Note: Descriptions are shown in the official language in which they were submitted.
CA 02346900 2001-04-17
H U2-21863/A
-1-
Method of aroducingi ketimines
The present invention relates to a process for the preparation of ketimines
suitable as
starting materials for the preparation of pharmaceutical active ingredients
such as, for
example, sertraline having antidepressant properties.
The best processes hitherto for the preparation of ketimines are described,
for example, in
US-A-4 536 518 or US-A-4 855 500.
In the process for the preparation of ketimines disclosed in US-A-4 536 518
(columns 9/10,
Example 1 (F)), the ketone is reacted, with cooling, in an aprotic solvent,
for example tetra-
hydrofuran, with methylamine in the presence of titanium tetrachloride. That
process has the
disadvantage that it is necessary to work with tetrahydrofuran, which is
readily combustible,
and with titanium tetrachloride, which is not free of ecological concern. In
addition, the
process is expensive to perform, because the reaction is carried out with
cooling. A further
disadvantage of that process relates to the working-up. The product has to be
precipitated
with additional hexane.
In the process for the preparation of ketimines disclosed in US-A-4 855 500
(columns 5/6,
claim 1 ), the ketone is reacted, with cooling, in an aprotic solvent, for
example methylene
chloride, toluene or tetrahydrofuran, with anhydrous methylamine in the
presence of a
molecular sieve.
That process too has the disadvantage that it is necessary to work under
anhydrous
conditions with solvents that are not free of ecological concern, for example
methylene
chloride, or with readily combustible solvents, for example tetrahydrofuran.
The molecular
sieve used is expensive and has to be recycled again in an additional step. A
further
disadvantage of that process is that the molecular sieve has to be separated
off and the
product has to be precipitated with additional hexane.
There is therefore still a need to find an efficient process for the
preparation of ketimines that
does not have the disadvantages mentioned above and that works especially in
protic
solvents, for example alcohols.
The present invention accordingly relates to a process for the preparation of
compounds of
formula
CA 02346900 2001-04-17
-2-
N~CH3
(1) , wherein
R~, R2 and R3 are each independently of the others hydrogen, halogen,
trifluoromethyl or
C~-C4alkoxy, in which process
(a) a compound of formula
R
(2) , wherein
R~, R2 and R3 are as defined for formula (1 ), is reacted with methylamine in
a protic
solvent, and
(b) the resulting compound of formula (1) is subjected to purification by
recrystallisation
and/or reaction step (a) is carried out in the presence of a catalyst.
Halogen is, for example, chlorine, bromine or iodine. Chlorine is preferred.
Alkoxy having up to 4 carbon atoms is a branched or unbranched hydrocarbon
radical, for
example methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy or tent-
butoxy. Methoxy
is preferred.
According to the invention, preference is given to a process wherein
(a) a compound of formula (2) is reacted with methylamine in a protic solvent
and
(b) the resulting compound of formula (1 ) is subjected to purification by
recrystallisation; or
a process wherein
(a) a compound of formula (2) is reacted with methylamine in a protic solvent
in the
presence of a catalyst to form a compound of formula (1).
CA 02346900 2001-04-17
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Very special preference is given to a process wherein
(a) a compound of formula (2) is reacted with methylamine in a protic solvent
in the
presence of a catalyst to form a compound of formula (1), and
(b) the resulting compound of formula (1 ) is subjected to purification by
recrystallisation.
Of interest is a process for the preparation of compounds of formula (1 )
wherein
R~ is hydrogen or chlorine.
Also of interest is a process for the preparation of compounds of formula (1)
wherein
R2 and R3 are each independently of the other hydrogen, chlorine or bromine.
Of special interest is a process for the preparation of compounds of formula
(1 ) wherein
R~ is hydrogen and
R2 and R3 are chlorine.
Particularly of special interest is a process for the preparation of compounds
of formula (1 )
wherein the protic solvent is an a-hydric alcohol wherein a is the number 1,
2, 3 or 4.
