FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"AN IMPROVED PROCESS FOR PREPARATION OF RUPATADINE"
2. APPLICANT (S):
(a) NAME: FDC Limited
(b)NATIONALITY: Indian Company incorporated under the Companies Act, 1956
(c) ADDRESS: 142-48, S.V. Road, Jogeshwari (West), Mumbai - 400 102, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF INVENTION:
The present invention relates to an improved process for preparation of Rupatadine of Formula 1 from desloratadine of Formula 2.

BACKGROUND OF INVENTION:
Rupatadine is an antihistamine with selective peripheral H1 receptor antagonist activity, and a platelet-activating factor (PAF) antagonist, used for the treatment of allergic rhinitis and urticaria (skin rash). It works by blocking the histamine Hi receptors and platelet-activating factor (PAF) receptors, thus preventing the release of allergy chemicals and subsequently controlling the symptoms of allergic reactions such as sneezing, itching, rhinorrhea and other inflammatory manifestations.

The chemical name for Rupatadine is 8-Chloro-6,l 1-dihydro-l1-[l-[(5-methyl-3-
pyridyl)methyl]-4-piperidylidene]-5H-benzo[5,6]cyclohepta[l,2-b]pyridine.
The molecular structure of Rupatadine is represented as follows:

US 5407941 discloses a process for preparation of Rupatadine from 3,5 lutidine, which involves N-alkylation of Desloratadine with a brominated derivative of 3,5 lutidine in presence of 4-(dimethylamino)pyridine at room temperature to provide Rupatadine in a reaction time of about 18 hours; wherein Rupatadine is obtained in an overall yield of 40% after work-up and chromatographic purification. The said process suffers from drawbacks like long reaction times of 18 hrs, lower yield of 40% and chromatographic purification to obtain pure Rupatadine. The N-alkylation of desloratadine as disclosed in US 5407941, is as shown in Scheme 1.
Scheme 1:


Indian patent application no. 2102/MUM/2006 discloses a process for preparation of Rupatadine from 5-methyl nicotinic acid, which involves N-alkylation of desioratadine with hydrochloride salt of 5-methyl-3-(chloromethyl)-pyridine in presence of powdered potassium carbonate and dimethylformamide at a temperature of 20-25°C to provide Rupatadine in a reaction time of about 16 hrs, wherein Rupatadine is obtained in an overall yield of about 85 % with high purity. The said process suffers from the drawback of long reaction time of 16 hrs for N-alkylation of desioratadine. The N-alkylation of desioratadine as disclosed in 2102/MUM/2006, is as shown in Scheme 2.
Scheme 2:

WO 2006114676 discloses a process for preparation of Rupatadine which involves N-alkylation of desioratadine with 3-halomethyl 5-methyl pyridine in presence of a biphasic solvent system, aqueous alkali and a phase transfer catalyst at a temperature up to 50°C, to provide Ruptadine in short reaction times of about 6-8 hours with yield of 74%. The said process achieves short reaction time for N-alkylation of desioratadine but with the use of biphasic solvent system and phase transfer catalyst. The N-alkylation of desioratadine as disclosed in WO 2006114676, is as shown in Scheme 3.


Indian patent application no. 864/MUM/2006 discloses a process for preparation of Rupatadine which involves N-alkylation of desloratadine with suitable pyridyl sulfonate in presence of a base and an organic solvent at a reaction temperature upto 45°C, wherein the base is selected from methyl amine, triethyfamine, dibenzoyl benzene (DBB), sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide and potassium tert-butoxide, preferably potassium carbonate. The N-alkylation of desloratadine as disclosed in 864/MUM/2006, is as shown in Scheme 4.
Scheme 4

