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 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.

A PROCESS OF PREPARING ALCAFTADINE
FIELD OF THE INVENTION:
The present invention relates to a process of preparing alcaftadine compound of structural formula 1 by employing pure compound of structural formula VIII.

BACKGROUND OF THE INVENTION:
Alcaftadine is chemically 6, ll-dihydro-ll-(l-methyl-4-piperidinylidene)-5H-irnidazo [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 processes of preparing compound of structural formula VIII according to the above mentioned references produce more than 25% of compound of structural formula XIV.

The compound of structural formula XIV is being carry-forwarded into the further steps of reactions of preparing alcaftadine compound of structural formula I and therefore there is a need in the art to develop an improved process of preparing compound of structural formula VIII, which obviates the prior-art problems.

SUMMARY OF THE INVENTION:
First aspect of the present invention is to provide a substantially pure compound of structural formula VIII.

According to another aspect, the present invention relates to process for the purification of compound of structural formula VIII.
According to another aspect, the present invention relates to a process for purification of compound of structural formula VIII comprising the steps of:
a. dissolving crude compound of structural formula VIII in an ether solvent and,
b. isolating substantially pure compound of structural formula VIII.
According to another aspect, the present invention relates to a process of preparing alcaftadine compound of structural formula I comprising the steps of:
a. dissolving crude compound of structural formula VIII in an ether solvent,
b. isolating substantially pure compound of structural formula VIII and
c. converting substantially pure compound of structural formula VIII into alcaftadine
compound of structural formula I.
According to another aspect, the present invention relates to solvated compound of structural formula XV.


According to another aspect, the present invention relates to tetrahydrofuran solvated compound of structural formula XVI.

According to another aspect, the present invention relates to a crystalline compound of structural formula VIII.
BRIEF DESCRIPTION OF THE DRAWINGS:
Figure I depicts X-ray diffraction pattern of crystalline compound of structural formula VIII. Figure 2 depicts Infra-Red spectra of crystalline compound of structural formula VIII.
DETAIL DESCRIPTION OF THE INVENTION:
In an embodiment the present invention relates to a process for the preparation of substantially pure compound of structural formula VIII.


The term "substantially pure compound of structural formula VIII" described herein referred to compound of structural formula VIII having less than 15% of compound of structural formula XIV.

In another embodiment, the present invention relates to a process for purification of compound of structural formula VIII comprising the steps of:
a. dissolving crude compound of structural formula VIII in an ether solvent and,
b. isolating substantially pure compound of structural formula VIII.
The crude 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 purification of compound of structural formula VIII is carried out by dissolving crude compound of structural formula VIII in an ether solvent at a temperature in the range of 40oC to 80°C and maintained for 30 minutes to 2 hours. The resulting solution was cooled to 20oC to 30°C to get substantially pure compound of structural formula VIII.

Ether solvents can be selected from the group comprising, but not limited to, tetrahydrofuran, 1, 4-dioxane, diethyl ether, diisopropyl ether, dibutyl ether, methyl tertiary butyl ether, methyl ethyl ether, methyl isobutyl ether or mixture(s) thereof.
The substantially pure compound of structural formula VIII may be isolated by any known process in the art such as filtration, centrifugation, washing, drying or the combinations thereof.
The isolated substantially pure compound of structural formula VIII may be dried at a temperature in the range of 40°C to 80°C for a period of 2 hours to 12 hours under reduced pressure.
The solvates of compound of structural formula XV can be selected from the group comprising, but not limited to, tetrahydrofuran solvate, 1, 4-dioxane solvate, diethyl ether solvate, diisopropyl ether solvate, dibutyl ether solvate, methyl tertiary butyl ether solvate, methyl ethyl ether solvate or methyl isobutyl ether solvate.
The example of solvated compound of structural formula XV may include tetrahydrofuran solvated compound of structural formula XVI.

