FIELD OF INVENTION:
The invention particularly relates to a purification process of Loratadine intermediate 11-(Nmethyl-
4-piperidiny1idine)-8-chloro-6,11- dihydro-5H-benzo(5,6)cyclohepta(1,2-b)pyridine
(compound of formula I) by its treatment with sulphuric acid followed by routine crystallization.
The purified loratadine intermediate is having 1 1 -(N-Methyl-4-piperidinyl)-l l -Fluoro-8-chloro-
6, 11-dihydro-5H-benzo(5,6) cyclohepta (1,2-b)pyridine impurity (compound of formula 11)
<0.10% which ultimately results in substantially pure (almost impurity free) Loratadine (API)
without extra purification. Also disclosed is a process for preparation of Loratadine using
sulphuric acid for its purification which also leads to reduction1 removal of its respective ethyl 4-
[(I 1R S)-8-chloro-1 1 - fluoro-6,11 -dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-1 1 -
yllpiperidine-1-carboxylate (LHIOF; Formula IV) along with reduction of another impurity at
RT - 22 minutes (RRT 1.40) which is otherwise difficult to remove by traditional purification
processes as disclosed in prior art.
Formula I
Formula ZZ
ethyl 4-[(I 1 R S)-8-chloro-11- fluoro-6I,1 -dihydro-5H-benzo[5,6]cyclohepta[l,2-b]pyridin-ll-
Formula ZV (LHl OF)
4-[(I 1R S)-8-chloro-11-fluoro-6,I 1 -dihydro-5H-benzo[ 5,6] cyclohepta [1,2-b]
(Formula VJ
BACKGROUD OF INVENTION:
Loratadine, chemically known as 8- chloro- 1 1 -(1 -ethoxycarbonyl -4-piperidy1idene)-6,lldihydro
-5 H-benzo[5,6]cyclohepta [1,2-b] pyridine is a non-sedating type anti-histamine HI
receptor antagonist having structure of formula I11
Formula ZZZ
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.
Various compounds having antihistaminic activity including Loratadine and process for their
preparation are disclosed in U.S. Patent nos. 3,326,924; 3,717,647, 4,282,233, 4,659,716,
4,731,447,6,608,202 and Journal of Medicinal Chemistry, 1972, Vol. 15, No. 7, pp 750-754.
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.
2 1 MAR 2011
2-cyano-3-(3-chlorophenthy1)pyridine as starting raw material which is reacted with a Grignard
reagent of 1-Methyl-4-chloropiperidne to give (1 methyl-4-piperidinyl)[3-[2-(3-chloro phenyll-
2-pyridinyllmethanone 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-piperidiny1idine)-8-chloro-11-
dihydro-5H-benzo(5,6)cyclohepta(1,2-b) pyridine having 1.5-2.5 % of 1 1 -fluoro impurity
(compound of formula II).This impurity does not reduce during purification at intermediate
stage. This intermediate on further treatment with an arnine such as triethylamine or
diisopropylethylamine in anhydrous toluene at about 80 "C undergoes reaction with
etkylchloroformate to give final product 8- chloro- 1 1 -(1 -ethoxycarbonyl -4-piperidy1idene)-6,lldihydro-
5H-benzo[5,6]cyclohepta [I ,2-b] pyridine i.e. Loratadine containing about same level
(1.5-2.5 %) of 1 1 -(N-Methyl-4-piperidiny1)- 1 1 -Fluoro-8-chloro-6, 1 1 -dihydro-5H-benzo(5,6)
cyclohepta (1,2-b)pyridine impurity (compound of formula 11) of Loratadine which is reduced
only by repeated purification and results yield loss.
Therefore, there was a need of the purification process for Loratadine intermediate 11-(Nmethyl-
4-piperidiny1idine)-8-chloro-6,1-1d ihydro-5H-benzo(5,6)cyclohepta(1,2-b) pyridine for
removal of this 1 1 -fluoro impurity of compound of formula 11.
SUMMARY OF THE INVENTION:
The present invention describes improved processes for the purification of highly pure Loratadine
intermediate 11 - (N-methyl-4-piperidiny1idine)-8-chloro-1, 1 - dihydro-5Hbenzo(
5,6)cyclohepta(l,2-b) pyridine containing critical 11-fluoro impurity below 0.10 % by
HPLC which ultimately results almost impurity free Loratadine. The analogous method is also
applicable on the purification of Loratadine as well as Desloratadine API.
