Method for synthesizing salbutamol sulfate

Abstract

The invention discloses a method for synthesizing salbutamol sulfate, and belongs to the technical field of organic chemical synthesis. The synthesis method comprises the following steps: (1) carrying out Friedel-Crafts acylation reaction on methyl salicylate to generate an intermediate 1; (2) carrying out substitution reaction on the intermediate 1 and tert-butylamine to generate an intermediate 2; (3) carrying out reduction reaction on the intermediate 2 to generate an intermediate 3, namely salbutamol; and (4) salbutamol and concentrated sulfuric acid are salified to generate salbutamol sulfate. According to the synthetic method of the salbutamol sulfate, the process steps are shortened, the raw materials are simple and easy to obtain, multi-step column chromatography is omitted, the cost is reduced, the high-pressure hydrogenation reaction is avoided, an autoclave is not needed, common production equipment is not needed, the reaction conditions are mild, and industrial production is facilitated.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a method for synthesizing salbutamol sulfate. Background Art

[0002] The chemical name of salbutamol sulfate is 1-(4-hydroxy-3-hydroxymethylphenyl)-2-(tert-butylamino)ethanol sulfate. It was first 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. It is now marketed worldwide under multiple trade names and is the preferred drug for the clinical treatment of bronchial asthma, chronic obstructive pulmonary disease, and asthmatic bronchitis.

[0003] There are many synthetic methods for salbutamol sulfate reported in the literature, mainly including the following synthetic routes:

[0004] U.S. Patent Application US5283359 discloses the following synthetic route:

[0005]

[0006] Although the process steps of this route are shorter than those of the original research process, the phenolic hydroxyl group of compound 2 is not protected and directly oxidized when using dimethyl sulfoxide (DMSO) to obtain compound 3, which is easy to produce oxidative impurities. In addition, in the process of synthesizing compound 5, highly toxic and explosive borane dimethyl sulfide water is used to reduce salicylate, and safety and toxicity production need to be strictly controlled. This method has harsh reaction conditions, serious three waste pollution and high cost.

[0007] U.S. Patent No. 5,399,765 discloses the following synthetic route:

[0008]

[0009] This route is based on 2-benzyl ether-5-acetyl benzoic acid methyl ester as raw material, through hydroxylation, ammoniation, reduction, chiral agent splitting, hydrolysis and reduction six-step reaction preparation. The hydrobromic acid / DMSO oxidation system reaction process used in this synthetic route can produce dimethyl sulfide, with certain environmental and personal hazards. Borane dimethyl sulfide is also used in this synthetic route and is not suitable for operation, benzyl protection is added to the phenyl ring, the step of deprotection is added, the production cycle is long, energy consumption is high, "three wastes" generation is large, and total recovery is particularly low, causing production cost to be very high, and is not suitable for industrialized production.

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

[0011]

[0012] This route uses methyl salicylate as raw material and is prepared through seven steps of reaction: Friedel-Crafts acylation, hydroxylation, amination, two-step reduction, cyclization and ring opening. This synthetic route has many steps and is complicated to operate. It requires two consecutive steps of reduction reaction. The hydrobromic acid reaction process used in hydroxylation is difficult to control and the refining process is complicated.

[0013] In summary, the above synthetic routes all have the problems of cumbersome process steps, complicated operation, low yield, difficult to remove impurities or the presence of highly toxic, pressurized hydrogenation and other high-risk reactions. Therefore, the development of a new salbutamol sulfate synthesis process is of great significance to both enterprises and society. Summary of the invention

[0014] The main purpose of the present invention is to provide a method for synthesizing salbutamol sulfate, so as to solve the technical defects of the existing synthesis process, such as heavy metal pollution, cumbersome process steps, complicated operation and low yield.

