FIELD OF THE INVENTION
The present invention provides an improved process for the preparation of highly pure duloxetine hydrochloride of formula-I:(Formula Removed)

The present invention also aims at providing a process for the purification of duloxetine hydrochloride for the removal of R-enantiomer impurity.
BACKGROUND OF THE INVENTON
Duloxetine hydrochloride of formula I, is marketed as 'cymbalta' by Eli Lilly and is
FORMULA I(Formula Removed)
chemically known as (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine hydrochloride,. Duloxetine belongs to a class of medicines called serotonin and norepinephrine reuptake inhibitors (SNRIs), and has been found to have application for the treatment of stress urinary incontinence (SUI), depression and pain management. It works by increasing the amounts of serotonin and
norepinephrine, natural substances in the brain that help maintain mental balance and stop the movement of pain signals in the brain.
Duloxetine and its pharmaceutical acceptable acid addition salts were first disclosed in U.S. patent No. 5,023,269. This patent discloses a process for the preparation of duloxetine which comprises converting 2-acetylthiophene to 3-dimethylamino-l-(2-thienyl)-l-propanone hydrochloride under Mannich reaction conditions, reducing the same to corresponding alcohol, and converting it to N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine by reacting with 1-fluoronaphthalene in the presence of sodium hydride. N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine is converted to the carbamate intermediate by reaction with phenyl chloroformate or trichloroethyl chloroformate. The carbamate intermediate is hydrolyzed with base to afford duloxetine free base. This patent further exemplifies the isolation of duloxetine base as its oxalate salt and crystallization of the same from ethyl acetate and methanol to yield duloxetine oxalate. Patent is completely silent about the chiral purity of the final product. (Formula Removed)
US patent no. 5,362,886 discloses a stereo specific process for the preparation of duloxetine hydrochloride, wherein (S)-(-)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine is reacted with 1-fluoronaphthalene in the presence of sodium
hydride, a potassium compound preferably potassium benzoate or potassium acetate, and in an organic solvent to form (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thieny1)propanamine that is isolated as its phosphoric acid salt. The patent further discloses the demethylation of the latter to form duloxetine base that is further converted to its hydrochloride salt. It is disclosed that duloxetine hydrochloride prepared by the above process is found to contain R-enantiomer having formula II, as impurity in more than 0.35% even after recrystallization.
FORMULA II(Formula Removed)
U.S. application no. 2006/0276660 discloses a process for the purification of duloxetine hydrochloride by crystallizing duloxetine hydrochloride from solvent selected from C3-8 ketone, C2-8 esters, C2-8 ethers, C2-8 alcohols, and mixture thereof with water to reduce impurities namely R-enantiomer and (+)-N-methyl-3-(l-naphthalenyloxy)-3-(3-thienyl)propanamine (DLX-ISO3). However over all yield during purification has reduced up to 7-8%, which is very low and may leads to increase in cost and hence making the process unattractive for commercial scale.
PCT application no. WO 2007/077580 discloses a process for the preparation of duloxetine hydrochloride which comprises reacting 2-acetylthiophene with dimethylamine hydrochloride followed by purifying and reducing the resulting ketone intermediate to N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine. The same compound is resolved with a chiral acid, purified, and treated with weak inorganic
base. The compound so formed is reacted with 1-fluoronaphthalene in the presence of alkaline base, and in situ treatment with oxalic acid to give duloxetine oxalate and converting the same into duloxetine hydrochloride. Conversion of duloxetine oxalate salt to hydrochloride salt is effected using ethyl acetate hydrochloride, methanolic hydrochloride, isopropyl alcohol hydrochloride, in a suitable solvent like alcohol or ester. The patent application also discloses a process for the purification of duloxetine hydrochloride from solvents including ester, alcohol, or mixture thereof.
