RS20050488A - A process for the preparation of racemic citalopram diol and/or s- or r-citalopram diols and the use of such diols for the preparation of racemic citalopram, r-citalopram and/or s-citalopram - Google Patents

Abstract

In the following, citalopram diol means 4-(4-(dimethylamino)-l --(4-fluorophenyl)-1-hydroxybutyl)-3-(hydroxymethyl)-benzonitrile, as free base and/or acid addition salt. The invention relates to a process for the preparation of racemic citalopram diol and/or R- or S- citalopram diol, comprising the separation of a non-racemic mixture of R- and S-citalopram diol with more than 50% of one of the enantiomers into a fraction being enriched with S- or R-citalopram diol and a fraction comprising RS-citalopram diol wherein the ratio of R-citalopram diol:S-citalopram diol is equal to 1:1 or closer to 1:1 than in the initial mixture. The method is characterized in that (i) RS-citalopram diol is precipitated from a solution of the initial non-racemic mixture, or R- or S-citalopram diol is dissolved into a solvent from the initial non-racemic mixture, leaving a residue of RS-citalopram diol, and in that (ii) the residue/precipitate formed is separated from the final solution phase, followed by optional steps of repetition, recrystallisation, purification, isolation and conversion between free base and salts. The invention also relates to a process for the preparation of RS-citalopram, S-citalopram or R-citalopram (all as free base and/or acid addition salt) comprising the method described above followed by ring closure.

Description

PROCEDURE FOR THE PREPARATION OF RACEMIC CITALOPRAM DIOL AND/OR

S- OR R-CITALOPRAM DIOLS AND THE USE OF SUCH DIOLS FOR

PREPARATION OF RACEMIC CITALOPRAM, R-CITALOPRAM

AND/OR S-CITALOPRAM

The invention relates to a process for the preparation of racemic citalopram diol and R- or S-citalopram diol by separating the initial non-racemic mixture of R- and S-citalopram diol compounds (R- and S-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile) into a racemic citalopram diol fraction and a fraction enriched with S-diol or R-diol. The invention also relates to the use of such isolated citalopram diols for the formation of the corresponding racemic citalopram and/or S- or R-citalopram to be contained in a pharmaceutical composition.

State of the art

Citalopram is a well-known antidepressant drug that has been on the market for several years and has the following structure:

Citalopram can be prepared by ring closure of 4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile (racemic citalopram diol) as described in US Pat. 4,650,884. The product citalopram is a racemic mixture of R- and S-enantiomers.

Furthermore, the S-enantiomer of citalopram (escitalopram) is a valuable selective serotonin reuptake inhibitor (SSRI) antidepressant. Escitalopram can be prepared by ring closure of S-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile (S-diol) keeping the configuration as described in EP B1 347 066. The amount of R-citalopram compared to S-citalopram in the escitalopram product should be less than 3%.

Furthermore, the procedure for preparing a mixture of R- and S-citalopram with more than 50% of the S-enantiomer from a mixture of R- and S-diol with more than 50% of R-diol is described in VVO03000672.

From the above, it follows that the products of racemic citalopram and escitalopram with the above-mentioned enantiomeric purity are necessary for the preparation of pharmaceutical compositions and that the products of racemic citalopram and escitalopram can be prepared by closing the ring of RS-diol and R-diol and/or S-diol. As a consequence, procedures are needed to prepare racemic diol and S-diol products that are suitably enantiomerically pure.

Procedures for the preparation and purification of the R- or S-diol products are available. Such procedures include for example enantio-selective synthesis as described in EP 0347066, classical separation and chromatographic separation as described in WO03006449. Depending on the specific process and conditions used, the enantiomeric purity of the S-diol product may be improved before the S-diol product will meet the above requirements.

Surprisingly, it has now been found that using the process of the invention the expensive but apparently useless S-diol product contaminated with R-diol can be easily converted into two valuable products, the racemic diol and the S-diol, which meet the enantiomeric purity requirements.

Further, using the process of the invention, the expensive but apparently useless R-diol product that is contaminated with S-diol can be easily converted into two valuable products, the racemic diol and the R-diol, which meet the enantiomeric purity requirements.

More specifically, the present invention provides a process for the separation of an initial non-racemic mixture of R- and S-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile with more than 50% of one of the enantiomers into a fraction enriched in S-diol or R-diol and a fraction containing RS-diol, wherein the ratio of R-diol:S-diol is 1:1 or closer. 1:1 than in the initial mixture of R- and S-diol.

The process of the invention is important and very useful, especially because it provides a convenient, cheap and efficient way to transform a mixture of R- and S-diols that do not meet the above requirements in terms of enantiomeric purity into two valuable products, RS-diol and S-diol (or R-diol), that meet the above requirements in terms of enantiomeric purity.

In a further aspect, the invention provides a convenient, inexpensive and efficient process for making an intermediate product to be used in the production of citalopram and escitalopram.

With the present invention, the process for producing racemic citalopram and escitalopram that meet the requirements of each individual marketing approval becomes more rational and economical in terms of process simplicity and utilization of reagents and resources.

The essence of the invention

Thus, the present invention relates to a process for preparing a racemic diol free base and/or acid addition salt and/or R- or S-diol free base and/or acid addition salt, which consists of separating the initial non-racemic mixture of R- and S-diol free base and/or acid addition salt with more than 50% of one of the enantiomers into a fraction enriched with S-diol or R-diol free base and/or acid addition salt and in a fraction containing RS-diol free base and/or acid addition salt, wherein the ratio of R-diol:S-diol is equal to 1:1 or closer to 1:1 than in the initial mixture of R- and S-diol, whereby i) RS-diol free base and/or acid addition salt is precipitated from the solution of the initial non-racemic mixture of R- and S-diol free base and/or acid addition salt; or

The R- or S-diol free base and/or acid addition salt is dissolved in the solvent from the initial non-racemic mixture of the R- and S-diol free base and/or acid addition salt in said solvent, leaving a residue containing the RS-diol free base and/or acid addition salt;

ii) the residue/precipitate that is formed is separated from the final phase of the solution;

iia) if the residue/precipitate is crystalline, it is optionally recrystallized

one or more times to form a racemic diol;

iib) if the residue/precipitate is not crystalline, steps i) and ii) are optionally repeated until a crystalline residue/precipitate is obtained and the crystalline residue/precipitate is optionally recrystallized one or more times to form the racemic diol;

iii) the final solution phase is optionally subjected to further purification and the S-diol and R-diol free base and/or acid addition salt is isolated from the final solution phase: iv) the free base diols obtained are optionally converted to their acid addition salts or the obtained acid addition salts of diols are optionally optionally converted to other acid addition salts

or the resulting acid addition salts of diols are optionally converted to the corresponding free bases.

