FORM 2
THE PATENT ACT, 1970
(39 of l970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"AN IMPROVED PROCESS OF PREPARING ALCAFTADINE"
Enaltec Labs Pvt. Ltd. an Indian Company, having its Registered Office at 17thFloor, Kesar Solitaire, Plot No.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705
1, The following specification particularly describes the invention and the manner in which it is to be performed.

AN IMPROVED PROCESS OF PREPARING ALCAFTADINE
FIELD OF THE INVENTION:
The present invention relates to an improved process of preparing substantially pure alcaftadine comprising reacting compound of structural formula VIII with more than 20 moles of oxidizing reagent in an organic solvent to get alcaftadine.

BACKGROUND OF THE INVENTION:
Alcaftadine is chemically 6, 11-dihydro-11-(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 H1 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 analogous processes of preparing alcaftadine compound of structural formula I as shown below in scheme no. I, scheme no. II and scheme no. III.

The prior art processes of preparing alcaftadine compound of structural formula I comprises treating compound of structural formula VIII with less than 20 moles of oxidizing reagent which leads to incomplete reaction and causes low yield of alcaftadine compound of structural formula I.
Accordingly there is a need in the art to develop an improved process of preparing alcaftadine compound of structural formula I, which obviates the prior-art problems.
SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide an improved process of preparing alcaftadine compound of structural formula I
A second aspect of the present invention is to provide an improved process of preparing alcaftadine comprising reacting compound of structural formula VIII with more than 20 moles of oxidizing reagent in an organic solvent to get alcaftadine compound of structural formula I.

A third aspect of the present invention is to provide substantially pure alcaftadine compound of structural formula I.
A fourth aspect of the present invention is to provide a process of preparing substantially pure alcaftadine compound of structural formula I comprising reacting compound of structural

formula VIII with more than 20 moles of oxidizing reagent in an organic solvent to get substantially pure alcaftadine compound of structural formula I.

DETAIL DESCRIPTION OF THE INVENTION:
The compound of structural formula VIII used according to the present invention can be prepared by methods disclosed in the art such as those described in U.S Patent No. 5,468,743, which is incorporated herein by reference.
The alcaftadine compound of structural formula I is prepared by reacting compound of structural formula VIII with more than 20 moles of oxidizing reagent in an organic solvent.
In another embodiment, the present invention relates to a process of preparing substantially pure alcaftadine compound of structural formula I comprising reacting compound of structural formula VIII with more than 20 moles of oxidizing reagent in an organic solvent to get substantially pure alcaftadine compound of structural formula I.
The reaction of compound of structural formula VIII with more than 20 moles of oxidizing reagent in an organic solvent can be carried out at a temperature in the range of 40°C to 80°C for a period of 2 hours to 24 hours.
The oxidizing reagent may added in one lot or in several lots.

Oxidizing reagent can be selected from the group comprising, but not limited to, manganese dioxide, silver nitrate, selenium dioxide or ceric ammonium nitrate or the like or mixtures thereof.
Organic solvent according to present invention can be selected from the group comprising, but not limited to, ketones, alcohols, esters, nitriles, halogenated aliphatic hydrocarbon solvents, ethers or mixtures thereof.
The ketone solvents can be selected from the group comprising, but not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, dibutyl ketone, diethyl ketone, dipropyl ketone, diisopropyl ketone, methyl butyl ketone, methyl propyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone or mixture(s) thereof.
The alcohol solvents can be selected from the group comprising, but not limited to, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, pentanol or mixture(s) thereof.
The ester solvents can be selected from the group comprising, but not limited to, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tertiary butyl acetate, pentyl acetate or mixture(s) thereof
The nitrile solvents can be selected from the group comprising, but not limited to, acetonitrile, propionitrile or mixture(s) thereof.
The halogenated aliphatic hydrocarbon solvents can be selected from the group comprising, but not limited to, dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixture(s) thereof.
The ether solvents can be selected from the group comprising, but not limited to, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dibutyl ether, methyl tertiary butyl ether, methyl ethyl ether, methyl isobutyl ether or mixture(s) thereof.

The alcaftadine compound of structural formula I can be isolated by cooling the reaction mixture at a temperature in the range of 25-35°C followed by filtering the reaction mixture to get filtrate. The filtrate obtained may be washed with organic solvent and then organic layer can be separated, washed with water and dried over sodium sulphate.
The resulting organic layer containing alcaftadine compound of structural formula I may be concentrated under reduced pressure to get residue of alcaftadine compound of structural formula I.
The residue of alcaftadine compound of structural formula I may be crystallized by an ether solvent to get substantially pure alcaftadine compound of structural formula I.
The isolated substantially pure alcaftadine compound structural formula I may be dried at a temperature in the range of 40-60°C for a period of 2 hours to 10 hours under reduced pressure.
The term "substantially pure alcaftadine compound of structural formula I" described herein referred to alcaftadine compound of structural formula I having less than 5% of compound of structural formula VIII.

EXAMPLES:
In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.