DETAILED DESCRIPTION OF THE INVENTION:
According to the first embodiment of the present invention, an improved process for the
purification of Loratadine intermediate 1 1 - (N-methyl-4-piperidiny1idine)-8-chloro-6,1-1d ihydro-
5H-benzo(5,6) cyclohepta(l,2-b) pyridine which comprises:
1) charging of sulphuric acid at 10-30 "C.
2) cooling of sulphuric acid under stirring to 8- 12 "C.
3) adding 11 - (N-methyl-4-piperidiny1idine)-8-chloro-1,1 - dihydro-5Hbenzo(
5,6)cyclohepta (1,2-b) pyridine containing 1.5-2.5 % of 1 1 -fluoro impurity
(compound of formula 11) in cooled sulphuric acid of step (2).
4) heating of the reaction mass.
5) stirring of reaction mass for 12-24 hrs at 40-60 "C.
6) Reaction monitoring for absence of 11-fluoro impurity (compound of formula 11) by
HPLC.
7) cooling of reaction mass to 8- 12 "C.
8) addition of reaction mass of step (7) in water at 8-12 "C.
9) addition of an aliphatic ester or aromatic hydrocarbon with stirring at 10-30 "C.
10) adjustment of pH to 8-9 by sodium hydroxide
- I
, : - . 4 1 3L 1 1) stirring and layer separation.
12) complete recovery of solvent under vacuum to get semi solid at 65-70 "C.
13) dissolving semi solid obtained in step (12) above in hexanes 65-70 "C.
14) charcoaling of reaction mass of step (13) followed by filtration through hyflow bed at 65-
70 "C.
15) partial recovery of hexanes filtrate obtained in step (14) till crystallization starts at 65-70
"C.
16) Cooling of reaction mass to 0-5 "C with stirring.
17) Isolation of wet cake by filtration & running washing with chilled hexanes at 0-5 "C.
18) Drying of wet cake obtained in step (17) at 60-70 "C for 6-10 hours.
According to one aspect of the present invention, the reaction temperature in step (4) is 40-60 "C,
more preferably 50-60 "C & most preferably 55-60 "C for removal of impurity of formula 11.
According to another aspect of present invention, the aliphatic ester used can be selected from
ethyl acetate, propyl acetate, isopropyl acetate or a mixture thereof.
According to yet another aspect of present invention, the aromatic hydrocarbon used can be
selected from toluene, o-xylene, m-xylene, p-xylene or a mixture thereof.
According to second embodiment of the present invention, an improved process for the
purification of 8- chloro- 1 1 -(1 -ethoxycarbonyl -4-piperidy1idene)-6,ll -dihydro -5 Hbenzo[
5,6]cyclohepta [1,2-b] pyridine or Loratadine which comprises:
1) charging of sulphuric acid at 10-30 "C.
2) cooling of sulphuric acid under stirring to 8-12 "C.
3) adding 8-chloro- 1 1 -(1 -ethoxycarbonyl-4-piperidy1idene)-6,11 -dihydro-5Hbenzo[
5,6]cyclo hepta[l,2-b] pyridine or Loratadine containing -14 % of 11-fluoro
impurity (compound of formula IV) in cooled sulphuric acid of step (2).
4) heating & stirring of the reaction mass till complete dissolution.
5) stirring of reaction mass for 50-60 min at 35-45 "C.
6) Reaction monitoring for absence of ethyl 4-[(l l RS)-8-chloro-l l -fluoro-6,11 -dihydro-
5H-benzo[5,6]cyclohepta[1,2-blpyridin-1 1 - yl]piperidine- 1- carboxylate (LH 1O F;
Formula IV) & unknown impurity at RRT 1.40 by HPLC.
7) cooling of reaction mass to 8-12 "C.
8) addition of reaction mass of step (7) in water at 8-12 "C.
9) addition of an aliphatic ester or aromatic hydrocarbon with stirring at 10-30 "C.
10) adjustment of pH to 8-9 by sodium hydroxide
1 1) stirring and layer separation.
12) complete recovery of solvent under vacuum to get semi solid at temperature below 85 "C.
13) trituration of semi-solid purified product in an straight chain or branched chain ether and
again performed its complete recovery under vaccum at temperature below 85 "C.
