1
PROCESS FOR THE PREPARATION OF ESCITALOPRAM Field of the Invention
5 The present invention relates to a process for the preparation of a pharmaceutlcally useful compound, namely escitalopram.
Background of the Invention
10 Citaloprann is a well-known antidepressant drug and is chemically known as 1-[3- (dimethylamino)propy!]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile. It is a selective, centrally acting serotonin (5-hydroxytryptamine; S-HT) reuptake inhibitor, accordingly having antidepressant activities.
15 Citalopram was first disclosed in a Genman patent DE 2,657,013. corresponding to US patent 4,136,193. A process for preparation of citalopram from the corresponding 5- bromo-derivative by reaction with cuprous cyanide in a suitable solvent and by alkylation of 5-bromo-phtalane is disclosed in DE 2,657.013.
20 Escitalopram is a pure S-enantiomer (single isomer) of the racemic citalopram.

4 NOV 2009

2
Escitalopram is at least 100 fold more potent than the R-enantiomer with respect to inhibition of 5-HT reuptake and inhibition of 5-HT neuronal firing rate and is widely used as an antidepressant.
5 Escitaloprahi and processes for Its preparation were first disclosed in EP347066. The failure of previous attempts to crystallize diastereofneric salts of citalopram enantiomers has been acknowledged in EP347066. The aforementioned European patent discloses two processes which provide a solution to the problem of obtaining diastereomeric salts of citalopram enantiomers by employing a racemic diol compound of Formufa A as a 10 starting material.
15
In accordance with a first process as disclosed In EP347066, the diol is reacted with an enantiomerically pure acid derivative, such as (+)- or (-)-a-methoxy-a-trifluoromethyl- phenylacetyl chloride to form a mixture of diastereomeric esters, which are separated by HPLC or fractional crystallization, whereupon the ester with the correct 20 stereochemistry is enantioselectively converted into escitalopram.
In accordance with a second process as disclosed in EP347066, the diol of Formula A is separated into the enantiomers by stereoselective crystallization with an enantiomerically pure acid such as (+)-dl-p-toluoyltartaric acid, whereupon the S- 25 enantlomerof the diol of the formula (I) is enantioselectively converted to escitalopram.




3
Several other different processes, for the preparation of escitalopram have been reported. However, all the hitherto reported processes for preparation of escitalopram employ a plurality of reagents and involve methods steps which make the overalL, processes uneconomical. Furthermore, the aforesaid reported processes do not give. 5 high purity enantiomers of citalopram. There is therefore a need for an economical process for the preparation of escitalopram that, results in products in high, yield with high purity.
Summary of the Invention
10
According to a first aspect of the present invent/on, there is provided a process for preparing a compound of formula III'
15
comprising demethylating citalopram of Formula IV

4
in the presence of a demethylating agent.
In an embodiment, the demethylating agent is a chlorofoimate. Suitably, the chlorpfon^ate is an alky!-, aryl-, substltuted-alkyl- or substituted-aryl-Chloroforrnate, 5 preferably l -chloroethylchldroformate.
Preferably, demethylation is carried out using a chloroformate, such as 1- chloroethylchlorofomnate, in the presence of a base such as Hunig's base (i.e. N,N- dlisopropylethylamine) to form a carbamate intermediate followed by cleavage of the 10 carbamate to yield the intermediate compound III,
Suitably, the solvent employed for carbamate formation is an inert solvent, for example toluene. EDC (ethylene dichloride or 1,2-dichloroethane), MDC (methylene dichloride or 1,2-dichloromethane), xylene; preferably toluene or MDC; most preferably MDC.
15
The cleavage of the carbamate may comprise hydrolysis. The hydrolysis may be carried out by refluxing the carbamate in an alcohol for example methanol, ethanol, isopropyl alcohol or butanol.
20 According to a second aspect of the present invention, there is provided a process for preparing a compound of Formula III comprising demethylating a cyano diol compound of Formula A


