Note: Descriptions are shown in the official language in which they were submitted.
CA 02511683 2005-07-08
TITLE OF THE INVENTION
AN EFFICIENT METHOD FOR PREPARING 3-ARYLOXY-3-
ARYLPROPYLAMINES AND THEIR OPTICAL STEREOISOMERS
FIELD OF THE INVENTION
The present invention relates to a process for producing 3-aryloxy-3-
arylpropylamines of formula I, including fluoxetine, tomoxetine,
norfluoxetine,
duloxetine, nisoxetine, and their optically enriched (R)- and (S)-enantiomers.
0
R
Ar 1
R2
1
Fluoxetine: Ar = Ph, Ari = 4-trifluoromethylphenyl, R1 = Me, R2 = H
Tomoxetine: Ar = Ph, Ari = 2-methylphenyl, R1 = Me, R2 = H
Norfluoxetine: Ar = Ph, Ari = 4-trifluoromethylphenyl, R1 = R2 = H
Nisoxetine: Ar = Ph, Ari = 2-methoxyphenyl, R1 = Me, R2 = H
Duloxetine: Ar = 2-thienyl, Ari = 1-naphthyl, R1 = Me, R2 = H
BACKGROUND OF THE INVENTION
The selective serotonin reuptake inhibitors and norepinephrine reuptake
inhibitor
class of antidepressants, which have the 3-aryloxy-3-arylpropylamine sub-
structure, e.g. fluoxetine, tomoxetine, nisoxetine, norfluoxetine, and
duloxetine,
are among the most important pharmaceuticals for the treatment of psychiatric
disorders such as anxiety and clinical depression (Drugs of the Future, 11,
134
(1986)). In addition, several members of this class have shown promise for the
treatment of alcoholism, chronic pain and eating disorders such as obesity and
bulimia (J. Med. Chem. 31, 1412 (1988)). Fluoxetine hydrochloride is marketed
as its racemate (ProzacTM, Eli Lilly Co.), but recently interest has been
shown for
marketing the more active (R)-enantiomer as an "Improved Chemical Entity"
version of the drug. Tomoxetine was the first norepinephrine reuptake
inhibiting
antidepressant without strong affinity for a- or 6-adrenergic receptor. The
(R)-
CA 02511683 2005-07-08
= 2
enantiomer, also called atomoxetine, is marketed as its hydrochloride salt
under
the name of StratteraTM and is purportedly ninefold more potent relative to
the
(S)-enantiomer.
There are several general synthetic methods reported in the prior art for the
synthesis of 3-aryloxy-3-arylpropylamines 1 and their optically pure
enantiomers.
For example, U.S. Patent No. 4,314,081 disclosed the racemic preparation of
compounds of formula 1 via alkylation of substituted phenols with benzyl
halide
intermediates followed by further chemical elaboration. Tetrahedron Left. 30,
5207-5210 (1989) disclosed the preparation of (R)-fluoxetine by the
nucleophilic
aromatic displacement reaction of (R)-N-methyl-3-hydroxy-3-phenylpropylamine
with p-chlorobenzotrifluoride. A stereoselective route for the preparation of
(S)-
tomoxetine was disclosed in Tetrahedron, 53, 6739-6746 (1997), which utilized
as a key step the coupling of lithiated o-cresol with a chiral iodoester to
furnish an
aryl ether intermediate. U.S. Patent No. 5,068,432 disclosed the preparation
of
optically pure fluoxetine and tomoxetine using a Mitsunobu reaction for the
coupling step.
More specifically, etherification by the nucleophilic aromatic displacement of
3-
hydroxy-3-arylpropylamines 2 with aryl halides represents the most
straightforward method of preparation.
OH
Ar
R2
2
For example, the reaction of N-methyl-3-hydroxy-3-phenylpropylamine with 4-
trifluoromethy1-1-chlorobenzene in the presence of a strong base in
dimethylsulfoxide (WO 94/00416), 1,3-dimethy1-2-imidazolidinone or N-
methylpyrrolidinone (U.S. Patent No. 5,847,214) have been reported to give N-
methyl-(4-trifluoromethylphenoxy)-3-phenylpropylamine (fluoxetine). In
addition,
the reaction of an unactivated substrate, 2-fluorotoluene, with the alkoxide
of (S)-
i
CA 02511683 2005-07-08
. 3
N-methyl-3-phenyl-3-hydroxypropylamine in dimethylsulfoxide gave a modest
yield and racemization (Tetrahedron Lett. 35, 1339-1342 (1994)). U.S. Patent
No. 6,541,668 disclosed that N-methy1-3-(2-methylphenoxy)-3-
phenylpropylamine (tomoxetine) can be prepared by coupling 2-fluorotoluene
with N-methyl-3-phenyl-3-hydroxypropylamine in 1,3-dimethy1-2-imidazolidinone
in the presence of a strong base, such as potassium t-butoxide at about 110 C.
These methods partially resolve some of the preparative problems associated
with 3-aryloxy-3-arylpropylamines; however, these methods still suffer from
various deficiencies including the use of expensive and undesired solvents,
harsh reaction conditions (e.g., high temperature), the need for strong bases,
and
the loss of chirality when unactivated aryl halides and optically pure
intermediates are used. Therefore, development of a process using a common
solvent, less expensive reagents and mild reaction conditions is desired.
The stereospecific synthesis of 3-aryloxy-arylpropylamines is known in the
art. In
many of these methods, the asymmetry is introduced by utilizing enantiomers of
3-hydroxy-3-arylpropylamines, prepared by either stereospecific reduction of a
ketone precursor or by resolution of the alcohol [J. Org. Chem. 53, 2916-2920
(1988); Tetrahedron Lett. 30, 5207-5210 (1989); US Patent No. 4,868,344; J.
Org. Chem. 53, 4081-4084(1988); and Tetrahedron Lett. 31, 7101 (1990)1 In
general, when employing a specific enantiomer of the alcohol, the 3-aryloxy
substituent is introduced by either the Mitsunobu reaction using a phenol or
by
nucleophilic aromatic displacement of the alkoxide on an aryl halide. However,
due to the expense and difficulty of the Mitsunobu reaction at large scale, a
commercial process that uses the nucleophilic aromatic displacement route is
preferred.
Unfortunately, nucleophilic aromatic displacement reactions with 3-hydroxy-3-
arylpropylamines normally require a strong base such as sodium hydride which
may lead to racemization of the stereochemical center (J. Org. Chem. 53, 4081-
4084 (1988); Tetrahedron Asymmetry, 3, 525-528 (1992); Tetrahedron Lett. 35,
1339-1342 (1994)). Also, low to modest yields are obtained when unactivated
1
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4
aryl halides are used. For example, the reaction of 2-fluorotoluene with the
alkoxide of (S)-N-methyl-3-phenyl-3-hydroxypropylamine gives modest chemical
yields of tomoxetine and epimerization of the chiral center was observed
(Tetrahedron Lett. 35, 1339-1342(1994)). For this reason, there are no
stereospecific methods for the preparation of optically pure (R)-N-methy1-3-
pheny1-3-(2-methylphenoxy)propylamine (Atomoxetine) and its enantiomer, (S)-
N-methy1-3-pheny1-3-(2-methylphenoxy)propylamine by the direct aromatic
displacement reaction of optically pure (R)- and (S)-3-hydroxy-3-
phenylpropylamine with aryl halides. Therefore, a general method of producing
optically active 3-aryloxy-3-arylpropylamines from optically active 3-hydroxy-
3-
arylpropylamines using a stereospeciflc aromatic displacement reaction,
especially for the preparation of optically enriched (R)-N-methy1-3-pheny1-3-
(2-
methylphenoxy)propylamine (Atomoxetine) and its enantiomer, (S)-N-methy1-3-
pheny1-3-(2-methylphenoxy)propylamine, is still attractive.
