The present invention provides a process for the purification of citalopram or its acid addition salt thereof.
Citalopram is chemically a racemic mixture of 1-(3-dimethylaminopropyl)-1- (4-fluorophenyl)-1,3-dihydroisobenzofuran -5-carbonitrile of Formula I,
(Formula Removed) 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 4,136,193 discloses a process for preparation of citalopram from corresponding 5-bromo derivative by reaction with cuprous cyanide. The processes provided in WO 00/11926 and WO 00/13648 also involve the exchange of 5-halogen with cyano group in order to obtain citalopram. The processes comprising such cyanide exchange reactions result in the formation of desmethylcitaiopram of Formula II in unacceptable quantities.
(Formula Removed)
Formula II
WO 01/45483 provides a method for purification of crude citalopram by removing desmethyl impurity as its acetamide. This method provides free base of citalopram having desmethyl impurity less than 0.1% mol/mol.
WO 03/057132 provides a method to remove desmethyl citalopram and other impurities from free base of citalopram by using the oxy compounds of phosphorous. The free base of citalopram so obtained is then converted into citalopram hydrobromide by conventional methods.
WO 03/072565 discloses a method to prepare citalopram oxalate and hydrobromide salts having desmethyl impurity less than 0.1%. As per this disclosure, citalopram free base is converted into its oxalate salt, followed by the liberation of free base of citalopram, and the free base is once again converted into its oxalate salt, wherein the oxalate salt contains desmethyl citalopram less than 0.1%. The oxalate salt so obtained is liberated into a free base, which is subsequently dissolved in isopropyl alcohol and treated with aqueous hydrobromic acid to obtain citalopram hydrobromide having a purity of 99.7%.
US Patent No 6,781,003 provides a process for methylation of desmethyl impurity present in crude citalopram by heating the crude citalopram free base in excess of formic acid (98%) and aqueous formaldehyde (35%), and the pure
citalopram is subsequently isolated as an oxalate salt, wherein desmethyl impurity is not detected. The pure citalopram oxalate so obtained is further converted into its hydrobromide salt having HPLC purity of 99.8%. A similar process for the methylation of desmethylcitalopram in the presence of excess of formic acid (98%) and aqueous formaldehyde (37%) is also described in WO 01/51478.
WO 05/042473 also discloses a process for methylation of desmethyl citalopram, wherein crude citalopram base is refluxed in chloroform layer in the presence of formic acid and formaldehyde for 8 h. However, isolation of citalopram from the chloroform layer and conversion of free base into hydrobromide salt is tedious in this process. The chloroform layer is dried over sodium sulfate, concentrated to thick residue, the residue dissolved in toluene, extracted with aqueous acetic acid, basified with sodium hydroxide, the free base extracted with isopropyl alcohol and converted into hydrobromide salt by adding hydrobromic acid.
Preparations of citalopram and its salts, which are free from desmethyl impurity through the prior art methods are not simple. These methods involve chemical reactions such as amidation, reagents like phosphoryl chloride or the repeated oxalate salt formation and free base liberation technique. The methylation methods provided in the prior art involve excess use of formic acid. As the excess formic acid cannot be recovered, it results in disadvantages in view of cost. The methylation reaction in water immiscible organic solvents such as chloroform results in a difficulty of removing water, which is formed during the methylation. Further, the prior art methods involve the methylation of desmethyl impurity using formic acid and formaldehyde only in the free base of citalopram, which is subsequently converted into desired hydrobromide or hydrochloride salts via oxalate salt formation requiring at least two or three processing steps.
The present inventors have found that the acid addition salts of citalopram can be prepared with improved purity by a simple process directly from crude acid
addition salts of citalopram and it does not require separate purification of the base and its subsequent conversion into acid addition salts. Thus the processing steps are minimized in the present invention, while ensuring the purity of the final product. The present process requires reduced quantity of formic acid when compared to prior art methods, and thus improving the process economy.
The present inventors have also observed that the pure citalopram or its acid addition salt thereof can be prepared from crude citalopram or its acid addition salt thereof by using formaldehyde alone and thus avoiding the use of formic acid. The present inventors have further observed that the entire purification step can be carried out in a water miscible inert organic solvent, and thereby avoiding the use of water immiscible solvents like chloroform and subsequent removal of water.
The acid addition salts of citalopram of the present invention are preferably salts of pharmaceutically acceptable non-toxic acids such as mineral acid, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and the like, and organic acids such as acetic acid, tartaric acid, maleic acid, citric acid, oxalic acid, benzoic acid, methane sulfonic acid, benzene sulfonic acid, embonic acid and the like.
The terms "crude citalopram" and "crude acid addition salt of citalopram" of the present invention refer to citalopram or acid addition salt thereof having desmethylcitalopram content of about 0.5% or more.
The terms "crude citalopram" and "crude acid addition salt of citalopram" of the present invention refer to citalopram or acid addition salt thereof having desmethylcitaiopram content from about 0.4% to non-detectable quantity.
A first aspect of the present invention provides a process for the preparation of a pure acid addition salt of citalopram, which comprises,
treating a crude acid addition salt of citalopram with formic acid and
formaldehyde,
a) isolating a pure acid addition salt of citalopram from the reaction mixture
thereof.
A crude acid addition salt of citalopram can be prepared by the method provided in US Patent No 4,136,193. The crude acid addition salt of citalopram is treated with a mixture of formic acid and formaldehyde. The reaction can be carried out in the presence of water and/or water miscible organic solvents. The water miscible organic solvent is selected from a group comprising of acetone, C1-3 alcohol, acetonitrile, tetrahydrofuran and dioxane. The formic acid is preferably used in a quantity of about 90% or less. The reaction mixture is heated to a reflux temperature for about 10 minutes to about 10 h. The reaction mixture is subsequently cooled to about 30°C or less, followed by optional stirring. The pure acid addition salt of citalopram is isolated from the reaction mixture by conventional methods such as filtration, concentration, and the like.
A second aspect of the present invention provides a process for the preparation of pure citalopram or acid addition salt thereof, which comprises
a) treating crude citalopram or its acid addition salt thereof with
formaldehyde,
b) isolating pure citalopram or its acid addition salts thereof from the reaction
mixture thereof,
wherein step a) is carried out in the presence of formic acid from about 0% to about 90%.
A crude citalopram or acid addition salt thereof can be prepared by the method provided in US Patent No 4,136,193. The crude citalopram or acid addition salt thereof is treated with formaldehyde. The reaction is carried out in the presence of formic acid from about 0% to about 90%. Preferably the reaction does not involve the addition of formic acid. The reaction can be carried out in the
presence of water and/or an organic solvent. The organic solvent can be water miscible or water immiscible. The reaction mixture is heated to a reflux temperature for about 10 minutes to about 10 h. The reaction mixture is subsequently cooled to about 30°C or less, followed by optional stirring. The pure citalopram or acid addition salt thereof is isolated from the reaction mixture by conventional methods such as filtration, concentration, and the like.
A third aspect of the present invention provides a process for the preparation pure citalopram or acid addition salt thereof, which comprises
a) treating crude citalopram or its acid addition salt thereof with formaldehyde
in a water miscible inert organic solvent,
b) isolating pure citalopram or its acid addition salts thereof from the reaction
mixture thereof,
A crude citalopram or acid addition salt thereof can be prepared by the method provided in US Patent No 4,136,193. The crude citalopram or acid addition salt thereof is treated with formaldehyde optionally in the presence of formic acid. The reaction is carried out in the presence of water miscible inert organic solvent. The water miscible inert organic solvent is selected from a group comprising of acetone, C1-3 alcohol, acetonitrile, tetrahydrofuran and dioxane. The formic acid can be used in a quantity of about 90% or less. The reaction mixture is heated to a reflux temperature for about 10 minutes to about 10 h. The reaction mixture is subsequently cooled to about 30°C or less, followed by optional stirring. The pure citalopram or acid addition salt thereof is isolated from the reaction mixture by conventional methods such as filtration, concentration, and the like.
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 PURE CITALOPRAM HYDROBROMIDE:
Citalopram hydrobromide (5.0 g, 0.0123 mole) containing 0.82% (HPLC) of desmethyl citalopram was added to the mixture of aqueous formaldehyde (37 %, 1.0 g, 0.0123 mole) in acetone (25 ml). The solution so obtained was heated to reflux temperature of 56° to 57°C for 2 h. The reaction mixture was cooled to 20° to 25°C and stirred for 2 h. The solid so obtained was filtered, washed with acetone (10 ml) and dried to obtain the title compound.
Yield 2.50 g (50 %)
Desmethylcitalopram content: 0.22% (HPLC)
EXAMPLE 2
PREPARATION OF PURE CITALOPRAM HYDROBROMIDE:
Citalopram hydrobromide (5.0 g, 0.0123 mole) containing 0.82% (HPLC) of desmethyl citalopram was added to a mixture of aqueous formaldehyde (37 %, 0.35 g, 0.0043 mole) and formic acid (85%, 0.5 g, 0.000923 mole) in acetone (25 ml). The solution so obtained was heated to reflux temperature of 56° to 57°C for 2 h. The reaction mixture was cooled to 20° to 25°C and stirred for 2 h. The solid so obtained was filtered, washed with acetone (10 ml) and dried to obtain the title compound.
Yield 3.60 g (72 %) Desmethylcitalopram content: 0.24% (HPLC)

