Note: Descriptions are shown in the official language in which they were submitted.
~2655~2
OPtical Resolution of Racemic Femoxetine
The present invention relates to a new process for the
optical resolution of racemic trans-3-~(4-methoxyphenoxy)
-methyl~ methyl-4-phenylpiperidine into its optical pure
forms, of which the (~)-enantiomer is the antidepressive
drug femoxetine having the structural formula
~H3
(~),trans ~ CH -O ~ O-CH3
~3 .
A conventional procedure for the optical resolution of a
racemate into its optical active components comprises
reacting the racemate with ~n optical compound to form
two diastereomeric compounds, which because of their
different physical properties can be separated by
fractionated crystallization from a solvent, in which the
solubility of the two compounds is different.
The preliminary step of the procedure for the optical
resolution of a racemic compound by employing an optical
active resolving agent usually comprises a step of mixing
equimolar amounts of the racemate and the resolving agent
each dissolved in a suitable solvent or mixing a hot
solution of the racemate with an equimolar amount of the
resolving agent. Following dissolution of the reactants
the solution is allowed to cool to a temperature at which
only one of the diastereomers precipitates. The optical
active component of the racemate to be resolved is then
recovered from the precipitated diastereomer by well known
procedures.
. . : ~ . ,
- 2 -
~2~iS522
British patent specification No~ 1 422 263 discloses a
process for the optical resolution of various racemates
of 3-substituted-4-phenylpiperidine compounds including
trans-3-C(4-methoxyphenoxy)-methyll-1-methyl-4-phenyl-
piperidine using (-)-dibenzoyltartaric acid as the
resolving agent. The process is examplified by the
optical resolution of racemic trans-3-methoxymethyl-1-
-methyl-4-phenylpiperidine.
However, the optical resolution of a mixture of the
enantiomers of trans-3-r(4-methoxyphenoxy)-methyl~
-methyl-4-phenylpiperidine using (-l-dibenzoyltartaric
acid as the resolving agent suffers from the defects
that the yield obtained is-only about 47~ of the theo-
retical value, that the precipitated (+)-trans-3- r(4-
-methoxyphenoxy)-methylJ-1-methyl-4-phenylpiperidine,
(-)-dibenzoyltartrate is impure, and that (-~-dibenzoyl-
tartaric acid is relatively costly. The high cost of the
(-)-dibenzoyltartaric acid makes it desirable to recover
it from the precipitated diastereomeric compound, but
this has turned out to be difficult. Therefore the prior
art process is of little value for commercial production
of femoxetine.
Surprisingly it has now been found that an improved
optical resolution of a mixture of the enantiomers of
trans-3-[(4-methoxyphenoxy)-methyl]-1-methyl-4-phenyl-
piperidine can be effected by use of less than equimolar
amounts of one of the enantiomers of mandelic acid or of
a derivative thereof as the resolving agent in an organic
solvent.
_ 7--
t
'~
~265522
Accordingly, the present invention provides an impr~ved
process for the production o (+)-trans-3-((4-methoxy-
-phenoxy)-methyl)-1-methyl-4-phenylpiperidine fxom racemic
trans-3-l(4 methoxyphenoxy)-methyl)-1-methyl-4-phenyl-
piperidine, which comprises reacting said racemic trans-3-
((4-methoxyphenoxy)-methyl)-1-methyl-4-phenylpiperidine
with one of the enantiomers of mandelic acid or of a
derivative thereof in less than stoichiometric amounts
in an organic solvent to form two diastereomeric compounds
in mixture with excess trans-3-((4-methoxyphenoxy)-methyl)-
-1-methyl-4-phenylpiperidine, and which process comprises,
from this mixture, precipitating one of said diastereomeric
compounds in high yield of ~he theoretical possible amount.
It is eviident that the present invention provides an
exceptional example to separation of optical isomers by
fractional crystallization as difference in solubilities
of diastereomers rarely if ever is great enough to effect
total separation with one crystallization (see J. March.,
Advanced Organic Chemistry, McGraw-Hill, Inc. (1977)).
In a preferred embodiment of the process according to the
present invention said enantiomer of mandelic acid of a
derivative thereof is reacted with a mixture of the enan-
tiomers of trans-3-[(4-methoxyphenoxy)-methyl] -1-methyl-4-
-phenylpiperidine dissolved in a hot organic solvent.