Preference is given to a process for the preparation of compounds of formula
(1 ) wherein the
protic solvent is a compound of formula
(3) X(OH)a
wherein
a is 1, 2, 3 or 4, and
.~ when a is 1,
X is C~-C$alkyl, C5-Cscycloalkyl or -CH2CH2(OCH2CH2)bR4,
b is 0, 1 or 2, and
R4 is C~-C4alkoxy, or
when a is 2,
X is C2-C8alkylene or -CH2CH2(OCH2CH2)b-, wherein b is as defined above, or
when a is 3,
X is C3-CBalkanetriyl or N(CH2CH2-)3, or
when a is 4,
X is C4-CBalkanetetrayl.
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Alkyl having up to 8 carbon atoms is a branched or unbranched hydrocarbon
radical, for
example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2-
ethylbutyl, n-pentyl,
isopentyl, 1-methylpentyl, 1,3-dimethylbutyl, n-hexyl, 1-methylhexyl, n-
heptyl, isoheptyl,
1,1,3,3-tetramethylbutyl, 1-methylheptyl, 3-methylheptyl, n-octyl, 2-
ethylhexyl or isooctyl.
C5-CBCycloalkyl is, for example, cyclopentyl, cycloheptyl or especially
cyclohexyl.
Alkoxy having up to 4 carbon atoms is a branched or unbranched hydrocarbon
radical, for
example methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy or tent-
butoxy. Methoxy
is preferred.
C2-CBAIkylene is a branched or unbranched radical, for example ethylene,
propylene,
trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene or
octa-
methylene.
Alkanetriyl having from 3 to 8 carbon atoms is derived from an alkane having
from 3 to 8
carbon atoms wherein 3 hydrogen atoms are absent and is, for example,
-CHZ CH-CH2 , -CHZ CH2 CH-CH2 , -CH2 CHZ CH-CHz CHZ Or
-cH2 cH2 cH2 CH-CHZ cHz cH2 . Glyceryl is preferred.
Alkanetetrayl having from 4 to 8 carbon atoms is derived from an alkane having
from 4 to 8
carbon atoms wherein 3 hydrogen atoms are absent and is, for example,
i Hz
-CHZ C-CHZ , -CHz CH-CH-CHZ , -CH2 CHZ CH-CH-CHZ Or
CHZ
I I
cHz cH2 CH-CHZ CH-CHZ cHz . Pentaerythrityl is preferred.
A preferred meaning of X (for a = 1) is, for example, C~-Csalkyl, especially
C~-C4alkyl, e.g.
ethyl or isopropyl.
A preferred meaning of X (for a = 2) is, for example, C2-C fialkylene,
especially C2-C4alkylene,
e.g. ethylene.
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Of special interest is a process for the preparation of compounds of formula
(1) wherein the
protic solvent is a compound of formula
(3) X(OH)a
wherein
a is 1 or 2, and
when a is 1,
X is C~-C4alkyl or C5-Cscycloalkyl, or
when a is 2,
X is C2-C4alkylene.
Special preference is given to a process for the preparation of compounds of
formula (1 )
wherein the protic solvent is methanol, ethanol, isoproponanol, n-butanol,
ethylene glycol,
methyl Cellosolve, cyclohexanol, diethylene glycol or triethanolamine.
Special preference is given to a process for the preparation of compounds of
formula (1)
wherein the protic solvent is ethanol or isopropanol.
The starting compounds of formula (2) are known or can be prepared analogously
to the
processes described in US-4 536 518.
Preferred reaction conditions for the process according to the invention
(reaction step (a))
are as follows:
The reaction can be carried out at room temperature or at elevated
temperature, especially
temperatures of from 20 to 100°C, e.g. from 25 to 65°C,
optionally under slight pressure.
The reaction is especially carried out with a large molar excess of
methylamine. Special
preference is therefore given to a process for the preparation of compounds of
formula (1 )
wherein the relative molar proportion of the compound of formula (2) to
methylamine is from
1:1 to 1:100, especially from 1:1.05 to 1:50, e.g. from 1:1.5 to 1:15.
The methylamine can be used in the form of methylamine gas or in the form of a
solution in
an alcohol, for example ethanol.
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Preferred catalysts for the process for the preparation of compounds of
formula (1 ) are
protonic acids, Lewis acids, aluminium silicates, ion exchange resins,
zeolites, naturally
occurring layer silicates or modified layer silicates.
