Preparation method of salbutamol

Abstract

The invention relates to the technical field of synthesis of pharmaceutical compounds, and particularly discloses a preparation method of salbutamol. According to the invention, salicylaldehyde is used as an initial raw material, and bromination, reduction and dihydroxyl protection are carried out to obtain a compound of formula (IV); the preparation method comprises the following steps: by taking methyl bromoacetate as a raw material, reacting with N-benzyl tert-butylamine, hydrolyzing methyl, and reacting with morpholine to obtain a compound shown as a formula (VIII); and reacting the compound shown in the formula (IV) with a compound shown in a formula (VIII), and carrying out reduction, hydrolysis deprotection and debenzylation to obtain salbutamol. The preparation method provided by the invention has the advantages of simple and easily available raw materials, mild reaction conditions and simple reaction operation, and does not need to use flammable and explosive dangerous goods and chemicals with higher toxicity; used raw materials, solvents and the like are environment-friendly; the prepared salbutamol is high in yield, easy to purify and high in product purity.

Description

Technical Field

[0001] The present invention relates to the technical field of synthesis of pharmaceutical compounds, in particular to a method for preparing salbutamol. Background Art

[0002] Salbutamol, chemical formula C 13 H 21 NO3 is a short-acting β2-adrenergic receptor agonist used as an antiasthmatic. It effectively inhibits the release of allergenic substances such as histamine and prevents bronchospasm. It is suitable for bronchial asthma, asthmatic bronchitis, bronchospasm, emphysema, and other conditions. Salbutamol is clinically effective and highly safe.

[0003] The early domestic preparation method of salbutamol was to use p-hydroxyacetophenone as the starting material to prepare salbutamol. The process route is as follows:

[0004]

[0005] This synthesis method has the problems of outdated process, many side reactions and by-products, low yield, and difficult purification. In addition, bromine is used in the bromination reaction during the preparation process, which is highly toxic.

[0006] Patent application publication number CN 103951568A provides a new process for synthesizing salbutamol and its sulfate, the process route being:

[0007]

[0008] This method uses p-hydroxybenzaldehyde as the starting material, and the subsequent process reactions are complex, contain many impurities, and are difficult to purify, making it unsuitable for large-scale industrial production.

[0009] The following synthesis route of salbutamol was reported in Tetrahedron Letters in 2020:

[0010]

[0011] The process uses methyl 5-acetylsalicylate as raw material, which is expensive and has high production costs. Red aluminum is used in the reduction of the ester, which easily absorbs water and produces a large amount of ethylene glycol monomethyl ether after quenching, increasing the treatment cost of the three wastes. At the same time, the sodium aluminate produced is difficult to filter, so it is not suitable for large-scale industrial production.

[0012] Based on the above situation, providing a low-cost, green and efficient method for preparing salbutamol to solve the defects in the current preparation process has become a technical problem that needs to be solved urgently. Summary of the Invention

[0013] The main technical problem solved by the present invention is to provide a preparation method of salbutamol.

[0014] In order to solve the above technical problems, the technical solution adopted by the present invention is: a preparation method of salbutamol, the reaction formula of the preparation method includes:

[0015]

[0016]

[0017] The preparation method comprises the following steps:

[0018] S1: Preparation of compound of formula (IV)

[0019] S1-1: contacting the compound represented by formula (I) with N-bromosuccinimide (NBS) to obtain the compound represented by formula (II);

[0020] S1-2: The compound represented by formula (II) reacts with reducing agent 1 in a solvent to obtain the compound represented by formula (III);

[0021] S1-3: The compound represented by formula (III) reacts with 2,2-dimethoxypropane in the presence of an organic acid to obtain a compound represented by formula (IV);

[0022] S2: Preparation of compound of formula (VIII)

[0023] S2-1: contacting the compound represented by formula (V) with N-benzyl tert-butylamine to obtain the compound represented by formula (VI);

[0024] S2-2: reacting the compound represented by formula (VI) in the presence of a base to obtain the compound represented by formula (VII);

[0025] S2-3: Add the compound represented by formula (VII) to a solvent, add morpholine and a condensing agent, and stir to react to obtain the compound represented by formula (VIII);

[0026] S3: Preparation of compound of formula (XII)

