HK1069386B - Method for the preparation of escitalopram - Google Patents

Description

Preparation method of escitalopram

Technical Field

The present invention relates to the preparation of the compound escitalopram, the S-enantiomer of the well-known antidepressant drug citalopram, i.e. (S) -1- [3- (dimethylamino) propyl ] -1- (4-fluorophenyl) -1, 3-dihydro-5-isobenzofuran-carbonitrile, or a pharmaceutically acceptable salt thereof for use in the preparation of pharmaceutical formulations.

Background

Cyanophthalein fluoroaniline is a well-known antidepressant drug that has been marketed for several years now, having the following structure:

it is a selective central-action serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, and thus has antidepressant activity.

Cyanophthalein fluoroaniline is disclosed for the first time in DE 2,657,013, corresponding to U.S. Pat. No. 4,136,193. This patent document outlines a process for the preparation of cyanophthalfluoroaniline from the corresponding 5-bromo-derivative by reaction with cuprous cyanide in a suitable solvent. WO 0011926 and WO 0013648 disclose the replacement of a 5-halogen atom or CF by a cyano group₃-(CF₂)_n-SO₂-O-, and n is 0 to 8, other methods for preparing cyanophthalfluoroaniline.

For example, U.S. Pat. No. 4,650,884 discloses a diol of formula II, 4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxy-1-butyl ] -3- (hydroxymethyl) -benzonitrile, and its use as an intermediate in the preparation of cyanophthalamide fluoroaniline.

The enantiomers of escitalopram, diol II and processes for their preparation are disclosed in U.S. patent No. 4,943,590. Two pathways for obtaining escitalopram are disclosed, both of which are initiated with racemic diol I I. In the first route, diol II is reacted with an enantiomeric acid derivative, for example (+) or (-) - α -methoxy- α -trifluoromethyl-phenylacetyl chloride, to give diastereomeric esters, which are separated by HPLC or fractional crystallization, and the ester with dextrorotatory stereochemistry is enantioselectively converted into escitalopram. In the second route, diol II is separated into enantiomers by stereoselective crystallization using an enantiomerically pure acid such as (+) -di-p-toluoyltartaric acid, wherein the S-enantiomer of diol II is enantioselectively converted to escitalopram. Both of these routes involve the consumption of expensive enantiomerically pure reagents and give relatively low yields, making them economically and environmentally unfeasible to produce industrially. U.S. Pat. No. 4,943,590 also discloses the stereoselectivity of the pharmaceutical action of cyanophthalfluoroaniline, i.e., the 5-HT-reuptake inhibition of S-enantiomer retention, and, correspondingly, the antidepressant action of said enantiomer. Escitalopram has now been developed as an antidepressant. Thus, improved methods of preparation of escitalopram are contemplated.

It is well known to those skilled in the art that the two enantiomers can be separated in some cases by liquid chromatography using a chiral stationary phase. Chiral stationary phases were found by screening chiral stationary phases effective for the enantiomers that were effective in the separation of the enantiomeric pairs studied, and were always effective chiral stationary phases suitable for the purpose.

Conventional liquid chromatography is a batch process that consumes large amounts of solvent and is generally not economically feasible for commercial production. Chromatographic methods are well known to those skilled in the art and have the advantage of being continuous and generally consuming a reduced amount of solvent. Simulated fluidized bed (SMB) chromatography is such a continuous chromatography.

EP 563,388 discloses a simulated fluidized bed (SMB) chromatography in which enantiomers of optically active compounds are separated and the stationary phase comprises a chiral material such as cellulose ester coated silica gel.

Therefore, a chiral stationary phase effective in separation of enantiomers of cyanophthalfluoroaniline or compounds that are intermediates for preparing cyanophthalfluoroaniline is desired.

No one has previously contemplated a chiral stationary phase as an effective method in separating a given pair of enantiomers. Chiral stationary phases for separating enantiomeric pairs were found by selecting chiral stationary phases via laborious experiments from a large number of available chiral stationary phases.

Objects of the invention

The object of the present invention is to provide a new economically viable chromatography method for the isolation of enantiomers of cyanophthalfluoroaniline or intermediate compounds for the preparation of cyanophthalfluoroaniline.

