HK1068627B - Process for the preparation of racemic citalopram and/or s-or r-citalopram by separation of a mixture of r- and s-citalopram - Google Patents

Description

Process for the preparation of racemic citalopram and/or S-or R-citalopram by separation of a mixture of R-and S-citalopram

The present invention relates to a process for the preparation of racemic citalopram and/or S-or R-citalopram by separation of a mixture of R-and S-citalopram having an enantiomeric amount of more than 50% by separation of said mixture of R-and S-citalopram into racemic citalopram components and/or S-or R-citalopram having a reduced amount of the other enantiomer. The invention also relates to a process for the preparation of racemic and enantiomerically pure citalopram from the compound R-4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) benzonitrile.

Background of the invention

S-citalopram (escitalopram) is the active ingredient of the product citalopram, a racemic mixture of R-and S-citalopram, which is a useful antidepressant of the selective serotonin re-release inhibitor (SSRI) type.

Both racemic citalopram and S-citalopram are marketed as antidepressants.

It has now surprisingly been found that a mixture of R-and S-citalopram containing more than 50% of one enantiomer, i.e. a diastereomeric mixture, may be separated into a racemic citalopram component and a S-or R-citalopram component by precipitation of citalopram as the free base or an acid addition salt thereof, the remainder of the S-citalopram or R-citalopram being free from the mother liquor of the precipitation.

This is an important and very useful process, especially since it allows the preparation of racemic citalopram and S-citalopram from a mixture of R-citalopram and S-citalopram obtained from a manufacturing process resulting in a mixture of racemic citalopram or S-citalopram which is not able to meet market approved specifications (in (escitalopram) the amount of R-citalopram is 3% less, preferably less than S-citalopram).

S-citalopram may be prepared by separation of R-and S-4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) benzonitrile (R-and S-diol) followed by cyclization of the S-diol with retention of the configuration as described in EP-B1-347066.

Other methods of preparing S-citalopram involving separation of the enantiomers by chromatography are also feasible, such as separation of the corresponding bromo-derivative, 1- (4-bromo-2-hydroxymethylphenyl) -4-dimethylamino-1- (4-fluorophenyl) butan-1-ol, from the corresponding R-diol, followed by cyclization to the retained configuration and cyanation to form S-citalopram. Processes for the cyanation of citalopram are well known and are described in U.S. Pat. No. 4,136,193, WO 00/11926 and WO 00/13648.

Depending on the specific process used and the conditions used, the enantiomeric purity of the resulting S-citalopram product may be improved.

Other methods of stereoselective synthesis of S-citalopram also result in mixtures of R-and S-citalopram which are not able to meet the specifications of the market approved S-citalopram.

It is therefore an aspect of the present invention to provide a simple method for improving the enantiomeric purity of S-citalopram obtained by said method.

In the preparation of S-citalopram by chromatographic separation of R-and S-4- [4- (dimethylamino) -1- (4 '-fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) benzonitrile followed by cyclization of S-4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) benzonitrile the R-enantiomer of formula (I) is formed as a by-product:

it has now been found that the compound of formula (I) can be cyclized under acidic conditions to give a reaction mixture containing more S-citalopram than R-citalopram, in other words, the cyclization is partly configurational transformed in an acidic environment.

The by-products of formula (I) can thus be used to prepare S-citalopram and racemic citalopram, which is more rational and more economical in terms of reagents and starting materials.

Summary of the invention

The present invention relates to a process for the preparation of racemic citalopram free base or an acid addition salt thereof and/or R-or S-citalopram as free base or in the form of an acid addition salt thereof by separation of a mixture of R-and S-citalopram with more than 50% of one enantiomer, by separation of said mixture into fractions consisting of racemic citalopram and/or fractions of S-citalopram or R-citalopram, characterized in that:

i) precipitating citalopram from a solvent as a free base or an acid addition salt thereof;

ii) separating the precipitate formed from the mother liquor,

iia) optionally recrystallizing one or more times, if the precipitate is crystalline, to form racemic citalopram, which is then optionally converted to its acid addition salt;

iib) if the precipitate is not crystalline, optionally repeating steps i) and ii) until a crystalline precipitate is obtained, and optionally recrystallizing the crystalline precipitate one or more times to form racemic citalopram, which is then optionally converted to its acid addition salt;

iii) optionally further purifying the mother liquor, freeing S-citalopram or R-citalopram from the mother liquor and optionally converting it into an acid addition salt.

