrial expansion, and to provide a preparation method of salbutamol sulfate with low cost, high yield, mild conditions, green environmental protection, simple operation, low equipment requirement, and suitable for industrial large-scale production.

[0017] To achieve the above technical purpose, the technical scheme adopted by the present application is:

[0018] A preparation method of salbutamol sulfate, comprising the following steps:

[0019] (1) acylation reaction: add catalyst AlCl3 to organic solvent A, heat and stir, and then add acylation reagent 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, and then purify to obtain compound 1, and the structural formula of compound 1 is .

[0020] (2) phenolic hydroxyl group protection reaction: dissolve compound 1 in organic solvent B, adjust the reaction temperature, then add base and hydroxyl protecting agent in sequence, keep warm and react, filter the filtrate after the reaction is complete, spin dry and purify to obtain compound 2, and the structural formula of compound 2 is .

[0021] (3) Substitution reaction: Compound 2 is dissolved in organic solvent C, and under nitrogen protection, tert-butylamine is added dropwise under ice water bath, then stirred and warmed to perform SN2 substitution reaction, TLC monitoring is performed until the reaction is completed, and then purification is performed to obtain compound 3, and the structural formula of compound 3 is ;

[0022] (4) Reduction reaction: Compound 3 is added in organic solvent D, and after being cooled to 0-5℃, a reducing agent is added in portions, and then warmed to perform reduction reaction, after the reaction is completed, separation and purification are performed to obtain compound 4, and the structural formula of compound 4 is ;

[0023] (5) Hydrolysis and deprotection reaction: Compound 4 is dissolved in organic solvent E and mixed with an alkali solution to perform hydrolysis reaction under a specific temperature, and after the hydrolysis is completed, the solvent is evaporated under reduced pressure to obtain salbutamol;

[0024] (6) Salt formation reaction: The obtained salbutamol is dissolved in organic solvent F and warmed to 45-50℃, and then 30% sulfuric acid solution is slowly added, after the dropwise addition is completed, cooling and incubation are performed to perform crystallization, after the reaction is completed, filtration and drying are performed to obtain salbutamol sulfate.

[0025] Preferably, 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.

[0026] Preferably, in the step (1), the reaction temperature is 10-80℃, and the reaction time is 6-20 hours.

[0027] Preferably, in the step (1), the organic solvent A is any one of dichloromethane, 1,2-dichloroethane and nitromethane; the reaction is performed by warming to 35-40℃ and incubation; and after the acylation reagent is added dropwise, the incubation is performed for 1-2 hours, then the salicylaldehyde is added, and the incubation is continued for 16-18 hours.

[0028] Further, the purification method of compound 1 is recrystallization or beating purification by using one or more mixed solvents of ethyl acetate, acetonitrile, acetone, petroleum ether, n-hexane and n-heptane, and the recrystallization of ethyl acetate / n-hexane is preferred.

[0029] Preferably, in the step (2), the organic solvent B is any one of tetrahydrofuran, acetonitrile, acetone and dichloromethane; the hydroxyl protection 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 compound 1, the hydroxyl protection agent and the base is 1:1-10:1.1-3; the reaction temperature is 10-20℃, and the reaction time is 4-8 hours.

[0030] Preferably, the molar ratio of compound 2 to tert-butylamine in step (3) is 1:1-10; the stirring and temperature rising to 40-45℃ is performed for 3-5h; the organic solvent C is any one of ethanol, isopropanol and tetrahydrofuran.

[0031] Further, the specific purification method of the product after the reaction in step (3) is as follows: slowly drop the mixture of concentrated hydrochloric acid and organic solvent in equal volume, drop to 20-25℃, stir for 6h, dry after filtration, and the molar ratio of concentrated hydrochloric acid to compound 2 is 1-5:1.

[0032] Preferably, the organic solvent D in step (4) is any one of methanol, tetrahydrofuran, anhydrous ethanol and isopropanol; the molar ratio of compound 3 to reducing agent is 1:2-5; the reaction temperature is 20-25℃, and the reaction time is 3-4h.

