A process for the synthesis of salbutamol sulfate

Abstract

The application discloses a method for synthesizing salbutamol sulfate, and belongs to the technical field of organic chemical synthesis. The method comprises the following steps: (1) subjecting methyl salicylate to a Friedel-Crafts acylation reaction to generate an intermediate 1; (2) subjecting the intermediate 1 to a substitution reaction with t-butylamine to generate an intermediate 2; (3) subjecting the intermediate 2 to a reduction reaction to generate an intermediate 3, i.e. the synthesis of salbutamol; and (4) subjecting the salbutamol to salt formation with concentrated sulfuric acid to generate the salbutamol sulfate. The method for synthesizing the salbutamol sulfate has shortened process steps, simple and easily-obtained raw materials, and eliminates multi-step column chromatography, thereby reducing the cost and avoiding high-pressure hydrogenation reaction, so that a high-pressure kettle is not needed, common production equipment can be used, the reaction condition is mild, and the industrialized production is facilitated.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis technology, specifically relating to a method for synthesizing salbutamol sulfate. Background Technology

[0002] Salbutamol sulfate, chemically known as 1-(4-hydroxy-3-hydroxymethylphenyl)-2-(tert-butylamino)ethanol sulfate, was originally developed by GlaxoSmithKline in the UK as a potent and fast-acting β2 receptor agonist. It was first approved for marketing in the UK in 1968 and registered in my country in 1988. Today, it is sold worldwide under multiple brand names and is the first-line drug for the clinical treatment of bronchial asthma, chronic obstructive pulmonary disease, and wheezing bronchitis.

[0003] Currently, there are many reported synthetic methods for salbutamol sulfate, mainly including the following synthetic routes:

[0004] US patent application US5283359 discloses the following synthetic route:

[0005]

[0006] Although this route shortens the process steps compared to the original research, the use of dimethyl sulfoxide (DMSO) oxidation to obtain compound 3 does not protect the phenolic hydroxyl group of compound 2, leading to the potential for oxidation impurities. Furthermore, the synthesis of compound 5 involves the reduction of salicylate using highly toxic and explosive borane dimethyl sulfide water, requiring strict control over safety and toxicity during production. This method also presents harsh reaction conditions, causes significant waste pollution, and is costly.

[0007] US Patent 5399765 discloses the following synthetic route:

[0008]

[0009] This route uses methyl 2-benzyl ether-5-acetylbenzoate as a starting material and proceeds through six steps: hydroxylation, amination, reduction, chiral resolution, hydrolysis, and reduction. The hydrobromic acid / DMSO oxidation system used in this synthetic route generates dimethyl sulfide, which poses certain environmental and health hazards. This route also uses borane dimethyl sulfide, which is difficult to handle; the addition of a benzyl group to the benzene ring increases the deprotection step; the production cycle is long; energy consumption is high; waste is generated in large quantities; and the overall yield is extremely low, resulting in very high production costs and making it unsuitable for industrial production.

[0010] Chinese patent CN108863819 discloses the following synthetic route:

[0011]

[0012] This route uses methyl salicylate as a starting material and involves seven steps: Friedel-Crafts acylation, hydroxylation, amination, two-step reduction, cyclization, and ring-opening. This synthetic route has many steps and is relatively complex, requiring two consecutive reduction reactions. The hydrobromic acid reaction used for hydroxylation is difficult to control, and the purification process is also complex.

[0013] In summary, all the above synthetic routes have problems such as cumbersome process steps, complicated operation, low yield, difficulty in removing impurities or high toxicity, and high-risk reactions such as pressurized hydrogenation. Therefore, the development of a new salbutamol sulfate synthesis process is of great significance to enterprises and society. Summary of the Invention

[0014] The main objective of this invention is to provide a method for synthesizing salbutamol sulfate, thereby overcoming the technical shortcomings of existing synthesis processes, such as heavy metal pollution, cumbersome process steps, complex operation, and low yield.