Methods of producing alkyl aryl ethers employing the traditional Williamson
ether
synthesis include direct nucleophilic substitution and the Cu(I)-catalyzed
cross-
coupling of alkoxides with aryl halides. However, these methods are limited in
that they typically require activated aryl halides, large excesses of
alkoxides, high
reaction temperature and undesirable solvents. Recently, the palladium-
catalyzed cross-coupling reaction of aryl halides with alcohols has been
reported
as an alternative method for the formation of the aryl-oxygen bond. Although
this
avoids many of the stated above limitations, the intermolecular reaction has
been
most successful using activated aryl halides.
A mild method for the etherification of aryl iodides and aliphatic alcohols
that
does not require the use of alkoxide bases was described in a recent article
(Org.
Lett. 4, 973-976 (2002)). The reaction was carried out in the presence of a
catalytic amount of copper iodide and about 20 mole percent of the expensive
(100-g = $309.50) and relatively toxic 1,10-phenanthroline catalyst. Also, a
method of 0-arylation of 13-amino alcohols catalyzed by Cu(I) catalyst has
also
been reported (Org. Left. 4, 3703-3706 (2002)), however all the examples in
this
CA 02511683 2005-07-08
article were for 13-amino alcohol substrates and the authors report the
complete
lack of reactivity of simple alcohols under their conditions. From an
industrial
perspective, these copper-mediated reactions are attractive since copper
reagents are relatively inexpensive and the reaction conditions are mild;
5 however, the requirement of the toxic 1,10-phenanthroline as a catalyst
is
unfortunate from a pharmaceutical perspective.
With respect to the intermediates, preparations of 3-hydroxy-3-
arylpropylamines
and their optically pure enantiomers have been disclosed in the prior art.
Among
them, the most straightforward method is treatment of the hydroxy compound of
formula 3 with the amine of formula 4 (Scheme 1), wherein LG is a leaving
group.
Scheme 1
OHR2NH (4) OH
Ar) LG Ar __________________________ N' R1
R2
3 2
However, although the conversion appears deceptively simple, it is well known
that the synthetic value of this method is limited when one of R1 and R2 is
hydrogen due to the concomitant over-alkylation, which results in mixtures of
primary, secondary and tertiary amines, as well as quatemary ammonium salts
(Tetrahedron, 57, 7785-7811(2001)). This deficiency is compounded by the fact
that compounds of formula 2 are difficult to purify since they are usually
isolated
as a viscous oil or low melting solid. Thus, in addition to the long-felt need
for an
efficient and cost-effective synthetic method for preparation of 3-aryloxy-3-
propylamines, it is furthermore desirable to develop an efficient and cost-
effective
process to prepare compounds of formula 2 from compounds of formula 3 and
isolate the compounds of formula 2 in pure form.
CA 02511683 2012-07-20
5a
SUMMARY
In illustrative embodiments there is provided a process for the preparation of
a
OH
Ar*-IN=""-NWAll
3-hydroxy-3-arylpropylamine of formula 2: R2 2, the process comprising:
(i) reacting a
OH
compound of formula 3: At LG 3, with an amine of formula 4:111112NH 4,
thereby forming a
product; (ii) treating the product with oxalic acid and isolating a
hemioxalate salt of formula 5:
OH
Ar
n(CO2H)2
R2 5; and (iii) treating the hemioxalate salt of
formula 5 with a base or
a basic ion-exchange resin to produce the 3-hydroxy-3-arylpropylamine of
formula 2; wherein Ar is an
aryl group; a carbon center marked with "*" is racemic or enantiomerically
enriched having the
(R)-configuration or enantiomerically enriched having the (S)-configuration;
LG is a leaving group; R1 and
R2 are independently selected from the group consisting of: hydrogen, C1-C10
alkyl, aryl, and aralkyl;
and n is 0.5.
In illustrative embodiments there is provided a process described herein,
wherein Ar is phenyl or
2-thienyl.
In illustrative embodiments there is provided a process described herein,
wherein LG is selected from
the group consisting of: chlorine, bromine, iodine and the mesylate and p-
tosylate sulfonate esters.
In illustrative embodiments there is provided a process described herein,
wherein a solvent for
hemioxalate salt formation is selected from the group consisting of: alcohols,
alkyl ethers, alkyl esters,
ketones, aliphatic hydrocarbons, aromatic hydrocarbons, halogenated
hydrocarbons and mixtures
thereof.
In illustrative embodiments there is provided a process described herein,
wherein a solvent for
hemioxalate salt formation is selected from the group consisting of: methanol,
ethanol, isopropanol,
n-propanol, butanol, diethyl ether, methyl t-butyl ether, diisopropyl ether,
butyl ether, ethyl acetate,
CA 02511683 2012-07-20
5b
hexanes, heptanes, dichloromethane, dichloroethane, toluene, xylenes, acetone,
methyl ethyl ketone,
methyl isobutyl ketone and mixtures thereof.
In illustrative embodiments there is provided a process described herein,
further comprising converting
a compound of formula 2 to a compound selected from the group consisting of:
fluoxetine, tomoxetine,
nisoxetine, norfluoxetine, duloxetine, optically enriched (R)- and (S)-
enantiomers thereof and
pharmaceutically acceptable addition salts thereof.
In illustrative embodiments there is provided a process described herein,
further comprising converting
a compound of formula 2 to fluoxetine.
In illustrative embodiments there is provided a process described herein,
further comprising converting
a compound of formula 2 to tomoxetine.
In illustrative embodiments there is provided a process described herein,
further comprising converting
a compound of formula 2 to nisoxetine.
In illustrative embodiments there is provided a process described herein,
further comprising converting
a compound of formula 2 to norfluoxetine.
In illustrative embodiments there is provided a process described herein,
further comprising converting
a compound of formula 2 to duloxetine.
In illustrative embodiments there is provided a process described herein,
further comprising converting
a compound of formula 2 to atomoxetine.
In illustrative embodiments there is provided a process described herein,
wherein the compound 2 is
N-methyl-3-hydroxy-3-phenylpropylamine or an (R)- or (5)- enantiomer thereof.
In illustrative embodiments there is provided N-Methyl-3-hydroxy-3-
phenylpropylamine hemioxalate
salt.
CA 02511683 2012-07-20
Sc
In illustrative embodiments there is provided (R)-N-Methyl-3-hydroxy-3-
phenylpropylamine hemioxalate
salt.
In illustrative embodiments there is provided (S)-N-Methyl-3-hydroxy-3-
phenylpropylamine hemioxalate
salt.
