The present invention provides a process for the preparation of citalopram hydrobromide.
Citalopram is chemically a racemic mixture of 1-(3-dimethylaminopropyl)-1- (4-fluorophenyl)-1,3-dihydroisobenzofuran -5-carbonitrile of Formula I,
Citalopram is commercially available in the form of its hydrochloride or hydrobromide salt which is indicated for the treatment of depression. Citalopram is known to be a selective centrally active serotonin reuptake inhibitor.
US Patent No 4,650,884 provides a process for preparing citalopram hydrobromide, which involves evaporating a toluene layer containing citalopram base under reduced pressure, dissolving the residue in acetone and isolating citalopram hydrobromide by passing gaseous hydrogen bromide. PCT Publication No WO 03/072563 provides a process of preparing citalopram hydrobromide by treating citalopram base dissolved in methanol with aqueous hydrobromic acid. PCT Publication No WO 03/072565 provides a process of preparing citalopram hydrobromide and the said process involves dissolving a residue obtained by evaporation of toluene layer, in isopropyl alcohol and treating the solution with aqueous hydrobromic acid to obtain citalopram hydrobromide crystals. A similar process of isolating citalopram hydrobromide from isopropyl alcohol is also provided in US 6,812,355 and WO 03/080589.
PCT Publication No WO 03/057132 provides a process for preparing citalopram hydrobromide by treating a mixture of citalopram oxalate and toluene, with hydrobromic acid. PCT Publication No WO 05/077927 provides a process for preparing citalopram hydrobromide by treating a toluene layer containing citalopram with pyridine hydrobromide.
PCT Publication No WO 02/072565 provides a process for preparing citalopram hydrobromide, wherein the process involves dissolving free base of citalopram in toluene and adding aqueous hydrobromic acid to the above solution to get citalopram hydrobromide. A similar process is also provided in WO 03/007872 and WO 03/029236.
The present invention provides a novel process for the preparation of citalopram hydrobromide. The present process does not involve the isolation of citalopram free base and the hydrobromide salt is isolated directly from the water immiscible layer of the reaction mixture. Thus the present process reduces the steps involved in the preparation of citalopram hydrobromide and at the same time, yield and purity of the product is also observed to be higher.
A first aspect of the present invention provides a process for the preparation of citalopram hydrobromide, which comprises
a) treating an acidic solution comprising citalopram, with an organic or inorganic
base,
b) extracting the reaction mixture of step a) with a water immiscible organic solvent,
c) treating the organic layer obtained in step b) with hydrobromic acid,
d) isolating citalopram hydrobromide from the reaction mixture thereof,
wherein the said process is characterized by the fact that citalopram base is not isolated at any stage.
An acidic solution comprising citalopram is treated with an organic or inorganic base so as to obtain a neutral or basic pH. The acidic solution can be a reaction mixture obtained in the process of preparing citalopram. Preferably the said solution is an aqueous solution, which contains a mineral acid selected from a group comprising of sulfuric acid and orthophosphoric acid. Aqueous ammonia solution or sodium
hydroxide can be used as a base and the treatment can be carried out at a temperature of about 0° to 40°C.
The reaction mixture so obtained is extracted with a water immiscible organic solvent. The water immiscible organic solvent is selected from a group comprising of aromatic hydrocarbons, C-i./ esters, CMO ethers and halogenated hydrocarbons. The water immiscible organic solvent is preferably toluene, ethyl acetate, diethyl ether, or dichloromethane. Without carrying out further concentration of the organic layer or the isolation of citalopram base, the organic layer so obtained is treated with hydrobromic acid at a temperature of about 0° to 40°C. The hydrobromic acid can be used in gaseous form, or in the form of alcoholic or aqueous solution. The solid product is subsequently isolated from the reaction mixture by filtration and recrystallized by conventional methods to obtain pure citalopram hydrobromide.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE
PREPARATION OF CITALOPRAM HYDROBROMIDE:
a) PREPARATION OF 4-[4-(DIMETHYLAMINO)-1-(4'-FLOUROPHENYL)-1-
HYDROXYBUTYL]-3-HYDROXYMETHYL)-BENZONITRILE:
A Grignard solution was prepared by slow addition of 1-bromo-4-flourobenzene (110 g, 0.628 M) to a suspension of magnesium turnings (15 g, 0.617 M) in dry tetrahydrofuran (0.3 L) at reflux temperature. After the completion of addition, the solution was stirred for 1.0 h at reflux temperature. This Grignard solution was added to a slurry of 5-cyanophthalide (50 g, 0.314 M) in dry tetrahydrofuran (0.3 L) over a period of 2.0 h. The temperature was kept at -25° to -20°C during the addition, followed by stirring the reaction mixture for 30 minutes. A second Grignard solution was prepared simultaneously from 3,3-dimethylaminopropyl chloride (57 g, 0.47 M) and magnesium turnings (12 g, 0.5 M) in a dry tetrahydrofuran (0.3 L). The solution of 3,3-dimethylaminopropyl magnesium chloride was added to the reaction mixture in
2.0 h time. The temperature was maintained at -40° to -35°C during the addition and the mixture was stirred for 60 minutes. The reaction mixture was poured into 20% aqueous ammonium chloride solution (1.0 L). Toluene (0.8 L) was added to the reaction mixture so obtained and stirred for 15 minutes. The toluene layer was separated and aqueous layer was extracted once with toluene (0.3 L). The combined toluene extracts were washed with water (0.5 L).
