A purification method for a key intermediate of citalopram
By treating the mixed solution with detergent and adding acid to form a salt, the aldehyde impurity in 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride was successfully removed, improving the product purity and maintaining a high yield, thus solving the problem of difficulty in improving purity in the prior art.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
- Filing Date
- 2021-01-14
- Publication Date
- 2026-05-26
AI Technical Summary
In the prior art, 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride contains aldehyde impurities that are difficult to remove, and their properties are similar to those of the product, making it difficult to improve purity.
A mixed solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile and a water-insoluble organic solvent was treated with an aqueous solution containing detergent. Impurities were removed by washing, separation, and acidification to form salts. Specifically, sulfites or thiosulfates were used as detergents, and the pH was adjusted with an appropriate inorganic base, preferably a carbonate base. Temperature and stirring time were controlled to separate and purify the target analyte.
It achieves efficient removal of impurities, improves product purity, has a high yield, is simple to operate, operates under mild conditions, and uses inexpensive raw materials.
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Abstract
Description
Technical Field
[0001] This invention relates to a method for purifying a key intermediate of citalopram. Background Technology
[0002] 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride is a key intermediate in the synthesis of citalopram hydrobromide and escitalopram oxalate, and its structural formula is shown below:
[0003]
[0004] Citalopram hydrobromide 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.
[0005] To date, the main method for preparing 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride is as follows: 5-cyanophthalide is first added to p-fluorophenyl magnesium bromide, then reacted with 3-dimethylaminopropyl magnesium chloride, followed by hydrolysis to obtain 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride. The route is shown below:
[0006]
[0007] Studies have shown that this synthesis process easily produces 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzaldehyde impurity (Formula I). This impurity has similar properties to the product and is extremely difficult to remove, with a content level of about 0.1-0.4%.
[0008]
[0009] In view of the above-mentioned impurities, it is essential to develop a purification method for 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride. Summary of the Invention
[0010] This invention provides a method for purifying 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile or a salt thereof, comprising the following steps:
[0011] (a) A mixed solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile and a water-insoluble organic solvent was treated with a washing solution to remove the aqueous layer, thereby obtaining an organic layer containing 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile;
[0012] (b) The organic layer obtained in step (a) is further separated to obtain a free base of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile; or acid is added to form a salt, and the acid salt of 4-[4-(dimethylamino)-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile is separated.
[0013] The washing solution in step (a) is an aqueous solution containing a detergent, which is selected from sulfites or thiosulfates.
[0014] As a preferred embodiment of the present invention:
[0015] The water-insoluble organic solvent mentioned in step (a) is selected from toluene, ethyl acetate, methyl isobutyl ketone, and chlorobenzene.
[0016] The mixed solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile and water-insoluble organic solvent in step (a) is the organic layer obtained by adding alkali to 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride and separating it; or it can be directly derived from the reaction solution of the synthesis process of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile, and the reaction solution can be prepared with reference to existing technical solutions, such as WO2016197320A1.
[0017] The detergent in the washing solution in step (a) is preferably sodium dithionite, sodium thiosulfate, and sodium sulfite, and more preferably sodium dithionite.
[0018] The molar ratio of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile to detergent in step (a) is 0.05 to 1.5.
[0019] The mass ratio of detergent to water in the washing solution in step (a) is 1-30%, preferably 5%.
[0020] The washing solution in step (a) preferably contains an appropriate inorganic base, preferably sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, and potassium hydroxide, and more preferably sodium bicarbonate. The addition of the inorganic base can protect the stability of sulfites and thiosulfates in aqueous solution.
[0021] The amount of alkali used is 5-30% of the weight of the detergent, preferably 10%. The pH range of the washing solution is preferably 9-10.
[0022] The acid in step (b) is preferably hydrochloric acid.
[0023] This invention provides a purification method for 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile or its salts, which is simple to operate, has a high impurity removal rate, uses inexpensive raw materials, and operates under mild conditions. Detailed Implementation
[0024] All raw materials used in the embodiments are commercially available. The following specific embodiments are merely preferred embodiments of the present invention and are used to further describe the present invention in detail. They should not be construed as limiting the scope of the present invention.
