HK1087994B - 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
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 Download PDFInfo
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Description
Technical Field
The present invention relates to a process for the preparation of racemic citalopram diol and R-or S-citalopram diol by separation of 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) into a racemic citalopram diol fraction and a fraction enriched in S-diol or R-diol. The invention also relates to the use of these isolated citalopram diols for the preparation of the corresponding racemic citalopram and/or S-or R-citalopram comprised in a pharmaceutical composition.
Technical Field
Citalopram is a well-known antidepressant drug which has been marketed for many years and has the following structure:
citalopram may be prepared by ring closure of 4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) -benzonitrile (racemic citalopram diol) as described in U.S. Pat. No. 4,650,884. The product citalopram is a racemic mixture of the R-and S-enantiomers.
Furthermore, the S-enantiomer of citalopram (escitalopram) is a valuable antidepressant in the Selective Serotonin Reuptake Inhibitor (SSRI) form. Escitalopram may be prepared by a ring closure reaction of S-4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) -benzonitrile (S-diol) with retention of configuration as described in EPB 1347066. The amount of R-citalopram should be less than 3% compared to S-citalopram in the product escitalopram.
Furthermore, WO 03000672 describes a process for the preparation of a mixture of R-and S-citalopram (more than 50% of the S-enantiomer) from a mixture of R-and S-diols (more than 50% of the R-diol).
From the above it can be seen that the racemic citalopram product as well as escitalopram having the above mentioned enantiomeric purity are required for the preparation of pharmaceutical compositions, and that the racemic citalopram and escitalopram products can be prepared by ring closure reaction of RS-diol and R-diol and/or S-diol. Thus, there is a need for methods of preparing racemic diol and S-diol (corresponding enantiomerically pure) products.
Processes for the preparation and purification of R-or S-diol products are known. These methods include, for example, enantioselective synthesis as described in EP 0347066, standard resolution and chromatographic separation as described in WO 03006449. Depending on the particular process and conditions used, the enantiomeric purity of the S-diol product must be improved in order for the S-diol product to meet the above-described needs.
Surprisingly, it has now been found that by using the process of the present invention, an expensive but apparently useless S-diol product contaminated with R-diol can be easily converted into two valuable products, namely racemic diol and S-diol, which meet the above requirements in terms of enantiomeric purity.
Furthermore, by using the process of the invention, an expensive, but apparently useless, R-diol product contaminated with S-diol can be easily converted into valuable products, namely racemic diol and R-diol, which meet the above-mentioned requirements in terms of enantiomeric purity.
More particularly, the present invention provides a separation process that separates an initial non-racemic mixture of R-and S-4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) -benzonitrile (one enantiomer over 50%) into a fraction enriched in S-diol or R-diol and a fraction comprising RS-diol, wherein the ratio of R-diol to S-diol is equal to 1: 1 or closer to 1: 1 than the initial mixture of R-and S-diols.
The process of the present invention is important and very useful, especially because it provides a convenient, inexpensive and efficient conversion of a mixture of R-and S-diols, which does not meet the requirements described above with respect to enantiomeric purity, into two valuable products, namely RS-diols and S-diols (or R-diols), which meet the requirements described above with respect to enantiomeric purity.
In another aspect, the present invention provides a convenient, inexpensive and efficient process for the preparation of intermediates useful in the preparation of citalopram and escitalopram.
The use of the process of the present invention for the preparation of racemic citalopram and escitalopram, which meet the respective market admission requirements, makes the process more rational and economical in terms of process simplicity and use of reagents and resources.
Disclosure of Invention
The present invention therefore relates to a process for the preparation of racemic diol free base and/or acid addition salts and/or R-or S-diol free base and/or acid addition salts, comprising separating an initial non-racemic mixture of R-and S-diol free base and/or acid addition salts having more than 50% of one enantiomer into a fraction enriched in S-diol or R-diol free base and/or acid addition salt and a fraction comprising RS-diol free base and/or acid addition salt, wherein the ratio R-diol: S-diol is equal to 1: 1 or closer to 1: 1 than the initial mixture of R-and S-diol, wherein
i) Precipitating the RS-diol free base and/or acid addition salt from a solution of an initial non-racemic mixture of the R-and S-diol free base and/or acid addition salt; or
Dissolving R-or S-diol free base and/or acid addition salt from an initial non-racemic mixture of R-and S-diol free base and/or acid addition salt in a solvent to said solvent, leaving a residue comprising RS-diol free base and/or acid addition salt;
ii) separating the formed residue/precipitate from the final solution phase;
iia) if said residue/precipitate is crystalline, optionally performing one or more recrystallizations to produce racemic diol;
iib) if said residue/precipitate is not crystalline, optionally repeating steps i) and ii) until a crystalline residue/precipitate is obtained, and then optionally subjecting the crystalline residue/precipitate to one or more recrystallizations to produce the racemic diol;
iii) optionally further purifying the final solution phase, isolating the S-diol or R-diol free base and/or acid addition salt from the final solution phase;
iv) optionally converting the obtained free base of the diol into an acid addition salt thereof, or optionally converting the obtained acid addition salt of the diol into another acid addition salt, or optionally converting the obtained acid addition salt of the diol into the corresponding free base.
Thus, the RS-diol free base and/or acid addition salt obtained results in a final solution phase enriched in S-or R-diol free base and/or acid addition salt. The remaining free base of R-or S-diol and/or acid addition salt is then separated from the final solution phase as described below.
According to a particular embodiment, the present invention relates to a process for the preparation of racemic diol free base and/or acid addition salts using the above-described process.
According to another particular embodiment, the present invention relates to a process for the preparation of the free base and/or acid addition salts of S-diol (or R-diol) using the above process.
According to yet another specific embodiment, the present invention relates to the use of racemic citalopram and/or S-citalopram (R-citalopram) 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 (R-citalopram) free base and/or acid addition salt using the process described below.
Detailed Description
As used herein, the terms "S-diol" and "S-citalopram diol" refer to S-4- [4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) benzonitrile.
As used herein, the terms "R-diol" and "R-citalopram diol" refer to R-4- [4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) benzonitrile.