[0027] S3-1: Under an inert gas atmosphere, the compound represented by formula (IV) is added to a solvent, a Grignard reagent is added, and then the compound represented by formula (VIII) is added, and the mixture is stirred to react to obtain a compound represented by formula (X);

[0028] S3-2: reacting the compound represented by formula (X) with reducing agent 2, extracting after completion of the reaction, concentrating the organic phase obtained by extraction to obtain an organic phase concentrate; adding acid to the organic phase concentrate, stirring, and adjusting the pH to 8-10 to obtain a compound represented by formula (XI);

[0029] S3-3: The compound represented by formula (XI) is contacted with hydrogen in the presence of a catalyst to react to obtain the compound represented by formula (XII), namely salbutamol.

[0030] As an embodiment of the present invention, in step S1-1, the molar ratio of the N-bromosuccinimide to the compound represented by formula (I) is (1.05-1.5):1.

[0031] As an embodiment of the present invention, in step S1-2, the reducing agent 1 is selected from at least one of sodium borohydride, potassium borohydride, and lithium aluminum tetrahydride.

[0032] As an embodiment of the present invention, the molar ratio of the reducing agent 1 to the compound represented by formula (II) is (1.5-2):1,

[0033] As an embodiment of the present invention, in step S1-3, the organic acid is selected from p-toluenesulfonic acid and / or trifluoroacetic acid.

[0034] As an embodiment of the present invention, the molar ratio of the organic acid to the compound represented by formula (III) is (1.5-2):1.

[0035] As an embodiment of the present invention, the molar ratio of the 2,2-dimethoxypropane to the compound represented by formula (III) is (1.1-1.5):1.

[0036] As an embodiment of the present invention, in step S2-1, the molar ratio of N-benzyl tert-butylamine to the compound represented by formula (V) is (1.05-1.5):1.

[0037] As an embodiment of the present invention, in step S2-2, the base is selected from at least one of sodium hydroxide, potassium hydroxide, and sodium carbonate.

[0038] As an embodiment of the present invention, the molar ratio of the base to the compound represented by formula (VI) is (1.45-2):1.

[0039] As an embodiment of the present invention, in step S2-3, the condensing agent is selected from at least one of DCC (dicyclohexylcarbodiimide), DIC (N,N'-diisopropylcarbodiimide), and EDCI.

[0040] As an embodiment of the present invention, the molar ratio of morpholine to the compound represented by formula (VII) is (1.05-1.5):1.

[0041] As an embodiment of the present invention, the molar ratio of the condensing agent to the compound represented by formula (VII) is (1.05-1.5):1.

[0042] As an embodiment of the present invention, in step S3-1, the Grignard reagent is selected from isopropylmagnesium chloride and / or n-butyllithium.

[0043] As an embodiment of the present invention, the molar ratio of the compound represented by formula (VIII) to the compound represented by formula (IV) is (0.95-1.3):1.

[0044] As an embodiment of the present invention, the molar ratio of the Grignard reagent to the compound represented by formula (IV) is (1.1-1.5):1.

[0045] As an embodiment of the present invention, in step S3-2, the reducing agent 2 is selected from at least one of sodium borohydride, potassium borohydride, sodium triacetoxyborohydride, and sodium cyanoborohydride.

[0046] As an embodiment of the present invention, the molar ratio of the reducing agent 2 to the compound represented by formula (X) is (1.5-2):1.

[0047] As an embodiment of the present invention, the acid solution is a dilute hydrochloric acid aqueous solution, and the molar ratio of hydrochloric acid to the compound represented by formula (X) in the dilute hydrochloric acid aqueous solution is (3-5):1.

[0048] As an embodiment of the present invention, an alkali solution is used to adjust the pH value, and the alkali solution contains at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and sodium bicarbonate.

[0049] As an embodiment of the present invention, in step S3-3, the catalyst is palladium carbon, and the mass ratio of the added mass of the catalyst to the compound represented by formula (XI) is (0.05-0.1):1.

[0050] As an embodiment of the present invention, in the above preparation process, the solvent used is selected from acetic acid, tetrahydrofuran (THF), butanol, methanol, toluene, and N,N-dimethylformamide (DMF).

