A method for purifying citalopram or S-citalopram

Abstract

The present invention provides a method for purifying citalopram or S-citalopram or their salts, comprising the following steps: treating a solution composed of citalopram and a water-immiscible organic solvent with a washing solution, and separating to obtain an organic layer containing citalopram; or treating a solution composed of S-citalopram and a water-immiscible organic solvent with a washing solution, and separating to obtain an organic layer containing S-citalopram; then taking the organic layer and further separating to obtain citalopram or S-citalopram; or further adding an acid to form a salt, and separating to obtain an acid salt of citalopram or S-citalopram. The purification method provided by the present invention is simple to operate and has a high impurity removal rate.

Description

[0001] This invention claims the priority of the Chinese patent application with the application number 202110047911.X, titled "A Purification Method for Citalopram or S-Citalopram", which was filed with the Chinese Patent Office on January 14, 2021. The entire content thereof is incorporated herein by reference. Technical Field

[0002] This invention relates to the technical field of pharmaceutical chemistry, and particularly to a purification method for citalopram or S-citalopram. Background Art

[0003] Citalopram hydrobromide is a racemic mixture, and the active ingredient is mainly its levorotatory form.

[0004]

[0005] 1-(3-Dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbaldehyde (Formula II), commonly known as aldehyde impurity, is an inherent impurity in citalopram hydrobromide and escitalopram oxalate (S-citalopram). This impurity has properties similar to the product and is extremely difficult to remove, with a general content of about 0.05% - 0.45%. Currently, there is no relevant literature reporting the source and removal of this impurity.

[0006]

[0007] In view of the above problems of impurities, it is highly necessary to develop a purification method for citalopram or S-citalopram impurities. Summary of the Invention

[0008] This invention provides a purification method for citalopram or S-citalopram or their salts, including the following steps:

[0009] (a) Treat a solution composed of citalopram and a water-immiscible organic solvent with a washing solution, and separate to obtain an organic layer containing the citalopram; or, treat a solution composed of S-citalopram and a water-immiscible organic solvent with a washing solution, and separate to obtain an organic layer containing the S-citalopram;

[0010] (b) Further separate the organic layer obtained in step (a) to obtain the citalopram or the S-citalopram; or further add acid to form a salt, and separate to obtain the acid salt of citalopram or S-citalopram;

[0011] Among them, the washing solution in step (a) is an aqueous solution containing a detergent, and the detergent is selected from any one of sulfites or thiosulfates.

[0012] As a preferred embodiment of this invention:

[0013] Among them, the water-insoluble organic solvent described in step (a) is selected from at least one of toluene, ethyl acetate, methyl isobutyl ketone, and chlorobenzene.

[0014] The solution composed of citalopram and a water-insoluble organic solvent or the solution composed of S-citalopram and a water-insoluble organic solvent described in step (a) is derived from the liberation of citalopram acid salt or S-citalopram acid salt, and is obtained by the following process: mixing citalopram acid salt or S-citalopram acid salt, water and a water-insoluble organic solvent, adding alkali for liberation, and separating to obtain an organic layer; it can also be derived from the reaction solution in the synthesis process of citalopram or S-citalopram, and the reaction solution can be prepared with reference to the prior art solutions. Preferably, it is derived from the liberation of citalopram hydrobromide or S-citalopram oxalate.

[0015] The detergent in the washing solution described in step (a) is selected from any one of sodium dithionite, sodium thiosulfate or sodium sulfite, and preferably sodium dithionite.

[0016] The molar ratio of the detergent to citalopram or S-citalopram is 0.05 - 1.5.

[0017] The mass ratio of the detergent to water in the washing solution described in step (a) is 1 - 30%.

[0018] In one embodiment, an inorganic base is added to the washing solution described in step (a), and the inorganic base is selected from at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide, and preferably sodium bicarbonate.

[0019] The mass ratio of the inorganic base to the detergent is 5 - 30%.

[0020] The acid described in step (b) is selected from any one of hydrochloric acid, hydrobromic acid, phosphoric acid, oxalic acid, fumaric acid, acetic acid, p-toluenesulfonic acid or methanesulfonic acid, and preferably hydrobromic acid or oxalic acid.

[0021] In the present invention, the washing solution described in step (a) is an aqueous solution containing a detergent. The present invention does not limit the preparation process, as long as the object of the present invention can be achieved. Exemplarily, it is prepared according to the following steps: successively adding a detergent and water into a container, and optionally adding an inorganic base, and stirring until clear to obtain a washing solution.

