Method for preparing bepotastine besilate racemate in one step

Abstract

The invention discloses a method for preparing bepotastine besilate racemate in one step, which comprises the following steps: adding (4-chlorphenyl) (pyridine-2-yl) methanol and 4-hydroxypiperidine into a toluene or methyl isobutyl ketone solvent, carrying out reflux reaction with water under the condition of p-toluenesulfonic acid monohydrate, carrying out alkali washing, adding 4-bromobutyric acid and inorganic alkali, carrying out reflux reaction, filtering, washing, and drying to obtain the bepotastine besilate racemate. And after the reaction is finished, adjusting the pH value to be 5-6, washing an organic layer with water to be neutral, refluxing with water, removing water, and adding benzenesulfonic acid to form salt, thereby obtaining the bepotastine besilate racemate. The method disclosed by the invention is simple and convenient to operate, mild in reaction condition, low in cost and high in yield, and has great significance on production and inspection of a bepotastine besilate bulk drug.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, and specifically relates to a one-step method for preparing the racemic mixture of betasine besylate. Background Technology

[0002] Bepotastine besilate, chemically named (S)-4-{4-[(4-chlorophenyl)(2-pyridine)methoxy]piperidine}butyric acid benzylsulfonate, is a histamine H1 receptor antagonist jointly developed by Tanabe Pharmaceuticals and Ube Industries, Ltd. of Japan, and was launched in Japan in 2000. Bepotastine besilate inhibits eosinophil infiltration into peripheral tissues and relieves inflammatory responses in the nasal mucosa, and is used to treat allergic rhinitis and urticaria. Furthermore, bepotastine besilate has no sedative effect; its anticholinergic and antihistamine effects are separate, with very few adverse reactions, demonstrating good efficacy and broad clinical application prospects.

[0003] With social development and technological advancements, people have gained a more comprehensive understanding of drug quality and safety. Among the key aspects closely related to drug quality and safety is the control of impurities within drugs. Impurity research is a crucial part of drug development. Adverse drug reactions are related not only to the drug's pharmacological activity but also to its impurities. Controlling impurities within a safe and reasonable range directly impacts the quality and safety of marketed drugs. Betasine besylate racemic mixture is one of the main impurities in betasine besylate and is of great significance in the qualitative quality research of betasine besylate.

[0004] CN 104003978 B discloses a method for preparing the racemic form of benzylbenz ...

[0005] In view of this, there is an urgent need to develop a rapid one-step preparation method for the racemic benzylsulfamate to solve the above problems. Summary of the Invention

[0006] To address the aforementioned problems in existing technologies, this invention provides a one-step method for preparing the racemic mixture of betahistine benzylsulfamate. This invention is simple to operate, operates under mild reaction conditions, and yields high output, making it suitable for industrial production and rapid preparation.

[0007] The technical solution adopted in this invention is as follows: A method for preparing the racemic mixture of betasine benzylsulfamate in one step, comprising the following steps: First, (4-chlorophenyl)(pyridin-2-yl)methanol and 4-hydroxypiperidine are added to a solvent and refluxed under p-toluenesulfonic acid monohydrate conditions to remove water. After washing with an alkali, 4-bromobutyric acid and an inorganic base are added and refluxed. After the reaction is complete, the pH is adjusted to 5-6, the organic layer is washed with water to neutralize, and then refluxed to remove water. Benzenesulfonic acid is then added to form a salt to obtain the racemic betamethasone benzylsulfonate, the structural formula of which is shown below. Figure 1 As shown.

[0008] In a preferred embodiment, the alkali used in the alkaline washing step is selected from any one of potassium hydroxide, sodium hydroxide, and cesium hydroxide; potassium hydroxide and sodium hydroxide are preferred.

[0009] In a preferred embodiment, the inorganic base is selected from any one of potassium hydroxide, sodium hydroxide, cesium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and cesium carbonate; preferably sodium bicarbonate, potassium carbonate, or sodium carbonate.

[0010] In a preferred embodiment, the solvent is toluene or methyl isobutyl ketone; toluene is preferred.

[0011] In a preferred embodiment, the reaction temperature of the reflux water-carrying reaction is 115~125℃, and the reaction time is 5~8 h.

[0012] In a preferred embodiment, the molar ratio of (4-chlorophenyl)(pyridin-2-yl)methanol to 4-hydroxypiperidine is 1:1.1~1.5.

[0013] In a preferred embodiment, the weight ratio of 4-hydroxypiperidine to solvent is 1:18~30.