Most of the prior art processes for preparation of Rupatadine suffer from the drawback of long reaction times for N-alkylation of desloratadine, particularly when halogen groups are used as leaving groups in the reaction. Attempts to shorten the reaction time for N-alkylation of desloratadine have been made in prior art by using sulphonyl groups as leaving groups or by using biphasic solvent system and phase transfer catalyst. The

present inventors have attempted to overcome the drawback, of long reaction times by carrying out N-alkylation of desioratadine in presence of sodium hydride and sodium iodide, while avoiding the use of phase transfer catalyst and biphasic solvent system.
SUMMARY OF INVENTION:
which involves N-alkylation of desloratadine of Formula 2
with a compound of Formula 3,
The present invention relates to an improved process for preparation of Rupatadine of Formula 1




where L is a leaving group selected from chloro, bromo. iodo or tosylate,
in presence of sodium hydride, a catalytic amount of sodium iodide and a solvent system. The solvent system comprises tetrahydrofuran (THF) and dimethylformamide (DMF). The said process is carried out at a reaction temperature of 40° - 50°C.
The process of present invention provides a facile, efficient and easy route for obtaining Rupatadine in faster reaction times of 6-8 hours with good yields & high purity of greater than 99.5%, and without the use of phase transfer catalyst and biphasic solvent system.
DETAILED DESCRIPTION OF THE INVENTION:
which involves N-alkylation of desloratadine of Formula 2
The present invention describes an improved process for preparation of Rupatadine of Formula 1



with a compound of Formula 3,

where L is a leaving group selected from chloro, bromo, iodo or tosylate,
in presence of sodium hydride, a catalytic amount of sodium iodide and a solvent system.
The solvent system comprises tetrahydrofuran (THF) and dimethylformamide (DMF).
The process of present invention is carried out at a reaction temperature of 40° - 50°C.
The process of present invention yields Rupatadine in faster reaction times of 6-8 hours with good yields & high purity of greater than 99.5%.
The reaction scheme of the present invention is depicted in Scheme 5 as follows:
Scheme 5:

wherein L is a leaving group selected from chloro, bromo, iodo or tosylate.
The inventive step of the present invention lies in carrying out N-alkylation of desloratadine in presence of sodium hydride and catalytic amount of sodium iodide. Sodium hydride acts as a base and sodium iodide initiates the N-alkylation reaction. The

said N-alkylation is carried out in a solvent system comprising tetrahydrofuran (THF) and dimethylformamide (DMF) and at a reaction temperature of 40° - 50°C.
The process of present invention provides Rupatadine in a short reaction time of 6 - 8 hrs which otherwise would take about 16 - 18 hrs in prior art processes when halogen groups were used as leaving groups during N-alkylation of desloratadine. Moreover, the process of present invention provides Rupatadine with good yields and a purity of greater than 99.5%.
Thus, the present invention provides a facile, efficient and easy route for obtaining Rupatadine in faster reaction times with high yield & high purity, without the use of pYiase transfer catalyst orb'ip'nasLC solvent system.
Compound of Formula 3 is obtained from 5-methyi nicotinic acid by its conversion to its methyl ester which gets converted to 3-(hydroxymethyl)-5-rnethylpyridine.HCl which further undergoes halogenation and then purification to yield compound of Formula 3.
As N-alkylation of desloratadine is carried out with known amounts of compound of Formula 3, less amount of unreacted desloratadine remains after the completion of the reaction. Thus, the present invention reduces wastage of the reactant material and provides an economical process for preparation of Rupatadine.
The pure Rupatdine base is further treated with organic acids such as fumaric acid, to obtain corresponding Rupatadine salts such as Rupatadine fumarate.


General method of preparation of Rupatadine (Formula 1):
In a round bottom flask under an atmosphere of nitrogen, charge sodium hydride, THF & DMF. Stir the contents for a few minutes followed by dropwise addition of Desloratadine of Formula 2 in THF & DMF. After completion of the addition, stir the reaction mixture for about an hour followed by addition of catalytic amount of sodium iodide. Add compound of Formula 3 lotwise & slowly heat the reaction mixture to 40-50° C. Continue stirring for further 3-4 hrs. Monitor the progress of the reaction by HPLC, if Desloratadine is <5% then proceed for work-up.
Charge water and ethyl acetate in another round bottom flask, and cool its contents to 0-5°C. Charge the reaction mass from the first round bottom flask into the second round bottom flask while maintaining the temperature between 0-5 °C. Stir the contents of round bottom flask for Vi hr. Separate the organic layer. Extract aqueous layer with ethyl acetate. Combine both the organic layers, and dry over sodium sulphate. Distill under vacuum at 45-50°C to obtain crude rupatadine base of Formula 1 in 75% yield which is further purified to obtain Rupatadine base with a purity of >99.5% and a yield of about 60%.
The pure Rupatdine base is then treated with organic acids such as fumaric acid, to obtain corresponding Rupatadine salts such as Rupatadine fumarate.
Preparations of compound of Formula 3 are widely described in literature and can be easily prepared from conventional methods.


