Method for purifying key intermediates of citalopram
The present invention relates to a method for purifying key intermediates of Citalopram, i.e. 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile and a salt thereof. The method comprises dissolving crude 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile (compound of formula I containing formaldehyde impurity) with an organic solvent, adding a washing solution, controlling the temperature, stirring, leaving to stand for layering, and removing the aqueous layer, so as to obtain a purified organic solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile. The method provided by the present invention can effectively remove aldehyde group-containing impurities in the intermediate. The method of the present invention has the advantages of simple operation, cheap raw materials and mild conditions, and is suitable for large-scale industrial production.
1 . A purification method for 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile, comprising the steps of:
dissolving a crude 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile in an organic solvent to obtain an organic solution of dissolved 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile;
adding an aqueous washing solution to the organic solution, and under a controlled temperature, stirring, standing and layering the mixed solution, and removing the aqueous layer to obtain a purified organic solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile; and
concentrating the purified organic solution to dryness to obtain a purified 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile.
2 . The purification method according to claim 1 , wherein the aqueous washing solution comprises dithionite, water, and optionally an inorganic base.
3 . The purification method according to claim 2 , wherein a weight to volume ratio of the dithionite and water ranges from 0.01 g/mL to 0.3 g/mL.
4 . The purification method according to claim 2 , wherein the inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, potassium carbonate, and sodium carbonate, or any combinations thereof.
5 . The purification method according to claim 2 , wherein a weight ratio of the inorganic base and dithionite ranges from 0 to 0.3.
6 . The purification method according to claim 1 , wherein the controlled temperature is 40° C. to 45° C.
7 . The purification method according to claim 1 , wherein a volume to weight ratio of the aqueous washing solution and the crude 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile ranges from 1 mL/g to 5 mL/g.
8 . The purification method according to claim 1 , wherein the organic solvent is a water-immiscible organic solvent selected from the group consisting of toluene, ethyl acetate, methyl isobutyl ketone and chlorobenzene.
9 . The purification method according to claim 1 , wherein a volume to weight ratio of the organic solvent and the crude 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile ranges from 2 mL/g to 10 mL/g.
10 . The purification method according to claim 1 , wherein the organic solution of dissolved 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile can be obtained by dissolving a crude 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride, liquid caustic soda to adjust pH, stirring the mixture to dissolve, standing and layering the thus obtained solution, and removing the aqueous layer.
11 . A purification method for 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride, comprising:
1) dissolving a crude 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride, adding liquid caustic soda to adjust pH, stirring the mixture to dissolve, standing and layering the thus obtained solution, and removing the aqueous layer to obtain an organic solution of dissolved 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile;
2) adding an aqueous washing solution to the organic solution of dissolved 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile in step 1), and under a controlled temperature, stirring, standing and layering the mixed solution, and removing the aqueous layer to obtain a purified organic solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile; and
3) adding a hydrochloric acid solution to the purified organic solution of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile to adjust pH, and layering, filtering the mixture and adding with acetone, purifying the resultant by trituration, and drying the product to obtain a purified 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride.
12 . The purification method according to claim 11 , wherein the crude 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride is dissolved by adding a mixture of an organic solvent and water, and the organic solvent is a water-immiscible organic solvent selected from the group consisting of toluene, ethyl acetate, methyl isobutyl ketone and chlorobenzene, and a volume ratio of the organic solvent and water ranges from 1:1 to 5:1.
13 . The purification method according to claim 11 , wherein a volume to weight ratio of the organic solvent and 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile hydrochloride ranges from 2 mL/g to 10 mL/g.
14 . Use of the purification method according to claim 1 in the purification of a salt of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile.
15 . The purification method according to claim 2 , wherein the dithionite is sodium dithionite.
16 . The purification method according to claim 2 , wherein a weight to volume ratio of the dithionite and water is 0.05 g/mL.
17 . The purification method according to claim 2 , wherein the inorganic base is selected from sodium bicarbonate and potassium carbonate, or combination thereof.
18 . The purification method according to claim 2 , wherein a weight ratio of the inorganic base and dithionite is 0.1.
19 . The purification method according to claim 1 , wherein a volume to weight ratio of the aqueous washing solution and the crude 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile is 2 mL/g.