FIELD OF THE INVENTION
The present invention relates to the process for the preparation of 8-chloro-6,ll-dihydro-n-(4-piperdinylidene)-5H-benzo[5,6]cyclohepta[l,2-b]pyridine of Formula
(I)

BACKGROUND OF THE INVENTION
8-Chloro-6,ll-dihydro-ll-(4-piperdinyIidene)-5H-benzo[5,6]cyclohepta[l,2-b]pyridine is generically known as Desloratadine, Desloratadine is an active metabolite of Loratadine, which is orally active' long-acting histamine H1 receptor antagonist. It belongs to a second generation of H1 histamine receptor antagonists that has advantages over the first generation compounds, Desloratadine is currently marketed under the trade name Clarinex® in the United States. Clarinex is indicated for the relief of the nasal and non-nasal symptoms of seasonal allergic rhinitis, nasal and non-nasal symptoms of perennial allergic rhinitis and symptomatic relief of pruritus, reduction in the number and size of hives in patients with chronic idiopathic urticaria. [Ref: Physician's Desk Reference, "Clarinex," 60th Edition, pp. 3009-12(2005)],
US 4,659,716 ("The 716 patent") assigned to Schering Corporation, discloses
Desloratadine,
The US '716' patent describes two different synthetic routes for the preparation of
Desloratadine.


The major disadvantage with the above process, is that the hydrolysis of ethoxycarbonyl group of Loratadine is carried out by boiling in an aqueous base for a longer time, which leads to degradation of Loratadine and the formation of colored product during the 24 hours reaction time. The removal of colored side products from Desloratadine requires repeated recrystallisations using mixture of benzene and hexanes, which results in low yield of Desloratadine.
Alternatively, US '716 patent also describes demethylation of 8-chloro-6,ll-
dihydro-11 -(1 -methyl-4-piperidinylidene)-5H-benzo[5,6]cyclohepta[ 1,2-b]pyridine
(Methyl Desloratadine) of Formula (III) by reacting with cyanogen bromide to
produce 8-chloro-6,11 -dihydro-11 -(1 -cyano-4-piperidinyliene)-5H-
benzo[5,6]cyclohepta[l,2-b]pyridine N-cyano compound of Formula (IV), which is hydrolysed by refluxing for 20 hours in a mixture of concentrated hydrochloric acid and acetic acid to produce Desloratadine of Formula (I), which is recrystallised from hexane. This process is shown in the Scheme-2 given below:


Scheme-2 The disadvantage with the above process is the use of cyanogen bromide, which is extremely toxic, undesirable on industrial scale and its use requires special safety measures.
US 2006/0058334 Al discloses a process for the preparation of the Desloratadine comprising acidic hydrolysis of Loratadine with a strong organic acid or a mineral acid. The acid hydrolysis is carried out at a temperature between 90°C to about 120X.
US 2007/0060756 Al discloses a process for the preparation of Desloratadine by hydrolysis of the ethoxycarbonyl group of Loratadine, which is carried out using a solvent mixture of toluene and polyethylene glycol (PEG 400).
In the instant invention, it has been found that the hydrolysis of novel intermediate
compound 8-chloro-11 -[ 1 -(1 -chloroethoxycarbonyl)-4-piperidinylidene]-6,11 -

dihydro-5H-benzo[5,6]-cyclohepta[l,2-b]pyridine (ACE Desloratadine) of Formula (V) requires less reaction time and controls the formation of undesired degradation colored by-products in Desloratadine.
OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide substantially pure Desloratadine with higher yields on industrial scale.
Yet another objective of the present invention is to provide a one-pot process without isolating the novel intermediate compound of Formula (V)*
SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of 8-chloro-6,ll" dihydro-ll-(4-piperidinylidene)-5H-benzo[5,6]cyclohepta[l,2-b]pyridine (Desloratadine) of Formula (I),

which comprises :
i. reacting 8-chloro-6,l 1-dihydro-l l-(l-methyl-4-piperidinylidene)-5H-
benzo[5,6]-cyclohepta[l,2-b]pyridine (Methyl Desloratadine) of Formula (III)