In illustrative embodiments there is provided a process for the preparation of
a compound of formula 1:
0
R2 1, the process comprising: reacting, in the presence of a
catalyst and a base, a
OH
compound of formula 2: R2 2, with an aryl halide of formula 6: AriX
6, thereby forming
the compound of formula 1, wherein Ar and Ari are independently an aryl group;
a carbon center
marked with "*" is racemic or enantiomerically enriched having the (R)-
configuration or
enantiomerically enriched having the (5)-configuration; R1 and R2 are
independently selected from the
group consisting of: hydrogen, C1-C10 alkyl, aryl, and aralkyl; the catalyst
comprises a copper-containing
catalyst, a palladium-containing catalyst, a nickel-containing catalyst, or a
mixture thereof; and X is a
halogen.
In illustrative embodiments there is provided a process described herein,
wherein Ar is phenyl or
2-thienyl.
In illustrative embodiments there is provided a process described herein,
wherein Ari is selected from
the group consisting of: 1-naphthyl, 2-methylphenyl, 2-methoxyphenyl, and 4-
trifluoromethylphenyl.
In illustrative embodiments there is provided a process described herein,
wherein X is selected from the
group consisting of: fluorine, chlorine, bromine and iodine.
In illustrative embodiments there is provided a process described herein,
wherein X is iodine.
CA 02511683 2012-07-20
5d
In illustrative embodiments there is provided a process described herein,
wherein the catalyst is a
copper-containing catalyst.
In illustrative embodiments there is provided a process described herein,
wherein the catalyst is
selected from the group consisting of: cupric chloride, cupric bromide, cupric
iodide, cupric sulfate,
cupric acetate, cupric triflate, cuprous chloride, cuprous bromide, cuprous
iodide, cuprous acetate,
cuprous triflate, copper (I) oxide, copper (II) oxide, and copper-zinc alloy.
In illustrative embodiments there is provided a process described herein,
wherein the base is selected
from the group consisting of: organic bases and inorganic bases.
In illustrative embodiments there is provided a process described herein,
wherein the base is selected
from the group consisting of: potassium carbonate, sodium carbonate, lithium
carbonate, cesium
carbonate, calcium carbonate, magnesium carbonate, magnesium oxide, sodium
bicarbonate,
potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, and, mixture
thereof.
In illustrative embodiments there is provided a process described herein,
wherein the compound of
formula 1 is N-methyl-3-(4-trifluoromethylphenoxy)-3-phenylpropylamine or a
pharmaceutically
acceptable salt thereof.
In illustrative embodiments there is provided a process described herein,
wherein the compound of
formula 1 is (R)-N-methyl-3-(4-trifluoromethylphenoxy)-3-phenylpropylamine or
a pharmaceutically
acceptable salt thereof.
In illustrative embodiments there is provided a process described herein,
wherein the compound of
formula 1 is (S)-N-methyl-3-(4-trifluoromethylphenoxy)-3-phenylpropylamine or
a pharmaceutically
acceptable salt thereof.
In illustrative embodiments there is provided a process described herein,
wherein the compound of
formula 1 is N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine or a
pharmaceutically acceptable salt
thereof.
CA 02511683 2012-07-20
5e
In illustrative embodiments there is provided a process described herein,
wherein the compound of
formula 1 is (R)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine or a
pharmaceutically acceptable
salt thereof.
In illustrative embodiments there is provided a process described herein,
wherein the compound of
formula 1 is (S)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine or a
pharmaceutically acceptable
salt thereof.
In illustrative embodiments there is provided a process described herein,
wherein the compound of
formula 1 is N-methyl-3-(2-nnethoxyphenoxy)-3-phenylpropylamine or a
pharmaceutically acceptable
salt thereof.
In illustrative embodiments there is provided a process described herein,
wherein the compound of
formula 1 is (R)-N-methyl-3-(2-methoxyphenoxy)-3-phenylpropylamine or a
pharmaceutically
acceptable salt thereof.
In illustrative embodiments there is provided a process described herein,
wherein the compound of
formula 1 is (S)-N-methyl-3-(2-methoxyphenoxy)-3-phenylpropylamine or a
pharmaceutically acceptable
salt thereof.
In illustrative embodiments there is provided a process described herein,
wherein the compound of
formula 1 is N-methyl-3-(1-naphthoxy)-3-(2-thienyl)propylamine or a
pharmaceutically acceptable salt
thereof.
In illustrative embodiments there is provided a process described herein,
wherein the compound of
formula 1 is (R)-N-methyl-3-(1-naphthoxy)-3-(2-thienyl)propylamine or a
pharmaceutically acceptable
salt thereof.
In illustrative embodiments there is provided a process described herein,
wherein the compound of
formula 1 is (S)-N-methyl-3-(1-naphthoxy)-3-(2-thienyl)propylamine or a
pharmaceutically acceptable
salt thereof.
CA 02511683 2012-07-20
5f
In illustrative embodiments there is provided a process described herein,
wherein the compound of
formula 1 is 3-(4-trifluoromethylphenoxy)-3-phenylpropylamine or a
pharmaceutically acceptable salt
thereof.
In illustrative embodiments there is provided a process described herein,
wherein the compound of
formula 1 is (R)-3-(4-trifluoromethylphenoxy)-3-phenylpropylamine or a
pharmaceutically acceptable
salt thereof.
In illustrative embodiments there is provided a process described herein,
wherein the compound of
formula 1 is (S)-3-(4-trifluoromethylphenoxy)-3-phenylpropylamine or a
pharmaceutically acceptable
salt thereof.
In illustrative embodiments there is provided a process for the preparation of
a compound of formula 1:
Ari
0'
ArN1 OH
R2LG 3
1, the process comprising: (i) reacting a compound of formula 3: Ar ,
with an amine of formula 4:121112NH 4, thereby forming a product; (ii)
treating the product with oxalic
OH
n(CO2H)2
acid and isolating a hemioxalate salt of formula 5:
5, (iii) treating the
hemioxalate salt of formula 5 with a base or a basic ion-exchange resin to
produce a
OH
Ri
Ar
3-hydroxy-3-arylpropylamine of formula 2: R2 2;
and (iv) reacting, in the presence of a
catalyst and a base, the compound of formula 2 with an aryl halide of formula
6: Ari-X 6, thereby
producing the 3-aryloxy-3-arylpropylamine of formula 1; wherein Ar and Ari are
independently an aryl
group; a carbon center marked with "*" is racemic or enantiomerically enriched
having the
(R)-configuration or enantiomerically enriched having the (S)-configuration;
R1 and R2 are independently
selected from the group consisting of: hydrogen, C1-C10 alkyl, aryl, and
aralkyl; LG is a leaving group; n is
CA 02511683 2012-07-20
5g
0.5; X is a halogen; and the catalyst comprises a copper-containing catalyst,
a palladium-containing
catalyst, a nickel-containing catalyst, or a mixture thereof.
In illustrative embodiments there is provided a process described herein,
further comprising formation
of an acid addition salt using a pharmaceutically acceptable acid.