According to a particular embodiment, the present invention relates to a process for the preparation of racemic citalopram free base or an acid addition salt thereof using the above described process.

According to another embodiment, the present invention relates to a process for the preparation of R-or S-citalopram free base or an acid addition salt thereof using the above process.

The acid used to precipitate the citalopram salt in step i) is an acid which precipitates a mixture of the R-and S-enantiomers leaving a mother liquor enriched in the S-or R-enantiomer of citalopram, which acid is hydrobromic acid.

According to a preferred embodiment of the present invention the free base of citalopram or the hydrobromide salt of citalopram is precipitated, preferably in crystalline form, in steps i) and ii).

According to another embodiment of the present invention the mixture of R-and S-citalopram used in step i) contains more than 50% S-citalopram, or more preferably more than 90% S-citalopram.

In step iii) the S-citalopram (or R-citalopram) may be separated from the mother liquor by evaporation of the mother liquor, and then optionally converting the S-citalopram (or R-citalopram) into an acid addition salt thereof, preferably an oxalate salt.

Alternatively, if the mother liquor obtained from the precipitation is acidic, S-citalopram (or R-citalopram) may be separated from the mother liquor by basification of the mother liquor followed by phase separation, or by solvent extraction and evaporation of the solvent followed by optional conversion of the S-citalopram (or R-citalopram) to its acid addition salt, preferably the oxalate salt.

Before the R-or S-citalopram is isolated, the mother liquor, extract or phase containing R-or S-citalopram may be subjected to conventional purification (e.g. treatment with activated carbon, chromatographic purification) and/or further precipitation as described in steps i) -ii) above.

More than 50% of a mixture of R-and S-citalopram of S-citalopram may be prepared from more than 50% of a mixture of R-and S-4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) -benzonitrile of the S-enantiomer by forming labile ester groups and then cyclizing in an alkaline environment.

In another embodiment of the invention, a mixture of R-and S-citalopram with more than 50% of the R-enantiomer may be prepared from a mixture of R-and S-4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) -benzonitrile with more than 50% of the R-enantiomer by forming labile ester groups and then cyclizing in an alkaline environment.

In another embodiment of the invention a mixture of R-and S-citalopram with more than 50% of the S-enantiomer may be prepared from a mixture of R-and S-4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) -benzonitrile with more than 50% of the R-enantiomer by ring closure in the presence of an acid.

In another embodiment of the invention a mixture of R-and S-citalopram with more than 50% of the R-enantiomer may be prepared from a mixture of R-and S-4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) -benzonitrile with more than 50% of the S-enantiomer by ring closure in the presence of an acid.

The starting R-4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) benzonitrile preferably has an enantiomeric purity of more than 90%.

Suitable acids for the acid cyclization are inorganic acids such as sulfuric acid or phosphoric acid, and also carboxylic, sulfonic or sulfonic acid derivatives.

As used herein, racemic mixture or racemic citalopram at any time refers to a 1: 1 mixture of R-and S-citalopram, non-racemic mixture or non-racemic citalopram refers to a mixture wherein the ratio of R-and S-citalopram is not 1: 1.

Citalopram refers to a mixture of R-and S-citalopram and the enantiomers or isomers of citalopram refer to S-or R-citalopram.

Precipitation as used herein refers to the formation of a precipitate as a crystalline, amorphous solid or solvent oil, and in the context of the present invention precipitation refers to an oil, amorphous solid or crystalline.

As used herein, the mother liquor refers to the solvent remaining after removal or isolation of the precipitate.

Detailed description of the invention

The process for the preparation of citalopram molecules as described above may result in a mixture of R-and S-citalopram which is not acceptable for use as a medicament. According to the present invention it has surprisingly been found that such a mixture can be efficiently separated into a racemic component and an S-citalopram or R-citalopram component. The novel process comprises precipitating citalopram free base or an acid addition salt thereof from a solvent as an oil, an amorphous solid or in crystalline form and then separating the S-citalopram (or R-citalopram) from the mother liquor of the precipitation process.

The precipitation of citalopram free base is performed by obtaining or dissolving a non-racemic mixture of R-and S-citalopram in a suitable solvent, optionally heated, and then cooling the solution. The precipitate is then separated from the mother liquor, preferably by filtration or decantation. If the precipitate is crystalline, the crystals may optionally be recrystallized and then the free base of racemic citalopram is converted into its salt, preferably the hydrobromide salt.