The presence of a therapeutically inactive enantiomer, R-enantiomer in duloxetine hydrochloride or any active pharmaceutical ingredient results in contamination of the main product, and reduces the yield by being a waste product and in extreme cases, might even be harmful to a patient being treated with a dosage form of the active pharmaceutical ingredient. The ICH Q7A guidance for active pharmaceutical ingredient manufacturers requires that such impurities be maintained below set limits.
The prior art provides processes for the purification of duloxetine hydrochloride wherein value of R-enantiomer in final product is reduced from 2-3% to nearly 0%.
There is a need in the art to develop a process for the preparation of the S-enantiomer of duloxetine substantially free of the R-enantiomer wherein the value of R-enantiomer in final product is reduced from more than 2% and preferably more than 3% to acceptable levels to comply with the pharmacopoeial requirements in a facile manner.
Present invention describes an improved, industrially applicable, facile, and reproducible process for the preparation and purification of duloxetine hydrochloride, which will enhance the purity, reducing the level of unwanted R-enantiomer from even 22% to 0.05% or nearly 0%.
SUMMARY OF INVENTION
The present invention provides an industrially advantageous process for the preparation of highly pure duloxetine hydrochloride of formula-1,
FORMULA I(Formula Removed)
which comprises:
a) treating duloxetine with suitable acid to prepare duloxetine acid addition salt,
b) converting duloxetine acid addition salt to duloxetine hydrochloride, and
c) purifying duloxetine hydrochloride.
Another aspect of the present invention provides a process for the purification of duloxetine hydrochloride by using suitable solvent preferably C1-5 alkylnitrile, or C1-5 alkylnitrile in mixture with solvent selected from a C2-8 ether, a C5-8 aliphatic or C6-12 aromatic hydrocarbon, C2-5 ketone, C 2-5 alkyl ester and halogenated hydrocarbons, straight chain or branched C1-8 aliphatic alcohol, tetrahydrofuran, dimethylsulfoxide, dimethylforamide, N-methylpyrrolidine and sulfolane.
DETAILED DESCRIPTION OF THE INVENTION
As used herein "Crystallization" refers to the formation of solid crystals from a homogeneous solution. It is essentially a solid-liquid separation technique. This process comprises: heating the product in a solvent to a temperature of between room temperature to reflux temperature of the solvent to obtain a solution, and cooling the solution to a room temperature.
As used herein "crude duloxetine hydrochloride " refers to duloxetine hydrochloride containing R-enantiomer as an impurity. The percentage of R-enantiomer is measured by chiral high performance liquid chromatography (HPLC). The percentage of R-enantiomer in the crude duloxetine hydrochloride ranges from 2.0 to 22.0%. Crude duloxetine hydrochloride can although synthetically be prepared by following prior art methods or by adding racemic duloxetine hydrochloride or by adding R-enantiomer of duloxetine hydrochloride obtained by concentrating the mother liquor of impure duloxetine hydrochloride.
The present invention provides enantiomerically pure duloxetine hydrochloride. "Enantiomeric purity" of duloxetine hydrochloride depends upon the level of its R-enantiomer, chemically known as (R)-(-)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine hydrochloride, having formula II:
(Formula Removed)

One embodiment of the present invention provides a process for the preparation of highly pure duloxetine hydrochloride of formula I from duloxetine free base via its other acid addition salts.

Specifically, duloxetine free base is dissolved in a suitable solvent preferably ethyl acetate followed by the addition of suitable acid. The reaction mixture is stirred for

few minutes to few hours at a suitable temperature till the completion of the reaction. Preferably, the reaction mixture is stirred for 1-3 hours at about ambient temperature, filtered and dried to afford duloxetine acid addition salt.
Preferred acid addition salts commonly employed include those formed with organic acid selected from C1-10 aliphatic carboxylic acid, aryl carboxylic acid, hetero-aryl carboxylic acid, aryl alkyl carboxylic acid, oxalic acid, citric acid, maleic acid, formic acid, fumaric acid, acetic acid; inorganic acid like hydrobromic acid, hydroiodic acid. Particularly oxalic acid and fumaric acid are employed.