WE CLAIM;
1. A process for the preparation of a pure acid addition salt of citalopram, which
comprises
a) treating a crude acid addition salt of citalopram with formic acid and
formaldehyde,
b) isolating a pure acid addition salt of citalopram from the reaction mixture
thereof.

2. A process as claimed in claim 1 wherein step a) is carried out in the presence
of water.
3. A process as claimed in claim 1 wherein step a) is carried out in the presence
of a water miscible organic solvent.
4. A process as claimed in claim 1 wherein the formic acid is used in a quantity of
about 90% or less.
5. A process for the preparation pure citalopram or acid addition salt thereof,
which comprises,

a) treating crude citalopram or its acid addition salt thereof with
formaldehyde,
b) isolating pure citalopram or its acid addition salts thereof from the reaction
mixture thereof,
wherein step a) is carried out in the presence of formic acid from about 0% to about 90%.
6. A process as claimed in claim 5 wherein step a) is carried out in the presence
an organic solvent.
7. A process as claimed in claim 6 wherein the organic solvent is a water
miscible solvent.

8. A process for the preparation pure citalopram or acid addition salt thereof,
which comprises
a) treating crude citalopram or its acid addition salt thereof with formaldehyde
in a water miscible inert organic solvent,
b) isolating pure citalopram or its acid addition salt thereof from the reaction
mixture thereof,
9. A process as claimed in claim 8 wherein step a) is carried out in the presence
of formic acid,
10. A process as claimed in claim 8 wherein the water miscible inert organic
solvent is selected from a group comprising of acetone, C1-3 alcohol, acetonitrile,
tetrahydrofuran and dioxane.