TECHNICAL FIELD OF THE INVENTION
The present invention relates to novel process for synthesis of duloxetine hydrochloride of
formula (1) in chiral purity of greater than 99 9%

BACK GROUND OF THE INVENTION
The chemical name of duloxetine hydrochloride is (S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-
thienyl)propanamine hydrochloride (1)
Duloxetine was disclosed in US 4,956,388 and its acid addition salts in US 5,362.886
Duloxetine hydrochloride is useful for the treatinent as an anti-depressant and also for
treatinent of urinary incontinence It is the active ingredient of drug "CYMBALTA"
Very few references are directed towards chiral synthesis of chiral starting compound (S)-
N N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine of formula

and it's use in the asymmetric synthesis of duloxetine.
Numbers of documents are cited in the patent as well as academic literature for the synthesis
of duloxetine and its enantiomerically pure intermediate compounds via an optical resolution
of racemic duloxetine or racemic intermediates that are formed in the synthesis of duloxetine
at different steps. These pathways are illustrated in the following synthetic scheme 1


Most of the literature data indicate that the initial step of duloxetine synthesis is condensation
of either racemic hydroxy compound 1 e (RS)-N N-dimethyl-3-hydroxy-3-(2-

thienyl)propanamine or enantiomencally pure (S)-NN-dimethyl-3-hydroxy-3-(2-
thienyl)propanamine with 1-fluronaphthalene by using sodium hydride as base in polar
aprotic solvent Sodium hydride is very hazardous reagent because it is pyrophonc and reacts
violently with water with evolution of hydrogen gas
The inventors of WO 2004/056,795 have successfully replaced sodium hydride with alkali
metal hydroxides, alkali metal carbonates, alkali metal bicarbonates preferably with
potassium hydroxide but the condensation reaction requires to be carried out in presence of
phase transfer catalyst such as crown ethers, quaternary ammonium salts, quaternary
phosphomum salts to facilitate the reaction The use of phase transfer catalysts render the
process economically non viable since they are much costlier
US 6,541,668 describes synthesis of 3-aryloxy-3-arylpropanamines by reaction of alkoxide
of 3-hydroxy-3-arylpropanamine with a halo-aromatic in l,3-dimethyl-2-imidazolidinone or
N-methylpyrrohdinone as solvent The alkoxides are very strong bases and therefore are
hazardous that brings limitation on their use on large scale
WO 2006/126,213 describe condensation of racemic hydroxy compound with 1-
fluronaphthalene in organic polar solvent such as dimethyl sulfoxide, dimethyl formamide,
dimethyl acetamide in presence of alkoxide base such as sodium methoxide, sodium ethoxide
and potassium tert butoxide As mentioned above, the alkoxides are very strong bases and
hazardous which restrict their use on plant scale reactions
Thus, the methods described in prior art for condensation of racemic hydroxy compound with
1-fluronaphthalene that utilizes sodium hydride, alkoxide or phase transfer catalyst for large-
scale reactions suffers from several drawbacks, such as:
1) potentially hazardous reagents are used,
2) sodium hydride pyrophonc, it catches fire on contact with moisture,
3) very toxic reagents are used,
4) requires special skills to handle,
5) requires anhydrous medium for performing the reaction,
6) costlier reagent and
7) difficult to carry out plant scale reactions

These drawbacks of the condensation reactions associated with the prior art processes are
overcome by the present invention in which the condensation is achieved by using milder
bases such as sodamide potassium amide and potassium bis(tnmethylsilyl)amide (see scheme
II)
There are several reports on optical resolution of racemic duloxetine and it's racemic
intermediates by using resolving chiral acids such as tartaric acid, dibenzoyl-L-tartaric acid,
di-p-toluoyl-L-tartanc acid, mandehc acid, camphor sulphonic acid, (S)-2-pyrohdine-2-one-
5-carboxyhc-acid and (-)-2,3,4,6-di-0-isopropylidine-2-keto-L-gulonic acid However, very
few of them are directed towards resolution of racemic condensed compound (RS)-N N-di
methyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine (5a + 5b) to obtain (S)-N, N-dimethyl-
3- (1-naphthylenyloxy)-3-(2-thienyl) propanamine (5a), which is key intermediate in
synthesis of duloxetine hydrochloride Theses references are discussed below.
The example 1 of US 5023269 discloses general method for preparation of (R,S) N, N-
dimethyl-3- (1-naphthylenyloxy)-3-(2-thienyl) propanamine (5a + 5b) that is isolated as its
oxalate salt This patent although mentions that the lesolution of racemic mixture 5a + 5b can
be carried out using resolving agent such as dibenzoyl-D-tartaric acid and dibenzoyl-L-
tartanc acid (referred to as DBTA hereafter) and the like, however, it does not provide an
enabling disclosure for the same
WO 2006/045255 teaches the use of D-tartanc acid to resolve racemic N, N-dimethyl-3- (1-
naphthylenyloxy)-3-(2-thienyl)propanamine (5a+5b) followed by two recrystallizations of
the resulting tartarate salt from tetrahydrofuran as solvent to preferentially isolate (S)- N,N-
dimethyl-3- (1-naphthylenyloxy)-3-(2-thienyl) propanamine-(D)-tartarate salt in 25% yield
and 99% chiral purity
WO 2006/027798 teaches use of di-p-toluloyl-L-tartanc acid as a resolving agent for
resolution of racemic N,N-dimethyl-3- (1-naphthylenyloxy)-3-(2-thienyl) propanamine (5a +
5b) to obtain (S)-N,N-dimethyl-3-(1-naphthylenyloxy)-3-(2-thienyl) propanamine-di-p-
toluoyl-(L)-tartarate salt in 34 8% yield and having chiral purity of about 98% This PCT
application further mentions about poor efficiency of dibenzoyl-L-tartanc acid and higher

cost of chiral resolving agents such as (S)-2-pyrohdine-2-one-5-carboxyhc-acid and (-)-
2,3,4,6-di-O-isopropyhdine-2-keto-L-gulonic acid
WO 2006/126213 teaches resolution of racemic N,N-dimethyl-3- (1-naphthylenyloxy)-3-(2-
thienyl) propanamine (5a + 5b) using D(-)-tartanc acid from ethyl acetate-isopropyl alcohol
solvent mixture to get (S)-N,N-dimethyl-3-(1-naphthylenyloxy)-3-(2-thienyl)propanamine-
(D)-tartarate salt as hemi hydrate in 22% yield
US 2006/0270861 Al covers a process for preparing enatiomerically enriched (S)-(+)- N N-
di methyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine (5b) by resolution of (R,S)- N N-di
methyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine (5a + 5b) with an enantiomencally pure
acid that include dibenzoyl-L-tartanc acid also, however, it does not provide any enabling
disclosure for use of dibenzoyl-L-tartaric acid
The inventors of the present invention have developed a novel process for optical resolution
of racemic condensed compound (RS)-NN-di mefhyl-3-(1-naphfhyloxy)-3-(2-
thienyl)propanamine (5a + 5b) with di-benzoyl-L-tartaric acid (DBTA) and di-p-anisoyl-L-
tartaric acid (DATA) as resolving agents.
None of the prior art references discussed above provide an enabling disclosure for use of
DBTA or DATA as a resolving agent for resolution of (R,S)-N,N-dimethyl-3-(1-
naphthylenyloxy)-3-(2-thienyl) propanamine (5a + 5b) Further the methods reported in prior
art for resolution of (R,S)-N,N-dimethyl-3-(1-naphthylenyloxy)-3-(2-thienyl) propanamine
(5a + 5b) either provide misleading information or have several disadvantages, as discussed
below
1 The patent application WO 2006/ 027798 states that chiral acids such as dibenzoyl
tartaric acids, mandelic acid and camphorsulphonic acid have been found to be
ineffective resolving agent,
2 The process as disclosed in the patent applications WO2006/126213 and
WO2006/027798 uses ethyl acetate- isopropyl alcohol mixture and ethyl acetate
respectively as solvents th epresent inventors have studied efficiency of DBTA in
these solvents along with other solvents The results of this comparative study is
provided in table 1 below which reveals that resolution was poor in ethyl acetate and