Suitable protonic acids are, for example, acids of inorganic or organic salts,
e.g. hydrochloric
acid; sulfuric acid; phosphoric acid or sulfonic acids, for example
methanesulfonic acid, p-
toluenesulfonic acid or camphor-10-sulfonic acid.
A suitable Lewis acid is, for example, scandium tristriflate [Sc(OTf)3].
Suitable aluminium silicates are, for example, those widely used in the
petrochemical
industry and also known as amorphous aluminium silicates. Such compounds
contain about
10-30 % silicon oxide and 70-90 % aluminium oxide.
Suitable ion exchange resins are, for example, styrene/divinyl benzene resins
that also carry
sulfonic acid groups, e.g. Amberlie 200~ and Amberlyst° from Rohm and
Haas or Dowex 50~
from Dow Chemicals; perfluorinated ion exchange resins, e.g. NafionH~ from
DuPont; or
other superacidic ion exchange resins such as those described by T. Yamaguchi,
Applied
Catalysis, 61, 1-25 (1990) or M. Hino et al., J. Chem. Soc. Chem. Commun.
1980, 851-852.
Suitable zeolites are, for example, those widely used as cracking catalysts in
the petro-
chemical industry and known as crystalline silicon-aluminium oxides having
different crystal
structures. Special preference is given to the faujasites from Union Carbide,
e.g. Zeolith X~
y Zeolith Y~ and ultrastable Zeolith Y~; Zeolith Beta~ and Zeolith ZSM-12~
from Mobil Oil Co.;
and Zeolith Mordenit~ from Norton.
Suitable naturally occurring layer silicates are also known as "acid earths"
and are, for
example, bentonites or montmorillonites, which are mined on a large scale,
ground, treated
with mineral acids and calcined. Especially suitable naturally occurring layer
silicates are the
Fulcat°types from Laporte Adsorbents Co., e.g. Fulcat 22A~, Fulcat
22B~, Fulcat 20~, Fulcat
30~ or Fulcat 40~; or the FulmontG types from Laporte Adsorbents Co., e.g.
Fulmont XMP-3~
or Fulmont XMP-4~. An especially preferred catalyst for the process according
to the
invention is Fulcat 22B~, but the other Fulcat° types and Fulmont~
types are also to be
included in this preferred class, because there are only very slight
differences between the
individual types, for example in the number of acidic centres.
Modified layer silicates are also known as "pillared clays" and are derived
from the naturally
occurring layer silicates described above in that they also contain, between
the silicate
CA 02346900 2001-04-17
_ 7 -
layers, oxides of, for example, zirconium, iron, zinc, nickel, chromium,
cobalt or magnesium.
That type of catalyst is widely known in the literature, as described e.g. by
J. Clark et al., J.
Chem. Soc. Chem. Commun. 1989, 1353-1354, but is produced by only very few
companies. Especially preferred modified layer silicates are, for example,
Envirocat
EPZ-10~, Envirocat EPZG~ or Envirocat EPIC~ from Contract Chemicals.
Special preference is also given to a process for the preparation of compounds
of formula,
wherein the catalyst is a sulfonic acid, especially p-toluenesulfonic acid,
methanesulfonic
acid or camphor-10-sulfonic acid.
1°' The relative molar proportion of the catalyst used to methylamine
used is advantageously
from 0.001:1 to 1:1, especially from 0.01:1 to 0.5:1, e.g. from 0.05:1 to
0.1:1.
The relative molar proportion of the catalyst to methylamine of 1:1 also means
that the
methylamine can also be used in the process according to the invention in the
form of a salt,
for example in the form of the methylamine hydrochloride.
Also of particular interest is a process for the preparation of compounds of
formula (1 )
wherein the compound of formula (1 ) is continuously crystallised out of the
reaction medium
during preparation and then filtered off.
Also of special interest is a process for the preparation of compounds of
formula (1 ) wherein
the filtrate is used for a further reaction for the preparation of compounds
of formula (1 ), the
consumed amounts of compound of formula (2) and methylamine being replaced.
The
filtrate is preferably recycled from 2 to 10 times.
The present process according to the invention is accordingly also suitable as
a continuous
process for the preparation of the compounds of formula (1).
The water formed during the process can optionally be bound with an additional
water-
binder, for example molecular sieves or orthoesters, e.g. orthoformic acid
trimethyl ester.
