The present invention relates to a process for the preparation of citalopram hydrobromide.
Citalopram hydrobromide is chemically 1-(3-dimethylaminopropyl)-1- (4-fluorophenyl)-1,3-dihydroisobenzofuran -5-carbonitrile hydrobromide of Formula I.
(Formula Removed)
FORMULA I
Citalopram hydrobromide is indicated for the treatment of depression. Citalopram hydrobromide is known to be a selective centrally active serotonin reuptake inhibitor.
US Patent No 4,650,884 provides a process for preparation of citalopram hydrobromide, wherein the process involves cyclization of 4-(dimethylamino)-1-(4-fluorophenyl)-1-[2-(hydroxymethyl)-4-isocyanophenyl]butan-1-ol of Formula II.
(Formula Removed)
FORMULA II
According to US '884 patent method, a toluene solution containing crude compound of Formula II in the form of free base heated at 80°C for 3 h in the presence of sulfuric acid and the pH is adjusted to 10 with aqueous ammonia and stirred at 50° to
60°C for 15 minutes. The toluene layer is separated, treated with magnesium sulfate and silica gel, and filtered. The solvent is removed from the filtrate and the residue is treated with charcoal in the presence of acetone. The charcoal is removed by filtration and the acetone solution is treated with gaseous hydrogen bromide. Citalopram hydrobromide so obtained is subjected repeated crystallization steps using different solvent systems such as methanol, acetone, 1-propanol and hexane to finally achieve desired purity. US '884 patent also provides a method to prepare hydrobromide salt of the compound of Formula II. The method involves treating diethyl ether solution containing the compound of Formula II in the form of free base with aqueous hydrogen bromide. However, US '884 patent does not disclose and method to convert hydrobromide salt of the compound of Formula II into citalopram or its salts.
The purification methods for citalopram salts are provided in various prior art references including WO 00/11926, WO 00/13648, WO 01/45483 US 6,781,003, WO 03/057132, WO 03/072565 and EP 1,169,314 A1. The methods involve crystallizations, isolation and purification of citalopram free base, salt exchange and the like.
The process provided in the prior art for cyclizing the free base form of the compound of Formula II at higher temperature conditions, which lead to the formation of impurities. Further, the purification of citalopram through the prior art methods are not simple. The use of various solvents for repeated crystallizations, purification of citalopram free base and salt exchange methods increase the number of steps involved in the process and also increase the cost of preparation.
The present inventors have surprisingly found that citalopram hydrobromide can be prepared with high purity by directly cyclizing the salts of the compound of Formula II. The present process does not require purification citalopram base and avoids repeated crystallizations. The process steps are minimized in the present invention, while ensuring the purity of the final product. Thus the present invention provides a simple, economic and industrially preferable process for preparing citalopram hydrobromide.
A first aspect of the present invention provides a process for the preparation of citalopram hydrobromide of Formula I,
(Formula Removed)
FORMULA I
wherein the process comprises
a) treating an acid addition salt of 4-(dimethylamino)-1-(4-fluorophenyl)-1-[2-(hydroxymethyl)-4-isccyanophenyl]butan-1-ol of Formula II with an acid,
(Formula Removed)

FORMULA II
to obtain citalopram as a free base,
b) treating the free base of citalopram with hydrogen bromide, and
c) isolating citalopram hydrobromide of Formula I from the reaction mixture
thereof.