14) drying of final material at 50-55 "C
.'.--.- a p'"" 1 , .' . - . & 4: '-
According to one aspect of ihe second embodiment, the reaction temperature in step 4 is 30-50 "C,
more preferably 35-50 "C & most preferably 35-45 "C for removal of at impurity ethyl 4-[(11RS)-
8-chloro- 1 1 - fluoro-6,11 -dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-1 1- yl]piperidine- 1-
carboxylate ( LH1 OF; Formula IV) & Unknown impurity RRT 1.40.
According to another aspect of the second embodiment, the aliphatic ester in step 9 used can be
selected from ethyl acetate, propyl acetate, isopropyl acetate or a mixture thereof.
According to yet another aspect of the second embodiment, the aromatic hydrocarbon used in
step 9 can be selected from toluene, o-xylene, m-xylene, p-xylene or a mixture thereof.
According to still another aspect of the second embodiment, the straight chain or branched chain
ether used in step 13 can be selected from diisopropyl ether, dimethyether, dimethyl ether methyl
tert butyl ether or mixture thereof.
According to third embodiment of the present invention, an improved process for the purification
of 8-Chloro-6,ll -dihydro- 1 1 -(4-piperidinylidene)-5H-benzo[5,6]cyclohepta[l,2-b]pyridine or
desloratadine which comprises:
1) charging of sulphuric acid at 10-30 "C.
2) cooling of sulphuric acid under stirring to 8-12 "C.
3) adding 8-Chloro-6,11 -dihydro-1 1 -(4-piperidinylidene)-5H-benzo[5,6]cyclohepta[l,2-b]
pyridine or desloratadine containing -1 4 % of 4-[(I 1 RS)-8-chloro- 1 1 -fluoro-6,lldihydro-
5H-benzo [5,6] cyclohepta [1,2-blpyridin-11-yllpiperidine (1 1-fluoro impurity;
Formula V) in cooled sulphuric acid of step (2).
4) heating & stirring of the reaction mass till complete dissolution.
9
5) stirring of reaction mass for 50-60 min at 35-45 "C.
6) Reaction monitoring for absence of 4-[(I 1 RS)-8-chloro- 1 1 -fluoro-6,11 -dihydro-5Hbenzo
[5,6] cyclohepta [1,2-blpyridin- 1 1 -yl]piperidine (1 1 -fluoro impurity; Formula
V) .
7) cooling of reaction mass to 8- 12 "C.
8) addition of reaction mass of step (7) in water at 8-12 "C.
9) addition of an aliphatic ester or aromatic hydrocarbon with stirring at 10-30 "C.
10) adjustment of pH to 8-9 by sodium hydroxide
1 1) stirring and layer separation.
12) complete recovery of solvent under vacuum to get semi solid at temperature below 85 "C.
13) trituration of semi-solid purified product in an straight chain or branched chain ether and
again performed its complete recovery under vaccum at temperature below 85 "C.
14) drying of final material at 50-55 "C
According to one aspect of the third embodiment, the reaction temperature in step 4 is 30-50 "C,
more preferably 35-50 "C & most preferably 35-45 "C for removal of at impurity 4-[(llRS)-8-
chloro-11 -fluoro-6,11 -dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11 -yl]piperidine (1 1 -fluoro
impurity; Formula V) .
According to another aspect of the third embodiment, the aliphatic ester in step 9 used can be
selected from ethyl acetate, propyl acetate, isopropyl acetate or a mixture thereof.
According to yet another aspect of the third embodiment, the aromatic hydrocarbon used in step
9 can be selected from toluene, o-xylene, m-xylene, p-xylene or a mixture thereof.
According to still another aspect of the third embodiment, the straight chain or branched chain
ether used in step 13 can be selected from diisopropyl ether, dimethyether, dimethyl ether methyl
tert butyl ether or mixture thereof.
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 ll-~-methyl-4-piperidinylidine)-8-chlor~6,ll-dihydro-5H-benzo(5,6)
cyclohepta(l,2-b)pyridine
Hydrogen fluoride (300 Liter) was charged in a precooled reactor at temperature -45 to -55 "C
followed by charging of (1 methyl-4-piperidinyl)[3-[2-(3-chloro phenyll-2-pyridinyllmethanone
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 -35 to -45 OC to the resulting
reaction mass by further stirring till reaction completion at -35 to -45 OC in 3-5 hours. The
reaction was monitored on HPLC (starting material should be < 1.0 %). In another reactor
potassium hydroxide (900 Kg) was charged in water (4000 Liter) and stirred and cooled to 0-5
OC. The reaction mass is slowly poured in the aqueous KOH solution. The toluene (1200 Liter)
, .
