Field of the invention:
The present invention relates to an improved process for the preparation of 11-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydrodibenz[b,e]oxepin-2-aceticacid compound of formula-1 and its pharmaceutically acceptable salts.

11 -[(Z)-3-(dimethylamino)propylidene]-6-11 -dihydrodibenz[b,e] oxepin-2-acetic acid hydrochloride pharmaceutically active substance known to be a known anti-allergy drug, useful for the treatment of the signs and symptoms of allergic conjunctivitis. In the United States, it is marketed by Kyowa Hakko Kogyo Co under the brand name Patanol® knd, in Europe it is marketed under the brand name Opatanol®. It has been approved for the treatment of the signs and symptoms of allergic conjunctivitis.

Background of the invention:
11 -[(Z)-3-(dimethylamino)propylidene]-6-11 -dihydrodibenz[b,e] oxepin-2-acetic acid free base and its pharmaceutically acceptable salts are described in U.S. Patent No. |4,871,865, although no specific examples for the preparation of 11-[(Z)-3-(dimethyl amino) propyHdene]-6-ll-dihydrodibenz[b,e]oxepin-2-aceticacid or its pharmaceutically acceptable salts are provided therein.

11 -[(Z)-3-(dimethylamino)propylidene]-6-l 1 -dihydrodibenz[b,e] oxepin-2-acetic
acid free base is specifically described in U.S. Patent No. 5,116,863. This U.S. patent does not provide any example describing the preparation of ll-[(Z)-3-(dimethylamino)
propylidene]-6-ll-dihydrodibenz[b,e]oxepin-2-aceticacid hydrochloride. It is believed that the11 -[(Z)-3-(dimethylamino)propylidene]-6-11 -dihydrodibenz[b,e]oxepin-2-iaceticacid hydrochloride was disclosed in US Patent No 5,116,863 (herein after "863') in 1992, assigned to Kyowa Hakko Kogyo Co., Ltd. The patent discloses the preparation of 11-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydrodibenz[b,e]oxepin-2-aceticacid through Wittig reaction by reacting l1-oxo-6,ll-dihydrodibenzo[b,e]oxepin-2-aceticacid compound of formuIa-2 with 3-dimethyl aminopropyl triphenyl phosphonium bromide hydrobromide compoimd of formula-3 in presence of base n-butyl lithium and solvent tetrahydrofuran. The obtained compound is purified by column chromatography and isolate pure ll-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydrodibenz[b,e] oxepin-2-aceticacid compound of formula-1. The detailed description of the synthesis of 1 l-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydrodibenz[b,e] oxepin-2-aceticacid and its salts has been disclosed Ohshima E. et., al by in J. Med. Chem. 1992, 35, 2074-2084.

In the above process, the cis: trans ratio of the product has not been reported. In
the above method, the preparation of ll-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydrodibenz[b,e] oxepin-2-aceticacid involves use of excess base and WJttig reagent. The isolation of pure cis isomer ll-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydrodibenz[b,e] oxepin-2-aceticacid employs the use of column chromatography. The final yield of the product is low.

Alternatively, the compound of formula-1 may be prepared by means of a
Grignard reaction, reacting compound of formula-2 with N,N-dimethyl propyl magnesium halide, the compound of formula-4 followed by dehydration with a strong acid.

The major disadvantages of the above process are non-selectivity in the formation of the E/Z isomers, and also the preparation of 1 l-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydrodibenz[b,e] oxepin-2-aceticacid involves protection and deprotection of the carboxylic acid group in formula-2 increasing the number of steps. Further, the isolation of pure compound employs the use of column chromatography. On following the above process the obtained cis; trans ratio was 10-15:90-85,

However all the processes described earlier to the present invention could not control the formation of impurities especially the E-isomer. Therefore it is necessary to develop an alternative process for preparing 11-[(Z)-3-(dimethylamino) propylidene]-6-11-dihydrodibenz[b,e]oxepin-2-aceticacid hydrochloride which overcomes the formation of E-isomer of ll-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride as well as above discussed problems. The present invention provides pure >99% z-isomer of 11-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride with good yield. The present invention avoids the purification in the final stage and provides a pure >99% of Z-isomer ck U-[(Z)-3-(dimethylamino)propylidene]-6-n-dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride according to HPLC.

Advantage of the Present invention:
The processes which were reported previous to the present invention used alkyl lithium bases for the preparation of 11-[(Z)-3-(dimethylamino)propylidene]-6-ll-oihydrodibenz[b,e] oxepin-2-aceticacid, but the reactions were preformed at low temperatures below 25-30°C, and the yield was very poor and the purity was not Satisfactory due to the formation of a mixture of E and Z isomers. It was identified that When the temperature of reaction medium was increased, the selectivity for the formation of Z-isomer in the final product increased, providing product with high purity and yield.

Brief description of the invention:
The present invention relates to an improved process for the preparation of
11-[(Z)-3-(dimethylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid or
its pharmaceutically acceptable salts.