[0025] Example 1
[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 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride (0.187% 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 for separation, and the aqueous layer was removed. Washing solution was added to the separated organic layer, and the temperature of the solution was controlled at 40–45 °C. The mixture was stirred for 60 minutes, allowed to stand for separation, and the aqueous layer was removed to obtain the organic layer. 30 mL of drinking water was added to the organic layer, and purified hydrochloric acid was added dropwise to adjust the pH of the aqueous layer to 4–5. The mixture separated, cooled to 0–5 °C, and filtered. 24 mL of acetone was added to the filter cake, and the mixture was pulped and dried to obtain 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride. Yield: 90%, Purity: 99.95%, Aldehyde impurities: 0.017%, Impurity removal rate: 90.9%.
[0028] Example 2
[0029] Add 0.5g of sodium dithionite, 50mL of drinking water, and 0.15g of sodium carbonate to a beaker in sequence, and stir until dissolved to obtain a washing solution.
[0030] In a three-necked flask, 25 g of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride (aldehyde impurity 0.2-10%), 200 mL of methyl isobutyl ketone, and 100 mL of drinking water were added sequentially. The temperature was raised to 45°C, and the pH of the aqueous solution was adjusted to 12 by slowly adding alkali from the ion-exchange membrane solution. The solution was stirred until dissolved, allowed to stand, and the aqueous layer was removed. The prepared washing solution was added to the separated organic layer, and the temperature of the solution was controlled at 40-45°C. The solution was stirred for 60 minutes, allowed to stand for separation, and the aqueous layer was removed to obtain the organic layer. 30 mL of drinking water was added to the organic layer, and purified hydrochloric acid was added dropwise to adjust the pH of the aqueous layer to 4-5. The solution separated, cooled to 0-5°C, and filtered. 24 mL of acetone was added to the filter cake, and the mixture was pulped and dried to obtain 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride. Yield: 92%, Purity: 99.91%, Aldehyde impurities: 0.018%, Impurity removal rate: 91.4%.
[0031] Example 3
[0032] 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.
[0033] In a three-necked flask, 25 g of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride (0.2-10% 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 from the ion-exchange membrane solution. The solution was stirred until dissolved, allowed to stand, and the aqueous layer was removed. A prepared washing solution was added to the separated organic layer, and the temperature of the solution was controlled at 40-45°C. The mixture was stirred for 60 minutes, allowed to stand, and the aqueous layer was removed to obtain the organic layer. 30 mL of drinking water was added to the organic layer, and purified hydrochloric acid was added dropwise to adjust the pH of the aqueous layer to 4-5. The layers separated, the solution was cooled to 0-5°C, and the mixture was filtered. 24 mL of acetone was added to the filter cake, and the mixture was pulped and dried to obtain 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride. Yield: 89%, Purity: 99.90%, Aldehyde impurities: 0.025%, Impurity removal rate: 88.1%.
[0034] Example 4
[0035] Add 0.5g of sodium sulfite, 50mL of drinking water, and 0.05g of sodium hydroxide to a beaker in sequence, and stir until dissolved to obtain a washing solution.
[0036] In a three-necked flask, 25 g of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride (0.2-10% aldehyde impurity), 200 mL of toluene, and 100 mL of drinking water were added sequentially. The temperature was raised to 45°C, and the pH of the aqueous solution was adjusted to 12 by slowly adding alkali from the ion-exchange membrane solution. The solution was stirred until dissolved, allowed to stand, and the aqueous layer was removed. Washing solution was added to the separated organic layer, and the temperature of the solution was controlled at 50-60°C. The solution was stirred for 120 minutes, allowed to stand, and the aqueous layer was removed to obtain the organic layer. 30 mL of drinking water was added to the organic layer, and purified hydrochloric acid was added dropwise to adjust the pH of the aqueous layer to 4-5. The solution separated, cooled to 0-5°C, and filtered. 24 mL of acetone was added to the filter cake, and the mixture was pulped and dried to obtain 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride. Yield: 90%, Purity: 99.92%, Aldehyde impurities: 0.021%, Impurity removal rate: 90%.