[0015] In order to achieve the above technical objectives, the technical solution adopted by the present invention is:

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

[0017] (1) Preparation of intermediate 1: Add catalyst AlCl3 and organic solvent A to a reaction flask, heat and stir, then dropwise add acylating agent bromoacetyl bromide dichloromethane solution, stir and keep warm for 1 hour, then dropwise add methyl salicylate dichloromethane solution, continue to keep warm and react, after the reaction is completed, purify and obtain intermediate 1, the structural formula of intermediate 1 is

[0018] (2) Preparation of Intermediate 2: Intermediate 1 was dissolved in organic solvent B, and tert-butylamine was added dropwise at the reaction temperature under nitrogen protection, followed by stirring and heating to carry out substitution reaction. After TLC monitoring until the reaction was complete, the temperature was lowered, crystallized and stirred, and then filtered and dried to constant weight to obtain Intermediate 2. The structural formula of Intermediate 2 is

[0019] (3) Intermediate 3: Dissolve intermediate 2 in organic solvent C, cool to -10-0°C, add reducing agent, and then control the temperature to react. Then add purified water and alkaline solution, heat and stir. After the reaction is completed, separate and purify to obtain crude salbutamol. Then add mixed solvent to the crude salbutamol to recrystallize. Filter and dry to obtain intermediate 3 salbutamol. The chemical structure of intermediate 3 is

[0020] (4) Preparation of salbutamol sulfate: The obtained salbutamol is dissolved in a mixed solvent D and heated to 50-55° C., concentrated sulfuric acid is slowly added dropwise, and after the addition is complete, the temperature is lowered to allow crystallization and the reaction is stirred. After the reaction is completed, the mixture is filtered and dried to obtain salbutamol sulfate.

[0021] Preferably, in the step (1), the molar ratio of the catalyst, methyl salicylate and bromoacetyl bromide is (3-4):1:(1.2-1.3); the concentration of the bromoacetyl bromide dichloromethane solution is 2-2.2 g / mL; and the concentration of the 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; and the heat preservation reaction is carried out at 40-45° C. for 10 hours.

[0023] Preferably, the purification method of intermediate 1 is to use one or more mixed solvents of ethyl acetate, acetonitrile, acetone, petroleum ether, n-hexane, n-heptane for recrystallization or slurry purification, and more preferably, ethyl acetate / n-hexane for recrystallization.

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

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

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

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

[0028] Preferably, the separation and purification of the crude salbutamol in step (3) comprises: adding anhydrous sodium sulfate, filtering, washing the filter cake twice with tetrahydrofuran, and concentrating the filtrate to dryness under reduced pressure.

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

[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 the step (3), the temperature is lowered to 0-5°C during the recrystallization process and the temperature is kept for crystallization for 3 hours.

[0033] Preferably, the mixed solvent D in step (4) is a mixed solution of water and alcohols, and the volume ratio of water to alcohols is 1:8-1:10; and the crystallization in step (4) is cooled to 0-10°C and stirred for 2-3h.

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

[0035] The reaction scheme of the present invention is as follows:

[0036]

[0037] Beneficial Effects

[0038] The synthesis method of salbutamol sulfate provided by the invention has shortened process steps, cheap and readily available raw materials, avoids the use of bromine and hydrogenation reaction in the original research patent, simplifies 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 The HPLC purity analysis spectrum of the salbutamol sulfate synthesized in Example 1 of the present invention. DETAILED DESCRIPTION

[0040] The technical solution of the present invention is further described below in conjunction with specific embodiments, but is not limited thereto.

[0041] Example 1

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

[0043] (1) Preparation of Intermediate 1

[0044] Add 105.16 g of anhydrous AlCl3 and 240 ml of dichloromethane into a reaction bottle, heat to 40-45°C, stir, and drop 63.68 g of bromoacetyl bromide and 30 ml of dichloromethane mixed solution. After the addition is complete, keep warm and stir for 1.0 h. Start to drop 40 g of methyl salicylate and 30 ml of dichloromethane mixed solution, keep warm at 40-45°C and react 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 of ice water and 200 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 20-25°C for 1 h, and the organic layer was separated. The aqueous layer was extracted twice with 200 ml of dichloromethane. The organic phases were combined and washed with saturated brine. The organic phases were separated and collected, and anhydrous sodium sulfate was added and dried for 30 min. The filtrate was filtered and dried by rotation. 264 ml of ethyl acetate was added and the temperature was raised until the solution was clear. 400 ml of n-hexane was added and stirred for 15 min. The temperature was lowered by 0-5°C, and the mixture was stirred and crystallized by filtration. The mixture was dried to constant weight to obtain intermediate 1 with a yield of 86.8%.

