Note: Descriptions are shown in the official language in which they were submitted.
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PREPARATION OF PAROXETINE INVOLVING NOVEL INTERMEDIATES
FIELD OF THE INVENTION
The present invention relates to processes for the synthesis of intermediates
useful
in preparing paroxetine (PRX); processes fox preparing paroxetine using such
intermediates; and, to intermediates of the disclosed processes. More
particularly, the
present invention relates to a novel process for the preparation of paroxetine
by
dealkylation of N-alkylparoxetine, such as N-methylparoxetine (Me-PRX), and to
novel
intermediates of this process.
BACKGROUND OF THE INVENTION
Paroxetine (PRX), (-)-tr~ans-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-
fluorophenyl) piperidine; (3S, 4R)-3-[5-(1,3-dioxaindanyl)oxymethyl]-4-(p-
fluorophenyl)piperidine, is a 5-hydroxytryptamine (5-HT, serotonin) re-uptake
inhibitor
and is useful as a therapeutic agent for various diseases, including,
inter° alia, depression,
Parlcinson's disease, anxiety disorders, obsessive-compulsive disorders; panic
disorder,
post-traumatic stress disorder, and pre-menstrual syndrome (PMS). Paroxetine
has
formula (I):
H
(I) Paroxetine
Example 2 of U.S. Patent No. 4,007,196 discloses formation ofparoxetine by
demethylation of N-methylparoxetine (Me-PRX) having formula (II):
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(II)
In the process disclosed in the ' 196 patent, Me-PRX is demethylated by
reaction
with phenylchloroformate in methylene chloride to form the corresponding
phenyl
carbamate intermediate. The phenyl carbamate intermediate is hydrolyzed to
yield
paroxetine by refluxing in benzene with potassium hydroxide and methyl
cellosolve for
four hours. Among the disadvantages of this process are the low conversion of
Me-PRX to
the phenyl carbamate, resulting in low yields of paroxetine. This process also
results in
large quantities of phenol as an undesirable by-product.
U.S. Patent No. 4,721,723 describes a process for preparing paroxetine wherein
Me-PRX is reacted with a-chloroethyl-chloroformate (1-chloroethyl-
chloroformate) to
form the corresponding 1-chloroethyl carbamate of paroxetine, which is then
hydrolyzed
under acidic conditions to yield paroxetine. A significant disadvantage of
this process is
the long time required for the conversion of Me-PRX to paroxetine under the
conditions
disclosed in, for example, Examples 6 and 7 of the '723 patent.
EP 0 810 225 A1 discloses a process for producing paroxetine by reacting Me-
PRX
with a lower alkyl, lower cycloallcyl, aralkyl or CmF2m+, ester of haloformic
acid to yield a
carbamate intermediate. The corresponding carbamate intermediate is hydrolyzed
in an
appropriate solvent under alkaline conditions to yield paroxetine, which is
extracted from
the reaction mixture with an appropriate solvent such as toluene. The
hydrolysis of the
carbamate intermediate took from 2-3 days of reflux with alkali and produced
low to
moderate yields of paroxetine.
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WO 00/78753 discloses forming a finely divided complex of a base (preferably
potassium hydroxide), and a carbamate intermediate obtained from the
demethylation of
Me-PRX and refluxing in a solvent (preferably toluene) to yield paroxetine.
In view of the foregoing, a need exists in the art for a high yield and time-
efficient
process for the preparation of paroxetine, which does not result in harmful by-
products. In
particular, there exists the need for such an improved process for preparing
paroxetine by
demethylation of N-methylparoxetine.
SUMMARY OF THE INVENTION
In one aspect, the present invention is directed to a compound of formula
(VII):
VII
wherein Rl is a haloallcyl other than 1-monohaloallcyl or perfluoroalkyl. In
one preferred
embodiment, Rl is 2-chloroethyl. In another preferred embodiment, RI is 2,2,2-
trichloroethyl.
In another aspect, the present invention is directed to a process for
preparing a
compound of formula (VII) comprising reacting a compound of formula (V) with
compound of formula (VI) in a suitable organic solvent,
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O
+ Z_Cw0_Rt >
V VI VII
wherein Z is a halogen, Rt is as defined above, and RZ is a lower alkyl. In
some preferred
embodiments, Z is chlorine, R, is 2-chloroethyl or 2,2,2-trichloroethyl and RZ
is methyl. In
another preferred embodiment, the reaction is conducted in the presence of a
tertiary amine
base. A particularly preferred tertiary amine base is a trialkylamine such as
triethylamine
or tributylamine.
In another aspect, the present invention is directed to a process for
preparing
paroxetine comprising hydrolyzing a compound of formula (VII), preferably
under alkaline
conditions. In a preferred embodiment, the hydrolysis is conducted in the
presence of a
glycol monoether. A particularly preferred glycol monoether is propylene
glycol
monomethyl ether (PGME).
