FORM 2
THE PATENT ACT 1970
(39 OF 1970)
& THE PATENTS RULES.2003

TITLE:-NOVEL PROCESS FOR THE PREPARATION OF
CITALOPRAM HYDROBOZOMIDE
APPLICANTS:-
NAME:-DANDINI R.PAI
NATIONALITY

INDIAN
2)MR.SANDESH G.VISHWASZAO
INDIAN
COMPLETE SPECIFICATION

3>DR.JITENDRA SURYAVANSHI
4)DEEPNANDAN DUBHAS
THE FOLLOWING SPECIFICATION PARTICULERLT DESCRIBES THE
INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

Novel process for the preparation of Citalopram Hydrobromide
The present invention relates to a novel process for the preparation of citalqpram hydrobromide an anti-depressant. Moreover the present invention particularly relates to a process for the preparation of 1-[3-(dimethylamino) propyl]-1-(4-fluorophenyl)-1, 3-dinydro-5-isobenzofurancarbonitrile of formula (I)
Background of the Invention
Citalopram is well-known antidepressant driJQ that has now been on the market for some years and has the following structure

It is a selective, centrally acting serotonin (5-hydroxytryptamine; 5-HT) reuptake . inhibitor, accordingly having antidepressant activities. The antidepressant activity of the compound has been reported in several publications such as J.Hyttel ProgNeuro-Psychopharmacol.and Biol Psychiat, 1982, 6,277-295 and A.Gravem Acta IPsychiatr Scand.1987, 75 478-486 The compounds has further been disclosed to show effects in the treatment of dementia and cerebrovascular disorders, EP-A-474580.
Citalopram was first disclosed in DE 2,657.013 corresponding to US Pat. No. 4,136,193. This patent publication describes the preparation of citaloipram by reacting 1-(4-fluorophenyl)-1, 3-dihydro ^5" isobanzofurancarbonitrile with 3-(N( N-dimethylamino) propyl-chloride in the presence of methylsulfinylmethide as condensing agent. The starting material was prepared from the corresponding 5-bromo derivatives by reaction with cuprous cynide.
According to the method, which is only outlined in general term, citaloipram may be obtained by ring closure of
4-bromo-alpha 1-[3-(dimethylamino) propyl]-alpha i-(4-fluorophenyl)-1, 2-benzenebis (methanol) of the formula (II) in the presence of a dehydrating agent and subsequent exchange of the 5-bromo group with cuprous cyanide. The starting material of formula (II) is obtained from 5-brorTiophthalide by two

successive Grignard reactions, i.e. with 4-fluo,rophenykmagnesium chloride and N, N-dimethylaminopropyl magnesium chloride, respectively.
Citalopram may be prepared by the process described in US patent No. 4650884, according to which 5-cyanophthalide is Subjected to two successive Grignard reaction i.e. with 4-fluorophenyl magnesium chloride and N, N -dimethyl amminopropyl magnesium chloride resp.and the resulting compound of the formula (III) is subjected to a ring closure reaction by dehydration with strong sulphuric acid.

Other processes involve: -
Conversion of a 5-amido or 5-ester group to a 5- cyano group (W09819513) Conversion of 5- amino group to a 5- cyano group (WQ9819512) Conversion of a 5-formyl group to a 5- cyano group (WO9900548) Conversion of a 5- oxazolinyl or 5-thiazolinyl group to a, 5- cyano group (WO0023431)
Further processes which are disclosed in International patent application Nos. WO98019513 relate to method wherejn a 5- amino, 5-carboxy-, or 5-ijsec.aminocarbonyl) phthalide is subjected to two successive Grignard reactions, ring closure and conversion of the resulting 1,3-dihydroisobenzofuranderivative to the corresponding 1-[3-(dimethylamino) propyl]-1-(4-fluorophenyl)-1, 3-dihydro-5-isobenzofurancarbonitrile i.e. citalopram. International patent application No. W098()19511 discloses a process for the manufacture of citalopram wherein a (4-substituted-2-hydroxy-methj/l-phenyl)-(4-fluorophenyl) methanol is subjected to ring closure and the resulting 5-substituted 1-(4-fluorophenyl) 5-1, 3-dihydrc)jsobenzofuran converted to th© corresponding 5-cyano derivative which is alkylated with a (3-diiinethylamino) propylhalogenide in order to obtain citalopram.