Examples: Example 1
a) Preparation of Rupatadine:
In a four-necked round bottom flask under an atmosphere of nitrogen, charged sodium hydride (56.1gms), THF (200 mL) & DMF (100 mL). Stirred the contents for a few minutes followed by dropwise addition of Desloratadine (139.2gms) of Formula 2 in (700ml) of THF & DMF (lOOmL). After completion of the addition, stirred the reaction mixture for about an hour followed by addition of catalytic amount of sodium iodide, added, 3-(chloromethyl)-5-methylpyridine hydrochloride salt of Formula 3, lotwise & slowly heated the reaction mixture to 40-50 °C. Continued stirring for further 3-4 hrs. Monitored the progress of the reaction by HPLC, if Desloratadine is <5% then proceeded for work-up.
Charged water (3.5 1) and ethyl acetate (2 1) in another round bottom flask, and cooled its contents to 0-5°C. Charged reaction mass from the first round bottom flask into the second round bottom flask while maintaining the temperature at 0°- 5 °C. Stirred the contents for Vi hr. Separated the organic layer. Extracted aqueous layer with ethyl acetate (2 1) . Combined both the organic layers and dried over sodium sulphate. Distilled under vacuum at 45-50°C to obtain crude Rupatadine base (225 gms) of Formula 1. Yield -75%
b) Purification of Rupatadine:

Charged the crude Rupatadine base (225 g) obtained from Step a) and methanol (1250 ml), with stirring, in a round bottom flask. Cooled the mixture to 0-5°C. Added a solution of isopropyl alcohol prepared in HC1, to the resulting mixture, till pH of the solution is 1 - 2. After the addition, maintained the temperature at 0-5 °C for 1 hr to obtain Rupatadine hydrochloride salt as a solid. Filtered the solid under vacuum and washed with chilled methanol (125 ml x 3). Suck dried for 20 min to obtain crude wet Rupatadine.HCl (340 g)-
Charged resulting crude wet Rupatadine.HCl (340 g) and water (1 L) into round bottom flask. Stirred at room temperature for 10-15 mins till clear solution is observed. Added 20% NaOH solution dropwise, to adjust the pH to 10-11. Added ethyl acetate (750 ml) and stirred for 15-20 mins. Separated the organic layer. Extracted aqueous layer with 750 ml of ethyl acetate. Combined both the organic layers and dried over sodium sulphate to obtain wet Rupatadine base. Distilled Rupatadine base under vacuum at 45-50°C to obtain dry & pure Rupatadine base (175 g). Yield = 60%
Example 2
a) Preparation of Rupatadine fumarate.
Charged Fumaric acid (58.5 g), methanol (750 ml) and ethyl acetate (750 ml) in a round bottom flask. Stirred the solution at room temperature for 30 minutes to obtain clear solution. Added pure Rupatadine base solution prepared by dissolving pure Rupatadine base ( 175 g ) in ethyl acetate (250 ml) and methanol (250 ml). Cooled the contents to 5-10°C till a solid is observed, continued the stirring for further 1 hr at 5-10°C. Filtered the solid under vacuum and washed with chilled ethyl acetate (500 ml). Suck dried for 30 min to obtain crude wet Rupatadine fumarate (310 g). Dried in oven at 65-70°C for 8-10 hrs to obtain crude dry Rupatadine fumarate (150 g).
b) Purification of Rupatadine fumarate
Charged Rupatadine fumarate (148 gms) obtained from Step a), and methanol (1 1) in a round bottom flask. Heated the contents to reflux and maintained at reflux for I hour.

