PROCEDE DE PREPARATION D'HYDROCHLORURE DE PAROXETINE

PROCESS FOR THE PREPARATION OF PAROXETINE HYDROCHLORIDE

Abrégé français

Cette invention concerne un procédé de préparation d'un solvat propan-2-ol d'hydrochlorure de paroxetine, lequel consiste à former une solution d'hydrochlorure de paroxetine dans un mélange comprenant du propan-2-ol et un co-solvant efficace. Le solvat propan-2-ol d'hydrochlorure de paroxetine est ensuite cristallisé à partir de cette solution.

Abrégé anglais

A process for the preparation of paroxetine hydrochloride propan-2-ol solvate
comprises forming a solution of paroxetine hydrochloride in a mixture of
propan-2-ol and an effective co-solvent, and crystallising paroxetine
hydrochloride propan-2-ol solvate from the solution.

Revendications

Claims
1. A process for the preparation of paroxetine hydrochloride propan-2-ol
solvate
which comprises forming a solution of paroxetine hydrochloride in a mixture of
propan-2-ol and an effective co-solvent, and crystallising paroxetine
hydrochloride
propan-2-ol solvate from the solution.
2. A process according to claim 1 wherein the cosolvent comprises toluene,
heptane or hexane.
3. A process according to claim 1 or 2 wherein the final stage of the
preparation
of paroxetine hydrochloride is carried out in the cosolvent, to which propan-2-
ol is
subsequently added for crystallisation.
4. A process for the preparation of a crystalline anhydrate of paroxetine
hydrochloride which comprises heating a propan-2-ol solvate , obtained using
the
process of any one of the preceding claims, to remove bound propan-2-ol.
5. A pharmaceutical composition for treatment or prophylaxis of the disorders
comprising paroxetine hydrochloride anhydrate prepared by the process of claim
4
and a pharmaceutically acceptable carrier.
6. The use of paroxetine hydrochloride anhydrate prepared by the process of
claim 4
to manufacture a medicament for the treatment or prophylaxis of the disorders:
7. A method of treating the disorders which comprises administering an
effective or
prophylactic amount of paroxetine hydrochloride anhydrate prepared by the
process of
claim 4 to a person suffering from one or more of the disorders.
5

Description

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PROCESS FOR THE PREPARATION OF PAROXETINE HYDROCHLORIDE
The present invention relates to a process for the preparation of a
pharmaceutically
active compound, and to the use of the so-prepared compound in therapy. In
particular this invention is concerned with a new process for the preparation
of a
paroxetine chloride propan-2-of solvate and its use to prepare a crystalline
anhydtate
form of paroxetine hydrochloride.
Pharmaceutical products with antidepressant and anti-Parkinson properties are
described in US-A-3912743 and US-A-4007196. An especially important compound
among those disclosed is paroxetine, the (-)traps isomer of 4-(4'-
fluorophenyl)-3-
(3',4'-methylenedioxy-phenoxymethyl)-piperidine. This compound is used in
therapy
as the hydrochloride salt for the treatment and prophylaxis of inter alia
depression,
obsessive compulsive disorder (OCD) and panic.
Paroxetine hydrochloride has been described in the literature as a crystalline
hemihydrate (see EP-A-0223403 of Beecham Group) and as various crystalline
anhydrate forms (see W096/24595 of SmithKline Beecham). WO96/24595 describes
the preparation of the form A anhydrate via an intermediate solvate with an
organic
solvent such as propan-2-oI.
When prepared conventionally (crystallisation from anhydrous propan-2-ol),
paroxetine hydrochloride propan-2-of solvate has very poor stirring
properties, and is
very difficult to isolate, wash, and dry. It is also very difficult to
desolvate by heat
treatment under vacuum. In W096/24595, the problem that conventional drying
techniques were incapable of efficient removal of solvent was addressed by
providing
an additional displacement stage before the product was finally dried.
The present invention is based on the finding that crystallisation of
paroxetine
hydrochloride from a mixture of propan-2-of and a co-solvent produces an
improved
crystalline form which is much easier to stir, filter, wash and dry.
Surprisingly it has
also been found that it is easier to remove solvent of crystallisation by heat
treatment.
Accordingly the present invention provides a process for the preparation of
pamxetine
hydrochloride propan-2-oI solvate which comprises forming a solution of
paroxetine
hydrochloride in a mixture of propan-2-of and an effective co-solvent, and
crystallising paroxetine hydrochloride propan-2-of solvate from the solution.