As per earlier reports published in patents and literatures,

(VI)
5-cyanophthalide (IV) is treated with bromoflurobenzene (V) and dimethylamino propyl chloride (VI) to get4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3~(hydroxymethyl)benzonitrile also called as diol base. But since above diol base is an oily residue it is isolated as hydrochloride salt. In the next step of cyclisation it is again converted to freebase before converting it to cyclised product using polyphosphoric acid. This Cit cyano-HCI is then converted again to its free base and treated with HBr to obtain crude hydro bromide salt followed by purification in IPA as citalopram -HBr salt is an active pharmaceutical^ acceptable salt.
Object of the invention
1 The main object of the invention is to provide a novel process for the preparation of Citalopram hydrobromide.
2 Another object of the present invention is to provide a novel process for the preparation of Citalopram hydrobromide with minimum number of steps.
3 Further object of the present invention is to provide a novel process for the preparation of Citalopram hydrobromide with good isolation process.
4 Yet another object of present invention is to provide a novel process for the preparation of Citalopram hydrobromidewhich avoids the use of hazardous reagents such as polyphosphoric acid.

5 Further object of the present invention is to provide a novel process which is simple, efficient, cost effective and environment friendly.
Summary of the Invention
Accordingly the present invention provides a novel one-pot process for the preparation of citaiopram hydro bromide of formula (I)


HBr

Formula (!)

As per new developed process diol base is prepared using the process, known in the literature, which is herein described. This diol base is then Converted directly to Citalopram hydro bromide with or without purification without forming hydrochloride salt /base ruling out multiple steps.
Hence in one aspect the present invention provides a one-pot synthesis of Citalopram hydro bromide.
In another aspect the present invention relates to a yield improvement process as the number of steps is reduced.
In a further aspect, the present invention relates to an cost effective process which does not require making of hydrochloride and repeatedly conversion of acid salt to free base hence saving the cost of solvents, reagents, alkali and acid.
In another aspect the present invention can be commercially viable as the process is one step and hence by increasing batch size, overheads and time consumtion can be minimized.
In yet another aspect the present process related to environmental friendly process, which does not involve the use of hazardous and toxic reagents ant solvents.
The improved process for the preparation of Citalopram and its conversion to pharmaceutical^ acceptable salt are described in detail with the specific embodiments/conditions hereafter.
It has now been found that new condition/process makes it possible to convert diol base to Citalopram and its acceptable hydro bromide salt in one^pot

process and thereby eliminating the isolation of acid salt and base, making the process industrially more feasible.
Consequently, the invention relates to a novel process of Citalopram hydro bromide by reacting 4-[4-(dimethy!amino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile with IPA-HBr, optionally with IPA and cone. HBr or HBr gas in a single step.
Accordingly, Cit-Bzn prepared is reacted in IPA with cone. HBr at reflux temperature of solvent for 4-5 hrs. After reflux, it is cooled slowly to room temperature and then to 0-5 deg. Product citalopram hydrobromide is obtained by filtration followed by drying.
According to present invention the cyclizatiori of diol freebase obtained takes place in-situ in presence of HBr and yields the stable Citalopram as its HBr salt. The acid salt is precipitate from the reaction medium and conveniently isolated in substantially pure form.
The acid catalysed cyclization of diol freebase and its HBr salt preparation is preferably carried out at reflux temperature for a period of 4-5 hours.
According to the above process of the present invention, where the diol free biase is reacted with HBr in IPA, the reaction is carried out at temperature range osf about 50°C to 90°C for about 4-5hourspreferable about 4.5hrs.at reflux temperature. In this step of the process, where acid HBr used as cyclization reagent as well as reactant and hence It 'is used 'in excess.
Although the reaction temperature is at reflux of the solvent impurity generation is limited.
In another embodiment of the present invention provides an improved industrial process for the preparation of Citalopram and its HBr salt, as it eliminates number of intermediates there by minimizing overheads, manpower and time consumption.
The present invention also provides a simple and one pot process for the preparation of Citalopram and its pharmaceutically acceptable salt in a operation-wise flexible and with excellent reproducibility making the process practical and plant friendly.
In a further embodiment the present invention provides a process for the preparation of Citalopram hydro bromide from a commonly used solvent like IPA making the process economical and environmental friendly.

