A preparation method of salbutamol sulfate impurity D

Abstract

The present invention provides a method for preparing a salbutamol sulfate impurity D. The preparation method uses salbutamolamine as a raw material to prepare a compound A; prepares a compound B from the compound A; prepares a compound C from the compound B; and obtains the salbutamol sulfate impurity D from the compound C. The product prepared by the preparation method of the salbutamol sulfate impurity D of the present invention has high purity and yield.

Description

Technical Field

[0001] The present invention relates to a preparation method of salbutamol sulfate impurity D, belonging to the technical field of compound preparation. Background Art

[0002] Salbutamol sulfate, chemically named 1-(4-hydroxy-3-hydroxymethylphenyl)-2-(tert-butylamino)ethanol sulfate, has the molecular formula C 13 H 23 NO 7 S and a molecular weight of 337.39. Salbutamol sulfate is a potent and rapid-acting selective β-receptor agonist developed by GlaxoSmithKline (GSK) in the UK, with the trade name Ventolin. It was first marketed in 1968 and registered in China in 1988. Its mechanism of action is to selectively activate β2 receptors to relax bronchial smooth muscle. Indications include: respiratory diseases such as asthmatic bronchitis, bronchial asthma, and bronchospasm in patients with emphysema. This drug still plays an irreplaceable role to date and has ranked among the top 20 in terms of sales in the world drug market in recent years. The dosage forms of salbutamol sulfate include tablets, capsules, aerosols, and injections, etc.

[0003] It is also known in the art that impurities in any active pharmaceutical ingredient (API) of salbutamol sulfate may come from the degradation of the API itself and the manufacturing process, including chemical synthesis. Process impurities include unreacted raw materials, impurities contained in the raw materials and their chemical derivatives, synthetic by-products, and degradation products.

[0004] In addition to 14 impurities in the quality standard of salbutamol sulfate in the European Pharmacopoeia 8.0 edition, there are also other impurities, and it is particularly important to study other impurities of salbutamol sulfate and control the impurity content. Summary of the Invention

[0005] In order to solve the above technical problems, the purpose of the present invention is to provide a preparation method of salbutamol sulfate impurity D with high product yield and high product purity.

[0006] In order to achieve the above technical purpose, the present invention provides a preparation method of salbutamol sulfate impurity D, and the preparation method includes the following steps:

[0007] Mix salbutamol amine, triethylamine, and DMF, cool down to 0°C - 10°C with stirring, add tert-butyldimethylchlorosilane (TBSCl), warm up to room temperature for reaction, react overnight, add water and ethyl acetate to the reaction solution, stir well, let it stand for liquid separation, extract the aqueous phase with ethyl acetate, combine the organic phases, dry, and spin-dry to obtain compound A;

[0008] Add pyridinium p-toluenesulfonate hydrochloride to compound A and ethanol, heat up to 55 °C - 65 °C (preferably 60 °C) and react overnight. After reacting for 35 h - 45 h (preferably 40 h), concentrate the reaction solution, add water and ethyl acetate, stir well and then let it stand for phase separation. Extract the aqueous phase with ethyl acetate, combine the organic phases, wash with water, dry and then concentrate. Add petroleum ether and ethyl acetate to the concentrated solution and stir to obtain compound B;

[0009] Mix compound B, sodium acetate and dichloromethane (DCM), cool down to 0 - 10 °C in an ice bath, add pyridinium chlorochromate (PCC), and stir the reaction overnight in the ice bath. Add silica gel to the reaction solution, stir, filter, and after concentrating the filtrate, obtain compound C;

[0010] Add a tetrahydrofuran solution of sulfuric acid to compound C and tetrahydrofuran, stir the reaction at room temperature for 3 h - 5 h, adjust the pH to 7.5 - 8.5 (preferably 8), add sodium chloride to saturate the aqueous phase, extract with dichloromethane, dry the organic layer, filter and dry, concentrate, adjust the pH to 5.5 - 6, filter, and dry to obtain salbutamol sulfate impurity D.

[0011] In a specific embodiment of the present invention, when preparing compound A, the mixing ratio of salbutamol, triethylamine, DMF, tert-butyldimethylchlorosilane, water, and ethyl acetate is 1 g: 2 g - 2.2 g: 8 mL - 8.2 mL: 3 g - 3.2 g: 8 mL - 8.2 mL: 4 mL - 4.1 mL.

[0012] In a specific embodiment of the present invention, when preparing compound B, the mixing ratio of compound A, ethanol, and pyridinium p-toluenesulfonate hydrochloride is 1 g: 4 mL - 4.2 mL: 0.85 g - 0.88 g. When standing for phase separation, the mixing ratio of compound A, water, and ethyl acetate is 1 g: 1.6 mL - 1.7 mL: 1.6 g - 1.7 g. When adding petroleum ether and ethyl acetate to the concentrated solution and stirring, the mixing ratio of compound A, petroleum ether, and ethyl acetate is 1 g: 1.6 mL - 1.7 mL: 0.016 mL - 0.017 mL.