If citalopram is formed as an oil or as an amorphous solid, the precipitation process may be repeated until a crystalline product is obtained, which may optionally be recrystallized, followed by conversion of the free base of racemic citalopram to its salt, preferably the hydrobromide salt.

Depending on the ratio of R-and S-citalopram in the starting material, several precipitations, in particular crystallizations, of the free base of citalopram may be necessary in order to obtain racemic citalopram, the mother liquors of each precipitation may be brought together and the enantiomers of citalopram contained therein may then be separated as described below.

Suitable solvents for precipitating citalopram free base are alkanes such as heptane or hexane, alcohols such as isopropanol, aromatic compounds such as toluene, benzene or xylene or mixtures of alcohols and water and alkanes and water. Thus, either protic or aprotic solvents may be used.

If necessary, crystallisation may be initiated by using a seed crystal of racemic citalopram base.

The precipitation of the acid addition salt of citalopram may be carried out by obtaining or dissolving a non-racemic mixture of R-and S-citalopram in a suitable solvent, optionally heated, and then adding the acid in solution or gas. If crystals are formed, the crystals are separated from the mother liquor, preferably by filtration. Recrystallization is selectively carried out by dissolving the crystals in a solvent, preferably by heating, and the solution is cooled.

If the precipitate formed is not crystalline but an amorphous solid or oil, the precipitation process is repeated until a crystalline product is obtained, and the obtained crystals are optionally recrystallized as described above to selectively convert the racemic citalopram salt into another salt.

Depending on the ratio of R-and S-citalopram in the starting material, it may be necessary to precipitate, in particular crystallize, the citalopram salt several times in order to obtain a racemic mixture, the mother liquors of each precipitation or crystallization may be brought together and the citalopram enantiomers contained therein may then be separated according to the following procedure.

The acid used to precipitate the citalopram salt is the acid used to precipitate a mixture of the R-and S-enantiomers, resulting in a mother liquor enriched in a certain S-or R-enantiomer of citalopram.

Suitable solvents for precipitating and recrystallizing the citalopram salt are protic solvents such as water, alcohols such as methanol and ethanol, ketones such as acetone, and mixtures thereof, or aprotic solvents such as acetonitrile or diglyme.

If necessary, seed crystals of racemic crystalline citalopram salt may be used to induce crystal formation.

Fine crystallization of the free base of citalopram or the hydrobromide salt of citalopram is preferred.

The S-citalopram (or R-citalopram) may be freed from the mother liquor using conventional methods, e.g. by evaporation of the solvent from the mother liquor or, when the mother liquor is acidic, basification followed by phase separation if an oil is present, or extraction of the S-citalopram (or R-citalopram) followed by evaporation of the solvent, the S-citalopram (or R-citalopram) then being converted into its salt, preferably the oxalate, and optionally recrystallized.

The mother liquor or an extract thereof before evaporation of the solvent may be subjected to conventional purification processes or, according to the present invention, to one or more precipitations of citalopram free base or citalopram salt in order to improve the enantiomeric purity of the enantiomeric product of citalopram.

The oil, which is likewise separated from the mother liquor, may be subjected to conventional purification procedures or, according to the invention, to one or more precipitations of citalopram free base or citalopram salt in order to improve the enantiomeric purity of the citalopram enantiomer product.

Another aspect of the present invention is the discovery that by-products of formula (I) are cyclized in an acidic environment to provide a reaction mixture containing a higher amount of the S-enantiomer.

The method is illustrated according to the following reaction scheme:

when the reaction is carried out in the presence of an acid, a mixture of R-citalopram and S-citalopram is obtained from the R-diol, the stereochemistry of the reaction is partly converted to yield more S-citalopram, the excess of S-citalopram to R-citalopram is dependent on the S/R ratio in the starting materials as explained below, the conversion/retention ratio is about 70: 30 to 75: 25, depending on the reaction conditions tested.

If more than 50% of the R-enantiomer of 4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) benzonitrile is used as starting material, more S-citalopram will be produced and the mixture thus produced can be further purified to S/R ratios higher than 95/5 by precipitation of the citalopram base from the solvent or by precipitation from the solvent as an acid addition salt of citalopram, pure S-citalopram (S/R ratio higher than 97/3) can be freed from the mother liquor and precipitated as an acid addition salt with an acid, such as oxalic acid.