Exampie-1
Preparation of 4-[-(dimethylamino)-l-(4-fluorophenyl)-l- hydroxybuty]-3-(hydroxymethyl) benzonitrile-
A) Grigrurd-l
Under a nitrogen atmosphere, turnings of magnesium were dispersed in THF and Iodine was added. Under a nitrogen atmosphere, a solution of 4-fluorobrobenzene in THF was added through addition jar initially at room temperature at such a rate gentle reflux (60-65°c) is maintained. Continue the reflux for 1 .Oh after the addition. Cool reaction mixture to roorn temperature
B) Grignard-II
Under a nitrogen atmosphere, turnings of magnesium were dispersed in THF and Iodine crystal and 4-fluorobromobenzene were added for initiation of reaction. Heated reaction mixture slowly to 50 °c. added toluene solution of DMAPCI in such a way as to maintain reflux. Continue reflux for 1 .Oh after the addition. Cooled the reaction mixture to room temperature.
C) Under nitrogen atmosphere, added 5-phthalide and Toluene in reaction-flask and cool it to -5 to -10°C. Added Grignard - I at -5 to-10 °C and stirred reaction mixture for 2.Oh at-5 to-10°C. Added Grignard - II at-5 to-10°C and stirred it for 2.Oh. Poured the reaction mixture in aqueous solution of NH4CI and stirred for 15 minute. Separated the layers. In organic layer added acetic acid and stirred it for 1 Oh and separated the layers. Adjusted Ph of aqueous layer to 8-9 with caustic solution stirred it for 30 min. at room temperature. Extracted the product in ethyl acetate. On recovery of ethyl acetate to get targeted product.
Example-2
Preparation of Citalopram hydrobromid: -
In the product obtained from example-1 added IPA and hydrobromic acid and reflux the reaction mixture for 4to5 hrs. Cooled it slowly to room temperature'and then to 0 to5 °C. Product obtained by filtration. Residue washed with chilled IPA to obtained citalopram hydro bromide on drying.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention

may be embodied in other specific forms without departing from the essentia! attributes there of, and it is there fore desired that the present embodiments and examples may be considered in all respects as illustrative and not restrictive, ref0rence being made to the appended claims rather than to the foregoing description and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced there in.
Claims;
We claim: -
1) A Novel process for the preparation of Citalopram hydrobromide of formula (I)
comprising
a) A reaction of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-_1-hydroxybutyl]-3-
(hydroxymethyl) benzonitrile with an acid in an alcoholic solvent in a single vessel without isolation of hydrochloride salt/base into acceptable Citalopram salt and
b) Isolation of the said Citalopram hydrobromide at lower temperature by way of
filtration.
2) The process for the preparation of Citalopram hydrobromide as claimed in
claim 1, wherein said acid catalyst is a mineral acid
3) The process for the preparation of Citalopram hydrobromide as claimed in
claim 2, wherein said acid catalyst is hydrobromic acid.
4) The process as claimed in any one of the preceding claims, where in 4-[4-
(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile is cyclised in-situ at 60-90°C and cyclised in presence hydrobromide
5) The process as claimed in any one of the above claim wherein said cyclisatton
is carried out at reflux temperature for 4 to 5 hrs.
6) The process as claimed in claim 3, wherein said solvent 2-propanol used in
cyclization step is ranging from 1 volume to 20 volumes.
7) The process as claimed in claim 2, wherein the mineral acid hydrobromide is
used as solution form in 2-propanol (i.e.lPA-HBr), optionally with IPA and cone. HBr or HBr gas.
8) The process as claimed in any one of the preceding claim wherein the
strength of said hydrobromide acid used is about 30 to 35 %

BA) The process as claimed in claim 2 wherein said mineral acid is used in excess with respect to. 4-[4-(dimethylarnino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3~(hydroxymethyl) benzonitrile.
9) The process as claimed in any one of the preceding claim wherein said
process is carried out in acid condition,
10) The process as claimed in claim 1 wherein said Citalopram hydrobromide is
isolated by way of filtration at lower temperature ranging from -5CC to 10°C,
preferably at0 to 5°C.