5
to obtain a compound of Formula VI
5 and cyclizing the compound of formula VI to obtain the compound of Formula III.
In an embodiment, the demethylating agent is selected from: a chloroformate, such as an alkyi, aryl or substituted alky or substituted aryl chloroformate, or thio chloro formate, to form a carbamate; K[Fe(CN)6]; acetone-DEAD/NH4CI-MeOH; photolytic using Rose 10 Bengal (an alkali metal salt of 4,5,6,7-tetrachloro-2',4',5',7'-tetraiodofluorescein) as a photosensitizing catalyst; H202-H/FeS04; and cyanogen bromide followed by cleavage of the resultant cyanamide (the Braun reaction). Reaction with a dialkyl azodicarboxylate followed by hydrolysis has also been used to effect the demethylation.
15
Preferably, demethylation Is carried out using 1-chloroethylchloroformate in the presence of a base such as Hunig's base (i.e. N,N-diisopropylethylamine) to form a carbamate intermediate followed by cleavage of the carbamate to yield the Intemedlate compound VI.
20
Suitably, the solvent employed for carbamate formation is an inert solvent, for example toluene, EDC (ethylene dichloride or 1,2-dichloroethane), MDC (methylene dichlortde or 1,2-dichloromethane), xylene; preferably toluene or MDC; most preferably MDC.



6
The cleavage of the carbamate may comprise hydrolysis. The hydrolysis of the carbamate may be carried out by refluxing in an alcohol for example methanol, ethanol, isopropyl alcohol or butanol.
5 The cyclizatlori of interlmediate compound VI may be carried out in thepresence of-a an: acid or a combination of mesyl chloride and triethylamine. Optionally, the acid is sulphuric acid, para toluene sulphonic acid, methane sulphonic add,, phosphoric acid or hydrochloric acid.
10 The cycfization reaction using the acid may be carried out in the presence of water, a water misclble solvent, or a mixture thereof The water miscible solvent may be an alcohol or a ketone.
According to a third aspect of the present invention, there is provided a process for 15 preparing a compound of formula II comprising resolving a mixture of the (S)- and (R)- enantiomers of the compound of formula III in the presence of a resolving agent.
20 In an embodiment, the resolving agent is an acid, typically a carboxylic acid. Preferably, the acid is enantiomerically pure. The preferred acid is enantiomerically pure di-para toluyl L-tartaric acid.

7
The acid may be present in a solvent such as an alcohol or an alcohol-water mixture, preferably an alcohol-water mixture.. The alcohol may be methanol, ethanol, n-, . prbpanol, isopropanol orbutanol.
5v Preferably,, the acid selectively reacts with the. desired enantiomer (the S-enantiomer) present in the mixture of enantiomers otthe compound of formula lll' to form an .acid addition salt of the S-ehantiomer of the compound of formula III. Thus the resolution may comprise forming a salt of the S-enantiomer of the compound of formula. III wirth the acid and converting the salt to the free base, i.e. the compound of formula II. the 10 conversion to the free base may comprise reaction with a base, such as an alkali metal hydroxide, for example sodium hydroxide. In an Embodiment, the salt of compound III is purified, for example by crystallisation or recrystallisatlon, prior to being converted to the free base.
15 Typically, the resolution Is carried out by reacting compound III with 1 molar equivalence of the carboxylic acid such as dl-para toluyl L-tartaric acid.
Altematively, the resolution may be carried out by reacting compound III with a mixture of 0.5 molar equivalence of the carboxylic acid (relative to compound III) and 0.5 molar 20 equivalence (relative to compound III) of an inorganic acid, for example hydrochloric acid. - Preferably, the resolution Is carried out In the presence of di-para toluyl L-tartaric acid and hydrochloric acid, most preferably 0.5 molar equivalence of di-para toluyl L- tartaric acid and 0.5 molar equivalence of hydrochloric acid.
25 The acid(s) may be present In a solvent such as water, alcohol, a water-alcohol mixture or a mixture of alcohols. The or each alcohol may be, for example, methanol, ethanol, isopropyl alcohol or butanol. Preferably, the resolution Is carried out In the presence of a water-alcohol mixture.

8
In an embodiment, the compound of formula III is prepared according to a process described above in the first or second aspects of the present invention.
According to another aspect of the present invention, there is provided a process for . 5 •: preparing: escitalopram or. avpharmcaeutically salt thereof, which process comprises preparing compound of fonmula II by a process as described above methylating the compound of formula II, in the priesence. of a methylating agent, and optionally-, converting the escitalopram to the salt thereof. .
10 In an embodiment, the methylating agent is selected from the group consisting of a combination of formaldehyde and formic acid, a combination of paraformaldehyde and sodium borohydride mixture and a combination of a methyl halide with a base, preferably Hunig's base. The halide may be chloride, bromide or iodide.
15 In an embodiment, methylation is carried out using a formaldehyde/fomriic acid combination in the presence of water, a water miscible solvent or a mixture thereof
In another embodiment, methylation is carried out using a paraformaldehyde/sodium borohydride combination in the presence of a solvent such as an alcohol, for example 20 methanol, ethanol, isopropyl alcohol or butanol. The reaction is preferably carried out below 300C, more preferably below 1O0C.
Escitalopram I obtained by the process of the present invention may be further converted to a suitable acid addition salt such as, for example, mesylate, besylate, 25 maleate, citrate, tartarate, oxalate, lactate, gluconate, hydrobromide, sulphate and nitrate. Preferably, escitalopram I is converted to its oxalate salt.
According to further aspects of the present invention, there is provided compound III prepared by a process as described above and compound II prepared by a process as 30 described above.