The first aspect of the present invention is to provide pure z-isomer of
11-[(Z)-3-(dimethylamino)propylidene]-6-11 -dihydrodibenz[b,e]oxepin-2-aceticacid hydrochloride of formula-la, which comprises of reacting the ll-oxo-6, 11-dihydrobenz {b,e)oxepin-2-acetic acid compound of formula-2 with (3-dimethyl aminopropyl)-triphenyl phosphoniumbromide hydrobromide compound of formula-3 in presence of n-butyl lithium in a suitable solvent, at a temperature of about 35°C to 80°C.

Second aspect of the present invention is to provide pure z-isomer of ll-[(Z)-3-
[dimethylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride
of formula-la, which comprises of reacting the 1 l-oxo-6, 11-dihydrobenz (b,e)oxepin-2-acetic acid compound of formula-2 with (3-dimethylaminopropyl)-triphenyl phosphoniumbromide hydrobromide compound of formula-3 in presence of n-hexyl lithium in a suitable solvent, at a temperature of about 35°C to 80°C.

The third aspect of the present invention is to provide a process for the preparation of 11-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride.

The fourth aspect of the present invention is to provide a process of the conversion of E-isomer or the mixture of E&Z isomers to Z-isomer of 11-[3-(dimethylamino)propylidene]-6-11 -dihydrodibenz[b,e]oxepin-2-aceticacid hydrochloride.

Detailed description of the invention:

As used here in the term "solvent" refers to "ester solvents" refers to ethyl acetate,
methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like; "hydrocarbon solvents" refers to toluene, xylene, cyclohexane, hexane, heptane and the like; "chloro solvents" refers to dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform and the like; "polar aprortic solvents" refers to dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran and the like; "nitrile solvents" refers to acetonitrile and the like; "ketone solvents" refers to acetone,
bethyl isobutyl ketone and the like,

As used here in "acid" refers to hydrochloric acid, sulphuric acid, nitric acid and
Organic acid such as acetic acid, lactic acid, formic acid, citric acid and oxalic acid

The present invention relates to an improved process for the preparation of ll-|[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydrodibenz[b,e] oxepin-2-aceticacid or its pharmaceutically acceptable salts.

The first aspect of the present invention is to provide 1 l-[(Z)-3-(dimethylamino)propylidene]-6-l 1 -dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride of formula-la, which comprises of
a) Adding n-butyllithium to the mixture of (3-dimethylaminopropyl)-triphenyl phosphoniumbromide hydrobromide compound of formula-3 in a suitable solvent,
b) adding a solution of 11 -oxo-6,11 -dihydrobenz(b,e)oxepin-2-acetic acid compound of formula-2 in a suitable solvent,
c) heating the reaction mixture to a temperature of about 40°C to 80°C,
d) stirring the reaction mixture till the completion of the reaction,
e) quenching the reaction mixture with aqueous acid, ;

f) washing the aqueous layer with a suitable solvent,
g) neutralizing the reaction mixture with a suitable basic solution,
h) washing the aqueous layer with a suitable solvent,
i) adding hydrochloric acid and organic acid to the reaction mixture, to reduce the
pH,

j) extracting the reaction mixture with suitable solvent,
k) distilling off the solvent from organic layer,
l) isolating the obtained residue in a suitable solvent,
m) purifying the ll-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydrodibenz[b,e]
oxepin-2-aceticacid hydrochloride compound of formula-1 a.

In a preferred embodiment, the process for the preparation of pure z-isomer of
11-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydrodibenz[b,e]oxepin-2-aceticacid
hydrochloride compound of formula-la comprises of the following steps,
a) Adding n-butyl lithium to the mixture of (3-dimethylaminopropyl)-triphenyl
phosphoniumbromide HBr compound of formula-3 in tetrahydrofuran,
b) adding the solution of 11-oxo-6, ll-dihydrobenz(b,e)oxepin-2-acetic acid
compound of formula-2 in tetrahydrofuran,
c) heating the reaction mixture to 65-70°C,
d) stirring the reaction mixture for 10-16 hours,
e) quenching the reaction mixture with aqueous hydrochloric acid,
f) washing the aqueous layer with toluene,
g) neutralizing the reaction mixture with sodium carbonate solution,
h) washing the aqueous layer with ethyl acetate,
i) adding acetic acid and hydrochloric acid to the reaction mixture, to reduce the pH
~ 1 to 2,
j) extracting the reaction mixture with dichloromethane,
k) distilling off the solvent from organic layer,
l) isolating the obtained residue in acetone,

m) purifying the 11-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydrodibenz[b,e]
oxepin-2-aceticacid hydrochloride compound of formula-la from aqueous
acetone.