[0015] To achieve the above-mentioned technical objectives, the technical solution adopted by the present invention is as follows:

[0016] A method for synthesizing salbutamol sulfate includes the following steps:

[0017] (1) Preparation of intermediate 1: Catalyst AlCl3 and organic solvent A were added to a reaction flask, heated and stirred, and then acylation reagent bromoacetyl bromide dichloromethane solution was added dropwise. After stirring and maintaining the temperature for 1 h, methyl salicylate dichloromethane solution was added dropwise, and the reaction was continued at the temperature. After the reaction was completed, intermediate 1 was obtained by purification. The structural formula of intermediate 1 is as follows:

[0018] (2) Preparation of intermediate 2: Intermediate 1 was dissolved in organic solvent B. Under nitrogen protection, tert-butylamine was added dropwise at the adjusted reaction temperature. The mixture was then stirred and heated to allow for a substitution reaction. TLC monitoring was maintained until the reaction was complete. The mixture was then cooled to allow crystallization, stirred, and finally filtered and dried to constant weight to obtain intermediate 2. The structural formula of intermediate 2 is as follows:

[0019] (3) Intermediate 3: Intermediate 2 was dissolved in organic solvent C, cooled to -10-0℃, a reducing agent was added, and the reaction was carried out under controlled temperature. Then, purified water and alkaline solution were added, the temperature was raised, and the mixture was stirred. After the reaction was completed, the crude salbutamol was separated and purified to obtain crude salbutamol. Then, a mixed solvent was added to the crude salbutamol for recrystallization, and the mixture was filtered and dried to obtain intermediate 3, salbutamol. The chemical structural formula of intermediate 3 is as follows:

[0020] (4) Preparation of salbutamol sulfate: Dissolve the obtained salbutamol in mixed solvent D and heat to 50-55℃. Slowly add concentrated sulfuric acid. After the addition is complete, cool down to allow crystals to precipitate and stir the reaction. After the reaction is complete, filter and dry to obtain salbutamol sulfate.

[0021] Preferably, in step (1), the molar ratio of catalyst, methyl salicylate and bromoacetyl bromide is (3-4):1:(1.2-1.3); the concentration of bromoacetyl bromide dichloromethane solution is 2-2.2 g / mL; and the concentration of methyl salicylate dichloromethane solution is 1.2-1.4 g / mL.

[0022] Preferably, in step (1), the organic solvent A is dichloromethane; the temperature is raised to 40-45°C and stirred; the heat preservation reaction is carried out at 40-45°C for 10 hours.

[0023] Preferably, the purification method for intermediate 1 is recrystallization or pulping purification using one or more of the following solvents: ethyl acetate, acetonitrile, acetone, petroleum ether, n-hexane, and n-heptane. More preferably, recrystallization is performed using ethyl acetate / n-hexane.

[0024] Preferably, in step (2), the organic solvent B is any one of ethanol, isopropanol, and tetrahydrofuran; the molar ratio of intermediate 1 to tert-butylamine is 1:1-4; the reaction temperature is 10-15℃; the stirring temperature is raised to 45-50℃, kept warm and stirred for 3h, and the reaction is monitored by TLC until the reaction is complete, then cooled to 20-25℃ and stirred for 5h.

[0025] More preferably, in step (2), the organic solvent B is isopropanol.

[0026] Preferably, in step (3), the organic solvent C is tetrahydrofuran; the molar ratio of intermediate 2 to reducing agent is 1:1-3; the temperature-controlled reaction temperature is -10 to 5°C, and the reaction time is 2 hours.

[0027] Preferably, the reducing agent in step (3) is one of potassium borohydride, sodium borohydride, and lithium aluminum hydride; the mass ratio of intermediate 2, purified water, and alkaline solution is (40-60)g:(34-39)g:(11-13)g; the internal temperature is controlled at 0-10℃ during the dropwise addition of purified water and alkaline solution, and after the dropwise addition is completed, the temperature is raised to 20-30℃ and stirred for 1h.

[0028] Preferably, the separation and purification of crude salbutamol in step (3) is as follows: anhydrous sodium sulfate is added, the mixture is filtered, the filter cake is washed twice with tetrahydrofuran, and the filtrate is concentrated to dryness under reduced pressure.

[0029] More preferably, the reducing agent in step (4) is lithium aluminum hydride.

[0030] More preferably, the alkaline solution is a 15% sodium hydroxide solution.

[0031] Preferably, the mixed solvent in the recrystallization process of step (3) is isopropanol and ethyl acetate in a volume ratio of 1:1.

[0032] Preferably, in step (3), the recrystallization process is cooled to 0-5°C and kept at that temperature for 3 hours to allow crystals to precipitate.

[0033] Preferably, in step (4), the mixed solvent D is a mixed solution of water and alcohol, and the volume ratio of water to alcohol is 1:8-1:10; in step (4), the crystallization temperature is lowered to 0-10℃ and stirred for 2-3 hours.

[0034] More preferably, in step (4), the alcohol in the mixed solvent D is one of methanol, ethanol, and isopropanol.