In another aspect, the present invention is directed to a compound of formula
(VIII):
OCIHCHZOCH3
CH3
VIII
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In another aspect, the present invention is directed to a process for
preparing a
compound of formula (VIII) comprising hydrolyzing of a compound of formula
(VII),
preferably under alkaline conditions, in the presence of propylene glycol
monomethyl ether
(PGME).
In another aspect, the present invention is directed to a process for
preparing
paroxetine comprising the steps of reacting N-allcyl paroxetine with a
haloformic acid ester
of formula (VI) in a suitable organic solvent to form a carbamate intermediate
of formula
(VII), and hydrolyzing the carbamate intermediate of formula (VII), preferably
under
alkaline conditions, to obtain paroxetine. In a preferred embodiment, the
carbamate
intermediate is hydrolyzed in the presence of a glycol monoether. Paroxetine
base may be
recovered from the reaction mixture. An acid addition salt, preferably a
pharmaceutically
acceptable acid addition salt of paroxetine may then be formed from the
paroxetine base.
Among preferred acid addition salts of paroxetine are included, for example,
paroxetine
HCl in any of the various polymorphic forms of paroxetine HCl as are known in
the art.
Among presently preferred polymorphic forms of paroxetine HCl are included
crystalline
paroxetine HCl hemihydrate, anhydrous paroxetine HCl and paroxetine HCl
solvates, for
example the isopropanolate of paroxetine HCI.
These and other aspects of the present invention will now be described in more
detail with reference to the following detailed description of the invention.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the present invention is directed to a process for preparing a
novel
carbamate intermediate of paroxetine having formula (VII) wherein Rl is a
haloalkyl
group, other than 1-monohaloalkyl or perfluoroalkyl, by the deallcylation of N-
alkylparoxetine of formula (V) wherein RZ is a lower alkyl.
The term "haloalkyl" refers to a C1-C6 alkyl group in which one or more of the
carbon atoms is substituted with one or more halogen atoms. Preferred
haloalkyl groups
are C,-C4 alkyl groups in which one or more of the carbon atoms is substituted
with one or
more halogen atoms. The alkyl group may be a straight or branched-chain alkyl
group.
The halogen atom is one or more of fluorine, chlorine, bromine and iodine.
Among
preferred haloallcyl groups are 2-haloallcyl groups such as 2-haloethyl and 2-
halopropyl.
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The term "2-haloallcyl" refers to a CZ-C~ allcyl group in which the carbon
atom at the 2-
position is substituted with one or more halogen atoms. Among preferred 2-
haloallcyl
groups are 2-chloroethyl and 2,2,2-trichloroethyl.
The term "1-monohaloalkyl" refers to a Cz C~ allcyl radical having only a
single
halogen atom, which halogen atom is at the 1-position of the alkyl radical.
Thus, the term
"1-monohaloalkyl," for example, does not include 1,2-dichloroethyl, l,l-
dichloroethyl or
chloromethyl.
The term "perfluoroalkyl" refers to the group CmFZm+1, where m is an integer
of
from 1 to 6.
The term "lower alkyl" as used herein refers to a straight or branched chain
C,-C~
allcyl group. Among particularly preferred lower alkyl groups, i.e., RZ in the
compound of
formula (V), are ethyl and methyl. Where RZ is methyl, the compound of formula
(V) is
N-methyl paroxetine (Me-PRX) having formula (II).
Compound (V) is dealkylated by reacting it with a haloformic acid ester of
formula
(VI), wherein Z is a halogen atom such as fluorine, chlorine, bromine or
iodine, and Rl is
as defined above. Among preferred haloformic acid esters of formula (VI) are
the 2-
haloallcyl esters. A particularly preferred 2-haloalkyl ester of haloformic
acid is the 2-
chloroethyl ester wherein Z is chlorine, i.e., 2-chloroethyl-chlorofonnate
("CECF").
Another preferred haloforlnic acid ester is 2,2,2-trichloroethyl-
chloroformate.
The deallcylation of compound (V), i.e., N-alkylparoxetine, is conducted in a
suitable organic solvent. Among suitable solvents are included, for example,
dichloromethane, chloroform, diethyl ether, t-butyl methyl ether,
tetrahydrofuran, 1,4-
dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, hexane, heptane,
petroleum ether,
methyl acetate, ethyl acetate, N,N-dimethylformamide and N,N-
dimethylacetamide.
Aromatic solvents such as toluene are among those preferred for conducting the
deallcylation of compound (V). Dry toluene is a particularly preferred solvent
for
conducting the dealkylation reaction. For example, toluene having a water
content within
the range of from about 0.10% (technical grade toluene) to about 0.001% (extra
dry
toluene) may be used as the solvent for conducting the dealkylation.
