FIELD OF INVENTION:
The invention particularly relates to a process of preparation of Loratadine intermediate 11 -(N-methyl-4-piperidinylidine)-8-chloro-6,11 -dihy dro-5H-benzo(5,6)cy clohepta(l ,2-b)pyridine (Compound of formula I) by extra purging of BF3 in l-methyl-4-piperidinyl-[3-[2-(3-chlorophenyl]-2-pyridinyl]methanone hydrochloride (Compound of formula IV) in HF. The purified Loratadine intermediate is having ll-(N-Methyl-4-piperidinyl)-l l-Fluoro-8-chloro-6, 1 l-dihydro-5H-benzo(5,6)cyclohepta (l,2-b)pyridine (Compound of formula II) <0.10% which ultimately results in substantially pure (almost impurity free) Loratadine (API; Compound of formula III) without extra purification. This ll-(N-Methyl-4-piperidinyl)-ll-hydroxy-8-chloro-6, ll-dihydro-5H-benzo(5,6) cyclohepta (l,2-b)pyridine (Formula II) compound is otherwise difficult to remove by traditional purification processes as disclosed in prior art.

CH3
Formula I

CH3

Formula II

CO2C2H5
Formula III

Formula IV
BACKGROUD OF INVENTION:
Loratadine, chemically known as 8- chloro-ll-(l-ethoxycarbonyl -4-piperidylidene)-6,11-dihydro -5 H-benzo[5,6]cyclohepta [1,2-b] pyridine is a non-sedating type anti¬histamine Hi receptor antagonist having structure of formula III

C02C2H5
Formula III
It is useful as anti-allergant for the treatment of allergic asthma, allergic seasonal rhinitis, diabetic retinopathy and small vessel disorders associated with the diabetic mellitus. It possesses low central nervous system (CNS) activity indicative of non-sedation.

U.S. Pat. No. 3,326,924 (Villani et al) discloses processes for preparing various aza-dibenzo[a,d]-cycloheptene derivatives which involve production of a tricyclic ketone which is reacted with a Grignard reagent derived from 4-chloro-N-methyl piperidine. Dehydration gives the N-methyl product. The process is, however, hindered by the amount up to 30% of 1,6-addition product which is generated in the Grignard reaction causing problems in yield and purification. U.S. Pat. No. 4,282,233 (Villani) discloses the preparation of loratadine from the product of the above reaction by demethylation/carboethoxylation.
Cid et al have reported (Tetrahedron, 1988, Vol 44, 6197-6200) that cross coupling reactions between a tricyclic ketone and a cyclic ketone can take place using low valent titanium to give biphenylmethylene piperidines or cyproheptadine. The process suffers from the disadvantages that low valent titanium has to be generated using lithium metal which is hazardous on industrial scale and by the need to use about 12 equivalents of titanium reagent to prevent the reaction stopping at the diol stage. In order to meet the stringent purity standards as per the ICH guidelines as well as to be competitive in the market, there was the requirement of cost-effective route for the manufacturing of Loratadine. Due to this reason, cost effective shorter route of Loratadine was followed.
A synthetic route to loratadine is disclosed in U.S. Pat. No. 4,659,716 (Villani et al), U.S. Pat. No. 4,731,447 (Schumacher et al), U.S. Pat. No. 4,873,335 (Schumacher et al) and Journal of organic Chemistry, 1989, Vol 54, 2242-2244 (Schumacher et al.) which involves alkylation of the dianion of the t-butylamide of 2-cyano-3-methyl-pyridine, re¬generation of the nitrile, Grignard reaction, cyclisation with HF/BF3 and demethylation/carboethoxylation. This process is, however, hampered by the need to use hazardous organometallic reagents (LDA or butyl lithium) and a super-acid environment of liquid HF and BF3gas. It involves the use of 2-cyano-3-(3-chlorophenthyl)pyridine as starting raw material which is reacted with a Grignard reagent of l-Methyl-4-chloropiperidne to give (1 methyl-4-piperidinyl)[3-[2-(3-chloro phenyl]-2-pyridinyl]methanone hydrochloride (compound of formula IV). The compound of formula IV is undergoes ring closure by its reaction in a super acid such as Hydrochloric acid and Boron trifluoride followed by dehydration to give 11 -(N-methyl-4-piperidinylidine)-8-chloro-6,ll-dihydro-5H-benzo(5,6) cyclohepta(l,2-b) pyridine. It

was observed by us after various lab experiments that it contains one impurity which is not reduced even by repeated purification and results yield loss. This impurity was identified by us the compound of formula II which is formed as intermediate during reaction and its unreacted content are not reduced even by repeated purification and results yield loss.
Therefore, there was a need of the purification process for Loratadine intermediate 11-(N-methyl-4-piperidinylidine)-8-chloro-6,ll-dihydro-5H-benzo(5,6)cyclohepta(l,2-b)pyridine for removal of compound of formula II.
SCOPE OF THE INVENTION:
The present invention describes improved processes for the purification of highly pure Loratadine intermediate 1 l-(N-methyl-4-piperidinylidine)-8-chloro-6,l l-dihydro-5H-benzo(5,6)cyclohepta(l,2-b) pyridine containing ll-(N-Methyl-4-piperidinyl)-ll-hydroxy-8-chloro-6, ll-dihydro-5H-benzo(5,6) cyclohepta (l,2-b)pyridine (Formula II) compound below 0.10 % by HPLC.