b) PREPARATION OF 1-(3-DIMETHYLAMINO)-1-(4'-FLOUROPHENYL)-1,3-
DIHYDROISOBENZOFURAN-5-CARBONITRILEHYDROBROMIDE
(CITALOPRAM HYDROBROMIDE):
Water (25 ml) was added to the toluene solution obtained in step a) and the mixture was heated to 45°C followed by the addition of orthophosphoric acid (0.2 L). The mixture was subsequently heated to 70°C and maintained at this temperature for 2.0 h followed by cooling to about 30°C. The reaction mixture was poured into water (1.15 L) and stirred for 15 minutes. The toluene layer was discarded and the aqueous layer was washed three times with toluene (3 x 0.25 L). Aqueous ammonia solution (280 ml, 20% w/w) and toluene (0.6 L) were added to the aqueous reaction mixture and stirred at 25°C for 15 minutes. The toluene layer was separated and the aqueous layer was extracted once with toluene (0.15 L). The combined toluene extracts were washed three times with water (3 x 0.25 L). The organic layer was subsequently filtered through Celite and the filtrate was cooled to 20°C. Aqueous hydrobromic acid solution (37.0 g, 48% w/w) was added to the filtrate in 30 minutes at 20°-25°C. The mixture was stirred overnight and the solid obtained was filtered and washed with toluene (2 x 0.05 L). The solid was dried at 30°C to obtain the title compound. Yield: 75 g Purity (HPLC): 97%
c) PREPARATION OF 1-(3-DIMETHYLAMINO)-1-(4'-FLOUROPHENYL)-1,3-
DIHYDROISOBENZOFURAN-5-CARBONITRILE HYDROBROMIDE
(CITALOPRAM HYDROBROMIDE):
Water (25 ml) was added to the toluene solution obtained in step a) and the mixture was then heated to 45°C followed by the addition of orthophosphoric acid (0.2 L). The mixture was heated to 70°C and maintained at this temperature for 2.0 h
followed by cooling to about 30°C. The reaction mixture was poured into water (1.15 L) and stirred for 15 minutes. The toluene layer was discarded and the aqueous layer was washed three times with toluene (3 x 0.25 L). Aqueous ammonia solution (280 ml, 20% w/w) and ethyl acetate (1.0 L) were added to the aqueous reaction mixture and stirred at 25°C for 15 min. The ethyl acetate layer was separated and the aqueous layer was extracted once with ethyl acetate (0.7 L). The combined ethyl acetate extracts were washed three times with water (3 x 0.25 L) and filtered through Celite. The filtrate was cooled to 20°C and aqueous hydrobromic acid solution (37.0 g, 48% w/w) was added in 30 minutes at 20°-25°C. The reaction mixture was stirred overnight and the solid obtained was filtered and washed with ethyl acetate (2 x 0.05 L). The solid was dried at 30°C to obtain the title compound. Yield: 50 g Purity (HPLC): 99%
d) PURIFICATION OF CITALOPRAM HYDROBROMIDE:
Citalopram hydrobromide (50.0 g) obtained in step b) was dissolved in a mixture of isopropyl alcohol (500 ml) and water (5 ml) at 80°-85°C and treated with activated carbon. The reaction mixture so obtained was filtered and washed with isopropyl alcohol (50 ml). The filtrate was cooled to 25°C to obtain the title compound.
Yield: 44 g
Purity (HPLC): 99.8%

WE CLAIM:
1. A process for the preparation of citalopram hydrobromide, which comprises
a) treating an acidic solution comprising citalopram, with an organic or inorganic
base,
b) extracting the reaction mixture of step a) with a water immiscible organic
solvent,
c) treating the organic layer obtained in step b) with hydrobromic acid,
d) isolating citalopram hydrobromide from the reaction mixture thereof,
wherein the said process is characterized by the fact that citalopram base is not
isolated at any stage.
2. A process as claimed in claim 1, wherein the acidic solution of step a) contains a
mineral acid.
3. A process as claimed in claim 2, wherein the mineral acid is selected from a group
comprising of sulfuric acid and orthophosphoric acid.
4. A process as claimed in claim 1, wherein the base is aqueous ammonia solution.
5. A process as claimed in claim 1, wherein step a) is carried out at a temperature of
about 0° to 40°C.
6. A process as claimed in claim 1, wherein the water immiscible solvent is selected
from a group comprising of aromatic hydrocarbons, d.7 esters, C-MO ethers and halogenated hydrocarbons.
7. A process as claimed in claim 6, wherein the water immiscible solvent is selected
from a group comprising of toluene, ethyl acetate, diethyl ether and dichloromethane.
8. A process as claimed in claim 1, wherein the hydrobromic acid is in the form of
aqueous or alcoholic solution.

9. A process as claimed in claim 1, wherein step c) is carried out at a temperature of
about 0° to 40°C.
10. A process as claimed in claim 1, wherein citalopram hydrobromide is isolated by
filtration.