with 1-chIoroethyl chloroformate in presence of base in an organic solvent to give 8-chloro-11 -[ 1 -(1 -chloroethoxycarbonyl)-4-piperidinylidene]-6,11 -dihydro-5H-benzo[5,6] cyclohepta[ 1,2'b]pyridine (ACE Desloratadine) of Formula (V),

ii. decarboethoxy lation of 8-chloro-11 - [ 1 -(1 -chloroethoxycarbonyl )-4-piperidinylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[l ,2'b]pyridine (ACE Desloratadine) of Formula (V) in a solvent to produce 8-chloro-6,11 -dihydro-11 -(4-piperidinylidene)-5H-benzo[5,6]cyclohepta[l ,2-bjpyridine (Desloratadine) of Formula (I),
ill. isolating Desloratadine of Formula (I) from the reaction mixture thereof.
1

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of 8-chloro-6,11 -dihydro-11 -(4-piperdinylidene)-5H-ben2o[5,6]cyclohepta[l ,2-b]pyridine (Desloratadine) of Formula (I).
The starting compound 8-chloro-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H" benzo[5,6]-cyclohepta[l,2-b]pyridine (Methyl Desloratadine) of Formula III of the present invention may be prepared by the procedures provided in US 4,659,716,
8-Chloro-6,11 -dihydro-11 -(1 -methyl-4-piperidinylidene)-5H-benzo[5,6]cyclohepta[l,2-b] pyridine (Methyl Desloratadine) of Formula III is treated with 1-chloroethyl chloroformate in a solvent selected from toluene, ethylene dichloride, methylene chloride in presence of a base selected from triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, N,N-diisopropylethylamine, preferably triethylamine to produce the intermediate compound 8-chloro-11 - [ 1 -(1 -chloroethoxycarbonyl)-4-piperidinylidene]-6,11 -dihydro-5H-
benzo[5,6]cyclohepta[l,2-b]pyridine (ACE Desloratadine) of Formula (V). The reaction is carried out at a temperature of about 20°C to about 80°C, most preferably at about 25-40°C for about 2-4 h. ACE Desloratadine (V) obtained from the above reaction need not be isolated from the reaction mixture in any solid form. However, the reaction mass is concentrated under reduced pressure to remove the solvent before proceeding to decarbethoxylation. The compound of Formula (V) is decarboxylated using a solvent selected from alcohols such as methanol, ethanol, preferably methanol. The decarboxylation process is carried out at a temperature of about 30 to 50°C in 2 to 5 hrs time. After completion of reaction, as ascertained by the known detection methods such as TLC, the reaction mass is concentrated to remove the solvent under reduced pressure. The obtained residue is dissolved in water and adjusted the pH to about 0.5 to 1,5. This aqueous solution containing Desloratadine is washed with organic solvent selected from methylene chloride, ethyl acetate, toluene followed by carbon treatment and filtered. The obtained aqueous solution is treated with an inorganic base selected from sodium carbonate.