Accordingly, the resulting RS-diol free base and/or acid addition salt gives lift to the final phase of the solution enriched with either the S- and R-diol free base and/or acid addition salt. Excess R- or S-diol free base and/or acid addition salt can then be isolated from the final solution phase as described below.

In accordance with a specific embodiment, the invention relates to a process for preparing a racemic diol free base and/or acid addition salt using the process described above.

In accordance with the following specific embodiment, the invention relates to a process for preparing an S-diol (or R-diol) free base and/or acid addition salt using the process described above.

In accordance with the following specific embodiment, the invention relates to the use of prepared racemic diol free base and/or acid addition salt and/or S-diol (or R-diol) free base and/or acid addition salt for the preparation of racemic citalopram and/or S-citalopram (or R-citalopram) free base and/or acid addition salt using the procedure described below.

Detailed description of the invention

Whenever used herein, the terms "S-diol" and "S-citalopram diol" mean S-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile.

Whenever used herein, the terms "R-diol" and "R-citalopram diol" mean R-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile.

Whenever used herein, the term "RS-diol" means a mixture of R- and S-diols such as a 0.5:1.5 or 0.9:1.1 or 0.95:1.05 or 0.98:1.02 or 0.99:1.01 mixture of R- and S-diols assumed to be a mixture with a 1:1 ratio of R- to S-diols.

Whenever used herein, the terms "diol enantiomer" and "diol isomer" mean either S- or R-diol.

Whenever used herein, the term "racemic diol" means a 1:1 mixture of R- and S-diol. The term "non-racemic mixture of diols" means mixtures containing R- and S-diols in a ratio other than 1:1.

Whenever used herein, the terms "citalopram enantiomer" and "citalopram isomer" mean either S- or R-citalopram.

Whenever used in this document, the term "racemic citalopram" means a 1:1 mixture of R- and S-citalopram. The term "non-racemic citalopram" means mixtures containing R- and S-citalopram in a ratio other than 1:1.

As used herein, the term "precipitation" means the formation of a precipitate, in the form of a crystal, an amorphous solid, or an oil, or a mixture thereof, from a solution of an initial non-racemic mixture of R- and S-diols in a solvent. In the present description, the precipitate may be an oil, an amorphous solid, or crystals or mixtures thereof.

As used herein, the term "residue" refers to the residue remaining after dissolution of the R- or S-diol in a solvent from the initial non-racemic mixture of the R- or S-diol. The residue may be in the form of crystals, amorphous solids or oils or mixtures thereof.

As used herein, the term "residue/residue" refers to either a residue or residue as defined above.

As used herein, the term "mother liquor" means the solvent remaining after removal or separation from the precipitate.

As used herein, the term "organic and/or aqueous phase resulting from the selective dissolution of the R- or S-diol" refers to the phase where the R- or S-diol is dissolved from the initial non-racemic mixture of the R- or S-diol.

As used herein, the term "final solution phase" refers to the mother liquor or organic and/or aqueous phase resulting from the selective dissolution of the R- or S-diol as described above.

As already mentioned, the above procedures for preparing citalopram free base and/or acid addition salt and/or escitalopram free base and/or acid addition salt may result in a mixture of R- and S-citalopram free base and/or acid addition salt that are not acceptable for pharmaceutical use. In accordance with the present invention, a surprisingly effective process has been found for the preparation of racemic diol and R- or S-diol free base and/or acid addition salt to be used for the preparation of racemic citalopram free base and/or acid addition salt and R- or S-citalopram free base and/or acid addition salt.

This new process involves separation of the initial non-racemic mixture of R- and S-diol free base and/or acid addition salt into a racemic diol free base and/or acid addition salt fraction and into an R- or S-diol free base and/or acid addition salt fraction. The racemic diol free base and/or acid addition salt fraction is precipitated as an oil, amorphous solid or crystalline form or a mixture thereof from the solvent, and the R- or S-diol free base and/or acid addition salt is isolated from the final phase of the solution. Then, racemic citalopram free base and/or acid addition salt and R- or S-citalopram free base and/or acid addition salt can be formed from the corresponding racemic diol free base and/or acid addition salt and R- or S-diol free base and/or acid addition salt by ring closure.

According to a further aspect of the invention, the initial non-racemic mixture of R- and S-diol free base and/or acid addition salt is separated into a fraction enriched with S-diol or R-diol free base and/or acid addition salt and into a fraction containing RS-diol free base and/or acid addition salt wherein the R-diol:S-diol ratio is 1:1 or closer to 1:1 than in the initial mixture R- and S-diols by mixing an initial non-racemic mixture of the R- and S-diol free base and/or acid addition salt with a solvent allowing the presumed R- or S-diol free base and/or acid addition salt to dissolve in the solvent followed by separation of the undissolved residual RS-diol free base and/or acid addition salt from the organic and/or aqueous phase resulting from the selective dissolution of the free R- or S-diol base and/or acid salt additions and isolations R- and S-diol free bases and/or acid addition salts from the specified solvent.

A solvent used in accordance with this embodiment is any solvent that allows the putative R- or S-diol free base and/or acid addition salt to dissolve leaving a mixture of RS-diol free base and/or acid addition salt wherein the ratio of R-diol:S-diol is 1:1 or closer to 1:1 than in the initial mixture of R- and S-diol as the residue. Useful solvents are solvents such as those mentioned for precipitation of RS-diol free base and/or RS-diol acid addition salts.

