ES2385975T3 - Procedure for the preparation of racemic citalopram diol and / or S-O R-citalopram diols and the use of such diols for the preparation of racemic citalopram, R-citalopram and / or S-citalopram - Google Patents

Abstract

A process for the preparation of the free base and / or the acid addition salt of 4- [4- (dimethylamino) -1- (4- fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) benzonitrile (diol) racemic and / or the free base and / or the acid addition salt of R- or S-diol comprising a separation of an initial non-racemic mixture from the free base and / or the acid addition salt of R- and S-diol with more than 50% of one of the enantiomers in a fraction that is enriched with the free base and / or the acid addition salt of S-diol or R-diol and a fraction comprising the free base and / or the acid addition salt of RS-diol in which 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 characterized because i) the free base and / or the acid addition salt of RS-diol is precipitated in a solution of the initial non-racemic mixture of the free base and / or the acid addition salt of R- and S-diol ; or the free base and / or the acid addition salt of R- or S-diol is dissolved in a solvent of the initial non-racemic mixture of the free base and / or the acid addition salt of R- and S- diol in said solvent, leaving a residue comprising the free base and / or the acid addition salt of RS-diol; ii) the residue / precipitate formed is separated from the final phase in solution; iia) if the residue / precipitate is crystalline it is optionally recrystallized one or more times to form 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 racemic diol; iii) the final solution phase is optionally subjected to another purification and the free base and / or the acid addition salt of S-diol or R-diol is isolated from the final phase in solution; iv) the free bases of the diols obtained are optionally converted into their acid addition salts or the acid addition salts of the obtained diols are optionally converted into other acid addition salts or the acid addition salts of the diols obtained optionally become the corresponding free bases.

Description

Procedure 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

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

Background of the invention

Citalopram is a well known antidepressant medication that has been marketed for some years and has the following structure:

Citalopram can be prepared by closing the 4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) benzonitrile (racemic citalopram diol) ring as described in US Pat. No. 4,650,884. The citalopram product is a racemic mixture of the R and S enantiomers.

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

In addition, a method for the preparation of a mixture of R- and S-citalopram, with more than 50% of enantiomer S from a mixture of R- and S-diol with more than 50% of R-diol is described in the WO 03000672.

According to the foregoing, it seems that racemic citalopram and escitalopram products with the enantiomeric purity mentioned above are necessary for the preparation of pharmaceutical compositions and that racemic citalopram and escitalopram products can be prepared by ring closure of RS-diol, R-diol and / or S-diol. As a consequence, processes are needed for the preparation of racemic diol and S-diol products that are to the same extent enantiomerically pure.

Procedures for the preparation and purification of R- or S-diol products are available. Such procedures involve, for example, the enantio-selective synthesis described in EP 0347066, the classical resolution and the chromatographic separation described in WO 03006449. Depending on the specific procedure and the conditions used, the enantiomeric purity of the S-diol product may have to be improved before the S-diol product meets the above requirements.

Surprisingly, it has now been discovered that by using the process of the invention an expensive product, but apparently useless S-diol contaminated with R-diol, can easily become the two valuable products, racemic diol and S-diol, which meet the previous requirements regarding enantiomeric purity.

Furthermore, using the method of the invention, an expensive product, but apparently useless R-diol that is contaminated with S-diol, can easily become valuable racemic, diol and R-diol products, which meet the above requirements as at enantiomeric purity.

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

5 of R-and S-diol.

The process of the invention is important and very useful, in particular because it provides a convenient, economical and efficient way to transform a mixture of Ry S-diols that does not meet the above requirements for enantiomeric purity into two valuable products, RS- diol and S-diol (or R-diol), which meets the above requirements for enantiomeric purity.

In another aspect, the invention provides a convenient, economical and efficient method for preparing an intermediate for use in the manufacture of citalopram and escitalopram.

With the present invention, the process for the production of racemic citalopram and escitalopram that meets the requirements of the respective commercial approvals has become more rational and more economical in terms of the simplicity of the procedure and the use of reagents and resources.

15 Summary of the invention

Therefore, the present invention relates to a process for the preparation of a racemic diol free base and / or an acid addition salt and / or a free base and / or an acid addition salt of Ro S- diol comprising a separation of an initial non-racemic mixture of free base and / or acid addition salt of Ry S-diol with more than 50% of one of the enantiomers in a fraction that is enriched with free base and / or salt of addition

20 of S-diol or R-diol acid and a fraction comprising free base and / or RS-diol acid addition salt in which the ratio of R-diol: S-diol is equal to 1: 1 or closer to 1: 1 than in the initial Ry S-diol mixture in which

i) the free base and / or the acid addition salt of RS-diol is precipitated in a solution of the initial non-racemic mixture of free base and / or acid addition salt of R-and S-diol; or

the free base and / or the acid addition salt of R-or S-diol is dissolved in a solvent of the mixture not

Initial racemic free base and / or R-and S-diol acid addition salt in said solvent, leaving a residue comprising free base and / or RS-diol acid addition salt;

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

iia) if the residue / precipitate is crystalline it is optionally recrystallized one or more times to form 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 racemic diol;

iii) the final phase in solution is optionally subjected to further purification and the free base of S-diol or R-diol and / or the acid addition salt is removed from the final phase in solution;

Iv) the free bases of the diols obtained are optionally converted into their acid addition salts or the acid addition salts of the obtained diols are optionally converted into other acid addition salts or the acid addition salts of the diols obtained optionally become the corresponding free bases.