As used herein, the term "RS-diol" refers to a mixture of R-and S-diols, for example a mixture of R-and S-diols of 0.5: 1.5 or 0.9: 1.1 or 0.95: 1.05 or 0.98: 1.02 or 0.99: 1.01, preferably a 1: 1 mixture of R-and S-diols.
As used herein, the terms "diol enantiomer" and "diol isomer" refer to S-or R-diols.
As used herein, the term "racemic diol" refers to a 1: 1 mixture of R-and S-diols. The term "non-racemic mixture of diols" refers to a mixture containing R-and S-diols in a ratio other than 1: 1.
The terms "citalopram enantiomer" and "citalopram isomer" as used herein refer to S-or R-citalopram.
The term "racemic citalopram" as used in this document refers to a 1: 1 mixture of R-and S-citalopram. The term "non-racemic citalopram" refers to a mixture of R-and S-citalopram in a ratio other than 1: 1.
The term "precipitate" as used in this specification means the formation of a precipitate from a solution of an initial non-racemic mixture of R-and S-diols in a solvent, said precipitate being present as a crystalline, amorphous solid or oil or a mixture thereof. In the context of the present invention, the precipitate may be an oil, an amorphous solid or a crystal or a mixture thereof.
The term "residue" when used in this specification refers to the residue remaining after dissolving an R-or S-diol from its original non-racemic mixture into a solvent. The residue may be present as a crystalline, amorphous solid or as an oil or a mixture thereof.
The term "residue/precipitate" as used herein refers to a precipitate or residue as defined above.
The term "mother liquor" as used herein refers to the solvent remaining after removal or separation of the precipitate.
As used herein, the term "organic and/or aqueous phase resulting from selective dissolution of R-or S-diol" refers to a phase wherein the R-or S-diol is dissolved from an initial non-racemic mixture of R-or S-diol.
The term "final solution phase" as used herein refers to a mother liquor 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 described process for the preparation of 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 which is not suitable for pharmaceutical use. According to the present invention, surprisingly, an efficient process for the preparation of racemic diols and R-or S-diol free base and/or acid addition salts for the preparation of racemic citalopram free base and/or acid addition salts and R-or S-citalopram free base and/or acid addition salts has now been found.
The novel method comprises the following steps: separating the initial non-racemic mixture of R-and S-diol free base and/or acid addition salts into a portion of racemic diol free base and/or acid addition salt and a portion of R-or S-diol free base and/or acid addition salt. Said racemic diol free base and/or acid addition salt fraction precipitates from a solvent as an oil, amorphous solid or crystal or mixture thereof, and said R-or S-diol free base and/or acid addition salt is isolated from the final solution phase. Racemic citalopram free base and/or acid addition salts and R-or S-citalopram free base and/or acid addition salts may then be prepared from the corresponding racemic diol free base and/or acid addition salts and R-or S-diol free base and/or acid addition salts by ring closure.
According to another aspect of the invention, the initial non-racemic mixture of R-and S-diol free base and/or acid addition salts is separated into a fraction enriched in S-diol or R-diol free base and/or acid addition salt and a fraction comprising RS-diol free base and/or acid addition salt, wherein the ratio of R-diol to S-diol is equal to 1: 1 or closer to 1: 1 than the initial mixture of R-and S-diol, by mixing the initial non-racemic mixture of R-and S-diol free base and/or acid addition salt with a solvent, preferably dissolving R-or S-diol free base and/or acid addition salt in the solvent, and then separating R-and S-from said solvent Separation of the insoluble RS-diol free base and/or acid addition salt residue from the organic and/or aqueous phase formed from the diol free base and/or acid addition salt.
The solvent used in this embodiment of the invention is any solvent which preferably dissolves the R-or S-diol free base and/or acid addition salt, leaving as a residue a mixture of the RS-diol free base and/or acid addition salt wherein the ratio of R-diol to S-diol is equal to 1: 1 or closer to 1: 1 than the initial mixture of R-and S-diols. Useful solvents are those as mentioned in the precipitation of the free base of RS-diol and/or the acid addition salt of RS-diol.
The initial non-racemic mixture of the free base and/or acid addition salts of R-and S-diols used in the process of the present invention may be an oil, an amorphous solid or crystalline or a mixture thereof.
The residue/precipitate formed in step i) may be an oil, an amorphous solid or crystals or a mixture thereof. The residue/precipitate formed in step i) is preferably crystalline.
According to one embodiment of the invention, the initial non-racemic mixture of the free base and/or acid addition salts of R-and S-diols used in the process of the invention contains more than 50% of S-diol, or more preferably more than 70% of S-diol, or most preferably more than 90% of S-diol.
According to another embodiment of the invention, the initial non-racemic mixture of the free base and/or acid addition salts of R-and S-diols used in the process of the invention contains less than 99.9% of S-diol, for example less than 99.5% of S-diol, or less than 99% of S-diol, or less than 98% of S-diol.
Thus, the initial non-racemic mixture of said R-and S-diol free base and/or acid addition salts may contain from 50% to 98% S-diol, or from 50% to 99% S-diol, or from 50% to 99.5% S-diol, or from 50% to 99.9% S-diol, or from 70% to 98% S-diol, or from 70% to 99% S-diol, or from 70% to 99.5% S-diol, or from 70% to 99.9% S-diol, or from 90% to 98% S-diol, or from 90% to 99% S-diol, or from 90% to 99.5% S-diol, or from 90% to 99.9% S-diol.
According to another embodiment of the invention, the initial non-racemic mixture of the free base and/or acid addition salts of R-and S-diols used in the process of the invention contains more than 50% of R-diol, or more preferably more than 70% of R-diol, or most preferably more than 90% of R-diol.
According to yet another embodiment of the invention, the initial non-racemic mixture of the free base and/or acid addition salts of R-and S-diols used in the process of the invention contains less than 99.9% of 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.
Thus, the initial non-racemic mixture of said free base and/or acid addition salts of R-and S-diols may contain 50% to 98% of R-diol, or 50% to 99% of R-diol, or 50% to 99.5% of R-diol, or 50% to 99.9% of R-diol, or 70% to 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 process may be repeated until a racemic mixture of the R-and S-diols is obtained, and/or until the enantiomeric purity of the R-and S-diols is to a desired degree.