[0022] In the present invention, the process of stirring and washing described in step (a) is not limited, as long as the object of the present invention can be achieved. Exemplarily, it can be achieved by controlling the temperature of the mixture to 40°C - 45°C and the stirring time to 60 - 90 minutes.

[0023] In the present invention, there is no limitation on the method for further separating citalopram or S-citalopram from the organic layer described in step (b), as long as the object of the present invention can be achieved. Exemplarily, the organic layer is concentrated under reduced pressure to dryness.

[0024] In the present invention, in the process of further acid addition for salt formation in step (b), first, the organic layer compressed to dryness is dissolved in an organic solvent, and the temperature is controlled. In the present invention, the organic solvent is selected from at least one of toluene, ethyl acetate, methanol, methyl isobutyl ketone, or absolute ethanol, and the temperature is controlled within the range of 40°C to 60°C. Exemplarily, the organic layer is concentrated under reduced pressure to dryness, added to ethyl acetate for dissolution, and the temperature is controlled at 50°C to 60°C.

[0025] In the process of further acid addition for salt formation in step (b), after the organic layer is dissolved, an acid needs to be added dropwise to adjust the pH = 4 ± 0.5 to form a salt, and the acid salt of citalopram or S-citalopram is obtained after separation. In the present invention, the acid is selected from any one of hydrochloric acid, hydrobromic acid, phosphoric acid, oxalic acid, fumaric acid, acetic acid, p-toluenesulfonic acid, or methanesulfonic acid. Exemplarily, hydrobromic acid is added dropwise to adjust the pH = 4 ± 0.5 to form a salt. After the addition is completed, reflux for 2 hours, cool down for crystallization, filter - dry to obtain citalopram hydrobromide.

[0026] The purification method of citalopram or S-citalopram provided by the present invention is simple in operation, high in impurity removal rate, cheap and easily available in raw materials and auxiliary materials, and mild in conditions, which is conducive to the simple and efficient purification of citalopram or S-citalopram. Detailed implementation mode

[0027] The present invention will be further described in detail below through specific examples, and all raw materials used in the examples are commercially available.

[0028] Example 1

[0029] In a beaker, 2.5 g of sodium dithionite and 50 mL of drinking water are added in sequence, and stirred until dissolved to obtain a washing solution.

[0030] In a three-necked flask, 25 g of citalopram hydrobromide (aldehyde impurity 0.364%), 200 mL of toluene, and 100 mL of drinking water are added in sequence. The temperature is raised to 45°C, and ion-exchange membrane liquid caustic soda is slowly added dropwise to adjust the pH of the aqueous solution to 12. Stir until dissolved and clear, let it stand for layering, and separate to obtain the organic layer. The washing solution is added to the organic layer, and the temperature of the mixture is controlled at 40°C to 45°C, stirred for 60 minutes, let it stand for layering, and separate to obtain the organic layer. The organic layer is concentrated under reduced pressure to dryness, added to 120 mL of ethyl acetate for dissolution, the temperature is controlled at 50°C to 60°C, hydrobromic acid is added dropwise to adjust the pH = 4 ± 0.5 to form a salt. After the addition is completed, reflux for 2 hours, cool down for crystallization, filter - dry to obtain citalopram hydrobromide. The yield is 90%, the purity is 99.7%, the aldehyde impurity is 0.04%, and the impurity removal rate is 89.0%.

[0031] Example 2

[0032] Add 2.5 g of sodium dithionite, 50 mL of drinking water, and 0.25 g of sodium bicarbonate into a beaker in sequence, and stir to dissolve and clarify to obtain a washing solution.

[0033] Add 25 g of citalopram hydrobromide (aldehyde impurity 0.470%), 200 mL of toluene, and 100 mL of drinking water into a three-necked flask in sequence, heat up to 45 °C, slowly add ion-exchange membrane liquid caustic soda dropwise to adjust the pH of the aqueous solution to 12, stir to dissolve and clarify, let it stand for layer separation, and separate to obtain the organic layer. Add the washing solution to the organic layer, control the temperature of the mixture to 40 °C - 45 °C, stir for 60 minutes, let it stand for layer separation, and separate to obtain the organic layer. Concentrate the organic layer under reduced pressure to dryness, add 120 mL of ethyl acetate to dissolve, control the temperature at 50 °C - 60 °C, add hydrobromic acid dropwise to adjust the pH = 4 ± 0.5 to form a salt, reflux for 2 hours after the addition is completed, cool down for crystallization, filter - dry to obtain citalopram hydrobromide. The yield is 91%, the purity is 99.8%, the aldehyde impurity is 0.029%, and the impurity removal rate is 93.8%.