[0046] (2) Preparation of Intermediate 2

[0047] 50.00g of intermediate 1 was added to 300ml of isopropanol, and 40.18g of tert-butylamine was added dropwise under nitrogen protection and cooled to 10-15°C. After the addition was complete, the mixture was heated in an oil bath and stirred to 45-50°C. The mixture was stirred for 3h at this temperature. The reaction was monitored by TLC until the reaction was complete, and the mixture was cooled to 20-25°C and stirred for 5h. 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] To 40.00g of intermediate 2, add 240ml of tetrahydrofuran, cool to -10-0°C, slowly add 11.44g of lithium aluminum hydride, control the temperature at -10-0°C during the addition, and control the temperature at -10-5°C for 2h after the addition. Add 34.32g of purified water and 11.44g of 15% sodium hydroxide solution dropwise to the reaction solution, respectively, control the internal temperature at 0-10°C during the addition, and heat the reaction solution to 20-30°C and stir for 1h after the addition. Then add anhydrous sodium sulfate, filter, wash the filter cake with tetrahydrofuran twice, and concentrate the filtrate under reduced pressure to dryness to obtain crude salbutamol. Add 120ml of isopropanol and 120ml of ethyl acetate to the crude product. Heat the reaction solution to reflux under stirring, stir for 0.5h, then cool to 0-5°C and keep crystallized for 3h, filter and dry to obtain salbutamol, with a two-step yield of 78%.

[0050] (4) Preparation of salbutamol sulfate:

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

[0052] Example 2

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

[0054] (1) Preparation of Intermediate 1

[0055] Add 10.33 g of anhydrous AlCl3 and 360 ml of dichloromethane into a reaction bottle, heat to 40-45°C, stir, and drop a mixed solution of 103.48 g of bromoacetyl bromide and 50 ml of dichloromethane. After the addition is complete, keep warm and stir for 1.0 h. Start to drop a mixed solution of 60 g of methyl salicylate and 50 ml of dichloromethane, and keep warm at 40-45°C 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 of ice water and 300 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 20-25°C for 1 h, and the organic layer was separated. The aqueous layer was extracted twice with 300 ml of dichloromethane. The organic phases were combined and washed with saturated brine. The organic phases were separated and collected, and anhydrous sodium sulfate was added and dried for 30 min. The filtrate was filtered and dried by rotation. 390 ml of ethyl acetate was added and the temperature was raised until the solution was clear. 600 ml of n-hexane was added and stirred for 15 min. The temperature was lowered by 0-5°C, and the crystallization was filtered by stirring at the temperature. The mixture was 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] 80.00g of intermediate 1 was added to 480ml of tetrahydrofuran, and 53.57g of tert-butylamine was added dropwise under nitrogen protection and the temperature was lowered to 10-15°C. After the addition was complete, the mixture was heated in an oil bath and stirred to 45-50°C. The mixture was stirred for 3h at this temperature. The reaction was monitored by TLC until the reaction was complete, and the mixture was cooled to 20-25°C and stirred for 5h. The mixture was filtered and dried to constant weight to obtain 61.40g of intermediate 2 with a yield of 80.2%.

[0059] (5) Preparation of Intermediate 3

[0060] To 60.00g of intermediate 2, add 360ml of tetrahydrofuran, cool to -10-0°C, slowly add 12.87g of lithium aluminum hydride, control the temperature at -10-0°C during the addition, and control the temperature at -5-5°C for 2h after the addition. Add 38.61g of purified water and 12.87g of 15% sodium hydroxide solution dropwise to the reaction solution, respectively, control the internal temperature at 0-10°C during the addition, and heat the reaction solution to 20-30°C and stir for 1h after the addition. Then, add anhydrous sodium sulfate, filter, wash the filter cake with tetrahydrofuran twice, and concentrate the filtrate under reduced pressure to dryness to obtain crude salbutamol. Add 171ml of isopropanol and 171ml of ethyl acetate to the crude product. Heat the reaction solution to reflux under stirring, stir for 0.5h, then cool to 0-5°C and keep crystallized for 3h, filter and dry to obtain 40.19g of salbutamol, with a two-step yield of 76.3%.