In one embodiment, the present invention describes the process for the preparation of duloxetine hydrochloride from duloxetine free base via its other acid addition salt using hydrochloric acid in the absence of organic solvent. Particularly duloxetine acid addition salt in water is treated with hydrochloric acid to prepare duloxetine hydrochloride. After completion of reaction duloxetine hydrochloride is extracted in non-polar organic solvent immiscible with water. The product can be isolated by conventional methods like spray drying, evaporation, vacuum drying and the like.
Non-polar organic solvents can be selected from chlorinated hydrocarbons like
dichloromethane, dichloroethane, chloroform, carbon tetrachloride; aromatic hydrocarbons like benzene, ethylbenzene, toluene, xylene; cyclic and acyclic hydrocarbons like pentane, hexane, heptane, cyclohexane; ethers like diethyl ether, isopropyl ether, methyl tert-butyl ether; esters like ethyl acetate, butyl acetate, methyl acetate; the preferred being dichloromethane.
In another embodiment, the present invention describes the process for the preparation of duloxetine hydrochloride from duloxetine free base via its other acid addition salt using hydrochloride salt of base in protic solvent.
Specifically, duloxetine free base is dissolved in a suitable solvent selected from ethyl acetate, CM alcohol, followed by the addition of suitable acid. The reaction mixture is stirred for few hours to few minutes at a suitable temperature till the completion of the reaction. Preferably, the reaction mixture is stirred for 1-3 hours at about ambient temperature, filtered and dried to afford duloxetine acid addition salt.
Duloxetine acid addition salt is further refluxed with hydrochloride salt of suitable base in a protic solvent. Suitable base can be selected from ammonia, N,N-dimethylamine, pyridine and the like. Protic solvent can be selected from water, C1-6 alcohol like methanol, ethanol, specifically methanol. The reaction mixture is then cooled to ambient temperature and protic solvent is distilled off under vacuum. The product is then extracted with non polar organic solvent immiscible with water. The non polar organic solvent is same as discussed above. The product can be isolated by conventional methods like spray drying, evaporation, vacuum drying, and the like.
The starting material, duloxetine free base can be prepared by the conventional procedures reported in prior art in patents such as U.S. Patent Nos. 5,023,269, 5,362,886, or as described and exemplified in the context of the present invention. Typically, a solution of (S)-(+)-N,N-dimethyl-3 -(1 -naphthalenyloxy)-3 -(2-thienyl) propanamine in an inert solvent like toluene is treated with of phenyl chloroformate in the presence of diisopropylethylamine to prepare (S)-(+)-[N-Methyl-[3-(l-naphthalenyloxy)-3-(2-thienyl)propyl] carbamic acid]phenyl ester. The resulting carbamic acid phenyl ester is converted to duloxetine by treatment with suitable base particularly alkali metal hydroxide in an inert solvent like toluene.
Another embodiment of the present invention provides a process for the purification of crude duloxetine hydrochloride for the removal of unwanted R-enantiomer to afford highly pure duloxetine hydrochloride.
Specifically, crude duloxetine hydrochloride, is crystallized in C1-5 alkylnitrile, or a mixture of alkylnitrile with solvent selected from a C5-8 ether, a C5-8 aliphatic or C6-12 aromatic hydrocarbon, C1-8 ester C3-10 ketone, and halogenated hydrocarbons, straight chain or branched C1-8 aliphatic alcohol, tetrahydrofuran, dimethylsulfoxide, dimethylforamide, N-methylpyrrolidine, and sulfolane. Preferably the solvent is acetonitrile, propionitrile, toluene, methylisobutyl ketone, diisopropyl ether, ethyl acetate. Typically, crude duloxetine hydrochloride in the suitable solvent is heated to the reflux temperature of the solvent till a clear solution is obtained for a time sufficient to obtain highly pure duloxetine hydrochloride having purity greater than 99% by HPLC, wherein the ratio of R-enantiomer is found to be less than 0.15%, more preferably less than 0.05%.