Therefore, the free base and / or the RS-diol acid addition salt obtained gives rise to the final phase in solution

40 which is enriched with the free base and / or the acid addition salt of S or R-diol. The excess free base and / or acid addition salt of R-or S-diol can then be isolated from the final solution phase as described below.

According to a specific embodiment, the invention relates to a process for the preparation of free base and / or racemic acid addition salt using the method described above.

According to another specific embodiment, the invention relates to a process for the preparation of a free base and / or S-diol acid addition salt (or R-diol) using the procedure described above.

According to yet another specific embodiment, the invention relates to the use of the preparations of a free base and / or the addition salt of racemic acid and / or of a free base and / or the acid addition salt of S -diol (or R-diol) for the preparation of racemic citalopram and / or a free base and / or the acid addition salt S-citalopram (or R

50 citalopram) using the procedure described below.

Detailed Description of the Invention

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

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

Each time it is used herein, the term "RS-diol" means a mixture of Ry S-diol such as a mixture 0.5: 1.5 or 0.9: 1.1 or 0.95: 1, 05 or 0.98: 1.02 or 0.99: 1.01 of Ry S-diol and preferably a mixture with a 1: 1 ratio of Ry S-diol.

Each time they are used herein, the terms "diol enantiomer" and "diol isomer" mean any S-or R-diol.

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

Each time they are used in this document, the terms "citalopram enantiomer" and "citalopram isomer" mean any S-or R-citalopram.

Each time it is used herein, the term "racemic citalopram" means a 1: 1 mixture of R-and Scitalopram. The term "non-racemic citalopram" means mixtures containing R-and S-citalopram in a ratio other than 1: 1.

As used in this description, the term "precipitation" means that it forms a precipitate, in the form of crystals, an amorphous solid or an oil or mixtures thereof, of a solution of the initial non-racemic mixture of Ry S-diol in a solvent In the present description, a precipitate may be an oil, an amorphous solid or crystals or mixtures thereof.

As used in this description, the term "residue" refers to the residue that remains after dissolving R-or S-diol in a solvent of an initial non-racemic mixture of R-or S-diols. The residue may be in the form of crystals, an amorphous solid, an oil or mixtures thereof.

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

As used herein, the term "stock solution" means the solvent remaining after removal or separation of the precipitate.

As used herein, the term "organic and / or aqueous phase resulting from the selective dissolution of Ro S-diol" refers to the phase in which Ro S-diol dissolves in an initial non-racemic mixture of R-

or S-diols.

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

As already mentioned, the above procedures for the preparation of the free base and / or salt of addition of citalopram acid and / or free base and / or of salt of addition of escitalopram acid can produce a mixture of free base and / or Ry S-citalopram acid addition salt that is not acceptable for pharmaceutical use. According to the present invention, a surprisingly effective process for the preparation of free base and / or racemic acid addition salt of diol and Ro S-diol intended for the preparation of free base and / or acid addition salt of racemic citalopram and free base and / or acid addition salt of Ro S-citalopram.

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

According to another aspect of the invention, the initial non-racemic mixture of free base or acid addition salt of Ry Sdiol is separated into a fraction that is enriched with free base and / or the acid addition salt S-diol or R- diol and a fraction comprising free base and / or the acid addition salt of RS-diol in which the ratio of R-diol: S-diol is equal to 1: 1 or closer to 1: 1 than in the initial mixture of Ry S-diol combining the initial non-racemic mixture

of the free base or acid addition salt of Ry S-diol with a solvent and preferably leaving the free base and / or the acid addition salt of Ro S-diol dissolved in the solvent followed by separation of the residue from the free base and / or the undissolved RS-diol acid addition salt of the organic and / or aqueous phase resulting from the selective dissolution of the free base and / or acid addition salt of the free base and / or the salt of addition of Ro S-diol acid from said solvent.

The solvent used according to this embodiment of the invention is any solvent that preferably dissolves the free base and / or the acid addition salt of Ro S-diol leaving a mixture of free base and / or an acid addition salt of RS-diol in which the ratio of R-diol: S-diol is equal to 1: 1 or closer to 1: 1 than in the initial Ry S-diol mixture as a residue. Useful solvents are solvents such as those mentioned for the precipitation of the RS-diol free base or / and the RS-diol acid addition salt.

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

The residue / precipitate formed in step i) may be in the form of oil, amorphous or crystalline solid; or in a mixture thereof. The residue / precipitate formed in step i) is preferably in crystalline form.

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

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

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

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

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

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

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

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

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

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

Precipitation of the RS-diol free base can be carried out by obtaining or dissolving the non-racemic mixture of the free base and / or the acid addition salt of Ry S-diol in a suitable solvent, optionally applying heat and then allowing the solution to cool or cooling below room temperature. The precipitate is then separated from the stock solution, preferably by filtration or decantation.

An RS-diol free base residue may be formed by selective dissolution of free base or Ro S-diol acid addition salt in a solvent of the initial non-racemic mixture of free base and / or acid addition salt of Ry S-diols in said solvent. The residues are then separated from the organic and / or aqueous phase resulting from the 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 a racemic diol free base. Next, the racemic citalopram free base can be formed from the racemic diol free base by ring closure. The racemic citalopram free base may optionally be converted into one of its acid addition salts, preferably in the hydrobromide salt.

