Title of Invention

"AN IMPROVED PROCESS FOR THE PREPARATION OF CITALOPRAM"

Abstract The present invention relates to an improved and industrially advantageous process for the preparation of citalopram and pharmaceutically acceptable acid addition salt thereof.
Full Text The present invention relates to an improved and industrially advantageous process for the preparation of citalopram of Formula I, as shown in the accompanied drawings, and pharmaceutically acceptable acid addition salt thereof.
Citalopram is a well known anti-depressant drug and is chemically known as 1-[3-(dimethylamino)propyl]-1 -(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile. It is a selective centrally acting serotonin (5-hydroxy-tryptamine; 5-HT) reuptake inhibitor and is known from the US Pat. No. 4,136,193 assigned to Kafalas of Germany. The compound is further known to have effects for the treatment of dementia and cerebrovascular disorders as disclosed in the European Patent No. 474,580.
A method for preparing citalopram is described in the US Pat. No. 4,136,193, according to which 4-halo-2-(hydroxymethyl)phenyl-(4'-fluorophenyl)-(3-dimethylaminopropyl)methanol of Formula II, as shown in the accompanied drawings, wherein X represents halogen, is reacted with a dehydrating agent to effect ring closure for obtaining 5-halophthalane compound of Formula III, as shown in the accompanied drawings wherein X represents halogen. The compound of Formula III is reacted with cuprous cyanide in an inert organic solvent to give citalopram of Formula I, as shown in the accompanied drawings. However, the process is unsuitable for accomplishment on an industrial scale since exchange reaction outlined in US Patent No. 4,136,193 does not go to completion even after, refluxing the 5-halophthalan compound and cuprous cyanide overnight in dimethyl formamide thereby making it very difficult to separate the resulting citalopram from the corresponding 5-halo compound.
According to the PCT application WO 00/13648, citalopram is prepared by reacting the 5-halophthalane compound of Formula III, as shown in the accompanied drawings wherein X is bromo or iodo or the corresponding triflate compound with a cyanide source in the presence of a palladium catalyst and a catalytic amount of Cu+ or Zn2+ or with zinc cyanide in the presence of a palladium catalyst, and isolation of the corresponding 5-cyano phthalane compound i.e. citalopram. The cyanide source is chosen from potassium cyanide, sodium cyanide, ammonium cyanide and tetra alkyl ammonium cyanide.

A variant of this process is described in the PCT application WO 00/11926 wherein the cyanide exchange is achieved with a cyanide source in the presence of a nickel catalyst.
The processes described in the above PCT applications for the manufacture of citalopram suffer from the following limitations and for various reasons stated below are not suitable for commercial purposes.
The reaction is carried out in the presence of palladium or nickel complexes which are very expensive, inconvenient to handle at commercial scale as they are air sensitive and light sensitive, highly flammable, cancer suspect agents and have limited commercial availability.
The reaction conditions are unsafe and are burdened with the risk of explosion and fire as the processes make use of solvents like tetrahydrofuran and diethyl ether.
Another process reported recently in PCT application WO 01/02383 comprises conversion of 5-halophthalane of Formula III to the corresponding Grignard reagent which is then converted to citalopram via reaction with compounds containing a cyano group bound to a leaving group. An alternative process involves obtaining an aldehyde from the Grignard reagent and its transformation to cyano group via an oxime or hydrazone intermediate.
The process described in the PCT application WO 01/02383 involves many steps and makes use of raw materials which are not available commercially.
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Hence, none of the processes described heretofore are completely satisfactory at a commercial scale.
it is an object of the present invention to solve the problems associated with the prior art and to provide an efficient and commercially viable process for producing citalopram via an improved cyano exchange process. The process is simple and provides obvious benefits with respect to economics and convenience to operate at a commercial scale.

In a further aspect the invention relates to the above process which produces s-enantiomer of Formula I.
More particularly, the present invention relates to a process for the preparation of citalopram of Formula I, as shown in the accompanied drawings, comprising reacting 5-halophthalane compound of Formula III, as shown in the accompanied drawings wherein X is bromo or iodo with a cyanide source in a suitable solvent, in the presence of an organic base and isolating corresponding 5-cyano compound i.e. citalopram of Formula I as the free base or a pharmaceutically acceptable acid addition salt thereof.
The cyanide source may be any source which is a cyanide ion donor. Preferred sources are potassium cyanide, sodium cyanide, ammonium cyanide, cuprous cyanide, zinc cyanide, tetra-alkylammonium cyanide or mixtures thereof. More preferred sources are cuprous cyanide and zinc cyanide. The cyanide source may be used in stoichiometric amount or in excess. Preferably, 1-2 molar equivalent per equivalent of compound of Formula III is used.
The term "suitable solvent" means any polar aprotic solvent. Preferably, the solvent may be selected from the group consisting of dimethylformamide, dimethylacetamide, N-methylpyrrolidone, N-methylpiperidinone, 1,3-dimethyl-3,4,5,6-tetrahydro(2H) pyrimidinone (DMPU) or mixtures thereof.
Suitable organic base includes trimethylamine, triethylamine, diisopropylamine, picolines, pyridine, pyridine derivatives such as 2,6-lutidine, 4-methylpyridine morpholine, morpholine derivatives, quinoline, 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU), piperidine, aryl substituted amines such as aniline and dicyclohexylamine or mixtures thereof. Preferably, pyridine or quinoline is used. The organic base may be used in stoichiometric amount or in excess. Preferably, 1 to 5 molar equivalents per equivalent of starting material of Formula III is used.
We believe that nitrogen containing organic base plays a crucial role and facilitates the completion of reaction. The base is believed to form a complex of Formula IV in case of cuprous cyanide, as shown in the accompanied drawings, with the cyanide