As mentioned above, when R-and S-4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) benzonitrile are cyclized under an acidic environment, partial stereochemical conversion is carried out, and any suitable acid can be used for the above cyclization reaction, and good results can be obtained using inorganic acids such as sulfuric acid, hydrochloric acid and phosphoric acid, and organic acids such as p-toluenesulfonic acid. In a preferred embodiment of the invention sulfuric acid is used, preferably an excess of acid to the starting material.

The reaction may be carried out in an organic solvent suitable for dissolving the starting materials, preferred solvents are those suitable for large-scale production, and good results may be obtained using toluene or acetonitrile.

When the cyclization of the starting material of formula (I) is carried out via a labile ester intermediate, i.e. in the presence of tosyl-chloride in a basic environment (as described in EP-B1-347, 066), the cyclization and stereochemical retention are simultaneously completed, yielding citalopram in the R-form substantially equal to the enantiomeric purity of the starting material.

The R-form of citalopram thus obtained can be mixed with a mixture of R-and S-citalopram containing more S-citalopram to obtain racemic citalopram. Racemic citalopram may be obtained by precipitation of the citalopram free base or a salt thereof one or more times and recrystallization as described above.

Examples

The optical purity in the following examples was determined by chiral HPLC.

Example 1

Citalopram was prepared from R-4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) benzonitrile (R/S ═ 95.7/4.3) by reaction with different acids in acetonitrile

General procedure

R-4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) benzonitrile (67.5g, R/S95.7/4.3) was dissolved in acetonitrile (37g), stirred at room temperature, a mixture of acid and ice (or water) (the amount of acid and the amount of ice are listed in table 1) was added, the reaction mixture was stirred at 78-85 ℃ (reaction time is listed in table 1), the reaction mixture was cooled, water and toluene (315ml) were added, then aqueous ammonia (25%, by weight) was added to reach ph9.5-10.5, the mixture was heated to 50-55 ℃ (5-10 min), the phases were separated, toluene (50ml) was added to the aqueous phase, and stirred at 50-55 ℃ (5-10 min). The phases were separated and the toluene phases were combined, washed 3 times with water (3X 65ml) and the toluene removed under reduced pressure at maximum 60 ℃ to give the product as an oil.

Citalopram is prepared by the general method described above. The type of acid and the amount of acid and ice (or water) in the acid mixture are listed in table 1. The percentage of S-citalopram obtained by chiral HPLC analysis is also given in Table 1.

TABLE 1 reaction of citalopram with different acids in acetonitrile

Examples	Type of acid	Amount of acid	Amount of water or ice in the mixture	Reaction time	Percentage of S-citalopram	Yield of the product
							1	Sulfuric acid	25g	10g of ice	3 hours	73.4	65.6g(～100％)
2	Sulfuric acid	87g	35g of ice	3 hours	72.0	57.0g(89％)
							3	Hydrochloric acid	22g	11g of ice	24 hours	＞65	64.6g(～100％)
4	P-toluenesulfonic acid	43g	40g of water	48 hours	73.0	61.6g(95％)

Example 2

Citalopram was prepared from R-4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) benzonitrile (R/S ═ 95.7/4.3) by reaction with different acids in toluene

General procedure

R-4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) benzonitrile (67.5g, R/S95.7/4.3) was dissolved in toluene (315ml), stirred at room temperature, a mixture of acid and ice (or water) (the amount of acid and the amount of ice are listed in table 2) was added, the reaction mixture was stirred at 78-85 ℃ (reaction time is listed in table 2), the reaction mixture was cooled, water was added, then aqueous ammonia (25% by weight) was added to reach ph9.5-10.5, the mixture was heated to 50-55 ℃ (5-10 min), the phases were separated, the toluene phase was washed 3 times with water (3 × 65ml), and toluene was removed under reduced pressure at up to 60 ℃ to give the product as an oil.

Citalopram acid was prepared by the general method described above, the type of acid and the amount of acid and water in the mixture are shown in table 2, and the percentage of S-citalopram obtained by chiral HPLC analysis is also shown in table 2.