The N-allcylparoxetine and haloformic acid ester are preferably added to
toluene
lcept at a temperature of from about 0 ° C to about 10 ° C, more
preferably about 5 ° C. The
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reaction temperature is preferably in the range of from about 10° to
about 150°C, more
preferably from about 20 ° to about 120 ° C. The reaction
mixture may be heated to a
temperature near or, preferably, at reflux conditions and the reaction is
preferably
conducted for a time sufficient to effect substantially complete conversion of
the N-
alkylparoxetine to the corresponding carbamate. Alternatively, the haloformic
acid ester
may be added dropwise at the reflux temperature of the reaction mixture and
continuing
reflux for up to about 10 hours, or until substantially complete conversion of
the N-
alkylparoxetine to the corresponding carbamate has occurred. The term
"substantially
complete conversion" as used herein refers to conversion of about 90% or more,
preferably
about 95% or more and, more preferably, about 99% or more of the N-
alkylparoxetine to
the corresponding carbamate.
In some preferred embodiments, the dealkylation of compound (~ is conducted in
the presence of a base. Examples of suitable bases include, for example, an
organic amine,
of which tertiary amines are preferred, an alkoxide, an alkali metal
hydroxide, an alkaline
earth metal hydroxide, an allcali metal hydride, an alkaline earth metal
hydride or an allcali
or alkaline earth metal carbonate or hydrogencarbonate salt. Specific examples
of suitable
bases include, for example, 1,8-bis(N,N-dimethylamino)napthalene, sodium
methoxide,
sodium ethoxide, sodium phenoxide, sodium hydroxide, potassium hydroxide,
calcium
hydroxide, magnesium hydroxide, sodium hydride, potassium hydride, calcium
hydride,
sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium
hydrogencarbonate, calcium carbonate and basic alumina. Preferred bases are
tertiary
amines such as trialkylamines of the general formula (R)3N, wherein each R is
the same or
different C,-C~ straight or branched-chain alkyl. Preferred trialkylamines are
tributylamine
(Bu3N) and triethylamine (Et3N). Tributylamine is a particularly preferred
trialkylamine
base. As illustrated by the Examples following this description, the presence
of a tertiary
amine in the dealkylation reaction mixture results in an increased yield of
the
corresponding carbamate and decreases the time required for effecting
substantially
complete conversion of the N-allcylparoxetine to the corresponding carbamate.
Upon substantially complete conversion to the corresponding carbamate, the
organic layer is separated, and preferably washed and dried. Water may be used
to wash
the separated organic layer and a suitable drying agent such as NaZS04 may be
used to dry
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the washed organic layer. Before separation of the organic layer, the mixture
is preferably
cooled, such as by adding water to cool the reaction mixture to room
temperature. The
preferably cooled reaction mixture is concentrated to dryness by, for example,
evaporation.
The resultant product is a carbamate intermediate of paroxetine having formula
(VII). The
compound of formula (VII) is novel compound in accordance with the present
invention. A
particularly preferred novel carbamate intermediate in accordance with this
aspect of the
present invention is a compound of formula (IV), i.e., the compound of formula
(VII)
wherein Rl is 2-chloroethyl:
F
O~O
N~
COOCHZCHZC1
IV
This compound is refereed to herein as the 2-chloroethyl carbamate of
paroxetine or
"CECB". Another preferred carbamate is the 2,2,2-trichloroethyl carbamate of
paroxetine,
which has the following structure (IX):
(Ix)
Another aspect of the present invention is a process for preparing paroxetine
by
hydrolyzing a carbamate intermediate of formula (VII), preferably under
alkaline
conditions, to yield paroxetine.
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The carbamate intermediate of formula (VII) is hydrolyzed in an appropriate
solvent to yield paroxetine. The reaction temperature is preferably from 10 to
150 °C,
more preferably from 20 to 120 °C. The reaction mixture may be heated
to a temperature
near or, preferably, at reflux conditions and the reaction is preferably
conducted for a time
sufficient to effect substantially complete conversion of the carbamate
intermediate of
formula (VII) to paroxetine.
The hydrolysis of the carbamate may be conducted under acidic or, preferably,
under alkaline conditions. Among suitable bases for conducting the alkaline
hydrolysis are
included, for example, an allcoxide, an alkali metal hydroxide, an alkaline
earth metal
hydroxide, or an allcali or alkaline earth metal carbonate or
hydrogencarbonate salt.
Specific examples of suitable bases include, for example, sodium methoxide,
sodium
ethoxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium
hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate,
potassium
hydrogencarbonate, and calcium carbonate. Preferred bases include, for
example, the
alkali metal hydroxides such as sodium hydroxide and potassium hydroxide and
the
alkaline earth metal hydroxides.