[0014] In a preferred embodiment, the molar ratio of 4-hydroxypiperidine to p-toluenesulfonic acid monohydrate is 1:1.1~1.3.

[0015] In a preferred embodiment, the molar ratio of the monohydrate to p-toluenesulfonic acid and the base is 1:1.5~2.5.

[0016] In a preferred embodiment, the molar ratio of 4-hydroxypiperidine to 4-bromobutyric acid is 1:1.1~1.5.

[0017] In a preferred embodiment, the molar ratio of 4-hydroxypiperidine to the inorganic base is 1:1.5~2.5.

[0018] In a preferred embodiment, the molar ratio of 4-hydroxypiperidine to benzenesulfonic acid is 1:1 to 1.2.

[0019] Compared with the prior art, the present invention has the following beneficial effects: 1) The preparation method of the present invention is simple to operate, safe, mild in reaction conditions, high in yield, and low in pollution. It is suitable for large-scale industrial production and has great significance for the production and testing of betasine besylate raw materials.

[0020] 2) This invention overcomes the problems of long routes, large amounts of waste solvents, and long preparation times in the prior art, and provides a new technology solution for rapid preparation that is more suitable for industrial production. Attached Figure Description

[0021] Figure 1 This is a structural diagram of the racemic benzylsulfamate of the present invention; Figure 2 This is the reaction formula for the preparation method of the present invention. Detailed Implementation

[0022] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described below with reference to specific embodiments. Unless otherwise specified, the technical means used in the following embodiments are all conventional means well known to those skilled in the art.

[0023] Example 1 This embodiment provides a one-step method for preparing the racemic mixture of bethastin benzylsulfamethoxazole, the reaction process is as follows: Figure 2 As shown, it includes the following steps: 0.11 mol of (4-chlorophenyl)(pyridin-2-yl)methanol and 0.1 mol of 4-hydroxypiperidine were added to 220 mL of toluene. 21 g of p-toluenesulfonic acid monohydrate was added with stirring at room temperature. The mixture was then refluxed for 6 h to remove water. After the reaction was complete, the temperature was lowered to 60 °C, and 8 g of [acid] was added. NaOH and 80 mL of alkaline solution were mixed and stirred at a constant temperature for 30 min. The mixture was then separated, and the lower aqueous layer was removed. 0.11 mol of 4-bromobutyric acid and 17 g of NaHCO3 were added to the toluene layer. The mixture was heated and refluxed to remove water, and the reaction was carried out for 8 h. After the reaction was completed, the temperature was lowered to 30 °C, and the pH was adjusted to 5-6 with 1 N hydrochloric acid aqueous solution. The lower aqueous layer was removed, and the organic layer was washed with water until neutral. The toluene layer was heated and refluxed to remove water until anhydrous, and then cooled to 60 °C. 16 g of benzenesulfonic acid was added, and the mixture was heated to 100 °C and stirred for 30 min. The temperature was lowered to 5 °C, and the mixture was frozen for 12 h to crystallize. The mixture was filtered, and the filter cake was washed twice with toluene and then dried under vacuum to obtain 49.2 g of racemic benzenesulfonate betastin, with a molar yield of 90% and a purity of 95.5%.

[0024] Example 2 This embodiment provides a one-step method for preparing the racemic mixture of betasine benzylsulfamethoxazole, comprising the following steps: 0.15 mol of (4-chlorophenyl)(pyridin-2-yl)methanol and 0.1 mol of 4-hydroxypiperidine were added to 300 mL of methyl isobutyl ketone. 23 g of p-toluenesulfonic acid monohydrate was added with stirring at room temperature. The mixture was then refluxed for 6 h to remove water. After the reaction was complete, the temperature was lowered to 60 °C, and 10 g of [acid] was added. KOH and 100 mL of alkaline solution were mixed and stirred at a constant temperature for 30 min. The mixture was then separated, and the lower aqueous layer was removed. 0.12 mol of 4-bromobutyric acid and 20 g of KHCO3 were added to the toluene layer. The mixture was heated and refluxed to remove water, and the reaction was carried out for 8 h. After the reaction was completed, the temperature was lowered to 30 °C, and the pH was adjusted to 5-6 with 1 N hydrochloric acid aqueous solution. The lower aqueous layer was removed, and the organic layer was washed with water until neutral. The organic layer was heated and refluxed to remove water until anhydrous, and then cooled to 60 °C. 17 g of benzenesulfonic acid was added, and the mixture was heated to 100 °C and stirred for 30 min. The temperature was lowered to 5 °C, and the mixture was frozen for 12 h to crystallize. The mixture was filtered, and the filter cake was washed twice with toluene and then dried under vacuum to obtain 50.3 g of racemic benzenesulfonate betasine, with a molar yield of 92% and a purity of 95.3%.