TABLE 2 citalopram reacted with different acids in toluene

Examples	Type of acid	Amount of acid	Amount of water or ice in the mixture	Reaction time	Percentage of S-citalopram	Yield of the product
							5	Sulfuric acid	26g	10g of ice	70 minutes	73.8	61.8g(97％)
6	Phosphoric acid	275g	11g of ice	4 hours	70.9	67.2g(～100％)

Example 3

Citalopram HBr was prepared from R-4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) benzonitrile (R/S95.7/4.3) by combining the products from the acidic and basic ring closure process

Acid cyclization

R-4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) benzonitrile (67.5g, R/S95.7/4.3) was dissolved in toluene (315ml), stirred at room temperature, a mixture of sulfuric acid (26g, 96%) and ice (10g) was added, the mixture was stirred at 78-85 ℃ for 2 hours, the reaction mixture was cooled, 40ml of water was added, then aqueous ammonia (25% by weight) was added to reach ph9.5-10.0, the mixture was heated to 55 ℃ (10 min) to effect phase separation, the toluene phase was washed 3 times with water (3 × 65ml), and toluene was removed under reduced pressure at up to 60 ℃ to give an oil (oil a) in a yield of 63g (99%).

Basic cyclization of labile esters

R-4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) benzonitrile (33.7g, R/S ═ 95.7/4.3) was dissolved in acetonitrile (16g) and toluene (135ml), and 21.4g of triethylamine was added. To this mixture was added a solution of p-toluenesulfonyl chloride (19.7g) and toluene (55ml) at such a rate that the temperature was kept below 50 ℃, the mixture was stirred at 10 ℃ for 20 minutes, 75ml of water was added, the mixture was stirred for 5 minutes, then aqueous ammonia (25% by weight) was added to reach pH9.5, the phases were separated, toluene (35ml) was added to the aqueous phase, stirred at 45 ℃ for 10 minutes, the toluene phases were combined, washed with water (2X 75ml), and toluene was removed under reduced pressure at 50 ℃ maximum to give an oil (oil B) in a yield of 32.3g (. about.100%).

Mixture of precipitated oils A and B

Oils A (57g) and B (28g) were mixed in acetone (310ml) at room temperature, 35ml of the solution removed, HPLC showed an S/R ratio of 49.6/50.4, the mixture was cooled, pH 3-4.5, 15ml of the solution was removed before addition of hydrogen bromide, gaseous hydrogen bromide was added until pH 1.5, the mixture was cooled to 15 ℃ and stirred overnight. The crystals were filtered, washed with a mixture of acetone (70ml) and hexane (70ml) to give, after drying, 75.7g of crystals (71%) with a crystal purity of 99.2% (HPLC) and an S/R ratio of 49.5/50.5 (chiral HPLC).

Recrystallizing in water

The crystals (29.9g) obtained by precipitation of the oils A and B were dissolved in 75ml of water at about 48 ℃, the solution was cooled and seeded, stirred at room temperature for 2.5 days, the mixture was cooled to 8 ℃, the crystals were filtered, washed with water (24ml) and after drying 27.9g (93.3%) citalopram HBr (racemate) was obtained with a crystal purity of 99.4% (HPLC) and an S/R ratio of 50/50% (chiral HPLC), thus obtaining the racemate.

Example 4

Preparation of S-citalopram oxalate from R-4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) benzonitrile (R/S ═ 95.7/4.3)

By cyclization in the presence of sulfuric acid

R-4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) benzonitrile (67.0g, R/S95.7/4.3%) was dissolved in toluene (315ml), a mixture of sulfuric acid (25g, 96%) and ice (10g) was added at room temperature, the mixture was stirred at 80-85 ℃ for 2 hours 40 minutes, and the reaction mixture was cooled to room temperature. 40ml of water and then aqueous ammonia (50ml, 25% w/w) were added, the pH adjusted to 10.5, the mixture was heated to 55 ℃ C (10 minutes), the phases were separated, the toluene phase was washed 3 times with water (3X 65ml) and the toluene was removed under reduced pressure at maximum 60 ℃ to give an oil (oil A) in 60.4g (95%).

The oil (60.4g) was dissolved in heptane (600ml) by heating to 89 ℃, the mixture was cooled to room temperature, stirred overnight, the mixture was filtered and the mother liquor was evaporated to give 20.4g (34%). The mother liquor was dissolved in ethanol (78ml), the mixture cooled to below 25 ℃ and a solution of oxalic anhydride (10.2g) in ethanol (48ml) was added, the mixture stirred at below 15 ℃ for 3 h, the mixture filtered, washed with ethanol (24ml) and dried to give 19.9g (76%) of crystalline purity 96.8% (HPLC) and S/R ratio 97.6/2.4 (chiral HPLC).