in the mixture of ethyl acetate-IPA as solvent In ethyl acetate as solvent, the content
of R isomer in the product obtained after resolution was as high as 8 2% while with
ethyl acetate-IPA mixture it was 7.0%.
3 The resolving agents like (S)-2-pyrolidine-2-one-5-carboxylic-acid, (-)-2,3,4,6-di-O-
isopropyhdine-2-keto-L-gulonic acid, mandehc acid and camphorsulphonic acid that
are used in prior art are very expensive, rendering the method uneconomical
4 The resolution methods discussed in prior art gives (S)- N,N-dimethyl-3-(1-
naphthylenyloxy)-3-(2-thienyl) propanamine (5b) in comparatively low chiral purity
e g the resolution method discussed in WO2006/45255 gives 99% chiral purity while
the process in WO2006/027798 gives 98% ee
The preparation 2 of example 2 of U S patent 5362886 describes crystallization of
duloxetine hydrochloride from ethyl acetate but without providing any data on the crystalline
form The later U S patent application 2006/0270859 state that the crystalline duloxetine
hydrochloride obtained by the process described in patent U S. 5362886 is anhydrous form
which is referred as Form A The patent application 2006/0270859 covers another crystalline
Form B of duloxetine hydrochloride and process for its preparation that comprises of
providing solution of duloxetine hydrochloride in water and a solvent selected from the
group consisting of C 1.4 alcohols and removing the solvent
Another U S patent application 2006/0276660 Al describe process for purification of
duloxetine hydrochloride comprising crystallization of duloxetine hydrochloride from water
or a solvent selected from group consisting of C3.8 ketones, C3.8 esters, C2-8 ethers, C2-8
alcohols and mixtures thereof with water.
WO 2007/007580 A2 describe process for purification of duloxetine hydrochloride
comprising crystallization of duloxetine hydrochloride from solvent or mixture of solvents
selected from ester solvents like methyl acetate, ethyl acetate, ethyl formate, propyl acetate,
isopropyl acetate, methyl isopropyl acetate and or alcohol solvents like methanol, ethanol,
isopropyl alcohol or mixture of ester and alcohol solvents
EP 1,820,800 Al mentions that Form A of duloxetine hydrochloride may be crystallized out
of a solution of-duloxetine hydrochloride in water; alcohols, such as, methanol, ethanol, 1-

propanol, 2-propanol, 1-butanol, isobutanol, tert-butanol, 2-methoxyethanol, 2,2,2-
tnfluroethanol, or acetonitrile, nitromethane, 1,2-dimethoxyethane, or esters, such as methyl
acetate, ethyl acetate, ethyl foimate; or ketones, such as e g. acetone, 2-butanone, or mixtures
thereof, or mixtures with water
The present invention provides a process for crystallization of duloxetine hydrochloride (1)
from a solvent selected from alcohols such as methanol, ethanol, n- propanol, isopropanol,
ketones such as acetone, methyl ethyl ketone, esters such as methyl acetate, ethyl acetate,
ethyl formate, propyl acetate or a mixtures thereof
In summary, the inventors of the present invention have developed a process for preparation
of duloxetine hydrochloride (1) having chiral purity greater than 99 9% that not only
overcome the disadvantages of processes in the prior art but also is safer, efficient,
economically viable and easy to operate on plant scale The process is discussed below in
detail
OBJECTIVE OF THE INVENTION
The objective of the present invention is to provide a method for synthesis of duloxetine
hydrochloride (1) having chiral purity greater than 99.9% that is safer and easy to operate on
plant scale
SUMMARY OF THE INVENTION
The present invention provides an improved, safer and easy to operate on plant scale process
for synthesis of duloxetine hydrochloride (1) having chiral purity of greater than 99 9% The
process is characterized by the following
(i) preparation of racemic condensed compound (RS)-N,N-di methyl-3-(1-naphthyloxy)-
3-(2-thienyl)propanamine (4) by reaction of racemic hydroxy compound (2) with 1-
fluronaphthalene (3) in presence of milder bases such as sodamide, potassium amide
or potassium bis(tnmethylsilyl)amide (KHDMS) in polar aprotic solvent,
(n) optical resolution of racemic condensed compound (5a + 5b) with di-benzoyl-L-
tartanc acid (7, R = H, referred as DBTA hereafter) or di-para-amsoyl-L-tartaric acid
(7, R = OCH3 referred as DATA hereafter) to obtain crude (S)-NN-dimethyl-3-(1-
naphthyloxy)-3-(2-thienyl)propanamine dibenzoyl tartarate salt (8a) or (S)-NN-

dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine di-p-anisoyl tartarate salt (9a)
respectively,
(in) optionally purification of crude tartarate salt (8a or 9a) by crystallization,
(iv) optionally purification of duloxetine hydrochloride (1) by crystallization and
(v) racemization of undesired (R)-N,N-di methyl-3-(1-naphthyloxy)-3-(2-
thienyl)propanamine (6b) by treatinent with base potassium bis(tnmethylsilyl)amide
(referred as KHDMS hereafter) to obtain racemic condensed compound (6a + 6b)
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a novel process for synthesis of duloxetine hydrochloride (1)
having chiral purity of greater than 99 9% that comprises of the following steps
i) reaction of (RS)-N N-di methyl-3-hydroxy-3-(2-thienyl)propanamine (2, racemic
hydroxy compound) with 1-fluronaphthalene (3) in aprotic polar organic solvent in
presence of a base selected from sodamide, potassium amide, potassium
bis(tnmethylsilyl)amide to obtain (RS)-N N-di methyl-3-(1-naphthyloxy)-3-(2-
thienyl)propanamine (4) (racemic condensed compound),
n) optionally isolation of racemic condensed compound as acid addition salt (5) of
organic or inorganic acid,
iii) conversion of salt (5) to free base (RS)-NN-di methyl-3-(1-naphthyloxy)-3-(2-
thienyl)propanamine (6a + 6b) by treatinent with base,
iv) optical resolution of free base of racemic condensed compound (6a + 6b) with DBTA
(7, R = H) or DATA (7, R = OCH3) in organic solvent to get tartarate salt of (S)-
lsomer (8a or 9a),
v) optionally purification of tartarate salt of (S)-isomer (8a or 9a) by crystallization from
suitable organic solvent or mixture of two or more solvents,
vi) conversion of tartarate salt (8a or 9a) to free base (S)-N.N-di methyl-3-(1-
naphthyloxy)-3-(2-thienyl)propanamine (5a) by treatinent with base,
vn) demethylation of free base (6a) by treatinent with phenyl chloroformate in presence
of dnsopropylethyl amine in toluene to get carbamate intermediate (10) in situ,

viii) hydrolysis of carbamate intermediate (10) with sodium hydroxide in dimethyl
sulfoxide solvent to give duloxetine base (11),
ix) conversion of duloxetine base (11) to duloxetine hydrochloride (1) in an organic
solvent or mixture of organic solvents, and
x) optionally purification of duloxetine hydrochloride (1) by crystallization.
The steps involved in the synthesis of duloxetine hydrochloride (1) according to the process
of present invention are depicted in synthetic scheme II given below.