Among suitable solvents for conducting the alkaline hydrolysis of the
carbamate
intermediate are included, for example, diethyl ether, t-butyl methyl ether,
tetrahydrofuran,
1,4-dioxane and 1,2-dimethoxyethane, benzene, toluene, xylene, hexane,
heptane,
petroleum ether, methanol, ethanol, isopropanol, t-butanol, glycol monoethers,
water, and
mixtures of any of the foregoing. Among preferred solvents for conducting the
alkaline
hydrolysis are included, for example, lower alkanols such as methanol,
ethanol,
isopropanol, t-butanol and mixtures of one or more of such lower alkanols with
water; and,
glycol monoethers and mixtures thereof with water and/or another solvent such
as
described above.
The term "glycol monoethers" refers to the mono-(C,-C6, straight- or branched-
chain)allcyl ethers of lower allcylene glycols such as, for example, ethylene
glycol,
propylene glycol, 1,3-butylene glycol and 2,3-butylene glycol. Among preferred
glycol
monoethers are, for example, ethylene glycol monomethyl ether ("methyl
cellosolve", 2-
methoxyethanol), ethylene glycol monoethyl ether ("ethyl cellosolve", 2-
ethoxyethanol)
and propylene glycol monomethyl ether ("PGME", 1-methoxy-2-propanol).
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Applicants have found that conducting the hydrolysis of the carbamate
intermediate
of formula (VII) in the presence of a glycol monoether results in a faster and
more efficient
conversion of the carbamate intermediate into paroxetine as compared with, for
example,
the hydrolysis conducted in solvent comprising a lower allcanol or a mixture
thereof with
water. Moreover, these results are surprisingly achieved utilizing a lower
solventlcarbamate ratio. Applicants believe, without wishing to be bound by
any.particular
theory, that when a solvent containing ethanol or similar lower alkanol is
used to conduct
the alkaline hydrolysis, hydrolysis to paroxetine proceeds through a
corresponding lower
alkyl carbamate intermediate. It is believed that the hydrolysis of this lower
allcyl
carbamate intermediate is a rate-limiting step in yielding paroxetine.
However, when the
alkaline hydrolysis is conducted in the presence of a glycol monoether, it is
believed that
the hydrolysis proceeds through a different carbamate intermediate. It is
believed, in
accordance with HPLC-MS data, that this carbamate intermediate is formed by
reesterification of the carbamate of formula (VII) with the glycol monoether.
The
hydrolysis of this intermediate evidently proceeds more quickly than that of
the alkyl
carbamate intermediate formed using a lower alkanol such as ethanol.
Accordingly, another aspect of the present invention is a process for the
preparation
of paroxetine comprising hydrolyzing a carbamate intermediate of formula (VII)
under
alkaline conditions in the presence of a glycol monoether. Applicants have
found that
conducting the alkaline hydrolysis of the carbamate intermediate of formula
(VII) in the
presence of PGME is particularly advantageous. Thus, where the glycol
monoether is
PGME, the present invention is directed to a novel intermediate of formula
(VIII) formed
during this alkaline hydrolysis:
o~
~N
COOCHCHZOCH3
CH3
VIII
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The compound of formula (VIII) is referred to herein as N-(1-methoxyprop-2-
yloxycarbonyl)-paroxetine.
Table 1, below, provides comparative data obtained by conducting the
hydrolysis
of the carbamate intermediate of formula (IV) in (a) a solvent comprising a
mixture of a
lower alkanol and water and (b) a solvent comprising a mixture of a glycol
monoether and
water. The lower alkanols used in these examples were (i) isopropanol ("IPA"),
(ii)
methanol ("MeOH"), and (iii) ethanol ("EtOH"). The glycol monoethers used in
these
examples were (i) propylene glycol monomethyl ether ("PGME") and (ii) glycol
ethyl
ether ("GEE"). The base used during the alkaline hydrolysis was either sodium
or
potassium hydroxide.
Table 1
Comparative data for h~ysis of compound (IV)
Solvent H20 Base Temp. ReactionHPLC
ROH purity
profile
(area
%)
Name Volume Volume Name eq C time, PRX IV
h
IPA 12.6 10 NaOH 7.1 80 4.5 72.8 8.3
MeOH 29 7 KOH 18.3 70 20 81.7 negligible
29 86 negligible
EtOH 12.6 10 NaOH 7.1 78 4 84.7 7.2
5.5 85.9 0.5
PGME 10 8 NaOH 7.1 94 2 90.3 negligible
16 90.4 negligible
GEE 12.6 10 NaOH 7.1 98 3 90.7 0.3
As evident from Table 1, when the hydrolysis of compound (IV) is conducted in
a
solvent comprising a mixture of a glycol monoether such as PGME or GEE and
water,
paroxetine yield is greater than about 90% and is achieved in a relatively
short time frame
of from about 2 to about 3 hours. Moreover, paroxetine formation is
substantially
complete in this time frame, as shown by the fact that extending the reaction
time to 16
hours only resulted in a 0.1% increase (i.e., from 90.3% to 90.4%) in
paroxetine yield
relative to the yield obtained after reaction for 2 hours. In contrast, the
paroxetine yield
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obtained using a solvent comprising a mixture of a lower alkanol such as IPA,
MeOH or
EtOH and water remains substantially lower despite a significantly longer
reaction time.