According to one embodiment of the invention, the residual/precipitated RS-diol is present in the form of a free base and/or an acid addition salt; and independently thereof the R-or S-diol of the final solution phase is present in the form of a free base and/or an acid addition salt. Thus, when the RS-diol contained in the residue/precipitate is present in the form of the free base, then the R-or S-diol contained in the final solution phase may be present in the form of the free base, an acid addition salt or a mixture of the free base and the acid addition salt. Furthermore, when the RS-diol contained in the residue/precipitate is present in the form of an acid addition salt, then the R-or S-diol contained in the final solution phase may be present 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 present in the form of a mixture of free base and acid addition salt, then the R-or S-diol contained in the final solution phase may be present in the form of a free base, an acid addition salt or a mixture of free base and acid addition salt.
The initial non-racemic mixture of R-and S-diols used in the process of the present invention may be present as the free base, a salt or a mixture of free base and salt.
Furthermore, the obtained free base of the diol is optionally converted into its acid addition salt, or the obtained acid addition salt of the diol is optionally converted into another acid addition salt, or the obtained acid addition salt of the diol is optionally converted into the corresponding free base by methods well known in the art.
Precipitation of the RS-diol free base can be carried out as follows: the non-racemic mixture of the free base and/or acid addition salts of R-and S-diols is present or dissolved in a suitable solvent, optionally with heating, and the solution is then cooled, or cooled to below ambient temperature. The precipitate is then separated from the mother liquor, preferably by filtration or decantation.
The residue of RS-diol free base can be prepared as follows: selectively dissolving R-or S-diol free base and/or acid addition salt into the solvent from an initial non-racemic mixture of R-and S-diol free base and/or acid addition salt in the solvent. The residue is 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 produce the racemic diol free base. Racemic citalopram free base may then be prepared from racemic diol free base by a ring closure reaction. Said racemic citalopram free base may optionally be converted into an acid addition salt thereof, preferably the hydrobromide salt.
If the residue/precipitate formed is an oil or an amorphous solid, steps i) and ii) may be repeated until a crystalline product is obtained. The crystals obtained are optionally subjected to one or more recrystallizations to prepare the racemic diol free base. Racemic citalopram free base may be prepared from racemic diol free base by a ring closure reaction. The racemic citalopram free base is optionally converted into its acid addition salt, preferably the hydrobromide salt.
The free base of RS-diol prepared according to the invention is optionally converted into its acid addition salt.
The oil phase separated from the final solution phase is optionally subjected to conventional purification steps.
The RS-diol free base prepared in the present invention may contain a slight excess of S-diol (or R-diol). It is therefore necessary to repeat steps i) and ii) (in particular recrystallization) of the RS-diol free base one or more times in order to obtain the racemic diol. The final solution phase may be collected and the diol enantiomer contained therein may be separated therefrom as described below.
Suitable solvents for obtaining a residue/precipitate containing the free base of RS-diol are non-polar 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 isopropanol, or ketones such as methyl isobutyl ketone; or mixtures of these solvents.
In a preferred embodiment, the free base of RS-diol is obtained in step i), preferably in crystalline form.
If necessary, racemic crystalline diol free base can be used as a seed to initiate crystallization.
Precipitation of the RS-diol acid addition salt may be carried out as follows: the non-racemic mixture of the R-and S-diol free base or acid addition salt is present in or dissolved in a suitable solvent, heated if necessary to promote dissolution, and an acid is added, for example as a solid, liquid, in solution or as a gas.
The acid used to precipitate the RS-diol acid addition salt is one which precipitates a mixture of the R-and S-enantiomers and leaves a mother liquor enriched in the R-or S-diol enantiomer of the diol or acid addition salt as the free base.
The acid used to precipitate the RS-diol acid addition salt may be:
after obtaining the initial non-racemic mixture of the free base and/or acid addition salts of R-and S-diols or after dissolving it in a suitable solvent; and/or
Present in a solvent during and/or before 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 free base and/or acid addition salt of R-and S-diols during and/or before dissolution in the solvent.
The residue of the RS-diol acid addition salt may be formed from the initial non-racemic mixture of the R-and S-diol free base and/or acid addition salt in the solvent by selective dissolution of the R-or S-diol free base and/or acid addition salt into the solvent, if necessary with addition of an acid, e.g. as a solid, liquid, in solution or as a gas or a mixture thereof.
The acidic part of the RS-diol acid addition salt of the residue formed in step i) is an acid which selectively dissolves the R-or S-diol free base and/or the acid addition salt and leaves the insoluble material rich in the RS-diol acid addition salt.
The acid used to form the residual RS-diol acid addition salt may be:
is 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 said solvent; and/or
Mixing together with a solvent and with the initial non-racemic mixture of the free base and/or acid addition salts of R-and S-diols; and/or
Mixing with a solvent after mixing with said solvent an 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 before mixing with the solvent.
Suitable acids for forming residues/precipitates 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 inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid or organic acids such as oxalic acid, p-toluenesulfonic acid, methanesulfonic acid and acetic acid. Hydrobromic acid, hydrochloric acid and oxalic acid are the preferred acids. When these acids are used, the hydrobromide, hydrochloride or oxalate salt of the RS-diol is formed, preferably in crystalline form. Suitably, up to 10 equivalents of acid are used. Thus:
from 0.2 to 10 moles of acid, for example from 0.2 to 0.4 moles, or from 0.4 to 0.6 moles, or from 0.9 to 1.1 moles or from 1.8 to 2.2 moles of acid per mole 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
For each mol of RS-diol contained in the residue/precipitate, 0.3 to 4.0mol, for example 0.4 to 0.6mol, or 0.9 to 1.1mol or 1.8 to 2.2mol of acid can be used.
To increase the ionic strength of the solution, a salt such as NaCl may be added to the solution before, during or after the RS-diol acid addition salt is obtained in step i). The person skilled in the art knows how to adjust the amount of salt added in order to obtain the desired effect.