[0035] The reaction route diagram of this invention is as follows:

[0036]

[0037] Beneficial effects

[0038] The method for synthesizing salbutamol sulfate in this invention has shortened the process steps, uses inexpensive and readily available raw materials, avoids the use of bromine and hydrogenation reaction in the original patent, simplifies the process operation, has mild reaction conditions, high total molar yield, is environmentally friendly, has low equipment requirements, reduces production costs, and is more suitable for industrial production. Attached Figure Description

[0039] Figure 1 This is the HPLC purity analysis chromatogram of salbutamol sulfate synthesized in Example 1 of the present invention. Detailed Implementation

[0040] The technical solution of the present invention will be further described below with reference to specific embodiments, but it is not limited thereto.

[0041] Example 1

[0042] A method for synthesizing salbutamol sulfate includes the following steps:

[0043] (1) Preparation of intermediate 1

[0044] 105.16 g of anhydrous AlCl3 and 240 ml of dichloromethane were added to a reaction flask. The temperature was raised to 40–45 °C and stirred. A mixed solution of 63.68 g of bromoacetyl bromide and 30 ml of dichloromethane was added dropwise. After the addition was completed, the mixture was kept warm and stirred for 1.0 h. Then, 40 g of methyl salicylate and 30 ml of dichloromethane were added dropwise. The mixture was kept warm at 40–45 °C and reacted for 10 h.

[0045] HPLC and TLC were used to monitor the reaction until it was complete. The reaction solution was slowly added dropwise to a mixture of 800 ml ice water and 200 ml dichloromethane with stirring. The pH was adjusted to 1.0–3.0 with concentrated hydrochloric acid. The mixture was stirred at 20–25 °C for 1 h. The organic layer was separated. The aqueous layer was extracted twice with 200 ml of dichloromethane. The combined organic phases were washed with saturated brine. The organic phase was collected by separation and dried with anhydrous sodium sulfate for 30 min. The filtrate was filtered and evaporated to dryness. 264 ml of ethyl acetate was added and the mixture was heated until it was clear. 400 ml of n-hexane was added and stirred for 15 min. The mixture was cooled to 0–5 °C and stirred to induce crystallization. The crystals were filtered and dried to constant weight to obtain intermediate 1 with a yield of 86.8%.

[0046] (2) Preparation of intermediate 2

[0047] 50.00 g of intermediate 1 was added to 300 ml of isopropanol under nitrogen protection. The mixture was cooled to 10–15 °C, and 40.18 g of tert-butylamine was added dropwise. After the addition was complete, the mixture was heated in an oil bath with stirring, and the temperature was raised to 45–50 °C. The mixture was kept at this temperature and stirred for 3 hours. The reaction was monitored by TLC until complete. The temperature was then lowered to 20–25 °C and stirred for 5 hours. The mixture was filtered and dried to constant weight to obtain intermediate 2, with a yield of 83.2%.

[0048] (3) Preparation of intermediate 3

[0049] 40.00 g of intermediate 2 was added to 240 ml of tetrahydrofuran. The mixture was cooled to -10 to 0 °C and 11.44 g of lithium aluminum hydride was slowly added while maintaining the temperature at -10 to 0 °C during the addition. After the addition was completed, the mixture was reacted at -10 to 5 °C for 2 h. 34.32 g of purified water and 11.44 g of 15% sodium hydroxide solution were added dropwise to the reaction solution while maintaining the internal temperature at 0 to 10 °C during the addition. After the addition was completed, the reaction solution was heated to 20 to 30 °C and stirred for 1 h. Then anhydrous sodium sulfate was added, and the mixture was filtered. The filter cake was washed twice with tetrahydrofuran. The filtrate was concentrated to dryness under reduced pressure to obtain crude salbutamol. A mixed solvent of 120 ml isopropanol and 120 ml ethyl acetate was added to the crude product. The reaction solution was heated to reflux with stirring for 0.5 h, then cooled to 0 to 5 °C and kept at this temperature for 3 h to crystallize. The crystals were then filtered and dried to obtain salbutamol. The yield of the two steps was 78%.

[0050] (4) Preparation of salbutamol sulfate:

[0051] Add 250 ml of anhydrous ethanol and 25 ml of purified water to the reaction flask in sequence, then add 25.0 g of salbutamol, heat in an oil bath, raise the temperature to 50-55°C to dissolve, slowly add 5.12 g of concentrated sulfuric acid dropwise, cool to 0-10°C and stir for 3 h, filter and dry under vacuum to obtain salbutamol sulfate, with a yield of 94.6%.