[0033] Preferably, the reducing agent in step (4) is sodium borohydride.

[0034] Preferably, the organic solvent E in step (5) is any one of methanol, anhydrous ethanol, water / methanol, water / ethanol or water / isopropanol mixture; the alkali solution is any one of sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium bicarbonate, potassium carbonate and potassium hydroxide; the amount of organic solvent E is 4-6 times the mass of compound 4; the concentration of alkali solution is 2mol / L, the amount ratio of compound 4 to alkali is 10g:0.01-0.015mol; the specific temperature is 10-70℃, and the reaction time is 2-4h; more preferably, the specific temperature is 40-50℃.

[0035] Preferably, the organic solvent F in step (6) is any one of anhydrous ethanol, isopropanol or acetone mixture; the crystallization temperature is -10-20℃, and the reaction time is 2-4h; more preferably, the organic solvent F is anhydrous ethanol, and the crystallization temperature is 0-10℃.

[0036] The reaction route of the present application is as follows:

[0037]

[0038] Compared with the prior art, the present application has the following beneficial effects:

[0039] 1. In the method for preparing salbutamol sulfate, the acetyl group is used to protect the phenolic hydroxyl group in the second step, which can prevent the formation of boron-containing complex and the production of oxidation type process impurities, avoid the complex purification process steps, and reduce the process difficulty and production cost.

[0040] 2. The method for preparing salbutamol sulfate according to the present application, which has shortened reaction steps, no bromination process in the whole reaction, no use of high-risk reagents in the whole process, mild reaction conditions, low equipment requirements, and is suitable for industrial production.

[0041] 3. The method for preparing salbutamol sulfate according to the present application, which uses all raw materials that are cheap and easily available in the market, significantly improves the total molar yield, and has a product purity of more than 99.7% after purification, thereby greatly reducing the product cost and being an ideal new preparation process of salbutamol sulfate with high popularization. BRIEF DESCRIPTION OF DRAWINGS

[0042] Figure 1 The HPLC purity analysis spectrum of salbutamol sulfate prepared in Example 1 of the present application. DETAILED DESCRIPTION

[0043] The technical solutions of the present application will be further described below in combination with specific examples, but are not limited thereto.

[0044] Example 1

[0045] A preparation method of salbutamol sulfate, which comprises the following steps:

[0046] (1) Preparation of compound 1

[0047] Anhydrous AlCl3 26.67 g and dichloromethane 40 ml were added to a reaction bottle, which was warmed to 35-40°C, stirred, and then 12.12 g of a mixed solution of bromoacetyl bromide and 5 ml of dichloromethane was added dropwise under nitrogen protection. After the dropwise addition was completed, the solution was stirred for 1.0 h, and then 6.10 g of a mixed solution of salicylaldehyde and 5 ml of dichloromethane was added dropwise. The reaction was carried out at 35-40°C for 18 h. HPLC and TLC were used to monitor the reaction until it was completed. The reaction solution was slowly added to a mixture of 150 ml of ice water and 50 ml of dichloromethane under stirring, and concentrated hydrochloric acid was added to adjust the pH value to 1.0-3.0. The solution was stirred at room temperature for 1 h, and then the organic layer was separated. The water layer was extracted with 30 ml of dichloromethane twice, and the combined organic phase was washed with saturated brine 2 x 60 ml. The organic phase was collected by separation, and then anhydrous sodium sulfate was added for drying for 30 min. The filtrate was rotary evaporated, 40 ml of ethyl acetate was added to dissolve the solution, 60 ml of n-hexane was added, and the solution was stirred for 15 min. The solution was cooled to 0-5°C, and then the solution was stirred for crystallization. The solution was filtered, and then dried to obtain compound 1, with a yield of 85.7%.

