A purification method for a key intermediate of citalopram

Abstract

This invention relates to a purification method for a key intermediate of citalopram, namely 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile and its salts. The method includes dissolving crude 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile (containing formaldehyde impurities, compound I) in an organic solvent, adding a washing solution, controlling the temperature, stirring, allowing the mixture to stand and separate into layers, and removing the aqueous layer to obtain a purified organic solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile. The method provided by this invention can effectively remove the aldehyde impurities from the intermediate. This method is simple to operate, uses inexpensive raw materials, and operates under mild conditions, making it suitable for large-scale industrial production.

Description

[0001] This application claims priority to Chinese Patent Application No. 202110047338.2, filed on January 14, 2021, entitled "A Purification Method for a Key Intermediate of Citalopram", the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to a method for purifying a key intermediate of citalopram. Background Technology

[0003] 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:

[0004]

[0005] To date, the main method for preparing 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride is as follows: 5-cyanophthalide undergoes an addition reaction with p-fluorophenyl magnesium bromide, followed by a reaction with 3-dimethylaminopropyl magnesium chloride, and then hydrolysis-salt formation to obtain 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride. The synthetic route is shown below:

[0006]

[0007] Studies have shown that this synthetic route is prone to producing 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzaldehyde impurity (Formula I). ​​This impurity is similar in nature 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 or its hydrochloride. Summary of the Invention

[0010] On the one hand, the present invention provides a purification method for 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile.

[0011] A purification method for 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile includes the following steps: dissolving crude 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile (containing formaldehyde impurities, i.e., compound of formula I) in an organic solvent to obtain an organic solution of dissolved 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile; then adding a washing solution containing water to the solution; controlling the temperature; stirring; allowing the solution to stand and separate into layers; removing the water layer to obtain a purified organic solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile; and concentrating the solution to dryness to obtain a purified organic solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile.

[0012] As a preferred technical solution, the aqueous washing solution comprises dithionite, water, and optionally an inorganic alkali; preferably, the dithionite is sodium dithionite.

[0013] Furthermore, the weight-to-volume ratio of sodium dithionite to water is from 0.01 g / mL to 0.3 g / mL, preferably 0.05 g / mL.

[0014] Furthermore, the inorganic base is one or more of sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, potassium carbonate, and sodium carbonate, preferably one or a combination of two of sodium bicarbonate or potassium carbonate.

[0015] Furthermore, the weight ratio of the inorganic base to sodium dithionite is 0 to 0.3, preferably 0.1.

[0016] Preferably, the controlled temperature is 40°C to 45°C.

[0017] Preferably, the volume-to-weight ratio of the aqueous washing solution to the crude 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile is 1 to 5 mL / g, preferably 2 mL / g.

[0018] Preferably, the organic solvent is a water-insoluble organic solvent selected from toluene, ethyl acetate, methyl isobutyl ketone, or chlorobenzene.

[0019] Preferably, the volume-to-weight ratio of the organic solvent to the crude 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile is 2 mL / g to 10 mL / g.

[0020] Preferably, the dissolved organic solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile can be obtained by dissolving crude 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride, adjusting the pH value with liquid alkali, stirring to dissolve, allowing to stand and separate into layers, and removing the aqueous layer.

[0021] On the other hand, the present invention provides a method for purifying 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride, comprising:

[0022] 1) After dissolving the crude product of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride, the pH value was adjusted by adding liquid alkali, the mixture was stirred and dissolved, and the layers were allowed to stand and separate. After removing the water layer, an organic solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile was obtained.

[0023] 2) Then, add an aqueous washing solution to the dissolved organic solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile in step 1), control the temperature, stir, let stand to separate the layers, remove the water layer, and obtain a purified organic solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile;

[0024] 3) Add hydrochloric acid solution to the purified organic solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile to adjust the pH value, separate the layers, filter, add acetone, slurry, and dry to obtain purified 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride.

[0025] Preferably, the crude 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride is dissolved by adding a mixed solution of an organic solvent and water, wherein the organic solvent is a water-insoluble organic solvent selected from toluene, ethyl acetate, methyl isobutyl ketone or chlorobenzene, and the volume ratio of the organic solvent to water is 1:1 to 5:1.

[0026] Furthermore, the volume-to-weight ratio of the organic solvent to 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride is from 2 mL / g to 10 mL / g.

[0027] The purification method of the present invention is also suitable for the purification of other 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile salts, such as 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile sulfate or 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrobromide.