The purification step (b) is carried out in a protic solvent, especially an
alcoholic solvent.
Especially preferred alcohols correspond to formula (3), especially ethanol or
isopropanol.
In an especially preferred embodiment, the purification step (b) is carried
out in the same
solvent as reaction step (a).
In a preferred process variant, the purification is carried out by
recrystallisation of sertraline-
imine (compound of formula (1 )) under reflux. For that purpose, the
isornerically pure
CA 02346900 2001-04-17
_ $ _
sertraline-imine, which is usually contaminated with from 2 to 10 % sertralone
and from 0.01
to 0.3 % sulfonic acid, in a suitable alcohol is introduced into a suitable
reaction vessel
having a stirrer and reflux condenser. The reaction mass is heated, with
stirring, at reflux
temperature in an inert gas atmosphere until a clear solution is obtained. The
solution is
cooled to the appropriate isolation temperature, the product slowly
precipitating out. The
suspension is filtered, the filter cake is washed with the solvent and dried.
The yield of imine
is from 80 to 90 %, with a sertralone content of from 0.1 to 0.3 % (HPLC),
catalyst
contamination of <_ 0.001 % and a water content of from 0.1 to 0.3 %.
. ~ In a further process variant, the recrystallisation of sertraline-imine is
carried out under
pressure. For that purpose, the crude sertraline-imine and the solvent are
introduced into a
suitable pressurised reactor having a stirrer. The reactor is rendered inert
with nitrogen and
sealed. The stirrer is started and the reaction mixture is heated at the
desired reaction
temperature until a clear solution is obtained. The solution is cooled to the
appropriate
isolation temperature, the product slowly precipitating out. The suspension is
filtered, the
filter cake is washed with the solvent and dried.
The dissolution temperatures in the chosen alcohols are in the range of from
50 to 150°C,
preferably in the range of from 70 to 140°C.
According to the boiling points of the solvents indicated, the dissolving
experiments can be
carried out under normal pressure or elevated pressure, but normally under
reflux.
For dissolving temperatures above the boiling point, the dissolving
experiments can be
carried out under pressure, normally in the range of from 0 to 10 bar excess
pressure,
preferably in the range of from 0 to 3 bar excess pressure.
The cooling gradients are in the range of from 0.05 to 10°C/min,
preferably from 0.1 to
1 °C/min.
The isolation temperatures are in the range of from -20 to 40°C,
preferably from 0 to 25°C.
The concentrations of crude sertraline-imine in the clear solution are in the
range of from 5 to
40 % by weight, preferably from 15 to 20 % by weight.
During the process, in order to remove discolouring impurities it is possible
to add
adsorbents such as activated carbon or adsorber resins. They are added to the
clear
CA 02346900 2001-04-17
_g_
solution in amounts of from 1 to 10 % and are removed while hot by filtration
prior to the
crystallisation process.
The present invention relates also to a process for the preparation of
optically pure (cis)-
and/or (trans)-sertraline or enantiomerically enriched mixtures of (cis)- and
(trans)-sertraline.
The process comprises the following reaction steps (I)-(III):
(I) reaction of pure sertraline-ketone of formula (2) to form the sertraline-
imine of formula
(1 ) in accordance with the process of claim 1,
(II) subsequent cis-selective hydrogenation using noble metal catalysts or
further copper- or
nickel-based catalysts to form cis-sertraline-enriched mixtures of racemic cis-
and trans-
sertraline,
(III) subsequent racemate cleavage using mandelic acid for the selective
preparation of the
desired enantiomerically pure cis-isomer.
Starting from pure setraline-ketone, sertraline-imine is prepared in
accordance with the
process described in claim 1. In a subsequent cis-selective hydrogenatiqn with
noble metal
catalysts or further copper- or nickel-based catalysts of a wide variety of
supports, e.g.
carbon, alox, silica, calcium carbonate, barium carbonate, barium sulfate
etc., the imine is
converted into cis-sertraline-enriched mixtures of racemic cis- and trans-
sertraline.
In a subsequent racemate cleavage using mandelic acid, the desired
enantiomerically pure
cis-isomer can be crystallised selectively.
The optically pure amine is freed with sodium hydroxide solution and converted
in hydro-
chloride form in suitable solvents into the desired polymorphous form.