It is another object of the present invention to provide novel optionally resolved intermediates useful in the preparation of cyanophthalamide.

Summary of The Invention

As used herein, the terms 'separation of enantiomers' and 'separation into enantiomers' refer to any process in which two or more fractions are obtained in which the ratio between the two enantiomers deviates from 1: 1. The term 'optically detachable' refers to the product of any such process.

As used herein, the term 'purity' means enantiomeric purity (ee) as measured in percent enantiomeric excess.

As used herein, the term 'carbohydrate derivative' is meant to refer to any compound that can be derived from a carbohydrate primarily by substitution of one or more hydroxyl groups with another substituent and leaving the stereochemical structure intact.

As used herein, the terms 'intermediate for the preparation of escitalopram' and 'intermediate compound in the preparation of cyanophthalamide' mean any intermediate in any well-known process for the preparation of escitalopram.

In the context of the present application, the structural formula of a chiral compound refers to a racemate if stereochemistry is not indicated.

Difficile experiments a novel inventive process for the preparation of cyanophthalfluoroaniline by chromatography using a chiral stationary phase has now been invented, comprising the separation of enantiomers of cyanophthalfluoroaniline, or the preparation of intermediates for cyanophthalfluoroaniline.

Accordingly, the present invention relates to a novel process for the preparation of escitalopram having the formula

Comprising preparing a compound of the formula:

wherein X is cyano, a halogen atom or any other group which can be converted into cyano by optical resolution by chromatography of a racemic compound of the formula

Wherein X is as defined above; if X is not cyano, then converting X to cyano and isolating escitalopram or a pharmaceutically acceptable salt thereof.

In a preferred embodiment of the invention, cyanophthalfluoroaniline is separated into its enantiomers by chromatography using a chiral stationary phase.

Accordingly, the present invention relates to a novel process for the preparation of escitalopram having the formula

Comprising optical resolution by chromatography of a compound of the formula

Wherein X is cyano, a halogen atom or any other group that can be converted to cyano and Z is hydroxy or a leaving group, to form a compound of the formula

If Z is OH, the group Z is converted to a leaving group and the resulting compound of formula (VII) wherein Z is a leaving group is then cyclized to form the compound of formula

Wherein X is as defined above, and if X is not cyano then converting the group X in the compound of formula (III) to a cyano group followed by isolation of escitalopram or a pharmaceutically acceptable salt thereof.

In another preferred embodiment of the invention, the intermediate diol II4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxy-1-butyl ] -3- (hydroxymethyl) -benzonitrile is separated into its enantiomers by chromatography using chiral stationary phase techniques. The obtained (S) -4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxy-1-butyl ] -3- (hydroxymethyl) -benzonitrile can be converted into escitalopram by methods well known in the art, e.g. treatment with p-toluenesulfonyl chloride and a base, e.g. triethylamine, according to US 4,943,590.

The invention also relates to intermediates having the formula

Wherein Z is as defined above.

In another embodiment, the invention relates to the S-enantiomer of 5-Br-cyanophthalamide having the formula

Or a salt thereof.

Racemic compounds of formulae (V) and (VI) can be resolved by liquid chromatography or supercritical chromatography or subcritical chromatography using a chiral stationary phase.

The chiral stationary phase may comprise an optically active polymer, such as a polysaccharide derivative, e.g. an ester or urethane of cellulose or amylose, a polyacrylate derivative (e.g. a methacrylate derivative like poly (triphenylmethyl methacrylate)) or a polyamide derivative, a protein with an asymmetric or asymmetric chain (bovine serum albumin bonded to silica, cellulase covalently bonded to aldehydic silica), a polymer with asymmetric centers in its side chains.

Another possibility is a chiral stationary phase comprising low molecular weight compounds with the possibility of optical resolution, such as crown ethers (on silica (S) or (R) -18-crown-6-ether) and cyclodextrin derivatives (silica-bound α -cyclodextrin).

Other important chiral separation factors that the chiral stationary phase may comprise are amino acids and derivatives thereof, esters or amides of amino acids, acetylated amino acids and oligopeptides.

Another possibility is a particulate polysaccharide material, such as microcrystalline cellulose triacetate.