[0028] The crude products of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile and the crude product of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile salt described in this invention both contain impurities of formula I.

[0029] This invention provides a purification method for 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile and its salts, which has a high formaldehyde impurity removal rate, is simple to operate, uses inexpensive raw materials, and operates under mild conditions, making it suitable for large-scale industrial production. Detailed Implementation

[0030] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the embodiments. Obviously, the described embodiments are merely some embodiments of this invention, and not all embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of this invention are within the scope of protection of this invention.

[0031] 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.

[0032] Example 1

[0033] Add 0.5g of sodium dithionite, 50mL of water, and 0.05g of sodium carbonate to a beaker in sequence, and stir until dissolved to obtain an aqueous washing solution.

[0034] In a three-necked flask, 20 g of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile (0.163% impurity in Formula I) and 100 mL of toluene were added sequentially. The mixture was heated to 40-45°C and stirred until dissolved. Then, a washing solution containing water was added, and the temperature of the solution was controlled at 40-45°C. The mixture was stirred for 30 minutes, allowed to stand and separate into layers, the water layer was removed, and the organic layer was concentrated and evaporated to dryness to obtain purified 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile with a purity of 99.93% and a yield of 95%. The impurity in Formula I was found to be 0.01%.

[0035] Example 2

[0036] Add 0.5g of sodium dithionite and 50mL of water to a beaker, stir until dissolved to obtain an aqueous washing solution.

[0037] In a three-necked flask, 20 g of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile (0.163% impurity in Formula I) and 100 mL of toluene were added sequentially. The mixture was heated to 40-45°C and stirred until dissolved. Then, washing solution was added, and the temperature of the solution was controlled at 40-45°C. The mixture was stirred for 30 minutes, allowed to stand and separate into layers, the aqueous layer was removed, and the organic layer was concentrated and evaporated to dryness to obtain purified 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile with a purity of 99.90% and a yield of 96%. The impurity in Formula I was found to be 0.022%.

[0038] Example 3

[0039] In a three-necked flask, 25 g of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride, 200 mL of toluene, and 100 mL of 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 an ion-exchange membrane. The solution was stirred until dissolved, allowed to stand, and the layers were separated. The aqueous layer was removed, and the organic layer was a toluene solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile. The content of impurities in Formula I was found to be 0.182%.

[0040] Example 4

[0041] Add 2.5g of sodium dithionite and 50mL of water to a beaker, stir until dissolved to obtain an aqueous washing solution.

[0042] A water-containing washing solution was added to the toluene solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile prepared in Example 3. The temperature of the solution was controlled at 40°C to 45°C, and the mixture was stirred for 60 minutes. After standing and separating the layers, the water layer was removed to obtain a purified toluene solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile. The content of impurities in Formula I was found to be 0.02%.

[0043] Example 5

[0044] Add 2.5g of sodium dithionite, 50mL of water, and 0.25g of potassium carbonate to a beaker in sequence, and stir until dissolved to obtain a washing solution.

[0045] A water-containing washing solution was added to the toluene solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile prepared in Example 3. The temperature of the solution was controlled at 40°C to 45°C, and the mixture was stirred for 60 minutes. After standing and separating the layers, the water layer was removed to obtain a purified toluene solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile. The content of impurities in Formula I was found to be 0.04%.

[0046] Example 6

[0047] Add 15g of sodium dithionite, 50mL of water, and 0.75g of potassium carbonate to a beaker in sequence, and stir until dissolved to obtain an aqueous washing solution.

[0048] A water-containing washing solution was added to the toluene solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile prepared in Example 3. The temperature of the solution was controlled at 40°C to 45°C, and the mixture was stirred for 60 minutes. After standing and separating the layers, the water layer was removed to obtain a purified toluene solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile. The content of impurities in Formula I was found to be 0.014%.

[0049] Example 7

[0050] Add 2.5g of sodium dithionite, 50mL of water, and 0.25g of sodium bicarbonate to a beaker in sequence, and stir until dissolved to obtain an aqueous washing solution.

[0051] A water-containing washing solution was added to the toluene solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile prepared in Example 3. The temperature of the solution was controlled at 40°C to 45°C, and the mixture was stirred for 60 minutes. After standing and separating the layers, the water layer was removed to obtain a purified toluene solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile. The content of impurities in Formula I was found to be 0.022%.