The following Examples further illustrate the invention. Parts or percentages
relate to weight.
CA 02346900 2001-04-17
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Example 1: Preparation of the compound of formula (101) without catalyst and
without
water-binder
N~CH3
(101)
I
i
ci
ci
20 ml of ethanol are introduced into a 50 ml round-bottomed flask. There are
added thereto
in succession, with stirring, 3.16 g (34.4 mmol) of a 33 % ethanolic
methylamine solution and
5.0 g (17.2 mmol) of 4-(3,4-dichlorophenyl)-3,4-dihydro-1 (2H)-naphthalinone
(prepared in
accordance with US-4 536 518, Example 1 (E)). The round-bottomed flask is then
sealed
tightly with a stopper and heated at 60°C in a preheated oil bath.
After about 30 minutes, a
clear solution is observed for 1 to 4 minutes. The product of formula (101)
then begins to
crystallise. After about 40 hours, a conversion of more than 95 % has been
achieved
(HPLC). The reaction mixture is cooled and filtered. The residue is washed
three times
using 25 ml of ethanol each time and then dried in a vacuum drying cabinet at
about
70°C/0.1-0.2 mbar.
4.41 g (84 %) of the compound of formula (101) are obtained.
M. p. 145-147°C.
Example 2: Preparation of the compound of formula (101 ) usin~p-
toluenesulfonic acid as
catalyst
20 ml of ethanol are introduced into a 50 ml round-bottomed flask. There are
added thereto
in succession, with stirring, 0.60 g (3.44 mmol) of dried p-toluenesulfonic
acid (dried at 100-
110°C and 100-200 mbar), 3.16 g (34.4 rnmol) of a 33 % ethanolic
methylamine solution and
5.0 g (17.2 mmol) of 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalinone
(prepared in
accordance with US-A-4 536 518, Example 1 (E)). The round-bottomed flask is
then sealed
tightly with a stopper and heated at 60°C in a preheated oil bath.
After about 30 minutes, a
clear solution is observed for 1 to 4 minutes. The product of formula (101 )
then begins to
crystallise. After about 3 hours, a conversion of more than 95 % has been
achieved (HPLC).
CA 02346900 2001-04-17
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The reaction mixture is cooled and filtered. The residue is washed three times
using 25 ml
of ethanol each time and then dried in a vacuum drying cabinet at about
70°C/0.1-0.2 mbar.
14.57 g (87 %) of the compound of formula (101 ) are obtained.
M.p.: 145-147°C.
Example 3: Preparation of the comlaound of formula (101) re-using the filtrate
(recycling
method) and using p-toluenesulfonic acid as catalyst
20 ml of ethanol are introduced into a 50 ml round-bottomed flask. There are
added thereto
in succession, with stirring, 0.6 g (3.44 mmol) of dried p-toluenesulfonic
acid (dried at
100-110°C and 100-200 mbar), 12.9 g (140.2 mmol) of a 33 % ethanolic
methylamine
solution and 5.0 g (17.2 mmol) of 4-(3,4-dichlorophenyl)-3,4-dihydro-1 (2H)-
naphthalinone
(prepared in accordance with US-A-4 536 518, Example 1 (E)). The round-
bottomed flask is
then sealed tightly with a stopper and heated at 30°C in a preheated
oil bath. At that temp-
erature at no time is a clear solution observed. After about 5 hours and 40
minutes, a
conversion of more than 95 % has been achieved (HPLC). The reaction mixture is
cooled
and filtered. The residue is washed once with 33 % ethanolic methylamine
solution. 5.0 g
(17.2 mmol) of 4-(3,4-dichlorophenyl)-3,4-dihydro-1 (2H)-naphthalinone
[prepared in
accordance with US 4 536 518, Example 1 (E)] is again added to the filtrate
(reaction
medium) and the mixture is subjected to a further reaction cycle as described
above. After
three further reaction cycles the residues are combined, washed three times
with ethanol
and then dried in a vacuum drying cabinet at about 70°C/0.1-0.2 mbar.
22.5 g (86 %) of the compound of formula (101), m.p. 145-147°C, are
obtained.