[0051] The preparation method of salbutamol provided by the present invention involves the following reaction formula:

[0052]

[0053]

[0054] When preparing the compound of formula (IV), salicylaldehyde (the compound represented by formula (I)) is used as a starting material, and the compound of formula (IV) is obtained by bromination with N-bromosuccinimide (NBS), reduction, and dihydroxy protection. When preparing the compound of formula (VIII), methyl bromoacetate (the compound represented by formula (V)) is used as a starting material, and the compound of formula (VIII) is obtained by reacting with N-benzyl tert-butylamine, hydrolyzing the methyl group, and reacting with morpholine. Thereafter, the compound of formula (IV) is reacted with the compound of formula (VIII), and then reduced, hydrolyzed, deprotected, and debenzylated to obtain salbutamol.

[0055] The preparation method provided by the present invention has readily available raw materials, mild reaction conditions, simple reaction operations, and does not require the use of flammable and explosive hazardous materials or highly toxic chemicals. The raw materials and solvents used are environmentally friendly. The yield of salbutamol is high, purification is easy, and the product is high in purity. The present invention provides a method for synthesizing salbutamol that can be industrially produced and is high in quality, suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1 This is the H NMR spectrum of the target compound salbutamol synthesized in Example 1 of the present invention. DETAILED DESCRIPTION

[0057] The following examples are intended to further illustrate the present invention, but are not intended to limit the scope of protection of the present invention.

[0058] In the following examples, unless otherwise specified, all reagents used are commercially available products.

[0059] In the following examples, unless otherwise specified, the experimental methods used are conventional experimental methods.

[0060] Example 1

[0061] This embodiment provides a method for preparing salbutamol, and the reaction formula involved is as follows:

[0062]

[0063] The preparation process specifically includes the following steps:

[0064] S1. 100 g of the compound represented by formula (I) (0.819 mol) was added to 1000 mL of acetic acid, and then 219 g of N-bromosuccinimide (NBS, 1.228 mol) was added. The mixture was refluxed at 80 ° C for 3 h. The reaction was completed by TLC detection. The reaction system was cooled to room temperature, and water and ethyl acetate were added for extraction. The organic phase was dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 161.3 g of the compound represented by formula (II) (0.802 mol).

[0065] S2. 161.3 g of the compound represented by formula (II) (0.802 mol) was added to 1600 mL of THF, and then 60.7 g of sodium borohydride (1.605 mol) was added. The mixture was stirred at room temperature for 3 h. The reaction was detected to be complete by TLC. Water and ethyl acetate were added to the reaction system for extraction. The organic phase was dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 151.5 g of the compound represented by formula (III) (0.746 mol).

[0066] S3. Add 151.5 g of the compound represented by formula (III) (0.746 mol) to 1500 mL of THF, and then add 257 g of p-toluenesulfonic acid (1.493 mol) and 117 g of 2,2-dimethoxypropane (1.119 mol) dropwise in sequence. Stir at 50°C for 3 h. The reaction is complete after TLC detection. The reaction system is cooled to room temperature, and water and ethyl acetate are added for extraction. The organic phase is dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 172.4 g of the compound represented by formula (IV) (0.709 mol).

[0067] S4. Add 100 g of the compound represented by formula (V) (0.654 mol) to 1000 mL of butanol, then add 160 g of N-benzyl tert-butylamine (0.981 mol), and stir at 30 ° C for 3 h. The reaction is complete when detected by TLC. Water and ethyl acetate are added to the reaction system for extraction. The organic phase is dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 136.9 g of the compound represented by formula (VI) (0.582 mol).

[0068] S5. 136.9 g of the compound represented by formula (VI) (0.582 mol) was added to 1400 mL of methanol, and then an aqueous solution containing 47 g of sodium hydroxide (1.163 mol) was slowly added. The mixture was stirred at 50° C. for 3 h. The reaction was completed by TLC detection. The reaction system was cooled to room temperature, and water and ethyl acetate were added for extraction. The organic phase was dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 115.9 g of the compound represented by formula (VII) (0.524 mol).