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Typically an effective cosolvent is one which will form a clear solution when
added to
a solution of paroxetine hydrochloride in propan-2-of and which does not form
a
competing solvate during crystallisation. Suitable cosolvents include toluene,
heptane
and hexane. Surprisingly toluene has been found to be particularly useful
despite the
fact that a toluene solvate of paroxetine hydrochloride can exist.
The cosolvent mixture may formed before addition of paroxetine hydrochloride,
or by
addition of a cosolvent to a solution of paroxetine hydrochloride in propan-2-
ol, or by
addition of propan-2-of to a solution of paroxetine hydrochloride in an
effective
cosolvent. In a preferred procedure, the final stage of the preparation of
paroxetine
hydrochloride is carried out in an effective cosolvent, to which propan-2-of
may be
added for crystallisation in accordance with the invention. For example when
toluene
is used as the cosolvent it can be used conveniently in the preceding
manufacturing
step. After washing and acidification, only partial evaporation is necessary,
followed
by addition of propan-2-of and crystallisation.
Crystallisation may be initiated by conventional procedures such as cooling a
heated
solution, or removing solvent by evaporation or heating. It may be
advantageous to
add seeds of crystalline paroxetine hydrochloride propan-2-of solvate prepared
by the
procedure of this invention or by the procedure of W096/24595.
A crystalline anhydrate of paroxetine hydrochloride may be formed by heating
the
propan-2-of solvate to remove bound propan-2-ol. The resultant product
desirably
contains less than 2% of the solvated solvent, preferably less than 1%, more
preferably less than 0.5%, and most preferably less than 0.1%. Advantageously
the
crystalline product is the Form A anhydrate of paroxetine hydrochloride.
The crystalline paroxetine hydrochloride product of this invention may be
formulated
for therapy as described in EP-A-0223403 or W096/00477.
Therapeutic uses of the paroxctine product of this invention include treatment
of:
alcoholism, anxiety, depression, obsessive compulsive disorder, panic
disorder,
chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social
phobia, pre-
menstrual syndrome (PMS), adolescent depression, trichotillomania, dysthymia,
and
substance abuse, referred to below as "the disorders".
Accordingly, the present invention also provides:
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a pharmaceutical composition for treatment or prophylaxis of the disorders
comprising paroxetine hydrochloride anhydrite prepared by this invention and a
pharmaceutically acceptable carrier;
the use of paroxetine hydrochloride anhydrite prepared by the process of this
invention to manufacture a medicament for the treatment or prophylaxis of the
disorders; and
a method of treating the disorders which comprises administering an effective
or
prophylactic amount of pamxetine hydrochloride anhydrite prepared by this
invention
to a person suffering from one or more of the disorders.
The invention is illustrated by the following Examples:
Ezampie 1
Paroxetine hydrochloride hemihydrate (160 g) was suspended in a mixture of
toluene
(250 mil) and isopropanol (1000 ml) and heated to boiling. Solvent was removed
by
distillation and replaced by fresh isopropanol (3 x 500 ml). The boiling point
was
then 81.2°C. Further solvent was removed by distillation until the
volume was about
1000 ml. The well stirred mixture was allowed to cool to about 70°C,
then hexane
(500 ml) was added slowly to give a clear solution at 57°C. Seeds of
paroxetine
hydrochloride isopropanol solvate were added, and as the crystallisation
proceeded the
temperature increased to 60°C. Stirring was continued until the
temperature had
fallen to about 30°C, then the product was collected, washed on the
filter with hexane
(2 x 500 mi) and dried in vacuo at ambient temperature.
Yield 171 g isopropanol content by NMR:10.5% wt/wt
Example 2
(-~Trans-4-(4-fluorophenyl)-3-(3',4'-methylenedioxyphenoxymethyl)-1-
phenoxycarbonylpiperidine (90 g) is heated with potassium hydroxide (8.5 g) in
toluene ( 1500 ml) at reflux for 3 hours, cooled, washed with hot water,
acidified with
hydrochloric acid, and distilled to approximately one quarter volume under
vacuum.
Hot propan-2-of (2000 ml) is added and the mixture cooled slowly with vigorous
stirring until the temperature reaches 20°C. After stirring for a
further 2 hours, the
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product is filtered, washed with propan-2-ol, and dried under vacuum, to give
paroxetine hydrochloride pmpan-2-of solvate.
Example 3
Paroxetine hydrochloride hemihydrate ( 122 g) was suspended in toluene ( 1000
ml)
and heated to reflux for 2 hours under Dean & Stark apparatus to remove water.
The
toluene solution was concentrated to approximately 250 ml volume at which
point it
was still mobile and easy to stir. Warm propan-2-of was added (1300 m1 at
about
50°C) and the reaction miacture stirred vigorously; the mixture
crystallised slowly but
did not become unstirrable. After about 30 minutes a further quantity of
propan-2-of
(300 ml) and n-heptane (300 ml) was added, and the mixture was cooled to
ambient
temperature (approximately 20°C), stirred for a further 30 minutes,
filtered and dried.
One part of the product was dried under vacuum at approximately 20°C
to give
pamxetine hydrochloride propan-2-of solvate with a composition ratio of
approximately 1:1.
Another part was dried under vacuum at a final tempcratiwe of 65°C
to give
paroxetine hydrochloride containing approximately I .6% propan-2-ol. By
comparison, a conventionally prepared sample of solvate heated overnight in a
vacuum oven at 70°C for 24 hours contained 4.1% pmpan-2-ol.
Ezample 4
Paroxetine hydrochloride hemihydrate (50 g) was heated to reflux with stirring
in
toluene (500 ml) and the water removed using a Dean and Stark apparatus. The
solution was allowed to cool to about 40°C, diluted with isopropanol
(200 ml), and
allowed to crystallize at ambient temperature. The product was collected,
washed
with toluene and dried at 40°C to give paroxetine hydmchioride
isopropanol solvate.
Yield 23 g
4