A method for purifying citalopram or S-citalopram

Abstract

The present application relates to a method for purifying citalopram or S-citalopram or their salts. The method comprises treating citalopram or S-citalopram with a water-soluble solution containing sulfite or thiosulfate, and then taking the organic layer, and further separating to obtain citalopram or S-citalopram free base; or adding acid to form a salt, and separating to obtain citalopram or S-citalopram acid salt. The purification method provided by the present application is simple in operation and high in impurity removal rate.

Description

Technical Field

[0001] This invention relates to a method for purifying citalopram or S-citalopram. Background Technology

[0002] Citalopram (I) is a new generation of antidepressants developed by Lundbeck in Denmark. It is a highly selective serotonin reuptake inhibitor (SSRI). Compared with other antidepressants, SSRIs have four major advantages: (1) high therapeutic index; (2) low incidence of adverse reactions; (3) broad spectrum of action; and (4) convenient administration. Citalopram hydrobromide is a racemic mixture, with its levorotatory isomer being the main active ingredient. The clinical dosage is 20–60 mg. It is considered the "purest" SSRI, rarely causing significant drug interactions and with few adverse reactions.

[0003]

[0004] 1-(3-Dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-aldehyde (Formula II), commonly known as an aldehyde impurity, is an inherent impurity in citalopram hydrobromide and escitalopram oxalate. This impurity is similar in properties to the product and is extremely difficult to remove, typically present at concentrations of around 0.05% to 0.45%. Currently, there are no literature reports on the source and removal of this impurity.

[0005]

[0006] In view of the problems with the above-mentioned impurities, it is essential to develop a purification method for citalopram or S-citalopram impurities. Summary of the Invention

[0007] This invention provides a novel method for purifying citalopram or S-citalopram or their salts, comprising the following steps:

[0008] (a) Pour the washing solution into a solution containing citalopram or S-citalopram and an organic solvent that is immiscible with water, stir and wash, and let stand to separate the layers to obtain an organic layer containing citalopram or S-citalopram.

[0009] (b) The organic layer obtained in step (a) is separated to obtain pure citalopram or S-citalopram; or further acidified to form an acid salt of citalopram or S-citalopram.

[0010] The washing solution in step (a) is an aqueous solution of a detergent, which is selected from sulfites or thiosulfates.

[0011] As a preferred embodiment of the present invention:

[0012] The organic solvent that is immiscible with water in step (a) is selected from toluene, ethyl acetate, methyl isobutyl ketone, and chlorobenzene.

[0013] The solution in step (a) containing citalopram or S-citalopram in an organic solvent immiscible with water originates from the release of citalopram acid salt or S-citalopram acid salt, or can be directly derived from the reaction solution in the synthesis process of citalopram or S-citalopram. The reaction solution can be prepared with reference to existing technical solutions. More preferably, it originates from the release of citalopram hydrobromide or S-citalopram oxalate, that is, the organic layer obtained by releasing citalopram hydrobromide or S-citalopram oxalate in water and a water-insoluble organic solvent with alkali.

[0014] The detergent in the washing solution in step (a) is preferably sodium dithionite, sodium thiosulfate, or sodium sulfite, and more preferably sodium dithionite.

[0015] The molar ratio of the above detergent to citalopram / S-citalopram is 0.05 to 1.5, preferably 0.2.

[0016] In step (a), the mass ratio of detergent to water in the washing solution is 1-30%, preferably 5%.

[0017] The washing solution in step (a) preferably contains an inorganic alkali, preferably sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, and potassium hydroxide, and more preferably sodium bicarbonate.

[0018] The mass ratio of the alkali to the detergent is 5-30%, preferably 10%.

[0019] The acid in step (b) is preferably hydrobromic acid and oxalic acid.

[0020] This invention provides a purification method for citalopram or S-citalopram that is simple to operate, has a high impurity removal rate, uses inexpensive raw materials, and operates under mild conditions. The method of this invention is simple to operate, and the raw materials are inexpensive and readily available. Detailed Implementation

[0021] The present invention will be further described in detail below through specific embodiments. All raw materials used in the embodiments are commercially available.

[0022] Example 1

[0023] Add 2.5g of sodium dithionite and 50mL of drinking water to a beaker, stir and dissolve to obtain a washing solution.

[0024] In a three-necked flask, 25 g of citalopram hydrobromide (0.364% aldehyde impurity), 200 mL of toluene, and 100 mL of drinking water were added sequentially. The mixture was heated to 45°C, and the pH of the aqueous solution was adjusted to 12 by slowly adding alkali through an ion-exchange membrane. The solution was stirred until dissolved, allowed to stand, and the layers were separated to obtain the organic layer. Washing solution was added to the organic layer, and the temperature of the mixture was controlled at 40–45°C. The mixture was stirred for 60 minutes, allowed to stand, and the layers were separated to obtain the organic layer. The organic layer was concentrated to dryness under reduced pressure, dissolved in 120 mL of ethyl acetate, and the temperature was controlled at 50–60°C. Hydrobromic acid was added dropwise to adjust the pH to 4 ± 0.5 to form a salt. After the addition was completed, the mixture was refluxed for 2 hours, cooled to allow crystallization, filtered, and dried to obtain citalopram hydrobromide. The yield was 90%, the purity was 99.7%, the aldehyde impurity was 0.04%, and the impurity removal rate was 89.0%.