Chiral stationary phases comprising polysaccharide derivatives and polyamides for separating enantiomers are described in EP 0147804, EP 0155637, EP 0157365, EP 0238044, WO 95/18833, WO 97/04011, EP 0656333 and EP 718625.

Polysaccharide particles for the separation of optical enantiomers are described in EP 0706982.

Preferably, the chiral stationary phase comprises a carbohydrate derivative, more preferably a polysaccharide derivative, most preferably an amylose or cellulose derivative.

Suitably, the polysaccharide adsorbed on silica gel bears groups like phenylcarbamoyl, 3, 5-dimethyl-phenylcarbamoyl, 4-chlorophenylcarbamoyl, 3, 5-dichloro-phenylcarbamoyl, acetyl, benzoyl, cinnamoyl, 4-methyl-benzoyl or S- α -phenethylcarbamoyl.

Preferably, the carbohydrate comprises a phenyl carbamate substituent, which may optionally be substituted by one or more C_1-4The alkyl group is preferably substituted by methyl.

The chiral compound, which is the chiral separation element of the stationary phase, may suitably be adsorbed on a support, such as silica gel.

Suitably, the chiral stationary phase is Chiralpak^TMAD, an amylose derivative supported on silica gel in which most of the hydroxyl groups are substituted with 3, 5-dimethylphenyl carbamate, or Chiralcel^TMOD, a cellulose derivative supported on silica gel in which most of the hydroxyl groups were substituted with 3, 5-dimethylphenyl carbamate. Chiralpak^TMAD and Chiralcel^TMOD was obtained from daicel chemical Industries ltd.

Chiral stationary phases comprising an amylose phenyl carbamate derivative are particularly suitable for the resolution of compounds of formula (VI). An example of such a chiral stationary phase is Chiralpak^TMAD。

Chiral stationary phases comprising cellulose phenyl carbamate derivatives are particularly suitable for the resolution of the compounds of formula (V). An example of such a chiral stationary phase is Chiralcel^TM OD。

The nature of the substituent X has little effect on the resolution of the compound because it is far from the chiral center.

Any liquid chromatographic separation method can be used for the separation of enantiomers. Preferably, the chromatographic separation method comprises a continuous chromatographic technique, suitably a simulated fluid bed technique.

The eluent is generally selected from acetonitrile, alcohols, such as methanol, ethanol or isopropanol, and alkanes, such as cyclohexane, hexane or heptane, and mixtures thereof. To the eluent, acids, such as formic acid, acetic acid and trifluoroacetic acid and/or bases, such as diethylamine, triethylamine, propylamine, isopropylamine and dimethyl-isopropyl-amine, may also be added.

Alternatively, supercritical or subcritical carbon dioxide containing a modifier may be used as the eluent. The modifier is selected from the group consisting of lower alcohols, such as methanol, ethanol, propanol and isopropanol. Amines such as diethylamine, triethylamine, propylamine, isopropylamine and dimethyl-isopropyl-amine and optionally an acid such as formic acid, acetic acid and trifluoroacetic acid may be added.

Suitably, the chromatography used is liquid chromatography.

A suitable eluent according to this embodiment of the invention is acetonitrile.

Another suitable eluent according to this embodiment of the invention is a mixture of isohexane and isopropanol. A suitable mixture contains 98% vol isohexane and 2% vol isopropanol.

Another suitable eluent according to the present invention is supercritical and subcritical carbon dioxide containing 10% vol methanol and 0.5% vol diethylamine and 0.5% vol trifluoroacetic acid.

One embodiment of the present invention includes novel optically resolved intermediates useful in the preparation of escitalopram.

When Z is OH in the compound of formula (VII), the alcohol group, Z, may be converted to a suitable leaving group such as a sulfonate or halide. The former is carried out by reaction with sulfonyl halides, such as methanesulfonyl chloride and p-toluenesulfonyl chloride. The latter is achieved by reaction with a halogenating agent, such as thionyl chloride or phosphorus tribromide.

The ring closure of the compound of formula (VII) wherein Z is a leaving group such as a sulfonate or a halogen atom may then be carried out by treatment with a base such as KOC (CH) in an inert organic solvent₃)₃Or other alkoxides, NaH or other hydrides, triethylamine, ethyldiisopropylamine or pyridine, and inert organic solvents such as tetrahydrofuran, toluene, DMSO, DMF, tert-butyl methyl ether, dimethoxyethane, dimethoxymethane, dioxane, acetonitrile or dichloromethane.