Suitable solvents for forming residues/precipitates 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 non-polar solvents such as toluene, ethyl acetate, diethyl ether, THF, alcohols such as isopropanol, 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 solution phase, preferably by filtration or decantation. The crystals are optionally recrystallized by dissolving the crystals in a solvent, preferably one that is heated, and then cooling the solution, or cooling the solution below ambient temperature. Racemic citalopram may be prepared from the crystalline racemic diol acid addition salt by a ring closure reaction. The racemic citalopram may be converted into a pharmaceutically acceptable salt, preferably the HBr salt.
If the residue/precipitate formed in step i) is not crystalline but an amorphous solid or oil or a mixture thereof, steps i) and ii) may be repeated until a crystalline product is obtained. The crystals obtained are optionally subjected to one or more recrystallizations as described above. Racemic citalopram may be prepared from the crystalline racemic diol acid addition salt by a ring closure reaction. The racemic citalopram may be converted into a pharmaceutically acceptable salt, preferably the HBr salt.
The oil phase separated from the final solution phase is optionally subjected to conventional purification treatments.
Thus, the RS-diol acid addition salts prepared in accordance with the present invention may contain a slight excess of S-diol (or R-diol). Thus, it may be necessary to carry out one or more repeated precipitations (in particular crystallizations) of the RS-diol acid addition salt in order to obtain a racemic mixture. The final solution phase may be collected together and the diol enantiomers contained therein may be separated as described below.
If necessary, the crystallization of the RS-diol acid addition salt can be initiated by the racemic crystalline diol acid addition salt as seed crystals.
The RS-diol acid addition salts prepared according to the invention are optionally converted into other acid addition salts or the corresponding free bases.
According to a preferred embodiment of the present invention, the free base of RS-diol or the hydrochloride, hydrobromide or oxalate salt of RS-diol is preferably obtained in crystalline form in steps i), iia) and iib).
The final solution phase, extract thereof, or phase enriched in the R-or S-diol free base and/or acid addition salt may be subjected to conventional purification (e.g. treatment with activated carbon, chromatography, etc.) prior to evaporation of the solvent, and/or one or more further purifications of the RS-diol free base or RS-diol acid addition salt of the invention may be carried out in order to improve the enantiomeric purity of the enantiomeric product of the diol.
The R-or S-diol free base and/or acid addition salt may be isolated from the final solution phase using conventional procedures, such as evaporation of the solvent, or when the final solution phase is acidic, by basification followed by separation of the phases or extraction of the R-or S-diol free base and/or acid addition salt, followed by evaporation of the solvent.
The final solution phase, an extract thereof, or a phase enriched in R-or S-diol free base and/or acid addition salt may be subjected to conventional purification (e.g. treatment with activated carbon, chromatography, etc.) prior to isolation from the R-or S-diol free base and/or acid addition salt. Suitably, the R-or S-diol may be precipitated as a phosphate or oxalate by methods known to those skilled in the art.
It has now been found that depending on the particular conditions used, the enantiomeric purity (ratio of the desired isomer to the sum of the two 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 higher (i.e., better).
Thus, the S-diol (or R-diol) free base and/or acid addition salt prepared in accordance with the present invention may contain minor amounts 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 more preferably less than 2%, or most preferably less than 1% (ratio of minor isomer to sum of two isomers).
The R-or S-diol free base and/or acid addition salt may be purified and isolated from the solvent or the above-mentioned final solution phase.
In one embodiment, the R-diol is obtained as a free base or as an acid addition salt.
In another embodiment, a free base or acid addition salt of S-diol is obtained.
When the free base of the R-or S-diol is obtained, it is optionally converted into an acid addition salt. When an acid addition salt of an R-or S-diol is obtained, it is optionally converted into another acid addition salt or into the corresponding free base.
Enantiomerically pure R-or S-diol free base and/or acid addition salts can be mixed with a non-racemic mixture of R-and S-diol free base and/or acid addition salt to obtain racemic diol free base and/or acid addition salt. The racemic diol free base and/or acid addition salt may then be obtained by precipitation of the racemic diol free base and/or acid addition salt one or more times, followed by recrystallization as described above.
The R-or S-citalopram free base and/or acid addition salt may be prepared from the corresponding R-or S-diol free base and/or acid addition salt by a ring closure reaction under conditions wherein the configuration is retained. The free base and/or acid addition salt of S-citalopram (or R-citalopram) may optionally be converted into an acid addition salt thereof, preferably the oxalate salt and optionally recrystallized.
The ring closure reaction of the R-or S-diol free base and/or acid addition salt may be carried out via a labile ester intermediate, for example in the presence of p-toluenesulfonyl chloride in a basic environment as described in EP-B1-347066. Then, the ring closure reaction is carried out with the stereochemistry preserved. Then, the free base and/or acid addition salt of R-or S-citalopram is obtained in an enantiomeric purity substantially equal to the starting diol.
The ring closure reaction of the resulting racemic diol free base and/or acid addition salt may be carried out in an acidic environment, as described in US 4,650,884, or by means of one of the above mentioned labile esters. Thus, racemic citalopram was obtained.
The enantiomerically pure R-or S-citalopram free base and/or acid addition salt thus obtained may be mixed with a non-racemic mixture of R-and S-citalopram free base and/or acid addition salt to obtain a racemic citalopram free base and/or acid addition salt. Racemic citalopram free base and/or acid addition salt may then be obtained by one or more precipitations of citalopram free base or acid addition salt thereof, followed by the above mentioned recrystallisation.
A particular embodiment of the invention relates to a process for the preparation of racemic diols as the free base or acid addition salts thereof and/or R-or S-diols in the form of the free base or acid addition salts thereof by separating an initial non-racemic mixture of R-and S-diols with more than 50% of one of the enantiomers into a fraction enriched in S-diol or R-diol and a fraction consisting of RS-diol, wherein the ratio R-diol to S-diol is equal to 1: 1 or closer to 1: 1 than the initial mixture of R-and S-diols, wherein
i) RS-diol is precipitated from a solvent as a free base or as an acid addition salt;
ii) separating the formed precipitate from the mother liquor:
iia) if the precipitate is crystalline, optionally performing one or more recrystallizations to produce racemic diol;
iib) if said precipitate is not crystalline, optionally repeating steps i) and ii) until a crystalline precipitate is obtained, and then optionally recrystallizing the crystalline precipitate one or more times to produce racemic diol;
iii) optionally further purifying the mother liquor and separating the S-diol or R-diol from the mother liquor:
iv) optionally converting the obtained free base of the diol into an acid addition salt thereof, or optionally converting the obtained acid addition salt of the diol into another acid addition salt, or optionally converting the obtained acid addition salt of the diol into the corresponding free base.