2 \ MAR 20\1 I. , . . -. .... ,
i . .
<.,. OJ ; '.: ,-
is charged followed by addition of potassium hydroxide so as 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 1 1-(Nmethyl-
4-piperidiny1idine)-8-chloro-6,11- 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 = 9 7.70%, 11 -Fluor0 impurity of Formula II = 1.64%.
Example 2:
Purification of 1l-~-methyl-4-piperidinylidine)-8-chloro-6,1l-dihydro-5H-benzo(5,6)
cyclohepta(l,2-b)pyridine.
11 -(N-methyl-4-piperidiny1idine)-8-chloro-1-1d ihydro-5H-benzo(5,6) cyclohepta(l,2-b)pyridine (1 00
g) was dissolved in precooled conc. sulphuric acid (150 g) at 5-35 "C followed by heating of reaction
mass to 40-60 "C and stirring for 12-24 hours. The absence of compound of formula I1 was checked by
HPLC reaction monitoring (compound of Formula I1 should be < 0.2 %). The reaction mass is cooled to
8-12 OC & was added to pre-cooled water (1200 ml) at 8-30 "C, followed by addition of toluene (800 ml).
The pH of reaction mass was adjusted to 8-9 with caustic solution at 10-30 "C followed by stirring and
layer separation. The organic layer was given water (500 ml) washing followed by layer separation. The
aqueous layer was re-extracted with toluene (400 ml followed by layer separation. The combined organic
layers are used for complete recovery of toluene under vacuum to get mass. The mass was dissolved in
hexanes (1500 ml) at 65-70 "C to get clarity followed by carbon treatment & filtration via hyflow bed.
Partial recovery of hexane filtrate was done till crystallization starts followed by cooling of reaction mass
to 0-5 "C & stirred at 0-5 "C till complete crystallization. The resulting solid, was filtered and dried at 60-
70 "C for 6-1 1 hours to get 83.0 g of compound of formula I.
Purity by HPLC = 99.81 %, 11-jluoro impurity of Formula 11 = 0.08%; Assay = 99.78%.
Example 3:
Purification of ll-(N-methyl-4-piperidinylidine)-8-chloro-6,ll-dihydro-5H-benzo(5,6)cyc1o
1 1 - (N-methyl-4-piperidiny1idine)-8-chloro-,1 1 - dihydro-5H-benzo(5,6) cyclohepta(l,2-b)pyridine (10 0
g) was dissolved in precooled conc. sulphuric acid (150 g) at 5-35 "C followed by heating of reaction
mass to 40-60 "C and stirring for 12-24 hours. The absence of compound of formula I1 was checked by
HPLC reaction monitoring (compound of Formula I1 should be < 0.2 %). The reaction mass is cooled to
8-12 OC & was added to pre-cooled water (1200 ml) at 8-30 OC, followed by addition of toluene (800 ml).
The pH of reaction mass was adjusted to 8-9 with caustic solution at 10-30 "C followed by stirring and
layer separation. The organic layer was given water (500 ml) washing followed by layer separation. The
aqueous layer was re-extracted with toluene (400 ml followed by layer separation. The combined organic
layers are used for complete recovery of toluene under vacuum to get mass. The mass was dissolved in
hexanes (1500 ml) at 65-70 "C to get clarity followed by carbon treatment & filtration via hyflow bed.
Partial recovery of hexane filtrate was done till crystallization starts followed by cooling of reaction mass
to 3-5 ^C & stirred at 0-5 "C till complete crystallization. The resulting solid, was filtered and dried at 60-
70 "C for 6-1 1 hours to get 89.0 g of compound of formula I.
Purity by HPLC = 99.89%; 11-Fluoro impurity of Formula 11 = 0.04 %; Other Single highest
impurity = 0.05%; Assay = 99.86%.
Example 4:
Purification of ll-(N-methyl-4-piperidinylidine)-8-chloro-6,ll-dihydro-5H-benzo(5,6)cyclo
,---. fr.!7:;-.- ,:-.- '. 7-
. . --. - q . ?
i: : P .. , 2 \ MAR jtf
; . ; .'