The cyclization is similar to the process described in US 4,943,590.

The compound of formula (IV) can be converted to escitalopram having the formula

As mentioned above, X in the compound of formula (IV) may be cyano, a halogen atom, preferably chlorine or bromine, or any other compound that can be converted into cyano.

Such may be converted to cyanogenThe other radical of (A), X, may be chosen from CF₃-(CF₂)_n-SO₂-O-wherein n is 0-8, -OH, -CHO, -CH₂OH，-CH₂NH₂，-CH₂NO₂，-CH₂Cl，-CH₂Br，-CH₃，-NHR¹，-COOR²，-CONR²R³Wherein R is¹Is hydrogen or alkylcarbonyl, and R²And R³Selected from hydrogen optionally substituted with alkyl aralkyl and aryl, and a group of the formula

Wherein Y is O or S;

R⁴-R⁵each independently selected from hydrogen and C_1-6Alkyl, or R⁴And R⁵Together form C_2-5An alkylene chain thereby forming a spiro ring; r⁶Selected from hydrogen and C_1-6Alkyl radical, R⁷Selected from hydrogen, C_1-6Alkyl, carboxyl or the parent radical of carboxyl, or R⁶And R⁷Together form C_2-5The alkylene chain thereby forms a spiro ring.

When X is a halogen atom, in particular bromine or chlorine, the compound of formula (IV) may be converted to form escitalopram according to the procedures described in U.S. Pat. No. 4,136,193, WO00/13648, WO 00/11926 and WO 01/02383 or other procedures suitable for such conversion.

According to US 4,136,193, the conversion of the 5-bromo group is carried out by reacting a compound of formula (IV) wherein X is bromine with CuCN.

WO00/13648 and WO 00/11926 describe the conversion of a 5-halogen atom or a triflate group to a cyano group by cyanation with a cyanide source in the presence of a Pd or Ni catalyst.

The cyanide source used in accordance with the catalyzed cyanide exchange reaction may be any useful source. Preference is given toIs KCN, NaCN or (R')₄NCN, wherein (R')₄Means that they may be the same or different and are selected from hydrogen or straight or branched C_1-6Four groups of alkyl groups.

The cyanide source is used in stoichiometric amounts or in excess, preferably from 1 to 2 equivalents per equivalent of starter. (R')₄N⁺Conveniently (Bu)₄N⁺. The cyanide source is preferably NaCN or KCN or Zn (CN)₂。

The palladium catalyst may be any suitable catalyst comprising Pd (O) or Pd (II), for example Pd (PPh)₃)₄，Pd₂(dba)₃，Pd(PPh)₂Cl₂And so on. The Pd catalyst is conveniently used in an amount of 1-10, preferably 2-6, most preferably about 4-5 mol%.

In one embodiment, the reaction is carried out in catalytic amounts of Cu⁺Or Zn²⁺In the presence of oxygen. Catalytic amount of Cu⁺Or Zn²⁺Respectively, means substoichiometric amounts, for example from 0.1 to 5, preferably from 1 to 3 mol. Suitably, about one-half equivalent is used for each equivalent of Pd. Any conventional Cu may be used⁺And Zn⁺⁺A source. Preference is given to using Cu in the CuI form⁺，Zn²⁺Conveniently used as Zn (CN)₂And (3) salt.

In a preferred embodiment, Pd (PPh) is preferred over the palladium catalyst₃)₄With ZnCN in the presence of (tetrakis (triphenylphosphine) palladium)₂The reaction of (2) is subjected to cyanation.

The nickel catalyst may be any suitable complex containing Ni (O) or Ni (II) functioning as a catalyst, such as Ni (PPh)₃)₃(. sigma. -aryl) -Ni (PPh)₃)₂Cl, and the like. Nickel catalysts and their preparation are described in WO 96/11906, EP-A-613720 and EP-A-384392.