[0034] Example 3

[0035] Add 0.5 g of sodium dithionite, 50 mL of drinking water, and 0.05 g of sodium bicarbonate into a beaker in sequence, and stir to dissolve and clarify to obtain a washing solution.

[0036] Add 25 g of escitalopram oxalate (aldehyde impurity 0.364%), 200 mL of methyl isobutyl ketone, and 100 mL of drinking water into a three-necked flask in sequence, heat up to 45 °C, slowly add 30% potassium hydroxide solution dropwise to adjust the pH of the aqueous solution to 12, stir to dissolve and clarify, let it stand for layer separation, and separate to obtain the organic layer. Add the washing solution to the organic layer, control the temperature of the mixture to 40 °C - 45 °C, stir for 60 minutes, let it stand for layer separation, and separate to obtain the organic layer. Concentrate the organic layer under reduced pressure to dryness, add 48 mL of absolute ethanol, stir to dissolve, control the temperature at 40 °C - 50 °C, add 9.1 g of oxalic acid, stir and react for 2 hours, cool down for crystallization, filter - dry to obtain escitalopram oxalate. The yield is 88%, the purity is 99.9%, the aldehyde impurity is 0.033%, and the impurity removal rate is 90.9%.

[0037] Example 4

[0038] Add 2.3 g of sodium thiosulfate, 50 mL of drinking water, and 0.23 g of sodium carbonate into a beaker in sequence, and stir to dissolve and clarify to obtain a washing solution.

[0039] Add 25 g of citalopram hydrobromide (aldehyde impurity 0.470%) , 200 mL of ethyl acetate and 100 mL of drinking water into a three-necked flask in sequence. Heat up to 45 °C, slowly add ion-exchange membrane caustic soda solution dropwise to adjust the pH of the aqueous solution to 12, stir until dissolved and clear, let it stand for stratification, and separate to obtain the organic layer. Add the washing solution to the organic layer, control the temperature of the mixture to 40 °C - 45 °C, stir for 60 minutes, let it stand for stratification, and separate to obtain the organic layer. Concentrate the organic layer under reduced pressure to dryness, add 120 mL of ethyl acetate to dissolve, control the temperature at 50 °C - 60 °C, add hydrobromic acid dropwise to adjust the pH to 4 ± 0.5 for salification, reflux for 2 hours after the addition is completed, cool down for crystallization, filter - dry to obtain citalopram hydrobromide. The yield is 92%, the purity is 99.8%, the aldehyde impurity is 0.06%, and the impurity removal rate is 87.2%.

[0040] Example 5

[0041] Add 1.8 g of sodium sulfite, 50 mL of drinking water and 0.54 g of potassium bicarbonate into a beaker in sequence, stir until dissolved and clear to obtain the washing solution.

[0042] Add 25 g of citalopram hydrobromide (aldehyde impurity 0.303%) , 200 mL of chlorobenzene and 100 mL of drinking water into a three-necked flask in sequence. Heat up to 45 °C, slowly add ion-exchange membrane caustic soda solution dropwise to adjust the pH of the aqueous solution to 12, stir until dissolved and clear, let it stand for stratification, and separate to obtain the organic layer. Add the washing solution to the organic layer, control the temperature of the mixture to 40 °C - 45 °C, stir for 60 minutes, let it stand for stratification, and separate to obtain the organic layer. Concentrate the organic layer under reduced pressure to dryness, add 120 mL of ethyl acetate to dissolve, control the temperature at 50 °C - 60 °C, add hydrobromic acid dropwise to adjust the pH to 4 ± 0.5 for salification, reflux for 2 hours after the addition is completed, cool down for crystallization, filter - dry to obtain citalopram hydrobromide. The yield is 91%, the purity is 99.7%, the aldehyde impurity is 0.023%, and the impurity removal rate is 92.4%.

[0043] Example 6

[0044] Add 15 g of sodium dithionite, 50 mL of drinking water and 0.75 g of potassium carbonate into a beaker in sequence, stir until dissolved and clear to obtain the washing solution.