.. ,v. .. :. . . is* $4 )..A &
, ... 1 qL d-
,,P ? . .,.,,.- ." i 'i .,=,- . - .-
3
11 - (Pi-methyl-4-piperidiny1idine)-8-chloro-6,1-1d ihydro-5H-benzo(5,6) cyclohepta(1,2-b)pyridine (100
g) was dissolved in precooled conc. sulphuric acid (150 g) at 5-35 "C followed by heating of reaction
mass to 40-60 "C and stirring for 12-24 hours. The absence of compound of formula I1 was checked by
HPLC reaction monitoring (compound of Formula I1 should be < 0.2 %). The reaction mass is cooled to
8-12 "C & was added to pre-cooled water (1200 ml) at 8-30 "C, followed by addition of toluene (800 ml).
The pH of reaction mass was adjusted to 8-9 with caustic solution at 10-30 "C followed by stirring and
layer separation. The organic layer was given water (500 ml) washing followed by layer separation. The
aqueous layer was re-extracted with toluene (400 ml followed by layer separation. The combined organic
layers are used for complete recovery of toluene under vacuum to get mass. The mass was dissolved in
hexanes (1500 ml) at 65-70 "C to get clarity followed by carbon treatment & filtration via hyflow bed.
Partial recovery of hexane filtrate was done till crystallization starts followed by cooling of reaction mass
to 0-5 "C & stirred at 0-5 "C till complete crystallization. The resulting solid, was filtered and dried at 60-
70 "C for 6-1 1 hours to get 90.0 g of compound of formula I.
Purity by HPLC = 99.71 %, 11-Fluor impurity of Formula II = 0.16 %; Other Single highest
impurity = 0.05 %; Assay = 99.66%.
Example 5:
Purification of 1l-~-methyl-4-piperidinylidine)-8-chloro-6,ll-dihydro-SHbenzof5,6)
cyclo hepta(l,2-b)pyridine.
11 - (N-methyl-4-piperidiny1idine)-8-chloro-1,1 - dihydro-5H-benzo(5,6) cyclohepta(l,2-b)pyridine
(quantity as obtained in example 1) was dissolved in precooled conc. sulphuric acid (300 Kg) at 5-35 OC
followed by heating of reaction mass to 40-60 "C and stirring for 12-24 hours. The absence of compound
of formula I1 was checked by HPLC reaction monitoring (compound of Formula I1 should be < 0.2 %).
The reaction mass is cooled to 8-12 "C & was added to pre-cooled water (2400 Liter) at 8-30 "C, followed
by addition of toluene (1 600 Liter). The pH of reaction mass was adjusted to 8-9 with caustic solution at
10-30 "C followed by stirring and layer separation. The organic layer was given water (1000 Liter)
washing followed by layer separation. The aqueous layer was re-extracted with toluene (800 Liter)
followed by layer separation. The combined organic layers are used for complete recovery of toluene
under vacuum to get mass. The mass was dissolved in hexanes (3000 Liter) at 65-70 "C to get clarity
followed by carbon treatment & filtration via hyflow bed. Partial recovery of hexane filtrate was done till
crystallization starts followed by cooling of reaction mass to 0-5 "C & stirred at 0-5 OC till complete
crystallization. The resulting solid, was filtered and dried at 60-70 OC for 6-1 1 hours to get 127.0 Kg of
compound of formula I.