In one aspect, the present invention provides a safer and convenient method for condensation
reaction of (±)-N, N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine (2) (racemic hydroxy
compound) with 1-fluronaphthalene (3) to obtain (±)-N, N-dimethyl-3-(2-thienyl)-3-(1-
naphthalenyloxy)propanamine (4) (racemic condensed compound). The reaction is carried
out in presence of base selected from sodamide, potassium amide and potassium
bis(tnmethylsilyl)amide; the most preferred base is sodamide The reaction is carried out
with molar ratio of racemic hydroxy compound to base in the range from 1 1 to 1 5,
preferably 1 1 5 The reaction is carried out in aprotic polar solvent selected from dimethyl
sulfoxide, sulfolane, dimethyl formamide, dimethyl acetamide, N-methylpyrolidine-2-one,
preferably in dimethyl sulfoxide The temperature of reaction at which it is carried out varies
from loom temperature to 150°C, preferably at 70-100°C, most preferably at 80-90°C The
racemic condensed compound (4) prepared according to the present invention as described
above can be isolated as acid addition salt (5) of organic or inorganic acid such as
hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic
acid, oxalic acid, maleic acid, succinic acid benzoic acid and acetic acid, the most preferred
acid is oxalic acid
The acid salt of racemic condensed compound (5) is converted to free base of racemic
condensed compound (6a + 6b) by treating it with in organic or inorganic base in aqueous or
organic or mixture of aqueous and water immiscible organic solvent. The organic base is
selected from triethyl amine, dnsopropylethyl amine, pyridine and the like while inorganic
base is selected from hydroxides of alkali metals or alkaline earth metals such as sodium
hydroxide, potassium hydroxide, lithium hydroxide, bicarbonates of alkali metals or alkaline
earth metals such as sodium bicarbonate, potassium bicarbonate and the like, carbonates of
alkali metals or alkaline earth metals such as sodium carbonate, potassium carbonate; and
ammonia and mixtures thereof The organic solvent is selected from aromatic hydrocarbon
such as benzene, toluene, xylene, aliphatic esters such as ethyl acetate, propyl acetate,
isopropyl acetate, ethers such as diisopropyl ether, tert -butyl methyl ether, chlorinated
hydrocarbons such as dichloromethane, ethylene dichlonde, chloroform, lower aliphatic
ketones such as acetone, methyl ethyl ketone, diethyl ketone, lower alcohols such as

methanol, ethanol, propanol, isopropanol; acetonitrile or mixtures thereof. In a preferred
reaction condition the oxalate salt (5, HA = oxalic acid) is converted to free base of racemic
condensed compound (6a + 6b) by treating it with aqueous ammonia in mixture of
cyclohexane and water, followed by separating the organic layer, drying and concentration
under reduced pressure.
In an another aspect of the present invention, there is provided a process for optical
resolution of (R,S)-N, N-dimethyl-3-(2-thienyl)-3-(1-naphthalenyloxy)-propanamine (6a +
6b) with DBTA (7, R = H) or DATA (7, R = OCH3) to obtain crude (S)-N.N-dimethyl-3-(1-
naphthyloxy)-3-(2-thienyl)propanamine dibenzoyl tartarate salt (8a) or (S)-N.N-dimethyl-3-
(1-naphthyloxy)-3-(2-thienyl)propanamine di-p-anisoyl tartarate salt (9a) respectively. The
solvents employed for the optical resolution is selected from aromatic hydrocarbon such as
benzene, toluene, xylene; lower alcohols such as methanol, ethanol, propanol, isopropanol;
lower aliphatic ketones such as acetone, methyl ethyl ketone, diethyl ketone; aliphatic esters
such as ethyl acetate, propyl acetate, isopropyl acetate; ethers such as diisopropyl ether, tert -
butyl methyl ether; acetonitrile or mixtures thereof. The most preferred solvent for the
resolution when DATA is used as resolving agent is toluene, ethyl acetate, isopropyl acetate,
acetone or mixtures thereof. The most preferred solvent for the resolution when DBTA is
used as resolving agent is ethyl acetate and methanol. The ratio of ethyl acetate: methanol in
the solvent mixture is in the range from 99.9: 0.1 to 0.1: 99.9 (v/v), preferably 90:10 to 10:90
(v/v). Most preferred solvent ratio of ethyl acetate: methanol is 95:5 (v/v).
The comparative study of resolution of (R,S)-N, N-dimethyl-3-(2-thienyl)-3-(1-
naphthalenyloxy)-propanamine (6a + 6b) with DBTA in different solvents is depicted in the
Table 1 below. The resolution was better in mixture of ethyl acetate: methanol is 95:5 (v/v).


The optical resolution is carried out with molar ratio of racemic condensed compound (6a +
6b) to resolving agent DBTA or DATA is in the range 1 0 1 to 1 10, more preferably 1 0 5 to
1.12, most preferably 1 0 9 to 1 11
The resolution is carried out at a temperature of 10-70°C, more preferably at 20-30°C. The
resolution involve heating the reaction mixture up to reflux temperature of the solvent, more
preferably to 50-60°C and then allowing the solution to cool to room temperature and stirring
for 5-20 houts, more preferably 8-15 hours
Further aspect of the present invention is the purification of (S)- (+)-N, N-dimethyl-3-(2-
thienyl)-3-(1-naphthalenyloxy)-propanamine dibenzoyl tartarate salt (8a) or (S)- (+)-N, N-
dimethyl-3-(2-thienyl)-3-(1-naphthalenyloxy)-propanamine di-p-anisoyl tartarate salt (9a) by
crystallization to obtain purity up to 99.8% The crystallization is carried out from solvent
selected from lower alcohols such as methanol, ethanol, isopropanol, lower aliphatic ketones
such as acetone, methyl ethyl ketone, diethyl ketone, aliphatic esters such as ethyl acetate,
propyl acetate, isopropyl acetate, ethers such as dnsopropyl ether, tert -butyl methyl ether,
acetonitrile or mixtures thereof The most preferred solvent for crystallization is mixture of
methanol and ethyl acetate The ratio of methanol to ethyl acetate is varied from 1 90 to 90 1,
preferably 1 1 to 1 10 The ratio of substrate to solvent mixture is 1 1 to 1 30, preferably 1 5
tol 15

preferably 1:1 to 1:10. The ratio of substrate to solvent mixture is 1:1 to 1:30, preferably 1:5
to 1:15.
The crystallization is carried out by heating the reaction mixture to get clear solution,
preferably up to reflux temperature of the solvent and then allowing the solution to cool to
room temperature. The study of purification of (S)- (+)-N, N-dimethyl-3-(2-thienyl)-3-(1-
naphthalenyloxy)-propanamine dibenzoyl tartarate salt (8a) by crystallization in different
solvents is shown in Table 2.
Thus, the inventors of the present invention have surprisingly found that dibenzoyl-L-tartaric
acid monohydrate is highly effective resolving agent for resolution of (R,S)- N, N-dimethyl-
3-(2-thienyl)-3-(1-naphthalenyloxy)-propanamine (6a + 6b). Moreover, use of DBTA
provides following advantages that overcome the drawbacks of prior art.
1. The desired (S)- (+)-N, N-dimethyl-3 -(2-thienyl)-3 -(1 -naphthalenyloxy)-propanamine
(6a) isomer is obtained in better chiral purity upto 99.53%,
2. The desired (S)-N.N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propanamine (6a)
isomer is obtained in comparable yield,
3. The present process avoids use of expensive solvents like tetrahydrofuran, and
4. The use of a cheaper resolving agent like DBTA makes the process highly cost
effective.
5. Simple process, therefore easy to operate on large scale.


In another embodiment, the present invention discloses a novel crystalline form of (S)-N.N-
dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine dibenzoyl-L-tartarate salt of formula
8a which is referred as Form I.