[0069] S6. Add 115.9 g of the compound represented by formula (VII) (0.524 mol) obtained to 1200 mL of toluene, cool the system to 0-10°C, add 68 g of morpholine (0.785 mol) dropwise, control the temperature within 0-10°C during the addition, add 162 g of N,N'-dicyclohexylcarbodiimide (DCC, 0.785 mol) after the addition is complete, naturally warm to room temperature and stir for 13 hours. TLC detection shows that the reaction is complete, then add water and ethyl acetate for extraction, dry the organic phase with anhydrous sodium sulfate, spin dry, and column chromatography to obtain 132.3 g of the compound represented by formula (VIII) (0.456 mol).

[0070] S7. Under a nitrogen atmosphere, 80 g of the compound represented by formula (IV) (0.329 mol) was added to 1000 mL of tetrahydrofuran, and the system was cooled to about -60°C. Then, 247 mL of isopropylmagnesium chloride (0.493 mol) was added dropwise, and the mixture was stirred at this temperature for 1 hour. Then, 124 g of the compound represented by formula (VIII) (0.428 mol) was added dropwise, and the mixture was stirred for 4 hours. The reaction was detected to be complete by TLC. The reaction solution was then slowly poured into water to quench the reaction, and ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 96.7 g of the compound represented by formula (X) (0.263 mol).

[0071] S8. 96.7 g of the compound represented by formula (X) (0.263 mol) was added to 1000 mL of methanol, and then 20 g of sodium borohydride (0.527 mol) was added. The mixture was stirred at room temperature for 3 h. The reaction was completed by TLC detection. Water and ethyl acetate were added to the system for extraction. The organic phase was concentrated and added to 444 mL of 3 M dilute hydrochloric acid aqueous solution (1.316 mol). The mixture was stirred at room temperature for 2 h, and then the pH was adjusted to 8.9 with 10 wt % sodium hydroxide aqueous solution. Ethyl acetate was added for extraction, and the organic phase was dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 78.9 g of the compound represented by formula (XI) (0.240 mol).

[0072] S9, 78.9g of the compound represented by formula (XI) (0.240mol) was added to 800mL of methanol, and 8g of palladium carbon was added under a nitrogen atmosphere, and then hydrogen was replaced. The mixture was stirred at room temperature for 12h. The reaction was complete when detected by TLC. The reaction solution was filtered and then concentrated. Water and ethyl acetate were added for extraction. The organic phase was dried over anhydrous sodium sulfate, dried by spin drying, and subjected to column chromatography to obtain 52.7g of the compound represented by formula (XII) (0.220mol), i.e., salbutamol. The nuclear magnetic hydrogen spectrum of salbutamol is shown in FIG. Figure 1 shown.

[0073] Example 2

[0074] This embodiment provides a method for preparing salbutamol. The reaction formula involved is the same as that in Example 1. The preparation process specifically includes the following steps:

[0075] S1. 100 g of the compound represented by formula (I) (0.819 mol) was added to 1000 mL of acetic acid, and then 160 g of N-bromosuccinimide (NBS, 0.9 mol) was added. The mixture was refluxed at 80° C. for 3 h. The reaction was completed by TLC detection. The reaction system was cooled to room temperature, and water and ethyl acetate were added for extraction. The organic phase was dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 156.4 g of the compound represented by formula (II) (0.778 mol).

[0076] S2. 156.4 g of the compound represented by formula (II) (0.778 mol) was added to 1600 mL of THF, and then 44 g of sodium borohydride (1.167 mol) was added. The mixture was stirred at room temperature for 3 h. The reaction was completed by TLC detection. Water and ethyl acetate were added to the reaction system for extraction. The organic phase was dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 140.6 g of the compound represented by formula (III) (0.692 mol).

[0077] S3. 140.6 g of the compound represented by formula (III) (0.692 mol) was added to 1400 mL of THF, and 179 g of p-toluenesulfonic acid (1.039 mol) and 79 g of 2,2-dimethoxypropane (0.762 mol) were added dropwise in sequence. The mixture was stirred at 50°C for 3 h. The reaction was completed after TLC detection. The reaction system was cooled to room temperature, and water and ethyl acetate were added for extraction. The organic phase was dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 153.2 g of the compound represented by formula (IV) (0.63 mol).

[0078] S4. Add 100 g of the compound represented by formula (V) (0.654 mol) to 1000 mL of butanol, then add 117 g of N-benzyl tert-butylamine (0.719 mol), and stir at 30 ° C. for 3 h. The reaction is complete when detected by TLC. Water and ethyl acetate are added to the reaction system for extraction. The organic phase is dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 130.8 g of the compound represented by formula (VI) (0.556 mol).