The crystallization process may be repeated in order to increase the purification even further either with the same or a different solvent or solvent mixture that is used for the first crystallization.
Major advantages realized in the present invention is that duloxetine hydrochloride obtained by processes of the present invention is highly pure, wherein the level of unwanted R-enantiomer is reduced from more than 2% or as high as 22% to nearly 0%.
Although, the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of the invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples. It is intended that the specification, including the examples, is considered exemplary only, with the scope and spirit of the invention being indicated by the claims which follow.
EXAMPLES
Reference Example 1: Preparation of duloxctine hydrochloride
A solution of (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine (25g) in toluene (125ml) was heated to reflux and azeotroped under stirring for 1 hour. The temperature was lowered to 35-40°C, diisopropylethylamine (11.4 g) followed by phenylchloroformate (18.85 g) were added and stirred at 30-35°C for 1 hour. The reaction mass was washed with 1N hydrochloric acid (50ml), demineralised water (50ml), 5% ammonium hydroxide (50ml) and finally with demineralised water (50ml). Toluene was distilled off under reduced pressure to give (S)-(+)-(N-Methyl-[3-(l-naphthalenyloxy)-3-(2-thienyl)propyl]carbamic acid]phenyl ester. This compound was added to a pre-azeotroped suspension of potassium hydroxide (13.5 g) in toluene (168ml) and again refluxed and azeotroped for 2 hours. The reaction mass was cooled to 25-30°C and washed with water. The organic layer was extracted with hydrochloric acid. The above hydrochloric acid solution was further extracted with dichloromethane. The dichloromethane solution was concentrated in vacuum to obtain 23g of crude title compound having purity of 93.17 % by HPLC containing 7 % R-enantiomer.Reference Example 02: Preparation of duloxetine hydrochloride
A solution of (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine (75.0 g) in toluene (375ml) was heated to reflux and azeotroped under stirring for 1 hour. The temperature was lowered to 35-40°C, diisopropylethylamine (34.2g) followed by phenylchloroformate (56.6g) were added and stirred at 30-35°C for 1 hour. The reaction mass was washed with 1N hydrochloric acid (150ml), demineralised water (150ml), 5% ammonium hydroxide (150ml) and finally with demineralised water (150ml). Toluene was distilled off under reduced pressure to give (S)-(+)-[N-Methyl-[3-(l-naphthalenyloxy)-3-(2-thienyl)propyl]carbamic acid] phenyl ester. This compound was added to a pre-azeotroped suspension of potassium hydroxide (54g) in toluene (500ml) and again refluxed and azeotroped for 2 hours.
The reaction mass was cooled to 25-30°C and washed with water. The organic layer was extracted with hydrochloric acid. The above hydrochloric acid solution was extracted further with dichloromethane. The dichloromethane solution was concentrated in vacuum to obtain 68.3g of crude title compound having purity of 91.32% by HPLC containing 7.2% R-enantiomer.
Reference example 03: Preparation of duloxetine free base
A solution of (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine (50.0g) in toluene (300ml) was heated to reflux and azeotroped under stirring for 1 hour. The temperature was lowered to 35-40°C, diisopropylethylamine (22.8g) followed by phenylchloroformate (37.7g) were added and stirred at 30-35°C for 1 hour. The reaction mass was washed with IN hydrochloric acid (100ml), demineralised water (100ml), 5% ammonium hydroxide (100ml) and finally with demineralised water (100ml). Toluene was distilled off under reduced pressure to obtain compound (S)-(+)-[N-Methyl-[3-(l -naphthalenyloxy)-3-(2-thienyl)propyl] carbamic acid]phenyl ester. This compound was added to a pre-azeotroped suspension of potassium hydroxide (27g) in toluene (336ml) and again refluxed and azeotroped for 2 hours. The reaction mass was cooled to 25-30°C and washed with water. The organic layer was distilled off in vacuum to obtain 46 g of crude duloxetine free base having purity of 90.0% by HPLC containing 7% R-enantiomer.
