FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
;'-A NOVEL PROCESS OF PREPARING ALCAFTADINE"
Ertaltcc Labs Pvt. Ltd. an Indian Company, having its Registered Office at 17,hFloor, Kesar Solitaire, Plot No.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705
I. The following specification particularly describes the invention and the manner in which it is to be performed.

A NOVEL PROCESS OF PREPARING ALCAFTADINE FIELD OF THE INVENTION:
The present invention relates to a novel process of preparing alcaftadine compound of structural formula 1 by employing an intermediate compound of structural formula II.

BACKGROUND OF THE INVENTION:
Alcaftadine is chemically 6, I l-dihydro-ll-(l-methyl-4-piperidinylidene)-5H-imidazo [2, 1-b] [3] benzazepine-3-carboxaldehyde and is known from U.S Patent No. 5,468,743 and is represented by a compound of structural formula I.


Alcaftadine is a H, histamine receptor antagonist sold in USA under the proprietary name of "LASTACAFT" and is indicated for the prevention of itching associated with allergic conjunctivitis.
U.S Patent No. 5,468,743 describes the analogous processes of preparing alcaftadine compound of structural formula 1 as shown below in scheme no. 1 and scheme no. II.



The prior art processes of preparing alcaftadine compound of structural formula I are not commercially viable therefore there is a need in the art to develop a commercially viable process of preparing alcaftadine compound of structural formula I.
SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide a novel process of preparing alcaftadine by employing an intermediate compound of structural formula II.


A second aspect of the present invention is to provide a process of preparing alcaftadine compound of structural formula 1 comprising the steps of:
a) reacting an intermediate compound of structural formula II with compound of structural formula III to get compound of structural formula IV and,

b) converting compound of structural formula IV in to alcaftadine compound of structural formula I.
A third aspect of the present invention is to provide a process of preparing intermediate compound of structural formula IV comprising reacting an intermediate compound of structural formula II with compound of structural formula III to get compound of structural formula IV,

Another aspect of the present invention is to provide use of an intermediate compound of structural formula II for the preparation of alcaftadine compound of structural formula I.


Another aspect of the present invention is to provide a process of preparing an intermediate compound of structural formula II.
Another aspect of the present invention is to provide a process of preparing alcaftadine compound of structural formula I as shown below in scheme no. III.

DETAIL DESCRIPTION OE THE INVENTION:
An intermediate compound of structural formula II may be prepared by reacting compound of structural formula XI with halogenating reagents like phosphorus trichloride, phosphorous pentachloride, oxalyl chloride, phosgene or thionyl chloride in an organic solvent.


The examples of organic solvents may include but not limited to toluene, xylene, chlorobenzene, dichloromethane, dichloroethane or carbon tetrachloride.
The reaction of a compound of formula XI with halogenating reagents like phosphorus trichloride, phosphorous pentachloride. oxalyl chloride, phosgene or thionyl chloride may be carried out at a temperature in the range of 20°C to 50°C for a period of 30 minutes to 4 hours.
The intermediate compound of formula II may be isolated from the reaction mixture by conventional methods or may be used as such for carry out the reaction of next step.
An intermediate compound of structural formula IV may be prepared by reacting intermediate compound of structural formula II with compound of structural formula III in the presence of Lewis acid in an organic solvent.
Examples of Lewis acid may include but not limited to aluminium halide, boron halide. tin halide, bismuth halide, iron halide or titanium halide. preferably aluminium chloride or stannic chloride.
Examples of organic solvent may include but not limited to toluene, xylene, ethyl acetate, chlorobenzene. dichloromethane. dichloroethane or carbon tetrachloride.