9
There' is also provided by the present invention, escitalopram or a salt thereof,
particularly the oxalate salt of escitalopram, prepared Py a process as.described above.
5 Accordlngf id another aspect of the prevent jrivention, thefre: is:; provided ^
pharmaceutical cbmpbsition cbmprising escitalopnarn or a salt thereof, particularly the
oxalaW'salt df escitalopram, P'r^^^ by a process as described above, together with
one or more phamiaceutically acceptable excipients. Such excipients are well known
to those skilled in the art.
10
According to another aspect of the present inventicn. t^ere is provided the use of
a process as described above in medicine.
15 According to another aspect of the present invention. there is provided the use of
escitalopram or a salt thereof, particularly the oxalate salt of escitalopram, prepared by
a process as described above In the treatment of depression.
According to another aspect of the present invention, there is provided a method of
20 treating depression In, a patient In need of such treatment, which method comprises .
administering to the patient a therapeutically effective amount of escitalopram or a salt
thereof, particulariy the oxalate salt of escitalopram. prepared by a process as
described above.
25 Detailed Description of the Invention
In accordance with the invention as herein described, there is provided a process for
preparation of escitalopram which is economical, fast and which results in high purity
enantiomers.

The compound of Formula 111 is one of the hitherto unreporte intermediates useful in the process for the preparation of escitalopram as described herein. The compound of 10 Fonmula III may be resolved using an enantiomerically pure acid, typically, di-para toluyl L-tartaric acid in alcohols, preferably an alcohol-water mixture to obtain a di-para toluyl tartrate salt of compound of formula II which may then be converted to a base.
Typically, the resolution is carried out by reacting compound III with 1 equivalence of an 15 enantiomerically pure carboxyllc acid such as di-para toluyl L-tartaric acid.
10
An embodiment of a process for the preparation of escitalopram in accordance with the present invention is exemplified in Scheme 1.:


11
Altematively, the resolution may be carried out by reacting compound III with a mixture
of 0.5 equivalence of an enantiomerically pure carboxylic acid and 0.5 equivalence of.
an inorganic acid, for example hydrochloric acid. When. 0.5 equivalence, of.
enantiomerically pure carboxylic acid Is used alone, the preferred salt of the. optically
5 pure compound II does not precipitate out due to undesired isomer. However, when 0.5
equivalence of Inorganic acid is employed In addition, the undesired isomer of formula
III, preferentially reacts with the inorganic acid and remains in the solution, which-
causes precipitation of the carboxylic acid salt of the desired isomer of formula II.
10 The acid may be present in a solvent such as water, alcohol, for example methanol,
ethanol, Isopropyl alcohol or butanol. The solvent may be present In pure form, in a
mixture of alcohols, in water or In a mixture of water and alcohol. Preferably, the
resolution is earned out in the presence of a water-alcohol mixture.
15 The compound of formula II may be further methylated using suitable methylating
agents to obtain escitalopram I which may then be converted to its pharmaceutically
acceptable acid addition salt.
In an embodiment a suitable methylating agent is selected from the group consisting of
20 fonnaldehyde/formic acid, paraformaldehyde/sodium borohydride and methyl hallde
with a base, preferably Hunig's base. The hallde may be chloride, bromide or Iodide.
In one embodiment, methylation is carried out using formaldehyde / formic acid in the
presence of water, a water miscilble solvent or a mixture thereof.
25
In another embodiment, methylation is carried out using paraformaldehyde/sodium
borohydride in the presence of a solvent such as an alcohol, for example methanol,
ethanol, isopropyl alcohol or butanol. The reaction is preferably carried out below 300C,
more preferably below 100C.
30

12
Escitalopram I obtained by the process of the present invention may be further converted to suitable acid addition salts such as,,for example, mesylate, besylate, maleate, citrate, tartarate, oxalate, lactate, gluconate, hydrobromide,. sulphate and nitrate.. Preferably; Escitalopram I is converted to Its oxalate salt.
5
According to another aspect of the present invention, there is provided processes for preparing a compound of formula III as exemplified in Scheme 2.