In a particularly preferred embodiment, the nickel (II) precursor, for example N, is reacted with a metal, for example zinc, magnesium or manganese, in the presence of an excess of a complex ligand, preferably triphenylphosphine, prior to the cyanation reactioniCl₂Or NiBr₂To prepare the nickel (O) complex in situ.

The Ni-catalyst is conveniently used in an amount of 0.5 to 10, preferably 2 to 6, most preferably about 4 to 5 mol%.

In one embodiment, in catalytic amounts of Cu⁺Or Zn²⁺The reaction is carried out in the presence of a catalyst.

Catalytic amount of Cu⁺And Zn²⁺Respectively, means substoichiometric amounts, for example from 0.1 to 5, preferably from 1 to 3%. Any suitable Cu may be used⁺And Zn²⁺A source. Preference is given to using Cu in the CuI form⁺，Zn²⁺Conveniently used as Zn (CN)₂The salts are alternatively prepared in situ by reduction of the nickel (II) compound with zinc.

The cyanation reaction can be carried out without solvent or in any conventional solvent, such solvents including DMF, NMP, acetonitrile, propionitrile, THF, and ethyl acetate.

The cyanide exchange reaction can also be carried out in the general formula (R')₄N⁺，Y^-Wherein R "is an alkyl group or two R" groups together form a ring, Y^-Is a counter ion. In one embodiment of the present invention, (R')₄N⁺Y^-Represents

In another embodiment, synthetic 1000 produced with a non-polar solvent such as benzene, xylene or trimethylbenzene and by using Prolabo^TMThe cyanide exchange reaction is carried out under the influence of microwaves.

The temperature range depends on the type of reaction. If no catalyst is present, the preferred temperature is in the range of 100 ℃ to 200 ℃. When the reaction is carried out under the influence of microwaves, the temperature of the reaction mixture may be raised to 300 ℃. More preferably between 120-170 ℃. The most preferred range is 130-150 ℃.

The preferred temperature range, if a catalyst is present, is between 0 and 100 ℃. More preferred is a temperature range of 40-90 ℃. The most preferred temperature range is between 60-90 ℃.

Other reaction conditions, solvents, etc., are conventional conditions for such reactions and are readily determined by one skilled in the art.

Another method for converting a compound of formula (IV) wherein X is Br to the corresponding 5-cyano derivative involves the reaction of 5-Br-cyanophthaleine fluoroaniline of formula (IV) with magnesium to form a Grignard reagent, followed by reaction with formamide to form the aldehyde. Aldehydes are converted to oximes or hydrazones, respectively, by dehydration and oxidation, respectively.

Alternatively, 5-Br-cyanophthalfluoroaniline of formula (IV) wherein X is Br can be reacted with magnesium to produce a Grignard reagent followed by reaction with a CN group containing compound bonded to a leaving group.

A detailed description of the above two steps can be found in WO 01/02383.

Compounds of formula (IV) wherein X is-CHO can be converted to escitalopram by methods similar to those described in WO 99/30548.

Wherein the group X is NHR by methods similar to those described in WO98/19512¹Wherein R is¹The compound of formula (IV), which is hydrogen or alkylcarbonyl, is converted to escitalopram.

Wherein the group X is-CONR may be prepared by methods analogous to those described in 98/19513 and WO 98/19511²R³Wherein R is²And R³A compound of formula (IV) selected from hydrogen optionally substituted by alkyl, aralkyl or aryl is converted to escitalopram.

Compounds of formula (IV) wherein the group X is a group of formula (X) can be converted to escitalopram by methods similar to those described in WO 00/23431.

Wherein the group X is OH, -CH may be prepared by methods similar to those described in WO 01/168632₂OH，-CH₂NH₂，-CH₂NO₂，-CH₂Cl，-CH₂Br，-CH₃And any other X groups described above to form escitalopram.

The starting materials of the formulae (V) and (VI) can be prepared according to the patents and patent applications mentioned above or by similar methods.

The acid addition salts used according to the invention can thus be obtained by treating the intermediates of the synthetic escitalopram with an acid in a solvent, followed by precipitation by well-known methods, isolation and optionally recrystallization, and, if desired, micronization of the crystalline product by wet or dry milling or other conventional methods or by preparing particles from a solvent emulsification process.