If the residue / precipitate formed is an oil or an amorphous solid, steps i) and ii) can be repeated until a crystalline product is obtained. The crystals obtained 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 racemic citalopram free base is optionally converted into one of its acid addition salts, preferably in the hydrobromide salt.

The free RS-diol base prepared according to the invention optionally becomes one of its acid addition salts.

An oily phase separated from the final phase in solution is optionally subjected to conventional purification procedures.

The free RS-diol base prepared according to the invention may contain a minor excess of S-diol (or R-diol). Thus, it may be necessary to repeat steps i) and ii) (in particular the crystallization) of the RS-diol free base one or more times in order to obtain racemic diol. The phases of the final solution can be grouped and the diol enantiomer contained herein can be isolated as described below.

Suitable solvents for obtaining the residue / precipitate comprising the 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 such as methanol and isopropyl alcohol or ketones such as methyl isobutyl ketone; or one of their mixtures.

In a preferred embodiment, an RS-diol free base is obtained in step i), preferably in crystalline form.

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

Precipitation of the RS-diol acid addition salt can be carried out by obtaining or dissolving the non-racemic free base mixture or the acid addition salt of Ry S-diol in a suitable solvent, if necessary by applying heat and adding an acid, for example in solid, liquid, solution or gas form.

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

The acid used for the precipitation of an RS-diol acid addition salt can:

•

be added once the initial non-racemic mixture of a free base and / or the acid addition salt of R-and Sdiol is obtained or dissolved in a suitable solvent; I

•

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

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

A residue of the RS-diol acid addition salt may be formed by selective dissolution of the free base or of the acid addition salt of Ro S-diol in a solvent of the initial non-racemic mixture of the free base and / or of the acid addition salt of the Ry S-diols in said solvent, if necessary by the addition of an acid, for example in solid, liquid, solution or gas form; or one of their mixtures.

The acid part of an RS-diol acid addition salt of the residue formed in step i) is an acid, which allows the selective dissolution of the free base and / or the acid addition salt of Ro S-diol and leave the undissolved material enriched with the acid addition salt of RS-diol.

The acid used to form the RS-diol acid addition salt of the residue can:

•

be present in the solvent before the initial non-racemic mixture of free base and / or the acid addition salt of R-and S-diol is mixed with the solvent; I

•

mixed with the solvent together with the initial non-racemic mixture free base and / or acid addition salt of R-and S-diol; I

•

mixed with the solvent after the initial non-racemic mixture of free base and / or acid addition salt of R-and S-diol is mixed with the solvent; I

•

be present in the initial non-racemic mixture of free base and / or acid addition salt of R-and S-diol during

or before mixing with the solvent.

Suitable acids for the formation of a residue / precipitate of an RS-diol acid addition salt of an initial non-racemic free base mixture and / or Ry S-diol acid addition salt are inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid and organic acids such as oxalic acid, ptoluenesulfonic acid, methanesulfonic acid and acetic acid. Bromhydric acid, hydrochloric acid and oxalic acid are the preferred acids. When these acids are used, a hydrobromide salt, a hydrochloride salt or an oxalate salt of RS-diol is formed, preferably in crystalline form. Conveniently, up to 10 equivalents of acid are used. Therefore:

• 0.2 to 10 moles of acid can be used, such as 0.2 to 0.4 moles, 0.4 to 0.6 moles, 0.9 to 1.1 moles

or 1.8 to 2.2 moles of acid are used for each mole of S- and R-diol formed in the initial non-racemic mixture of free base and / or acid addition salt of R- and S-diol; I

• 0.3 to 4.0 moles, such as 0.4 to 0.6 moles, 0.9 to 1.1 moles or 1.8 to 2.2 moles of acid are used per mole of RS-diol included in the residue / precipitate.

In order to increase the ionic strength of the solution, salts such as ClaCl can be added to the solution before, during or after obtaining the acid addition salt of RS-diol 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 the formation of a residue / precipitate of the RS-diol acid addition salt of an initial non-racemic mixture of free base of and / or of acid addition salt Ry S-diol are polar and apolar solvents such as toluene, ethyl acetate, diethyl ether, TH�, alcohols such as isopropyl alcohol, acetonitrile 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, preferably by filtration or decantation. The crystals obtained are optionally recrystallized by dissolving the crystals in a solvent, preferably by heating and allowing the solution to cool, or by cooling below room temperature. Racemic citalopram can be formed in the crystalline acid addition salt of racemic diol by ring closure. Racemic citalopram can be converted into a pharmaceutically acceptable salt, preferably the HBr salt.

If the residue / precipitate formed in step i) is not crystalline, but amorphous or an oil or a mixture thereof, steps i) and ii) can be repeated until a crystalline product is obtained. The crystals obtained 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 may become one of its pharmaceutically acceptable salts, preferably the HBr salt.

An oily phase separated 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 minor excess of S-diol (or R-diol). Thus, it may be necessary to repeat one or more times the precipitation (in particular the crystallization) of the acid addition salt of RS-diol to obtain a racemic mixture. The final solution phase can be mixed and the enantiomeric diol contained therein can be isolated as described below.

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

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

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

The final solution phase, the extracts thereof, or an enriched phase with free base and / or acid addition salt of Ro S-diol can be subjected to conventional purification procedures (such as treatment with active carbon, chromatography, etc.) before solvent evaporation, and / or may be subjected to one or more precipitations of the RS-diol free base or the RS-diol acid addition salt according to the invention, in order to improve the enantiomeric purity of the enantiomeric product of diol.