[0025] Example 2

[0026] Add 2.5g of sodium dithionite, 50mL of drinking water, and 0.25g of sodium bicarbonate to a beaker in sequence, and stir until dissolved to obtain a washing solution.

[0027] In a three-necked flask, 25 g of citalopram hydrobromide (0.470% aldehyde impurity), 200 mL of toluene, and 100 mL of drinking water were added sequentially. The mixture was heated to 45 °C, and the pH of the aqueous solution was adjusted to 12 by slowly adding alkali through an ion-exchange membrane. The solution was stirred until dissolved, allowed to stand, and the layers were separated to obtain the organic layer. Washing solution was added to the organic layer, and the temperature of the mixture was controlled at 40–45 °C. The mixture was stirred for 60 minutes, allowed to stand, and the layers were separated to obtain the organic layer. The organic layer was concentrated to dryness under reduced pressure, dissolved in 120 mL of ethyl acetate, and the temperature was controlled at 50–60 °C. Hydrobromic acid was added dropwise to adjust the pH to 4 ± 0.5 to form a salt. After the addition was completed, the mixture was refluxed for 2 hours, cooled to allow crystallization, filtered, and dried to obtain citalopram hydrobromide. The yield was 91%, the purity was 99.8%, the aldehyde impurity was 0.029%, and the impurity removal rate was 93.8%.

[0028] Example 3

[0029] Add 0.5g of sodium dithionite, 50mL of drinking water, and 0.05g of sodium bicarbonate to a beaker in sequence, and stir until dissolved to obtain a washing solution.

[0030] In a three-necked flask, 25 g of escitalopram oxalate (0.364% aldehyde impurity), 200 mL of methyl isobutyl ketone, and 100 mL of drinking water were added sequentially. The mixture was heated to 45°C, and 30% potassium hydroxide solution was slowly added dropwise to adjust the pH of the aqueous solution to 12. The mixture was stirred until dissolved, allowed to stand, and the layers were separated to obtain the organic layer. Washing solution was added to the organic layer, and the temperature of the mixture was controlled at 40–45°C. The mixture was stirred for 60 minutes, allowed to stand, and the layers were separated to obtain the organic layer. The organic layer was concentrated to dryness under reduced pressure, and 48 mL of anhydrous ethanol was added. The mixture was stirred until dissolved, and the temperature was controlled at 40–50°C. 9.1 g of oxalic acid was added, and the reaction was stirred for 2 hours. The mixture was cooled to allow crystals to precipitate, and the crystals were filtered and dried to obtain escitalopram oxalate. The yield was 88%, the purity was 99.9%, the aldehyde impurity was 0.033%, and the impurity removal rate was 90.9%.

[0031] Example 4

[0032] Add 2.3g of sodium thiosulfate, 50mL of drinking water, and 0.23g of sodium carbonate to a beaker in sequence, and stir until dissolved to obtain a washing solution.

[0033] In a three-necked flask, 25 g of citalopram hydrobromide (0.470% aldehyde impurity), 200 mL of ethyl acetate, and 100 mL of drinking water were added sequentially. The mixture was heated to 45°C, and the pH of the aqueous solution was adjusted to 12 by slowly adding alkali through an ion-exchange membrane. The solution was stirred until dissolved, allowed to stand, and the layers were separated to obtain the organic layer. Washing solution was added to the organic layer, and the temperature of the mixture was controlled at 40–45°C. The mixture was stirred for 60 minutes, allowed to stand, and the layers were separated to obtain the organic layer. The organic layer was concentrated to dryness under reduced pressure, dissolved in 120 mL of ethyl acetate, and the temperature was controlled at 50–60°C. Hydrobromic acid was added dropwise to adjust the pH to 4 ± 0.5 to form a salt. After the addition was completed, the mixture was refluxed for 2 hours, cooled to allow crystallization, filtered, and dried to obtain citalopram hydrobromide. The yield was 92%, the purity was 99.8%, the aldehyde impurity was 0.06%, and the impurity removal rate was 87.2%.

[0034] Example 5

[0035] Add 1.8g of sodium sulfite, 50mL of drinking water, and 0.54g of potassium bicarbonate to a beaker in sequence, and stir until dissolved to obtain a washing solution.

[0036] In a three-necked flask, 25 g of citalopram hydrobromide (0.303% aldehyde impurity), 200 mL of chlorobenzene, and 100 mL of drinking water were added sequentially. The mixture was heated to 45°C, and the pH of the aqueous solution was adjusted to 12 by slowly adding alkali through an ion-exchange membrane. The solution was stirred until dissolved, allowed to stand, and the layers were separated to obtain the organic layer. Washing solution was added to the organic layer, and the temperature of the mixture was controlled at 40–45°C. The mixture was stirred for 60 minutes, allowed to stand, and the layers were separated to obtain the organic layer. The organic layer was concentrated to dryness under reduced pressure, dissolved in 120 mL of ethyl acetate, and the temperature was controlled at 50–60°C. Hydrobromic acid was added dropwise to adjust the pH to 4 ± 0.5 to form a salt. After the addition was completed, the mixture was refluxed for 2 hours, cooled to allow crystallization, filtered, and dried to obtain citalopram hydrobromide. The yield was 91%, the purity was 99.7%, the aldehyde impurity was 0.023%, and the impurity removal rate was 92.4%.