[0061] (4) Preparation of salbutamol sulfate:

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

[0063] It should be noted that the above embodiments are only partial embodiments of the preferred methods of implementing the present invention, rather than all embodiments. Obviously, based on the above embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work should fall within the scope of protection of the present invention.

Claims

1. A method for synthesizing salbutamol sulfate, characterized in that: The following steps are involved: (1) Preparation of intermediate 1: Add catalyst AlCl3 and organic solvent A to a reaction flask, heat and stir, then dropwise add acylating agent bromoacetyl bromide dichloromethane solution, stir and keep warm for 1 hour, then dropwise add methyl salicylate dichloromethane solution, continue to keep warm and react, after the reaction is completed, purify and obtain intermediate 1, the structural formula of intermediate 1 is (2) Preparation of Intermediate 2: Intermediate 1 was dissolved in organic solvent B, and tert-butylamine was added dropwise at the reaction temperature under nitrogen protection, followed by stirring and heating to carry out substitution reaction. After TLC monitoring until the reaction was complete, the temperature was lowered, crystallized and stirred, and then filtered and dried to constant weight to obtain Intermediate 2. The structural formula of Intermediate 2 is (3) Preparation of intermediate 3: Dissolve intermediate 2 in organic solvent C, cool to -10-0°C, add reducing agent, and then control the temperature to react. Then add purified water and alkaline solution, heat and stir. After the reaction is completed, separate and purify to obtain crude salbutamol. Then add mixed solvent to the crude salbutamol for recrystallization, filter and dry to obtain intermediate 3 salbutamol. The chemical structure of intermediate 3 is (4) Preparation of salbutamol sulfate: The obtained salbutamol is dissolved in a mixed solvent D and heated to 50-55° C., concentrated sulfuric acid is slowly added dropwise, and after the addition is complete, the temperature is lowered to allow crystallization and the reaction is stirred. After the reaction is completed, the mixture is filtered and dried to obtain salbutamol sulfate.

2. The method for synthesizing salbutamol sulfate according to claim 1, characterized in that: In the step (1), the molar ratio of the catalyst, methyl salicylate and bromoacetyl bromide is (3-4):1:(1.2-1.3); the concentration of the bromoacetyl bromide dichloromethane solution is 2-2.2 g / mL; and the concentration of the 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 the 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, and the intermediate 1 is recrystallized or slurried and purified 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 the step (2), the organic solvent B is any one of ethanol, isopropanol and tetrahydrofuran; the molar ratio of the intermediate 1 to tert-butylamine is 1:1-4; the reaction temperature is 10-15°C; the temperature is raised to 45-50°C with stirring, and the mixture is kept stirred for 3 hours. After the reaction is completely monitored by TLC, the temperature is lowered to 20-25°C and stirred for 5 hours.

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

6. The method for synthesizing salbutamol sulfate according to claim 1, characterized in that: The reducing agent in step (3) is one of potassium borohydride, sodium borohydride, and lithium aluminum tetrahydride; the mass ratio of the intermediate 2, purified water, and alkaline solution is (40-60) g: (34-39) g: (11-13) g; the internal temperature during the dropwise addition of purified water and alkaline solution is controlled at 0-10°C, and after the dropwise addition is completed, the temperature is raised to 20-30°C 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 the recrystallization process of step (3), the mixed solvent is isopropanol and ethyl acetate in a volume ratio of 1:1; in the recrystallization process of step (3), the temperature is lowered to 0-5°C and the temperature is kept for crystallization for 3 hours.

9. The method for synthesizing salbutamol sulfate according to claim 1, characterized in that: In the 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 the step (4), the crystallization is cooled to 0-10°C and stirred for 2-3h.

10. The method for synthesizing salbutamol sulfate according to claim 9, characterized in that: The alcohol in the mixed solvent D in step (4) is one of methanol, ethanol and isopropanol.

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