The Form I of crystalline (S)-N.N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine
dibenzoyl-L-tartarate salt (8a) of the present invention is characterized by the following
data:
i) Powder X-ray diffraction pattern (PXRD): As represented in figure 1 that has
significant reflections at 5.94, 7.29, 8.95 10.43, 11.64, 12.39, 13.42, 13.65, 14.99,
16.13, 16.96, 17.79, 17.96, 19.17, 20.08, 20.58, 20.95, 21.19, 21.39, 21.61, 22.00,
22.47, 22.73, 23.42, 24.38°, 24.93, 25.57, 25.84, 26.87, 27.10, 27.84, 28.76, 29.30,
30.00, 30.25, 31.27, 36.61 ± 0.2 degrees two-theta;
ii) Infra red Spectrum: As depicted in figure 2 that has significant peaks at 3515, 3101.7,
2656.7,2486.3, 1724.53, 1557.76, 1490.9,1451.2, 1395.4, 1260.14, 1237.06, 1151.97,
1093.68, 1043.89, 797.19, 772.85, 712.27 cm _1;
iii) Differential Scanning Calorimetry: As depicted in figure 3 which shows an
endothermal maximum of melting at 123.19°C;
iv) Melting point: At 118-120.5°C and
v) Moisture content (by KF): In the range 2.69- 2.84 %
In yet another embodiment, the present invention provides a novel salt (S)-N.N-dimethyl-3-
(1-naphthyloxy)-3-(2-thienyl)propanamine di-p-anisoyl-L-tartarate of formula 9a


The (S)- (+)-N, N-dimethyl-3-(2-thienyl)-3-(1-naphthalenyloxy)-propanamine DBTA or
DATA salt (8a or 9a) is treated with inorganic or inorganic base in aqueous or organic or
mixture of aqueous and water immiscible organic solvent The organic base is selected from
tnethyl amine, diisopropylethyl amine, pyridine and the like while inorganic base is selected
from hydroxides of alkali metals or alkaline earth metals such as sodium hydroxide,
potassium hydroxide, lithium hydroxide, bicarbonates of alkali metals or alkaline earth
metals such as sodium bicarbonate, potassium bicarbonate and the like, carbonates of alkali
metals or alkaline earth metals such as sodium carbonate, potassium carbonate, and
ammonia and mixtures thereof The organic solvent is selected from aromatic hydrocarbon
such as benzene, toluene, xylene, aliphatic esters such as ethyl acetate, propyl acetate,
isopropyl acetate, ethers such as dnsopropyl ether, tert -butyl methyl ether, chlorinated
hydrocarbons such as dichloromethane, ethylene dichlonde, chloroform, lower aliphatic
ketones such as acetone, methyl ethyl ketone, diethyl ketone, lower alcohols such as
methanol, ethanol, propanol, isopropanol; acetonitrile or mixtures thereof In a preferred
reaction condition the (S)- (+)-N, N-dimethyl-3-(2-thienyl)-3-(1-naphthalenyloxy)-
propanamine DBTA or DATA salt (8a or 9a) is treated with aqueous ammonia in mixture of
dichloromethane and water, followed by separating the organic layer, drying and
concentration under reduced pressure to obtain enantiomencally pure (S)-(+)-N, N-dimethyl-
3-(2-thienyl)-3-(1-naphthalenyloxy)-propanamine (6a) of chiral purity up to 99 8%
The demefhylation of (S)-(+)-N, N-dimethyl-3-(2-thienyl)-3-(1-naphthalenyloxy)-
propanamine (6a) is achieved by treatinent with phenyl chloroformate in presence of
dnsopropyl amine as base to obtain carbamate inteimediate (10) in situ which is then

subjected to hydrolysis with alkali such as sodium hydroxide or potassium hydroxide in polar
aprotic solvent selected from dimethyl sulfoxide, sulfolane, dimethyl formamide, dimethyl
acetamide, N-methylpyrohdine-2-one, preferably in dimethyl sulfoxide to provide duloxetine
base (11) The demethylation of racemic condensed product with phenyl chloroformate to
carbamate intermediate and its subsequent alkaline hydrolysis is carried out according to
procedure given in the product patent US 5023269 Duloxetine free base (11) is an oily
material which can be converted to oxalate salt by treating with oxalic acid in ethyl acetate to
obtain duloxetine oxalate salt as solid compound.
In further embodiment, the present invention is characterized by the process for preparing
duloxetine hydrochloride (1) that involves treatinent of duloxetine base (11) with solution of
10-20% hydrochloric acid in lower alkanol such as methanol, ethanol, propanol, isopropanol
preferably isopropanol; lower aliphatic ketones such as acetone, methyl ethyl ketone, diethyl
ketone, aliphatic esters such as ethyl acetate, propyl acetate, isopropyl acetate, ethers such as
dnsopropyl ether, tert -butyl methyl ether, acetonitrile or mixtures thereof The most
prefeired solution of 10-20% hydrochloric acid is in isopropanol or ethyl acetate The
acidification is carried out solvent selected from lower alkanol such as methanol, ethanol,
propanol, isopropanol preferably isopropanol; lower aliphatic ketones such as acetone,
methyl ethyl ketone, diethyl ketone; aliphatic esters such as ethyl acetate, propyl acetate,
isopropyl acetate, ethers such as diisopropyl ether, tert -butyl methyl ether, acetomtrile or
mixtures thereof, most preferably in isopropyl acetate or ethyl acetate The acidification is
carried out up to pH in the range 1-6, preferably in the range 2-3 The temperature during
acidification is maintained in the range 0-50°C, preferably at 10-20°C
Yet in another aspect, the present invention provides a process for purification of duloxetine
hydrochloride by crystallization that comprises of
I) adding crude duloxetine hydrochloride to a solvent selected from alcohols, such
as methanol, ethanol, n- propanol, isopropanol, ketones, such as acetone, methyl
ethyl ketone, esters, such as methyl acetate, ethyl acetate, ethyl formate, propyl
acetate or a mixtures thereof,
n) heating the mixture to obtain clear solution,

in) cooling the solution, and
IV) isolation of solid
Preferred solvent for crystallization of duloxetine hydrochloride is a mixture of ethyl acetate
and or acetone and methanol or ethyl acetate, acetone and methanol. The ratio of duloxetine
hydrochloride to the solvent is in the range 2-10 times (weight by volume), preferably 4 to 7
times (weight by volume)
The heating is performed at temperature in the range 40 °C to reflux temperature of the
mixture, most preferably at 50-60 °C
The ratio of duloxetine hydrochloride to the solvent is in the range 4 to 8 times weight by
volume, preferably 5-7 times weight by volume
The crystalline solid is isolated either by evaporation or by filtration
In another aspect, the present invention provides crystalline Form A of duloxetine
hydrochloride (1) characterized by PXRD as shown in figure 4. The PXRD of the crystalline
duloxetine hydrochloride (1) obtained by the process of the present invention is similar to
that of crystalline Form A described in patent application US 2006/0270859
In an alternative embodiment, the present invention provides piocess for racemization of
undesired isomer (R)-(-)-N, N-dimethyl-3-(1-naphthalenyloxy)-3-(2-ihienyl) propanamine
(6b) with KHMDS as base to obtain racemic compound (RS)-N,N-di methyl-3-(1-
naphthyloxy)-3-(2-fhienyl)propanamine free base (6a + 6b) as shown in scheme III