The present invention will be described in detail below with reference to examples. However, the examples are only for illustrating the present invention in detail and should not be construed as limiting.

Example 1

Separation of enantiomers of 4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxy-1-butyl ] -3- (hydroxymethyl) -benzonitrile

4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxy-1-butyl ] -3- (hydroxymethyl) -benzonitrile, which can be prepared according to U.S. Pat. No. 4,650,884, is isolated as its enantiomer as described below.

Mounting of 8 50mm diameter pillars to Novasep Licosep using standard techniques^TM10-50 simulated fluidized bed chromatograph equipped with Chiralpak of 15cm bed length per column^TMAD (20 micron) filler material. An 8-column SMB system in a 2-2-2-2 configuration was chosen for this separation. Acetonitrile (Baker HPLC grade) was used as mobile phase.

The SMB operating conditions are as follows:

temperature: 30 deg.C

Feed flow rate (65 mg/ml): 10 ml/min

Eluent flow rate (make up): 102 ml/min

Extract flow rate: 69 ml/min

Flow rate of the residual liquid: 48 ml/min

Recirculation flow rate: 210 ml/min

Switching time: 1.18 minutes

The product was separated from the eluent by evaporation to give a viscous oil.

The two enantiomers were separated with a purity of more than about 99%.

The resulting (S) -4- [4- (dimethylamino) -1- (4' -fluorophenyl) -1-hydroxy-1-butyl ] -3- (hydroxymethyl) -benzonitrile is converted to escitalopram by methods well known in the art, e.g. treatment with p-toluenesulfonyl chloride and a base such as triethylamine, as disclosed in US 4,943,590.

Example 2

Isolation of 1- (4-bromo-2-hydroxymethyl-phenyl) -4-dimethylamino-1- (4-fluorophenyl) -butan-1-ol

Is provided with Chiral PakA 280x110mm size column (20 micron particle size) was used as the chiral stationary phase. A mixture of 95% acetonitrile and 5% methanol was used as the mobile phase.

The operating conditions were as follows:

temperature: 29 deg.C

Flow rate: 500 ml/min

And (3) detection: UV 280nm

500g of crude cyanophthalamide containing 89% of the racemate are isolated on a column. The first eluted enantiomer was separated from the eluent with an enantiomeric excess of 99.5%, yield of 99% and retention time of 11.0 min. The second eluted enantiomer was separated from the eluent with an enantiomeric excess of 99.2%, yield 98% and retention time of 14.1 min.

Example 3

1- (4' -fluorophenyl) -1- (3-dimethylaminopropyl) -5-bromophtalane into its enantiomers

Equipped with a ChiralcelA 280x110mm size column of OD (20 micron particle size) was used as the chiral stationary phase. A mixture of 98% vol isohexane and 2% vol isopropanol was used as the mobile phase.

The operating conditions were as follows:

temperature: at room temperature

Flow rate: 500 ml/min

And (3) detection: UV 285nm

500g of crude product containing 89% of racemate are isolated on a column. The first eluted enantiomer was separated from the eluent with an enantiomeric excess of 99.5%, yield of 96% and retention time of 5.4 minutes. [ alpha ] to]_D-0.81 degrees (c ═ 0.99, MeOH); the second eluted enantiomer was separated from the eluent with an enantiomeric excess of 99.4%, yield of 99% and retention time of 6.7 minutes. [ alpha ] to]_D+0.95 degrees (c ═ 1.26, MeOH);

example 4

Separation of 1- (4' -fluorophenyl) -1- (3-dimethylaminopropyl) -5-bromophtalane into its enantiomers using supercritical liquid chromatography

Equipped with a ChiralcelA 250x10mm size column of OD (10 micron particle size) was used as the chiral stationary phase. The mobile phase used carbon dioxide and modifier in a ratio of 90: 10. The modifiers were methanol, diethylamine (0.5%) and trifluoroacetic acid (0.5%).

The operating conditions were as follows:

temperature: at room temperature

Flow rate: 18.9 ml/min

Pressure: 20kPa

And (3) detection: UV 254nm

75mg of the racemic mixture were separated on the column.

The two enantiomers were separated from the eluent. The enantiomers were separated with an enantiomeric excess of 86.1% (RT 3.25 min) and 87.1% (RT 3.67 min), respectively.