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

The final solution phase, the extracts thereof or an enriched phase with free base and / or acid addition salt of R- or S-diol can be subjected to conventional purification procedures (such as treatment with active carbon, chromatography , etc.) before isolation of the free base and / or acid addition salts of Ro S-diol. Properly, R-or S-diol can precipitate in the form of phosphate salt or oxalate salt by the methods known to those skilled in the art.

It has been found that the enantiomeric purity (the ratio between the desired isomer and the sum of both isomers) of the free base and / or the acid addition salt of So R-diol can be up to 97-98% or even higher (that is, better) depending on the specific conditions used.

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

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

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

In another embodiment, the free base and / or the acid addition salt of S-diol is obtained.

When the R-or S-diol free base is obtained, it optionally becomes one of its acid addition salts. When the acid addition salt of R-oS-diol is obtained, it is optionally converted to other acid addition salts or the corresponding free base.

The free base or the addition salt of Ro S-diol acid of enantiomeric purity can be mixed with a non-racemic mixture of free base and / or acid addition salt of Ry S-diol to obtain free base and / or salt of acid addition of racemic diol. The free base and / or the acid addition salt of the racemic diol can then be obtained by one or more precipitations of a free base or an acid addition salt of the racemic diol, followed by recrystallization as described above.

The free base and / or the acid addition salt of R-or S-citalopram can be formed from the corresponding free base and / or the acid addition salt of R-or S-diol by ring closure preserving the configuration. The free base of and / or the acid addition salt S-citalopram (or R-citalopram) can optionally be converted into an acid addition salt, preferably the oxalate salt and optionally recrystallized.

The ring closure of the free base of and / or the acid addition salt Ro S-diol can be carried out by means of an intermediate labile ester, for example, in the presence of tosyl chloride, in basic medium, as described in the patent EPB1-347 066. Thereafter, the ring closure reaction proceeds by preserving the stereochemistry. The free base and / or the acid addition salt of R-or S-citalopram with an enantiomeric purity substantially equal to that of the starting diol is then obtained.

The ring closure of the racemic diol free base and / or the acid addition salt obtained can be carried out in acidic medium, as described in US 4,650,884, or by a labile ester as described above. With which the racemic citalopram is obtained.

The free base and / or the addition salt of Ro S-citalopram acid of enantiomeric purity obtained in this way can be mixed with a non-racemic mixture of free base and / or acid addition salt of Ro S-citalopram to obtain the free base and / or the acidic salt of racemic citalopram acid. The free base and / or the racemic acid addition salt of racemic citalopram can then be obtained by one or more free base precipitations or a salt of citalopram acid addition, followed by recrystallization as described above.

A specific embodiment of the invention relates to a process for the preparation of a free base or one of its racemic acid addition salts and / or as a free base or one of its acid addition salts of R-

or S-diol, by separating an initial non-racemic mixture of R-and S-diol with more than 50% of one of the

enantiomers in a fraction that is enriched with S-diol or R-diol and a fraction consisting of RS-diol in which the ratio of R-diol: S-diol is equal to 1: 1 or closer to 1: 1 than in the initial Ry S-diol mix in which

i) RS-diol is precipitated in a solvent as a free base or one of its acid addition salts;

ii) the precipitate formed separates the stock solution;

iia) if the precipitate is crystalline it is optionally recrystallized one or more times in the racemic diol form;

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 in the racemic diol form;

iii) the stock solution is optionally subjected to another purification and S-diol or R-diol is removed from the stock solution;

iv) the free bases of the optionally obtained diols are converted into one of their acid addition salts or the acid salts of the obtained diols are optionally converted to other acid addition salts or the acid addition salts of the diols obtained optionally become the corresponding free bases.

Another specific embodiment of the invention relates to a process for the preparation of a free base or one of its racemic acid addition salts, and / or as a free base or an acid addition salt of Ro S-diol acid, by separating an initial non-racemic mixture of Ry S-diol with more than 50% of one of the enantiomers in a fraction that is enriched with S-diol or R-diol and a fraction consisting of RS-diol in which the R-diol: S-diol ratio is equal to 1: 1 or closer to 1: 1 than in the initial Ry S-diol mixture in which:

i) RS-diol precipitates in a solvent as a free base or as one of its acid addition salts; or

R-o S-diol is dissolved in a solvent of the initial non-racemic mixture of R-or S-diols in the form of a free base or in the form of one of its acid addition salts in said solvent, leaving a residue;

ii) the precipitate formed separates the stock solution;

iia) if the precipitate is crystalline it is optionally recrystallized one or more times in racemic diol form;

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 the racemic diol form;

iii) the stock solution is optionally subjected to further purification and S-diol or R-diol are isolated from the stock solutions;

iv) the free bases of the diols obtained are optionally converted into their acid addition salts or the acid addition salts of the obtained diols are optionally converted into other acid addition salts or acid addition salts of the diols obtained optionally become the corresponding free bases.

The invention is illustrated by the following examples, which cannot be considered as restrictive.