The second aspect of the present invention is to provide ll-[(Z)-3-
(dimethylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid ydrochloride
of formula-la, which comprises of

a) Adding n-hexyllithium to the mixture of (3-dimethylaminopropyl)-triphenyl
phosphoniumbromide hydronromide compound of formula-3 in a suitable solvent,
b) adding the solution of 11-0X0-6,11-dihydrobenz(b,e)oxepin-2-acetic acid
compound of formula-2 in a suitable solvent,
c) heating the reaction mixture to temperature of about 40°C to 80°C,
d) stirring the reaction mixture till the completion of the reaction,
e) quenching the reaction mixture with aqueous acid,
f) washing the aqueous layer with a suitable solvent,
g) neutralizing the reaction mixture with a suitable basic solution,
h) washing the aqueous layer with a suitable solvent,

i) adding hydrochloric acid and organic acid to the reaction mixture, to reduce the
pH,
j) extracting the reaction mixture with suitable solvent,
k) distilling off the solvent from organic layer,
l) isolating the obtained residue in a suitable solvent,
m) purifying the 11-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydrodibenz[b,e]
oxepin-2-aceticacid hydrochloride compound of formula-1 a.

Preferred embodiment of the present invention is to provide pure z-isomer of
11-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydrodibenz[b,e]oxepin-2-aceticacid
liydrochloride compound of formula-la, which comprises of

a) Adding n-hexyllithium to the mixture of (3-dimethylaminopropyl)-triphenyl
phosphoniumbromide HBr compound of formuIa-3 in tetrahydrofliran,
b) adding the solution of ll-oxo-6,ll-dihydrobenz(b,e)oxepin-2-acetic acid
compound of formula-3 in tetrahydrofuran,
c) heating the reaction mixture to reflux,
d) stirring the reaction mixture for 10-16 hours,
e) quenching the reaction mixture with aqueous hydrochloric acid,
f) washing the aqueous layer with toluene,
g) neutralizing the reaction mixture with sodium carbonate solution,
h) washing the aqueous layer with ethyl acetate,
i) adding hydrochloric acid and organic acid to the reaction mixture, to reduce the
pH ~ 1 to 2,
j) extracting the reaction mixture with dichloromethane,
k) distilling off the solvent from organic layer,
1) isolating the obtained residue in acetone,
m) purifying the 11-[(Z)-3-(dimethylamino)propylidene]-6-11-dihydrodibenz[b,e]
oxepin-2-aceticacid hydrochloride compound of formula-la from aqueous
acetone.

The third aspect of the present invention is to provide 11-[(Z)-3-
(dimethylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride
of formula-la, which comprises of

a) Adding n-alkyllithium to the mixture of (3-dimethylaminopropyl)-triphenyl
phosphoniumbromide hydronromide compound of formula-3 in a suitable solvent,
b) heating the reaction mixture to temperature of about 40°C to 80°C,
c) adding the solution of ll-oxo-6,ll-dihydrobenz(b,e)oxepin-2-acetic acid
compound of formula-2 in a suitable solvent,
d) stirring the reaction mixture till the completion of the reaction,
e) quenching the reaction mixture with aqueous acid,
f) washing the aqueous layer with a suitable solvent,
g) neutralizing the reaction mixture with a suitable basic solution,
h) washing the aqueous layer with a suitable solvent,
i) adding hydrochloric acid and organic acid to the reaction mixture, to reduce the
pH~l-2,
j) extracting the reaction mixture with suitable solvent,
k) distilling off the solvent from organic layer,
1) isolating the obtained residue in a suitable solvent,
m) purifying the 11-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydrodibenz[b,e]oxepin-2-aceticacid hydrochloride compound of formula-1 a.

The present invention is schematically represented Scheme-I

The fourth aspect of the of the present invention is the conversion process of
E-isomer of 11-[3-(dimethylamino)propylidene]-6-ll-dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride or a mixture of E&Z-isomer into its Z-isomer. The process comprising of;
a) Adding hydrochloric acid to a solution containing the mixture of E&Z isomers of
11 -[3-(dimethylamino)propylidene]-6-11 -dihydrodibenz[b,e]oxepin-2-aceticacid
hydro- chloride having major amount of E-isomer,
b) heating the reaction mixture,
c) cooling down and adding an organic acid to the reaction mixture,
d) washing the reaction mixture with a suitable hydrocarbon solvent,
e) adding a suitable chloro solvent to the aqueous layer,
f) separating both aqueous layer and organic layer,
g) distilling off the solvent from organic layer,
h) adding ethyl acetate HCl to obtained residue,
i) distilling off the solvent from reaction mixture,
j) isolating the solid from the residue using a suitable solvent.