In accordance with a further aspect, the present invention is directed to a
process
for preparing paroxetine comprising (a) dealkylating N-allcylparoxetine of
formula (V) by
reacting it with a haloformic acid ester of formula (VI) in a suitable solvent
to form a
paroxetine carbamate intermediate of formula (VII) and (b) hydrolyzing the
paroxetine
carbamate intermediate of formula (VII) under alkaline conditions in a
suitable solvent to
yield paroxetine. In a preferred embodiment, N-methylparoxetine is dealkylated
by
reaction with 2-chloroethylchloroformate in the presence of a trialkylamine
base and the
coiTesponding carbamate intermediate is hydrolyzed under alkaline conditions
in the
presence of a glycol monoether. The resultant product of the hydrolysis is
paroxetine base.
Paroxetine base, in crude form, may then be recovered from the reaction
mixture
by, e.g., extraction into an appropriate organic solvent, such as toluene,
benzene or xylene,
or a mixture of any one or combination of such solvents with water. The
organic phases)
obtained from the extraction are preferably washed with, for example, water
and brine.
The extraction solvent may optionally be removed by, e.g., evaporation and a
solution of
paroxetine base in a different solvent may be formed.
Paroxetine base in solution may then be converted to a pharmaceutically
acceptable
acid addition salt. A preferred pharmaceutically acceptable acid addition salt
is paroxetine
HCI, which may be made in any of the various polymorphic forms thereof known
in the
art. Among the presently preferred polymorphic forms of paroxetine HCl are
included
crystalline paroxetine hydrochloride hemihydrate as disclosed in U.S. Patent
No.
4,721,723, which is incorporated herein in its entirety; and, any of the
paroxetine
hydrochloride anhydrate and solvate forms, particularly the isopropanolate,
disclosed in
U.S. Patent No. 6,080,759, which is incorporated herein in its entirety.
Paroxetine base in solution may be converted into paroxetine HCl by, for
example,
contacting a solution of paroxetine base, such as the toluenic solution
obtained from the
alkaline hydrolysis and extraction steps, as described above, with aqueous or
gaseous HCl
followed by crystallization in an appropriate solvent to obtain the desired
polymorphic
form. Where the desired polymorphic form is the hemihydrate, it is preferable
to contact
the solution of paroxetine base with aqueous HCl followed by crystallization
as generally
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disclosed in U.S. Patent No. 4,721,723. Where the desired polymorphic form is
anhydrous
paroxetine or the ispropanolate, a solvent solution of paroxetine base is
preferably
contacted with dry hydrogen chloride gas or a solvent substantially free of
water wherein
the solvent has hydrogen chloride gas dissolved therein. U.S. Patent No.
6,080,759
discloses methods for the preparation of anhydrous forms of paroxetine HCI.
The
solvents used to foam the anhydrates are substantially free of water, meaning
that there is
insufficient water present at the time of crystallization to effect conversion
to a hydrated
form of paroxetine HCl such as the hemihydrate. A solvent substantially free
of water may
be obtained by drying the solvent with a conventional drying agent such as a
molecular
sieve. Anhydrous solvents may also be purchased commercially.
Thus, crude paroxetine hydrochloride hemihydrate may be formed, for example,
from a toluenic solution of paroxetine base by contacting the solution of
paroxetine base
with aqueous HCl followed by crystallization in an appropriate solvent as
generally
disclosed in U.S. Patent No. 4,721,723.
Crystalline paroxetine hydrochloride hemihydrate may then be prepared by
recrystallization of the crude paroxetine hydrochloride hemihydrate in a
suitable solvent.
Among suitable solvents are included, for example, lower alkanols such as
methanol and
ethanol; lcetones such as acetone; esters such as ethyl acetate; and, mixtures
of any of the
foregoing such as methanol/acetone.
Anhydrous foams of paroxetine hydrochloride may be formed by the methods as
generally disclosed in U.S. Patent No. 6,080,759. The anhydrous form is free
of bound
solvents. Anhydrous paroxetine hydrochloride may be prepared by contacting, in
a dry NZ
environment, a solution of paroxetine base in an organic solvent, such as
isopropanol, with
dry hydrogen chloride gas. Alternatively, the solution of paroxetine base in
an organic
solvent may be contacted with a solvent substantially free of water wherein
the solvent has
dry hydrogen chloride gas dissolved therein. The reaction mixture is heated to
ensure
complete dissolution of the paroxetine hydrochloride. Seed crystals of
anhydrous
paroxetine may be added to improve the crystallization process.