In a preferred embodiment of the present invention one of
said dlastereomeric compounds is precipitated by cooling
the solution to a temperature at which only said diastereo-
meric compound precipitates.
The organic solvent used as reaction medium is preferably
an aromatic solvent including for example alkylated and
halogenated derivatives, an aliphatic ester, an aliphatic
alcohol or a mixture thereof. The organic solvent is most
preferably toluene, ethyl acetate, met~yl isobutyl carbinol
or mixtures thereof.
~26S522
The resolving agent is preferable (+)-mandelic acid or a
derivative thereof, most preferably (+)-mandelic acid.
Derivatives of (+)-mandelic acid include derivatives
which is halogenated, hydroxylated, nitrated, alkylated
and alkoxylated. Most preferred derivatives are those
which i5 halogenated. Most preferred halogenated deri-
vatives are those whic~h is halogenated in 4 position of
the phenyl group.
h~hen using (~)-mandelic acid as the resolving agent and
toluene as the solvent the precipitation is preferably
carried out by coolin~ the solution to a temperature
between 0 and 30C.
The mixture of the enantiomers of trans-3-[(4-methoxyphenoxy)-
-methyl]-1-methyl-4-phenylpiperidine is preferably dissolved
in 0.3 to 0.4 1 of toluene for each mol of trans-3-[(4-
-methoxyphenoxy)-methyl]-1-methyl-4-phenylpipe~ridine, and
the toluene is preferably heated to a temperature between
50 and 75C.
The amount of (+)-mandelic acid is preferably from 0.5 to
0.6 mol for each mol of trans-3-[(4-methoxyphenoxy)-methyl]
-1-methyl-4-phenylpiperidine. Despite the small amount of
the resolving agent used the yield of (+)-trans-3-~(4-methoxy-
phenoxy)-methyl~-1-methyl-4-phenylpiperidine,(+)-mandelate
is approximately 75% of the theoretical value and said
mandelate is of a very high purity.
Not only does said preferred embodiments of the process
require less than equimolar amounts of the t+)-mandelic
acid, but it has also been found that the (+)-mandelic acid
as well as racemic trans-3-[~4-methoxyphenoxy)-methyl]-1-
-methyl-4-phenylpiperidine left in the solution can easily
be recovered and recycled, thus only leaving the (-)-trans-
-3-[(4-methoxyphenoxy)-methyl~-1-methyl-4~phenylpiperidine
as waste product.
1265522
The following examples illustrate the invention:
EXAMPLE 1.
-
116.4 kg (383.7 mol) of racemic trans-3-~(4-methoxyphenoxy)-
-methyl~ methyl-4-phenylpiperidine was dissolved in 10Q l
of toluene. The solution was stirred while the temperature
was raised to 60C. 31.2 kg (205.5 mol) of (~)-mandelic
acid was added and the mixture was stirred at 60C until .
the mixture was clear. The solution was allowed to cool
to room temperature. The temperature of the mixture was
then reduced to 10C while stirring during the next 15
hours. The mixture was then centrifuged and the precipitate
was washed with toluene and iso-propanol. The yield was
64.8 ky (75% of the theoretical value) of (~)-trans-3-~(4-
-methoxyphenoxy)-methyl]-1-methyl-4-phenylpiperidine,
(+)-mandelate, m.p. 126-30C, ~a]D + 90.2 ~C = 2 in
96% ethanol). Recrystallization of said mandelate salt
did not change the value of ,aJ 20.
50 kg of ~+)-trans-3- [(4-methoxyphenoxy)-methyl]-1-methyl-
-4-phenylpiperidine,(+)-mandelate was mixed with 27.5 l
of distilled water, 67.5 l of toluene and 6.1 l of 50% w/w
NaOH. The toluene phase was separated and stirred w$th
3.3 kg of potassium carbonate and filtered. 10 1 of conce~-
trated hydrochloric acid and 45 l of isopropanol was mixed
with the toluene phase and the mixture was evaporated.
The residue was recrystallized from iso-propanol to give
33.8 kg (90%) o~ ~)-trans-3-~4 methoxyphenoxy)-methyl]-1-
-methyl-4-phenylpiperidine as the hydrochloride. M.p. 189-90C,
-~20 = 75 3 ~C = 5 in H2O)-
~265522
EXAMPLES 2-5.
In a similar manner but by use of different solvents and
different mandelic acid derivatives in an amount counting
for 55% of the racemic trans-3-~4-methoxyphenoxy)-methyl~
-1-methyl-4-phenylpiperidine the experiment were repeated.