Another embodiment of the invention relates to a process for the preparation of racemic diol free base or acid addition salt thereof and/or R-or S-diol in free base or acid addition salt form, by separating an initial non-racemic mixture of R-and S-diols with more than 50% of one enantiomer into a fraction enriched in S-diol or R-diol and a fraction consisting of RS-diol, wherein the ratio R-diol to S-diol is equal to 1: 1 or closer to 1: 1 than the initial mixture of R-and S-diols, wherein
i) RS-diol is precipitated from a solvent as a free base or as an acid addition salt; or
Dissolving an R-or S-diol from an initial non-racemic mixture of R-or S-diols in free base or acid addition salt form thereof in said solvent to leave a residue;
ii) separating the formed precipitate from the mother liquor:
iia) if the precipitate is crystalline, optionally performing one or more recrystallizations to produce racemic diol;
iib) if said precipitate is not crystalline, optionally repeating steps i) and ii) until a crystalline precipitate is obtained, and then optionally recrystallizing the crystalline precipitate one or more times to produce racemic diol;
iii) optionally further purifying the mother liquor and separating the S-diol or R-diol from the mother liquor:
iv) optionally converting the obtained free base of the diol into an acid addition salt thereof, or optionally converting the obtained acid addition salt of the diol into another acid addition salt, or optionally converting the obtained acid addition salt of the diol into the corresponding free base.
Detailed Description
The invention is illustrated by the following examples, which however do not limit the invention.
Examples
In the following examples, optical purity was determined by chiral SCFC (supercritical fluid chromatography) HPLC.
Example 1
Purification of S-diols by precipitation of the racemic diol as the hydrochloride
The general method comprises the following steps:
a mixture of R-and S-diols (as defined in the following table) (10g) was dissolved in toluene (60 mL). Aqueous hydrochloric acid (32mL, 1M) was added, and in some cases solid sodium chloride (to bring the concentration of NaCl in water to about 1M) was added. The mixture was stirred overnight, followed by filtration. The residue was dried to give racemic diol hydrochloride crystals contaminated with a little S-diol hydrochloride. The mother liquor was basified with aqueous ammonia to a pH > 9 and the toluene layer was separated. The aqueous layer was again washed with toluene and the combined toluene extracts were dried over magnesium sulfate and evaporated under reduced pressure to give S-diol contaminated with a small amount of R-diol. See table below for details. The recovery of material is quantitative in nature with the expected dispensed weight between samples.
| Before precipitation | After precipitation | ||||
| Mixtures of isomers | Precipitation (mixture of R and S-diols) | Basified, separated and evaporated oil (enriched with S-enantiomer) | |||
| S％ | R％ | S％ | R％ | S％ | R％ |
| 98.4 | 1.6 | 54 | 46 | 97.9 | 2.1* |
| 95.4 | 4.6 | 55 | 45 | 98.7 | 1.3* |
| 90.3 | 9.7 | 51 | 49 | 96.7 | 3.3 |
| 80 | 20 | 51 | 49 | 96.7 | 3.3 |
| 69 | 31 | 50 | 50 | 94.8 | 5.2 |
| 59 | 41 | 54 | 46 | 92 | 8.0 |
Denotes that sufficient solid NaCl was added to the mixture so that the NaCl concentration in the resulting aqueous phase was about 1M.
In the following examples, optical purity was determined by chiral HPLC.
Example 2
Purification of S-diols by precipitation of racemic diol free base
A solution of S-diol in acetonitrile (500mL, about 50-55% w/w, S: R ratio 95.72: 4.28) was cooled to-14 ℃ with stirring at room temperature. After every 2 ℃ reduction in temperature, the mixture was seeded with almost racemic diol (S: R ratio of about 60: 40). After 16 hours, the mixture was filtered and the filter cake was then dried. Analysis of the filter cake showed an S: R ratio of 57.97: 42.03. Analysis of the mother liquor showed that the S: R ratio was 98.065: 1.935.
Example 3
Purification of S-diols by precipitation of racemic diol free base
A solution of S-diol in acetonitrile (500mL, about 50-55% w/w, S: R ratio 95.72: 4.28) was cooled to-10 ℃ at 1 ℃/h with stirring at room temperature. After every 5 ℃ reduction in temperature, the mixture was seeded with almost racemic diol (S: R ratio of about 60: 40). After 40 hours at-10 ℃, the mixture was filtered and the filter cake was then dried. Analysis of the filter cake showed an S: R ratio of 59.19: 40.81. Analysis of the mother liquor showed that the S: R ratio was 98.52: 1.48.
Example 4
Purification of S-diols by precipitation of the racemic diol as the hydrochloride
The general method comprises the following steps:
a mixture of R-and S-diols (as defined in the following table) (1g) was dissolved in toluene (10 mL). Aqueous hydrochloric acid (1.0 eq; concentration as specified in the table below) was added followed by solid sodium chloride (sufficient to provide a concentration of NaCl in the water of about 1 or 2M; see table below). The mixture was stirred overnight, followed by filtration. The residue was dried to give racemic diol hydrochloride crystals contaminated with a little S-diol hydrochloride. The mother liquor was basified with aqueous ammonia to a pH > 9 and the toluene layer was separated. The aqueous layer was again washed with toluene and the combined toluene extracts were dried over magnesium sulfate and evaporated under reduced pressure to give S-diol contaminated with a small amount of R-diol. See table below for details. The recovery of material is quantitative in nature with the expected dispensed weight between samples.