Examples

In the following examples the optical purities were measured by chiral SC�C HPLC (supercritical liquid chromatography)

Example 1

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

General Method:

A mixture of R-and S-diols (as defined in the following table) (10 g) was dissolved in toluene (60 ml). Aqueous solution of hydrochloric acid (32 ml, 1 M) was added and in some cases solid sodium chloride was added (sufficient for the concentration of ClaCl in the water to be approximately 1 M). The mixture was stirred overnight and filtered. The residue was dried to give racemic diol hydrochloride crystals, contaminated with some S-diol hydrochloride. The stock solution was basified with an aqueous solution of ammonia at pH> 9, and the toluene layer was separated. The aqueous layer was washed once more with toluene and the combined toluene extracts were dried over

magnesium sulfate and evaporated under reduced pressure to give mainly S-diol, contaminated with a small amount of R-diol. See the table for more details.

Material recovery was practically quantitative, with the expected distribution of weight between the respective samples.

Before the precipitation

After the precipitation

Mixtures of isomers

Precipitate (Ry S-diols mixtures) Oil after basification, separation and evaporation (enriched S enantiomer)

S%

R% S% R% S% R%

98.4

1.6 54 46 97.9 2.1 *

95.4

4.6 55 Four. Five 98.7 1.3 *

90.3

9.7 51 49 96.7 3.3

80

twenty 51 49 96.7 3.3

69

31 fifty fifty 94.8  5.2

59

41 54 46 92  8.0

* Indicates that solid araaCl was added to the mixture, sufficient for the resulting aqueous phase to be approximately 1 M in �aCl

In the following examples the optical purity is measured by chiral HPLC.

Example 2

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

A solution of S-diol in acetonitrile (500 ml, approx. 50-55% w / w, ratio S: R 95.72: 4.28) at room temperature was cooled with stirring to -14 ° C. The mixture was seeded with almost racemic diol (S: R ratio approx. 60:40) after each drop at a temperature of 2 ° C. After 16 hours the mixture was filtered, and the filter cake dried. The analysis of the filter cake indicated that the S: R ratio was 57.97: 42.03. Analysis of the mother solution indicated that the ratio of S: R was 98,065: 1,935.

Example 3

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

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

Example 4

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

General Method:

A mixture of R-and S-diols (as defined in the table below) (1 g) was dissolved in toluene (10 ml). Aqueous hydrochloric acid solution was added (1.0 equivalent; concentration as defined in the table below) and solid sodium chloride was added (sufficient for the concentration of aCl in the water to be approximately 1 or 2 M ; see the table below). The mixture was stirred overnight and filtered. The residue was dried to give racemic diol hydrochloride crystals, contaminated with some S-diol hydrochloride. The stock solution was basified with aqueous ammonia solution at pH> 9, and the toluene layer was separated. The aqueous layer was washed once more with toluene and the combined toluene extracts were dried over magnesium sulfate and evaporated under reduced pressure to give mainly S-diol, contaminated with a small amount of R-diol. See the table for more details. Material recovery was practically quantitative, with the expected distribution of weight between the respective samples.

Before the precipitation

After the precipitation

Mixture of isomers

Aqueous HCl conc. (M) Aqueous HCl conc. (M) Precipitate (mixtures of R-and S-diols) Oil after basification, separation and evaporation (enriched S enantiomer)

S%

R% S% R% S% R%

82.3

17.7 1.0 1.0 58.4 41.6 99.4 0.6

82.3

17.7 2.0 1.0 49.7 50.3 97.7 2.3

82.3

17.7 1.0 2.0 81.3 18.7 86.2 13.8

82.3

17.7 2.0 2.0 60.1 39.9 99.7 0.3

5 Example 5

Purification of S-diol by precipitation of racemic diol as salts of p-toluenesulfonyl, methanesulfonyl or acetate

General Method:

A mixture of R-and S-diols (as defined in the table below) (1 g) was dissolved in toluene or ether (10 ml; as described in the table below). Aqueous Cl solution (1 M, 3 ml) was added. The acid was scratched

10 pure (as defined in the table below) in liquid form. The mixture was stirred overnight and filtered or decanted. The residue was dried to give an oil or a solid. The stock solution was basified with aqueous ammonia solution of pH> 9 and the toluene or ether layer was separated. The aqueous layer was washed once more with toluene or ether and the combined organic extracts were dried over magnesium sulfate and evaporated under reduced pressure to give mainly a solid or an oil. See the table for more details. Material recovery was

15 practically quantitative, with the expected distribution of weight between the respective samples.

Before the precipitation

After the precipitation

Mixture of isomers

Solvent Acid Precipitate (mixtures of R- Oil after basification,

S%

R% S% R% S% R%

82.3

17.7 Toluene MsOH (1) 64.4 35.6 94.3 5.7

82.3

17.7 Toluene MsOH (2) 48.2 51.8 90.0 10.0

82.3

17.7 Ether MsOH (1) 62.9 37.1 91.0 9.0

82.3

17.7 Ether MsOH (2) 55.1 44.9 89.3 10.7

82.3

17.7 Toluene AcOH (1) 71.3 28.7 96.2 3.8

82.3

17.7 Toluene AcOH (2) 65.9 34.1 94.8 5.2

82.3

17.7 Ether AcOH (1) 65.0 35.0 91.6 8.4

82.3

17.7 Ether AcOH (2) 65.7 34.3 87.2 12.8

Example 6

Purification of S-diol by precipitation of a racemic diol salt in the absence of water 11

General Method:

A mixture of R-and S-diols (as defined in the table below) (1 g) was dissolved in toluene or ether (10 ml; as described in the table below). The acid (as defined in the table below) was added pure in solid form. The mixture was stirred overnight and filtered. The residue was dried to give an oil or a solid. Be

Water was added to the mother solution and the mother solution was basified with an aqueous solution of ammonia to pH> 9, and the toluene or ether layer was separated. The aqueous layer was washed once more with toluene or ether, and the combined organic extracts were dried with magnesium sulfate and evaporated under reduced pressure to give mainly a solid or an oil. See the table for more details. Material recovery was practically quantitative, with the expected distribution of weight between the respective samples.