[0037] Example 5
[0038] Add 0.05g of sodium thiosulfate, 50mL of drinking water, and 0.02g of potassium hydroxide to a beaker in sequence, and stir until dissolved to obtain a washing solution.
[0039] In a three-necked flask, 25 g of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride (0.2-10% aldehyde impurity), 200 mL of methyl isobutyl ketone, and 100 mL of drinking water were added sequentially. The temperature was raised to 45°C, and the pH of the aqueous solution was adjusted to 12 by slowly adding alkali from the ion-exchange membrane. The solution was stirred until dissolved, allowed to stand for separation, and the aqueous layer was removed. Washing solution was added to the separated organic layer, and the temperature of the solution was controlled at 40-45°C. The solution was stirred for 60 minutes, allowed to stand for separation, and the aqueous layer was removed to obtain the organic layer. 30 mL of drinking water was added to the organic layer, and purified hydrochloric acid was added dropwise to adjust the pH of the aqueous layer to 4-5. The solution separated, cooled to 0-5°C, and filtered. 24 mL of acetone was added to the filter cake, and the mixture was pulped and dried to obtain 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride. Yield: 92%, purity: 99.91%, aldehyde impurities: 0.030%, impurity removal rate: 85.7%.
[0040] Example 6
[0041] Add 0.5g of sodium sulfite, 50mL of drinking water, and 0.05g of potassium bicarbonate to a beaker and stir until dissolved to obtain a washing solution. In a three-necked flask, add 25g of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride (aldehyde impurity 0.2-10%), 200mL of methyl isobutyl ketone, and 100mL of drinking water. Heat to 45℃, slowly add alkali from the ion-exchange membrane to adjust the pH of the solution to 12, stir until dissolved, allow to stand and separate into layers, and remove the aqueous layer. Add the washing solution to the separated organic layer, control the temperature of the solution at 40-45℃, stir for 60 minutes, allow to stand and separate into layers, remove the aqueous layer, and obtain the organic layer. Add 30 mL of drinking water to the organic layer, and adjust the pH of the aqueous layer to 4–5 by adding purified hydrochloric acid dropwise. After separation, cool the aqueous solution to 0–5 °C, filter, add 24 mL of acetone to the filter cake, and slurry-dry to obtain 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride. Yield: 90%, purity: 99.89%, aldehyde impurities: 0.022%, impurity removal rate: 89.5%.
Claims
1. A method for purifying 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile or a salt thereof, comprising the following steps: (a) A mixed solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile and a water-insoluble organic solvent was treated with a washing solution to remove the aqueous layer, thereby obtaining an organic layer containing 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile; (b) The organic layer obtained in step (a) is further separated to obtain the free base of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile; or acid is added to form a salt to separate the acid salt of 4-[4-(dimethylamino)-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile; The washing solution in step (a) is an aqueous solution containing a detergent, which is selected from sodium dithionite, sodium thiosulfate, and sodium sulfite. The 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile or its salts include impurities, said impurities being 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzaldehyde.
2. The method according to claim 1, wherein the water-insoluble organic solvent in step (a) is selected from toluene, ethyl acetate, methyl isobutyl ketone, and chlorobenzene.
3. The method according to claim 1, wherein the molar ratio of detergent to 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile is 0.05 to 1.
5.
4. The method according to claim 1, wherein the washing solution in step (a) further contains an inorganic base.
5. The method according to claim 4, wherein the inorganic base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, and potassium hydroxide.
6. The method according to claim 4, wherein the mass ratio of the inorganic alkali to the detergent is 5-30%.
7. The method according to claim 1, wherein the acid in step (b) is hydrochloric acid.
8. The method according to claim 1, wherein the mixed solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile and water-insoluble organic solvent in step (a) is the organic layer obtained by adding alkali to 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride and separating it.