The racemization is carried out in organic solvent selected from aromatic hydrocarbons su^H
as benzene, toluene, xylene, cyclic and acyclic ethers such as diethyl ether, dnsopropyl eth^^|

methyl tert butyl ether, tetrahydrofuran, dioxane, esters such as ethyl acetate, isopropyl
acetate, nitriles such as acetonitrile, propionitrile or mixtures thereof, most preferably
toluene The racemization is performed at temperature varying from 0-110 °C, preferably at
room temperature to 80 °C, most preferably at 50-60 °C. The racemic condensed compound
(6a + 6b) thus obtained is subjected to subsequent steps and converted to duloxetine
hydrochloride (1) as described above
The invention is further illustrated in the following representative examples and is not limit
to the scope of the invention.
The room temperature refers to the temperature range of 25-30°C
Example 1: Preparation of (±)-N, N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)
piopanamine oxalate salt (5, HA = oxalic acid)
N, N-dimethyl-3- (2-thienyl)-3-hydroxypropanamine (2, racemic hydroxy compound) (50
gm) was dissolved in dimethyl sulfoxide (250 ml) To the clear solution sodamide (13.7 gm)
was added at 20-25°C in small lots within 10-15 minutes under nitrogen atmosphere. The
resulting reaction mass was stirred for half an hour to get a clear solution To this solution 1-
fluoronaphthalene (3) (43 4 gm) was added in 20-25 minutes The temperature was raised to
80-95°C and stirred for 3-5 hours, then cooled to 25-30°C Reaction mass added into cold-
water (500 ml), pH was adjusted to 5 5-6 0 with acetic acid Aqueous reaction mass washed
with cyclohexane followed by pH adjustinent between 10 5-11 0 with caustic solution
Reaction mixture was extracted with cyclohexane and organic layer concentrated under
reduced pressure to provide thick oily mass of (±)-N, N-dimethyl-3-(1-naphthalenyloxy)-3-
(2-thienyl) propanamine (4). The oily mass was dissolved in ethyl acetate (250 ml) and
oxalic acid (30 gm) was added Stirred at 50-60°C for 1 hour then at 25-30°C for 2 hours
Solid was filtered and dried to give racemic N, N-dimethyl-3- (1- naphthalenyloxy)-3-(2-
thienyl) propanamine oxalate (5, HA = oxalic acid) as white solid Yield 75 gm

Example 2: Preparation of (±)-N, N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)
propanamine oxalate salt (5, HA = oxalic acid)
Racemic hydroxy compound (2) (20 gm) was dissolved in N-methylpyrrolidinone (100 ml)
to get clear solution To this solution was added potassium bis(tnmethylsilyl)amide (15%
solution in toluene) (186 5 gm) slowly withinlO-15 minutes Stirred for half an hour then 1-
fluoronaphthalene (3) (15 7 gm) was added in 20-25 minutes Temperature was slowly raised
to 80-90°C and stirred further for 5-7 hours Reaction mixture was cooled to 25-30°C and
then poured into cold-water (500 ml) The pH was adjusted to 5 5-6 0 with acetic acid The
aqueous layer was washed with toluene (100 ml) The pH of aqueous mass was adjusted
tolO 5-11.0 with caustic solution then extracted with cyclohexane The organic layer was
concentrated under reduced pressure to give thick oily mass of (±)-N, N-dimethyl-3-(1-
naphthalenyloxy)-3-(2-thienyl) propanamine (4) The oily mass was dissolved in ethyl
acetate (100 ml) To this oxalic acid (12.15 gm) was added and stirred at 50-60°C for 1 hour
then at 25-30°C for 2 hour Solid was filtered, dried to give racemic N, N-dimethyl-3- (1-
naphthalenyloxy)-3-(2-thienyl) propanamine oxalate (5, HA = oxalic acid) as off white solid
Yield 28 gm
Example 3: Preparation of (+)-N, N-dimethyl-3- (1- naphthalenyloxy)-3-(2-thienyl)
propanamine di-p-amsoyl-(L)-tartarate salt (9a)
Racemic N, N-dimethyl-3- (1- naphthalenyloxy)-3-(2-thienyl) propanamine oxalate salt (5,
HA = oxalic acid) (15 gm) was suspended in mixture of water (100 ml) and cyclohexane (50
ml). This suspension was basified with aqueous ammonia and then layers were separated
The cyclohexane layer was washed with water and concentrated under reduced pressure to
give oily mass of (±)-N, N-dimethyl-3- (1- naphthalenyloxy)-3-(2-thienyl) propanamine free
base (6a + 6b) Yield 10 gm
Oily mass (10 gm) obtained above was dissolved in ethyl acetate (80 ml) Solution of di-p-
anisoyl- (L)-tartanc acid (6 7 gm) in ethyl acetate (45 ml) was added in 10-15 minutes at 25-
30°C Temperature of mixture was slowly increased to 55-60°C and then maintained under
stirring for 15-20 minutes Solution was cooled to 25-30°C within 2 hours and then stirred for

8-10 hours Solid was filtered, washed with 20 ml ethyl acetate and dried Yield 5 6 gm (off
white solid) and chiral purity 94 4%
Example 4: Preparation of (S)-(+)-N, N-dimethyl-3- (1- naphthalenyloxy)-3-(2-thienyl)
propanamine di-p-anisoyl-(L)-tartarate salt (9a)
Racemic N, N-dimethyl-3- (1- naphthalenyloxy)-3-(2-thienyl) propanamine free base (6a +
6b) (10 gm) was dissolved in toluene or isopropyl acetate (120 ml) Solution of di-p-anisoyl-
(L)-tartanc acid (6 7 gm) in acetone (15 ml) was added in 10-15 minutes at 25-30°C
Temperature was slowly increased to 50-55°C and then maintained under stirring for 15-20
minutes Reaction mixture cooled to room temperature in 2 hours and stirred for 10-12 hours.
Solid was filtered, washed with ethyl acetate (20 ml) and dried Yield 4 8 gm (off white
solid) and chiral purity 94 2%
Example 5: Preparation of pure (S)-(+)-N, N-dimethyl-3- (1- naphthalenyloxy)-3-(2-
thienyl) propanamine di-p-anisoyl-(L)-tartarate salt (9a)
The tartarate salt (25 gm) obtained in example 4 was suspended in mixture of ethyl acetate
(275 ml) and methanol (50 ml). Temperature of the mixture was raised to 60-65°C to get a
clear solution. The clear solution was then allowed to cool to room temperature and stirred
for 1 5 -2 hours. Solid was filtered, washed with ethyl acetate and dried Yield- 18 8 gm and
chiral purity 99 8%
Example 6: Preparation of (S)- (+)-N-methyl-3- (1- naphthalenyloxy)-3-(2-thienyl)
propanamine (11, duloxetine free base)
The (S)- N, N-dimethyl-3- (1- naphthalenyloxy)-3-(2-thienyl) propanamine di-p-anisoyl-L-
tartarate salt (9a) (100 gm) was added to biphasic solvent mixture of water (500 ml) and
dichloromethane (250 ml) To the slurry aqueous ammonia was added to adjust the pH to
10 8 and stirred further for 15-30 minutes Organic layer was separated, washed with water,
brine and concentrated to get thick oily mass of (S)- (+)-N,N-dimethyl-3- (1-
naphthalenyloxy)-3-(2-thienyl) propanamine (6a) Yield 44 gm.