13
In one embodiment, citalopram, the compound of Formula IV is demethyiated using a suitable demethylating agent such as a chloroformate, for example an alkyl, aryl or substituted alky 6r substituted aryl chloroformate, preferably l-chloro: ;ethyl 5 chiorofonnate. The demethylation is suitably carried out in a suitable organic solvent to obtain desmethyl citalopram of Formula. III.
Altematfveiy, the compound of Formula III may be prepared by an alternate process wherein a cyanodiol compound of Formula A is subjected to demethylation to obtain a 10 compound of Formula VI, which may then be cyciized, for example under acidic conditions, to afford a compound of Formula III.
Suitably, the demethylating agent employed is selected from: a chloroformate, such as an alkyl, aryl or substituted alky or substituted aryl chloroformate, or thio chloro formate; 15 K [Fe (CN)6]; acetone-DEAD/NH4CMeOH; photolytic using Rose Bengal (an alkali metal salt of 4,5,6,7-tetrachloro-2',4*,5',7'-tetraiodof]uorescein) as a photosensitizing catalyst; H202-H/FeS04; and cyanogen bromide followed by cleavage of the resultant cyanamide (the Braun reaction). Reaction with a dialkyi azodicarboxylate followed by hydrolysis has also been used to effect the demethylation. Reaction of compound A 20 with with a chloroformate results in a carbamate compound VI.
More preferably, demethylation is carried out using 1-chloro ethyl chloroformate in the presence of a base such as Hunig's base (I.e. N,N-diisopropylethylamlne) followed by cleavage of the resultant carbamate to yield intermediate compound VI.
25
Suitably, the solvent employed for carbamate formatlon may be selected from Inert solvents such as, for example, toluene, EDC (ethylene dichloride or 1,2- dlchloroethane), MDC (methylene dichloride or 1,2-dichloromethane), xylene; preferably toluene or MDC; most preferably MDC.

14
The hydrolysis of the carbamate may be carried out by refluxing in. an alcohol for example methanpl, ethanol, isopropyl alcohol or butanol.
The cyclization of interriiediate compound VI may be carried out using acids such as 5 sulphuric add, para toluene sulphonic acid, methane sulphonic acid, phosphoric acid and hydrochloric acid. The reaction may be carried out in the presence of water, a water miscible solvent or in a mixture thereof. The water miscible solvent may be an alcohol or a ketone.
10 In accordance with another aspect of the present invention, a process for the synthesis of escitalopram Is as shown in Scheme 3, wherein a cyano diol of formula A is protected and dehydrated to obtain a compound of Formula VII which is then subjected to epoxidation to obtain a compound of Formula VIII. The compound of Formula VIII is finally cyclised, for example under acidic conditions, to obtain escitalopram. The 15 escitalopram may be converted to a salt thereof.



15
In accordance with still another aspect of the present invention, a process for the synthesis of escitalopram is as shown in Scheme 4, wherein a cyano benzoic acid IX is reacted with a Weinreb amine B in the presence of carbbnyl diimldazole tO:obtain a 5 compound :pf Formula X, ..which is reacted vyith dimethyl propyl amine magnesium chloride tp obtain a cpmpound of Formula XI which is, further treated with 4-fluoro phenyl magnesium bromide In the presence of taddol C to afford a compound of fomiula XII. Compound of Formula XII Is further cyciized to obtain escitalopram.
While emphasis has been placed herein on the specific steps of the preferred process, It will be appreciated that many steps can be made and that many changes can be 15 made In the preferred steps without departing from the principles of the Invention. These and other changes in the preferred steps of the Invention will be apparent to