Example 4: Preparation of the compound of formula (101) using scandium
tristriflate as
catalyst and montmorillonite as water-binder
60 ml of ethanol are introduced into a 50 ml round-bottomed flask. There are
added thereto
in succession, with stirring, 14.2 g (155 mmol) of a 33 % ethanolic
methylamine solution,
3.0 g of dried G62 montmorillonite (water-binder), 50 mg (0.3 %, 0.13 mmol) of
Sc(OTf)3
(scandium tristriflate) and 15.0 g (55 mmol) of 4-(3,4-dichlorophenyl)-3,4-
dihydro-1 (2H)-
naphthalinone (prepared in accordance with US-A-4 536 518, Example 1 (E)). The
round-
CA 02346900 2001-04-17
-12-
bottomed flask is then sealed tightly with a stopper and heated at 60°C
in a preheated oil
bath. After about 20 hours, a conversion of more than 95 % has been achieved
(HPLC). The
reaction mixture is cooled and filtered. The residue is taken up in
tetrahydrofuran. The
insoluble montmorillonite is filtered off and washed with tetrahydrofuran. The
filtrate is
concentrated using a vacuum rotary evaporator.
The residue yields 13.5 g (86 %) of the compound of formula (101 ).
M. p.: 145-147°C.
Example 5: Preparation of the compound of formula (101) using scandium
tristriflate as
catalyst and using orthoformic acid trimethyl ester as water-binder
20 ml of ethanol are introduced into a 50 ml round-bottomed flask. There are
added thereto
in succession, with stirring, 4.73 g (50 mmol) of a 33 % ethanolic methylamine
solution,
2.55 g of -orthoformic acid trimethyl ester (water-binder), 100 mg (2.0 %,
0.26 mmol) of
Sc(OTf)3 [scandium tristriflate] and 5.0 g (17.2 mmol) of 4-(3,4-
dichlorophenyl)-3,4-dihydro-
1 (2H)-naphthalinone (prepared in accordance with US-A-4 536 518, Example 1
(E)). The
round-bottomed flask is then sealed tightly with a stopper and heated at
60°C in a preheated
oil bath. After about 6 hours, a conversion of more than 95 % has been
achieved (HPLC).
The reaction mixture is cooled and filtered. The residue is washed three times
using 4 ml of
W_ ethanol each time and then dried in a vacuum drying cabinet at about
70°C/0.1-0.2 mbar.
4.5 g (86 %) of the compound of formula (101 ) are obtained.
M. p.: 145-147°C.
Example 6: Preparation of the compound of formula (101) without catalyst but
using ortho
formic acid trimethyl ester as water-binder
20 ml of ethanol are introduced into a 50 ml round-bottomed flask. There are
added thereto
in succession, with stirring, 4.73 g (50 mmol) of a 33 % ethanolic methylamine
solution,
2.55 g of orthoformic acid trimethyl ester (water-binder) and 5.0 g (17.2
mmol) of 4-(3,4-
dichlorophenyl)-3,4-dihydro-1 (2H)-naphthalinone (prepared in accordance with
US-A-4 536 518, Example 1 (E)). The round-bottomed flask is then sealed
tightly with a
stopper and heated at 60°C in a preheated oil bath. After about 7
hours, a conversion of
CA 02346900 2001-04-17
-13-
more than 95 % has been achieved (HPLC). The reaction mixture is cooled and
filtered. The
residue is washed three times using 4 ml of ethanol each time and then dried
in a vacuum
drying cabinet at about 70°C/0.1-0.2 mbar. 4.5 g (86 %) of the compound
of formula (101)
are obtained.
M.p.: 145-147°C.
Examples 7 to 14: Preparation of sertraline-imine using various
solvent/catalyst
combinations
20 g of solvent (a) are introduced into a 50 ml round-bottomed flask. 0.33
equivalent (relative
to the ketone used) of catalyst (b) are added to 2.9 g of a 33 % ethanolic
methylamine
solution. Heating is carried out for 4 hours at the temperature indicated. An
HPLC sample is
taken, heating is carried out for a further 16 hours and the solid product of
formula (101 ) is
filtered. Finally, HPLC samples of both the product and the mother liquor are
taken.