The acid addition salt of 4-(dimethylamino)-1-(4-fluorophenyl)-1-[2-(hydroxymethyl)-4-isocyanophenyl]butan-1-ol of Formula II used as a starting material can be prepared according to the method provided in US Patent No 4,650,884. The acid addition salt can be organic or inorganic acid addition salts. The phosphate,
hydrochloride, hydrobromide or oxalate salt of the compound of Formula II is preferably used as a starting material. The acid addition salt of the compound of Formula II is treated with an acid. The treatment with an acid is carried out in the presence or the absence of a solvent. The solvent can be water or an organic solvent. The organic solvent may be water miscible or water immiscible. The organic solvent is preferably selected from the group consisting of toluene, pentane, methyl ethyl ketone, methyl t-butyl ether, diethyl ether, hexane, heptane, octane, cyclohexane, and halogenated hydrocarbons. The organic solvent is more preferably toluene. The acid is preferably an inorganic acid. The acid is more preferably phosphoric acid. The treatment with the acid is carried out at a temperature below 0°C to reflux temperature, preferably at a temperature of about -10°C to about 100°C. The reaction is carried out for about 10 minutes to about 100 h, preferably for about 0.5 h to about 10 h. The reaction mixture is subsequently treated with a base. The base can be an organic or inorganic base. The base is preferably ammonia. The base can be used in the form of its aqueous solution. Subsequent to the treatment with base, the organic layer containing the citalopram in the form of free base is separated and the solvent is partially or completely removed. The residue or the concentrated solution is treated with an organic solvent. The organic solvent is preferably C!.3 alkanol, more preferably isopropanol. The mixture is treated with hydrogen bromide to attain a pH of about 1 to about 3. The hydrogen bromide can be used in gaseous or solution form. An aqueous hydrogen bromide is preferably used. The treatment with aqueous hydrogen bromide can be carried out at a temperature of about 0°C to about 60°C, preferably of about 5°C to about 40°C. The citalopram hydrobromide so obtained is isolated from the reaction mixture. The isolation can be carried out by methods such as concentration, distillation, layer separation, filtration and a combination thereof.
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 1
PREPARATION OF CITALOPRAM HYDROBROMIDE:
Toluene (50 ml) was added to 4-(dimethylamino)-1-(4-fluorophenyl)-1-[2-(hydroxymethyl)-4-isocyanophenyl] butan-1-ol phosphate (10 g) at about 25°C. The mixture was cooled to 0° to 2°C. Orthophosphoric acid (40 g) was added to the mixture at 0° to 2°C and stirred for 2 to 3 h at 10° to 15°C. The lower layer of the mixture was dispersed in a mixture of toluene (50 ml), aqueous ammonia (about 70 ml) and de-ionised water (130 ml) at 10° to 20°C. The layers were separated and the aqueous layer was extracted with toluene (20 ml) at 10° to 15°C. The toluene layers were combined and treated with de-ionised water (20 ml). The toluene was recovered completely under vacuum at 40° to 42°C. Isopropyl alcohol (10 ml) was added to the residue and recovered completely under vacuum at 40° to 42°C to obtain an oil. Isopropyl alcohol (50 ml) was added to the oil so obtained at about 25°C and cooled to 10° to 15°C, followed by the addition of aqueous hydrogen bromide (about 4.5 g) at 10° to 15°C in 5 to 10 minutes to obtain a pH of 1.0 to 1.5. The mixture was stirred for 12 to 14 h at 30° to 32°C. The mixture was filtered and washed with isopropyl alcohol (2X15 ml) to obtain the title compound. Yield: 7 g Purity by HPLC: 99.5%
EXAMPLE 2
PREPARATION OF CITALOPRAM HYDROBROMIDE:
4-(dimethylamino)-1-(4-fluorophenyl)-1-[2-(hydroxymethyl)-4-isocyanophenyl]butan-1-ol phosphate (10 g) was added to Orthophosphoric acid (40 g) at about 10°C and stirred for 3 to 6 h at 10° to 15°C. Toluene (40 ml), de-ionized water (130 ml) and aqueous ammonia (~70 ml) were added to reaction mixture at 10° to 20°C to attain a pH of 9.0 to 9.2. The layers were separated and the aqueous layer was extracted with toluene (20 ml) at 10° to 15°C. The toluene layers were combined and treated with de-ionized water (20 ml). The toluene was recovered completely under vacuum at 40° to 45°C. Isopropyl alcohol (10 ml) was added to the residue and recovered completely under vacuum at 40° to 45°C to obtain an oil. Isopropyl alcohol (50 ml) was added to the oil so obtained at about 25°C and cooled to 10° to 15°C, followed
by the addition of aqueous hydrogen bromide (about 4.5 g) at 10° to 15°C in 5 to 10
minutes to obtain a pH of 1.0 to 1.5. The mixture was stirred for 12 to 14 h at 15-
20°c. The mixture was filtered and washed with isopropyl alcohol (2 X 15 ml) to
obtain the title compound.