The initial non-racemic mixture of R- and S-diol free base and/or acid addition salt used in the process of the invention may be an oil, an amorphous solid or a crystalline form; or mixtures thereof.

The residue/precipitate formed in step i) can be oil, amorphous solid or in crystalline form; or mixtures thereof. The residue/precipitate formed in step i) is assumed to be in crystalline form.

According to one embodiment of the invention, the initial non-racemic mixture of R- and S-diol free base and/or acid addition salt used in the process of the invention contains more than 50% S-diol, or more preferably more than 70% S-diol or most preferably more than 90% S-diol.

According to the next embodiment of the invention, the initial non-racemic mixture of R- and S-diol free base and/or acid addition salt used in the process of the invention contains less than 99.9% S-diol, less than 99.5% S-diol, or less than 99% S-diol, or less than 98% S-diol.

Accordingly, the initial non-racemic mixture of R- and S-diol free base and/or acid addition salt may contain 50%-98% S-diol, or 50%-99% S-diol, or 50%-99.5% S-diol, or 50%-99.9% S-diol, or 70%-98% S-diol, or 70%-99% S-diol, or 70%-99.5% S-diol, or 70%-99.9% S-diol, or 90%-98% S-diol, or 90%-99% S-diol, or 90%-99.5% S-diol, or 90%-99.9% S-diol.

According to the next embodiment of the invention, the initial non-racemic mixture of R- and S-diol free base and/or acid addition salt used in the process of the invention contains more than 50% R-diol, or more preferably more than 70% R-diol or most preferably more than 90% R-diol.

According to another embodiment of the invention, the initial non-racemic mixture of R- and S-diol free base and/or acid addition salt used in the process of the invention contains less than 99.9% R-diol, less than 99.5% R-diol, or less than 99% R-diol, or less than 98% R-diol.

Accordingly, the initial non-racemic mixture of R- and S-diol free base and/or acid addition salt may contain 50%-98% R-diol, or 50%-99% R-diol, or 50%-99.5% R-diol, or 50%-99.9% R-diol, or 70%-98% R-diol, or 70%-99% R-diol, or 70%-99.5% R-diol, or 70%-99.9% R-diol, or 90%-98% R-diol, or 90%-99% R-diol, or 90%-99.5% R-diol, or 90%-99.9% R-diol.

The procedure can be repeated until a racemic mixture of R- and S-diol is obtained and/or until the desired degree of enantiomeric purity of R- and S-diol is obtained.

According to one embodiment of the invention, the RS-diol of the residue/precipitate is in the form of a free base and/or acid addition salt; and independently of it R- or S-diol the final phase of the solution is in the form of a free base and/or an acid addition salt. Accordingly, when the RS-diol contained in the residue/solution is in the form of a free base, then the R- or S-diol contained in the final phase of the solution may be in the form of a free base, an acid addition salt, or a mixture of an acid base and an acid addition salt. Furthermore, when the RS-diol contained in the residue/precipitate is in the form of an acid addition salt, then the R- or S-diol contained in the final phase of the solution may be in the form of a free base, an acid addition salt or a mixture of a free base and an acid addition salt. Finally, when the RS-diol contained in the residue/precipitate is a mixture of a free base and an acid addition salt, then the R- or S-diol contained in the final phase of the solution may be in the form of a free base, an acid addition salt or a mixture of a free base and an acid addition salt.

The initial non-racemic mixture of R- and S-diols used in the process of the invention may be present as the free base, as salts, or as free bases and salts.

Further, the obtained free diol bases are optionally converted to their acid addition salts or the obtained acid addition salts of diol are optionally converted to other acid addition salts or the obtained acid addition salts of diol are optionally converted to the corresponding free bases by methods known to those skilled in the art.

Precipitation of the RS-diol free base can be accomplished by obtaining or dissolving a non-racemic mixture of the R- and S-diol free base and/or acid addition salt in a suitable solvent, optionally by applying heating, and then allowing the solution to cool, or by cooling below ambient temperature. The precipitate is then separated from the mother liquor, presumably by filtration or decantation.

The remaining RS-diol free base can be formed by selectively dissolving the R- or S-diol free base and/or acid addition salt in a solvent from the initial non-racemic mixture of the R- and S-diol free base and/or acid addition salt in said solvent. The residue is then separated from the organic and/or aqueous phase resulting in selective dissolution of the R- or S-diol.

If the residue/precipitate is crystalline, the crystals are optionally recrystallized one or more times to form the racemic diol free base. Then, the racemic citalopram free base can be formed from the racemic diol free base by ring closure. The free base of racemic citalopram can optionally be converted to its acid addition salt, presumably the hydrobromide salt.

If the residue/precipitate forms as an oil or an amorphous solid, steps i) and ii) can be repeated until a crystalline product is obtained. The resulting crystals are optionally recrystallized one or more times to form the racemic diol free base. The racemic citalopram free base can be formed from the racemic diol free base by ring closure. The free base of racemic citalopram can optionally be converted to its acid addition salt, presumably the hydrobromide salt.

The RS-diol free base prepared according to the invention is optionally converted to its acid addition salt.

The oil phase separated from the final solution phase is optionally subjected to conventional purification procedures.

The RS-diol free base prepared according to the invention may contain

a small excess of S-diol (or R-diol). Thus, it may be necessary to repeat steps i) and ii) (especially the crystallization) of the free base RS-diol one or more times to obtain the racemic diol. The final solution phases can be collected together and the diol enantiomer contained therein can be isolated as described below.

Suitable solvents for obtaining the residue/precipitate containing RS-diol free base are apolar solvents for example alkanes such as heptane or hexane, aromatic hydrocarbons such as toluene, benzene and xylene, polar solvents such as acetonitrile, alcohols such as methanol and iso-propyl alcohol or ketones such as methyl isobutyl ketone; or mixtures thereof.

In an assumed embodiment, the free base RS-diol is obtained in step i), presumably in crystalline form.

If necessary, crystallization can be initiated by seeding with a racemic crystalline diol free base.