Example 5

Cyanation of (+) -1- (4-fluorophenyl) -1- (3-dimethylaminopropyl) -5-bromophtalane

Using 3.1g of Zn (CN) under the conditions described in WO00/13648₂And 0.76g of Pd (PPh)₃)₄5.0g of the (+) -enantiomer were treated. The enantiomeric purity of the product was analyzed by chiral electrophoresis. Based on results of chiral electrophoresis and supercritical liquid chromatography, the product is the same as escitalopram. Yield: 80 percent; about 99.6%.

Claims (14)

1. A process for the preparation of escitalopram having the formula

Comprising isolating enantiomers of a compound of formula (V) or (VI),

wherein X in the formula (V) is halogen, or

Wherein X in the formula (VI) is cyano or halogen and Z is hydroxy,

the compound of formula (V) or (VI) is an intermediate compound in the preparation of cyanophthalamide of formula (I)

Characterized in that the separation of the enantiomers is carried out by enantiomeric liquid chromatography using a chiral stationary phase for chromatography, wherein:

a) separating the enantiomers of the compound of formula (V) by liquid chromatography using a chiral stationary phase for chromatography which is a cellulose derivative supported on silica gel in which most of the hydroxyl groups are substituted with 3, 5-dimethylphenyl carbamate to give the enantiomer of formula (IV)

(IV) subsequently converting the X group in the compound of formula (IV) to a cyano group and then isolating escitalopram or a pharmaceutically acceptable salt thereof; or

b) Separating the enantiomers of the compound of formula (VI) by liquid chromatography using a chiral stationary phase for chromatography, which is an amylose derivative supported on silica gel, wherein a majority of the hydroxyl groups are substituted with 3, 5-dimethylphenyl carbamate when separating the enantiomers of formula VI, to give the enantiomer of formula (VII)

Wherein X is a cyano group or a halogen,

followed by conversion of the Z group to a leaving group and cyclization of the resulting compound to form the compound of formula (IVa)

Wherein X is cyano or halogen, and in the case where X is not cyano, then converting the X group of the compound of formula (IV) to cyano, and then isolating escitalopram or a pharmaceutically acceptable salt thereof.

2. The process according to claim 1, wherein the group X in formulae (VI), (VII) and (IVa) is cyano.

3. A process according to claim 1, wherein the group X is bromine.

4. A process according to any one of claims 1-3, characterized in that the chiral stationary phase comprising a silica gel-supported amylose derivative in which a majority of the hydroxyl groups are substituted with 3, 5-dimethylphenyl carbamate is Chiralpak^TMAD。

5. Process according to any one of claims 1 to 3, characterized in that the chiral stationary phase comprising a silica gel-supported cellulose derivative in which a majority of the hydroxyl groups are substituted by 3, 5-dimethylphenyl carbamate is Chiralcel^TMOD。

6. A process according to any one of claims 1 to 3, characterized in that the cellulose or amylose derivative is adsorbed on silica gel.

7. A method according to any one of claims 1-3, characterized in that the chromatographic separation method is continuous chromatography.

8. A method according to any one of claims 1-3 wherein a compound of formula (IV) wherein X is a halogen atom is converted to escitalopram by reacting the compound of formula (IV) with CuCN followed by purification or isolation of escitalopram or a pharmaceutically acceptable salt thereof.

9. A process according to any one of claims 1 to 3 wherein a compound of formula (IV) wherein X is a halogen atom is converted to escitalopram by reacting the compound of formula (IV) with a cyanide source in the presence of a palladium catalyst followed by purification or isolation of escitalopram or a pharmaceutically acceptable salt thereof.

10. A process according to any one of claims 1 to 3 wherein a compound of formula (IV) wherein X is a halogen atom is converted to escitalopram by reacting the compound of formula (IV) with a cyanide source in the presence of a nickel catalyst followed by purification or isolation of escitalopram or a pharmaceutically acceptable salt thereof.

11. The process according to claim 8, wherein X is bromine.

12. The process according to claim 9, wherein X is bromine.

13. The method according to claim 10, wherein X is bromine.

14. The method according to claim 7, characterized in that the chromatographic separation is a simulated fluid bed technique.