In illustrative embodiments there is provided a process described herein,
wherein Ar is phenyl or
2-thienyl.
In illustrative embodiments there is provided a process described herein,
wherein LG is selected from
the group consisting of: chlorine, bromine, iodine nnesylate and p-tosylate.
In illustrative embodiments there is provided a process described herein,
wherein a solvent for oxalic
acid salt formation is selected from the group consisting of: alcohols, alkyl
ethers, alkyl esters, ketones,
aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons and
mixtures thereof.
In illustrative embodiments there is provided a process described herein,
wherein a solvent for oxalic
acid salt formation is selected from the group consisting of: methanol,
ethanol, isopropanol,
n-propanol, butanol, diethyl ether, methyl t-butyl ether, diisopropyl ether,
butyl ether, ethyl acetate,
hexanes, heptanes, dichloromethane, dichloroethane, toluene, xylenes, acetone,
methyl ethyl ketone,
methyl isobutyl ketone and mixtures thereof.
In illustrative embodiments there is provided a process described herein,
wherein Ar is selected from
the group consisting of: 1-naphthyl, 2-methylphenyl, 2-methoxyphenyl, and 4-
trifluoromethylphenyl.
In illustrative embodiments there is provided a process described herein,
wherein X is selected from the
group consisting of: fluorine, chlorine, bromine and iodine.
In illustrative embodiments there is provided a process described herein,
wherein X is iodine.
CA 02511683 2012-07-20
5h
In illustrative embodiments there is provided a process described herein,
wherein the catalyst is
selected from the group consisting of: copper-containing catalysts, palladium-
containing catalysts, and
nickel-containing catalysts.
In illustrative embodiments there is provided a process described herein,
wherein the catalyst is a
copper-containing catalyst.
In illustrative embodiments there is provided a process described herein,
wherein the catalyst is
selected from the group consisting of cupric chloride, cupric bromide, cupric
iodide, cupric sulfate,
cupric acetate, cupric triflate, cuprous chloride, cuprous bromide, cuprous
iodide, cuprous acetate,
cuprous triflate, copper (I) oxide, copper (II) oxide, and copper-zinc alloy.
In illustrative embodiments there is provided a process described herein,
wherein the base is selected
from the group consisting of organic bases and inorganic bases.
In illustrative embodiments there is provided a process described herein,
wherein the base is selected
from the group consisting of: potassium carbonate, sodium carbonate, lithium
carbonate, cesium
carbonate, calcium carbonate, magnesium carbonate, magnesium oxide, sodium
bicarbonate,
potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, and mixtures
thereof.
In illustrative embodiments there is provided a process described herein,
wherein the compound of
formula 1 is N-methyl-3-(4-trifluoromethylphenoxy)-3-phenylpropylamine or a
pharmaceutically
acceptable salt thereof.
In illustrative embodiments there is provided a process described herein,
wherein the compound of
formula 1 is (R)-N-methyl-3-(4-trifluoromethylphenoxy)-3-phenylpropylamine or
a pharmaceutically
acceptable salt thereof.
In illustrative embodiments there is provided a process described herein,
wherein the compound of
formula 1 is (S)-N-methyl-3-(4-trifluoromethylphenoxy)-3-phenylpropylamine or
a pharmaceutically
acceptable salt thereof.
CA 02511683 2012-07-20
5'
In illustrative embodiments there is provided a process described herein,
wherein the compound of
formula 1 is N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine or a
pharmaceutically acceptable salt
thereof.
In illustrative embodiments there is provided a process described herein,
wherein the compound of
formula 1 is (R)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine or a
pharmaceutically acceptable
salt thereof.
In illustrative embodiments there is provided a process described herein,
wherein the compound of
formula 1 is (S)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine or a
pharmaceutically acceptable
salt thereof.
In illustrative embodiments there is provided a process described herein,
wherein the compound of
formula 1 is N-methyl-3-(2-methoxyphenoxy)-3-phenylpropylamine or a
pharmaceutically acceptable
salt thereof.
In illustrative embodiments there is provided a process described herein,
wherein the compound of
formula 1 is (R)-N-methyl-3-(2-methoxyphenoxy)-3-phenylpropylamine or a
pharmaceutically acceptable
salt thereof.
In illustrative embodiments there is provided a process described herein,
wherein the compound of "
formula 1 is (S)-N-methyl-3-(2-methoxyphenoxy)-3-phenylpropylamine or a
pharmaceutically acceptable
salt thereof.
In illustrative embodiments there is provided a process described herein,
wherein the compound of
formula 1 is N-methyl-3-(1-naphthoxy)-3-(2-thienyppropylannine or a
pharmaceutically acceptable salt
thereof.
In illustrative embodiments there is provided a process described herein,
wherein the compound of
formula 1 is (R)-N-methyl-3-(1-naphthoxy)-3-(2-thienyl)propylamine or a
pharmaceutically acceptable
salt thereof.
CA 02511683 2012-07-20
5j
In illustrative embodiments there is provided a process described herein,
wherein the compound of
formula 1 is (5)-N-methyl-3-(1-naphthoxy)-3-(2-thienyl)propylamine or a
pharmaceutically acceptable
salt thereof.
In illustrative embodiments there is provided a process described herein,
wherein the compound of
formula 1 is 3-(4-trifluoromethylphenoxy)-3-phenylpropylamine or a
pharmaceutically acceptable salt
thereof.
In illustrative embodiments there is provided a process described herein,
wherein the compound of
formula 1 is (R)-3-(4-trifluoromethylphenoxy)-3-phenylpropylamine or a
pharmaceutically acceptable
salt thereof.
In illustrative embodiments there is provided a process described herein,
wherein the compound of
formula 1 is (5)-3-(4-trifluoromethylphenoxy)-3-phenylpropylamine or a
pharmaceutically acceptable
salt thereof.
CA 02511683 2012-07-20
6
DETAILED DESCRIPTION OF THE INVENTION
According to one aspect of the invention, a process is provided for the
preparation of 3-hydroxy-3-arylpropylamines of formula 2,
PH
R2
2
wherein Ar is an aryl group, of which phenyl and 2-thienyl are preferred; RI
and R2
individually represent hydrogen, C1-C10 alkyl, phenyl, and benzyl groups; the
carbon center marked with "*" can be racemic or enantiomerically enriched (R)-
or
(S)- configuration; and pharmaceutically acceptable addition salts thereof
comprising the steps of:
(1) reacting compounds of formula 3,
OH
Ar LG
3
wherein Ar and "*" are as defined above; LG is a leaving group selected
from halogens such as chloro, bromo, and lodo and sultanate esters such
as mesyiate and p-tosylate, with an amine of formula R1R2NH (4), wherein
R1 and R2 are as defined above, and purifying and isolating the coupled
product as its oxalic acid salt of formula 5,
OH
R2n (CO2H)2
5
wherein Ar, R1, R2, and ``*"are as defined above and n is 0.5 or 1; and
CA 02511683 2005-07-08
7
(2) treating the salt 5 with a base to produce 3-hydroxy-3-
arylpropylamines of
formula 2,
OH
R2
2
wherein Ar, R1, R2, and "*" are as defined above.