| Before precipitation | After precipitation | ||||||
| Mixtures of isomers | Concentration of HCl in water (M) | Concentration of NaCl aqueous solution (M) | Precipitation (R and S-diols)Of (2) | Basified, separated and evaporated oil (enriched with 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 |
Example 5
Purification of S-diols by precipitation of racemic diols in the form of p-toluenesulfonyl, methanesulfonyl or acetate salts
The general method comprises the following steps:
a mixture of R-and S-diols (as specified in the following table) (1g) was dissolved in toluene or ether (10 mL; as described in the following table). Aqueous NaCl (1M, 3mL) was added. The acid was added neat as a liquid (as specified in the table below). The mixture was stirred overnight, followed by filtration or decantation. The residue is dried to give an oil or a solid. The mother liquor is basified to pH > 9 with aqueous ammonia solution and the toluene or ether layer is separated. The aqueous layer is again washed with toluene or ether and the combined organic extracts are dried over magnesium sulfate and evaporated under reduced pressure to give in essence a solid or an oil. See table below for details. The recovery of material is quantitative in nature with the expected dispensed weight between samples.
| Before precipitation | After precipitation | ||||||
| Mixtures of isomers | Solvent(s) | Acid (equivalent) | Precipitation (mixture of R and S-diols) | Basified, separated and evaporated oil (enriched with S-enantiomer) | |||
| 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 compounds | MsOH(1) | 62.9 | 37.1 | 91.0 | 9.0 |
| 82.3 | 17.7 | Ether compounds | 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 compounds | AcOH(1) | 65.0 | 35.0 | 91.6 | 8.4 |
| 82.3 | 17.7 | Ether compounds | AcOH(2) | 65.7 | 34.3 | 87.2 | 12.8 |
Example 6
Purification of S-diols by precipitation of a racemic diol salt in the absence of water
The general method comprises the following steps:
a mixture of R-and S-diols (as specified in the following table) (1g) was dissolved in toluene or ether (10 mL; as described in the following table). The acid was added neat as a solid (as specified in the table below). The mixture was stirred overnight, followed by filtration. The residue is dried to give an oil or a solid. Water is added to the mother liquor, which is then basified to a pH > 9 with aqueous ammonia solution and the toluene or ether layer is separated. The aqueous layer is again washed with toluene or ether and the combined organic extracts are dried over magnesium sulfate and evaporated under reduced pressure to give in essence a solid or an oil. See table below for details. The recovery of material is quantitative in nature with the expected dispensed weight between samples.
| Before precipitation | After precipitation | ||||||
| Mixtures of isomers | Solvent(s) | Acid (equivalent) | Precipitation (mixture of R and S-diols) | Basified, separated and evaporated oil (enriched with 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 compounds | 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 compounds | (CO2H)2(0.2) | 58.0 | 42.0 | 97.7 | 2.3 |
| 82.3 | 17.7 | Ether compounds | (CO2H)2(0.4) | 55.4 | 44.6 | 98.4 | 1.6 |
| 82.3 | 17.7 | Ether compounds | (CO2H)2(1) | 72.0 | 28.0 | 99.5 | 0.5 |
Example 7
Purification of S-diols by precipitation of a racemic diol salt using various solvents in the absence of water
The general method comprises the following steps:
a mixture of R-and S-diols (specified in the table below) (1g) was dissolved in a solvent (10 mL; as described in the table below). The acid was added neat as a solid (as specified in the table below). The mixture is stirred overnight, followed by filtration or decantation if a precipitate forms. If a precipitate forms, the residue is dried to give an oil or a solid. The mother liquor was evaporated and the residue was dissolved in a mixture of ether and water. The mixture was basified to pH > 9 with aqueous ammonia solution and the ether layer was separated. The aqueous layer was washed again with ether and the combined ether extracts were dried over magnesium sulfate and evaporated under reduced pressure to give in essence a solid or an oil. See table below for details. The recovery of material is quantitative in nature with the expected dispensed weight between samples.
| Before precipitation | After precipitation | ||||||
| Mixtures of isomers | Solvent(s) | Acid (equivalent) | Precipitation (mixture of R and S-diols) | Basified, separated and evaporated oil (enriched with S-enantiomer) | |||
| S％ | R％ | S％ | R％ | S％ | R％ | ||
| 82.3 | 17.7 | MeOH | TsOH(0.4) | Without precipitation | |||
| 82.3 | 17.7 | MeOH | (CO2H)2(0.2) | Without 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) | Without precipitation | |||
| 82.3 | 17.7 | Acetonitrile | (CO2H)2(0.2) | 57.2 | 42.8 | 97.2 | 2.8 |
| 82.3 | 17.7 | THF | TsOH(0.4) | Without precipitation | |||
| 82.3 | 17.7 | THF | (CO2H)2(0.2) | 53.2 | 46.8 | 98.9 | 1.1 |
| 82.3 | 17.7 | Acetone (II) | TsOH(0.4) | Without precipitation | |||
| 82.3 | 17.7 | Acetone (II) | (CO2H)2(0.2) | 56.7 | 43.3 | 98.2 | 1.8 |
| 82.3 | 17.7 | MIBK | TsOH(0.4) | 56.8 | 43.2 | 98.5 | 1.5 |
| 82.3 | 17.7 | MIBK | (CO2H)2(0.2) | 58.7 | 41.3 | 99.6 | 0.4 |
Example 8
Purification of S-diols by precipitation of racemic diol oxalates
The general method comprises the following steps:
a mixture of R-and S-diols (as specified in the table below) (1g) was dissolved in toluene (10 mL). Aqueous NaCl (1M, 3mL) was added followed by oxalic acid (as specified in the table below) neat as a solid. The mixture is stirred overnight, followed by filtration or decantation if a precipitate forms. If a precipitate forms, the residue is dried to give an oil or a solid. The mother liquor was basified with aqueous ammonia to a pH > 9 and the toluene layer was separated. The aqueous layer was again washed with toluene and the combined toluene extracts were dried over magnesium sulfate and evaporated under reduced pressure to give in essence a solid or an oil. See table below for details. The recovery of material is quantitative in nature with the expected dispensed weight between samples.