Precipitation of the RS-diol acid addition salt can be performed by obtaining or dissolving a non-racemic mixture of the R- and S-diol free base or acid addition salt in a suitable solvent, if necessary by applying heating, and adding the acid, for example as a solid, liquid, solution or gas.

The acid used to precipitate the RS-diol acid addition salt is an acid that precipitates a mixture of the R- and S-enantiomers and leaves the mother liquor enriched with either the R- or S-diol enantiomer of the diol as the free base or acid addition salt.

The acid used for precipitation of the RS-diol acid addition salt can be: • added after the initial non-racemic mixture of the R- and S-diol free base and/or acid addition salt obtained or dissolved in the appropriate solvent" and/or • present in the solvent during and/or before the dissolution of the initial non-racemic mixture of the R- and S-diol free base and/or acid addition salt;

and/or

• present in the initial non-racemic mixture of R- and S-diol free base and/or acid addition salt during and/or before dissolution in the solvent.

The remaining RS-diol acid addition salt can be formed by selective dissolution of the R- or S-diol free base and/or acid addition salt in a solvent from the initial non-racemic mixture of the R- and S-diol free base and/or acid addition salt in said solvent, if necessary by adding an acid, for example as a solid, liquid, solution or gas; or their mixtures.

The acidic portion of the RS-diol acid addition salt of the residue formed in step i) is an acid, which allows selective dissolution of either the R- or S-diol free base and/or the acid addition salt and leaves undissolved material enriched in the RS-diol acid addition salt.

The acid used to form the RS-diol acid addition salt of the residue may be: • present in the solvent before the initial non-racemic mixture of the R- and S-diol free base and/or acid addition salt is mixed with the solvent; and/or • mixed with a solvent together with an initial non-racemic mixture of R- and S-diol free bases and/or acid addition salts; and/or • mixed with the solvent after the initial non-racemic mixture of R- and S-diol free base and/or acid addition salt is mixed with the solvent; and/or • present in the initial non-racemic mixture of the R- and S-diol free base and/or acid addition salt during and/or prior to mixing with the solvent.

Suitable acids for forming a residue/precipitate of RS-diol acid addition salt from the initial non-racemic mixture of R- and S-diol free base and/or acid addition salt are inorganic acids such as hydrochloric acid, hydrobromic acid<<>sulfuric acid or organic acids such as oxalic acid, p-toluene sulfonic acid, methane sulfonic acid and acetic acid. Hydrobromic acid, hydrochloric acid, and oxalic acid are assumed acids. When these acids are used, the hydrobromide salt, hydrochloride salt or oxalate salt of RS-diol is formed, presumably in crystalline form. Suitably, up to 10 acid equivalents are used. Accordingly: • 0.2-10 mol of acid can be used, such as 0.2-0.4 mol, or 0.4-0.6 mol, or 0.9-1.1 mol or 1.8-2.2 mol of acid is used for each mol of S- and R-diol contained in the initial non-racemic mixture of R- and S-diol free base and/or acid addition salt; and/or • 0.3-4.0 mol, such as 0.4-0.6 mol, or 0.9-1.1 mol or 1.8-2.2 mol of acid is used for each mol of RS-diol present in the residue/precipitate.

To increase the ionic strength of the solution, salts such as NaCl can be added to the solution before, during, and after the RS-diol acid addition salt is obtained in step i). Those skilled in the art will know how to adjust the amount of salt added to obtain the desired effect.

Suitable solvents for forming a residue/precipitate of the RS-diol acid addition salt from the initial non-racemic mixture of the R- and S-diol free base and/or acid addition salt are polar and apolar solvents such as toluene, ethyl acetate, diethyl ether, THF, alcohols such as iso-propyl alcohol, and ketones such as acetone and methyl isobutyl ketone, and water.

If the residue/precipitate formed in step i) is crystalline, the crystals are separated from the final phase of the solution, presumably by filtration or decantation. The crystals are optionally recrystallized by dissolving the crystals in a solvent, presumably by heating, and allowing the solution to cool, or by cooling to below ambient temperature. Racemic citalopram can be formed from the crystalline racemic diol acid addition salt by ring closure. Racemic citalopram can be converted to its pharmaceutically acceptable salt, presumably the HBr salt.

If the residue formed in step i) is not crystalline, but amorphous or oil, or their mixture, steps i) and ii) can be repeated until a crystalline product is obtained. The resulting crystals are optionally recrystallized one or more times as described above. Racemic citalopram can be formed from the crystalline racemic diol acid addition salt by ring closure. Racemic citalopram can be converted to its pharmaceutically acceptable salt, presumably the HBr salt.

The oil phase that separates from the final solution phase is optionally subjected to conventional purification procedures.

Thus, the RS-diol acid addition salt prepared according to the invention may contain a small excess of S-diol (or R-diol). Thus, it may be necessary to repeat the precipitation (especially the crystallization) of the RS-diol acid addition salt one or more times to obtain a racemic mixture. The final solution phase can be collected together and the diol enantiomer contained herein can be isolated as described below.

If necessary, crystallization of the RS-diol acid addition salt can be initiated by seeding with the racemic crystalline diol acid addition salt.

The RS-diol acid addition salt prepared according to the invention is optionally converted into other acid addition salts or the corresponding free base.

According to an assumed embodiment of the invention, the free base of RS-diol or the hydrochloride salt, hydrobromide salt or oxalate salt of RS-diol is obtained, presumably in crystalline form in steps i), iia) and iib).

The final solution phase, its extracts, or the phase enriched with R- or S-diol free base and/or acid addition salt may be subjected to conventional purification procedures (such as treatment with activated carbon, chromatography, etc.) before solvent evaporation, and/or may be subjected one or more times to further precipitation of RS-diol free base or RS-diol acid addition salt according to the invention, in order to improve the enantiomeric purity diol enantiomer of the product.

The R- or S-diol free base and/or acid addition salt can be isolated from the final phase of the solution using conventional procedures such as solvent evaporation, or in case the final phase of the solution is acidified by basification followed by phase separation or extraction of the R- or S-diol free base and/or acid addition salt followed by solvent evaporation.