Before the precipitation

After the precipitation

Mixture of isomers

Solvent Acid (equiv.) Precipitate (Ry S-diols mixtures) Oil after basification, separation and evaporation (enriched S enantiomer)

S%

R% S% R% S% R%

82.3

17.7 Toluene TsOH (0.4) 54.9 45.1 90.9 8.1

82.3

17.7 Ether TsOH (0.4) 57.4 42.6 98.1 7.9

82.3

17.7 Toluene (CO2H) 2 (0.2) 78.4 21.6 93 7

82.3

17.7 Toluene (CO2H) 2 (0.4) 72.1 27.8 99.97 0.03

82.3

17.7 Toluene (CO2H) 2 (1) 82.2 17.8 99.6 0.4

82.3

17.7 Ether (CO2H) 2 (0.2) 58.0 42.0 97.7 2.3

82.3

17.7 Ether (CO2H) 2 (0.4) 55.4 44.6 98.4 1.6

82.3

17.7 Ether (CO2H) 2 (1) 72.0 28.0 99.5 0.5

Example 7

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

15 General Method:

A mixture of R-and S-diols (as defined in the following table) (1 g) was dissolved in a solvent (10 ml; as described in the following table). The acid (as defined in the table below) was scratched pure as a solid. The mixture was stirred overnight, and filtered or decanted if a precipitate had formed. When a precipitate had formed, the residue was dried to give an oil or a solid. The mother solution evaporated and the

The residue was collected in a mixture of ether and water. This mixture was basified with aqueous ammonia solution at pH> 9, and the ether layer was 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 mainly a solid or an oil. See the table for more details. The material recovery was practically quantitative, with the expected weight distribution among the respective samples.

25 Example 8

Before the precipitation

After the precipitation

Mixture of isomers

Solvent Acid (equiv.) Precipitate (mixtures of R-and S-diols) Oil after basification, separation and evaporation (enriched S enantiomer)

S%

R% S% R% S% R%

82.3

17.7 MeOH TsOH (0.4) No precipitation

82.3

17.7 MeOH (CO2H) 2 (0.2) No precipitation

82.3

17.7 IPA TsOH (0.4) 51.5 48.5 91.6 8.4

82.3

17.7 IPA (CO2H) 2 (0.2) 54.9 45.1 98.3 1.7

82.3

17.7 Acetonitrile TsOH (0.4) No precipitation

82.3

17.7 Acetonitrile (CO2H) 2 (0.2) 57.2 42.8 97.2 2.8

82.3

17.7 TH� TsOH (0.4) No precipitation

82.3

17.7 TH� (CO2H) 2 (0.2) 53.2 46.8 98.9 1.1

82.3

17.7 Acetone TsOH (0.4) No precipitation

82.3

17.7 Acetone (CO2H) 2 (0.2) 56.7 43.3 98.2 1.8

82.3

17.7 MI�� TsOH (0.4) 56.8 43.2 98.5 1.5

82.3

17.7 MI�� (CO2H) 2 (0.2) 58.7 41.3 99.6 0.4

Purification of S-diol by precipitation of racemic diol oxalate

General Method:

A mixture of R-and S-diols (as defined in the following table) (1 g) was dissolved in toluene (10 ml). An aqueous solution of Cl (1 M, 3 ml) and oxalic acid (as defined in the table below) was scratched pure purely. The mixture was stirred overnight, and filtered or decanted if a precipitate had formed. When a precipitate had formed, the residue was dried to give an oil or a solid. The stock solution was basified with aqueous ammonia solution at pH> 9, and the toluene layer was separated. The aqueous layer is

It was washed once more with toluene, and the combined toluene extracts were dried over magnesium sulfate and evaporated under reduced pressure to give mainly a solid or an oil. See the table for more details. Material recovery was practically quantitative, with the expected distribution of weight between the respective samples.

Before the precipitation

After the precipitation

Mixture of isomers

Oxalic acid (equiv.) Precipitate (Ry Sdioles mix) Oil after basification, separation and evaporation (enriched S enantiomer)

Before the precipitation

After the precipitation

Mixture of isomers

Oxalic acid (equiv.) Precipitate (Ry Sdioles mix) Oil after basification, separation and evaporation (enriched S enantiomer)

S%

R%  S% R%  S% R%

82.3

17.7 0.2 51.8 48.2 98.5 1.5

82.3

17.7 0.4 62.6 37.4 99.8 0.2

82.3

17.7 1.0 58.6 41.4 97.0 3.0

82.3

17.7 2.0 56.7 43.3 92.7 7.3

Example 9

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

General Method:

5 A mixture of R-and S-diols (as defined in the following table) (1 g) was stirred with an aqueous solution of HCl (1 equivalent; see the concentration table). The mixture was stirred overnight, and sufficient Cl was added (in solid form) so that the concentration of Cl was 1 M. The mixture was filtered to give a solid. Water and ether were added to the mother solution, basified with aqueous ammonia solution at pH> 9, and the ether layer was separated. The aqueous layer was washed once more with ether, and the combined ether extracts dried over sodium sulfate.