[0045] Add 25 g of citalopram hydrobromide (aldehyde impurity 0.303%) , 200 mL of toluene and 100 mL of drinking water into a three-necked flask in sequence. Heat up to 45 °C, slowly add ion-exchange membrane liquid caustic soda dropwise to adjust the pH of the aqueous solution to 12. Stir until it dissolves clearly, let it stand for layering, and separate to obtain the organic layer. Add the washing solution to the organic layer, control the temperature of the mixture to 40 °C - 45 °C, stir for 60 minutes, let it stand for layering, and separate to obtain the organic layer. Concentrate the organic layer under reduced pressure to dryness, add 120 mL of ethyl acetate to dissolve it, control the temperature at 50 °C - 60 °C, add hydrobromic acid dropwise to adjust the pH to 4 ± 0.5 to form a salt. After the addition is completed, reflux for 2 hours, cool down to crystallize, filter - dry to obtain citalopram hydrobromide. The yield is 90%, the purity is 99.8%, the aldehyde impurity is 0.041%, and the impurity removal rate is 86.5%.

[0046] Example 7

[0047] Add 2.5 g of sodium dithionite, 50 mL of drinking water and 0.25 g of sodium hydroxide into a beaker in sequence. Stir until it dissolves clearly to obtain the washing solution.

[0048] Add 25 g of citalopram hydrobromide (aldehyde impurity 0.522%) , 200 mL of methyl isobutyl ketone and 100 mL of drinking water into a three-necked flask in sequence. Heat up to 45 °C, slowly add ion-exchange membrane liquid caustic soda dropwise to adjust the pH of the aqueous solution to 12. Stir until it dissolves clearly, let it stand for layering, and separate to obtain the organic layer. Add the washing solution to the organic layer, control the temperature of the mixture to 40 °C - 45 °C, stir for 60 minutes, let it stand for layering, and separate to obtain the organic layer. Concentrate the organic layer under reduced pressure to dryness, add 120 mL of ethyl acetate to dissolve it, control the temperature at 50 °C - 60 °C, add hydrobromic acid dropwise to adjust the pH to 4 ± 0.5 to form a salt. After the addition is completed, reflux for 2 hours, cool down to crystallize, filter - dry to obtain citalopram hydrobromide. The yield is 93%, the purity is 99.8%, the aldehyde impurity is 0.04%, and the impurity removal rate is 92.3%.

[0049] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the scope of protection of the present invention.

Claims

1. A purification method of citalopram or S-citalopram or their salts, comprising the following steps: (a) Treat a solution composed of citalopram and a water-immiscible organic solvent with a washing solution, and separate to obtain an organic layer containing the citalopram; or, treat a solution composed of S-citalopram and a water-immiscible organic solvent with a washing solution, and separate to obtain an organic layer containing the S-citalopram. (b) Further separate the citalopram or the S-citalopram from the organic layer obtained in step (a); or further add an acid to form a salt, and separate to obtain the acid salt of citalopram or S-citalopram. Wherein, the washing solution in step (a) is an aqueous solution containing a detergent, and the detergent is selected from any one of sodium dithionite, sodium thiosulfate or sodium sulfite. The citalopram or S-citalopram or their salts contain impurities, and the impurity is 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbaldehyde.

2. The purification method according to claim 1, wherein, The water-immiscible organic solvent in step (a) is selected from at least one of toluene, ethyl acetate, methyl isobutyl ketone or chlorobenzene.

3. The purification method according to claim 1, wherein, The detergent is selected from sodium dithionite.

4. The purification method according to claim 1, wherein, In the washing solution in step (a), the mass ratio of the detergent to water is 1% - 30%.

5. The purification method according to claim 1 or 3, wherein, The molar ratio of the detergent to the citalopram or the S-citalopram is 0.05 - 1.

5.

6. The purification method according to claim 1, wherein, An inorganic base is added to the washing solution in step (a).

7. The purification method according to claim 6, wherein, The inorganic base is selected from at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide.

8. The purification method according to claim 6, wherein, The inorganic base is selected from sodium bicarbonate.

9. The purification method according to claim 6, wherein, The mass ratio of the inorganic base to the detergent is 5% - 30%.

10. The purification method according to claim 1, wherein, The acid in step (b) is selected from any one of hydrochloric acid, hydrobromic acid, phosphoric acid, oxalic acid, fumaric acid, acetic acid, p-toluenesulfonic acid or methanesulfonic acid.

11. The purification method according to claim 1, wherein, The acid in step (b) is selected from hydrobromic acid or oxalic acid.

12. The purification method according to claim 1, wherein, The solution composed of citalopram and a water-immiscible organic solvent or the solution composed of S-citalopram and a water-immiscible organic solvent in step (a) is obtained by the following process: Mix citalopram hydrobromide or S-citalopram oxalate, water and a water-immiscible organic solvent, add a base to free, and separate to obtain an organic layer.

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