The above oily mass of 6a (44 gm) was added to toluene (220 ml). To the solution
diisopropylethylamtne (21.9 gm) was added and mixture was warmed to 45°C. To the
mixture phenyl chloroformate (33.2 gm) was added dropwise and stirred for 2 hours at 55°C.
Reaction mixture was cooled to room temperature and then basified with 2% NaHCCb
solution (220 ml) Organic layer was separated, washed with water and concentrated to give
oily mass of carbamate intermediate (10). The oily mass of carbamate intermediate was
added to dimethyl sulfoxide (285 mi) followed by addition of solution of caustic lye (42 5 gm
in 210 ml water) Reaction mixture was stirred for 3 hours at 90-92°C Cooled to 15-20°C
and pH was adjusted between 5 5-6 with acetic acid. Aqueous layer was separated and
washed with cyclohexane. The pH of aqueous mass was adjusted between 10 5-11 with
acetic acid and then extracted with cyclohexane twice. Combined organic layer was washed
with water and concentrated under reduced pressure to give duloxetine free base (11) as oily
mass Yield. 35 gm
Example 7: Preparation of (S)-N.N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) I
propanamine di-benzoyl-(L)-tartaric acid salt (8a) I
(R,S)-N, N-dimethyl-3- (1- naphthaIenyloxy)-3-(2-thienyl) propanamine oxalate salt (5,' HA ■
= oxalic acid) (255 gm) was suspended in a mixture of water (1275 ml) and cyclohexane ■
(765 ml) This suspension was basified with aqueous ammonia solution (pH 12 5-13.5) ^|
Organic layer was separated, washed with water and concentrated under reduced pressure to^H
give oily mass of racemic condensed compound, (R,S)-N.N-dimethyl-3-(1-naphthyloxy)-3-^H
(2-thienyl) propanamine (6a + 6b) (195 gm). The oily mass was dissolved in 2000 ml <^^|
mixture of methanol (5%) and ethyl acetate (95%) To this clear solution 1 0 mole equivale^^B
of di-benzoyl-(L)-tartaric acid monohydrate (236.4 gm) was added. The clear solution v^^H
stirred for half an hour and seeded with crystals of (S)-N,N-dimethyl-3-(1-naphthylenylox^^H
3-(2-thienyl) propanamine dibenzoyl- (L)-tartarate salt (8a). The solution was stirred lor^^H
15 hours at 25-30°C to get white thick slurry. The solid obtained was filtered, washed ^^^M
ethanol (255 ml) and dried under reduced pressure. ^^^^H
Yield 155 gm and chiral purity 97 32%. ^^^^B

Example 8: Purification of (S)-N, N-dimethyl-3- (1-naphthylenyloxy)-3-(2-thienyl)
propanamine dibenzoyl-L-tartanc acid salt (8a)
The (S)-NN-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propanamine di-benzoyl-(L)-tartanc
acid salt (8a) (155 gm) obtained in example 7 was suspended in a mixture of ethyl acetate
(775 ml) and methanol (77 5 ml) and the slurry so obtained was slowly warmed to 55-60°C
to get a clear solution The solution was stirred for 15 minutes and allowed to cool down to
room temperature slowly. The solution was stirred for 12-15 hours. The solid obtained was
filtered, washed with ethyl acetate (2 x 127 ml) and dried under reduced pressure to get
crystalline off white solid Yield 112.6 gm and chiral purity 99 53%
Example 9: Preparation of (S)-N-methyl-3-(1-naphthylenyloxy)-3-(2-thienyl)
propanamine (duloxetine free base) (11)
Pure (S)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine dibenzoyl-L-
tartanc acid salt (8a) (100 gm) obtained in example 8 was stirred in a mixture of water
(500ml) and cyclohexane (250 ml). Aqueous ammonia solution (100 ml) was charged to
adjust the pH of slurry to 10 8 and the biphasic mass was stirred for 15-30 minutes The
organic layer was separated and aqueous layer was extracted with cyclohexane (250 ml).
Organic layers were combined, washed with water and concentrated to get thick oily mass
(S)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine (6a) Yield- 45 0 gm
The oily mass obtained above was dissolved in toluene (225 ml) and dnsopropylethylamine
(23 18 gm) was added followed by phenyl chloroformate (35 10 gm) in drop wise manner.
The solution was warmed to 55°C and stirred for 2 hours The reaction mass was cooled
down, basified with 2% NaHC03 solution (225 ml) and organic layer was separated Organic
layer was washed with water and concentrated under reduced pressure to get oily mass of
carbamate intermediate (10)
The oily mass of carbamate intermediate was dissolved in dimethyl sulfoxide (300 ml) to get
clear solution followed by addition of NaOH solution (44.85 gm in 225 ml water). The
mixture was stirred for 3 hours at 90°C and then cooled to 15-20°C The reaction mass was

diluted with 2 liters of water and pH was adjusted between 5 5-60 with acetic acid
followed by washing of aqueous mass with cyclohexane (2 x 200 ml). Combined organic
layer was washed with water and concentrated under reduced pressure to get duloxetine free
base (11) as oily mass Yield 38 0 gm
Example 10: Preparation of (S)-N-methyl-3- (1-naphthylenyloxy)-3-(2-thienyl)
propanamine oxalic acid salt (duloxetine oxalate salt)
Duloxetine free base (38 gm) was dissolved m ethyl acetate (650 ml) and 1 mole equiv of
oxalic acid was added to the solution The reaction mass was kept under stirring at 50-60°C
for 1 hour and then at room temperature for 2-3 hours Solid obtained was filtered, washed
with ethyl acetate and dried under reduced pressure to give duloxetine oxalate salt Yield 44
gm
Example 11: Preparation of duloxetine hydrochloride salt (1)
Duloxetine free base (35 gm) was dissolved in ethyl acetate (500 ml) and the resulting
solution was cooled to 5-10°C To this solution was added to ethyl acetate-HCl solution
(about 12%) dropwise in 10-15 minutes Slowly white solid started to precipitate out
Addition of ethyl acetate-HCl solution was continued till the pH of slurry reached between 2-
3 The thick slurry mass was stirred at 15-20°C for one hour Solid was filtered, washed with
ethyl acetate and dried under reduced pressure at 45-50°C Yield 35 3 gm, chemical purity.
99 8% (by HPLC) and chiral purity 99.95%(by HPLC)
Example 12: Preparation of duloxetine hydrochloride salt (1)
Duloxetine free base (10 gm) was dissolved in isopropyl acetate (100 ml) and cooled to 5-
10°C To this solution isopropyl alcohol-HCl solution (about 15%) was added dropwise till
pH was between 2-3 The resulting thick slurry stirred at 15-20°C for two hours Solid was
filtered, washed with isopropyl acetate (20 ml), dried under reduced pressure at 45-50°C
Yield 8 2 gm; chemical purity 99.8% (by HPLC) and chiral purity 99.95%

Example 13: Purification of duloxetine hydrochloride (1)
Duloxetine hydrochloride (115 gm) was suspended in mixture of cyclohexane (350 ml) and
water (575 ml) The biphasic mass was treated with aqueous ammonia (pH 12 5 -13 0).
Organic layer was separated, washed with water and concentrated under reduced pressure to
afford the oily mass (100 gm) This oily mass was dissolved in ethyl acetate (1800 ml) and
solution was cooled to 5-10°C A solution of HC1 in ethyl acetate (10-15% strength) was
added till the pH is 5 5-6 0. The thick slurry was maintained under stirring Solid obtained
was filtered, washed with ethyl acetate (150 ml) and dried under reduced pressure to obtain
pure duloxetine hydrochloride as white solid. Yield: 100 gm and chiral purity 99 93%
Example 14: Purification of duloxetine hydrochloride (1) by crystallization from mixture of
ethyl acetate and methanol
Duloxetine hydrochloride (100 gm) was suspended in mixture of ethyl acetate (600 ml) and
methanol (50 ml) The mixture was heated to 60-65°C and stirred for 1 hour The slurry was
then cooled to room temperature and stirred for 2 hours The solid obtained was filtered,
washed with ethyl acetate (2 x 100 ml) and dried under reduced pressure for 10-12 hours.
Pure duloxetine hydrochloride was obtained as off white colored solid Yield. 90 gm
Example 15: Purification of duloxetine hydrochloride (1) by crystallization from mixture of
acetone and methanol
Duloxetine hydrochloride (50 gm) was added to mixture of acetone (200ml) and methanol
(25 ml) at 25-35°C The slurry was heated to 55-60°C and stirred for 30 minutes Cooled to
25-35°C, stirred for 15-20 minutes and again cooled to 5-10°C and stirred for 2 hours Solid
was filtered, washed with acetone (50 ml), ethyl acetate (2 x 100 ml) and dried under reduced
pressure at 45°C for 10 hours to get 43 g of white to off white solid having purity 99 92% by
HPLC