As disclosed in U.S. Patent No. 6,080,759, anhydrous forms of paroxetine free
of
bound solvent may also be prepared from the paroxetine hemihydrate by
dissolving the
hemihydrate in an appropriate solvent substantially free of water which forms
an azeotrope
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with water. Suitably, solvent is removed by distillation and fresh solvent is
added until all
of the water is removed.
The anhydrous forms free of bound solvent may also be made by crystallizing
paroxetine hydrochloride in an organic solvent or a mixture of solvents which
form a
solvate with the paroxetine hydrochloride and displacing the solvated solvent
or solvents
from the paroxetine hydrochloride solvate using a displacing agent.
Preferably, gaseous or
liquid water may be used as the displacing agent. It is important that the
paroxetine
hydrochloride solvate is contacted with enough water and for sufficient time
to displace the
solvent but insufficient to cause conversion to the hydrochloride hemihydrate.
Paroxetine HCl can also be prepared in various solvate forms as disclosed in
U.S.
Pat. No. 6,080,759. Among the preferred solvate forms is paroxetine
hydrochloride
isopropanolate as disclosed in Examples 1-3 of U.S. Patent No. 6,080,759.
Paroxetine
HCl isopropanolate may be formed by displacing water from paroxetine HCl
hemihydrate
in, e.g., a mixture of toluene and isopropanol followed by crystallization.
Paroxetine HCl
isopropanolate may also be formed by contacting a solution of paroxetine base
in
isopropanol with dry hydrogen chloride gas followed by crystallization. The
isopropanolate may also be formed by contacting a solution of paroxetine base
in dry
isopropanol with a solution of dry hydrogen chloride gas in dry isopropanol
followed by
crystallization. Solvates other than the isopropanolate can be made by similar
methods as
disclosed in U.S. Patent No. 6,080,759. Among such solvates are included
solvates from
solvents such as alcohols other than isopropanol such as 1-propanol and
ethanol; from
organic acids such as acetic acid; from organic bases such as pyridine; from
nitrites such as
acetonitrile; from ketones such as acetone and butanone; from ethers such as
tetrahydrofuran; from chlorinated hydrocarbons such as chloroform and from
hydrocarbons
such as toluene. These solvates may be used to form the anhydrous forms free
of bound
solvent by either displacing the solvent as described above or by removing the
solvent by
conventional techniques such as vacuum oven drying.
The present invention is illustrated in further detail with reference to the
following
non-limiting Examples:
Examples 1-3 disclose the formation of the 2-chloroethyl carbamate of
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paroxetine ("CECB", 1-(2-chloroethoxycarbonyl)-4-(p-fluorophenyl)-3-[5-(1,3-
dioxanindanyl)oxymethyl]piperidine) by reaction of N-methyl paroxetine with 2-
chloroethyl-chlorofonnate ("CECF"). Example 4 discloses the alkaline
hydrolysis of the
2-chloroethyl carbamate of paroxetine to yield paroxetine. Example 5 discloses
the
alkaline hydrolysis of the 2-chloroethyl carbamate of paroxetine in propylene
glycol
monomethyl ether ("PGME") and water. Example 6 discloses the alkaline
hydrolysis of
the 2-chloroethyl carbamate of paroxetine in ethanol and water. Example 7
discloses the
alkaline hydrolysis of the 2-chloroethyl carbamate of paroxetine in propylene
glycol
monomethyl ether to form paroxetine base. Example ~ discloses the formation of
2,2,2-
trichloroethyl-carbamate of paroxetine (1-(2,2,2-trichloroethoxycarbonyl)-4-(p-
fluorophenyl)-3-[5-(1,3-dioxanindanyl)oxymethyl]piperidine) by reaction of N-
methylparoxetine with 2,2,2-trichloroethyl-chlorofornzate. Example 9 discloses
a multi-
stage process for producing paroxetine hydrochloride hemihydrate comprising
preparation
of the 2-chloroethyl carbamate of paroxetine; hydrolysis thereof to yield
paroxetine base;
formation of crude paroxetine hydrochloride hemihydrate from the paroxetine
base; and,
recrystallization of the crude paroxetine hydrochloride hemihydrate to yield
crystalline
paroxetine hydrochloride hemihydrate. Example 10 discloses the preparation of
paroxetine
hydrochloride anhydrous from a solution of paroxetine base in toluene.
Example 1
Reaction with 2-Cl-ethylchloroformate (CECF) in dry conditions
Me-PltX (3 g) and extra dry toluene (40 ml, less than 0.001 % water) are
charged
into dried equipment under a dry NZ stream. The reaction mixture is cooled to
4 ° C with an
ice bath. CECF (2.7 mL, 3 eq., purchased from SNPE) is added dropwise for
several
minutes. The mixture is heated to reflux for 7 hours providing the
substantially complete
conversion of Me-PRX (HPLC) to the carbamate. Water (50 mL) is added to cool
the
reaction mixture to room temperature. The organic layer is separated, washed
with water,
dried with NaZS04 and evaporated to dryness to give 1-(2-chloroethoxycarbonyl)-
4-
fluorophenyl-3-[5-(1,3-dioxaindanyl)oxymethyl]piperidine, i.e., the 2-
chloroethyl
carbamate of paroxetine (CECB).