[0048] (2) Preparation of compound 2

[0049] Into a reaction flask, add 60 ml of tetrahydrofuran, add 10.0 g of compound 1, stir and cool to 10-20 °C, add 5.0 g of acetic anhydride, 4.8 g of triethylamine, and stir and react at 10-20 °C for 5 h, monitor the reaction completion by TLC, filter the filtrate, spin dry, add 25 ml of dichloromethane, warm to 35-40 °C, add 40 ml of n-hexane, stir for 20 min, cool to 0-5 °C, stir and crystallize, filter, and dry to obtain compound 2 in a yield of 92.8%.

[0050] (3) Preparation of compound 3

[0051] Into 50 ml of isopropyl alcohol, add 10.00 g of compound 2, protect with nitrogen, add 10.24 g of tert-butylamine dropwise under ice water bath, after the dropwise addition is completed, heat on an oil bath, stir and warm to 40-45 °C, and react for 3 h, monitor the reaction completion by TLC, slowly add a mixture of 10 ml of concentrated hydrochloric acid and 10 ml of isopropyl alcohol, after the dropwise addition is completed, cool to 20-25 °C, and stir for 6 h. Filter and dry to obtain compound 3 in a yield of 86.7%.

[0052] (4) Preparation of compound 4

[0053] Into a three-necked flask, add 150 ml of anhydrous methanol, add 10.0 g of compound 3, cool to 0-5 °C, add 3.0 g of sodium borohydride in batches, after the addition is completed, warm to 20-25 °C, react for 3 h, filter, add 150 ml of ethyl acetate, stir, filter, and dry to obtain 11.8 g of compound 4 in a yield of 91.3%.

[0054] (5) Preparation of salbutamol

[0055] Into a reaction flask, add 50 ml of methanol, add 10.0 g of compound 4, add 6 ml of 2 mol / L NaOH solution, stir and warm to 40-50 °C, react for 3 h, monitor the reaction completion by TLC, evaporate the solvent under reduced pressure to obtain salbutamol.

[0056] (6) Preparation of salbutamol sulfate

[0057] Into the salbutamol obtained in step (5), add 80 ml of anhydrous ethanol, warm to 45-50 °C to dissolve, slowly add an aqueous sulfuric acid solution (2.1 g of concentrated sulfuric acid and 5 g of deionized water are mixed uniformly), cool to 0-10 °C, stir for 3 h, filter, and dry under vacuum to obtain salbutamol sulfate in a yield of 92.6%.

[0058] Refining of salbutamol sulfate: 10 g of salbutamol sulfate crude product, 200 mL of anhydrous ethanol and 50 mL of purified water were added to a reaction bottle, stirred and warmed to 70°C, stirred for 15 min, and then cooled to 0°C. Crystallization was performed by stirring for 4 h, and then filtered under suction. The filter cake was washed with 30 mL of ethyl acetate, and dried under reduced pressure to obtain salbutamol sulfate refined product, with a yield of 95.2% and a purity of 99.7%.

[0059] Example 2

[0060] A method for preparing salbutamol sulfate, comprising the following steps:

[0061] (1) Preparation of compound 1

[0062] Anhydrous AlCl3 78.60 g and dichloromethane 120 ml were added to a reaction bottle, warmed to 35-40°C, and stirred under nitrogen protection. A mixed solution of 35.70 g of bromoacetyl bromide and 30 ml of dichloromethane was added dropwise. After the dropwise addition was completed, the solution was stirred for 1.0 h. A mixed solution of 18.0 g of salicylaldehyde and 30 ml of dichloromethane was then added dropwise, and the reaction was allowed to proceed at 35-40°C for 18 h.