[0037] Example 6

[0038] Add 15g of sodium dithionite, 50mL of drinking water, and 0.75g of potassium carbonate to a beaker in sequence, and stir until dissolved to obtain a washing solution.

[0039] In a three-necked flask, 25 g of citalopram hydrobromide (0.303% aldehyde impurity), 200 mL of toluene, and 100 mL of drinking water were added sequentially. The mixture was heated to 45°C, and the pH of the aqueous solution was adjusted to 12 by slowly adding alkali through an ion-exchange membrane. The solution was stirred until dissolved, allowed to stand, and the layers were separated to obtain the organic layer. Washing solution was added to the organic layer, and the temperature of the mixture was controlled at 40–45°C. The mixture was stirred for 60 minutes, allowed to stand, and the layers were separated to obtain the organic layer. The organic layer was concentrated to dryness under reduced pressure, dissolved in 120 mL of ethyl acetate, and the temperature was controlled at 50–60°C. Hydrobromic acid was added dropwise to adjust the pH to 4 ± 0.5 to form a salt. After the addition was completed, the mixture was refluxed for 2 hours, cooled to allow crystallization, filtered, and dried to obtain citalopram hydrobromide. The yield was 90%, the purity was 99.8%, the aldehyde impurity was 0.041%, and the impurity removal rate was 86.5%.

[0040] Example 7

[0041] Add 2.5g of sodium dithionite, 50mL of drinking water, and 0.25g of sodium hydroxide to a beaker in sequence, and stir until dissolved to obtain a washing solution.

[0042] In a three-necked flask, 25 g of citalopram hydrobromide (0.522% aldehyde impurity), 200 mL of methyl isobutyl ketone, and 100 mL of drinking water were added sequentially. The mixture was heated to 45°C, and the pH of the aqueous solution was adjusted to 12 by slowly adding alkali through an ion-exchange membrane. The solution was stirred until dissolved, allowed to stand, and the layers were separated to obtain the organic layer. Washing solution was added to the organic layer, and the temperature of the mixture was controlled at 40–45°C. The mixture was stirred for 60 minutes, allowed to stand, and the layers were separated to obtain the organic layer. The organic layer was concentrated to dryness under reduced pressure, dissolved in 120 mL of ethyl acetate, and the temperature was controlled at 50–60°C. Hydrobromic acid was added dropwise to adjust the pH to 4 ± 0.5 to form a salt. After the addition was completed, the mixture was refluxed for 2 hours, cooled to allow crystallization, filtered, and dried to obtain citalopram hydrobromide. The yield was 93%, the purity was 99.8%, the aldehyde impurity was 0.04%, and the impurity removal rate was 92.3%.

Claims

1. A method for purifying citalopram or S-citalopram or their salts, comprising the following steps: (a) Treat a solution containing citalopram or S-citalopram in an organic solvent that is immiscible with water with a washing solution to separate an organic layer containing citalopram or S-citalopram. (b) The organic layer obtained in step (a) is further separated to obtain citalopram or S-citalopram; or further acidified to form a salt, and the acid salt of citalopram or S-citalopram is separated. The washing solution in step (a) is an aqueous solution containing a detergent, which is selected from sulfites or thiosulfates. The citalopram or S-citalopram or their salts include impurities, said impurities being 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-aldehyde. The detergents mentioned are sodium dithionite, sodium thiosulfate, and sodium sulfite. In step (a), the mass ratio of the detergent to water is 1-30%. The molar ratio of detergent to citalopram or S-citalopram is 0.05-1.

5.

2. The method according to claim 1, wherein the water-immiscible organic solvent in step (a) is selected from toluene, ethyl acetate, methyl isobutyl ketone, and chlorobenzene.

3. The method according to claim 2, wherein the mass ratio of the detergent to water in step (a) is 5%.

4. The preparation method according to claim 1, wherein the molar ratio of detergent to citalopram or S-citalopram is 0.

2.

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

6. The method according to claim 5, wherein the inorganic base is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, and potassium hydroxide.

7. The method according to claim 5, wherein the mass ratio of the alkali to the detergent is 5-30%.

8. The method according to claim 5, wherein the mass ratio of the alkali to the detergent is 10%.

9. The method according to claim 1, wherein the acid in step (b) is hydrobromic acid and oxalic acid.

10. The method according to claim 1, wherein the solution containing citalopram or S-citalopram in an organic solvent immiscible with water in step (a) is obtained by the following process: adding alkali to citalopram hydrobromide or S-citalopram oxalate in water and a water-insoluble organic solvent to release it, and separating to obtain an organic layer.

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