Example 1: Preparation of substantially pure alcaftadine compound of structural formula I.
The solution of compound of structural formula VIII (40gm) in chloroform (4000ml) was added first lot of manganese dioxide (200gm) at 25-3 5°C and then the resulting reaction mixture was heated to 60-65°C and stirred for 4 hours. The second lot of manganese dioxide (200gm) was then added to the reaction mixture at 60-65°C and stirred for 4 hours. In this manner third, fourth, fifth and sixth lot of manganese dioxide (200gm) was added to the reaction mixture at 60-65°C after each lot addition reaction mixture stirred for 4 hours. The resulting reaction mixture was cooled to 25-35°C, filtered and washed with chloroform (1000ml). The resulting organic layer was washed with water (2x400ml), dried over sodium sulphate (200gm) and concentrated under reduced pressure to get residue. The resulting residue was added diethyl ether (150ml) and stirred for 2 hours at 25-35°C to get suspension. The resulting suspension was filtered, wash with diethyl ether (50ml) and dried under reduced pressure at 45-55°C for 8 hours to get title compound. Yield: 30gm Purity: 98.7% (By HPLC)
Example 2: Preparation of substantially pure alcaftadine compound of structural formula I.
The solution of compound of structural formula VIII (20gm) in chloroform (2000ml) was added manganese dioxide (600gm) at 25-35°C and then the resulting reaction mixture was heated to 60-65°C and stirred for 18 hours. The resulting reaction mixture was cooled to 25-35°C, filtered and washed with chloroform (500ml). The resulting organic layer was washed with water (2x200ml), dried over sodium sulphate (l00gm) and concentrated under reduced pressure to get residue. The resulting residue was added diethyl ether (100ml) and stirred for 1 hours at 25-35°C to get suspension. The resulting suspension was filtered, wash with diethyl ether (25ml) and dried under reduced pressure at 45-55°C for 6 hours to get title compound. Yield: 15gm Purity: 98.8% (By HPLC)

Example 3: Preparation of substantially pure alcaftadine compound of structural formula I.
The solution of compound of structural formula VIII (40gm) in chloroform (4000ml) was added manganese dioxide (1200gm) at 25-35°C and then the resulting reaction mixture was heated to 60-65°C and stirred for 16 hours. The resulting reaction mixture was cooled to 25-35°C, filtered and washed with chloroform (1000ml). The resulting organic layer was washed with water (2x400ml), dried over sodium sulphate (200gm) and concentrated under reduced pressure to get residue. The resulting residue was added diethyl ether (200ml) and stirred for 1 hours at 25-35°C to get suspension. The resulting suspension was filtered, wash with diethyl ether (50ml) and dried under reduced pressure at 45-55°C for 8 hours to get title compound. Yield: 30gm Purity: 98.9% (By HPLC)

WE CLAIM:
1. An improved process of preparing alcaftadine compound of structural formula I comprising reacting compound of structural formula VIII with more than 20 moles of oxidizing reagent in an organic solvent to get alcaftadine compound of structural formula I.

2. The process according to Claim 1, wherein the reaction is carried out at a temperature in the range of 40°C to 80°C for a period of 2 hours to 24 hours
3. The process according to Claim 1, wherein oxidizing reagent is selected from the group consisting of manganese dioxide, silver nitrate, selenium dioxide or ceric ammonium nitrate or mixtures thereof.
4. The process according to Claim 1, wherein the oxidizing reagent is added in one lot or in several lots
5. The process according to Claim 1, wherein organic solvent is selected from the group consisting of ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, dibutyl ketone, diethyl ketone, dipropyl ketone, diisopropyl ketone, methyl butyl ketone, methyl propyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone or mixture(s) thereof; alcohol solvents such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, pentanol or mixture(s) thereof; ester solvents such as ethyl

acetate, propyl acetate, isopropyl acetate, butyl acetate, tertiary butyl acetate, pentyl acetate or mixture(s) thereof; nitrile solvents such as acetonitrile, propionitrile or mixture(s) thereof; halogenated aliphatic hydrocarbon solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixture(s) thereof; and/or ether solvents such as tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dibutyl ether, methyl tertiary butyl ether, methyl ethyl ether, methyl isobutyl ether or mixture(s) thereof.
6. An improved process of preparing alcaftadine compound of structural formula I
comprising the steps of:
reacting compound of structural formula VIII with more than 20 moles of oxidizing
reagent in an organic solvent,
cooling the reaction mixture at a temperature in the range of about 25-3 5°C,
filtering the reaction mixture to get filtrate,
washing the filtrate with organic solvent and then with water and
drying to get residue of alcaftadine compound
crystallizing the residue using ether solvent to get substantially pure alcaftadine
compound.
7. The process according to Claim 6, wherein oxidizing reagent is selected from the group consisting of manganese dioxide, silver nitrate, selenium dioxide or ceric ammonium nitrate or mixtures thereof.
8. The process according to Claim 6, wherein organic solvent is selected from the group consisting of ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, dibutyl ketone, diethyl ketone, dipropyl ketone, diisopropyl ketone, methyl butyl ketone, methyl propyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone or mixture(s) thereof; alcohol solvents such as methanol, ethanol, propanoi, isopropanol, butanol, isobutanol, t-butanol, pentanol or mixture(s) thereof; ester solvents such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tertiary butyl acetate, pentyl

acetate or mixture(s) thereof; nitrile solvents such as acetonitrile, propionitrile or mixture(s) thereof; halogenated aliphatic hydrocarbon solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixture(s) thereof; and/or ether solvents such as tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dibutyl ether, methyl tertiary butyl ether, methyl ethyl ether, methyl isobutyl ether or mixture(s) thereof.
9. The process according to Claim 6, wherein the isolated substantially pure alcaftadine compound structural formula I is dried at a temperature in the range of 40-60°C for a period of 2 hours to 10 hours under reduced pressure.
10. A substantially pure alcaftadine compound of structural formula I having less than 5% of compound of structural formula VIII.