The N-alkylation of amines of formula 4 with compounds of formula 3 to provide
crude 3-hydroxy-3-arylpropylamines 2 can be carried out using methods
previously described in the art, for example, the methods disclosed in:
Advanced
Organic Chemistry, fifth edition, by J. March, John Wiley & Sons, Inc. (2001),
pp
499-502; Tetrahedron, 57, 7785-7811(2001); Tetrahedron Asymmetry, 3, 525-
528 (1992); Tetrahedron Lett. 30, 5207-5210 (1989); and J. Org. Chem. 53,
2916-2920 (1988).
Surprisingly, we have discovered that 3-hydroxy-3-arylpropylamines 2 can be
isolated in high yield and purity as their oxalate salts. This process
provides a
commercially practical preparation of 3-hydroxy-3-arypropylamines 2 via the
reaction of compounds of formula 3 with amines of formula 4 followed by
isolation and purification of the coupled product as their oxalate salt 5
using
readily available and inexpensive oxalic acid as the acid source. Salts of
formula
5 can then be readily free-based to provide the useful intermediates of
formula 2.
There are no literature reports for the use of simple organic or inorganic
acids to
purify compounds of formula 2.
According to an aspect of the present invention, the 3-hydroxy-3-
arylpropylamine
product is treated with oxalic acid in an organic solvent or mixture of
solvents, to
furnish 3-hydroxy-3-arylpropylamine oxalate salts of formula 5. The amount of
oxalic acid ranges from 0.3 to 5 equivalents relative to 3, and preferably 0.5
to
1.0 eq. The suitable solvents include alcohols, alkyl ethers, alkyl esters,
ketones,
CA 02511683 2005-07-08
8
aromatic and aliphatic hydrocarbons, and halogenated hydrocarbons. Examples
of suitable alcohols include methanol, ethanol, propanols, and butanols;
examples of suitable alkyl ethers include diethyl ether, methyl t-butyl ether,
diisopropyl ether, butyl ether; examples of suitable alkyl esters include
ethyl
acetate; examples of suitable aliphatic hydrocarbons include hexanes and
heptanes; examples of suitable aromatic hydrocarbons include toluene and
xylenes; examples of suitable halogenated hydrocarbons include
dichloromethane and dichloroethane; examples of suitable ketones include
acetone, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof.
The regeneration of 3-hydroxy-3-arylpropylamines of formula 2 from their
oxalic
acid salts of formula 5 may be effected by treatment of the salt with a base
or by
a basic ion-exchange resin. Suitable bases include organic and inorganic
bases,
of which sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium
carbonate, potassium carbonate, lithium carbonate, ammonia, and triethylamine
are preferred.
According to another aspect of the present invention, a process for the
preparation of 3-aryloxy-3-arylpropylamines of the formula 1,
0
Ar
R2
is provided wherein Ar is an aryl group, of which phenyl and 2-thienyl are
preferred; Ari is an aryl group, of which 1-naphthyl, 2-methylphenyl, 2-
methoxyphenyl, and 4-trifluoromethylphenyl are preferred; R1 and R2
individually
represent hydrogen, C1-C10 alkyl, phenyl, and benzyl groups; the carbon center
marked with "*" can be racemic or enantiomerically enriched (R)- or (S)-
configuration; including fluoxetine, tomoxetine, nisoxetine, norfluoxetine,
duloxetine and their optically enriched (R)- and (S)-enantiomers, and
pharmaceutically acceptable addition salts thereof comprising the steps of:
CA 02511683 2005-07-08
9
(1) reacting compounds of formula 2,
OH
A(NI'R1
R2
2
wherein Ar, R1, R2, and "*" are as defined above with an aryl halide of
formula AO( (6), wherein Ari is as defined above; and X is selected from
halogens such as fluoro, chloro, bromo, and iodo, of which iodo is
preferred, in the presence of a suitable catalyst and a base or mixture of
bases to produce 3-aryloxy-3-arylpropylamines of formula 1; and
2) optional formation of an acid addition salt using a pharmaceutically
acceptable acid.
The 3-aryloxy-3-arylpropylamines described herein form pharmaceutically
acceptable acid addition salts with a wide variety of organic and inorganic
acids.
Previously, the general synthesis of 3-aryloxy-3-arylpropylamines 1 and their
optically pure enantiomers have been carried out using methods such as, for
example, the methods disclosed in: U.S. Patent No. 4,314,081; U.S. Patent No.
5,068,432; Tetrahedron Lett. 30, 5207-5210 (1989); and Tetrahedron, 53, 6739-
6746 (1997).
Surprisingly, we have discovered that aromatic displacement of 3-hydroxy-3-
arylpropylamines 2 can be carried out with aryl halides, including unactivated
aryl
halides such as 2-methylphenyl halides and 2-methoxyphenyl halides, in the
presence of a suitable catalyst and a base or mixture of bases. When using
this
method, the 3-aryloxy-3-arylpropylamine product (1) is obtained in high
chemical
yield and of excellent purity. Also, when optically enriched 3-hydroxy-3-
arylpropylamines (2) are used, the process produces optically enriched 3-
aryloxy-3-arylpropylamines (1). In other words, the stereochemical integrity
of
CA 02511683 2005-07-08
the chiral center is maintained. For this reason, this method is particularly
useful
for the preparation of optically enriched 3-aryloxy-3-arypropylamines such as
atomoxetine.
Compound 2 can be obtained using the process disclosed in the present
5 invention or the methods previously described in the art, for example,
the
methods disclosed in: Tetrahedron Leff., 30, 5207-5210 (1989); Tetrahedron,
57,
7785-7811 (2001); U.S. Patent No. 6,686,505; U.S. Patent No. 6,008,412; U.S.
Patent No. 4,324,081; Adv. Synth. Catal. 345, 261-274(2003); Tetrahedron Lett.
43, 5435-36 (2002); Tetrahedron: Asym. 13, 2039-51 (2002); Synth. Commun.
10 25, 1231-38 (1995); Tetrahedron Lett. 35, 1339-1342 (1994); Indian J.
Chem.
31B, 803-809 (1992); and J. Org. Chem. 52, 4081-4084(1988).
According to an aspect of the present invention, the etherification of
compound 2
with aryl halide 6 is carried out in the presence of a suitable catalyst and a
base
or a mixture of bases. The suitable catalysts include copper, palladium and
nickel containing catalysts, of which copper-containing catalysts are
preferred.
More preferably, the copper-containing catalyst is selected from cupric
chloride,
cupric bromide, cupric iodide, cupric sulfate, cupric acetate, cupric
triflate,
cuprous chloride, cuprous bromide, cuprous iodide, cuprous acetate, cuprous
triflate, copper (I) oxide, copper (II) oxide, and copper-zinc alloy. Suitable
bases
for this transformation include organic and inorganic bases, of which
potassium
carbonate, sodium carbonate, lithium carbonate, cesium carbonate, calcium
carbonate, magnesium carbonate, magnesium oxide, sodium bicarbonate,
potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, their mixture
thereof, and the like are preferred.