[0079] S5. 130.8 g of the compound represented by formula (VI) (0.556 mol) was added to 1300 mL of methanol, and then an aqueous solution containing 33 g of sodium hydroxide (0.833 mol) was slowly added. The mixture was stirred at 50° C. for 3 h. The reaction was completed by TLC detection. The reaction system was cooled to room temperature, and water and ethyl acetate were added for extraction. The organic phase was dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 109.4 g of the compound represented by formula (VII) (0.495 mol).

[0080] S6. Add 109.4 g of the compound represented by formula (VII) (0.495 mol) obtained to 1100 mL of toluene, cool the system to 0-10°C, add 47 g of morpholine (0.544 mol) dropwise, and control the temperature within 0-10°C during the addition process. Then add 112 g of N,N'-dicyclohexylcarbodiimide (0.544 mol). After the addition is completed, naturally warm to room temperature and stir for 13 hours. TLC detection shows that the reaction is complete. Water and ethyl acetate are added to the reaction system for extraction. The organic phase is dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 119.2 g of the compound represented by formula (VIII) (0.41 mol).

[0081] S7. Under a nitrogen atmosphere, 80 g of the compound represented by formula (IV) (0.329 mol) was added to 1500 mL of tetrahydrofuran, the system was cooled to about -60°C, and then 181 mL of isopropylmagnesium chloride (0.362 mol) was added dropwise. The mixture was stirred at this temperature for 1 hour, and then 97 g of the compound represented by formula (VIII) (0.322 mol) was added dropwise. The mixture was stirred for 4 hours. The reaction was detected to be complete by TLC. The reaction solution was then slowly poured into water to quench the mixture, and then ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 95.5 g of the compound represented by formula (X) (0.26 mol).

[0082] S8. 95.5 g of the compound represented by formula (X) (0.26 mol) was added to 1000 mL of methanol, and then 15 g of sodium borohydride (0.39 mol) was added. The mixture was stirred at room temperature for 3 h. The reaction was completed by TLC detection. Water and ethyl acetate were added to the reaction system for extraction. The organic phase was concentrated and added to 260 mL of 3 M dilute hydrochloric acid aqueous solution (0.78 mol). The mixture was stirred at room temperature for 2 h, and then the pH was adjusted to 9.1 with 10 wt % sodium hydroxide aqueous solution. Ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 71.1 g of the compound represented by formula (XI) (0.216 mol).

[0083] S9. Add 71.1 g of the compound represented by formula (XI) (0.216 mol) to 800 mL of methanol, add 3.6 g of palladium carbon under a nitrogen atmosphere, and then replace the hydrogen. Stir at room temperature for 12 hours. TLC detection shows that the reaction is complete. The reaction liquid is filtered and concentrated, and then water and ethyl acetate are added for extraction. The organic phase is dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 41.8 g of the compound represented by formula (XII) (0.175 mol), i.e., salbutamol.

[0084] Example 3

[0085] This embodiment provides a method for preparing salbutamol. The reaction formula involved is the same as that in Example 1. The preparation process specifically includes the following steps:

[0086] S1. 100 g of the compound represented by formula (I) (0.819 mol) was added to 1000 mL of acetic acid, followed by the addition of 189 g of N-bromosuccinimide (NBS, 1.065 mol), and the mixture was refluxed at 80 ° C for 3 h. The reaction was completed by TLC detection. The reaction system was cooled to room temperature, extracted with water and ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 158 g of the compound represented by formula (II) (0.786 mol).

[0087] S2. 158 g of the compound represented by formula (II) (0.786 mol) was added to 1600 mL of THF, and then 60 g of lithium aluminum tetrahydride (1.572 mol) was added. The mixture was stirred at room temperature for 3 h. The reaction was completed by TLC detection. Water and ethyl acetate were added to the reaction system for extraction. The organic phase was dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 140.5 g of the compound represented by formula (III) (0.692 mol).