[0013] In a specific embodiment of the present invention, when preparing compound C, the mixing ratio of compound B, sodium acetate, DCM, and PCC is 1 g: 0.19 g - 0.20 g: 8 mL - 8.1 mL: 0.4 g - 0.6 g. The mass ratio of compound B to silica gel is 1: 0.65 - 0.75.

[0014] In a specific embodiment of the present invention, when preparing salbutamol sulfate impurity D, the pH is adjusted to 8 with an aqueous sodium bicarbonate solution; the pH is adjusted to 5.5 - 6 with a sulfuric acid dichloromethane solution. When preparing salbutamol sulfate impurity D, the mass concentration of the sulfuric acid tetrahydrofuran solution is 30% - 40%. Among them, the mixing ratio of compound C, tetrahydrofuran, and the sulfuric acid tetrahydrofuran solution is 1 g:0.4 g - 0.5 g:1.2 mL - 1.3 mL.

[0015] The salbutamol sulfate impurity D prepared by the preparation method of the salbutamol sulfate impurity D of the present invention has high product purity and high yield. Brief Description of the Drawings

[0016] Figure 1 It is a schematic diagram of the synthesis mechanism of the preparation method of salbutamol sulfate impurity D in Example 1 of the present invention.

[0017] Figure 2 It is the HNMR spectrum of salbutamol sulfate impurity D in Example 1 of the present invention.

[0018] Figure 3 It is the mass spectrum of salbutamol sulfate impurity D in Example 1 of the present invention. Detailed Description of the Invention

[0019] Example 1

[0020] This example provides a preparation method of salbutamol sulfate impurity D, as Figure 1 shown, including the following steps.

[0021] Salbutamol 18559 - 94 - 9 (987 g, 4.12 mol 1 eq), triethylamine (2086.6 g, 20.62 mol 5 eq) and DMF (8 L) were put into a 20 L reaction flask, cooled to 5 °C with stirring, and TBSCl (3108 g, 20.62 mol 5 eq) was slowly added while maintaining the internal temperature at 5 °C. After addition, the temperature was naturally raised to room temperature for reaction overnight. The next day, TLC (PE:EA = 3:1) was used to detect that the raw materials had completely reacted. 8 L of water and 4 L of ethyl acetate were added to the reaction solution, stirred well, allowed to stand for liquid separation, and the aqueous phase was extracted with ethyl acetate 2 times (4 L × 2 times). The organic phases were combined, dried, and concentrated by rotary evaporation to obtain 3400 g of a yellow oil - compound A (with DMF residue), which was directly put into the next - step reaction.

[0022] Compound A (2400 g, 4.12 mol, 1.0 eq) and ethanol (10 L) were added to a 20 L reaction flask. While stirring, pyridinium p-toluenesulfonate hydrochloride (2070 g, 8.25 mol, 2.0 eq) was added. The temperature of the system was raised to 60 °C and the reaction was carried out overnight. After about 40 h of reaction, TLC showed that the raw materials had almost completely reacted, and then post-treatment was carried out. The reaction solution was concentrated, 4 L of water and 4 L of ethyl acetate were added, and after sufficient stirring, it was left to stand for liquid separation. The aqueous phase was extracted once with 2 L of ethyl acetate, and TLC showed that there was no product residue in the aqueous phase. The organic phases were combined, washed 3 times (5 L × 3 times), dried and then concentrated. 4 L of petroleum ether and 40 ml of ethyl acetate were added to the concentrated solution and stirred. A white solid product precipitated out, which was collected by filtration. After drying, about 1930 g of compound B was obtained.

[0023] Compound B (1485 g, 2.33 mol, 1 eq), sodium acetate (287 g, 3.5 mol, 1.5 eq) and DCM (12 L) were added to a reaction flask. The temperature was lowered to 5 °C in an ice bath, and PCC (754 g, 3.5 mol, 1.5 eq) was added. The reaction was stirred in the ice bath. It was frozen overnight in the refrigerator. The next day, about 1 kg of silica gel was added to the reaction solution, stirred, filtered, and after the filtrate was concentrated, 800 g of compound C was obtained by column chromatography.

[0024] 800 g of compound C and tetrahydrofuran were added to a reaction flask, and a tetrahydrofuran solution of sulfuric acid (2.0 eq) was added. The reaction was stirred at room temperature. TLC detected that the raw materials had completely reacted. The pH was adjusted to about 8 with an aqueous sodium bicarbonate solution, sodium chloride was added to saturate the aqueous phase, and it was extracted three times with dichloromethane. The organic layer was dried, filtered and dried, concentrated, the pH was adjusted to 6 with a sulfuric acid dichloromethane solution, filtered, and dried to obtain 350 g of salbutamol sulfate impurity D.

[0025] The 1H NMR spectrum of salbutamol sulfate impurity D in this example is as Figure 2 shown, and the mass spectrum of salbutamol sulfate impurity D in this example is as Figure 3 shown. It can be seen from Figure 2 and Figure 3 that salbutamol sulfate impurity D was indeed obtained in this example.