Yield: 8 g
Purity by HPLC: 99.5%
EXAMPLE 3
PREPARATION OF CITALOPRAM HYDROBROMIDE:
4-(dimethylamino)-1-(4-fluorophenyl)-1-[2-(hydroxymethyl)-4-isocyanophenyl]butan-1-ol phosphate (10 g) was added to orthophosphoric acid (40 g) at about 25-30°C and stirred for 2 to 3 h at 45° to 50°C. Toluene (40 ml), de-ionized water (130 ml) and aqueous ammonia (-70 ml) was added to reaction mixture at 10° to 20°C to attain a pH of 9.0 to 9.2. The layers were separated and the aqueous layer was extracted with toluene (20 ml) at 10° to 15°C. The toluene layers were combined and treated with de-ionized water (20 ml). The toluene was recovered completely under vacuum at 40° to 45°C. Isopropyl alcohol (10 ml) was added to the residue and recovered Isopropyl alcohol completely under vacuum at 40° to 45°C to obtain an oil. Isopropyl alcohol (50 ml) was added to the oil so obtained at about 25°C and cooled to 10° to 15°C, followed by the addition of aqueous hydrogen bromide (about 4.5 g) at 10° to 15°C in 5 to 10 minutes to obtain a pH of 1.0 to 1.5. The mixture was stirred for 12 to 14 h at 15-20°c. The mixture was filtered and washed with isopropyl alcohol (2X15 ml) to obtain the title compound. Yield: 8 g Purity by HPLC: 99.5%
EXAMPLE 4
PREPARATION OF CITALOPRAM HYDROBROMIDE:
Toluene (50 ml) was added to 4-(dimethylamino)-1-(4-fluorophenyl)-1-[2-(hydroxymethyl)-4-isocyanophenyl] butan-1-ol hydrochloride salt (10 g) at about 25°C. The mixture was cooled to 0° to 2°C. Orthophosphoric acid (40 g) was added to the mixture at 0° to 2°C and stirred for 2 to 3 h at 10° to 15°C. The lower layer of

the mixture was dispersed in a mixture of toluene (50 ml), aqueous ammonia (~ 70 ml) and de-ionised water (130 ml) at 10° to 20°C. The layers were separated and the aqueous layer was extracted with toluene (20 ml) at 10° to 15°C. The toluene layers were combined and treated with de-ionised water (20 ml). The toluene was recovered completely under vacuum at 40° to 42°C. Isopropyl alcohol (10 ml) was added to the residue and recovered completely under vacuum at 40° to 42°C to obtain an oil. Isopropyl alcohol (50 ml) was added to the oil so obtained at about 25°C and cooled to 10° to 15°C, followed by the addition of aqueous hydrogen bromide (about 4.5 g) at 10° to 15°C in 5 to 10 minutes to obtain a pH of 1.0 to 1.5. The mixture was stirred for 12 to 14 h at 30° to 32°C. The mixture was filtered and washed with isopropyl alcohol (2X15 ml) to obtain the title compound. Yield: 7 g Purity by HPLC: 99.0%
EXAMPLE 5
PREPARATION OF CITALOPRAM HYDROBROMIDE:
Toluene (50 ml) was added to 4-(dimethylamino)-1-(4-fluorophenyl)-1-[2-(hydroxymethyl)-4-isocyanophenyl] butan-1-ol oxalate salt (10 g) at about 25°C. The mixture was cooled to 0° to 2°C. Orthophosphoric acid (40 g) was added to the mixture at 0° to 2°C and stirred for 2 to 3 h at 10° to 15°C. The lower layer of the mixture was dispersed in a mixture of toluene (50 ml), aqueous ammonia (about 70 ml) and de-ionised water (130 ml) at 10° to 20°C. The layers were separated and the aqueous layer was extracted with toluene (20 ml) at 10° to 15°C. The toluene layers were combined and treated with de-ionised water (20 ml). The toluene was recovered completely under vacuum at 40° to 42°C. Isopropyl alcohol (10 ml) was added to the residue and recovered completely under vacuum at 40° to 42°C to obtain an oil. Isopropyl alcohol (50 ml) was added to the oil so obtained at about 25°C and cooled to 10° to 15°C, followed by the addition of aqueous hydrogen bromide (about 4.5 g) at 10° to 15°C in 5 to 10 minutes to obtain a pH of 1.0 to 1.5. The mixture was stirred for 12 to 14 h at 30° to 32°C. The mixture was filtered and washed with isopropyl alcohol (2X15 ml) to obtain the title compound. Yield: 7 g Purity by HPLC: 99.5%