Purity by HPLC = 99.88%; 11-Fluoro impurity of Formula II = not detected; Other Single
highest impurity = 0.06 %;Assay = 99.82 %
Example 6:
Purification of 8- chloro-l1-(1-ethoxycarbonyl-4-piperidylidene)d,ll-dihydro-5H-benzo
[5,6]cyclohepta [1,2-b] pyridine or Loratadine
8- chloro- 1 1 -(1 -ethoxycarbonyl -4-piperidy1idene)-6,11 -dihydro -5 H-benzo[5,6]cyclohepta
[1,2-b] pyridine or Loratadine (100 g; HPLC Purity = 85.08 %; 11 Fluoro impurity = 13.69% ,
Impurity at RRT 1.40 = 0.20%) was dissolved in precooled conc. sulphuric acid (320 g) at 8-35
"C followed by heating of reaction mass to 35-45 OC and stirring for 50-60 minutes. The absence
of ethyl 4-[(I 1 RS)-8-chloro- 1 1 -fluoro-6,11 -dihydro-5H-benzo[5,6]cyclohepta[l,2-b]pyridin1-1 -
yllpiperidine- 1 -carboxylate ( 1 1 -Fluoro impurity, Formula IV) & Unknown impurity RRT 1.40
was checked by HPLC 1 TLC (11-Fluoro impurity should be < 0.2%). The reaction mass is
cooled to 8-12 OC & was added to pre cooled water (1200 ml) at 8-30 OC, followed by addition of
toluene I ethyl acetate (500 ml). The pH of reaction mass was adjusted to 8-9 with caustic
15
solution at 10-30 "C followed by stirring and layer separation. The aqueous layer was extracted
with toluene / ethyl acetate (300 ml & 200 ml) twice. The combined organic layer was given
washing with water (250 ml) followed by layer separation. The organic layer was heated and its
complete recovery was done at max. 85 "C to get semi solid product. This semi solid material
WLS triturated with diisopropyl ether (50 ml) and its complete recovery was performed at
temperature < 85 "C, so as to remove traces of toluene / ethyl acetate. The wet mass is dried at
50-55 "C to get final purified material.
Purity by HPLC = 99.94%, 11-Fluoro impurity = Not Detected; unknown impurity at 1.40
RRT = 0.04 %; Assay = 99.85 %.
Example 7:
Purification of 8-Chloro-6,11-dihydro-ll-(4-piperidinylidene)-5Hbenzo[
5,6]cyclohepta[l,2-blpyridine or desloratadine
8-Chloro-6,ll -dihydro-1 1 -(4-piperidiny1idene)-5 H-benzo[5,6]cyclohepta[l,2-blpyridine or
desloratadine (100 g; HPLC Purity = 84.78 %; 11-Fluoro impurity = 14.09%) was dissolved in
precooled conc. sulphuric acid (320 g) at 8-35 O C followed by heating of reaction mass to 35-45
"C and stirring for 50-60 minutes. The absence of 4-[(11RS)-8-chloro-11-fluoro-6,ll- dihydro-
5H-benzo [5,6] cyclohepta[l,2-blpyridin- 1 1 -yl]piperidine (1 1 -Fluor0 impurity; Formula V) was
checked by HPLC 1 TLC (1 1 -Fluor0 impurity should be < 0.2%). The reaction mass is cooled to
8-12 "C & was added to pre cooled water (1200 ml) at 8-30 "C, followed by addition of toluene /
ethyl acetate (500 ml). The pH of reaction mass was adjusted to 8-9 with caustic solution at 10-
3C "C followed by stirring and layer separation. The aqueous layer was extracted with toluene /
ethyl acetate (300 ml & 200 ml) twice. The combined organic layer was given washing with
water (250 ml) followed by layer separation. The organic layer was heated and its complete
recovery was done at max. 85 "C to get semi solid product. This semi solid material was
triturated with diisopropyl ether (50 ml) and its complete recovery was performed at temperature
< 85 "C, so as to remove traces of toluene / ethyl acetate. The final material is dried at 50-55 "C
to get final purified material.
Purity by HPLC = 99.96%, 11-Fluoro impurity = Not Detected; Assay = 99.89 %.
We claim:
1. An improved process for the purification of 1 1-(N-methyl-4-piperidiny1idine)-8-chloro-
6,11 -dihydro-5H-benzo(5,6) cyclohepta(l,2-b)pyridine which comprises:
i. charging of sulphuric acid at 10-30 "C.
ii. cooling of sulphuric acid under stirring to 8-12 "C.
iii. adding 1 1 - (N-methyl-4-piperidiny1idine)-8-chloro-1,1 - dihydro-5H-benzo
(5,6)cyclohepta(l,2-b)pyridine in sulphuric acid of step (ii) at 8-12 "C.
iv. heating of the reaction mass.
v. stirring of reaction mass for 12-24 hrs at 40-60 "C.
vi. reaction monitoring for absence of impurity of formula I1 (HPLC content should
be not more than 0.20%)
vii. cooling of reaction mass to 8-12 OC.