[0025] Example 3 This embodiment provides a one-step method for preparing the racemic mixture of betasine benzylsulfamethoxazole, comprising the following steps: 0.13 mol of (4-chlorophenyl)(pyridin-2-yl)methanol and 0.1 mol of 4-hydroxypiperidine were added to 180 mL of toluene. 25 g of p-toluenesulfonic acid monohydrate was added with stirring at room temperature. The mixture was then refluxed for 6 h to remove water. After the reaction was complete, the temperature was lowered to 60 °C, and 13 g of [acid] was added. NaOH and 130 mL of alkaline solution were mixed and stirred at a constant temperature for 30 min. The mixture was then separated, and the lower aqueous layer was removed. 0.15 mol of 4-bromobutyric acid and 21 g of NaHCO3 were added to the toluene layer. The mixture was heated and refluxed to remove water, and the reaction was carried out for 8 h. After the reaction was completed, the temperature was lowered to 30 °C, and the pH was adjusted to 5-6 with 1 N hydrochloric acid aqueous solution. The lower aqueous layer was removed, and the organic layer was washed with water until neutral. The organic layer was heated and refluxed to remove water until anhydrous, and then cooled to 60 °C. 19 g of benzenesulfonic acid was added, and the mixture was heated to 100 °C and stirred for 30 min. The temperature was lowered to 5 °C, and the mixture was frozen for 12 h to crystallize. The mixture was filtered, and the filter cake was washed twice with toluene and then dried under vacuum to obtain 49.7 g of racemic benzenesulfonate, with a molar yield of 91% and a purity of 95.1%.

[0026] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the described embodiments. The embodiments and features in the embodiments of this application can be arbitrarily combined with each other without conflict. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention should be considered equivalent substitutions and are included within the protection scope of the present invention. Furthermore, technical details not described in detail in this specification are well-known to those skilled in the art, and therefore will not be repeated here.

Claims

1. A process for the one-step preparation of the racemate of benzylsulphistatin, characterized in that, First, (4-chlorophenyl) (pyridin-2-yl) methanol and 4-hydroxypiperidine are added into a solvent, and refluxed with water under the condition of monohydrate p-toluenesulfonic acid, and then washed with a base, and then 4-bromobutyric acid and an inorganic base are added and refluxed, after the reaction is completed, the pH is adjusted to 5-6, the organic layer is washed with water until neutral, then water is removed by refluxing, and then benzenesulfonic acid is added to form a salt to obtain the racemate of benzenesulfobastine.

2. The method of claim 1, wherein, The base in the base washing step is selected from any one of potassium hydroxide, sodium hydroxide, cesium hydroxide; the inorganic base is selected from any one of potassium hydroxide, sodium hydroxide, cesium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate; and the solvent is toluene or methyl isobutyl ketone.

3. The method of claim 1, wherein, The inorganic base is selected from any one of sodium bicarbonate, potassium carbonate, and sodium carbonate; and the solvent is toluene.

4. The method of claim 1, wherein, The reaction temperature of the refluxing water reaction is 115-125°C, and the reaction time is 5-8 h.

5. The method of claim 1, wherein, The molar ratio of (4-chlorophenyl) (pyridin-2-yl) methanol to 4-hydroxypiperidine is 1:1.1-1.

5.

6. The method of claim 1, wherein, The weight ratio of 4-hydroxypiperidine to solvent is 1:18-30; and the molar ratio of 4-hydroxypiperidine to monohydrate p-toluenesulfonic acid is 1:1.1-1.

3.

7. The method of claim 1, wherein, The molar ratio of monohydrate p-toluenesulfonic acid to base is 1:1.5-2.

5.

8. The method of claim 1, wherein, The molar ratio of 4-hydroxypiperidine to 4-bromobutyric acid is 1:1.1-1.

5.

9. The method of claim 1, wherein, The molar ratio of 4-hydroxypiperidine to inorganic base is 1:1.5-2.

5.

10. The method of claim 1, wherein, The molar ratio of 4-hydroxypiperidine to benzenesulfonic acid is 1:1-1.2.

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