16
those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be Interpreted merely as illustrative of the invention and not as a limitjatign.
5 The details of the Invention given in the examples Which are provided below .are for illustration only and therefore these examples should hot be. construed to limit the scope of the invention.
Preparation of citalopram base
10
A solution of citalopram hydrobromide (200 kg, 0.49 kmoles), in toluene (300 lit) and water (200 lit) were stirred at room temperature. The mixture was cooled to 20°C, basifted with 10% NaOH solution (100 lit) to pH 9-10 and the phases separated. The aqueous layer was extracted with toluene (2 X 15Olit). The combined organic solutions 15 were washed with water, dried on sodium sulphate, filtered and used for the next step.
Preparation of desmethyl citalopram
The toluene solution containing citalopram base was mixed with 1,2-dichloromethane 20 (400 lit) and cooled to 10-150C. A solution of i-chloro ethyl chloroformate (110.8Kg, 0.77 kmoles) was added to the reaction mass below 20''C. The reaction mass was further stin-ed for 30 minutes at 15-20°C. Diisopropylethyl amine (30.24Kg, 0.23 kmoles) was added to the reaction mixture below 200C and further stirred for 30 minutes. The temperature of the reaction mass was raised to 60-650C and maintained 25 for 2-3 hrs. The reaction mass was diluted with methanol (320 lit) at 60-65''C, heated further for 2-4 hrs' at 60-65''C and evaporated. The reaction mass was cooled to 25- 300C, diluted with water (480 lit) and stirred for 30 minutes. The phases were separated, aqueous layer was extracted with toluene (2 X 200 lit) and pH of the aqueous layer was adjusted to 9-10 with ammonia solution (320 lit). Toluene (400 lit) 30 was added and the reaction mass stirred for 30 minutes. The organic layer was

17
separated. Aqueous layer was extracted with toluene (2 X 200 lit). The combined
toluene layer was washed with water, followed by brine. The toluene layer was dried on
sodium sulphate, .filtered and stirred with charcoal (15 kg). The reaction.mass was.,
filtered and evaporated under reduced pressure to afford the title compound. Yield
5 140kg. 91.5%
Preparation of (+)-desmethyl citalopram DPTTA salt
Desmethyi citalopram (140kg, 0.45kmoles) was dissolved in isopropyl alcohol (700 lit)
10 at room temperature and heated to 450C. Di-p-toluoyl-L-tartaric acid (174Kg,
0.43kmoles) was added to the reaction mass at 450C and stirred further for 2-3 hrs at
same temperature. Distilled water (140lit) was added slowly over 1 hr and stirring
continued for 1 hour more. The reaction mass was cooled to 25-300C, and solid
Isolated by filtration. The compound was further purified by crystallization in 6 volumes
15 of isopropyl alcohol :water (isopropyl alcohol: water 5:1) to yield title compound.
Yield = 70kg, 44.6%
Chiral purity:- >99%
Preparation of (-i-).de5methyl citalopram base
20
The salt obtained in the previous step, was stirred in a mixture of 1,2-dichloromethane
(130llt) and water (65llt). The pH of the reaction mass was adjusted to 9-10 by using
10% NaOH solution (- 65 lit). The phases were separated. The aqueous layer was
extracted with 1,2-dichloromethane (2 X 100 lit). The combined 1,2-dichloromethane
25 layers were washed with water, dried on sodium sulphate, filtered and evaporated
under reduced pressure to afford the title compound.
Preparation of escitalopram base

18
Example 1 - Methylation using formaldehyde/formic acid
The residue obtained in the previous step was stirred in water (210lit). A solution of
formaldehyde (27.25 kg, 0.9 kmoles) was added to the reaction mass followed by
addition of formic acid (15.6kg, 0.34km61es): The resultant mass was;heated 80-900C :
5 cooled to 25-300C and acidified .with concentrated hydrochloric acid; (30.ollt); The
aqueous layer was washed with toluene (50 lit) and basified with 10% NaOH solution to
reaqh a pH of 9-10 maintaining temperature below 20°C. The reaction mass was stirred
with 1,2-dichloromethane (200 lit) and phases were separated. The aqueous layer was
extracted with 1,2-dichloromethane (2 X 100 lit). The combined organic layers were
10 washed with water, dried on sodium sulphate, filtered and evaporated to dryness.
Example 2 - Methylation using paraformaldehyde/sodium borohydride
(+)-Desmethyl citalopram base (lOgms, 0.032 moles) was dissolved in 50 ml
methanol. A solution of paraformaldehyde (1.16 gms, 0.039 moles) was added to the
15 reaction mass at 25-30C and stin-ed further for 2 hours. The reaction mass was cooled
to 0°C and sodium borohydride (1.47 gms, 0.039 moles) was added maintaining
temperature below 5°C. The reaction mass was further stirred for 1 hour at 0-5°C and
evaporated under reduced pressure below 350C. The residue obtained was stirred in
30 ml water and extracted with 1,2-dichloromethane (3 x 50 ml) . The combined 1,2- ,
20 dichloromethane layer was washed with water, dried on sodium sulfate, filtered and the
clear filtrate was evaporated under reduced pressure below 350C to yield the title
compound 8.0 gms, 76.55%.
Chiral purity:- > 99.5%
25 Preparation of escitalopram oxalate
The residue obtained in Example 1 was dissolved in acetone (120 lit) at 25-30®C. A
solution of oxalic acid dihydrate (17Kg, 0.135kmoles) in acetone (34 lit) was introduced
over 30 minutes. The reaction mass was stirred for 2 hours, cooled to 10®C and further
30 stirred for 1 hour. The solid obtained was Isolated by filtration, washed with acetone (2
X 40 lit) and dried in a vacuum oven for 4-5 hrs at 50-55°C to obtain the title compound.