[0026] Comparative Example 1

[0027] This comparative example provides a preparation method of salbutamol sulfate impurity D, which includes the following steps.

[0028] Salbutamol 18559-94-9 (987 g, 4.12 mol, 1 eq), triethylamine (2086.6 g, 20.62 mol, 5 eq) and DMF (8 L) were charged into a 20 L reaction flask. The temperature was lowered to 20 °C with stirring, and TBSCl (3108 g, 20.62 mol, 5 eq) was slowly added while maintaining the internal temperature at 15 °C. After addition, the temperature was allowed to rise to room temperature naturally and the reaction was carried out overnight. The next day, TLC (PE:EA = 3:1) detected that the raw material reaction was complete. 8 L of water and 4 L of ethyl acetate were added to the reaction solution, stirred well, allowed to stand for liquid separation, and the aqueous phase was extracted with ethyl acetate twice (4 L × 2 times). The organic phases were combined, dried, and concentrated to obtain a yellow oily substance - Compound A (with DMF residue), which was directly used in the next reaction step.

[0029] Compound A (2400 g, 4.12 mol, 1.0 eq) and ethanol (10 L) were added to a 20 L reaction flask. Pyridinium p-toluenesulfonate hydrochloride (2070 g, 8.25 mol, 2.0 eq) was added with stirring, and the system was heated to 30 °C and reacted overnight. After about 20 h of reaction, TLC showed that the raw material was almost completely reacted, and work-up was carried out. The reaction solution was concentrated, 4 L of water and 4 L of ethyl acetate were added, stirred well, and allowed to stand for layer separation. The aqueous phase was extracted once with 2 L of ethyl acetate, and TLC showed that there was no product residue in the aqueous phase. The organic phases were combined, washed with water three times (5 L × 3 times), dried and concentrated. 4 L of petroleum ether and 40 ml of ethyl acetate were added to the concentrated solution and stirred to precipitate a white solid product, which was collected by filtration, dried to obtain approximately Compound B.

[0030] Compound B (1485 g, 2.33 mol, 1 eq), sodium acetate (287 g, 3.5 mol, 1.5 eq) and DCM (12 L) were added to a reaction flask. The temperature was lowered to 15 °C in an ice bath, and PCC (754 g, 3.5 mol, 1.5 eq) was added, and the reaction was stirred in an ice bath. It was frozen overnight in a refrigerator. The next day, about 1 Kg of silica gel was added to the reaction solution, stirred, filtered, and the filtrate was concentrated and then purified by column chromatography to obtain Compound C.

[0031] 800 g of Compound C and tetrahydrofuran were added to a reaction flask, and a tetrahydrofuran solution of sulfuric acid (2.0 eq) was added. The reaction was stirred at room temperature. TLC detected that the raw material reaction was complete. The pH was adjusted to about 10 with an aqueous sodium bicarbonate solution, sodium chloride was added to saturate the aqueous phase, and the mixture was extracted three times with dichloromethane. The organic layer was dried, filtered and dried, concentrated, and the pH was adjusted to 2 with a sulfuric acid dichloromethane solution, filtered, and dried to obtain Salbutamol Sulfate Impurity D (yield 78%).

[0032] The above embodiments are only used to illustrate the technical concept and features of the present invention, and the purpose is to enable those skilled in the art to understand the content of the present invention and implement it accordingly. It is not intended to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.

Claims

1. A method for preparing salbutamol sulfate impurity D, It is characterized in that The reaction process includes the following: ； The preparation method specifically comprises the following steps: Mix salbutanolamine, triethylamine and DMF, cool down to 0°C-10°C with stirring, add tert-butyldimethylsilyl chloride, heat to room temperature for reaction, react overnight, add water and ethyl acetate to the reaction solution, stir well, stand for separation, extract the aqueous phase with ethyl acetate, combine the organic phases, dry, and spin-dry to obtain compound A; Add p-toluenesulfonic acid pyridinium hydrochloride to the compound A and ethanol, heat to 55°C-65°C and react overnight. After reacting for 35h-45h, concentrate the reaction solution, add water and ethyl acetate, stir well, and stand for stratification. Extract the aqueous phase with ethyl acetate, combine the organic phases, wash with water, dry and concentrate, add petroleum ether and ethyl acetate to the concentrate and stir to obtain substance B; The substance B, sodium acetate and dichloromethane are mixed, cooled to 0-10°C in an ice bath, pyridinium chlorochromate is added, stirred and reacted overnight in an ice bath, silica gel is added to the reaction solution, stirred, filtered, and the filtrate is concentrated to obtain substance C; To the substance C and tetrahydrofuran, add a tetrahydrofuran solution of sulfuric acid, stir and react at room temperature for 3h-5h, adjust the pH to 7.5-8.5, add sodium chloride to saturate the aqueous phase, extract with dichloromethane, dry the organic layer, filter and dry, concentrate, adjust the pH to 5.5-6, filter, and dry to obtain salbutamol sulfate impurity D.

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