[0088] S3. 140.5 g of the compound represented by formula (III) (0.692 mol) was added to 1400 mL of THF, and 158 g of trifluoroacetic acid (1.384 mol) and 108 g of 2,2-dimethoxypropane (1.038 mol) were added dropwise in sequence. The mixture was stirred at 50° C. for 3 h. The reaction was completed by TLC detection. The reaction system was cooled to room temperature, and water and ethyl acetate were added for extraction. The organic phase was dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 156.4 g of the compound represented by formula (IV) (0.643 mol).

[0089] S4. Add 100 g of the compound represented by formula (V) (0.654 mol) to 1000 mL of butanol, then add 139 g of N-benzyl tert-butylamine (0.85 mol), and stir at 30 ° C for 3 h. The reaction is complete when detected by TLC. Water and ethyl acetate are added to the reaction system for extraction. The organic phase is dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 134.6 g of the compound represented by formula (VI) (0.572 mol).

[0090] S5. 134.6 g of the compound represented by formula (VI) (0.572 mol) was added to 1400 mL of methanol, and then an aqueous solution containing 121 g of sodium carbonate (1.144 mol) was slowly added. The mixture was stirred at 50° C. for 3 h. The reaction was detected to be complete by TLC. The reaction system was cooled to room temperature, and water and ethyl acetate were added for extraction. The organic phase was dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 110.1 g of the compound represented by formula (VII) (0.498 mol).

[0091] S6. Add 110.1 g of the compound represented by formula (VII) (0.498 mol) obtained to 1100 mL of toluene, cool the system to 0-10°C, add 56 g of morpholine (0.647 mol) dropwise, and control the temperature within 0-10°C during the addition process. Then add 94 g of N,N'-diisopropylcarbodiimide (DIC, 0.746 mol). After the addition is completed, naturally warm to room temperature and stir for 13 hours. TLC detection shows that the reaction is complete. Then, water and ethyl acetate are added for extraction. The organic phase is dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 124.3 g of the compound represented by formula (VIII) (0.428 mol).

[0092] S7. Under a nitrogen atmosphere, 80 g of the compound represented by formula (IV) (0.329 mol) was added to 800 mL of tetrahydrofuran, the system was cooled to about -60°C, and then 197 mL of n-butyllithium (0.494 mol) was added dropwise. The mixture was stirred at this temperature for 1 hour, and then 124 g of the compound represented by formula (VIII) (0.428 mol) was added dropwise. The mixture was stirred at room temperature for 5 hours. The reaction was detected to be complete by TLC. The reaction solution was then slowly poured into water to quench the mixture, and then ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 88.3 g of the compound represented by formula (X) (0.24 mol).

[0093] S8. 88.3 g of the compound represented by formula (X) (0.24 mol) was added to 900 mL of methanol, and 26 g of potassium borohydride (0.48 mol) was added. The mixture was stirred at room temperature for 3 h. The reaction was completed by TLC detection. Water and ethyl acetate were added to the reaction system for extraction. The organic phase was concentrated and added to 400 mL of 3 M dilute hydrochloric acid aqueous solution (1.201 mol). The mixture was stirred at room temperature for 2 h, and then 10 wt % sodium hydroxide aqueous solution was added to adjust the pH to 9.5. Ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 67.3 g of the compound represented by formula (XI) (0.204 mol).

[0094] S9. Add 67.3 g of the compound represented by formula (XI) (0.204 mol) to 700 mL of methanol, add 5.4 g of palladium carbon under a nitrogen atmosphere, and then replace the hydrogen. Stir at room temperature for 12 hours. TLC detection shows that the reaction is complete. The reaction solution is filtered and concentrated, and then water and ethyl acetate are added for extraction. The organic phase is dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 41 g of the compound represented by formula (XII) (0.172 mol), i.e., salbutamol.

[0095] The above descriptions are merely embodiments of the present invention and are not intended to limit the patent scope of the present invention. Any equivalent transformations made using the contents of the present invention specification, or any direct or indirect application in other related technical fields, are included in the patent protection scope of the present invention.