[0063] The reaction was monitored by HPLC and TLC until completion. The reaction solution was slowly added dropwise to a mixture of 450 ml of ice water and 150 ml of dichloromethane under stirring. Concentrated hydrochloric acid was added to adjust the pH value to 1.0-3.0. The solution was stirred at room temperature for 1 h. The organic layer was separated, and the aqueous layer was extracted with dichloromethane 90 ml x 2. The combined organic phase was washed with saturated brine 2 x 180 ml. The organic phase was collected by liquid separation, and anhydrous sodium sulfate was added for drying for 30 min. The filtrate was filtered under suction and rotary evaporated. Ethyl acetate 120 ml was added to the solution, which was warmed to dissolve. N-hexane 180 ml was added and stirred for 15 min. The solution was cooled to 0-5°C, and the product was crystallized by stirring at 0-5°C. The product was filtered under suction and dried to obtain compound 1, with a yield of 83.1%.

[0064] (2) Preparation of compound 2

[0065] Anhydrous tetrahydrofuran 120 ml was added to a reaction bottle, and 20.0 g of compound 1 was added. The solution was stirred and cooled to 0-5°C. Acetic anhydride 10.0 g and potassium carbonate 12 g were added in sequence. The solution was stirred and reacted at 0-5°C for 5 h. The reaction was monitored by TLC until completion. The filtrate was filtered and rotary evaporated. Dichloromethane 50 ml was added, and the solution was warmed to 35-40°C. N-hexane 80 ml was added and stirred for 20 min. The solution was cooled to 0-5°C, and the product was crystallized by stirring at 0-5°C. The product was filtered under suction and dried to obtain compound 2, with a yield of 91.8%.

[0066] (3) Preparation of compound 3

[0067] Into a three-necked flask, 150 ml of anhydrous ethanol was added, 10.0 g of compound 3 was added, and the temperature was lowered to 0-5°C. 3.0 g of sodium borohydride was added in portions, and the temperature was raised to 20-25°C. After 3 hours of reaction, filtration was performed, and anhydrous sodium sulfate was added for drying. 150 ml of ethyl acetate was added dropwise, and stirring and filtration were performed, and 11.8 g of compound 4 was obtained by drying, with a yield of 90.6%.

[0068] (4) Preparation of compound 4

[0069] Into a three-necked flask, 150 ml of anhydrous ethanol was added, 10.0 g of compound 3 was added, and the temperature was lowered to 0-5°C. 3.0 g of sodium borohydride was added in portions, and the temperature was raised to 20-25°C. After 3 hours of reaction, filtration was performed, and anhydrous sodium sulfate was added for drying. 150 ml of ethyl acetate was added dropwise, and stirring and filtration were performed, and 11.8 g of compound 4 was obtained by drying, with a yield of 90.6%.

[0070] (5) Preparation of salbutamol

[0071] Into a three-necked flask, 75 ml of anhydrous ethanol was added, 10.0 g of compound 5 was added, 5 ml of 2 mol / L KOH solution was added, and the temperature was raised to 40-50°C. After 3 hours of reaction, the solvent was evaporated under reduced pressure to obtain salbutamol.

[0072] (6) Preparation of salbutamol sulfate

[0073] Into a three-necked flask, 75 ml of anhydrous ethanol was added, 10.0 g of compound 5 was added, 5 ml of 2 mol / L KOH solution was added, and the temperature was raised to 40-50°C. After 3 hours of reaction, the solvent was evaporated under reduced pressure to obtain salbutamol.

[0074] Into a three-necked flask, 75 ml of anhydrous ethanol was added, 10.0 g of compound 5 was added, 5 ml of 2 mol / L KOH solution was added, and the temperature was raised to 40-50°C. After 3 hours of reaction, the solvent was evaporated under reduced pressure to obtain salbutamol.

[0075] It should be noted that the above examples are only part of the preferred modes of implementing the present application, and not all of them. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application should be included in the protection scope of the present application.