The reaction of an intermediate compound of structural formula I] with a compound of structural formula III may be carried out at a temperature in the range of -5°C to 50°C for a period of 1 hour to 12 hours.
The intermediate compound of structural formula IV may be isolated from the reaction mixture by quenching the reaction mixture with water, followed by the extraction with dichloromethane or ethyl acetate solvent, washing with saturated aqueous sodium bicarbonate solution, drying over anhydrous sodium sulfate and concentrated under reduced pressure to get an intermediate compound of structural formula IV.
The intermediate compound of structural formula IV may be converted into alcaftadine compound of structural formula 1 by methods known in the art such as those described in U.S Patent No. 5,468.743. which are incorporated herein by reference only.
EXAMPLES:
in the following examples, the preferred embodiment of the present invention is described only by way of illustrating the processes of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example 1: Preparation of l-methylpiperidine-4-carbonyl chloride intermediate compound of structural formula II.
A solution of l-methylpiperidine-4-carboxylic acid compound of structural formula XI (20gm) in dichloromethane (200ml) was added thionyl chloride (15ml) and then resulting reaction mixture was stirred for 3 hours at 40-45°C. The resulting reaction mixture was concentrated under reduced pressure to get title compound. Yield: 22.5gm

Example 2: Preparation of (l-methylpiperidine-4-yl) (l-phenethyl-IH-imidazol-2-yl) methanone intermediate compound of structural formula IV.
A solution of 1-methyl piperidine-4-carbonyl chloride intermediate compound of structural formula II (20gm) in toluene (300ml) was added 1-phenethyl-lH-imidazole (21.3gm) and aluminum chloride (16.4gm) and resulting reaction mixture was refluxed at 45°C for 8 hours. The resulting reaction mixture was cooled to 20-25°C and quenched with water (500ml) followed by extract with dichloromethane (400ml), washed with saturated aqueous sodium bicarbonate solution (40ml) and dry over anhydrous sodium sulfate (20gm). The resulting organic layer was then concentrated under reduced pressure to get title compound. Yield: 36.7gm

WE CLAIM:
1. A process of preparing alcaftadine compound of structural formula I comprising the steps of:
a) reacting an intermediate compound of structural formula 11 with compound of structural formula III to get compound of structural formula IV and,

b) converting compound of structural formula IV in to alcaftadine compound of structural formula I.
2. The process according to claim no. 1 wherein, an intermediate compound of structural formula II is reacted with compound of structural formula Til in the presence of Lewis acid in an organic solvent to get compound of structural formula IV.
3. The process according to claim no. 2 wherein, Lewis acid is selected from the group comprising of aluminium halide. boron halide, tin halide, bismuth halide, iron halide or titanium halide.
4. The process according to claim no. 2 wherein, an examples of organic solvent is selected from the group comprising of toluene, xylene, ethyl acetate, chlorobenzene, dichloromethane. dichloroethane or carbon tetrachloride.

5. The- process according to claim nos. 1 and 2 wherein, reaction of an intermediate compound of structural formula II with a compound of structural formula III is carried out at a temperature in the range of -5°C to 50°C for a period of 1 hour to 12 hours.
6. The process according to claim nos. 1 and 2 wherein, an intermediate compound of structural formula IV is isolated from the reaction mixture by quenching the reaction mixture with water, followed by the extraction with dichloromethane or ethyl acetate solvent, washing with saturated aqueous sodium bicarbonate solution, drying over anhydrous sodium sulfate and concentrated under reduced pressure to get an intermediate compound of structural formula IV.
7. The process according to claim no. 1 wherein, an intermediate compound of structural formula II is prepared by reacting compound of structural formula XI with halogenating reagents like phosphorus trichloride, phosphorous pentachhride, oxalyl chloride, phosgene or thionyl chloride in an organic solvent.

8. The process according to claim no. 6 wherein, an examples of organic solvent is selected from the group comprising of toluene, xylene, chlorobenzene, dichloromethane, dichloroethane or carbon tetrachloride.
9. The process according to claim no. 6 wherein, reaction of a compound of formula XI with halogenating reagents like phosphorus trichloride, phosphorous pentachloride, oxalyl chloride, phosgene or thionyl chloride is carried out at a temperature in the range of 20°C to 50°C for a period of 30 minutes to 4 hours.

10. Use of an intermediate compound of structural formula II for the preparation of atcaftadine compound of structural formula I.