sodium hydroxide, potassium hydroxide, aqueous ammonia, most preferably aqueous sodium hydroxide, until the pH is about 9.0-10.0 at a temperature of about 15-40°C. The product is extracted with methyl isobutyl ketone or methylene chloride and concentrated at about 20-80°C under reduced pressure. The resulting residue is dissolved in methyl isobutyl ketone and cyclohexane is added at about 50-90°C and slowly cooled to about 0-5 °C to crystallize Desloratadine, which is isolated by filtration. The wet product is finally dried at 45-50°C under reduced pressure. Desloratadine, produced by the above-described process is crystalline polymorphic mixture of Form-I and Form-II, which contains 2-10% of Form II.
Desloratadine produced by the present invention via intermediate compound 8-chloro-11 -[1 -(l-chloroethoxycarbonyl)-4-piperidinylidene]-6,11 -dihydro-5H-benzo[5,6]cyclohepta[l,2-b] pyridine (ACE Desloratadine) of Formula (V) results in lesser reaction time i.e. 2 to 5 hrs to complete decarboxylation instead 24 hrs as reported in the prior-art process and also obtained Desloratadine without undesired degradation colored by-products.
The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.
EXAMPLES:
EXAMPLE -1
PREPARATION OF DESLORATADINE:
Methyl Desloratadine (50 g) was dissolved in toluene (250 ml) at 18-20''C and triethylamine (15.57 g) was added. 1-Chloroethyl chloroformate (57.30 g) was added in 7 min at 22-40°C and the reaction mass was stirred at 30-40°C for 2 h. The reaction mass was concentrated to remove toluene at 50-60°C under reduced pressure (100-10 mm Hg). Methanol (250 ml) was added to the residue and the reaction solution was stirred at 38-40°C for 2 h. Thereafter, the reaction solution

was concentrated under reduced pressure (300-20 mm Hg) to remove methanol at 40-50°C. The residue was dissolved in water (400 ml) and adjusted the pH of the solution to 1.0 with hydrochloric acid (13 ml) at 22-25°C, and washed with methylene chloride (3 x 350 ml) at 20-25°C and treated with carbon (5 g) at 20-25°C for 30 min. Carbon was removed by filtration and the residue was washed with water (100 ml). Thereafter, pH of the aqueous solution was adjusted to 7.5 with 20% w/w aqueous sodium hydroxide solution (30 ml). Methyl isobutyl ketone (175 ml) was added to the reaction mass and continued addition of 20% w/w aqueous sodium hydroxide solution (36 ml) at 20-25 °C to adjust the pH to 9.6. The temperature of the mass was raised to 50-55°C. The upper methyl isobutyl ketone layer was separated and the aqueous layer was extracted with methyl isobutyl ketone (75 ml). The combined methyl isobutyl ketone was washed with water (100 ml) at 50-55°C and concentrated to -- 50 ml at 50-60°C under reduced pressure (200-20 mm Hg). To the residue, added methyl isobutyl ketone (150 ml) and stirred at 78-85°C to get a clear solution. This was then diluted with cyclohexane (200 ml) at 75-85°C. The solution-containing Desloratadine was cooled to 28°C and stirred at 25-28°C under stirring for 1 h. The resulting slurry was further cooled to 2 "^C and stirred at 2-5 °C for 5 h to complete the crystallization. The product was filtered, washed with precooled cyclohexane (2 x 25 ml, 10-12°C) and dried at 50-55°C under reduced pressure (--10 mm Hg) to obtain 33.5 g of Desloratadine having purity 99.85 % (By HPLC). The X-ray powder diffraction showed that product to be a mixture of Desloratadine Form-I and Form-II containing 3.0% of Form-Il.
EXAMPLE - II
PREPARATION OF DESLORATADINE:
Methyl Desloratadine (50 g) was dissolved in toluene (250 ml) at 18-20°C and triethylamine (15.57 g) was added. 1-Chloroethyl chloroformate (57.30 g) was added in 5 min at 22-40*^C and the reacfion mass was sfirred at 30-40*^C for 2 h. The reaction mass was concentrated to remove toluene at 50-60°C under reduced pressure (100-10 mm Hg). Methanol (250 ml) was added to the residue and the reaction solution was stirred at 38-40°C for 2 h. Thereafter, the reaction solution