EXAMPLE 6
PREPARATION OF CITALOPRAM HYDROBROMIDE:
Toluene (50 ml) was added to 4-(dimethylamino)-1-(4-fluorophenyl)-1-[2-(hydroxymethyl)-4-isocyanophenyl] butan-1-ol hydrobromide salt (10 g) at about 25°C. The mixture was cooled to 0° to 2°C. Orthophosphoric acid (40 g) was added to the mixture at 0° to 2°C and stirred for 2 to 3 h at 10° to 15°C. The lower layer of the mixture was dispersed in a mixture of toluene (50 ml), aqueous ammonia (about 70 ml) and de-ionised water (130 ml) at 10° to 20°C. The layers were separated and the aqueous layer was extracted with toluene (20 ml) at 10° to 15°C. The toluene layers were combined and treated with de-ionised water (20 ml). The toluene was recovered completely under vacuum at 40° to 42°C. Isopropyl alcohol (10 ml) was added to the residue and recovered completely under vacuum at 40° to 42°C to obtain an oil. Isopropyl alcohol (50 ml) was added to the oil so obtained at about 25°C and cooled to 10° to 15°C, followed by the addition of aqueous hydrogen bromide (about 4.5 g) at 10° to 15°C in 5 to 10 minutes to obtain a pH of 1.0 to 1.5. The mixture was stirred for 12 to 14 h at 15° to 20°C. The mixture was filtered and washed with isopropyl alcohol (2X15 ml) to obtain the title compound. Yield: 7.8 g Purity by HPLC: 99%

WE CLAIM:
1. A process for the preparation of citalopram hydrobromide of Formula I,
(Formula Removed)
FORMULA I
wherein the process comprises
a) treating an acid addition salt of 4-(dimethylamino)-1-(4-fluorophenyl)-1-[2-(hydroxymethyl)-4-isocyanophenyl]butan-1-ol of Formula II with an acid,
(Formula Removed)
FORMULA II
to obtain citalopram as a free base,
b) treating the free base of citalopram with hydrogen bromide, and
c) isolating citalopram hydrobromide of Formula I from the reaction mixture
thereof.
2. A process according to claim 1, wherein the acid addition salt is organic or inorganic acid addition salt.
3. process according to claim 2, wherein the acid addition salt is phosphate,
hydrochloride, hydrobromide or oxalate salt.
4. A process according to claim 1, wherein step a) is carried out in the presence or
the absence of a solvent.
5. A process according to claim 4, wherein the solvent is water or an organic solvent.
6. A process according to claim 5, wherein the organic solvent is water miscible or
water immiscible.
7. A process according to claim 6, wherein the organic solvent is selected from the
group consisting of toluene, pentane, methyl ethyl ketone, methyl t-butyl ether,
diethyl ether, hexane, heptane, octane, cyclohexane, and halogenated
hydrocarbons.
8. A process according to claim 1, wherein the acid is an inorganic acid.
9. Use of an acid addition salt of 4-(dimethylamino)-1-(4-fluorophenyl)-1-[2-
(hydroxymethyl)-4-isocyanophenyl]butan-1-ol for the preparation of citalopram
hydrobromide.
10. Use of phosphate, hydrochloride, hydrobromide or oxalate salt of 4-
(dimethylamino)-l -(4-fluorophenyl)-1 -[2-(hydroxymethyl)-4-isocyanophenyl]butan-1 -
ol for the preparation of citalopram hydrobromide.