_► HO
HF / BF3 (In situ)

(l-methyl-4-prperidinyl)[3-[2-(3-
chlorophenyl]-2-pyridinyl]
methanone hydrochloride.
(Formula IV)
Mol. Wt : QoHaNjOCLHCl
Mol. Wt : 379.31

Formula II (in-situ)

1 l-(N-methyl-4-piperidinylidine)-8-chloro-6,l 1-
dihydro-5H-benzo(5,6) cyclohepta(l,
b)pydridine (Formula I)
Mol. Wt : C2„H21C1N2 Mol. Wt : 324.90

Schematic Representation

DETAILED DESCRIPTION OF THE INVENTION:
According to the first embodiment of the present invention, an improved process for the
preparation as well as purification of Loratadine intermediate ll-(N-methyl-4-
piperidinylidine)-8-chloro-6,ll-dihydro-5H-benzo(5,6) cyclohepta(l,2-b)pyridine
(Formula I) which comprises:
1) charging ofHF at-50 to-60 °C.
2) adding l-methyl-4-piperidinyl-[3-[2-(3-chlorophenyl]-2-pyridinyl]methanone hydrochloride with stirring
3) Purging of Boron Trifluoride (BF3) gas at -50 to -60 °C.
4) stirring of reaction mass for 12-15 hrs at -50 to -60 °C.
5) Reaction monitoring for absence of l-methyl-4-piperidinyl-[3-[2-(3-chlorophenyl]-2-pyridinyl]methanone hydrochloride by HPLC.
6) Extra purging of Boron Trifluoride (BF3) gas
7) Further stirring of reaction mass for 2-4 hrs at -50 to -60 °C.
8) Reaction monitoring for absence of ll-(N-Methyl-4-piperidinyl)-ll-Fluoro-8-chloro-6, ll-dihydro-5H-benzo(5,6)cyclohepta (l,2-b)pyridine (Formula II) by HPLC.
9) Quenching of reaction mass in aq KOH solution 0 -15°C.
10) Extraction of 1 l-(N-methyl-4-piperidinylidine)-8-chloro-6,l l-dihydro-5H-benzo(5,6) cyclo hepta(l,2-b)pyridine (Formula I) with Toluene at 35-45°C.
11) Washing of Toluene layer with water
12) Complete recovery of Toluene at 70-80°C under vacuum.
13) charcoaling of reaction mass of step (12) followed by filtration through hyflow bed at 65-70 °C.

14) partial recovery of hexanes filtrate obtained in step (14) till crystallization starts at 65-70 °C.
15) Cooling of reaction mass to 0-5 °C with stirring.
16) Isolation of wet cake by filtration & running washing with chilled hexanes at 0-5 °C.
17) Drying of wet cake obtained in step (16) at 60-70 °C for 6-10 hours.
According to one aspect of the present invention, the reaction temperature in step (3,4 & 6,7) is -40-60 °C, more preferably 50-60 °C & most preferably 55-60 °C for removal of 1 l-(N-Methyl-4-piperidinyl)-l l-Fluoro-8-chloro-6,l l-dihydro-5Hbenzo(5,6)cyclohepta (l,2-b)pyridine (Formula II).
Although the invention has been described with reference to several to a specific example, it will be appreciated by those skilled in the art that the invention may be embodied in many other forms. The processes of the present invention will be explained in more detail with reference to the following non limiting examples, which are provided by the way of illustration only and should not be constructed as limit to the scope of the claims in any manner.
EXAMPLES:
Example 1:
Preparation of crude ll-(N-methyl-4-piperidinylidine)-8-chloro-6,ll-dihydro-5H-benzo(5,6) cyclohepta(l ,2-b)pyridine
Hydrogen fluoride (300 Liter) was charged in a precooled reactor at temperature -50 to -60 °C followed by charging of (1 methyl-4-piperidinyl)[3-[2-(3-chloro phenyl]-2-pyridinyl]methanone hydrochloride (200 Kg) to this pre-cooled reactor followed by stirring at -40 to -50 for 25-30 minutes. The borontrifluoride gas (150 Kg) was slowly purged at -50 to -60°C to the resulting reaction mass by further stirring till reaction completion at —50 to -60 °C in 10-15 hours. The reaction was monitored on HPLC (starting material LN8 should be < 1.0 %). Then boron trifluoride gas (5 Kg) is further slowly purged at -50 to -60°C to the resulting reaction mass by further stirring till reaction completion at —50 to -60 °C in 3-5 hours. The reaction was monitored on