The experiment parameters and results are given in Table 1:
CA 02346900 2001-04-17
-14-
Table
1:
ExampleTemp. Solvent Catal sy Yield Isolated rel. imine
(a) t (b) yield
after L/o]/ concentra-
4 h
[%] _ tion in
contaminatedthe
HPLC with % mother
lipuor
ketone [%1, HPLC
7 60 Ethanol - 76 74/2.5 17
8 60 Isopropanolp-TsOH 93 81/4.5 <1
9 30 Ethanol Methane- 46 84/3.2 6
sulfonic
acid
30 IsopropanolMethane- 29 86/8.5 6
sulfonic
acid
11 60 Triethanol-p-TsOH 92 77/4.0 28
amine
12 60 Ethylene p-TsOH 93 84/3.8 <20
glycol
13 60 Cyclo- p-TsOH 81 64/12 18
hexanol
14 30 Ethanol Camphor- 49 80/2.9 17
sulfonic
acid
Example 15: Preparation of sertraline-imine using methanesulfonic acid as
catalyst
Sertralone (240.0 g; 0.825 mol) is introduced with ethanolabs (800 ml) into a
suitable reaction
vessel equipped with a stirrer and gas inlet line.
CA 02346900 2001-04-17
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The suspension is cooled to 0°C and methylamine (55.0 g; 1.762 mol) is
introduced under
the level, i.e. below the surface, of the solvent. Methanesulfonic acid (10
ml) is then fed in
over a period of 5 minutes using a syringe.
The reaction mass is heated and stirred for 3 hours at 50°C and for 1
hour at 70°C in order
to obtain conversion into the imine (> 94 %).
The reaction mixture is then cooled to 10°C, filtered and washed with
cold ethanol
(2 x 250 ml). The crude filter cake is dried overnight in vacuo and yields 213
g of dry
N-methyl-sertraline-imine.
Quality and yield of the resulting imine (determined by means of HPLC):
88 % yield of sertraline.
The imine contains:
1.8 % sertralone
0.1 % water.
0.05 % methanesulfonic acid (determined using CE)
Example 16: Purification of sertraline-imine by recrystallisation from
ethanol:
12 g of sertraline-imine from Example 15 are introduced into 200 ml of ethanol
in a suitable
reaction vessel having a stirrer, nitrogen inlet line and reflux condenser.
The stirrer is started
.~ and the reaction mixture is heated at reflux temperature until a clear
solution is obtained.
The solution is slowly cooled to 20°C, the product crystallising out.
The suspension is
filtered, the filter cake is washed with the solvent and dried.
10.6 g of sertraline-imine having the following composition (HPLC) are
obtained:
88 % yield of sertraline-imine
The imine contains:
0.2 % sertralone
< 0.05 % water
< 0.001 % methanesulfonic acid (determined using CE).
By means of the recrystallisation it is possible both to improve product
purity and to remove
troublesome impurities such as water or catalyst residues.
CA 02346900 2001-04-17
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Example 17: Preparation of sertraline-imine without catalyst (see Example 1 )
Quality and yield of the imine (determined by means of HPLC):
84 % yield of sertraline-imine
The imine contains:
% sertralone
0.1 % water
Example 18: Recrysallisation of sertraline-imine from catal st-y free
preparation
The recrystallisation of imine from Example 16 is carried out with the
addition of 480 mg of
activated carbon. 1 hour at reflux is followed by hot (at T>70°C)
clarifying filtration and
subsequent cooling. The following results are obtained:
88 % yield of sertraline-imine
The imine contains:
0.2 % sertralone
<0.05 % water
Example 19: Recrystallisation of sertraline-imine in ethanol at temperatures
above the boiling
point (under pressure)
g of sertraline-imine from Example 18 are introduced into 20 ml of ethanol in
a suitable
pressurised reaction vessel having a stirrer. The reaction mixture is heated,
with stirring, at
from 110°C to 115°C (pressure range from 2 to 5 bar) until a
clear solution is obtained. The
solution is slowly cooled to 20°C, the product precipitating out. The
suspension is filtered,
the filter cake is washed with the solvent and dried.
8.6 g of sertraline-imine of the following composition (HPLC) are obtained:
86 % yield of sertraline-imine
The imine contains:
0.9 % sertralone
< 0.05 % water
0.001 % methanesulfonic acid (determined using CE)