| Before precipitation | After precipitation | |||||
| Mixtures of isomers | Oxalic acid (equivalent) | Precipitation (mixture of R and S-diols) | Basified, separated and evaporated oil (enriched with 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
The general method comprises the following steps:
a mixture (1g) of R-and S-diols (as specified in the table below) was stirred with aqueous HCl (1 eq.; concentration see table below). The mixture was stirred overnight and sufficient NaCl (as a solid) was added so that the NaCl concentration was 1M. The mixture was filtered to give a solid. Water and ether were added to the mother liquor, which was then basified to pH > 9 with aqueous ammonia solution and the ether layer was separated. The aqueous layer was washed again with ether and the combined ether extracts were dried over magnesium sulfate and evaporated under reduced pressure to give in essence a solid or an oil. See table below for details. The recovery of material is quantitative in nature with the expected dispensed weight between samples.
| Before precipitation | After precipitation | |||||
| Mixtures of isomers | Hydrochloric acid concentration (M)) | Precipitation (mixture of R and S-diols) | Basified, separated and evaporated oil (enriched with S-enantiomer) | |||
| S％ | R％ | S％ | R％ | S％ | R％ | |
| 82.3 | 17.7 | 1 | 59.4 | 40.6 | 99.2 | 0.8 |
| 82.3 | 17.7 | 2 | 63.7 | 36.3 | 99.3 | 0.7 |
Example 10
Purification of S-diol by preferential dissolution of S-diol hydrochloride in water
The general method comprises the following steps:
a mixture of R-and S-diol hydrochloride (17.7: 82.3; 5.5g) was stirred with aqueous NaCl (1M, 12 mL). The mixture was stirred overnight and filtered to give a solid. Water and ether were added to the mother liquor, which was basified with aqueous ammonia to a pH > 9, and the ether layer was separated. The aqueous layer was washed again with ether and the combined ether extracts were dried over magnesium sulfate and evaporated under reduced pressure to give in essence a solid or an oil. The residue after filtration contained R-diol and S-diol in a ratio of 1.0: 99.0. The product obtained after the filtrate work-up contained R-diol and S-diol in a ratio of 38.8: 61.2. The recovery of material is quantitative in nature with the expected dispensed weight between samples.
Claims (28)
1. A process for the preparation of racemic citalopram diol free base and/or acid addition salt and/or R-or S-citalopram diol free base and/or acid addition salt comprising separating an initial non-racemic mixture of R-and S-citalopram diol free base and/or acid addition salt having more than 50% of one enantiomer into a fraction enriched in S-citalopram diol or R-citalopram diol free base and/or acid addition salt and a fraction comprising RS-citalopram diol free base and/or acid addition salt, wherein the ratio R-citalopram diol to S-citalopram diol is equal to 1: 1 or closer to 1: 1 than the initial mixture of R-and S-citalopram diol, characterized in that
i) Separating the RS-citalopram diol free base and/or acid addition salt from a solution of an initial non-racemic mixture of R-and S-citalopram diol free base and/or acid addition salt; or
Dissolving R-or S-citalopram diol free base and/or acid addition salt from an initial non-racemic mixture of R-and S-citalopram diol free base and/or acid addition salt in a solvent to said solvent leaving a residue comprising RS-citalopram diol free base and/or acid addition salt;
ii) separating the formed residue/precipitate from the final solution phase;
iia) if said residue/precipitate is crystalline, optionally performing one or more recrystallizations to prepare racemic citalopram diol;
iib) if said residue/precipitate is not crystalline, optionally repeating steps i) and ii) until a crystalline residue/precipitate is obtained, and then optionally subjecting the crystalline residue/precipitate to one or more recrystallizations to prepare racemic citalopram diol;
iii) optionally further purifying the final solution phase, separating the S-citalopram diol or R-citalopram diol free base and/or acid addition salt from the final solution phase;
iv) optionally converting the obtained free base of citalopram diol into an acid addition salt thereof, or optionally converting the obtained acid addition salt of citalopram diol into another acid addition salt, or optionally converting the obtained acid addition salt of citalopram diol into the corresponding free base.
2. A process according to claim 1 for the preparation of S-citalopram diol or R-citalopram diol as a free base and/or acid addition salt, characterised in that
i) Separating the RS-citalopram diol free base and/or acid addition salt from a solution of an initial non-racemic mixture of R-and S-citalopram diol free base and/or acid addition salt; or
Dissolving R-or S-citalopram diol free base and/or acid addition salt from an initial non-racemic mixture of R-and S-citalopram diol free base and/or acid addition salt in a solvent to said solvent leaving a residue comprising RS-citalopram diol free base and/or acid addition salt;
ii) separating the formed residue/precipitate from the final solution phase, and
iii) optionally further purifying the final solution phase and isolating the S-citalopram diol or R-citalopram diol free base and/or acid addition salt from the final solution phase.
3. The process according to claim 2, wherein the citalopram diol prepared is a free base and/or an acid addition salt of S-citalopram diol.
4. The process according to claim 2, wherein the citalopram diol prepared is a free base and/or an acid addition salt of R-citalopram diol.
5. Process for the preparation of the free base and/or acid addition salts of racemic citalopram diol according to claim 1, characterised in that
i) Separating the RS-citalopram diol free base and/or acid addition salt from a solution of an initial non-racemic mixture of R-and S-citalopram diol free base and/or acid addition salt; or
Dissolving R-or S-citalopram diol from an initial non-racemic mixture of R-and S-citalopram diol free base and/or acid addition salts in a solvent to said solvent, leaving a residue comprising RS-citalopram diol free base and/or acid addition salt;
ii) separating the formed residue/precipitate from the final solution phase;
iia) if said residue/precipitate is crystalline, optionally performing one or more recrystallizations to prepare racemic citalopram diol;
iib) if said residue/precipitate is not crystalline, repeating steps i) and ii) until a crystalline residue/precipitate is obtained, and then optionally subjecting the crystalline residue/precipitate to one or more recrystallizations to prepare racemic citalopram diol.
6. The process according to any one of claims 1-5, wherein more than 50% of the initial non-racemic mixture of R-and S-citalopram diol free base and/or acid addition salts of one of the enantiomers contains more than 50% S-citalopram diol.