Example 16: Purification of duloxetine hydrochloride (1) by crystallization from mixture of
acetone, ethyl acetate and methanol
Duloxetine hydrochloride (50 gm) was added to mixtuie of acetone (200ml), ethyl acetate
(100 ml) and methanol (25 ml) at 25-35°C The slurry was heated to 55-60°C and stirred for
30 minutes Cooled to 25-35°C stirred for 15-20 minutes and again cooled to 5-10°C and
stined for 2 hours Solid was filtered, washed with acetone (50 ml), ethyl acetate (2 x 100
ml) and dried under reduced pressure at 45°C for 10 hours to get white to off white solid.
Yield 43 gm and purity 99 92% by HPLC
Example 17: Purification of duloxetine hydrochloride (1) by crystallization from mixture of
acetone, ethyl acetate and methanol
Duloxetine hydrochloride (50 gm) was added to mixture of ethyl acetate (300 ml), methanol
(25 ml) and acetone (25 ml) at 25-35°C The slurry was heated to 55-60°C and stirred for 30
minutes Cooled to 25-35°C stirred for 15-20 minutes and again cooled to 5-10°C and stirred
for 2 hours Solid was filtered, washed with acetone (50 ml), ethyl acetate (2X 100 ml) and
dried under reduced pressure at 45°C for 10 hours to get white to off white solid Yield 45
gm and purity 99 9% by HPLC
Example 18: Process for racemization of (R)-(-) - N, N-dimethyl-3-(1-naphthalenyloxy)-3-
(2-thienyl) propanamine (6b) to obtain racemic (RS)-N, N-dimethyl-3-(1-naphthalenyloxy)-
3-(2-thienyl) propanamine (6a + 6b)
The ethyl acetate solution (mother liquor from resolution step, examples 3 and 4) that is
enriched with R isomer, (R)-(-)-N, N-dimethyl-3- (1-naphthalenyloxy)-3-(2-thienyl)
propanamine (6b) was concentrated under reduced pressure to obtain thick oily mass Thick
oily mass was dissolved in toluene (120 ml) To the solution water (60 ml) was added and pH
of biphasic system was adjusted tolOO -10 5 with caustic lye solution Toluene layer was
separated, washed with water and concentrated to afford oily residue (30 gm) The oily
residue was again dissolved in toluene (150 ml) having moisture content less than 0 2% and
to this solution dimethyl sulfoxide (75 ml) was added To this mixture solution of potassium

bis(trimethylsilyl)amide (15% solution in toluene) (63.8 gm) was added. Temperature was
slowly raised to 50-60°C and maintained under stirring for 4-6 hours. Reaction mass was
cooled to room temperature and water (250 ml) was added. Stirred for 15 minutes and
separated the organic layer. Organic layer was washed with water and concentrated under
reduced pressure to get racemic condensed compound, (R,S)-N, N-dimethyl-3-(1-
naphthalenyloxy)-3-(2-thienyl) propanamine (6a + 6b) as an oily mass. Yield: 30 gm.

WE CLAIM :
i
1. A novel process for synthesis of duloxetine hydrochloride of formula (1)

1
having chiral purity of greater than 99.9% comprising steps of:
i) reaction of (RS)-N.N-di methyl-3-hydroxy-3-(2-thienyl)propanamine (2, racemic hydroxy
compound) of formula (2)

with 1-fluronaphthalene of formula (3)
J
in aprotic polar organic solvent in presence of a base selected from sodamide, potassium
amide, potassium bis(tnmethylsilyl)amide to obtain (RS)-N.N-di methyl-3-(1-
naphthyloxy)-3-(2-thienyl)propanamine of formula (4) (racemic condensed compound)


n) optionally isolation of racemic condensed compound as acid addition salt of organic or
inorganic acid of formula (5),

iii) conversion of acid salt (5) to free base (R,S)-N.N-di methyl-3-(1-naphthyloxy)-3-(2-
thienyl)propanamine of formula (6a + 6b)

by treatinent with organic or inorganic base in aqueous or organic or mixture of aqueous
and water immiscible organic solvent,

iv) optical resolution of racemic condensed compound free base (6a + 6b) with dibenzoyl-L-
tartanc acid (formula 7, R = H, DBTA) or di-p-anisoyl-L-tartaric acid (7, R = OCH3, DATA)

is carried out in organic solvent selected from aromatic hydrocarbon such as benzene,
toluene, xylene; lower alcohols such as methanol, ethanol, isopropanol; lower aliphatic
ketones such as acetone, methyl ethyl ketone, diethyl ketone; aliphatic esters such as
ethyl acetate, propyl acetate, isopropyl acetate; ethers such as dnsopropyl ether, tert-
butyl methyl ether; acetonitrile or mixtures thereof to get crude corresponding (S)-isomer
tartarate salt of formula3a or 9a,

v) optionally purification of (S)-isomer tartarate salt (8a or 9a) by crystallization from a
suitable organic solvent or mixture of two or more solvents,
vi) conversion of (S)-isomer tartarate salt (8a or 9a) to free base (S)-N.N-di methyl-3-(1-
naphthyloxy)-3-(2-thienyl)propanamine of formula 6a


by treatinent with orgamic or inorganic base in aqueous or organic or mixture of aqueous
and water immiscible organic solvent,
vii) demethylation of free base (6a) by treatinent with phenyl chloroformate in presence of
dnsopropylethyl amine in toluene to get carbamate intermediate of formula 10,

viii) hydrolysis of carbamate intermediate (10) with sodium hydroxide in polar aprotic solvent
to give duloxetine base of formula 11,

ix) conversion of duloxetine base (11) to duloxetine hydrochloride (1) in an organic solvent
or mixture of organic solvents, and
x) optionally purification of duloxetine hydrochloride (1) by crystallization.
2. The process as claimed in claim 1, wherein the aprotic solvent used in step (i) is selected from
dimethyl sulfoxide, sulfolane, dimethyl formamide, dimethyl acetamide, N-methylpyrohdine-2-
one, preferably dimethyl sulfoxide.
3. The process as claimed in claim 1, wherein the reaction is carried out at temperature room
temperature to 150°C, preferably at 70-100°C, most preferably at 80-90°C.