The reaction may be carried out in the absence or presence of an organic
solvent
or a mixture of solvents. Suitable solvents includes aliphatic and aromatic
hydrocarbons such as heptanes, octanes, toluene, and xylenes; nitriles such as
acetonitrile, propionitrile, butyronitrile, and benzonitrile; N,N-
dialkylamides such
as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methy1-2-
CA 02511683 2005-07-08
11
pyrrolidinone; cyclic and acyclic alkyl sulfoxides and sulfones such as
dimethyl
sulfoxide and sulfolane; aliphatic and aromatic ethers such as dibutyl ether,
diphenyl ether, and anisole; and halogenated hydrocarbons such as
dichloromethane and dichloroethane; of which hydrocarbons such as heptanes,
octanes, toluene, and xylenes; and nitriles such as acetonitrile,
propionitrile,
butyronitrile, and benzonitrile are preferred.
The reaction may be carried out at temperatures of from about 0 C to about
200 C, with temperatures of about 50 C to 150 C being preferred, and
temperatures from 90 C to 140 C being more preferred. The product can be
isolated and purified by techniques well known in the art, such as filtration,
extraction, evaporation, trituration, and crystallization. The reaction yield
ranges
from 20% to 99%, typically from 60% to 95%.
Thus according to another aspect of the invention, a process is provided for
the
preparation of 3-aryloxy-3-arylpropylamines of formula 1,
0
ArN1' R1
R2
1
wherein Ar is an aryl group, of which phenyl and 2-thienyl are preferred; Arl
is an
aryl group, of which 1-naphthyl, 2-methylphenyl, 2-methoxyphenyl, and 4-
trifluoromethylphenyl are preferred; R1 and R2 individually represent
hydrogen,
C1-C10 alkyl, phenyl, and benzyl groups; the carbon center marked with "*" can
be racemic or enantiomerically enriched (R)- or (S)-- configuration; including
fluoxetine, tomoxetine, nisoxetine, norfluoxetine, duloxetine and their
optically
enriched (R)- and (S)-enantiomers, and pharmaceutically acceptable addition
salts thereof comprising the steps of:
(1) reacting compounds of formula 3,
CA 02511683 2005-07-08
12
OH
AflLG
3
wherein Ar and "*" are as defined above; LG is a leaving group selected
from halogens such as chloro, bromo, and iodo and sulfonate esters such
as mesylate and p-tosylate, with an amine of formula R1R2NH (4), wherein
R1 and R2 are as defined above, and purifying and isolating the coupled
product as its oxalic acid salt of formula 5,
OH
,
Ar N R1
. n (CO2H)2
rN2
5
wherein Ar, R1, R2, and ""are as defined above and n is 0.5 or 1;
(2) treating the salt 5 with a base to produce 3-hydroxy-3-arylpropylamines
of
formula 2,
OH
ArN'R1
R2
2
wherein Ar, R1, R2, and "*" are as defined above;
(3) reacting compounds of formula 2 with an aryl halide of formula AriX
(6),
wherein An is an aryl group, of which 1-naphthyl, 2-methylphenyl, 2-
methoxyphenyl, and 4-trifluoromethylphenyl are preferred; X is selected
from halogens such as fluoro, chloro, bromo, and iodo, of which iodo is
preferred, in the presence of a suitable catalyst and a base or mixture of
bases to produce 3-aryloxy-3-arylpropylamines of formula 1; and
CA 02511683 2005-07-08
13
(4) optional formation of an acid addition salt using a pharmaceutically
acceptable acid.
Further, according to an aspect of the present invention, a process is
provided for
the preparing fluoxetine, tomoxetine, and nisoxetine and their optically
enriched
(R)- and (S)-enantiomers, and pharmaceutically acceptable addition salts
thereof
comprising the steps of:
(1) reacting compounds of formula 7,
OH
Ph LG
7
wherein LG is a leaving group selected from halogens such as chloro,
bromo, and iodo and sulfonate esters such as mesylate and p-tosylate;
with methylamine and isolating the resulting crude N-methy1-3-hydroxy-3-
phenylpropylamine followed by treatment with oxalic acid to form the
oxalate salt compound of formula 8,
OH
M
Ph e IT . 0.5 (CO2H)2
8
(2) treating the salt 8 with a base to produce N-methy1-3-hydroxy-3-
phenylpropylamine 9;
OH
Ph Me
9
CA 02511683 2005-07-08
14
(3) reacting compound 9 with aryl halide AriX (6), wherein Ari is 2-
methylphenyl, 2-methoxyphenyl or 4-trifluoromethylphenyl; X is selected
from halogens such as fluoro, chloro, bromo, and iodo, of which iodo is
preferred, in the presence of a suitable catalyst and a base or mixture of
bases to produce fluoxetine, tomoxetine, or nisoxetine or their (R)- or (S)-
enantiomer; and
(4) optional formation of an acid addition salt using a pharmaceutically
acceptable acid.
The 3-aryloxy-3-arylpropylamines described herein form pharmaceutically
acceptable acid addition salts with a wide variety of organic and inorganic
acids.
The present preparation of 3-aryloxy-3-arylpropylamines is carried out
according
to reaction Scheme 2 below where all substituents are as previously defined.
Scheme 2
OH
OH R2NH (4)
___________________________________ 3== Arr=J'Ri Base
Ar µ'LG
Oxalic acid I n (CO2H)2
step 1 R2 step 2
3 5
OH0
Catalyst, Base
________________________________________ = ArtµI'R.1
Ar =
Ari X (6)
R2 R2
2 step 3 1
The etherification of compounds of formula 2 with aryl halides of formula 6
may
be carried out in the presence of a suitable catalyst and a base or a mixture
of
bases. The suitable catalysts include copper, palladium and nickel containing
catalysts, of which copper-containing catalysts are preferred. More
preferably,
the copper-containing catalyst is selected from cupric chloride, cupric
bromide,
CA 02511683 2005-07-08
,
cupric iodide, cupric sulfate, cupric acetate, cupric triflate, cuprous
chloride,
cuprous bromide, cuprous iodide, cuprous acetate, cuprous triflate, copper (I)
oxide, copper (II) oxide, and copper-zinc alloy. Suitable bases for this
transformation include organic and inorganic bases, of which potassium
5 carbonate, sodium carbonate, lithium carbonate, cesium carbonate, calcium
carbonate, magnesium carbonate, magnesium oxide, sodium bicarbonate,
potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, and their
mixture thereof, and the like are preferred.
The reaction may be carried out in the absence or presence of an organic
solvent
10 or a mixture of solvents. The suitable solvents includes aliphatic and
aromatic
hydrocarbons such as heptanes, octanes, toluene, and xylenes; nitriles such as
acetonitrile, propionitrile, butyronitrile, and benzonitrile; N,N-
dialkylamides such
as N,N-dimethylformamide, N,N-dimethylacetamide and N-methy1-2-
pyrrolidinone; cyclic and acyclic alkyl sulfoxides and sulfones such as
dimethyl
15 sulfoxide and sulfolane; aliphatic and aromatic ethers such as dibutyl
ether,
diphenyl ether, and anisole; and halogenated hydrocarbons such as
dichloromethane and dichloroethane; of which hydrocarbons such as heptanes,
octanes, toluene, and xylenes; and nitriles such as acetonitrile,
propionitrile,
butyronitrile, and benzonitrile are preferred.