The table below shows the overall yield of the salt of
~ trans-3- [(4-methoxyphenoxy)-methyl~-1-methyl-4-phenyl-
piperidine Ifemoxetine) and (+)-mandelic acid or a deri-
vative thereof.
- Overall yi~ld of the
~ - salt of femoxetine
and (+)-~andelic acid
or a derivative thereof
Ex. Solvent Resolving agent _ (%)
2 toluene ~ 2-hydroxy-2-(4-fluoro- 74.0
phenyl)-acetic acid
3 toluene (~)-2-hydroxy-2-(4-chloro- 66.5
phenyl)-acetic acid
4 ethyl (+)-2-hydroxy-2-phenyl- 67.5
acetate ~cetic acid
MIBC* (~-2-hydroxy-2-phenyl- 59.0
acetic acid
~ MIBC = methyl iso-~utyl carbinol
The results thus obtained clearly show that the present
invention provides an improved process for the production
of femoxetine in that the yield of the salt of femoxetlne
and (+)-mandelic acid or a derivative thereof is 65-75%
of the theoretical value compared to 47% obtained by the
known methods. Furthermore said salt of femoxetine and
~ mandelic acid or a derivative thereof is of very
high purity.
7 --
1265522
EXAMPLE 6
15~0 g (48.2 mmol) of racemic trans-3((4-methoxyphenoxy)-
-methyl)-1-methyl-4-phenylpiperidine was dissolved in
11.5 ml of toluene. The solution was stirred while the
temperature was raised to 60C. 6.55 g (43.1 mmol) of
(+)-mandelic acid was added and the mixture was stirred
at 60C until the m~xture was-clear~ The solutisn was
allowed to cool to room temperature. The temperature of
the mixture was then reduced to 10C and the mixture
was left at this temperature for the next 15 hours. The
mixture was then filtered and the precipitate was washed
with toluene and iso-propanol. The yield was 6.1 y
(55% of the theoretical value) of (+)-trans-3-((4-methoxy-
phenoxy)-methyl)-1-methyl-4-phenylpiperidine,(+)-mandelate,
m.p. 121C, a D + 81.6 (C = 2 in 96% ethanol~.
12~;5S~Z
EXAMPLE 7
_
a) 20 g (64 mmol) of racemic trans-3-~(4-methoxyphenoxy~-
-methyl~ methyl-4-phenylpiperiaine and 22 g (62 mmol~
of (-)-dibenzoyl tartaric acid $s dissolved in 200 ml
of ethanol. The mixture is evaporated under vacuum.
The residue is optimally recrystallized from 50 ml
methanol to yield.16.2 g of product. M.p. 84.1-84.6~C
[~D0 0.38 (c = 5 in 99~ ethanol).
b) 1~ g of the product of a is mixed with 20 ml of 4M
NaOH~ 40 ml of water and 100 ml of ether. The organi~
phase is dried with potassium carbonat, filtered and
evaporated under vacuum to give 4.2 g of product. The
product is dissolved -n 75 ml of iso-propanol. 1 ml of
konc. hydrochloric acid is added and the mixture is
evaporated to give 4.7 g of product. M.p. 182.7-184.2C.
1.9 g of this product is recrystallized from 6 ml of
iso-propanol to give 1.4 g of (+)-trans-3-C(4-methoxy-
phenoxy)-methyl~ methyl-4-phenylpiperidine as the
hydrochloride. M.p. 189.4C 20 7S.6 (c = 5 in H2O)
Overall yield of the hydrochloride is 47% of theoretical
amount.
126ss22
EXAMPLE 8.
The toluene solution of example 1 from which (+)-trans-
-3-~(4-methoxyphenoxy)-methyl-J-1-methyl-4-phenylpiperidine
(~)-mandelate is precipitated is mixed with 13 1 of 9 M
a~ueous NaOH and 14 l of water. The mixture is stirred
and ~e aqueous phase is mixed with the aqueous phase
of example 1 and heated to 40C. To this mixture is
added 23 l of conc. hydrochloric acid ensuring that pH
is around 1.5. The mixture is cooled and stirred. When
the temperature is around 10C the precipitate is
separated and washed 1 time with 10 l of water giving
26.5 kg of (~)-mandelic acid. M.p. 130-3C.
Yield of theoretical amount is 85%. - -