In the preferred embodiment, the conversion E or a mixture E&Z isomers of 11-
[3 -(dimethylamino)propylidene] -6-11 -dihydrodibenz[b,e] oxepin-2-aceticacid into required Z-isomer is carried in the following manner,

a) Adding hydrochloric acid to a solution containing the mixture of E and Z isomers of 11 -[3-(dimethylamino)propylidene]-6,11-dihydrodibenzo[b,e]oxepin-2-acetic
acid hydrochloride having major amount of E-isomer,
b) heating the reaction mixture to 90-95 °C for 10-12 hours, c) cooling it to 25-30°C and adding acetic acid to the reaction mixture,
d) washing the reaction mixture with toluene,
e) adding dichloromethane to the aqueous layer,
f) separating both aqueous layer and organic layer,
g) distilling off the solvent from organic layer,
h) adding ethyl acetate HCl to obtained residue at 40-45°C,
i) stirring the reaction mixture at 40-45°C for 20-30 minutes,
j) distilling off the solvent from the reaction mixture,
k.) isolating the solid from the residue using acetone.

The present invention is schematically represented
Scheme-II


The related substance of olopatadine hydrochloride was analyzed by HPLC using (the following conditions: A liquid chromatograph equipped with variable wavelength UV detector and Column: Symmetry shield RP18, 250X4.6 mm, 5 nm or equivalent; Flow irate: 1.0 ml/min; wavelength: 220 nm; Temperature; 25°C; Load: 20 µ1; Run time: 45
min; Elution; Gradient; and using buffer and acetonitrile as a mobile phase. Buffer aqueous mixture of octane-1-sulfonic acid sodium salt and sodium dihydrogen phosphate idehydrate solution.

The process described in the present invention was demonstrated in examples
illustrated below. These examples are provided as illustration only and therefore should
hot be construed as limitation of the scope of the invention.

Examples:
Example-1: Preparation of 11-((Z)-3-(dimethylamino)propylidene]-6-ll-dihydro
dibenz[b,e] oxepin-2-aceticacid hydrochloride compound of formula-la

n-Butyl lithium (100 ml) was added to the solution of 3-dimethylaminopropyl)-
triphenyl phosphoniumbromide HBr compound of formula-3 (37.94 grams) in
tetrahydrofiiran (200 ml) at 0-5°C under nitrogen atmosphere. The reaction mixture was
stirred for an hour at the same temperatue. A mixture of ll-oxo-6, 11-dihydrobenz
(b,e)oxepin-2-acetic acid compound of formula-2 (10 grams) and tetrahydrofuran (30 ml)
Was added to the reaction mixture at 0-5ºC. Slowly raised the temperature of the reaction
mixture to 65-70°C and then hated to reflux. The reaction mixture was stirred for
12 hours at 65-70°C. After completion of the reaction, the reaction mixture was cooled to
5-10°C. The reaction mixture was quenched with aqueous hydrochloric acid at 5-10°C.
Raised the temperature of the reaction mixture to 25-30°C and stirred for an hour. Both
brganic and aqueous layers were separated. The aqueous layer was washed with toluene
and then the aqueous layer was neutralizing with aqueous sodium carbonate solution at
5-10°C. The reaction mixture was washed with ethyl acetate. Hydrochloric acid (20 ml)
and acetic acid (40 ml) was added to the reaction mixture at 25-30°C. The reaction
mixture was stirred for 15 minutes and then dichloromethane was added to it. Both
organic and aqueous layers were separated. The organic layer was washed with brine
solution and the organic layer was distilled off under reduced pressure. Acetone (100 ml)
was added to the residue at 25-30°C and stirred the reaction mixture for 45 minutes at
25-30°C. The solid was filtered, washed with acetone and dried to get the title compound.
Yield: 5 grams,
M.P: 238-241ºC (Decomposition)
purity by HPLC: 97.7% (Z-isomer), 1.15% (E-isomer)

Example-2: Purification of 11-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride
33%aqueous acetone (31.5 ml) was added to {(11Z)-11-[3-
(dimethylamino)propyHdene]-6,ll-dihydrodibenzo[b,e]oxepin-2-yl}acetic acid
hydrochloride (4.5 grams) obtained in example-1 and then carbon was added to the reaction mixture at 25-30°C. The reaction mixture was stirred for 30 minutes and filtered the reaction mixture on highflow bed and washed with 33%aqueous acetone (13.5 ml). Distilled off the solvent from the filtrate and then acetone (22.5 ml) was added to the obtained solid at 25-30°C. The reaction mixture was stirred for an hour at 25-30°C and filtered the solid. Washed the solid with acetone and dried to get the pure 1(11Z)-1 l-[3-(dimethylamino)propylidene]-6,l l-dihydrodibenzo[b,e]oxepin-2-yl} acetic acid hydrochloride.
Yield: 2.6 grams,
M.P: 244-248.5°C (Decomposition)
Purity by HPLC: 98.19% (Z-isomer), 0.5% (E-isomer)