Example 5

Citalopram is prepared from R-4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) benzonitrile (R/S ═ 69.0/31.0) in acetonitrile by reaction with sulfuric acid

R-4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) benzonitrile (31.1g, R/S69.0/31.0%) was dissolved in acetonitrile (420g), stirred at room temperature, a mixture of sulfuric acid (50g, 96%) and ice (17g) was added, the mixture was stirred at 78-80 ℃ for 1 hour, the reaction mixture was cooled, water and toluene (160ml) were added, and then aqueous ammonia (25% w/w) was added to reach ph 10.5. The mixture was heated to 50-55 deg.C (5-10 min), the phases separated, toluene (25ml) was added to the aqueous phase, stirred at 50-55 deg.C for 5-10 min, the phases separated, the combined toluene phases washed 3 times with water (3X 50ml), and the toluene removed under reduced pressure at maximum 60 deg.C to give an oil in 32.9g (90%) yield with an evaporated mother liquor purity of 96.9% and an S/R ratio of 59.5/40.5 (chiral HPLC).

Example 6

Citalopram is prepared from S-4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) benzonitrile (S/R ═ 99.1/0.9) in toluene by reaction with sulfuric acid

S-4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) benzonitrile (67.0g, R/S ═ 99.1/0.9) was dissolved in toluene (315ml), a mixture of sulfuric acid (25.8g, 96%) and ice (10.7g) was added at room temperature, the mixture was stirred at 78-85 ℃ for 2 hours, the reaction mixture was cooled, 40ml of water was added, ammonia (50ml, 25% by weight) was then added to a pH of 10.5-11.0, the mixture was heated to 57 deg.C (10 minutes), the phases were separated, the toluene phase was washed 3 times with water (3X 50ml), and the toluene was removed under reduced pressure at a temperature of up to 60 deg.C to give an oil (oil A) in a yield of 63.9g (. about.100%), an oil purity of 94.9% and an S/R ratio of 26.3/73/7 (chiral HPLC).

Example 7

Purification of S-citalopram by precipitation of the free base

Precipitation tests were performed to determine the effect of the process on the removal of small amounts of a mixture of R-and S-citalopram from S-citalopram and the results are given in table 3. The general method is as follows: to a mixture of R-and S-citalopram (as described in the "Pre-precipitation" column) heptane (10ml/1g citalopram) was added and the mixture warmed until back-distillation to dissolve the citalopram sample. The heating was stopped and the sample was slowly cooled to room temperature, in all cases some material precipitated out of solution. The residue is usually a solid when a large amount of R-citalopram is present in the starting material, but is usually an oil when only a small amount of R-citalopram is present in the starting material. The mother liquor was removed by filtration in all cases (decantation when the precipitate was an oil) and the R/S ratio of the precipitate is given in Table 3. Evaporation of the filtrate gave an oil/amorphous solid with R/S ratio indicated in table 3 under "oil after evaporation/amorphous solid" column, in each case the product was analysed by chiral SCFC HPLC.

TABLE 3 precipitation of free racemic citalopram base

The last 5 rows of Table 3 show that when the S/R ratio in the feed is less than 97/3, there is an enrichment of the S-isomer in the oil after evaporation of the filtrate, and in all cases an S/R ratio in the final product of greater than 95/5.

Example 8

Purification of S-citalopram by precipitation of citalopram as hydrobromide

The citalopram isomer mixture was dissolved in isopropanol (IPA, 10ml/1g citalopram), a solution of anhydrous hydrogen bromide in IPA (2.0eq, 5.2M) was added dropwise, the solution was seeded with racemic citalopram HBr crystals, the solution was stirred overnight, filtered and the filtrate evaporated to give an oil/amorphous solid, the results of which are given in table 4. "Pre-precipitation" refers to the composition of the mixture before addition of HBr and "post-precipitation" refers to the two products liberated after filtration, the first case not liberating crystalline material (when the "isomer mixture" is S: 98.2% and R: 1.8%), the products being analyzed by chiral SCFC HPLC.