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Example 2
Reaction with CECF in the presence of Bu3N
The same procedure as described in Example 1 is repeated, except that the
equipment is not previously dried, technical grade toluene (less than 0.10%
water) is used
instead of extra dry toluene, and the reactants are not charged under a dry NZ
stream. The
reaction mixture, before addition of CECF, also contains 2.05 g (1.2 eq.) of
Bu3N. After
1.5 hours of reflux, substantially complete conversion of Me-PRX to the
corresponding
carbamate takes place. The carbamate, i.e., the 2-chloroethyl carbamate of
paroxetine
(CECB) is separated from the reaction mixture using the same procedures as
described in
Example 1.
Example 3
Reaction with CECF in the presence of Et3N
The same procedure as described in Example 2 is repeated, but with 1.1 g Et3N
(1.2
eq.) used in place of Bu3N. After 4 hours of reflux, conversion of the Me-PRX
to the
corresponding carbamate is 74% (reaction stopped).
Example 4
Reaction with CECF without amine
The same procedure as described in Example 1 is repeated, except that the
equipment is not previously dried, technical grade toluene is used instead of
extra dry
toluene, and the reactants are not charged under a dry NZ stream. Conversion
of Me-PRX
to the corresponding carbamate after 3 hours is 47% (reaction stopped).
Example 5
Hydrolvsis of CECB
A mixture of 6.13 g of the product of Example l, 12 mL IPA, 6.Sg NaOH and 44
mL HZO are refluxed for 18 hours. At this point, the conversion of CECB to PRX
is more
than 95% (HPLC). The mixture is cooled and the organic phase is evaporated to
give
crude paroxetine with quantitative yield (95%) from Me-PRX.
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Example 6
Hydrolysis of CECS
A mixture of 4.24 g of compound (IV) (8.7 mmol), 48 ml ethanol, 2.5 g NaOH
(62.5 mmol) and 38 ml water is refluxed for 4 hours. The reaction mixture
contains
(HPLC) 84.7% of PRX and 1.5% of (IV). After an additional 1.5 hours of reflux,
the
content of PRX increases only 1 %.
Example 7
Hvdrolysis of CECB
A mixture of 9.8 g compound (IV) (18.3 mmol), PGME (100 mL), 5.2 g NaOH
(129 mmol) and water (80 mL) is heated with stirring to 90-95 °C. The
stirring is
continued at this temperature for 2 hours. At this point, the reaction mixture
contains
(HPLC) 90.3% of PRX. In the another experiment, GEE is used in place of PGME,
and
paroxetine is obtained in a yield of 90.7% after 3 hours.
Example 8
Reaction with 2,2,2-trichloroeth~l-chloroformate
Me-PRX (150g) is dissolved in toluene (450m1) at room temperature. The mixture
is then heated to reflux. At reflux, 2,2,2-trichloroethyl-chloroformate
(120m1) is added
dropwise for about 2.5 hours. After about 3 hours at reflux, the
reaction mixture is cooled, and ammonia 20% (300m1) and water (300m1) is
added. The organic phase is separated and washed with water (SOOmI),
followed by brine (SOOmI). The organic phase is then separated, dried over
MgS04, filtered. Toluene is then removed under reduced pressure to give
280.2g of the 2,2,2-trichloroethyl carbamate of paroxetine. The carbamate is
then
hydrolyzed according to procedures set forth, for example, in Examples 5-7 to
give
paroxetine base. Paroxetine base may then be converted into the desired
polymorphic
form of, e.g., the hydrochloride acid addition salt such as the hemihydrate,
anhydrite or
solvate form as disclosed herein.
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Example 9
Preparation of Paroxetine Hydrochloride Hemihydrate from N-methyl Paroxetine
Preparation of CECB
N-methylparoxetine ( 100g) and toluene (300m1) are charged into a one liter
flasle. The
mixture is heated to reflux. CECF (125g) is added dropwise during about 3
hours at reflux.
Stirring at reflux of the reaction mixture is continued for about 10 hours.
The mixture is
cooled to room temperature. Water (75m1) and NH40H (75m1) are added to the
reaction
mixture. The mixture is heated to 40°C and stirred for 30 minutes. The
organic phase is
separated, washed twice with water (2x100m1) and with brine (100m1). Toluene
is replaced
with isopropyl alcohol during distillation and the carbamate (CECB) is
filtered and dried to
give 117g CECB.