Example-3: Preparation of 11-[(Z)-3-(dimethylaniino)propylidene]-6-ll-dihydro dibenz[b,e] oxepin-2-aceticacid hydrochloride compound of formula-la

n-Hexyl lithium (123.3 ml) was added to the solution of (3-dimethylaminopropyl)-triphenyl phosphoniumbromide HBr compoimd of formula-3 (59.3 grams) in tetrahydrofuran (500 ml) at 0-5°C under nitrogen atmosphere. The reaction mixture was stirred for an hour at same temperature. A mixture of 11 -oxo-6,11 -dihydrobenz (b,e)oxepin-2-acetic acid compound of formula-2 (25 grams) and tetrahydrofuran (75 ml) to the reaction mixture at 0-5°C. Slowly raised the temperature of the reaction mixture to 25-30°C and then hated to 65-70°C. The reaction mixture was stirred for 12 hours at 65-70°C. After completion of the reaction, the reaction mixture Was cooled to 5-10°C. The reaction mixture was quenched with aqueous hydrochloric acid at 5-10°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for an hour. Both organic and aqueous layers were separated. The aqueous layer was washed With toluene and neutralized the aqueous layer with sodium carbonate solution at 5-10°C. The reaction mixture was washed with ethyl acetate. Hydrochloric acid (50 ml) and acetic
acid (100 ml) was added to the reaction mixture at 25-30°C. The reaction mixture was
stirred for 15 minutes and dichloromethane was added to it. Both organic and aqueous
layers were separated. The organic layer was washed with brine solution and the organic
layer was distilled off under reduced pressure. Acetone (250 ml) was added to the residue
at 25-30°C and stirred the reaction mixture for 45 minutes at 25-30°C. The solid was
filtered, washed with acetone and dried to get the title compound.

Yield: 13 grams,
M.P: 237-239°C (Decomposition)

Example-4: Purification of ll-[(Z)-3-(diinethylamino)propylidene]-6-ll-dihydro
dibenz[b,e] oxepin-2-aceticacid hydrochloride

33%aqueous acetone (87.5 ml) was added to {(11Z)-1 l-[3-dimethylamino)propylidene]-
6,ll-dihydrodibenzo[b,e]oxepin-2-yl}acetic acid hydrochloride (12.5 grams) obtained in
example-3 and then carbon was added to the reaction mixture at 25-30°C. The reaction
mixture was stirred for 30 minutes and filtered the reaction mixture on highflow bed and
washed with 33% aqueous acetone (37.5 ml). Distilled off the solvent from the filtrate
and then acetone (62.5 ml) was added to the obtained solid at 25-30°C. The reaction
mixture was stirred for an hour at 25-30°C and filtered the solid. Washed the solid with
acetone and dried to get the pure {(llZ)-ll-[3-(dimethylamino)propylidene]-6,ll-
dihydrodibenzo[b,e]oxepin-2-yl} acetic acid hydrochloride.

Yield: 10 grams,
M.P: 246.7-248.5°C (Decomposition)
purity by HPLC: 99.22% (Z-isomer), 0.12% (E-isomer)

Example-5: Preparation of 11-[(Z)-3-(diinethylamino)propylidene]-6-ll-dihydro
dibenz[b,e] oxepin-2-aceticacid hydrochloride compound of formula-la
n-Butyl lithium (100 ml) was added to the solution of 3-dimethylaminopropyl)-
triphenyl phosphoniumbromide HBr compound of formula-3 (37.94 grams) in tetrahydrofuran (100 ml) at 0-5 °C under nitrogen atmosphere. The reaction mixture was Stirred for an hour at same temperature. A mixture of ll-oxo-6,11-dihydrobenz(b,e)oxepin-2-acetic acid compound of formula-2 (10 grams) and
tetrahydrofuran (30 ml) was added to the reaction mixture at 0-5°C, Slowly raised the
temperature of the reaction mixture to 25-30°C and then hated to 40-45°C. The reaction
hiixture was stirred for 24 hours at 40-45°C. After completion of the reaction, the
reaction mixture was cooled to 5-10°C. The reaction mixture was quenched with aqueous
hydrochloric acid at 5-10°C. Raised the temperature of the reaction mixture to 25-30°C
and stirred for an hour. Both organic and aqueous layers were separated. The aqueous
layer was washed with toluene and then neutralized the aqueous layer with sodium
carbonate solution at 5-10°C. The reaction mixture was washed with ethyl acetate.
Hydrochloric acid (20 ml) and acetic acid (40 ml) was added to the reaction mixture at
25-30°C. The reaction mixture was stirred for 15 minutes and then dichloromethane was
added to it. Both organic and aqueous layers were separated. The organic layer was
washed with brine solution and the organic layer was distilled off under reduced pressure.
Acetone (100 ml) was added to the residue at 25-30°C and stirred the reaction mixture for
45 minutes at 25-30°C. The solid was filtered, washed with acetone and dried to get the
title compound.

Yield: 8.5 grams,
M.P: 203-207°C (Decomposition)

Example-6: Preparation of 11-[(Z)-3-(dimethylamino)propyIidene]-6-ll-dihydro
dibenz[b,e] oxepin-2-aceticacid hydrochloride compound of formula-la

n-Butyl lithium (100 ml) was added to the solution of 3-dimethylaminopropyl)-triphenyl phosphoniumbromide HBr compound of formula-3 (37.94 grams) in tetrahydrofiiran (100 ml) at 0-5°C under nitrogen atmosphere. The reaction mixture was stirred for an hour at same temperature. A mixture of ll-oxo-6,ll-dihydrobenz(b,e)oxepin-2-acetic acid compound of formula-2 (10 grams) and tetrahydrofuran (30 ml) was added to the reaction mixture at 0-5°C. Slowly raised the temperature of the reaction mixture to 25-30°C and then hated to 50-55°C. The reaction mixture was stirred for 18 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 5-10°C. The reaction mixture was quenched with aqueous hydrochloric acid at 5-10°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for an hour. Both organic and aqueous layers were separated. The aqueous layer was washed with toluene and then
neutralized the aqueous layer with sodium carbonate solution at 5-10°C. The reaction mixture was washed with ethyl acetate. Hydrochloric acid (20 ml) and acetic acid (40 ml) Was added to the reaction mixture at 25-30°C. The reaction mixture was stirred for 15 minutes and then dichloromethane was added to it. Both organic and aqueous layers were Separated. The organic layer was washed with brine solution and the organic layer was distilled off under reduced pressure. Acetone (100 ml) was added to the residue at 25-30°C and stirred the reaction mixture for 45 minutes at 25-30°C. The solid was filtered, washed with acetone and dried to get the title compound.

Yield: 7.5 grams,
M.P: 223-227°C (Decomposition)

Example 7: Preparation of 11-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydro
dibenz[b,e] oxepin-2-aceticacid hydrochloride compound of formula-la

n-Hexyl lithium (49.32 ml) was added to the solution of (3-dimethylaminopropyl)-
triphenyl phosphoniumbromide HBr compound of formula-3 (23.72 grams) in
tetrahydrofUran (100 ml) at 0-5°C under nitrogen atmosphere. The reaction mixture was
kirred for an hour at same temperature. A mixture of ll-oxo-6,ll-dihydrobenz
(b,e)oxepin-2-acetic acid compound of formula-2 (10 grams) and tetrahydrofuran (30 ml)
to the reaction mixture at 0-5°C. Slowly raised the temperature of the reaction mixture to
25-30°C and then hated to 40-45°C. The reaction mixture was stirred for 24 hours at 40-
45°C. After completion of the reaction, the reaction mixture was cooled to 5-10°C. The
reaction mixture was quenched with aqueous hydrochloric acid at 5-10°C. Raised the
temperature of the reaction mixture to 25-30°C and stirred for an hour. Both organic and
aqueous layers were separated. The aqueous layer was washed with toluene and
neutralized the aqueous layer with sodium carbonate solution at 5-10°C. The reaction
mixture was washed with ethyl acetate. Hydrochloric acid (20 ml) and acetic acid (40 ml)
Was added to the reaction mixture at 25-30°C. The reaction mixture was stirred for 15
minutes and dichloromethane was added to it. Both organic and aqueous layers were
Separated. The organic layer was washed with brine solution and the organic layer was
distilled off under reduced pressure. Acetone (100 ml) was added to the residue at 25-
30°C and stirred the reaction mixture for 45 minutes at 25-30°C. The solid was filtered, washed with acetone and dried to get the title compound.

Yield: 8 grams,
M.P:203-205°C (Decomposition)

ExampIe-8: Preparation of 11-[(Z)-3-(dimethyIamino)propyHdene]-6-ll-dihydro dibenz[b,e] oxepin-2-aceticacid hydrochloride compound of formula-la

n-Hexyl lithium (49.32 ml) was added to the solution of (3-
dimethyIaminopropyl)-triphenyl phosphoniumbromide HBr compound of formula-3
1(23.72 grams) in tetrahydrofuran (100 ml) at 0-5°C under nitrogen atmosphere. The
reaction mixture was stirred for an hour at same temperature. A mixture of 1 l-oxo-6,11-
dihydrobenz(b,e) oxepin-2-acetic acid compound of fonnuIa-2 (10 grams) and
tetrahydrofuran (30 ml) to the reaction mixture at 0-5°C. Slowly raised the temperature of
the reaction mixture to 25-30°C and then hated to 50-55°C. The reaction mixture was
stirred for 18 hours at 50-55°C. After completion of the reaction, the reaction mixture
was cooled to 5-10°C. The reaction mixture was quenched with aqueous hydrochloric
acid at 5-10°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for
an hour. Both organic and aqueous layers were separated. The aqueous layer was washed
with toluene and neutralized the aqueous layer with sodium carbonate solution at 5-10°C.
The reaction mixture was washed with ethyl acetate. Hydrochloric acid (20 ml) and acetic
acid (40 ml) was added to the reaction mixture at 25-30°C. The reaction mixture was
stirred for 15 minutes and dichloromethane was added to it. Both organic and aqueous
layers were separated. The organic layer was washed with brine solution and the organic
layer was distilled off under reduced pressure. Acetone (100 ml) was added to the residue
at 25-30°C and stirred the reaction mixture for 45 minutes at 25-30°C. The solid was
filtered, washed with acetone and dried to get the title compound.

Yield: 7 grams,
M.P:213-215°C (Decomposition)

Example-9: Preparation of Z-isomer of 11-[3-(dimethylainino)propyIidene]-6-ll-dihydrodibenz[b,e]oxepin-2-aceticacid hydrochloride from the mixture of E&Z isomers

Added aqueous hydrochloric acid (15 ml) into the mixture of E&Z isomers of 11-[-3-(dimethylamino)propylidene]-6-l 1 -dihydrodibenz[b,e]oxepin-2-aceticacid hydrochloride (5 grams) at 25-30°C and then heated the reaction mixture to 90-95°C. Stirred the reaction mixture for 12 hours at the same temperature. The reaction mixture was tooled to 25-30°C and then added acetic acid (10 ml) to it. The reaction mixture was washed with toluene and then reaction mixture was extracted with dichloromethane. Distilled off the solvent from the organic layer under reduced pressure and co-distillation with ethyl acetate. Ethyl acetate HCl (5 ml) was added to the obtained residue at 40-45°C land stirred the reaction mixture for 30 minutes at the same temperature. Distilled off the solvent from the reaction mixture under reduced pressure and acetone (15 ml) was added to the obtained residue at 25-30°C. The reaction mixture was stirred for 45 minutes at the same temperature. The obtained solid was filtered, washed with acetone and dried get pure Z-isomer of 11-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydrodibenz[b,e] bxepin-2-aceticacid hydrochloride.

Yield: 3 grams
Purity by HPLC: 96.93% (Z-isomer), 0.9% (E-isomer)

We claim:
1. A process for the preparation of pure Z-isomer of 11-[(Z)-3-(dimethylamino)propylidene] -6-11 -dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride of formula-la.

Which comprising of the following steps;
a) Adding n-alkyllithium to the mixture of (3-dimethylaminopropyl)-triphenyl
phosphoniumbromide hydrobromide compound of formula-3 in a suitable solvent,

b) adding 11-oxo-6,11-dihydrobenz(b,e)oxepin-2-acetic acid compound of formula-
2 in a suitable solvent,

c) heating the reaction mixture to a temperature of about 40°C to 80°C,

d) stirring the reaction mixture till the completion of the reaction,

e) quenching the reaction mixture with aqueous acid,

f) washing the aqueous layer with a suitable water immiscible solvent,

g) neutralizing the aqueous layer with a suitable basic solution,

h) washing the aqueous layer with a suitable solvent.

i) adding hydrochloric acid and organic acid to the reaction mixture, to reduce the
pH to l-2,

j) extracting the reaction mixture with suitable solvent,

k) distilling off the solvent from organic layer,

l) isolating the obtained residue in a suitable solvent,

m) purifying the 11-[(Z)-3-(dimethylamino)propylidene]-6-11-dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride compound of formula-1 a.

2. A process for the preparation of pure Z-isomer of 11-Z)-3- (dimethylamino)propylidene]-6-ll-dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride of formula-la,

Which comprising of the following steps;
a) Adding n-butyl lithium to the mixture of (3-dimethylaminopropyl)-triphenyl
phosphoniumbromide hydrobromide compound of formula-3 in tetrahydrofuran,

b) adding the ll-oxo-6,ll-dihydrobenz(b,e)oxepin-2-acetic acid compound of
formula-2 in tetrahydrofuran,

c) heating the reaction mixture to 65-70°C,

d) stirring the reaction mixture for 10-16 hours,

e) quenching the reaction mixture with aqueous hydrochloric acid,

f) washing the aqueous layer with toluene,

g) neutralizing the aqueous layer with sodium carbonate solution,

h) washing the aqueous layer with ethyl acetate,

i) adding hydrochloric acid and acetic acid to the reaction mixture, to reduce the pH
~ 1 to 2,

j) extracting the reaction mixture with dichloromethane,

k) distilling off the solvent from organic layer,

1) isolating the obtained residue in acetone,

m) purifying the 11-(Z) -3-(dimethylamino)propylidene]-6-ll-dihydrodibenz[b,e]
oxepin-2-aceticacid hydrochloride compound of formula-la in aqueous acetone.

3. A process for the preparation of pure z-isomer of 11-[(Z)-3-
(dimethylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride of formula-1 a,

Formula-la
Which comprising of the following steps,

a) Adding n-hexyllithium to the mixture of (3-dimethylaminopropyl)-triphenyl
phosphoniumbromide hydrobromide compound of formula-3 in tetrahydrofuran.


b) adding the ll-oxo-6,ll-dihydrobenz(b,e)oxepin-2-acetic acid compound of
fonnula-2 in tetrahydrofuran,

c) heating the reaction mixture to 65-70°C,

d) stirring the reaction mixture for 10-16 hours,

e) quenching the reaction mixture with aqueous hydrochloric acid,

f) washing the aqueous layer with toluene,

g) neutralizing the aqueous layer with sodium carbonate solution,

h) washing the aqueous layer with ethyl acetate,
i) adding hydrochloric acid and acetic acid to the reaction mixture, to reduce the pH
~ 1 to 2,

j) extracting the reaction mixture with dichloromethane,

k) distilling off the solvent from organic layer,

l) isolating the obtained residue in acetone,

m) purifying the 11-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydrodibenz[b,e]
oxepin-2-aceticacid hydrochloride compound of formula-la in aqueous acetone.

4. A process for the preparation of pure Z-isomer of n-[(Z)-3-(dimethylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-aceticacid hydrochloride of formula-la,

Which comprising of the following steps;

a) Adding n-alkyllithium to the mixture of (3-dimethylaminopropyl)-triphenyl
phosphoniumbromide hydrobromide compound of formuIa-3 in a suitable solvent,

b) heating the reaction mixture to a temperature of about 40°C to 80°C,

c) adding ll-oxo-6,ll-dihydrobenz(b,e)oxepin-2-acetic acid compound of formula-2 in a suitable solvent,

d) stirring the reaction mixture till the completion of the reaction,

e) quenching the reaction mixture with aqueous acid,

f) washing the aqueous layer with a suitable water immiscible solvent,

g) neutralizing the aqueous layer with a suitable basic solution,

h) washing the aqueous layer with a suitable solvent,

i) adding hydrochloric acid and organic acid to the reaction mixture, to reduce the
pHto 1-2,

j) extracting the reaction mixture with suitable solvent,
k) distilling off the solvent from organic layer,
l) isolating the obtained residue in a suitable solvent,

m) purifying the 11-[(Z)-3-(dimethylamino)propylidene]-6-11-dihydrodibenz[b,e]
oxepin-2-aceticacid hydrochloride compound of formula-la.

5. Use of n-hexyllithium at temperature of 0-80°C for the condensation of 1 r-oxo-6,11-dihydrobenz(b,e)oxepin-2-acetic acid compound of formula-2 with (3-dimethylaminopropyl)-triphenyl phosphoniumbromide hydrobromide compound of formula-3 to provide ll-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydrodibenz [b,e]oxepin-2-acetic acid hydrochloride compound of formula-la.

6. Use of n-butyl lithium at temperature of 40-80°C for the condensation of 11-oxo-
6,11-dihydrobenz(b,e)oxepin-2-acetic acid compound of formula-2 with (3-
dimethylaminopropyl)-triphenyl phosphoniumbromide hydrobromide compound of formula-3 to provide 11-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydrodibenz [b,e]oxepin-2-acetic acid hydrochloride compound of formula-1 a,

7. A process for producing 11-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydro
dibenz[b,e] oxepin-2-aceticacid hydrochloride compound of formula-1 by reacting
the 11-0X0-6,1 l-dihydrobenz(b,e)oxepin-2-acetic acid compound of formula-2 with

(3-dimethylaminopropyl)-triphenylphosphonium bromide hydrobromide compound of formula-3 in presence of n-butyllithium in a suitable solvent, at temperature of about 40-80°C.

8. A process for producing 11-[(Z)-3-(dimethylamino)propylidene]-6-n-dihydro
dibenz[b,e]oxepin-2-aceticacid hydrochloride compound of formula-1 by reacting the
11 -0x0-6,11 -dihydrobenz(b,e)oxepin-2-acetic acid compound of formula-2

with (3-dimethylaminopropyl)-triphenylphosphoniumbromide hydrobromide compound of formula-3 in presence of n-hexyllithium in a suitable solvent at a temperature of about 0-80°C.

9. A process according to any of the preceding claims, wherein obtained 11-[(Z)-3-
(dimethylamino)propylidene]-6-l l-dihydrodibenz[b,e]oxepin-2-aceticacid hydro-
chloride containing 1.0% or less of corresponding E-isomer.

10. A process for the conversion of E-isomer or the mixture of E&Z-isomers of
11-[3-(dimethylamino)propylidene]-6-ll-dihydrodibenz[b,e]oxepin-2-aceticacid
hydrochloride into its Z-isomer, which comprising of,
a) Adding hydrochloric acid to a solution containing the mixture of E and Z isomers
having major amount of E-isomer,

b) heating the reaction mixture,

c) cooling down and adding acetic acid to the reaction mixture,

d) washing the reaction mixture with toluene,

e) adding dichloromethane to the aqueous layer,

f) separating both aqueous layer and organic layer,

g) distilling off the solvent from organic layer,

h) adding ethyl acetate HCl to obtained residue,

i) distilling off the solvent from the reaction mixture,

j) isolating the solid from the residue using acetone.