Preparation of pure citalopram

Details Preparation of pure citalopram Preparation of pure citalopram

2003-06-09

2004-08-24

Owens, Amelia A. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S469000

Reexamination Certificate

active

06781003

ABSTRACT:

CROSS REFERENCE TO RELATED APPLICATIONS
Indian Patent Application
Filing Date Mar. 19, 2003
Application No. 225/MAS/2003
Status Not issued
STATEMENTS REGARDING FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
Not Applicable
BACKGROUND OF THE INVENTION
Citalopram of Formula I is a well known antidepressant drug that has now been on the market for several years and is chemically known as 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile.
Citalopram is a selective centrally acting serotonin reuptake inhibitor and it has further been shown to be effective in the treatment of dementia and cerebrovascular disorder as described in European Patent 0 474 580.
Citalopram was first disclosed in U.S. Pat. No. 4,136,193. This patent publication outlines a process for preparation of Citalopram from corresponding 5-bromo derivative by reaction with cuprous cyanide. Further, variants of this method are disclosed in PCT Applications, WO 00/13648 and WO 00/11926 wherein the exchange of 5-nalogen or 5-CF
3
—(CF
2
)
n
—SO
2
—O—with cyano is achieved with cyanide source in the presence of palladium or nickel catalyst.
The processes comprising exchange of 5halogen with cyano as described above have been found to give high molecular weight impurities and desmethyl citalopram in unacceptable quantities. PCT Application WO 01/47877 describes a process of film distillation to remove high molecular weight impurities formed during cyanide exchange reaction, however, desmethyl citalopram distils along with Citalopram. Removal of desmethyl impurity by usual purification procedures, such as recrystallization, distillation, reprecipitation, washing, salt formation or the like, is difficult and requires extensive and expensive purification processes.
PCT Application WO 01/45483 teaches an acylation method that effectively removes desmethyl citalopram. This comprises treating the crude product with an acylating agent such as an acid anhydride or an acid halide wherein desmethyl citalopram forms an amide derivative and is removed by acid/base wash followed by crystallization to obtain pure Citalopram. While desmethyl citalopram gets removed in this process as an amide derivative, yield loss coupled with purification involving a chemical step makes this process untenable to operate on industrial scale.
It is an object of the present invention to devise a simple and commercially attractive process for removing desmethyl impurity. It has been found that crude Citalopram containing desmethyl impurity can be methylated to produce highly pure Citalopram in high yield.


REFERENCES:
patent: 6258842 (2001-07-01), Petersen et al.
patent: 6291689 (2001-09-01), Petersen et al.

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