19
Yield : 40.0 kg , 98.57% Ghiral purity :- > 99.5%
Preparation of (+)-desmethyl citalopram DPTTA salt
.5.
besnriethyl citalopram (140kg, 0.45kmoles) Was dissolved in isopropyl alcohol (700lit) at room temperature and heated to 450C. DI-p-toiuoyl-L-tartaric acid (91.22Kg, 0.225 kmoles) was added to the reaction mass at 450C and stirred further for 30 minues at same temperature. A solution of concentrated hydrochloric acid (22.89Kg, 0.225 10 kmoles) was introduced Into the reaction mass at 40-45°C. The resultant mixture was stirred at 40-450C for 2-3 hrs and at room temperature for 1 hr. The solid obtained was isolated by filtration and washed with isopropyl alcohol. The compound was stirred in 700 litres of Isopropyl alcohol at reflux. Distilled water was slowly introduced at reflux temperature until a clear solution was observed. The reaction mass was cooled to room 15 temperature and stin-ed at 25 - 300C for 1 hour. The solid was isolated by filtration, washed with Isopropyl alcohol and dried to yield title compound.
Yield = 70kg, 43.4%
Chiral purity:- >99%
20 It will be appreciated that the invention may be modified within the scope of the appended claims.

10
in the presence of a denriethylating agent.
2. A process according to claim 1, wherein the demethylating agent is a chloroformate.
15
3. A process according to claim 2, wherein the chloroformate is an alkyl-, aryl-, substituted-alkyl- or substituted-aryl-chloroformate. preferably 1- chloroethylchloroformate.
20
CLAIMS
1. A process for preparing a compound of formula III


comprising demethylating citalopram of Formula IV

21
4. A process according to claim 1, wherein demethylation is canied out using 1 chloroethylchloroformate in the presence of a base to form a carbamate intermediate followed by cleavage of the carbamate to yield the intermediate corripound III.
5
5. A process according to claim 4, wherein the base is N,N-diisbpropyliethylamine.
6. A process according to claim 4 or 5. wherein the solvent employed for carbamate formation is an inert solvent selected from toluene, 1,2-dichioroethane, 1,2-
10 dichloromethane or xylene.
7. A process according to claim 4. 5 or 6, wherein the cleavage of the carbamate comprises hydrolysis involving refluxing the carbamate in an alcohol.
15 8. A process according to claim 7, wherein the alcohol is methanol, ethanol, isopropyl alcohol or butanol.
9. A process for preparing a compound of Formula III comprising demethylating a cyano diol compound of Formula A

to obtain a compound of Formula VI

and cyclizing the compound of fonnula VI to obtain the compound of Fomiula III.
5 10, A process according to claim 9, wherein the demethylating agent is selectec
from: a chloroformate; a substituted chloroformate-carbamate; K[Fe(CN)6]; acetone
DEAD/NH4CI-MeOH; H202-H+/FeS04; and cyanogen bromide.
11. A process according to claim 10, wherein the chloroformate is an alkyl, aryl or
10 substituted alky or substituted aryl chloroformate, or thio chloro formate.
12. A process according to claim 11, wherein demethylation is earned out using 1
chloroethylchlorofomnate in the presence of a base to form a carbamate intermediate
followed by cleavage of the carbamate to yield the intermediate compound VL
15
13. A process according to claim 12, wherein the base is N,N-diisopropylethylamine
14. A process according to claim 12 or 13, wherein the solvent employed foi
carbamate formation is an Inert solvent selected from toluene, 1,2-dichloroethane, 1,2
20 dichloromethane or xylene.
15. A process according to claim 12, 13 or 14, wherein the cleavage of the
carbamate comprises hydrolysis involving refluxing in an alcohol.