Cooled the contents to room temperature. Further cooled the contents to 10-15°C. Stirred the content for 1 hr at 10-15°C. Filtered the solid under vacuum. Washed with chilled methanol (150 ml). Dried the solid at 60-65°C for 8-10 hrs to obtain pure Rupatadine Fumarate (132 gm s).
Example 3
a) Preparation of 3-(hydroxyrnethyl)-5-rnethylpyridine.HCl

Charged 5- methylnicotinic acid (150 gms) and methanol (1050 ml) in a round bottom flask set up on a water bath. Stirred continuously. Cooled the reaction mass to 10-15°C. Added sulphuric acid slowly at 10-30°C. Heated the reaction mass to reflux (66-70 °C). Digested the reaction mass at 66-70X for 5 hrs. After completion of the reaction distilled out methanol under vacuum. After complete distillation, cooled to room temperature and then cooled to 10-15 °C. Added water (300 ml) and dichloromethane (450 ml) and stirred for 15 mins. Adjusted the pH of reaction mass to 7-8 by using sodium bicarbonate solution. Extracted aqueous layer using dichloromethane (45.0 ml x 2). Distilled out clear solution completely at 40-50°C. Cooled to room temp. Added methanol (900 ml). Cooled to 15-20 °C. Added sodium borohydride (lOOg) lotwise at 20-30°C. Stirred the reaction mass at 3.0-40°C for 15 hrs till completion of the reaction and then distilled out methanol under vacuum. After complete distillation, cooled to room temperature. Diluted reaction mass with 750 ml water. Adjust pH of reaction mass to 7-8 by using dilute HC1 (45 ml). Added dichloromethane (450 ml) and stirred for 30 min. Filtered the reaction mass to remove inorganic salts. Separated two layers. Extracted aqueous layer using dichloromethane (200 ml x 2). Combined all dichloromethane layers. Distilled out clear solution at 50-55°C and the oily mass left behind is 3-(hydroxymethyl)-5-methylpyridine. Charged the resulting oily mass and acetone (900 ml) with stirring in round bottom flask. Cooled to 0-5°C. Added isopropyl alcohol hydrochloride (200 ml=10%) dropwise to

adjust pH= 2-3 for precipitation. Stirred at 0-5°C for 2 hrs. Filtered & washed with chilled acetone (100 ml). Dried in oven at 60-65°C to obtain dry 3-(hydroxymethyl)-5-methylpyridine.HCl (110 g).
b) Preparation of 3-(chloromethyl)-5-rnethylpyridine.HCl (Formula 3)

Charged the hydroxy compound (110 gms) obtained from Step a), and DCM (550 ml) in a round bottom flask under stirring. Added DMF (7.5 ml). Cooled the reaction mass to 15-20°C. Added thionyl chloride slowly at 15-20°C for 30 mins. Stirred the reaction mass at 15-20°C for 30 min then at 35-40°C for 1 hr. Distilled out excess of thionyl chloride at 35-40°C under vacuum. Removed traces of thionyl chloride by stripping with DCM (220 ml x 3). Cooled to room temperature. Added ethyl acetate (550 ml) and stirred for 1 hr at room temp. Filtered under vacuum and washed with ethyl acetate (275 ml). Dried crude compound at 70-75 °C to obtain dry crude 3-(chloromethyl)-5-methylpyridine.HCl (119 gms). Purified the resulting dry crude compound with isopropyl alcohol/carbon to yield dry, pure 3-(chloromethyl)-5-methylpyridine.HCl (102 gms).

We claim:
1. An improved process for preparation of Rupatadine of Formula 1


with a compound of Formula 3,
Formula 1 comprises N-alkylation of desloratadine of Formula 2

where L is a leaving group selected from chloro, bromo, iodo or tosylate,
in presence of sodium hydride, a catalytic amount of sodium iodide and a solvent system.
2. The process for preparation of Rupatadine as claimed in claim 1, wherein the solvent system comprises tetrahydrofuran and dimethylformamide.
3. The process for preparation of Rupatadine as claimed in claim 1, wherein the process is carried out at a reaction temperature of 40° - 50°C.

4. The process for preparation of Rupatadine as claimed in claim 1, wherein the process yields Rupatadine in a short reaction time of 6 - 8 hrs.
5. The process for preparation of Rupatadine as claimed in claim 1, wherein the process yields Rupatadine with a purity of greater than 99.5%.