... viii. addition of reaction mass of step (vii) in water at 8-12 "C.
ix. addition of an aliphatic ester or aromatic hydrocarbon with stirring at 10-30 "C.
x. adjustment of pH to 8-9 by sodium hydroxide
xi. stirring and layer separation.
xii. complete recovery of solvent under vacuum to get semi solid at 65-70 "C.
xiii. dissolving semi solid obtained in step (xii) above in hexanes 65-70 "C.
xiv. charcoaling of reaction mass of step (xiii) followed by filtration through hyflow
bed at 65-70 PC.
xv. partial recovery of hexanes filtrate obtained in step (xiv) till crystallization starts
at 65-70 "C.
xvi. Cooling of reaction mass to 0-5 "C with stirring.
xvii. Isolation of wet cake by filtration & running washing with chilled hexanes at 0-5
"C.
xviii. Drying of wet cake obtained in step (xvii) 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 as claimed in 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 as claimed in 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 as claimed in claim 1, wherein the given process is specific for removal of
1 1 -(N-Methyl-4-piperidiny1)- 1 1 -Fluoro-8-chloro-6,11 -dihydro-5Hbenzo(
5,6)cyclohepta(1,2-b)pyridine impurity (compound of formula 11) from
Loratadine intermediate 1 1 - (N-methyl-4-piperidiny1idine)-8-chloro-1,1 - dihydro-5Hbenzo(
5,6)cyclohepta(l,2-b)pyridine (compound of formula I).
6. An improved process for the purification of 8- chloro- 1 1 -(1 -ethoxycarbonyl-4-
piperidy1idene)-6,ll-dihydro -5 H-benzo[5,6]cyclohepta [1,2-b] pyridine or Loratadine
which comprises:
i. charging of sulphuric acid at 10-30 "C.
ii. cooling of sulphuric acid under stirring to 8-12 "C.
iii. adding 8- chloro-1 1 -(1 -ethoxycarbonyl -4-piperidy1idene)-6,11 -dihydro -5 Hbenzo[
5,6]cyclohepta [1,2-b] pyridine or Loratadine in sulphuric acid of step (ii)
at 8-12 "C.
iv. stirring & heating of the reaction mass.
v. stirring of reaction mass for 50-60 min at 35-45 "C.
20
vi. reaction monitoring for absence of ethyl 4-[(l l RS)-8-chloro- 1 1 -fluoro-6,lldihydro-
5H-benzo[5,6]cyclohepta[l,2-b]pyridin-ll -yl]piperidine-1 -carboxylate
(1 1 -Fluor0 impurity; Formula IV) & unknown impurity RRT 1.40 impurity
vii. cooling of reaction mass to 8-12 "C.
viii. addition of reaction mass of step (vii) in water at 8-12 "C.
ix. addition of an aliphatic ester or aromatic hydrocarbon with stirring at 10-30 "C.
x. adjustment of pH to 8-9 by sodium hydroxide
xi. stirring and layer separation.
xii. complete recovery of solvent under vacuum from organic layer to get semi solid
at temp below 85 OC.
xiii. triturating semi solid obtained in step (xii) above in diisopropyl ether followed by
its complete recovery again at temp below 85 "C.
xiv. Drying of wet cake obtained in step (xiii) at 50-55 "C for 6-10 hours
7. A process as claimed in claim 1, wherein the reaction temperature in step (iv) is 30-50
"C, more preferably 35-50 "C & most preferably 35-45 "C.
8. A process as claimed in claim 1, wherein the aliphatic ester used in step (ix) can be
selected from ethyl acetate, propyl acetate, isopropyl acetate or mixture thereof.
9. A process as claimed in 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.
10. A process as claimed in claim 1, wherein the given process is specific for removal of
ethyl 4-[(ll RS)-8-chloro- 1 1 -fluoro-6,11 -dihydro-5H-benzo[5,6]cyclohepta[l,2-
blpyridin- 1 1 -yl] piperidine- 1 -carboxylate (I 1 -Fluoro impurity; Formula IV) &
unknown impurity RRT 1.40 impurity from 8-chloro-l l -(1 -ethoxycarbonyl-4-
piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclo hepta [1,2-b] pyridine or Loratadine
(compound of formula UI).
11. A process as claimed in claim 6, 7, 8 & 9 where starting material is 8-Chloro-6,lldihydro-
1 1 -(4-piperidinylidene)-5H-benzo[5,6]cyclohepta[l,2-b]pyridine or
desloratadine & impurity that is reduced is 4-[(I 1 RS)-8-chloro- 1 1 -fluoro-6,lldihydro-
5H-benzo [5,6] cyclohepta [1,2-blpyridin- 1 1 -yl]piperidine (formula V).