23
16. A process according to claim 15, wherein the alcohol is selected from methanol, ethanol. isopropyl alcohol and butanol,
17. A process according to any one of claims 9 to 16, wherein the cyclization of 5 intermediate compound VI is carried out in the presence of a an acid or 5 combination
of mesyl chloride and triethylamine.
18. A process according to claim 17, wherein the acid is sulphuric acid, para toluene sulphonic acid, methane sulphonic acid, phosphoric acid or hydrochloric acid.
10
19.. A process according to claim 17 or 18, wherein the cyclization reaction using the acid is carried out in the presence of water, a water miscible solvent, or a mixture thereof.
15 20. A process according to claim 19, wherein the water miscible solvent is an alcohol or a ketone.
21. A process for preparing a compound of formula II comprising resolving a mixture of the (S)- and (R)-enantiomers of the compound of fonmula III


Resolution
in the presence of a resolving agent

24
22. A. process according to. claim 21, ..wherein the. resolving agent is ..an
enantioerically pure carboxylic acid.
23. A process according to claim 22, wherein the acid is di-para toluyl L^artaric acid.:
5
24. A process according to claim 22 or 23, wherein the acid is present in a solvent
comprising an alcohol or an alcohol-water mixture.
25. A process according to claim 24, wherein the solvent is an alcohol-water mixture
10 and the alcohol is selected from methanol, ethanol, n-propanol, isopropanol or butanol.
26. A process according to any one of claims 21 to 25, wherein the resolution
comprises forming a salt of the S-enantiomer of the compound of formula III with the
acid and converting the salt to the compound of formula II.
15
27. A process according to claim 26, wherein the conversion to the free base
comprises reaction with a base.
28. A process according to claim 27, wherein.the base is sodium hydroxide.
20
29. A process according to claim 26, 27 or 28, wherein the salt of compound III is
purified prior to being converted to the compound of formula II.
30. A process according to any one of claims 21 to 29, wherein the resolution is
25 carried out by reacting compound III with 1 molar equivalence of the carboxylic acid
relative to compound III.

25
31. A process according to any one of claims 21 to 29, wherein the resolution: is
earned out by reacting compound III with a mixture of 0.5 molar equivalence of the:
carboxylic acid relative to compound Ml and 0.5 molar equivalence of an inorganic acid .
relative to compound III
5
32. A process according to claim 31, wherein the inorganic acid is hydrochloric acid:
33. A process according to claim 30, 31 or 32, wherein the or each acid is present in
a solvent selected from water, alcohol, a water-alcohol mixture or a mixture of alcohols.
10
34. A process according to claim 33. wherein the resolution is carried out in the
presence of a water-alcohol mixture.
35. A process according to any one of claims 21 to 34, wherein the compound of
15 formula III is prepared by a process according to any one of claims 1 to 20.
36. A process for preparing escitalopram or a pharmcaeutically salt thereof, which
process comprises preparing a compound of formula il by a process according to any
one of claims 21 to 35, methylating the compound of formula II in the presence of a
20 methylating agent, and optionally converting the escitalopram to the salt thereof.
37. A process according to claim 36, wherein the methylating agent is selected from
the group consisting of a combination of formaldehyde and formic acid, a combination
of parafonnaldehyde and sodium borohydride mixture and a combination of a methyl
25 hallde with a base.
38. A process according to claim 36, wherein methylation is carried out using a
formaldehyde/formic acid combination in the presence of water, a water miscible
solvent or a mixture thereof.

26
39. A process according to claim 36, wherein methylation is carried out using a paraforrtialdehyde/sodium borohydride combination in the presence of a solvent selected from methanol, ethanol, isopropyl alcohol or butanol.
5
40. A process according to any. one of claims 36 to 39, wherein estltalopram is converted to an acid addition salt thereof selected from the mesylate, besylate, maleate, citrate, tartarate, oxalate, lactate, gluconate, hydrobromide, sulphate or nitrate salt.
10
41. A process according to claim 40, wherein escitalopram is converted to its oxalate salt.
42. A process substantially as herein described with reference to the examples.
15
43. Escitalopram or a salt thereof substantially as herein described with reference to the examples.