TABLE 4 citalopram HBr salt crystals

In almost all cases virtually no R-isomer remained in the mother liquor, as illustrated by the yield of precipitate and the yield of oil after evaporation, the first and penultimate columns showing that in most cases there is essentially an enriched S-isomer and that in all cases the S/R ratio in the oil after evaporation is greater than 96/4.

Claims (16)

1. A process for the preparation of racemic citalopram free base or its hydrobromide and R-or S-citalopram as free base or oxalate by separating a mixture of R-and S-citalopram with more than 50% of one enantiomer into a fraction consisting of racemic citalopram and a fraction of S-citalopram or R-citalopram, the process being characterized in that:

i) precipitating racemic citalopram as the free base or its hydrobromide from a solvent;

ii) separating the formed precipitate from the mother liquor;

a) if the precipitate is not crystalline, repeating redissolving said precipitate after steps i) and ii) until a crystalline precipitate is obtained;

b) separating S-citalopram or R-citalopram from the mother liquor.

2. A process for the preparation of S-citalopram or R-citalopram according to claim 1, characterised in that:

i) precipitating racemic citalopram from a mixture of R-and S-citalopram as the free base or its hydrobromide from a solvent;

ii) separating the formed precipitate from the mother liquor; and

iii) separating S-citalopram or R-citalopram from the mother liquor.

3. A process for the preparation of racemic citalopram according to claim 1, characterised in that:

i) precipitating racemic citalopram from a mixture of R-and S-citalopram as the free base or its hydrobromide from a solvent;

ii) separating the formed precipitate from the mother liquor;

a) if the precipitate is not crystalline, repeating the redissolving of the precipitate after steps i) and ii) until a crystalline precipitate is obtained.

4. A process according to any one of claims 1 to 3 wherein the racemic citalopram formed is thereafter converted to its hydrobromide salt.

5. The process according to claim 4, wherein the hydrobromide salt is precipitated in crystalline form.

6. A process according to any one of claims 1 to 3 wherein the precipitation material in step i) is a free base.

7. A process according to any one of claims 1-2, characterized in that the mixture of R-and S-citalopram containing more than 50% of a certain enantiomer contains more than 50% S-citalopram.

8. A process according to any one of claims 1-2, characterized in that the mixture of R-and S-citalopram containing more than 50% of a certain enantiomer contains more than 90% S-citalopram.

9. A process according to any one of claims 1-2, characterized in that S-citalopram is separated from the mother liquor by evaporation.

10. A process according to any of the claims 1-2, characterized in that the mother liquor is acidic and S-citalopram is isolated from the mother liquor by alkalizing the mother liquor followed by phase separation or solvent extraction and evaporation of the solvent.

11. A process according to any of claims 1-2, characterized in that the mother liquor is subjected to one or more further precipitations of racemic citalopram as described in step i) before separating excess R-or S-citalopram from the mother liquor.

12. A process according to any one of claims 1 to 3 wherein the isolated R-or S-citalopram is thereafter converted into its oxalate salt.

13. A process according to any one of claims 1 to 3, characterized in that the mixture of R-and S-citalopram containing more than 50% of the S-enantiomer is prepared from a mixture of R-and S-4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) -benzonitrile containing more than 50% of the S-enantiomer by forming unstable ester groups and then cyclizing in an alkaline environment.

14. A process according to any one of claims 1 to 3, characterized in that the mixture of R-and S-citalopram containing more than 50% of the R-enantiomer is prepared from a mixture of R-and S-4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) -benzonitrile containing more than 50% of the R-enantiomer by forming labile ester groups and then cyclizing in an alkaline environment.

15. A process according to any one of claims 1 to 3, characterized in that the mixture of R-and S-citalopram containing more than 50% of the S-enantiomer is prepared from a mixture of R-and S-4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) -benzonitrile containing more than 50% of the R-enantiomer by cyclization in the presence of an acid selected from the group consisting of sulfuric acid, hydrochloric acid, phosphoric acid and p-toluenesulfonic acid.

16. A process according to any one of claims 1 to 3, characterized in that the mixture of R-and S-citalopram containing more than 50% of the R-enantiomer is prepared from a mixture of R-and S-4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) -benzonitrile containing more than 50% of the S-enantiomer by ring closure in the presence of an acid selected from the group consisting of sulfuric acid, hydrochloric acid, phosphoric acid and p-toluenesulfonic acid.