Claims

1. A method for preparing salbutamol sulfate, characterized in that, Includes the following steps: (1) Acylation reaction: Catalyst AlCl3 was added to organic solvent A, heated and stirred, and under nitrogen protection, acylation reagent bromoacetyl bromide dichloromethane solution was added. After stirring and maintaining the temperature for a period of time, salicylaldehyde dichloromethane solution was added, and the reaction was continued at the temperature. After the reaction was completed, compound 1 was obtained by purification. The structural formula of compound 1 is as follows: ; (2) Phenolic hydroxyl protection reaction: Compound 1 was dissolved in organic solvent B, and after adjusting to the reaction temperature, a base and a hydroxyl protecting agent were added sequentially. The reaction was maintained at this temperature until complete. After filtration, the filtrate was evaporated to dryness and purified to obtain compound 2. The structural formula of compound 2 is as follows: ; (3) Substitution reaction: Compound 2 was dissolved in organic solvent C. Under nitrogen protection, tert-butylamine was added dropwise in an ice-water bath. Then, the mixture was stirred and heated to carry out an SN2 substitution reaction. The reaction was monitored by TLC until complete, and then purified to obtain compound 3. The structural formula of compound 3 is as follows: ; (4) Reduction reaction: Compound 3 was added to organic solvent D, the temperature was lowered to 0-5℃, and then the reducing agent was added in portions while the temperature was raised to the reaction temperature to carry out the reduction reaction. After the reaction was completed, compound 4 was obtained by separation and purification. The structural formula of compound 4 is as follows: ; (5) Hydrolysis protection reaction: Compound 4 is dissolved in organic solvent E and mixed with alkaline solution and stirred at a specific temperature to carry out hydrolysis reaction. After hydrolysis is completed, the solvent is evaporated under reduced pressure to obtain salbutamol. (6) Salt formation reaction: Dissolve the obtained salbutamol in organic solvent F and heat to 45~50℃, slowly add 30% sulfuric acid solution, cool down and stir the reaction after the addition is complete, filter and dry to obtain salbutamol sulfate; The organic solvent A is any one of dichloromethane, 1,2-dichloroethane, and nitromethane; The organic solvent B is selected from any one of tetrahydrofuran, acetonitrile, acetone, and dichloromethane; The organic solvent C is any one of ethanol, isopropanol, and tetrahydrofuran; The organic solvent D is selected from any one of methanol, tetrahydrofuran, anhydrous ethanol, and isopropanol; The organic solvent E is any one of methanol, anhydrous ethanol, water / methanol, water / ethanol, or a mixture of water / isopropanol; The organic solvent F is any one of anhydrous ethanol, isopropanol, or acetone.

2. The method for preparing salbutamol sulfate according to claim 1, characterized in that, In step (1), the molar ratio of catalyst, salicylaldehyde and bromoacetyl bromide is 4:1:1.2; the concentration of bromoacetyl bromide dichloromethane solution is 1-3 g / mL; and the concentration of 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 step (1), the temperature is raised to 35-40℃ and kept at that temperature for the reaction. The heat preservation reaction is carried out by first keeping the reaction at that temperature for 1-2 hours after the addition of the acylation reagent, and then continuing to keep the reaction at that temperature for 16-18 hours after the addition of salicylaldehyde. Compound 1 is purified by recrystallization or pulping using one or more of the following solvents: 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 hydroxyl protecting agent in step (2) 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 compound 1, hydroxyl protecting agent, and base is 1:1-10:1.1-3; the reaction temperature is 10~20℃, and the reaction time is 4-8h.

5. The method for preparing salbutamol sulfate according to claim 1, characterized in that, In step (3), the molar ratio of compound 2 to tert-butylamine is 1:1-10; the stirring and heating to 40-45℃ takes 3-5 hours.

6. The method for preparing salbutamol sulfate according to claim 1, characterized in that, In step (4), the molar ratio of compound 3 to reducing agent is 1:2-5; the reaction temperature is 20-25℃ 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 step (5), the alkaline solution is any one of sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium bicarbonate, potassium carbonate, and potassium hydroxide; the amount of 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℃, and the reaction time is 2-4 h.

9. The method for preparing salbutamol sulfate according to claim 1, characterized in that, In step (6), the temperature is lowered to 0-10℃ and the reaction is carried out for 2-4 hours.

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