4. The process as claimed in claim 1, wherein the reaction is carried out in presence of sodamide as
preferred base.
5. The process as claimed in claim 1, wherein the reaction is carried out with molar ratio of
racemic hydroxy compound (2) to base in the range from 1: 1 to 1: 5, preferably 1:1.5.
6 The process as claimed in claim 1, wherein the (RS)-N.N-di methyl-3-(1-naphthyloxy)-3-(2-
thienyl)propanamine of formula 4 (racemic condensed compound)

isolated as acid addition salt of formula 5

of organic or inorganic acid, such as hydrochloric acid, sulfuric acid, phosphoric acid,
methanesulfonic acid, p-toluenesulfonic acid, oxalic acid, maleic acid, succinic acid benzoic acid
and acetic acid, the most preferred acid is oxalic acid.
7. The process as claimed in claim 1, wherein the step (iii) is carried out by treating the acid salt of
formula 5


with base such as aqueous ammonia in mixture of organic solvent such as cyclohexane and
water.
8. The process as claimed in claim 1, wherein the solvent employed in step (iv) for optical resolution
is selected from aromatic hydrocarbon such as benzene, toluene, xylene; lower alcohols such as
methanol, ethanol, isopropanol; lower aliphatic ketones such as acetone, methyl ethyl ketone,
diethyl ketone; aliphatic esters such as ethyl acetate, propyl acetate, isopropyl acetate; ethers
such as dnsopropyl ether, tert.-butyl methyl ether; acetonitrile or mixtures thereof.
9. The process as claimed in claim 8, wherein the most preferred solvent for the resolution when
DATA is used as resolving agent is toluene, ethyl acetate, isopropyl acetate, acetone or mixtures
thereof.
10. The process as claimed in claim 8, wherein the most preferred solvent for the resolution when
DBTA is used as resolving agent is ethyl acetate and methanol.
11. The process as claimed in claim 10, wherein the ratio of ethyl acetate: methanol in the solvent
mixture is in the range from 99.9: 0.1 to 0.1: 99.9 (v/v), preferably 90:10 to 10:90 (v/v), most
preferably 95:5 (v/v).
12. The process as claimed in claim 9 or 10, wherein the optical resolution is carried out with molar
ratio of racemic condensed compound (6a + 6b) to resolving agent DBTA or DATA is in the range
1:0.1 to 1:10, more preferably 1:0.5 to 1:1.2, most preferably 1:0.9 to 1:1.1.

13. The process as claimed in claim 9 or 10, wherein the optical resolution is carried out at a
temperature of 10-70°C, more preferably at 2Q-30°C.
14. The process as claimed in claim 1, wherein the step (v) of optionally purification of tartarate salt
of (S)-isomer (8a or 9a) by crystallization is carried out from solvent selected from lower alcohols
such as methanol, ethanol, isopropanol; lower aliphatic ketones such as acetone, methyl ethyl
ketone, diethyl ketone; aliphatic esters such as ethyl acetate, propyl acetate, isopropyl acetate;
ethers such as dnsopropyl ether, tert.-butyl methyl ether; acetonitrile or mixtures thereof,
preferably mixture of methanol and ethyl acetate.
15. The process as claimed in claim 14, wherein the ratio of methanol to ethyl acetate is 1:90 to
90:1, preferably 1:1 to 1:10 (volume/volume).

16. The process as claimed in claim 15, wherein the crystallization is carried out with the ratio of
substrate to solvent in the range from 1:1 to 1:30, preferably from 1:5 to 1:15 (weight by
volume).
17. The process as claimed in claim 16, wherein the crystallization is carried out by heating the
reaction mixture to get clear solution, preferably up to reflux temperature of the solvent and then
allowing the solution to cool to room temperature.
18. The process as claimed in claim 1, wherein the step (vi) is carried out by treating the tartarate
salt (8a or 9a) with base such as aqueous ammonia in mixture of organic solvent such as
dichloromethane and water.
19. The process as claimed in claim 1, wherein the step (vii) is carried out by treatinent of (S)-isomer
of condensed compound (6a) with phenyl chloroformate in presence of dnsopropyl amine base in
toluene as solvent.
20. The process as claimed in claim 1, wherein the step (viii) is carried out with sodium hydroxide in
polar aprotic solvent selected from dimethyl sulfoxide, sulfolane, dimethyl formamide, dimethyl
acetamide, N-methylpyrolidine-2-one, preferably in dimethyl sulfoxide.
21. The process as claimed in claim 1, wherein the step (ix) is carried out with solution of 10-20%
hydrochloric acid in an organic solvent.
22. The process as claimed in claim 21, wherein the solvent is selected from lower aliphatic ketones
such as acetone, methyl ethyl ketone, diethyl ketone; aliphatic esters such as ethyl acetate,
propyl acetate, isopropyl acetate; ethers such as dnsopropyl ether, tert.-butyl methyl ether;
acetonitrile or mixtures thereof, the most preferred solvent is ethyl acetate and isopropyl acetate.
23. The process as claimed in claim 22, wherein the reaction is carried out at pH in the range 1-6,
preferably in the range 2-3.

24. The process as claimed in claim 23, wherein the reaction is carried out at 0-50°C, preferably at
10-20°C.
25. The process as claimed in claim 1, wherein the step (x) of purification of duloxetine hydrochloride
by crystallization comprises of:
i) adding crude duloxetine hydrochloride to a solvent selected from alcohols, such as methanol,
ethanol, n- propanol, isopropanol; ketones, such as acetone, methyl ethyl ketone; esters,
such as methyl acetate, ethyl acetate, ethyl formate, propyl acetate or a mixtures thereof,
n) heating the mixture to obtain clear solution,
in) cooling the solution, and
iv) isolation of solid.

26. The process as claimed in claim 25, wherein the preferred solvent for crystallization of duloxetine
hydrochloride is a mixture of ethyl acetate and methanol or acetone and methanol or ethyl
acetate, acetone and methanol.
27. The process as claimed in claim 26 wherein the ratio of duloxetine hydrochloride to the solvent is
in the range 2-10 times (weight by volume), preferably 4 to 7 times (weight by volume).
28. The process as claimed in claim 27, wherein the heating is performed at temperature in the
range 40 °C to reflux temperature of the mixture, most preferably at 50-60 °C.
29. The process as claimed in claim 28, wherein the crystalline solid is isolated either by evaporation
or by filtration.

ABSTRACT

NOVEL PROCESS FOR PREPARATION OF DULOXETINE HYDROCHLORIDE
An improved, safer and easy to operate on plant scale process for synthesis of duloxetine
hydrochloride (1) having chiral purity greater than 99 9% that is characterized by the
following
(l) preparation of racemic condensed compound (RS)-N,N-di methyl-3- (1-
naphthyloxy)-3-(2-thienyl)propanamine (4) by reaction of racemic hydroxy
compound (2) with 1-fluronaphthalene (3) in presence of a base such as sodamide,
potassium amide or potassium bis(tnmethylsilyl)amide (KHDMS) in polar aprotic
solvent,
(n) optical resolution of racemic condensed compound (5a + 5b) with di-benzoyl-L-
tartanc acid (7, DBTA, R = H) or di-para-anisoyl-L-tartanc acid (7, DATA, R =
OCH3) to obtain crude (S)-N N-dimethyl-3-(1-naphthyloxy)-3-(2-
thienyl)propanamine dibenzoyl tartarate salt (8a) or (S)-N.N-dimethyl-3-(1-
naphthyloxy)-3-(2-thienyl)propanamine di-p-anisoyl tartarate salt (9a) respectively,
(iii) optionally purification of crude tartarate salts (8a or 9a) by crystallization,
(IV) optionally purification of duloxetine hydrochloride (1) by crystallization and
(v) racemization of undesired (R)-N,N-di methyl-3-(1-naphthyloxy)-3-(2-
thienyl)propanamine (5b) by treatinent with base potassium bis(tnmethylsilyl)amide
(KHDMS) to obtain racemic mixture of condensed compounds (5a and 5b)
A novel salt S(+)-N N-dimethyl-3-(1-naphthylenyloxy)-3-(2-thienyl)propanamine dibenzoyl
-(L)- tartarate (8a) and S(+)-N N-dimethyl-3-(1-naphthylenyloxy)-3-(2-thienyl)propanamine
di-p-anisoyl-(L)- tartarate (9a).
Novel process for racemization of undesired (R)-N,N-di methyl-3-(1-naphthyloxy)-3-(2-
thienyl)propanamine (5b) by treatinent with KHDMS to obtain racemic mixture condensed
compounds (5 a and 5 b)