The reaction may be carried out at temperatures of from about 0 C to about
200 C, with temperatures of about 50 C to 150 C being preferred, and
temperatures from 90 C to 140 C being more preferred. The product can be
isolated and purified by techniques well known in the art, such as filtration,
extraction, evaporation, trituration, and crystallization. The reaction yields
range
from 20% to 99%, typically from 60% to 95%.
The present invention relates to processes for the preparation of 3-aryloxy-3-
arylpropylamines 1, which include tertiary amines, secondary amines, and
primary amines (R1 = R2 = H). It is understood by the skilled person that the
amine moiety of these compounds can be modified by the methods known in the
= CA 02511683 2005-07-08
16
art to produce desired target compounds. For example, N,N-dimethylamines or
N,N-methylbenzylamines can undergo mono-N-demethylation or debenzylation
to form the N-methylamine compounds such as fluoxetine, tomoxetine,
nisoxetine, and duloxetine as shown in Scheme 3. Similarly, primary amines can
be converted to N-methylamine compounds such as fluoxetine, tomoxetine,
nisoxetine, and duloxetine by N-methylation (Scheme 4) and N-benzyl amines
can be converted to primary amines such as norfluoxetine by debenzylation
(Scheme 5).
Scheme 3
Ari Demethylation
0
ArNY Me or
(R2 = Me) 1
Ar N' Me
___________________________________________________ =
R2 Debenzylation
1 (R2 = Bn)
Scheme 4
Ari
Methylation 0
Ar N' Me
Ar N H2
1
Scheme 5
Ari
0 Debenzylation 0
Ar 'N"Bn
ArIN H2
1
The processes of the instant invention are capable of preparing both
enantiomerically enriched (R)- and (S)-stereoisomers and racemic mixtures of 3-
aryloxy-3-arylpropylamines 1. It is also understood by the skilled person that
the
CA 02511683 2005-07-08
6
17
specific enantiomerically enriched stereoisomers may be obtained by resolution
of the racemic product, intermediates, or in some cases the starting
materials.
Thus, when racemic mixtures of 3-aryloxy-3-arylpropylamines 1 are produced
using the present processes, the product can be resolved into their specific
isomers; namely, the (R)- or (S)-enantiomer.
Overall using the processes of the instant invention, a convenient and high-
yielding method for the preparation of 3-aryloxy-3-arylpropylamines is
achieved.
Furthermore and of similar importance, these processes are highly
stereospecific
and yield pure material, thus providing 3-aryloxy-3-arylpropylamines of
suitable
quality for their use as pharmaceuticals.
The following non-limiting examples further illustrate the manner of carrying
out
the inventive process described herein.
Example 1
A solution of (R)-3-chloro-1-phenylpropanol (1.0 g, 5.85 mmol) and a catalytic
amount of sodium iodide in ethanol (7 mL) and 40% methylamine aqueous
solution (15 mL) was stirred at 60 C for 7 hours. The reaction mixture was
evaporated to 3 mL, and the pH of the solution was adjusted to pH > 12 via the
addition of aqueous NaOH solution. The mixture was then extracted with toluene
twice and the combined extracts were washed with brine. The toluene layer was
evaporated to dryness and the residue dissolved in toluene (5 mL) and
isopropanol (5 mL) and oxalic acid dihydrate (0.4 g, 3.2 mmol) was added. It
was stirred at room temperature for 2 hours and the suspension was filtered
and
rinsed with toluene/isopropanol to provide 0.9 g of (R)-N-methyl-3-hydroxy-3-
phenylpropylamine oxalic salt as an off-white solid. 1H NMR (D20) 6 7.5-7.2
(m,
5H), 4.8 (at, J = 6.6 Hz, 1H), 5.15-2.9 (m, 2H), 2.64 (s, 3H), 2.2-2.0 (m,
2H). The
solid (0.85 g) was free based with sodium hydroxide solution and extracted
with
toluene. The extracts were washed with brine and then evaporated to dryness to
give 0.62 g of (R)-N-methyl-3-hydroxy-3-phenylpropylamine as an off-white
solid
CA 02511683 2005-07-08
18
[a]D23 = 370 (c 1, CHCI3). 1H NMR (CDC13) 6 7.4-7.2 (m, 5H), 4.96 (dd, J =
8.6,
3.1 Hz, 1H), 3.0-2.8 (m, 2H), 2.46 (s, 3H), 1.9-1.7 (m, 2H).
Example 2
A solution of (R)-3-iodo-1-phenylpropanol (5.0 g, 19 mmol) and catalytic
amount
of sodium iodide in tetrahydrofuran (20 mL) and 40% aqueous methylamine (40
mL) was stirred at room temperature for 5 hours. The reaction mixture was
evaporated to 15 mL and the pH of the solution was adjusted to pH > 12 via the
addition of aqueous NaOH solution. The mixture was then twice extracted with
toluene and the combined extracts were washed with brine. The toluene layer
was evaporated to dryness and the residue dissolved in toluene (25 mL) and
isopropanol (25 mL) and oxalic acid dihydrate (1.2 g, 9.5 mmol) was added and
the mixture was stirred at room temperature for 2 hours. The resulting
suspension was filtered and rinsed with toluene/isopropanol to give 3.0 g of
(R)-
N-methy1-3-hydroxy-3-phenylpropylamine oxalic salt as an off-white solid. The
solid (2.9 g) was free based with sodium hydroxide solution and extracted with
toluene. The extracts were washed with brine and then evaporated to dryness to
give 2.2 g of (R)-N-methyl-3-hydroxy-3-phenylpropylamine as an off-white solid
[4:123 = 36 (c 1, CHCI3).
Example 3
A mixture of (R)-N-methyl-3-hydroxy-3-phenylpropylamine (0.33 g, 2 mmol), 4-
iodobenzotrifluoride (0.82 g, 3 mmol), cuprous iodide (0.1 g), cesium
carbonate
(1.3 g, 4 mmol) and butyronitrile (0.5 mL) was stirred under nitrogen at 130-
140 C until reaction completion as determined by 1H NMR (16-24 hours). The
reaction mixture was cooled to room temperature, diluted with methyl t-butyl
ether (10 mL), filtered, and rinsed with more methyl t-butyl ether. A 20% HC1
solution in isopropanol (1 mL) was added and the resulting solution was
evaporated to dryness to give a solid residue. The residue was stirred with
methyl t-butyl ether (5 mL) for 1 hour at room temperature and the suspension
was filtered and washed with more methyl t-butyl ether to give 0.59 g of (R)-N-
CA 02511683 2005-07-08
19
methyl-3-(4-trifluoromethylphenoxy)-3-phenylpropylamine hydrochloride ((R)-
Fluoxetine hydrochloride) as a white solid [4323 = -16.1 (c 1, CHCI3). 1H NMR
(CDC13) 6 9.73 (br s, 2H), 7.42 (d, J = 8.7 Hz, 2H), 7.4-7.2 (m, 5H), 6.91 (d,
J =
8.7 Hz, 2H), 5.48 (dd, J = 8.0, 4.5 Hz, 1H), 3.2-3.0 (m, 2H), 2.63 (at, J =
5.4 Hz,
3H), 2.6-2.4 (m, 2H).