[0052] Example 8

[0053] Add 2.5g of sodium dithionite, 50mL of water, and 0.25g of sodium bicarbonate to a beaker in sequence, and stir until dissolved to obtain an aqueous washing solution.

[0054] In a three-necked flask, 25 g of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride (formula I, impurity 0.187%), 200 mL of toluene, and 100 mL of 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 for separation, and the aqueous layer was removed. Aqueous washing solution was added to the separated organic layer, and the temperature of the solution was controlled at 40 °C to 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 water was added to the organic layer, and concentrated hydrochloric acid was added dropwise to adjust the pH of the aqueous layer to 4 to 5. The layers separated, the aqueous solution was cooled to 0 to 5 °C, centrifuged and filtered, and 24 mL of acetone was added to the filter cake. The mixture was then pulped and dried to obtain 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride. Yield: 90%, purity: 99.95%, Formula I impurities: 0.017%, impurity removal rate: 90.9%.

[0055] Example 9

[0056] Add 0.5g of sodium dithionite, 50mL of water, and 0.15g of sodium carbonate to a beaker in sequence, and stir until dissolved to obtain an aqueous washing solution.

[0057] In a three-necked flask, 25 g of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride (formula I, impurity 0.2-10%), 200 mL of methyl isobutyl ketone, and 100 mL of 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 aqueous washing solution was added to the separated organic layer, and the temperature of the solution was controlled at 40°C to 45°C. The mixture was stirred for 60 minutes, allowed to stand, and the layers were separated. The aqueous layer was removed to obtain the organic layer. 30 mL of water was added to the organic layer, and concentrated hydrochloric acid was added dropwise to adjust the pH of the aqueous layer to 4 to 5. The layers separated, and the aqueous solution was cooled to 0-5°C. The mixture was centrifuged 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%, Formula I impurities: 0.018%, impurity removal rate: 91.4%.

[0058] Example 10

[0059] Add 15g of sodium dithionite, 50mL of water, and 0.75g of potassium carbonate to a beaker in sequence, and stir until dissolved to obtain an aqueous washing solution.

[0060] In a three-necked flask, 25 g of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride (formula I, impurity 0.2-10%), 200 mL of ethyl acetate, and 100 mL of 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 aqueous washing solution was added to the separated organic layer, and the temperature of the solution was controlled at 40°C to 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 water was added to the organic layer, and concentrated hydrochloric acid was added dropwise to adjust the pH of the aqueous layer to 4 to 5. The layers separated, and the aqueous solution was cooled to 0°C to 5°C. The mixture was centrifuged 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: 89%, purity: 99.90%, Formula I impurities: 0.025%, impurity removal rate: 88.1%.

[0061] Example 11

[0062] Add 0.5g of sodium sulfite, 50mL of water, and 0.05g of sodium hydroxide to a beaker in sequence, and stir until dissolved to obtain an aqueous washing solution.

[0063] In a three-necked flask, 25 g of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride (Formula I, impurity 0.2-10%), 200 mL of toluene, and 100 mL of 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. Aqueous washing solution was added to the separated organic layer, and the temperature of the solution was controlled at 50°C to 60°C. The mixture was stirred for 120 minutes, allowed to stand, and the aqueous layer was removed to obtain the organic layer. 30 mL of water was added to the organic layer, and concentrated hydrochloric acid was added dropwise to adjust the pH of the aqueous layer to 4 to 5. The layers separated, and the aqueous solution was cooled to 0°C to 5°C. The mixture was centrifuged 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%, Formula I impurities: 0.021%, impurity removal rate: 90%.

[0064] Example 12

[0065] Add 0.05g of sodium thiosulfate, 50mL of water, and 0.02g of potassium hydroxide to a beaker in sequence, and stir until dissolved to obtain an aqueous washing solution.

[0066] In a three-necked flask, 25 g of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride (Formula I, impurity 0.2-10%), 200 mL of methyl isobutyl ketone, and 100 mL of 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 to the ion-exchange membrane solution. 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°C to 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 water was added to the organic layer, and concentrated hydrochloric acid was added dropwise to adjust the pH of the aqueous layer to 4 to 5. The layers separated, and the aqueous solution was cooled to 0°C to 5°C. The mixture was centrifuged 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%, Formula I impurities: 0.030%, impurity removal rate: 85.7%.