10 mg and evaporated under reduced pressure to give mainly a solid or an oil. See the table for more details. Material recovery was practically quantitative, with the expected distribution of weight between the respective samples.

Before the precipitation

After the precipitation

Mixture of isomers

Conc. HCl (equiv.) Precipitate (Ry Sdioles mix) Oil after basification, separation and evaporation (enriched S enantiomer)

S%

R%  S% R%  S% R%

82.3

17.7 one 59.4 40.6 99.2 0.8

82.3

17.7 2 63.7 36.3 99.3 0.7

Example 10

15 Purification of S-diol by preferred dissolution of S-diol hydrochloride in water

General Method:

A mixture of R-and S-diol hydrochloride salts (17.7: 82.3; 5.5 g) was stirred with an aqueous solution of Cl (1 M, 12 ml). The mixture was stirred overnight, and filtered to give a solid. Water was added to the mother solution and ether, basified with aqueous ammonia solution at pH> 9, and the ether layer was separated. The aqueous layer was washed once

20 more with ether, and the combined ether extracts were dried over magnesium sulfate and evaporated under reduced pressure to give mainly a solid or an oil. The filtration residue contained R-diol and S-diol in a ratio of 1.0: 99.0. The filtrate preparation product contained R-diol and S-diol in a ratio of 38.8: 61.2. Material recovery was practically quantitative, with the expected distribution of weight between the respective samples.

Claims (26)

1. A process for the preparation of the free base and / or the acid addition salt of 4- [4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) benzonitrile (diol) racemic and / or the free base and / or the acid addition salt of Ro S-diol comprising a separation of an initial non-racemic mixture of the free base and / or the addition salt of 5 Ry S-diol acid with more than 50% of one of the enantiomers in a fraction that is enriched with the free base and / or the acid addition salt of S-diol or R-diol and a fraction comprising the free base and / or the acid addition salt of RS-diol in which the ratio of R-diol: S-diol is equal to 1: 1 or closer to 1: 1 than in the initial mixture of Ry S- diol characterized because i) the free base and / or the acid addition salt of RS-diol is precipitated in a solution of the initial non-racemic mixture 10 of the free base and / or the acid addition salt of R-and S-diol; or the free base and / or the acid addition salt of Ro S-diol is dissolved in a solvent of the initial non-racemic mixture of the free base and / or the acid addition salt of Ry S-diol in said solvent, leaving a residue comprising the free base and / or the acid addition salt of RS-diol; ii) the residue / precipitate formed is separated from the final phase in solution; Iia) if the residue / precipitate is crystalline it is optionally recrystallized one or more times to form 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 racemic diol; Iii) the final phase in solution is optionally subjected to another purification and the free base and / or the acid addition salt of S-diol or R-diol is separated from the final phase in solution; iv) the free bases of the diols obtained are optionally converted into their acid addition salts or the acid addition salts of the diols obtained are optionally converted into other acid addition salts or the acid addition salts of the diols obtained optionally become the 25 corresponding free bases. 2. A process according to claim 1, for the preparation of the free base and / or the acid addition salt of S-diol or R-diol characterized in that i) the free base and / or the acid addition salt of RS-diol precipitates in a solution of the initial non-racemic mixture 30 of free base and / or acid addition salt of R-and S-diol; or the free base and / or the acid addition salt of Ro S-diol is dissolved in a solvent of the initial non-racemic mixture of the free base and / or the acid addition salt of Ry S-diol in said solvent, leaving a residue comprising free base and / or RS-diol acid addition salt; ii) the residue / precipitate formed is separated from the final phase in solution, and Iii) the final phase in solution is optionally subjected to another purification and the free base and / or the acid addition salt of S-diol or R-diol is separated from the final phase in solution. 3. A process according to claim 2, wherein the prepared diol is the free base and / or the acid addition salt of S-diol. 4. A process according to claim 2, wherein the prepared diol is the free base and / or the acid addition salt of R-diol. 5. A process according to claim 1, for the preparation of the free base and / or the acid addition salt of racemic diol characterized in that i) the free base and / or the acid addition salt of RS-diol is precipitated in a solution of the initial non-racemic mixture of free base and / or acid addition salt of R-and S-diol; or Ro S-diol is dissolved in a solvent of the initial non-racemic mixture of free base and / or acid addition salt of Ry S-diol in said solvent, leaving a residue composed of free base and / or the addition salt RS-diol acid; II) the residue / precipitate formed is separated from the final phase in solution, iia) if the residue / precipitate is crystalline it is optionally recrystallized one or more times to form racemic diol; iib) if the residue / precipitate is not crystalline, steps i) and ii) are 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 to 5, wherein the initial non-racemic mixture of free base and / or acid addition salt of Ry S-diol with more than 50% of one of the enantiomers contains more than 50 % S-diol, more preferred more than 70% S-diol or even more preferred more than 90% S-diol.

7.

The method according to any one of claims 1 to 5, wherein the initial non-racemic mixture of free base and / or acid addition salt of Ry S-diol with more than 50% of one of the enantiomers contains more than 50 % R-diol, more preferred more than 70% R-diol or even more preferred more than 90% R-diol.