Example 4
A mixture of N-methyl-3-hydroxy-3-phenylpropylamine (1.65 g, 10 mmol), 4-
iodobenzotrifluoride (3.25 g, 12 mmol), cuprous bromide (0.17 g), cesium
carbonate (3.9 g, 12 mmol) and xylenes (1 mL) was stirred under nitrogen at
130 C until reaction completion as determined by 1H NMR (16 hours). The
reaction mixture was cooled to room temperature, diluted with methyl t-butyl
ether (20 mL), filtered, and rinsed with more methyl t-butyl ether. 20% HC1
solution in isopropanol (3 mL) was added and the resulting solution was
evaporated to dryness to yield a solid residue. The residue was stirred with
methyl t-butyl ether (20 mL) for 1 hour at room temperature and the suspension
was filtered and washed with more methyl t-butyl ether to give 2.4 g of N-
methy1-
3-(4-trifluoromethylphenoxy)-3-phenylpropylamine hydrochloride (Fluoxetine
hydrochloride) as a white solid. 1H NMR spectrum of the product is identical
to
that of Example 3.
Example 5
A mixture of (R)-N-methyl-3-hydroxy-3-phenylpropylamine (0.33 g, 2 mmol), 2-
iodotoluene (0.65 g, 3 mmol), cuprous iodide (0.1 g), cesium carbonate (1.3 g,
4
mmol) and xylenes (1.2 mL) was stirred under nitrogen at 130 C until reaction
completion as assessed by 1H NMR. The reaction mixture was cooled to room
temperature, diluted with methyl t-butyl ether (10 mL), filtered, and rinsed
with
more methyl t-butyl ether. A 20% HC1 solution in isopropanol (1 mL) was added
and the resulted suspension stirred at 0-5 C and filtered and washed with more
methyl t-butyl ether to give 0.48 g of (R)-N-methy1-3-(2-methylphenoxy)-3-
phenylpropylamine hydrochloride (Atomoxetine hydrochloride) as an off-white
,
CA 02511683 2005-07-08
solid [a]D23 = -41 (c 1, Methanol). 1H NMR (CDCI3) 9.7
(br s, 2H), 7.4-7.2 (m,
5H), 7.1 (d, J = 7.5 Hz, 1H), 6.95 (dd, J = 8.1, 7.0 Hz, 1H), 6.78 (dd, J=
7.5, 7.0
Hz, 1H), 6.6 (d, J = 8.1 Hz, 1H), 5.38 (dd, J = 7.9, 4.5 Hz, 1H), 3.14 (t, J =
7.7 Hz,
2H), 2.61 (s, 3H), 2.6-2.4 (m, 2H), 2.30 (s, 3H).
5 Example 6
A mixture of (R)-N-methyl-3-hydroxy-3-phenylpropylamine (0.3 g, 1.8 mmol), 2-
iodotoluene (0.59 g, 2.7 mmol), cuprous iodide (0.1 g), potassium carbonate
(0.14 g, 1 mmol) and xylenes (1 mL) was stirred under nitrogen at 130 C until
reaction completion as determined by 1H NMR. The reaction mixture was cooled
10 to room temperature and washed with saturated aqueous potassium
carbonate
and water. The organic layer was twice extracted with dilute hydrochloric acid
solution. The combined aqueous layers were adjusted to pH > 10 via the
addition of NaOH solution and extracted with methyl t-butyl ether. The
combined
extracts were washed with an aqueous EDTA (0.1g) solution (3 mL) and
15 additional water. The organic layer was evaporated to dryness and the
residue
dissolved in ethyl acetate (10 mL). A 20% HCI solution in isopropanol (1 mL)
was added and the resulting suspension stirred at 0-5 C, filtered, and washed
with more ethyl acetate to give 0.3 g of (R)-N-methy1-3-(2-methylphenoxy)-3-
phenylpropylamine hydrochloride (Atomoxetine hydrochloride) as an off-white
20 solid [a]D23 = -40 (c 1, Methanol). 1H NMR spectrum of the product is
identical to
that of Example 5.
Example 7
A mixture of N-methyl-3-hydroxy-3-phenylpropylamine (0.3 g, 1.8 mmol), 2-
iodotoluene (0.59 g, 2.7 mmol), cupric sulfate (0.06 g), cesium carbonate
(0.65 g,
2.0 mmol) and xylenes (0.5 mL) was stirred under nitrogen at 130-140 C until
reaction completion as determined by 1H NMR. The reaction mixture was cooled
to room temperature and filtered, washed with toluene. The filtrate was washed
with 5% aqueous ammonia solution and water. The organic layer was
evaporated to dryness and the residue dissolved in ethyl acetate (5 mL). A 20%
I "
= CA 02511683 2005-07-08
' = t
21
HCI solution in isopropanol (0.5 g) was added and the resulting suspension
stirred at 0-5 C, filtered, and washed with more ethyl acetate to give 0.22 g
of N-
methy1-3-(2-methylphenoxy)-3-phenylpropylamine hydrochloride (Tomoxetine
hydrochloride) as an off-white solid. 1H NMR spectrum of the product is
identical
to that of Example 5.
Example 8
A mixture of N,N-dimethy1-3-hydroxy-3-phenylpropylamine (0.9 g, 5 mmol), 2-
iodotoluene (1.31 g, 6 mmol), cuprous iodide (0.2 g) and cesium carbonate (1.8
g, 5.5 mmol) was stirred under nitrogen at 130 C until the reaction was
complete
as determined by 1H NMR. The reaction mixture was cooled to room
temperature, diluted with methyl t-butyl ether (10 mL), filtered, and rinsed
with
more methyl t-butyl ether. The filtrate was extracted with diluted
hydrochloric
acid solution and the aqueous layer was washed with more methyl t-butyl ether.
The aqueous was adjusted to pH > 10 by the addition of sodium hydroxide
solution, then extracted with methyl t-butyl ether twice. The combined
extracts
were washed with water and then evaporated to dryness to give 1.2 g of N,N-
dimethy1-3-(2-methylphenoxy)-3-phenylpropylamine as a light yellow oil. 1H NMR
(CDC13) 6 7.45-7.2 (m, 5H), 7.12 (d, J = 6.8 Hz, 1H), 7.0 (dd, J = 8.0, 7.6
Hz,
1H), 6.78 (dd, J = 8.4, 6.8 Hz, 1H), 6.63 (d, J = 8.1 Hz, 1H), 5.24 (dd, J =
8.1, 4.8
Hz, 1H), 2.46 (t, J = 7.3 Hz, 2H), 2.33 (s, 3H), 2.24 (s, 6H), 2.3-2.1 (m,
1H), 2.05-
1.9 (m, 1H).
While the foregoing provides a detailed description of a preferred embodiment
of
the invention, it is to be understood that this description is illustrative
only of the
principles of the invention and not limitative. Furthermore, as many changes
can
be made to the invention without departing from the scope of the invention, it
is
intended that all material contained herein be interpreted as illustrative of
the
invention and not in a limiting sense.