[0067] Example 13

[0068] Add 0.5g of sodium sulfite, 50mL of water, and 0.05g of potassium bicarbonate to a beaker, and stir until dissolved to obtain an aqueous washing solution. In a three-necked flask, add 25g of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride (0.210% impurity of Formula I), 200mL of methyl isobutyl ketone, and 100mL of water, and heat to 45℃. Slowly add alkali from the ion-exchange membrane solution to adjust the pH to 12, stir until dissolved, and allow to stand to separate the layers. Remove the aqueous layer. Add the aqueous washing solution to the separated organic layer, control the temperature of the solution at 40℃ to 45℃, stir for 60 minutes, allow to stand to separate the layers, remove the aqueous layer, and obtain the organic layer. Add 30 mL of water to the organic layer, and adjust the pH of the aqueous layer to 4-5 by adding concentrated hydrochloric acid dropwise. Separate the layers, cool the aqueous solution to 0-5°C, centrifuge and filter. Add 24 mL of acetone to the filter cake, slurry and dry to obtain 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride. Yield: 90%, purity: 99.89%, Formula I impurities: 0.022%, impurity removal rate: 89.5%.

[0069] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for purifying 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile, comprising the following steps: The crude product of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile was dissolved in an organic solvent to obtain an organic solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile. Then, an aqueous washing solution was added to the solution, the temperature was controlled, the mixture was stirred, and the layers were allowed to separate. The aqueous layer was removed to obtain a purified organic solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile. The solution was concentrated to dryness to obtain a purified organic solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile. The aqueous washing solution comprises dithionite, water, and optionally an inorganic base; the dithionite is sodium dithionite.

2. The purification method according to claim 1, characterized in that... The weight-to-volume ratio of the dithionite to water is from 0.01 g / mL to 0.3 g / mL.

3. The purification method according to claim 2, characterized in that... The weight-to-volume ratio of the dithionite to water is 0.05 g / mL.

4. The purification method according to claim 1, characterized in that... The inorganic base is one or more of sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, potassium carbonate, and sodium carbonate.

5. The purification method according to claim 4, characterized in that... The inorganic base is one or a combination of sodium bicarbonate or potassium carbonate.

6. The purification method according to claim 1 or 4, characterized in that... The weight ratio of the inorganic base to the dithionite is 0 to 0.

3.

7. The purification method according to claim 6, characterized in that... The weight ratio of the inorganic base to the dithionite is 0.

1.

8. The purification method according to claim 1, characterized in that... The temperature should be controlled between 40°C and 45°C.

9. The purification method according to claim 1, characterized in that... The volume-to-weight ratio of the aqueous washing solution to the crude 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile is 1 mL / g to 5 mL / g.

10. The purification method according to claim 9, characterized in that... The volume-to-weight ratio of the aqueous washing solution to the crude 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile is 2 mL / g.

11. The purification method according to claim 1, characterized in that... The organic solvent is a water-insoluble organic solvent, selected from toluene, ethyl acetate, methyl isobutyl ketone, or chlorobenzene.

12. The purification method according to claim 1, characterized in that... The volume-to-weight ratio of the organic solvent to 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile is from 2 mL / g to 10 mL / g.

13. The purification method according to claim 1, characterized in that... The dissolved organic solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile can be obtained by dissolving crude 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride, adjusting the pH value with liquid alkali, stirring to dissolve, allowing to stand and separate into layers, and removing the aqueous layer.

14. A method for purifying 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride, comprising: 1) After dissolving the crude product of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride, the pH value was adjusted by adding liquid alkali, the mixture was stirred and dissolved, and the layers were allowed to stand and separate. After removing the water layer, an organic solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile was obtained. 2) Then, add an aqueous washing solution to the dissolved organic solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile from step 1), control the temperature, stir, allow to stand and separate into layers, remove the water layer, and obtain a purified organic solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile; wherein, the aqueous washing solution contains dithionite, water, and optionally an inorganic base; the dithionite is sodium dithionite; 3) Add hydrochloric acid solution to the purified organic solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile to adjust the pH value and separate the layers. After filtration, add acetone, slurry and dry to obtain purified 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride.

15. The purification method according to claim 14, characterized in that... The crude 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride was dissolved by adding a mixed solution of an organic solvent and water. The organic solvent was a water-insoluble organic solvent selected from toluene, ethyl acetate, methyl isobutyl ketone, or chlorobenzene, and the volume ratio of the organic solvent to water was 1:1 to 5:

1.

16. The purification method according to claim 14, characterized in that... The volume-to-weight ratio of the organic solvent to 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride is from 2 mL / g to 10 mL / g.

17. The application of the purification method according to claim 1 in the purification of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile salt.

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