[0052] Example 2

[0053] A method for synthesizing salbutamol sulfate includes the following steps:

[0054] (1) Preparation of intermediate 1

[0055] 10.33 g of anhydrous AlCl3 and 360 ml of dichloromethane were added to a reaction flask. The temperature was raised to 40–45 °C and stirred. 103.48 g of a mixed solution of bromoacetyl bromide and 50 ml of dichloromethane was added dropwise. After the addition was complete, the mixture was kept warm and stirred for 1.0 h. Then, 60 g of methyl salicylate and 50 ml of dichloromethane were added dropwise. The mixture was kept warm at 40–45 °C and reacted for 10 h.

[0056] HPLC and TLC were used to monitor the reaction until it was complete. The reaction solution was slowly added dropwise to a mixture of 1200 ml ice water and 300 ml dichloromethane with stirring. The pH was adjusted to 1.0–3.0 with concentrated hydrochloric acid. The mixture was stirred at 20–25 °C for 1 h. The organic layer was separated. The aqueous layer was extracted twice with 300 ml of dichloromethane (300 ml × 2). The combined organic phases were washed with saturated brine. The organic phase was collected by separation and dried with anhydrous sodium sulfate for 30 min. The filtrate was filtered and evaporated to dryness. 390 ml of ethyl acetate was added and the mixture was heated until it was clear. 600 ml of n-hexane was added and stirred for 15 min. The temperature was lowered to 0–5 °C and stirred to induce crystallization. The crystals were filtered and dried to constant weight to obtain 87.23 g of intermediate 1, with a yield of 85.4%.

[0057] (4) Preparation of intermediate 2

[0058] 80.00 g of intermediate 1 was added to 480 ml of tetrahydrofuran under nitrogen protection. The mixture was cooled to 10–15 °C, and 53.57 g of tert-butylamine was added dropwise. After the addition was complete, the mixture was heated in an oil bath with stirring, and the temperature was raised to 45–50 °C. The mixture was kept at this temperature and stirred for 3 hours. The reaction was monitored by TLC until complete. The temperature was then lowered to 20–25 °C and stirred for 5 hours. The mixture was filtered and dried to constant weight to obtain 61.40 g of intermediate 2, with a yield of 80.2%.

[0059] (5) Preparation of intermediate 3

[0060] 60.00 g of intermediate 2 was added to 360 ml of tetrahydrofuran. The mixture was cooled to -10 to 0 °C and 12.87 g of lithium aluminum hydride was slowly added while maintaining the temperature at -10 to 0 °C during the addition. After the addition was completed, the mixture was reacted at -5 to 5 °C for 2 h. 38.61 g of purified water and 12.87 g of 15% sodium hydroxide solution were added dropwise to the reaction mixture while maintaining the internal temperature at 0 to 10 °C during the addition. After the addition was completed, the reaction mixture was heated to 20 to 30 °C and stirred for 1 h. Then anhydrous sodium sulfate was added, and the mixture was filtered. The filter cake was washed twice with tetrahydrofuran. The filtrate was concentrated to dryness under reduced pressure to obtain crude salbutamol. A mixed solvent of 171 ml isopropanol and 171 ml ethyl acetate was added to the crude product. The reaction mixture was heated to reflux with stirring for 0.5 h, then cooled to 0 to 5 °C and kept at this temperature for 3 h to crystallize. The crystals were then filtered and dried to obtain 40.19 g of salbutamol. The two-step yield was 76.3%.

[0061] (4) Preparation of salbutamol sulfate:

[0062] Add 320 ml of anhydrous ethanol and 40 ml of purified water to the reaction flask in sequence, then add 40.0 g of salbutamol, heat in an oil bath to 50-55 °C to dissolve, slowly add 8.19 g of concentrated sulfuric acid dropwise, cool to 0-10 °C and stir for 3 h, filter and dry under vacuum to obtain 43.37 g of salbutamol sulfate, yield 93.6%.

[0063] It should be noted that the above embodiments are merely some preferred embodiments of the present invention, and not all embodiments. Obviously, based on the above embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of the present invention.