The isolated substantially pure compound of structural formula VIII may be crystalline or amorphous in nature.
In another embodiment, the present invention relates to a crystalline compound of structural formula VIII characterized by X-ray diffraction pattern having peaks at 8.0, 11.0, 12.8, 14.0,

15.0, 15.7, 16.9, 18.7, 19.3, 20.3, 20.6, 21.8, 22.2, 22.6, 25.2, 25.8, 27.1, 27.8, 28.8, 30.7 ± 0.2 degrees two theta.
In another embodiment the present invention relates to a crystalline compound of structural formula VIII characterized by X-ray diffraction pattern as depicted in Figure 1.
In another embodiment the present invention relates to a crystalline compound of structural formula VIII characterized by Infra-Red spectrum as depicted in Figure 2.
The pure compound of structural formula VIII may be converted into alcaftadine compound of structural formula I 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 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: Purification of compound of structural formula VIII
A crude compound of structural formula VIII (50gm) was dissolved in tetrahydrofuran (500ml)
at 60-65°C and maintained for 1 hour. The resulting solution was cooled to 25-35°C to get solid.
The resulting solids were filtered, washed with tetrahydrofuran (50ml) and dried at 45-55°C
under reduced pressure for 8 hours to get pure compound of structural formula VIII.
Yield: 35gm
Purity: 99.9% (By HPLC)
Example 2: Purification of compound of structural formula VIII
A crude compound of structural formula VIII (l0gm) was dissolved in tetrahydrofuran (100ml) at 60-65°C and maintained for 1 hour. The resulting solution was cooled to 25-35°C to get solid.

The resulting solids were filtered, washed with tetrahydrofuran (10ml) and dried at 45-55°C
under reduced pressure for 5 hours to get pure compound of structural formula VIII.
Yield: 8.5gm
Purity: 99.9% (By HPLC)
Example 3: Purification of compound of structural formula VIII
A crude compound of structural formula VIII (lOgm) was dissolved in 1, 4-dioxane (100ml) at
60-65°C and maintained for 1 hour. The resulting solution was cooled to 25-35°C to get solid.
The resulting solids were filtered, washed with 1, 4-dioxane (20ml) and dried at 45-55°C under
reduced pressure for 6 hours to get pure compound of structural formula VIII.
Yield: 8.7gm
Purity: 99.8% (By HPLC)

WE CLAIM:
1. A process for purification of compound of structural formula VIII comprising the steps of:
a. dissolving crude compound of structural formula VIII in an ether solvent and,
b. isolating substantially pure compound of structural formula VIII.

2. The process according to Claim 1, wherein crude compound of structural formula VIII was dissolved at a temperature in the range of 40°C to 80°C maintained for 30 minutes to 2 hours and then cooled to 20°C to 30°C to get substantially pure compound of structural formula VIII.
3. The process according to Claim 1, wherein ether solvent is selected from the group consisting of tetrahydrofuran, 1, 4-dioxane, diethyl ether, diisopropyl ether, dibutyl ether, methyl tertiary butyl ether, methyl ethyl ether, methyl isobutyl ether or mixture(s) thereof.
4. The process according to Claim 1, wherein the substantially pure compound of structural formula VIII is isolated by the steps of filtration, centrifugation, washing, drying or combinations thereof.
5. The process according to Claim 4, wherein the isolated substantially pure compound of structural formula VIII is dried at a temperature in the range of 40°C to 80°C for a period of 2 hours to 12 hours under reduced pressure.
6. A substantially pure compound of structural formula VIII, having less than 15% of compound of structural formula XIV.


7. A process of preparing alcaftadine compound of structural formula I comprising the steps
of:
a. dissolving crude compound of structural formula VIII in an ether solvent and,
b. isolating substantially pure compound of structural formula VIII and
c. converting substantially pure compound of structural formula VIII in to alcaftadine
compound of structural formula I.
8. The process according to Claim 7, wherein crude compound of structural formula VIII was dissolved at a temperature in the range of 40°C to 80°C maintained for 30 minutes to 2 hours and then cooled to 20°C to 30°C to get substantially pure compound of structural formula VIII.
9. The process according to Claim 7, wherein ether solvent is selected from the group consisting of tetrahydrofuran, 1, 4-dioxane, diethyl ether, diisopropyl ether, dibutyl ether, methyl tertiary butyl ether, methyl ethyl ether, methyl isobutyl ether or mixture(s) thereof.
10. The process according to Claim 7, wherein the substantially pure compound of structural formula VIII is isolated by the steps of filtration, centrifugation, washing, drying or combinations thereof.