The final phase of the solution, its extracts, or the phase enriched in R- or S-diol free base and/or acid addition salt may be subjected to conventional purification procedures (such as treatment with activated carbon, chromatography, etc.) before isolation from the R- or S-diol free base and/or acid addition salts. Suitably, the R- or S-diol may be precipitated as a phosphate salt or oxalate by methods known to those skilled in the art.

It has been found that the enantiomeric purity (ratio between the desired isomer and the sum of both isomers) of the S- or R-diol free base and/or acid addition salt remaining in the final solution phase can be as high as 97-98% or even higher (or better) depending on the specific conditions used.

Accordingly, the S-diol (or R-diol) free base and/or acid addition salt prepared according to the invention may contain a small amount of the R-diol (or S-diol) free base and/or acid addition salt. In one embodiment, this minor amount may be less than 3%, or preferably less than 2%, or most preferably less than 1% (the ratio of the minor isomer to the sum of both isomers).

The R- or S-diol free base and/or acid addition salt may be purified and isolated from said solvent or final solution phase as described above.

In one embodiment, the R-diol free base or acid addition salt is obtained.

In the next embodiment, the S-diol free base or acid addition salt is obtained.

Once the R- or S-diol free base is obtained, it is optionally converted to its acid addition salt. Once the R- or S-diol acid addition salt is obtained, it is optionally converted to other acid addition salts or the corresponding free base.

The enantiomerically pure R- or S-diol side base and/or acid addition salt can be mixed with a non-racemic mixture of the R- and S-diol free base and/or acid addition salt to give the racemic diol free base and/or acid addition salt. The racemic diol free base and/or acid addition salt can be obtained by one or more precipitations of the racemic diol free base and/or acid addition salt, followed by recrystallization as described above.

The R- and S-citalopram free base and/or acid addition salt can be formed from the corresponding R- or S-diol free base and/or acid addition salt by ring closure with retention of configuration. The S-citalopram (or R-citalopram) free base and/or acid addition salt may optionally be converted to its acid addition salt, presumably the oxalate salt, and optionally recrystallized.

Ring closure of the R- or S-diol free base and/or acid addition salt can be performed via a labile ester intermediate, e.g. in the presence of tosyl chloride, in a basic environment, as described in EP-B1-347 066. The ring closure then proceeds with retention of the stereochemistry. R- or S-citalopram free base and/or acid addition salt of enantiomeric purity essentially equal to the starting part is obtained.

Ring closure of the resulting racemic diol free base and/or acid addition salt can be performed in an acidic environment, as described in US 4,650,884, or via a labile ester as described above. This gives racemic citalopram.

The thus obtained enantiomerically pure R- or S-citalopram free base and/or acid addition salt can be mixed with a non-racemic mixture of R- and S-citalopram free base and/or acid addition salt to obtain racemic citalopram free base and/or acid addition salt. Recem citalopram free base and/or acid addition salt can then be obtained by one or more precipitations of its citalopram free base or acid addition salt, followed by recrystallization as described above.

One particular embodiment of the invention relates to the process of preparing the racemic diol free base or its acid addition salt and/or the R- or S-diol free base or its acid addition salt by separating the initial non-racemic mixture of R- and S-diol with more than 50% of one of the enantiomers into a fraction enriched with S-diol or R-diol and into a fraction containing RS-diol where the ratio R-diol:S-diol is equal to 1:1 or closer to 1:1 than in the initial mixture of R- and S-diol where

i) RS-diol is precipitated from the solvent as a free base or as

its acid addition salt;

ii) the precipitate formed is separated from the mother liquid;

iia) if the precipitate is crystalline, it is optionally recrystallized

one or more times to form a racemic diol;

iib) if the precipitate is not crystalline, steps i) and ii) are optionally repeated until a crystalline precipitate is obtained and the crystalline precipitate is optionally recrystallized one or more times to form the racemic diol;

iii) the mother liquor is optionally subjected to further purification and the S-diol or R-diol is isolated from the mother liquor;

iv) obtained free diol bases are optionally converted to their acid addition salts or obtained acid addition salts of diol are optionally converted to other acid addition salts or obtained acid addition salts of diol are optionally converted to corresponding free bases.

A further specific embodiment of the invention relates to a process for the preparation of a racemic diol free base or its acid addition salt and/or R- or S-diol as a free base or its acid addition salt by separating the initial non-racemic mixture of R- and S-diol with more than 50% of one of the enantiomers into a fraction enriched with S-diol or R-diol and into a fraction containing RS-diol where the ratio R-diol:S-diol is equal 1:1 or closer to 1:1 than in the initial mixture of R- and S-diol whereby

i) RS-diol is precipitated from the solvent as a free base or as its acid addition salt; or

The R- or S-diol is dissolved in a solvent from the initial non-racemic mixture of the R- or S-diol as the free base or its acid addition salt in said solvent, leaving a residue;

ii) the precipitate formed is separated from the mother liquid;

iia) if the precipitate is crystalline, it is optionally recrystallized

one or more times to form a racemic diol;

iib) if the precipitate is not crystalline, steps i) and ii) are optionally repeated until a crystalline precipitate is obtained and the crystalline precipitate is optionally recrystallized one or more times to form the racemic diol;

iii) the mother liquor is optionally subjected to further purification and the S-diol or R-diol is isolated from the mother liquor;

iv) obtained free diol bases are optionally converted to their acid addition salts or obtained acid addition salts of diol are optionally converted to other acid addition salts or obtained acid addition salts of diol are optionally converted to corresponding free bases.

The invention is illustrated by the following examples, which are not to be construed as limiting.

Examples

In the following examples, optical purities are measured by Chiral SCFC (Super Critical Fluid Chromatography) HPLC.