Preparation of PRX base
CECB (1 OOg), PGME (SOOml) and KOH (180g) are charged into a one liter flask.
The
mixture is heated to 60°C and stirred at this temperature for about 10
hours. PGME is
removed by distillation at a temperature of 70°C under vacuum. Water
(470m1) and toluene
(470m1) are added to the remaining mixture. The organic phase is separated and
the aqueous
phase is washed with toluene (290m1). The combined toluene phases are washed
with water
(2x290m1) and with brine (290m1). The toluene solution of PRX base (761 g,
assay by titration
9.89%) is obtained, which is used in the next step without evaporation.
Preparation of Paroxetine hydrochloride hemihydrate crude
The toluenic solution of PRX base (SOOg), PGME (8lml), water (81m1), ammonium
chloride (21.9g) and hydrochloric acid 32% (14.94g) are charged into a one
liter flask. The
mixture is cooled to 2-4°C and stirred at this temperature for about 3
hours (precipitation starts
after about 1 hour). The precipitate is filtered, washed consecutively with
SOmI water, SOmI
toluene and SOmI acetone, and dried to give 49.Sg of crude PRX HCl
hemihydrate.
Preparation of Crystalline Paroxetine hydrochloride hemihydrate
Crude paroxetine hydrochloride hemihydrate (40g), acetone (400m1) and methanol
(20m1) are charged into a one liter flask. The mixture is heated to reflux to
dissolve the crude
PRX HCl hemihydrate. Stirring is continued for 15 minutes. The hot solution is
filtered
through a charcoal bed. The filter cake is washed with Sml of a mixture of
acetone and
methanol (20:1). The combined filtrates are cooled to 2-3°C and stirred
for 1.5 hours. The
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precipitate is filtered, washed with 40m1 acetone and dried to give 35g of
crystalline PRX HCl
hemihydrate.
Example 10
Preparation of Paroxetine Hydrochloride Anhydrous
A solution of paroxetine base in toluene (355g, 9.9% w/w) is charged into a
batch
stirred reactor. The solvent is distilled under reduced pressure at a
temperature not higher
than 90°C. The distillation is continued until distillate is no longer
observed. Nitrogen gas
is purged into the reactor to obtain ambient pressure. A nitrogen environment
is
maintained throughout the conversion to paroxetine hydrochloride anhydrous.
Isopropanol extra dry (80 mL, water content less than 0.01 %) is charged into
the
reactor. Isopropanol is then distilled under reduced pressure until distillate
is no longer
observed. Nitrogen gas is then purged into the reactor to obtain ambient
pressure. The
process of feeding isopropanol extra dry and distilling under reduced pressure
is repeated
two additional times. After the end of the third distillation, isopropanol
extra dry (598.4
grams) and isopropanol solution (91.94 grams) containing 3.31 grams of
hydrogen chloride
gas are charged into the reactor under an inert nitrogen environment. The
reaction mixture
is heated to 70°C to obtain complete dissolution of the paroxetine
hydrochloride. After'
achieving full dissolution at 70°C, the solution is cooled to
51°C. At 51°C, the solution is
seeded with crystals of paroxetine hydrochloride anhydrous to facilitate the
crystallization
process. After the seeding, the solution is stirred at 51°C and
subsequently cooled to 25°C
over 12 hours. After the temperature of the reaction mixture reaches
25°C, the mixture is
stirred for an additional hour. The resultant slurry is filtered under
nitrogen and dried to
give 25.4 g paroxetine hydrochloride anhydrous. Even though this Example
crystallizes
out of isopropanol, the product is paroxetine hydrochloride anhydrous rather
than the
isopropanolate. The main reason for obtaining anhydrous form rather than the
isopropanolate is the use of extra dry isopropanol along with a dry atmosphere
throughout
the process.
Relative to Example 1 wherein Bu3N is not present, Example 2 shows that the
presence of Bu3N reduces the reaction time necessary to obtain substantially
complete
conversion of Me-PRX to the corresponding carbamate. The same procedure with
Et3N
(Example 3) also reduces the reaction time relative to that required for
substantially
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complete conversion of Me-PRX to the carbamate in Example 1. In Example 3,
reflux for
four hours in the presence of Et3N produces a 74% conversion to the carbamate
while in
the Comparative Example, conducted in the absence of Et3N, only a 47%
conversion is
achieved. These results demonstrate a significant advantage in conducting the
deallcylation
of paroxetine, e.g., the demethylation of paroxetine, to achieve a compound
(VII) in
accordance with the present invention, when the dealkylation is conducted in
the presence
of a tertiary amine such as Bu3N or Et3N.
Having thus described the invention with reference to particular preferred
embodiments and illustrated it with examples, those in the art may appreciate
modifications to the invention as described and illustrated that do not depart
from the spirit
and scope of the invention as disclosed in the specification.