Claims

1. A method for preparing salbutamol, characterized in that: The reaction formula of the preparation method includes: The preparation method comprises the following steps: S1: Preparation of compound of formula (IV) S1-1: contacting the compound represented by formula (I) with N-bromosuccinimide to obtain a compound represented by formula (II); S1-2: The compound represented by formula (II) reacts with a reducing agent 1 in a solvent to obtain a compound represented by formula (III); S1-3: The compound represented by formula (III) reacts with 2,2-dimethoxypropane in the presence of an organic acid to obtain a compound represented by formula (IV); S2: Preparation of compound of formula (VIII) S2-1: contacting the compound represented by formula (V) with N-benzyl tert-butylamine to obtain a compound represented by formula (VI); S2-2: reacting the compound represented by formula (VI) in the presence of a base to obtain a compound represented by formula (VII); S2-3: adding the compound represented by formula (VII) to a solvent, adding morpholine and a condensing agent, and stirring to react to obtain a compound represented by formula (VIII); S3: Preparation of compound of formula (XII) S3-1: Under an inert gas atmosphere, the compound represented by formula (IV) is added to a solvent, a Grignard reagent is added, and then the compound represented by formula (VIII) is added, and the mixture is stirred to react to obtain a compound represented by formula (X); S3-2: reacting the compound represented by formula (X) with reducing agent 2, extracting after the reaction, concentrating the organic phase obtained by extraction to obtain an organic phase concentrate; adding acid solution to the organic phase concentrate, stirring and adjusting the pH value to 8-10 to obtain a compound represented by formula (XI); S3-3: The compound represented by formula (XI) is contacted with hydrogen in the presence of a catalyst to obtain a compound represented by formula (XII), namely salbutamol.

2. The preparation method according to claim 1, characterized in that: In step S1-1, the molar ratio of the N-bromosuccinimide to the compound represented by formula (I) is (1.05-1.5):

1.

3. The preparation method according to claim 1, characterized in that: In step S1-2, the reducing agent 1 is selected from at least one of sodium borohydride, potassium borohydride, and lithium aluminum tetrahydride; and / or the molar ratio of the reducing agent 1 to the compound represented by formula (II) is (1.5-2):

1.

4. The preparation method according to claim 1, characterized in that: In step S1-3, the organic acid is selected from p-toluenesulfonic acid and / or trifluoroacetic acid; and / or, The molar ratio of the organic acid to the compound represented by formula (III) is (1.5-2):1, and / or, The molar ratio of the 2,2-dimethoxypropane to the compound represented by formula (III) is (1.1-1.5):

1.

5. The preparation method according to claim 1, characterized in that: In step S2-1, the molar ratio of N-benzyl tert-butylamine to the compound represented by formula (V) is (1.05-1.5):

1.

6. The preparation method according to claim 1, characterized in that: In step S2-2, the base is selected from at least one of sodium hydroxide, potassium hydroxide and sodium carbonate; and / or, The molar ratio of the base to the compound represented by formula (VI) is (1.45-2):

1.

7. The preparation method according to claim 1, characterized in that: In step S2-3, the condensing agent is selected from at least one of DCC, DIC, and EDCI; and / or, The molar ratio of morpholine to the compound represented by formula (VII) is (1.05-1.5):1; and / or, The molar ratio of the condensing agent to the compound represented by formula (VII) is (1.05-1.5):

1.

8. The preparation method according to claim 1, characterized in that: In step S3-1, the Grignard reagent is selected from isopropylmagnesium chloride and / or n-butyllithium; and / or, The molar ratio of the compound represented by formula (VIII) to the compound represented by formula (IV) is (0.95-1.3):1; and / or, The molar ratio of the Grignard reagent to the compound represented by formula (IV) is (1.1-1.5):

1.

9. The preparation method according to claim 1, characterized in that: In step S3-2, the reducing agent 2 is selected from at least one of sodium borohydride, potassium borohydride, sodium triacetoxyborohydride, and sodium cyanoborohydride; and / or, The molar ratio of the reducing agent 2 to the compound represented by formula (X) is (1.5-2):1; and / or, The acid solution is a dilute hydrochloric acid aqueous solution, wherein the molar ratio of hydrochloric acid to the compound represented by formula (X) in the dilute hydrochloric acid aqueous solution is (3-5):1; and / or, The pH value is adjusted by using an alkali solution, wherein the alkali solution contains at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium bicarbonate.

10. The preparation method according to claim 1, characterized in that: In step S3-3, the catalyst is palladium carbon, and the mass ratio of the added mass of the catalyst to the compound represented by formula (XI) is (0.05-0.1):1.

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