7. The process according to any one of claims 1-5, wherein more than 50% of the initial non-racemic mixture of R-and S-citalopram diol free base and/or acid addition salts of one of the enantiomers contains more than 50% R-citalopram diol.
8. The process according to any one of claims 1 to 7 wherein the ratio of R-and S-citalopram diol in the residue/precipitated RS-citalopram diol 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 1: 1.
9. The process according to any one of claims 1 to 8, wherein the RS-citalopram diol contained in the residue/precipitate is present in the form of its free base and/or acid addition salt; and its R-or S-citalopram diol, independently comprised in the final solution phase, in the form of the free base and/or its acid addition salt.
10. The process according to any one of claims 1 to 9, wherein the RS-citalopram diol free base and/or acid addition salt is precipitated from a solution of an initial non-racemic mixture of R-and S-citalopram diol free base and/or acid addition salt.
11. The process according to any one of claims 1 to 10, wherein the RS-citalopram diol acid addition salt is precipitated by addition of an acid.
12. The process according to claim 11, wherein the acid used to precipitate RS-citalopram diol as a salt in step i) is an acid which precipitates a mixture of the R-and S-enantiomers and leaves a mother liquor enriched in the S-or R-enantiomer of citalopram diol as a free base and/or an acid addition salt.
13. The method of claim 12, wherein the acid is selected from the group consisting of:
after obtaining the initial non-racemic mixture of the free base and/or acid addition salts of R-and S-citalopram diol or after dissolving the mixture in a suitable solvent; and/or
Present in a solvent during and/or before dissolving the initial non-racemic mixture of R-and S-citalopram diol free base and/or acid addition salt; and/or
The initial non-racemic mixture of the free base and/or acid addition salts of R-and S-citalopram diol is present in the solvent during and/or before its dissolution in the solvent.
14. The process according to any one of claims 1 to 9, wherein the R-or S-citalopram diol free base and/or acid addition salt is dissolved from the initial non-racemic mixture of R-and/or S-citalopram diol free base and/or acid addition salt in a solvent leaving a residue comprising RS-citalopram diol free base and/or acid addition salt.
15. The process according to any one of claims 1-9 and 14, wherein the acidic moiety of the RS-citalopram diol acid addition salt in the residue formed in step i) is an acid, which selectively dissolves the R-or S-citalopram diol free base and/or acid addition salt and leaves an insoluble material rich in the RS-citalopram diol acid addition salt.
16. The method of claim 12, wherein the acid may be
Is present in the solvent before the initial non-racemic mixture of the free base and/or acid addition salts of R-and S-citalopram diol is mixed with said solvent; and/or
Mixing together with a solvent and with the initial non-racemic mixture of the free base and/or acid addition salts of R-and S-citalopram diol; and/or
Mixing with a solvent after mixing the initial non-racemic mixture of R-and S-citalopram diol free base and/or acid addition salts with said solvent; and/or
In the initial non-racemic mixture of the free base and/or acid addition salts of R-and S-citalopram diol during and/or before mixing with the solvent.
17. The process of claims 1-16, wherein the RS-citalopram diol acid addition salt is obtained from an initial non-racemic mixture of R-and S-citalopram diol free base and/or acid addition salts in a solvent selected from the group consisting of toluene, ethyl acetate, diethyl ether, THF, water, alcohols, acetonitrile, and ketones, or mixtures thereof.
18. The process as claimed in any of claims 1 to 17, wherein the acid used in step i) is HCl, HBr, H2SO4P-toluenesulfonic acid, methanesulfonic acid, acetic acid or oxalic acid.
19. The process of claim 18, wherein the acid used in step i) is HCl, HBr or oxalic acid; whereby the hydrobromide, hydrochloride or oxalate salt of RS-citalopram diol is obtained in crystalline form.
20. The process according to any one of claims 1 to 19, wherein 0.2 to 10mol of acid per mol of S-and R-citalopram diol contained in the initial non-racemic mixture of R-and S-citalopram diol free base and/or acid addition salts may be used.
21. The process of any one of claims 1 to 19, wherein 0.3 to 4.0mol of acid is used per mol of RS-citalopram diol contained in the residue/precipitate.
22. The process according to any one of claims 1-10 and 14, wherein the free base of RS-citalopram diol is obtained in step i), in crystalline form.
23. The process of any one of claims 1 to 10, 14 and 22 wherein the RS-citalopram diol free base is obtained from an initial non-racemic mixture of R-and S-citalopram diol in a solvent selected from the group consisting of alkanes, aromatics, polar solvents, and ketones, or mixtures thereof.
24. The process according to any one of claims 1 to 23, wherein the final solution phase is subjected to one or more further separations of RS-citalopram diol as described in steps i) and ii) before separation of S-citalopram diol or R-citalopram diol from the final solution phase.
25. The process of any one of claims 1 to 4 and 6 to 24, wherein S-citalopram diol or R-citalopram diol is separated from the final solution phase by evaporation of the solvent.
26. The process of any one of claims 1 to 4 and 6 to 25, wherein the final solution phase is acidic and S-citalopram diol or R-citalopram diol is separated from the final solution phase by basification of the final solution phase followed by phase separation or extraction with a solvent, followed by evaporation of the solvent.
27. The process according to any one of claims 1 to 4 and 6 to 25, wherein the S-citalopram diol or the R-citalopram diol free base and/or acid addition salt is separated from the final solution phase by precipitation of the R-or S-citalopram diol free base and/or acid addition salt; suitably, the R-or S-citalopram diol is precipitated as a phosphate or oxalate salt.
28. The process according to any one of claims 1-4 and 6-27, wherein the S-citalopram diol or R-citalopram diol obtained contains a small amount of the opposite enantiomer.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US43611702P | 2002-12-23 | 2002-12-23 | |
| DKPA200202004 | 2002-12-23 | ||
| DKPA200202004 | 2002-12-23 | ||
| PCT/DK2003/000907 WO2004056754A1 (en) | 2002-12-23 | 2003-12-18 | 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 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1087994A1 HK1087994A1 (en) | 2006-10-27 |
| HK1087994B true HK1087994B (en) | 2008-03-28 |
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