was concentrated under reduced pressure (300-50 mm Hg) to remove methanol at 40-50°C, The residue was dissolved in water (400 ml) and adjusted the pH of the solution to 1.0 with hydrochloric acid (14 ml) at 22-25°C. This was then washed with methylene chloride (3 x 350 ml) at 20-25°C and treated with carbon (5 g) at 20-25°C for 30 min. Carbon was removed by filtration and the residue was washed with water (100 ml). Thereafter, pH of the aqueous solution was adjusted to 7.8 with 20% w/w aqueous sodium hydroxide solution (40 ml). Methylene chloride (200 ml) was added to the reaction mass and continued addition of 20% w/w aqueous sodium hydroxide solution (22 ml) at 20-25°C to adjust the pH to 9.6. Stirred the contents for 10 min at 20-25°C. Methylene chloride layer was separated and the aqueous layer was extracted with methylene chloride (50 ml). The combined methylene chloride layer was washed with water (100 ml) at 20-25°C and concentrated at 30-45°C under reduced pressure (200-80 mm Hg). To the residue, added methyl isobutyl ketone (100 ml), co-distilled to remove traces of methylene chloride at 55°C under reduced pressure (200-20 mm Hg). The residue was dissolved in methyl isobutyl ketone (200 ml) at 80-85°C. This was then diluted with cyclohexane (200 ml) at 72-85°C. The solution containing product was stirred while allowing it to cool to 28°C and stirred at 25-28°C for 1 h. The resulting slurry was cooled to 2°C and stirred at 2-5 °C for 5 h to complete the crystallization. The product was filtered, washed with precooled cyclohexane (2 x 25 ml, 10-12°C) and dried at 50-55°C under reduced pressure (-10 mm Hg) to obtain 32.4 g of Desloratadine having purity 99,77% (by HPLC), The X-ray powder diffraction showed that product to be a mixture of Desloratadine Form-I and Form-II containing 4.9%of Form-II.

We Claim:
1. A process for the preparation of 8-chloro-6,l l-dihydro-l l-(4-piperdinyIidene)-5H-benzo[5,6]cyclohepta[l,2-b]pyridine (Desloratadine) of Formula (I),

with 1-Chloroethyl chloroformate in presence of base in an organic solvent to give 8-chloro-l l-[l-(l-chloroethoxycarbonyl)-4-piperidinylidene]-6,ll-dihydro-5H-benzo[5,6]cyclohepta[l,2-b]pyridine (ACE Desloratadine) of Formula (V),

>
(ii) decarboethoxylation of 8-chloro-l l-[l-(l-chloroethoxycarbonyl)-4-piperidinylidene]-6, 11 -dihydro-5//-benzo[5,6]cyclohepta[l ,2-b]pyridine (ACE Desloratadine) of Formula (V) insitu in a solvent to produce 8-chloro-6,11 -dihydro-11 -(4-piperidinylidene)-5//-benzo-[5,6]cyclohepta[l,2-b] pyridine (Desloratadine) of Formula (I),
(iii) isolating Desloratadine (I) from the reaction mixture thereof, and
(iv) purifying the Desloratadine to produce mixture of Form II and Form III
9. A process according to claim 1, wherein the base used in step (i) is selected
from triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, N,N-
diisopropylethylamine, or mixtures thereof.
3. A process according to claim 1, wherein the solvent used in step (i) is selected
from toluene, ethylenedichloride, methylenechloride or mixtures thereof
4. A process according to claim 1, wherein the solvent used in step (ii) is selected
from alcohols such as methanol, ethanol.
5. A process according to claim 1, wherein compound (V) need not be isolated as
a solid for further processing.

6. A process according to claim 1, wherein isolating Desloratadine (I) from the reaction mixture by concentrating the reaction mass to remove solvent to produce residue, which is dissolved in a water followed by treating with base and extracting with organic solvent and the organic solvent containing Desloratadine is concentrated to produce Desloratadine.
7. A process according to claim 1, further comprising,
(i) preparing a solution of Desloratadine in a ketonic solvent;
(ii) optionally, treating the resulting solution with carbon,
(iii) adding anti solvent,
(iv) isolating mixture of crystalline Desloratadine Form I and Form II.
8. The process according to claim 7, wherein the ketone is selected from acetone,
methyl ethyl ketone, methyl isobutyl ketone, methyl propyl ketone, methyl
isopropyl ketone, diethyl ketone or mixtures thereof
9. The process according to claim 7, wherein the anti solvent is selected from
hexanes, heptane, cyclohexane, preferably cyclohexane.