HPLC (Impurity ll-(N-Methyl-4-piperidinyl)-ll-hydroxy-8-chloro-6, ll-dihydro-5H-benzo(5,6) cyclo hepta(l,2-b)pyridine (Formula II) should be < 0.30 %). In another reactor potassium hydroxide (900 Kg) was charged in water (4000 Liter) and stirred and cooled to 0-5 °C. The reaction mass is slowly poured in the aqueous KOH solution. The toluene (1200 Liter) is charged followed by addition of potassium hydroxide to adjust the pH to 7.5 to 8.0. The reaction mass was heated to 35-40 °C followed by stirring and layer separation. The aqueous layer is re-extracted with toluene (400 L) followed by layer separation. The combined toluene layer, thus obtained, is given washing with 10% sodium chloride solution followed by layer separation. The solvent toluene was recovered completely under vacuum to get product ll-(N-methyl-4-piperidinylidine)-8-chloro-6,ll-dihydro-5H-benzo(5,6) cyclohepta(l,2-b)pyridine as residue, which was purified by recrystallization in hexane to get desire product of Formula I.
Purity by HPLC = 99.50%, ll-(N-Methyl-4-piperidinyl)-ll-hydroxy-8-chloro-6, ll-dihydro-5H-benzo(5,6) cyclohepta (l,2-b)pyridine (Formula II) = Not Detected

WE CLAIMS

1. An improved process for Loratadine intermediate 1 l-(N-methyl-4-piperidinylidine)-8-chloro-6,ll-dihydro-5H-benzo(5,6) cyclohepta(l,2-b)pyridine which comprises:
a) charging of HF at -50 to -60 °C.
b) adding(l-methyl-4-piperidinyl)[3-[2-(3-chlorophenyl]-2-pyridinyl]methanonehydro chloride (Formula IV) with stirring
c) Purging of Boron Trifluoride (BF3) gas.
d) stirring of reaction mass for 12-15 hrs at -50 to -60 °C.
e) Reaction monitoring for absence of l-methyl-4-piperidinyl-[3-[2-(3-chlorophenyl]-2-pyridinyl]methanone hydrochloride by HPLC.
f) Extra purging of Boron Trifluoride (BF3) gas
g) Further stirring of reaction mass for 2-4 hrs at -50 to -60 °C.
h) Reaction monitoring for absence of ll-(N-Methyl-4-piperidinyl)-ll-
hydroxy-8-chloro-6, ll-dihydro-5H-benzo(5,6) cyclohepta (l,2-b)pyridine (Formula II) by HPLC.
i)Quenching of reaction mass in aq KOH solution 0 -15°C.
j)Extraction of 1 l-(N-methyl-4-piperidinylidine)-8-chloro-6,l l-dihydro-5H-benzo(5,6)cyclohepta (l,2-b)pyridine (Formula I) with Toluene at 35-45°C.
k) Washing of Toluene layer with water
l)Complete recovery of Toluene at 70-80°C under vacuum.
m) charcoaling of reaction mass of step (12) followed by filtration through
hyflow bed at 65-70 °C.
n) partial recovery of hexanes filtrate obtained in step (14) till
crystallization starts at 65-70 °C.
o) Cooling of reaction mass to 0-5 °C with stirring.

p) Isolation of wet cake by filtration & running washing with chilled
hexanes at 0-5 °C.
q) Drying of wet cake obtained in step (16) at 60-70 °C for 6-10 hours.
2. A process of claim 1, wherein the reaction temperature in step (iv) is 40-60 °C, more preferably 50-60 °C & most preferably 55-60 °C.
3. A process of claim 1, wherein the aliphatic ester used in step (ix) can be selected from ethyl acetate, propyl acetate, isopropyl acetate or mixture thereof.
4. A process of claim 1, wherein the aromatic hydrocarbon used in step (ix) can be selected from toluene, o-xylene, m-xylene or p-xylene or mixture thereof.
5. A process of claim 1, wherein the given process is specific for removal of 11-(N-
Methyl-4-piperidinyl)-l l-Fluoro-8-chloro-6,l l-dihydro-5H-
benzo(5,6)cyclohepta(l,2-b)pyridine impurity (compound of formula II) from
Loratadine intermediatel l-(N-methyl-4-piperidinylidine)-8-chloro-6,l 1-dihydro-
5H-benzo(5,6)cyclohepta(l,2-b)pyridine