Example 1

Purification of S-diol by precipitation of racemic diol as hydrochloride

salt

General procedure:

A mixture of R- and S-diols (as defined in the table below) (10 g) was dissolved in toluene (60 ml_). Aqueous hydrochloric acid (32 ml_, 1M) is added, and in some cases solid sodium chloride is added (enough to make the NaCl concentration approximately 1M). The mixture is stirred overnight and filtered. The residue is dried to give crystals of racemic diol hydrochloride, contaminated with some S-diol hydrochloride. The basicity of the mother liquor is increased with an aqueous ammonia solution to pH>9, and the toluene layer is separated. The aqueous layer was washed again with toluene, and the combined toluene extracts were dried over magnesium sulfate and evaporated under reduced pressure to give mostly S-diol, contaminated with a small amount of R-diol. See table for more details. Material recovery is practically quantitative, with the expected weight distribution between individual samples.

In the following examples, optical purity is measured by Chiral HPLC.

Example 2

Purification of S-diol by precipitation of the racemic diol free base

A solution of S-diol in acetonitrile (500 ml_, 50-55% by mass, S:R ratio 95.72:4.28) at room temperature was cooled to -14°C with stirring. The mixture is seeded with an almost racemic diol (S:R ratio 60:40) after each temperature drop of 2°C. After 16 hours, the mixture is filtered, and the filter cake is dried. Analysis of the filter cake shows that the S:R ratio is 57.97:42.03. Analysis of the mother liquor shows that the S:R ratio is 98.065:1.935.

Example 3

Purification of S-diol by precipitation of the racemic diol free base

A solution of S-diol in acetonitrile (500 mL, 50-55% by mass, S:R ratio 95.72:4.28) at room temperature was cooled with stirring to -10°C with a cooling rate of 1°C/h. The mixture is seeded with an almost racemic diol (S:R ratio 60:40) after each temperature drop of 5°C. After 40 hours at -10°C, the mixture is filtered, and the filter cake is dried. Filter cake analysis shows that the S:R ratio is 59.19:40.81. Analysis of the mother liquor shows that the S:R ratio is 98.52:1.48.

Example 4

Purification of S-diol by precipitation of racemic diol as hydrochloride

salt

General procedure:

A mixture of R- and S-diols (as defined in the table below) (1 g) was dissolved in toluene (10 ml_). An aqueous solution of hydrochloric acid (1.0 equivalent; concentration as defined in the table below) is added, and solid sodium chloride is added (enough to make the NaCl concentration approximately 1 or 2 M; see the table below). The mixture is stirred overnight and filtered. The residue is dried to give crystals of racemic diol hydrochloride, contaminated with some S-diol hydrochloride. The basicity of the mother liquor is increased with an aqueous ammonia solution to pH>9, and the toluene layer is separated. The aqueous layer was washed again with toluene, and the combined toluene extracts were dried over magnesium sulfate and evaporated under reduced pressure to give mostly S-diol, contaminated with a small amount of R-diol. See table for more details. Material recovery is practically quantitative, with the expected weight distribution between individual samples.

Example 5

Purification of S-diol by precipitation of racemic diol as

p-toluenesulfonyl, methanesulfonyl or acetate salts

General procedure:

A mixture of R- and S-diols (as defined in the table below) (1 g) is dissolved in toluene or ether (10 ml_; as described in the table below). Aqueous NaCl solution (1 M, 3 mL) was added. Fine acid is added as a liquid (as defined in the table below). The mixture is stirred overnight, and filtered or decanted. The residue is dried to obtain an oil or solid form. The basicity of the mother liquor is increased with an aqueous ammonia solution to pH>9, and a layer of toluene or ether is separated. The aqueous layer was washed again with toluene or ether, and the combined organic extracts were dried over magnesium sulfate and evaporated under reduced pressure to give a mostly solid or oil. See table for more details. Material recovery is practically quantitative, with the expected weight distribution between individual samples.

Example 6

Purification of S-diol by precipitation of the racemic diol salt in the absence of water

General procedure:

A mixture of R- and S-diols (as defined in the table below) (1 g) is dissolved in toluene or ether (10 ml_; as described in the table below). Fine acid is added as a solid (as defined in the table below). The mixture is stirred overnight and filtered. The residue is dried to obtain an oil or solid form. Water is added to the mother liquor, and the mother liquor is basified with an aqueous ammonia solution to pH>9, and the toluene or ether layer is separated. The aqueous layer was washed again with toluene or ether, and the combined organic extracts were dried over magnesium sulfate and evaporated under reduced pressure to give a mostly solid or oil. See table for more details. Material recovery is practically quantitative, with the expected weight distribution between individual samples.

Example 7

Purification of S-diol by precipitation of racemic diol salt in the absence of water using different solvents

General procedure:

A mixture of R- and S-diol (as defined in the table below) (1 g) is dissolved in solvent (10 ml_; as described in the table below). Fine acid is added as a solid (as defined in the table below). The mixture is stirred overnight, and filtered or decanted if a precipitate has formed. Where a precipitate has formed, the residue is dried to obtain an oil or solid form. The mother liquor is evaporated, and the residue is introduced into a mixture of ether and water. This mixture is basified with an aqueous ammonia solution to pH>9, and the ether layer is separated. The aqueous layer was washed once more with ether, and the combined ether extracts were dried over magnesium sulfate and evaporated under reduced pressure to give a mostly solid or oil. See table for more details. Material recovery is practically quantitative, with the expected weight distribution between individual samples.

Example 8

Purification of S-diol by precipitation of racemic diol oxalate

General procedure:

A mixture of R- and S-diols (as defined in the table below) (1 g) was dissolved in toluene (10 ml_). Aqueous NaCl solution (1 M, 3ml_) was added and fine oxalic acid in solid form (as defined in the table below) was added. The mixture is stirred overnight, and filtered or decanted if a precipitate forms. Where a precipitate has formed, the residue is dried to obtain an oil or solid form. The basicity of the mother liquor is increased with an aqueous ammonia solution to pH>9, and the toluene layer is separated. The aqueous layer was washed again with toluene, and the combined toluene extracts were dried over magnesium sulfate and evaporated under reduced pressure to give a mostly solid or oil. See table for more details. Material recovery is practically quantitative, with the expected weight distribution between individual samples.