8.

The process according to any one of claims 1 to 7, wherein the RS-diol comprised in the residue / precipitate is in the form of a free base and / or an acid addition salt thereof; and independently thereof, the R-or S-diol included in the final phase in solution is in the form of a free base and / or as an acid addition salt thereof.

9.

The process according to any one of claims 1 to 8, wherein the free base and / or the RS-diol acid addition salt precipitates in a solution of the initial non-racemic mixture of free base and / or addition salt of acid from Ry S-diol.

10.

The process according to any one of claims 1 to 9, wherein the acid used to precipitate the RS-diol in the form of salt in step i) is an acid that precipitates a mixture of the Ry Sy enantiomers leaving the mother solution enriched with S-or R-enantiomer of the free base and / or the acid addition salt of the diol.

eleven.

The process according to claim 10, wherein the acid can:

•

being added once the initial non-racemic mixture of free base and / or acid addition salt of R-and S-diol is obtained or dissolved in a suitable solvent; I

•

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

•

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

12.

The process according to any one of claims 1 to 8, wherein the free base and / or the acid addition salt of Ro S-diol is dissolved in a solvent of the initial non-racemic mixture of the free base and / or the acid addition salt of Ro S-diol in said solvent, leaving a residue comprising free base and / or acid addition salt of RS-diol.

13.

The process according to any one of claims 1 to 8 and 12, wherein the acid part of the RS-diol acid addition salt comprised in the residue formed in step i) is an acid that allows the selective dissolution of the free base and / or the acid addition salt of Ro S-diol and leaves the undissolved material enriched with the acid addition salt of RS-diol.

14.

The process according to claim 12, wherein the acid can:

•

be present in the solvent before the initial non-racemic mixture of the free base and / or the acid addition salt of R-and S-diol is mixed with the solvent; I

•

mixed with the solvent together with the initial non-racemic mixture of free base and / or acid addition salt of R-and S-diol; I

•

mixed with the solvent after the initial non-racemic mixture of free base and / or acid addition salt of R-and S-diol is mixed with the solvent; I

•

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

fifteen.

A method according to claims 1 to 14, wherein the RS-diol acid addition salt is obtained from the initial non-racemic mixture of the free base and / or the acid addition salt of Ry S-diol in a solvent selected from the group consisting of toluene, ethyl acetate, diethyl ether, TH�, water, alcohols such as isopropyl alcohol, acetonitrile and ketones such as acetone and methyl isobutyl ketone; or their mixtures.

16.

The method according to any one of claims 1 to 15, wherein the acid used in step i) is HCl, HBr, H2SO4, p-toluenesulfonic acid, methanesulfonic acid, acetic acid or oxalic acid.

17.

The method according to claim 16, wherein the acid used in step i) is HCl, HBr or oxalic acid; whereby a hydrobromide salt, a hydrochloride salt or an oxalate salt of RS-diol is formed, preferably in crystalline form.

18.

The method according to any one of claims 1 to 17, in which 0.2-10 moles of acid can be used, such as 0.2 to 0.4 moles, 0.4 to 0.6 moles, 0.9 at 1.1 moles or 1.8 to 2.2 moles of acid are used for each mole of S- and R-diol comprised in the initial non-racemic mixture of free base and / or acid addition salt of Ry S- diol

19.

The method according to any one of claims 1 to 17, in which 0.3 to 4.0 moles are used, such as 0.4 to 0.6 moles, or 0.9 to 1.1 moles or 1, 8 to 2.2 moles of acid for each mole of RS-diol in the residue / precipitate.

twenty.

The method according to any one of claims 1 to 9 and 12, wherein an RS-diol free base is obtained in step i), preferably in crystalline form.

twenty-one.

A method according to any one of claims 1 to 9, 12 and 20, wherein the RS-diol free base is obtained from the initial non-racemic mixture of Ry S-diols in a solvent selected from the group consisting of alkanes such 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 and ketones such as methyl isobutyl ketone; or their mixtures.

22

The method according to any one of claims 1 to 21, wherein the final solution phase is subjected to one or more additional RS-diol separations as described in steps i) and ii) before the isolation of S-diol or (R-diol) of the final phase in solution.

2. 3.

The process according to any one of claims 1 to 4 and 6 to 22, wherein the S-diol (or R-diol) is removed from the final phase in solution by evaporation of the solvent.

24.

The method according to any one of claims 1 to 4 and 6 to 23, wherein the final phase in solution is acidic and the S-diol (or R-diol) is removed from the final phase in solution by basifying the final phase. in solution, followed by phase separation or extraction with a solvent followed by evaporation of the solvent.

25.

The process according to any one of claims 1 to 4 and 6 to 23, wherein the free base and / or the acid addition salt of S-diol (or R-diol) is isolated from the final phase in solution by precipitation of the free base and / or the acid addition salt of R-diol or S-diol; properly a phosphate salt or an oxalate salt of R-or Sdiol is precipitated.

26.

A method for the preparation of the free base and / or as an additive salt of citalopram acid and / or free base and / or as an addition salt of S-citalopram acid and / or free base and / or as an addition salt of R-citalopram acid comprising the preparation of the free base and / or as an acid addition salt of RS-diol and / or the free base and / or as an acid addition salt of S-diol and / or the free base and / or as an acid addition salt of R-diol according to any one of claims 1 to 25 followed by ring closure.