Claims

1. A method for synthesizing salbutamol sulfate, characterized in that, Includes the following steps: (1) Preparation of intermediate 1: Catalyst AlCl3 and organic solvent A were added to a reaction flask, heated and stirred, and then acylation reagent bromoacetyl bromide dichloromethane solution was added dropwise. After stirring and keeping warm for 1 h, methyl salicylate dichloromethane solution was added dropwise, and the reaction was continued at the temperature. After the reaction was completed, intermediate 1 was obtained by purification. The structural formula of intermediate 1 is as follows: ; (2) Preparation of intermediate 2: Intermediate 1 was dissolved in organic solvent B. Under nitrogen protection, tert-butylamine was added dropwise at the adjusted reaction temperature. The mixture was then stirred and heated to carry out the substitution reaction. The reaction was monitored by TLC until complete. After cooling, crystallization was carried out with stirring. The crystals were then filtered and dried to constant weight to obtain intermediate 2. The structural formula of intermediate 2 is as follows: ; (3) Preparation of intermediate 3: Intermediate 2 was dissolved in organic solvent C, cooled to -10-0℃, a reducing agent was added, and the reaction was carried out under controlled temperature. Then, purified water and alkaline solution were added, the temperature was raised and stirred. After the reaction was completed, crude salbutamol was obtained by separation and purification. Then, a mixed solvent was added to the crude salbutamol for recrystallization. After filtration and drying, intermediate 3 salbutamol was obtained. The chemical structural formula of intermediate 3 is as follows: ; (4) Preparation of salbutamol sulfate: Dissolve the obtained salbutamol in mixed solvent D and heat to 50~55℃, slowly add concentrated sulfuric acid, cool down to precipitate crystals and stir the reaction, filter and dry after the reaction to obtain salbutamol sulfate; In step (1), organic solvent A is dichloromethane; In step (2), organic solvent B is any one of ethanol, isopropanol, and tetrahydrofuran; In step (3), the organic solvent C is tetrahydrofuran; In step (4), the mixed solvent D is a mixed solution of water and alcohol, with a volume ratio of water to alcohol of 1:8-1:10; the alcohol is one of methanol, ethanol, and isopropanol.

2. The method for synthesizing salbutamol sulfate according to claim 1, characterized in that, In step (1), the molar ratio of catalyst, methyl salicylate and bromoacetyl bromide is (3-4):1:(1.2-1.3); the concentration of bromoacetyl bromide dichloromethane solution is 2-2.2 g / mL; and the concentration of methyl salicylate dichloromethane solution is 1.2-1.4 g / mL.

3. The method for synthesizing salbutamol sulfate according to claim 1, characterized in that, In step (1), the temperature is raised to 40-45℃ and stirred; the heat preservation reaction is carried out at 40-45℃ for 10 hours, and intermediate 1 is purified by recrystallization or pulping using one or more mixed solvents selected from ethyl acetate, acetonitrile, acetone, petroleum ether, n-hexane, and n-heptane.

4. The method for synthesizing salbutamol sulfate according to claim 1, characterized in that, In step (2), the molar ratio of intermediate 1 to tert-butylamine is 1:1-4; the reaction temperature is 10-15℃; the stirring temperature is raised to 45-50℃, kept warm and stirred for 3h, and monitored by TLC until the reaction is complete, then cooled to 20-25℃ and stirred for 5h.

5. The method for synthesizing salbutamol sulfate according to claim 1, characterized in that, In step (3), the molar ratio of intermediate 2 to reducing agent is 1:1-3; the temperature-controlled reaction temperature is -10 to 5℃, and the reaction time is 2h.

6. The method for synthesizing salbutamol sulfate according to claim 1, characterized in that, In step (3), the reducing agent is one of potassium borohydride, sodium borohydride, or lithium aluminum hydride; the mass ratio of intermediate 2, purified water, and alkaline solution is (40-60) g: (34-39) g: (11-13) g; the internal temperature is controlled at 0-10℃ during the dropwise addition of purified water and alkaline solution, and after the dropwise addition is completed, the temperature is raised to 20-30℃ and stirred for 1 hour.

7. The method for synthesizing salbutamol sulfate according to claim 6, characterized in that, The alkaline solution is a 15% sodium hydroxide solution.

8. The method for synthesizing salbutamol sulfate according to claim 1, characterized in that, In step (3), the mixed solvent during recrystallization is isopropanol and ethyl acetate in a volume ratio of 1:1; in step (3), the temperature is lowered to 0-5℃ and kept at this temperature for 3 hours to allow crystals to precipitate.

9. The method for synthesizing salbutamol sulfate according to claim 1, characterized in that, In step (4), the crystallization temperature is lowered to 0-10℃ and stirred for 2-3 hours.

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