Example 9

Purification of S-diol by precipitation of racemic diol hydrochloride in water

General procedure:

A mixture of R- and S-diols (as defined in the table below) (1 g) is mixed with aqueous HCl (1 equivalent; see table for concentration). The mixture is stirred overnight, and enough NaCl (as solid) is added to make the NaCl concentration 1 M. The mixture is filtered to obtain a solid. Water and ether are added to the mother liquor, basicity is increased with an aqueous ammonia solution to pH>9, and the ether layer is separated. The aqueous layer was washed once more with ether, and the combined ether extracts were dried over magnesium sulfate and evaporated under reduced pressure to give a mostly solid or oil. See table for more details. Material recovery is practically quantitative, with the expected weight distribution between individual samples.

Example 10

Purification of S-diol by putative dissolution of S-diol

hydrochloride in water

General procedure:

A mixture of the R- and S-diol hydrochloride salts (17.7; 82.3; 5.5 g) was mixed with aqueous NaCl (1 M, 12 ml_). The mixture is stirred overnight, and filtered to obtain a solid form. Water and ether are added to the mother liquor, basicity is increased with an aqueous ammonia solution to pH>9, and the ether layer is separated. The aqueous layer was washed once more with ether, and the combined ether extracts were dried over magnesium sulfate and evaporated under reduced pressure to give a mostly solid or oil. The filter residue contains R-diol and S-diol in the ratio 1.0:99.0. The product from the filtrate production contains R-diol and S-diol in the ratio 38.8:61.2. Material recovery is practically quantitative, with the expected weight distribution between individual samples.

Claims (29)