source which facilitates the exchange of halogen with nitrile via a transient state which involves a coordination complex of formula V, as shown in the accompanied drawings.
The reaction is generally carried out at a temperature ranging from 120°C to 170°C, preferably, at 135°C to 145°C. The reaction completion may take 3 hours to several hours.
The intermediate of Formula III wherein X is bromo or iodo may be prepared from bromo or iodophthalide respectively, as described in US Pat. No. 4,136,193.
Citalopram of Formula I may be obtained as the free base or converted into its pharmaceutically acceptable acid addition salts. Examples of such salts include those formed with organic acids such as maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, aspartic, stearic, palmitic, itaconic, glycolic, glutamic and benzene sulfonic acids or with inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acid.
The acid addition salts of the compounds may be prepared by methods known in the art. The base is reacted with either the calculated amount of acid in a water miscible solvent such as ethanol or acetone and the salt isolated after concentration and cooling or with an excess of the acid in a water immiscible solvent such as ether, dichloromethane or toluene with the salt separating out spontaneously.
The invention is further illustrated by the following example which should not be construed to be limiting the scope of the present invention.
EXAMPLE 1 PREPARATION OF CITALOPRAM BASE
1-(4'-Fluorophenyl)-1-(3-dimethylaminopropyl)-5-iodophthalne (7.5g, 18 mmol), cuprous cyanide powder (2.4g, 27 mmol) and pyridine (5.6 g, 71 mmol) were added to dimethylformamide (40ml) and the mixture so obtained was heated to 140-141°C. The reaction mixture was further stirred at 140-145°C for about 3 hours. The reaction mixture was then cooled to 35°C, diluted with a cooled mixture of toluene and water. The organic layer was separated, washed with ammonia solution and water. The toluene was recovered completely under vacuum to get the product as a free base in the form of an oil (6.0 g)
PREPARATION OF CITALOPRAM HYDROBROMIDE
Toluene (40ml) was added to the above obtained free base of citalopram (6.0 g) and stirred to obtain a homogeneous solution. To this solution was added aqueous HBr solution (48%, 3.6 gm). The reaction mixture so obtained was then stirred for about 4 hours at 5-10°C and toluene layer was decanted off. Fresh toluene (40ml) was added to it and further stirred at 5-10°C. The separated solid was filtered, washed with toluene and dried to obtain citalopram hydrobromide (6.7g, yield 93.7%, purity >98,5% by HPLC) as a crystalline powder.





WE CLAIM :
1. A process for the preparation of citalopram of Formula I,
(Formula Removed)
FORMULA I
comprising reacting 5-halophthalane compound of Formula
(Formula Removed)
2.
FORMULA III
wherein X is bromo or iodo with a cyanide source in a suitable organic solvent in the presence of an organic base and isolating the cyano compound (citalopram) of Formula I, as the free base or as a pharmaceutically acceptable salt thereof.
The process as claimed in claim 1 wherein cyanide source is selected from the group consisting of potassium cyanide, sodium cyanide, ammonium cyanide, cuprous cyanide, zinc cyanide, ammonium cyanide, tetra alkylammonium cyanide, and mixtures thereof.
3. The process as claimed in claim 1 wherein suitable organic solvent is selected
from the group consisting of dimethylformamide, dimethylacetamide, N-
methylpyrrolidone, N-methylpiperidinone, 1,3-dimethyl-3,4,5,6-tetrahydro (2H)
pyrimidinone (DMPU) and mixtures thereof.
4. The process as claimed in claim 3 wherein suitable organic solvent is
dimethylformamide.
5. The process as claimed in claim 1 wherein organic base is selected from the
group consisting of trimethylamine, triethylamine, diisopropylamine, picolines,
pyridine, pyridine derivatives (wherein pyridine derivatives are 2,6-lutidine or
4-methyl pyridine), quinoline, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU),
piperidine, aryl substituted amines (e.g. aniline), dicyclohexylamine, and
mixtures thereof.
6. The process as claimed in claim 5 wherein organic base is pyridine or
quinoline.
7. The process as claimed in claim 1 wherein the pharmaceutically acceptable
salt is citalopram hydrobromide.
8. The process for the preparation of citalopram, substantially as herein
described and illustrated by the examples herein.


Documents:

264-del-2001-abstract.pdf

264-del-2001-claims.pdf

264-del-2001-correspondence-others.pdf

264-del-2001-correspondence-po.pdf

264-del-2001-description (complete).pdf

264-del-2001-drawings.pdf

264-del-2001-form-1.pdf

264-del-2001-form-19.pdf

264-del-2001-form-2.pdf

264-del-2001-form-3.pdf


Patent Number 226563
Indian Patent Application Number 264/DEL/2001
PG Journal Number 01/2009
Publication Date 02-Jan-2009
Grant Date 18-Dec-2008
Date of Filing 09-Mar-2001
Name of Patentee RANBAXY LABORATORIES LIMITED
Applicant Address 19 NEHRU PLACE, NEW DELHI- 110 019, INDIA.
Inventors:
# Inventor's Name Inventor's Address
1 YATENDRA KUMAR PLOT NO.20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001 (HARYANA), INDIA.
2 SWARGAM SATHYANARAYANA PLOT NO.20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001 (HARYANA), INDIA.
3 BAKTHAVATHSALAN VIJAYARAGHAVAN PLOT NO.20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001 (HARYANA), INDIA.
4 SUJAY BISWAS PLOT NO.20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001 (HARYANA), INDIA.
5 TARUN KANT SHARMA PLOT NO.20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001 (HARYANA), INDIA.
PCT International Classification Number A61K 31/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA