Title of Invention

A METHOD FOR PRODUCING OLOPATADINE OR AN ACID ADDITION SALT THEREOF

Abstract (Z)-11-(3-dimethylaminopropylidene)-6,11- dihydrodibenzo[b,e]oxepin-2-acetic acid (common name: olopatadine) or an acid addition salt, which is useful as a medicament, is produced by treating a dibenzoxepin derivative represented by the formula [I]: wherein R1, R2 and R3 each independently represents an alkyl group having 1 to 2 carbon atoms, with a dehydrating agent to obtain a mixture of a dibenzoxepin derivative represented by the formula [II]: wherein R1, R2 and R3 are as defined above, and a dibenzoxepin derivative represented by the formula [III] : wherein R1, R2 and R3 are as defined above, and treating this mixture with an acid.
Full Text

DESCRIPTION
METHOD FOR PRODUCING DIBENZOXEPIN COMPOUND
TECHNICAL FIELD
The present invention relates to a method for producing
a dibenzoxepin compound which is useful as a medicament, and
particularly to a method for producing (Z)-ll-(3-
dimethylaminopropylidene)-6,11-dihydrodibenzo[b,e]oxepin-2-
acetic acid.
BACKGROUND ART
(Z)-11-(3-dimethylaminopropylidene)-6,11-
dihydrodibenzo [b, e] oxepin-2-acetic acid (common name:
olopatadine) is a compound represented by the formula [IV]:

It is known that this compound or an acid addition salt thereof
is a pharmaceutical compound useful as an antiallergic drug
which is applied for allergic rhinitis, urticaria and so on (JP
5-86925B).
Since olopatadine that is a Z-isomer is usually produced
with its E-isomer in chemical synthesis of olopatadine,
isomerization is required so as to efficiently obtain a Z-isomer
that is an objective substance.

JP 5-86925B and JP 7-116174B describe that, when the
objective substance is obtained as a cis-trans mixture (E-Z
mixture), the cis-trans mixture can be separated by column
chromatography or recrystallization and, if necessary, a
cis-isomer (Z-isomer) can be isomerized into a trans-isomer
(E-isomer) by refluxing in acetic acid in the presence of a
proper acid catalyst such as paratoluenesulfonic acid for 1 to
24 hours. However, these documents do not describe about
isomerization of an E-isomer into a Z-isomer.
Further, J. Med. Chem., 35, 2074-2084 (1992) describes
that methyl 11-(3-dimethylaminopropylidene)-6,11-
dihydrodibenzo[b,e]oxepin-2-acetate is saponified to obtain a
corresponding carboxylic acid as a mixture of an E-isomer and
a Z-isomer at a mixing ratio of 1:2 and the E-isomer is isolated
from the mixture using a column, and then an acetic acid solution
of the E-isomer is heated at 100°C for 21 hours in the presence
of paratoluenesulfonic acid, and isomerization arises to obtain
a mixture of the E-isomer and the Z-isomer at a mixing ratio
of 65:35.
However, according to the isomerization method described
above, the objective substance of the Z-isomer could not be
efficiently obtained.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide a method

for producing olopatadine, which is useful as a medicament,
efficiently and industrially advantageously.
According to the present invention, a Z-isomer
represented by the following formula [IV] is efficiently
produced by treating an ester compound represented by the
following formula [I] with a dehydrating agent to obtain a
mixture of a compound represented by the following formula [II]
and a compound represented by the following formula [III], and
treating the mixture with an acid.
That is, the present invention relates to:
[1] A method for producing a tertiary alkyl ester of
(EZ)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenzo[b,
e]oxepin-2-acetic acid, namely, a mixture of a tertiary alkyl
ester of (E)-11-(3-dimethylaminopropylidene)-6,11-
dihydrodibenzo [b, e] oxepin-2-acetic acid represented by the
formula [II]:

wherein R1, R2 and R3 are as defined below,
and a tertiary alkyl ester of (Z)-ll-(3-
dimethylaminopropylidene)-6,11-dihydrodibenzo[b,e]oxepin-2-
acetic acid represented by the formula [III] :


wherein R1, R2 and R3 are as defined below,
which comprises treating a tertiary alkyl ester of
11-hydroxy-11-(3-dimethylaminopropyl)-6,11-dihydrodibenzo
[b,e]oxepin-2-acetic acid represented by the formula [I]:

wherein R1, R2 and R3 each independently represents an alkyl
group having 1 to 2 carbon atoms,
with a dehydrating agent;
[2] The method of production according to [1], wherein the
dehydrating agent is an acid anhydride or a chloride;
[3] The method of production according to [1], wherein the
dehydrating agent is at least one acid anhydride selected from
the group consisting of acetic anhydride, propionic anhydride,
butyric anhydride, trifluoroacetic anhydride and
trichloroacetic anhydride;
[4] The method of production according to [1], wherein the
dehydrating agent is at least one chloride selected from the
group consisting of thionyl chloride, phosphorus oxychloride,
phosphorus pentachloride, phosphorus trichloride and hydrogen
chloride;

[5] The method of production according to [1], wherein the
dehydrating agent is trifluoroacetic anhydride or acetic
anhydride;
[6] A method for producing olopatadine represented by the
formula [IV]:

or an acid addition salt thereof, which comprises treating a
mixture of a tertiary alkyl ester of (E)-11-(3-
dimethylaminopropylidene)-6,11-dihydrodibenzo[b, e]oxepin-2-
acetic acid represented by the formula [II]:

wherein R1, R2 and R3 are as defined above,
and a tertiary alkyl ester of (Z)-11-(3—
dimethylaminopropylidene)-6,11-dihydrodibenzo[b,e]oxepin-
2-acetic acid represented by the formula [III]:

wherein R1, R2 and R3 are as defined above,
with an acid;
[7] A method for producing olopatadine represented by the

formula [IV]:

or an acid addition salt thereof, which comprises treating a
tertiary alkyl ester of 11-hydroxy-11-(3-
dimethylaminopropyl)-6,11-dihydrodibenzo[b,e]oxepin-2-
acetic acid represented by the formula [I]:

wherein R1, R2 and R3 are as defined above,
with a dehydrating agent to obtain a tertiary alkyl ester of
(EZ)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenzo
[b,e]oxepin-2-acetic acid, namely, a mixture of a tertiary
alkyl ester of (E)-11-(3-dimethylaminopropylidene)-6,11-
dihydrodibenzo [b, e] oxepin-2-acetic acid represented by the
formula [II]:

wherein R1, R2 and R3 are as defined above,
and a tertiary alkyl ester of (Z)-11-(3-
dimethylaminopropylidene)-6,11-dihydrodibenzo[b,e]oxepin-2-
acetic acid represented by the formula [III]:


wherein R1, R2 and R3 are as defined above,
and treating this mixture with an acid;
[8] A tertiary alkyl ester of (E)-11-(3-
dimethylaminopropylidene)-6,11-dihydrodibenzo[b,e)oxepin-2-
acetic acid represented by the formula [II]:

wherein R1, R2 and R3 are as defined above,
or an acid addition salt thereof; and
[9] A tertiary alkyl ester of (Z)-11-(3-
dimethylaminopropylidene)-6,11-dihydrodibenzo[b,e]oxepin-2-
acetic acid represented by the formula [III] :

wherein R1, R2 and R3 are as defined above,
or an acid addition salt thereof.
In the present invention, by treating a tertiary alkyl
ester of 11-hydroxy-11-(3-dimethylaminopropyl)-6,11-
dihydrodibenzo [b,e]oxepin-2-acetic acid represented by the

formula [I]:

wherein R1, R2 and R3 are as defined above
(hereinafter may be referred to as compound [I]), with a
dehydrating agent, a mixture of a tertiary alkyl ester of
(E)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenzo
[b,e]oxepin-2-acetic acid represented by the formula [II]:

wherein R1, R2 and R3 are as defined above
(hereinafter may be referred to as compound [II] ) and a tertiary
alkyl ester of (Z)-11-(3-dimethylaminopropylidene)-6,11-
dihydrodibenzo [b, e] oxepin-2-acetic acid represented by the
formula [III] :

wherein R1, R2 and R3 are as defined above
(hereinafter may be referred to as compound [III]) can be
produced. Although olopatadine or an acid addition salt
thereof can be derived from the mixture as it is, as described
hereinafter, each of a compound [II] and a compound [III] can

be isolated by conventional separation means such as
chromatography.
Typical examples of the alkyl group represented by R1,
R2 and R3 include a methyl group and an ethyl group.
In the present invention, the tertiary alkyl ester of
11-hydroxy-11-(3-dimethylaminopropyl)-6,11-dihydrodibenzo
[b, e] oxepin-2-acetic acid represented by the above formula [I]
is preferably t-butyl 11-hydroxy-11-(3-dimethylaminopropyl)-
6,11-dihydrodibenzo[b,e]-dibenzoxepin-2-acetate represented
by the formula [V] shown below.

Examples of the dehydrating agent include acid anhydrides
such as acetic anhydride, propionic anhydride, butyric
anhydride, trifluoroacetic anhydride and trichloroacetic
anhydride, and chlorides such as thionyl chloride, phosphorus
oxychloride, phosphorus pentachloride, phosphorus trichloride
and hydrogen chloride. Trifluoroacetic anhydride is
preferable. These dehydrating agents may be used alone, or two
or more kinds of dehydrating agents may be used in combination.
The amount of the dehydrating agent to be used is usually from
about 1 mole to 10 moles, and preferably from about 1 mole to
2 moles, per 1 mole of the compound [I].
The dehydration reaction temperature is usually from

about 20°C to 70°C, and more preferably about 40°C to 60°C. The
dehydration reaction time varies depending on the reaction
temperature, the amount of raw material to be used, and so on.
It is usually from about 1 to 8 hours, and preferably from about
2 to 4 hours. This reaction is preferably carried out under
stirring.
In the present invention, olopatadine represented by the
formula [IV]:

or an acid addition salt thereof can be produced by treating
the above mixture of the compound [II] and the compound [III],
obtained by treating the above compound [I] with a dehydrating
agent, with an acid.
Examples of the acid include hydrogen chloride (hydrogen
chloride gas or hydrochloric acid) and sulfuric acid, and
hydrogen chloride gas is particularly preferable. The amount
of the acid to be used is preferably from about 1 mole to 5 moles
per 1 mole of the mixture of the compound [II] and the compound
[III].
The method of charging raw materials in a reactor is
preferably a method in which the mixture of the compound [II]
and the compound [III] dissolved in a solvent is charged by
adding dropwise in a heated solvent. The dropwise addition time

varies depending on the amount of the solvent, and is usually
from about 30 minutes to 10 hours, and preferably about 1 to
5 hours, when 1 kg of the mixture of the compound [II] and the
compound [III] is used. When hydrogen chloride is used as the
acid, it is preferred to add dropwise the mixture of the compound
[II] and the compound [III] dissolved in the solvent while the
hydrogen chloride gas is bubbling.
The reaction temperature is usually from about 50°C to
150°C, and preferably from about 80°C to 110°C. The reaction
time varies depending on the reaction temperature, raw
materials to be used, and so on. It is usually from about 3
to 20 hours, and preferably from about 5 to 10 hours, when 1
kg of the mixture of the compound [II] and the compound [III]
is used. This reaction is preferably carried out under
stirring.
The solvent is preferably an organic solvent. Examples
of the organic solvent include ketone solvents (for example,
methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone,
cyclopentanone, etc.) and aromatic solvents (for example,
benzene, toluene, xylene, chlorobenzene, dichlorobenzene,
nitrobenzene, etc.), and chlorobenzene is preferable. The
amount of the solvent to be used is not particularly limited
as long as the amount enables complete dissolution of the
mixture of the compound [II] and the compound [III]. It is
usually from about 5 L to 40 L, and preferably from about 10

L to 20 L, per 1 kg of a mixture of the compound [II] and the
compound [III].
Thus, isomerization from an E-isomer to a Z-isomer of the
resultant compound proceeds simultaneously with the
deesterification reaction of the compound [II] and the compound
[III]. A compound [IV] can be obtained, as an acid addition
salt corresponding to the acid used, by cooling the reaction
solution after isomerization proceeded nearly completely,
collecting the precipitated crystal through filtration, and
washing the crystal with a proper solvent (for example, acetone,
etc.). Typical examples of the acid addition salt include
hydrochloride and sulfate. Further, a free compound [IV] that
is not an acid addition salt can be usually obtained by an alkali
treatment.
t-Butyl 11-hydroxy-11-(3-dimethylaminopropyl)-6,11-
dihydrodibenzo[b,e]oxepin-2-acetate in the present invention
can also be nomenclatured as, for example, t-butyl (11-hydroxy-
ll- (3-dimethylaminopropyl)-6,11-dihydrodibenzo[b,e]oxepin-
2-yl)acetate.
EXAMPLES
The present invention will be described by examples, but
the present invention is not limited thereto. In the following
examples, purity of an E-isomer and that of a Z-isomer were
measured by HPLC under the following conditions.

(HPLC conditions)
Column: Inertsil ODS-2.5 µm (4.6 mmID × 15 cm)
Mobile phase: A = aqueous solution of sodium dodecyl sulfate
(5 mmol) (pH = 3.0 H3PO4)
B = acetonitrile
A/B = 5/5 → 3/7(20 minutes)
Flow rate: 1.0 ml/min
Column temperature: 30°C
Detection wavelength: UV 254 nm
Example 1
Production of t-butyl (E)-11-(3-dimethylaminopropylidene)-6,
11-dihydrodibenzo[b,e]oxepin-2-acetate and t-butyl (Z)-11-
(3-dimethylaminopropylidene)-6,11-dihydrodibenzo[b,e]oxepin
-2-acetate
In a flask, 20.0 g (0.0486 mol) of t-butyl 11-hydroxy-11-
(3-dimethylaminopropyl)-6,11-dihydrodibenzo[b,e]oxepin-2-
acetate and 60 ml of toluene were charged and then 11.2 g (0.0535
mol) of trifluoroacetic anhydride (= trifluoroacetic
anhydride) was added dropwise at room temperature while
stirring. After dropwise addition, the solution was stirred
in a warm bath at 50oC for 2 hours and then cooled to 25°C. To
this reaction solution, 90 ml of water was added, followed by
liquid separation. After 60 ml of water was further added to
separate the solution, a solution of 7.34 g (0.053 mol) of

potassium carbonate and 60 ml of water was added, followed by
liquid separation. The solution was dried by adding 10 g of
magnesium sulfate and then filtered. This solution was
concentrated to obtain 18.94 g (0.0481 mol) of a mixture of
t-butyl (E)-11-(3-dimethylaminopropylidene)-6,11-
dihydrodibenzo[b,e]oxepin-2-acetate and t-butyl (Z)-11-(3-
dimethylaminopropylidene)-6,11-dihydrodibenzo[b,e]oxepin-2-
acetate. Apparent yield was 99%. A Z-isomer had purity
measured by HPLC of 19. 9%, and an E-isomer had purity of 77.4%.
Physical properties of the E-isomer and the Z-isomer are shown
below.
t-butyl (E)-11-(3-dimethylaminopropylidene)-6,11-
dihydrodibenzo [b,e]oxepin-2-acetate
1H NMR( 4 00MHz, CDCl3) δ 1.44(s, 9H) , 2.16(s, 6H) , 2.34(t,
J=7.6Hz, 2H) , 2.36(dt, J=7.6, 7.6Hz, 2H) , 3.42(s, 2H) , 4.75(brs,
1H) , 5.56 (brs, 1H) , 6.03(t, J=7.6Hz, 1H) , 6.70(d, J=8.4, 1H) ,
7.02(dd, J=8.8, 1.6Hz, 1H), 7.17-7.35(m, 5H)
t-butyl (Z)-11-(3-dimethylaminopropylidene)-6,11-
dihydrodibenzo [b,e]oxepin-2-acetate
1H NMR(400MHz, CDCl3) δ 1.42(s, 9H) , 2.22(s, 6H) , 2.44(t,
J=7.2Hz, 2H), 2.60(dt, J=7.2, 7.2Hz, 2H) , 3.42(s, 2H) , 5.19(brs,
2H), 5.70(t, J=7.2Hz, 1H) , 6.80(d, J=8.0Hz, 1H) , 7.05(dd, J=8.8,
2.0Hz, 1H), 7.06(s, 1H), 7.22-7.32(m, 4H)
Melting point 68.8°C

Example 2
Production of (Z)-11-(3-dimethylaminopropylidene)-6,11-
dihydrodibenzo[b,e]oxepin-2-acetic acid hydrochloride
In a flask, 190 ml of monochlorobenzene was charged and
then stirred at a bath temperature of 100 to 105°C (inner
temperature increased to 96°C). To this solution, a solution
produced by dissolving 19 g (0.048 mol) of a mixture of t-butyl
(E)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenzo
[b,e]oxepin-2-acetate and t-butyl (Z)-11-(3-
dimethylaminopropylidene)-6,11-dihydrodibenzo[b,e]oxepin-2-
acetate obtained in Example 1 in 76 ml of monochlorobenzene was
added dropwise over 30 minutes. During dropwise addition, 5.4
g (0.148 mol) of hydrogen chloride was bubbled, followed by
stirring for 12 hours. At this time, a ratio of an E-isomer
to a Z-isomer was 2.5:97.5. The reaction solution was cooled
to room temperature and crystals were obtained by filtration.
The resultant crystals were washed with 30 ml of toluene twice
and then washed with 50 ml of acetone twice. The crystals were
vacuum-dried at 50°C under 7 hPa to obtain 17.81 g of (Z)-11-
(3-dimethylaminopropylidene)-6,11-dihydrodibenzo[b,e]oxepin
-2-acetic acid hydrochloride. Apparent yield was 98.0%. A
Z-isomer had purity measured by HPLC of 93.9%, and an E-isomer
had purity of 2.5%.
INDUSTRIAL APPLICABILITY

According to the present invention, it is possible to
provide a method for producing (Z)-11-(3-
dimethylaminopropylidene)-6,11-dihydrobenzo[b,e]oxepin-2-
acetic acid (common name: olopatadine) and an acid addition salt
thereof, which are useful as a medicament, efficiently and
industrially advantageously.

CLAIMS
1. A method for producing a tertiary alkyl ester of
(EZ)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenzo[b,
e]oxepin-2-acetic acid, which comprises treating a tertiary
alkyl ester of 11-hydroxy-11-(3-dimethylaminopropyl)-6,11-
dihydrodibenzo [b, e] oxepin-2-acetic acid represented by the
formula [I]:

wherein R1, R2 and R3 each independently represents an alkyl
group having 1 to 2 carbon atoms,
with a dehydrating agent.
2. The method for production according to claim 1, wherein
the dehydrating agent is an acid anhydride or a chloride.
3. The method for production according to claim 1, wherein
the dehydrating agent is at least one acid anhydride selected
from the group consisting of acetic anhydride, propionic
anhydride, butyric anhydride, trifluoroacetic anhydride and
trichloroacetic anhydride.
4. The method for production according to claim 1, wherein

the dehydrating agent is at least one chloride selected from
the group consisting of thionyl chloride, phosphorus
oxychloride, phosphorus pentachloride, phosphorus trichloride
and hydrogen chloride.
5. The method for production according to claim 1, wherein
the dehydrating agent is trifluoroacetic anhydride or acetic
anhydride.
6. A method for producing olopatadine or an acid addition
salt thereof, which comprises treating a mixture of a tertiary
alkyl ester of (E)-11-(3-dimethylaminopropylidene)-6,11-
dihydrodibenzo[b,e]oxepin-2-acetic acid represented by the
formula [II]:

wherein R1, R2 and R3 each independently represents an alkyl
group having 1 to 2 carbon atoms,
and a tertiary alkyl ester of (Z)-11-(3-
dimethylaminopropylidene)-6,11-dihydrodibenzo[b,e]oxepin-2-
acetic acid represented by the formula [III]:


wherein R1, R2 and R3 are as defined above,
with an acid.
7. A method for producing olopatadine or an acid addition
salt thereof, which comprises treating a tertiary alkyl ester
of 11-hydroxy-11-(3-dimethylaminopropyl)-6,11-
dihydrodibenzo[b,e]oxepin-2-acetic acid represented by the
formula [I]:

wherein R1, R2 and R3 each independently represents an alkyl
group having 1 to 2 carbon atoms,
with a dehydrating agent to obtain a tertiary alkyl ester of
(EZ)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenzo
[b,e]oxepin-2-acetic acid, and treating the product with an
acid.
8. A tertiary alkyl ester of (E)-11-(3-
dimethylaminopropylidene)-6,11-dihydrodibenzo[b,e)oxepin-2-
acetic acid represented by the formula [II]:

wherein R1, R2 and R3 each independently represents an alkyl

group having 1 to 2 carbon atoms,
or an acid addition salt thereof.
9. A tertiary alkyl ester of (Z)-11-(3-
dimethylaminopropylidene)-6,11-dihydrodibenzo[b,e]oxepin-2-
acetic acid represented by the formula [III]:

wherein R1, R2 and R3 each independently represents an alkyl
group having 1 to 2 carbon atoms,
or an acid addition salt thereof.


(Z)-11-(3-dimethylaminopropylidene)-6,11-
dihydrodibenzo[b,e]oxepin-2-acetic acid (common name:
olopatadine) or an acid addition salt, which is useful as a
medicament, is produced by treating a dibenzoxepin derivative
represented by the formula [I]:

wherein R1, R2 and R3 each independently represents an alkyl
group having 1 to 2 carbon atoms,
with a dehydrating agent to obtain a mixture of a dibenzoxepin
derivative represented by the formula [II]:

wherein R1, R2 and R3 are as defined above,
and a dibenzoxepin derivative represented by the formula [III] :

wherein R1, R2 and R3 are as defined above,
and treating this mixture with an acid.

Documents:

http://ipindiaonline.gov.in/patentsearch/GrantedSearch/viewdoc.aspx?id=Y1BaEssRlKO66mYLHDyeJA==&loc=wDBSZCsAt7zoiVrqcFJsRw==


Patent Number 280043
Indian Patent Application Number 948/KOLNP/2010
PG Journal Number 06/2017
Publication Date 10-Feb-2017
Grant Date 08-Feb-2017
Date of Filing 12-Mar-2010
Name of Patentee SUMITOMO CHEMICAL COMPANY, LIMITED
Applicant Address 27-1, SHINKAWA 2-CHOME, CHUO-KU, TOKYO 104-8260 JAPAN
Inventors:
# Inventor's Name Inventor's Address
1 TADASHI KATSURA 2-19-32-703, UENOHIGASHI, TOYONAKA-SHI, OSAKA JAPAN
2 TAKETO HAYASHI 1-1-1, FUJIGAOKA, SANDA-SHI, HYOGO JAPAN
3 KEI, KOMATSU 2-11-7-302, SONEHIGASHINO-CHO, TOYONAKA-SHI, OSAKA, JAPAN
4 MASAHIDE TANAKA 4-11-201, NAKAJIMA-CHO, NISHINOMIYA-SHI, HYOGO JAPAN
PCT International Classification Number C07D 313/12
PCT International Application Number PCT/JP2008/067982
PCT International Filing date 2008-09-26
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 2007-262591 2007-10-05 Japan