1. Process for the preparation of racemic diol free base and/or acid addition salt and/or R- or S-diol free base and/or acid addition salt, which consists of separating the initial non-racemic mixture of R- and S-diol free base and/or acid addition salt with more than 50% of one of the enantiomers into a fraction enriched with S-diol or R-diol free base and/or acid addition salt and into a fraction containing RS-diol free base and/or acid addition salt, where the ratio R-diol:S-diol is equal to 1:1 or closer to the ratio 1:1 than in the initial mixture of R- and S-diol, indicated by the fact that i) RS-diol free base and/or acid addition salt is precipitated from the solution of the initial non-racemic mixture of R- and S-diol free base and/or acid addition salt; or The R- or S-diol free base and/or acid addition salt is dissolved in the solvent from the initial non-racemic mixture of the R- and S-diol free base and/or acid addition salt in said solvent, leaving a residue containing the RS-diol free base and/or acid addition salt; ii) the residue/precipitate that is formed is separated from the final phase of the solution; iia) if the residue/precipitate is crystalline, it is optionally recrystallized one or more times to form a racemic diol; iib) if the residue/precipitate is not crystalline, steps i) and ii) are optionally repeating until a crystalline residue/precipitate is obtained and the crystalline residue/precipitate is optionally recrystallized one or more times to form the racemic diol; iii) the final phase of the solution is optionally subjected to further purification and the S-diol and R-diol free base and/or acid addition salt is isolated from the final phase of the solution: iv) the obtained free bases of diols are optionally converted to their acid addition salts or the obtained acid addition salts of diols are optionally optionally converted to other acid addition salts or the obtained acid addition salts of diols are optionally converted to the corresponding free bases. 2. The method according to claim 1 for the preparation of S-diol or R-diol free base and/or acid addition salt, indicated by the fact that i) RS-diol free base and/or acid addition salt is precipitated from the solution of the initial non-racemic mixture of R- and S-diol free base and/or acid addition salt; or The R- or S-diol free base and/or acid addition salt is dissolved in the solvent from the initial non-racemic mixture of the R- and S-diol free base and/or acid addition salt in said solvent, leaving a residue containing the RS-diol free base and/or acid addition salt; ii) the residue/precipitate formed is separated from the final solution phase, and iii) the final solution phase is optionally subjected to further purification and the S-diol and R-diol free base and/or acid addition salt is isolated from the final solution phase. 3. Method according to claim 2, characterized in that the prepared diol is S-diol free base and/or acidic addition salt. 4. Process according to claim 2, characterized in that the prepared diol is R-diol free base and/or acid addition salt. 5. Method according to claim 1 for the preparation of racemic diol free base and/or acid addition salt, indicated by the fact that i) RS-diol free base and/or acid addition salt is deposited from the solution of the initial non-racemic mixture of R- and S-diol free base and/or acid addition salt; or The R- or S-diol is dissolved in a solvent from the initial non-racemic mixture of the R- and S-diol free base and/or acid addition salt in said solvent, leaving a residue containing the RS-diol free base and/or acid addition salt; ii) the residue/precipitate that is formed is separated from the final phase of the solution; iia) if the residue/precipitate is crystalline, it is optionally recrystallized one or more times to form a racemic diol; iib) if the residue/precipitate is not crystalline, steps i) and ii) are optionally repeated until a crystalline residue/precipitate is obtained and the crystalline residue/precipitate is optionally recrystallized one or more times to form the racemic diol. 6. The method according to any one of claims 1-5, characterized by the fact that the initial non-racemic mixture of R- and S-diol of the free base and/or acid addition salt with more than 50% of one of the enantiomers contains more than 50% of S-diol, preferably more than 70% of S-diol or most preferably more than 90% of S-diol. 7. The method according to any one of claims 1-5, characterized by the fact that the initial non-racemic mixture of R- and S-diol of the free base and/or acid addition salt with more than 50% of one of the enantiomers contains more than 50% of R-diol, preferably more than 70% of R-diol or most preferably more than 90% of R-diol. 8. The process according to any one of claims 1-7, characterized in that the ratio of R-diol:S:diol in the RS-diol of the residue/precipitate is 0.5:1.5 or 0.9:1.1 or 0.95:1.05 or 0.99:1.01 or 0.98:1.02 or assumed to be 1:1. 9. The method according to any of claims 1-8, indicated by the fact that the RS-diol contained in the residue/precipitate is in the form of a free base and/or its acid addition salt; and independently of that the R- or S-diol contained in the final phase of the solution is in the form of the free base and/or its acid addition salt. 10. The method according to any one of claims 1-9, characterized in that RS-diol free base and/or acid addition salt is precipitated from the solution of the initial non-racemic mixture of R- and S-diol free base and/or acid addition salt. 11. The method according to any one of claims 1-10, characterized in that the acid used to precipitate RS-diol as a salt in step i) is an acid that precipitates a mixture of R- and S-enantiomers and leaves the mother liquor enriched with either the S- or R-enantiomer of the diol free base and/or acid addition salt. 12. The method according to claim 11, indicated by the fact that the acid can be: • added after the initial non-racemic mixture of R- and S-diol free base and/or acid addition salt which is obtained or dissolved in a suitable solvent; and/or • present in the solvent during and/or before the dissolution of the initial non-racemic mixture of the R- and S-diol free base and/or acid addition salt; and/or • present in the initial non-racemic mixture of the R- and S-diol free base and/or acid addition salt during and/or prior to dissolution in the solvent. 13. The method according to any one of claims 1-9, characterized in that the R- or S-diol free base and/or acid addition salt is dissolved in a solvent from the initial non-racemic mixture of the R- and/or S-diol free base and/or acid addition salt in said solvent, leaving a residue containing the RS-diol free base and/or acid addition salt. 14. The method according to any one of claims 1-9 and 13, characterized in that the acidic portion of the RS-diol acid addition salt contained in the residue formed in step i) is an acid that allows the selective dissolution of either the R- or S-diol free base and/or the acid addition salt and leaves undissolved material enriched with the RS-diol acid addition salt. 15. The method according to claim 13, characterized by the fact that the acid can be: • present in the solvent before the initial non-racemic mixture of R- and S-diol free base and/or acid addition salt is mixed with the solvent; and/or • mixed with a solvent together with an initial non-racemic mixture of R- and S-diol free bases and/or acid addition salts; and/or • mixed with the solvent after the initial non-racemic mixture of R- and S-diol free base and/or acid addition salt is mixed with the solvent; and/or • present in the initial non-racemic mixture of the R- and S-diol free base and/or acid addition salt during and/or prior to mixing with the solvent. 16. Process according to claims 1-15, characterized in that the RS-diol is an acid addition salt obtained from an initial non-racemic mixture of R- and S-diol free base and/or acid addition salt in a solvent selected from the group consisting of toluene, ethyl acetate, diethyl ether, THF, water, alcohol such as iso-propyl alcohol, acetonitrile, and ketones such as acetone and methyl isobutyl ketone; or their mixtures. 17. The method according to any one of claims 1-16, characterized in that the acid used in step i) is HCI, HBr, H2SO4, p-toluene sulfonic acid, methane sulfonic acid, acetic acid or oxalic acid. 18. The method according to claim 17, indicated by the fact that the acid used in step i) is HCI, HBr, or oxalic acid, so that a hydrobromide salt, a chlorhydrate salt, or an oxalate salt of RS-diol is formed, presumably in crystalline form. 19. The process according to any one of claims 1-18, characterized in that 0.2-10 mol of acid can be used, such that 0.2-0.4 mol, or 0.4-0.6 mol, or 0.9-1.1 mol or 1.8-2.2 mol of acid is used for each mol of S- and R-diol contained in the initial non-racemic mixture of R- and S-diol free base and/or acid addition of salts. 20. The process according to any one of claims 1-18, characterized in that 0.3-4.0 mol, such as 0.4-0.6 mol, or 0.9-1.1 mol or 1.8-2.2 mol of acid can be used for each mol of RS-diol present in the residue/precipitate. 21. The method according to any one of claims 1-10 and 13, characterized in that the free base RS-diol is obtained in step i), presumably in crystalline form. 22. The process according to any one of claims 1-10, 13 and 21, characterized in that the free base RS-diol is obtained from an initial non-racemic mixture of R- and S-diol in a solvent selected from the group consisting of alkanes such as heptane or hexane, aromatic hydrocarbons such as toluene, benzene and xylene, polar solvents such as acetonitrile, alcohols such as methanol and isopropyl alcohol or a ketone such as methyl isobutyl ketone; or their mixtures. 23. A process according to any one of claims 1-22, characterized in that the final phase of the solution is subjected one or more times to further separations of the RS-diol as described under steps i) and ii) before isolating the S-diol (or R-diol) from the final phase of the solution. 24. The method according to any of claims 1-4 and 6-23, characterized in that the S-diol (or R-diol) is isolated from the final phase of the solution by evaporation of the solvent. 25. The method according to any of claims 1-4 and 6-24, characterized in that the final phase of the solution is acidic and the S-diol (or R-diol) is isolated from the final phase of the solution by increasing the basicity of the final phase of the solution, followed by a phase of separation or extraction with a solvent followed by evaporation of the solvent. 26. The method according to any of claims 1-4 and 6-24, indicated by the fact that S-diol (or R-diol) free base and/or acid addition salt is isolated from the final phase of the solution by precipitation of R- or S-diol free base and/or acid addition salt; the phosphate salt or oxalate salt of the R- or S-diol precipitates accordingly. 27. The process according to any one of claims 1-4 and 6-26, characterized in that the obtained S-diol (or R-diol) contains a small amount of the opposite enantiomer such as less than 3%, preferably less than 2%, or most preferably less than 1%. 28. Use of RS-diol free base and/or acid addition salt and/or S-diol free base and/or acid addition salt and/or R-diol free base and/or acid addition salt prepared according to any of claims 1-27 for the preparation of citalopram free base and/or acid addition salt and/or R-citalopram free base and/or acid addition salt and/or S-citalopram free base and/or acid addition salt. 29. Process for preparing citalopram free base and/or as acid addition salt and/or S-citalopram free base and/or as acid addition salt and/or R-citalopram free base and/or as acid addition salt, indicated by the fact that it consists of preparing RS-diol free base and/or as acid addition salt and/or S-diol free base and/or as acid addition salt and/or R-diol free base and/or as acid addition salts according to any of claims 1-27 by ring closure.