Example 01: Preparation of duloxetine hydrochloride (I) Preparation of duloxetine oxalate
Duloxetine free base (23.0 g), containing 7% R-enantiomer was dissolved in ethyl acetate (46ml) and then solution of oxalic acid (9.8g) in ethyl acetate (69ml) was added. Stirred for 1 hour at 25-30°C. Filtered and dried the solid to obtain 27g of duloxetine oxalate having purity of 94.51% by HPLC.
(II) Preparation of duloxetine hydrochloride
A solution of duloxetine oxalate salt prepared above, in water (27ml), 2N hydrochloric acid (54ml) was stirred for 30 minutes. After completion of reaction, dichloromethane (135ml) was added. The layers were separated and the organic was washed with brine (saturated aqueous sodium chloride solution).Organic layer was concentrated in vacuum to obtain 21.0g of crude title compound having purity of 94.77% by HPLC containing 6.4% R-enantiomer.
(III) Purification of duloxetine hydrochloride
Method A:
A mixture of duloxetine hydrochloride (l.Og, HPLC purity: 94.77%, containing 6.4% R-enantiomer), toluene (4.5ml) and acetonitrile (0.5ml) was heated to 90-95°C, followed by stirring at 25-30°C for 2 hours. The solid was filtered and dried in a vacuum oven, to obtain 0.8g of duloxetine hydrochloride having purity of 97.78% by HPLC containing 3.2% R-enantiomer.
A mixture of duloxetine hydrochloride (0.8g, containing 3.2% R-enantiomer) in 5.5ml acetonitrile was heated to reflux to clear solution, followed by stirring at 25-30°C for 3 hours. The solid was filtered and dried in a vacuum oven to afford 0.52g of duloxetine hydrochloride having purity of 99.55% by HPLC containing 0.01% R-enantiomer.
Method B:
A mixture of duloxetine hydrochloride (l.Og, HPLC purity : 94.77% containing 6.4% R-enantiomer), toluene (4ml) and acetonitrile (1ml) was heated to 90-95°C, followed by stirring at 25-30°C for 2 hours. The solid was filtered and dried in a vacuum oven, to obtain 0.65g of duloxetine hydrochloride having purity of 99.58% by HPLC containing 0.85% R-enantiomer.
The resulting compound in acetonitrile (4.5ml )was heated to reflux to obtain clear solution, followed by stirring at 25-30°C for 3 hours. The solid was filtered and dried
in a vacuum oven to afford 0.50g of duloxetine hydrochloride having purity of 99.65% by HPLC containing 0.02% R-enantiomer.
Method C:
A mixture of duloxetine hydrochloride (l.0g, HPLC purity : 94.77% containing 6.4% R-enantiomer), toluene (2.5ml) and acetonitrile(2.5ml ) was heated to 80-95°C till complete dissolution, followed by stirring at 25-30°C for 2 hours. The solid was filtered and dried in a vacuum oven, to obtain 0.4g of duloxetine hydrochloride having purity of 99.51% by HPLC containing 0.6% R-enantiomer. A mixture of duloxetine hydrochloride (0.4g, containing 0.6% R-enantiomer) in acetonitrile (2.7ml) was heated to reflux to obtain clear solution, followed by stirring at 25-30°C for 3 hours. The solid was filtered and dried in a vacuum oven to afford 0.26g of duloxetine hydrochloride having purity of 99.58% by HPLC containing 0.05% R-enantiomer.
Method D:
A mixture of duloxetine hydrochloride (l.Og, HPLC purity: 94.77% containing 6.4% R-enantiomer), diisopropyl ether (2.5ml) and acetonitrile (2.5ml) was heated to reflux, followed by stirring at 25-30°C for 2 hours. The solid was filtered and dried in a vacuum oven, to obtain 0.75g of duloxetine hydrochloride having purity of 97.86% by HPLC containing 3.4% R-enantiomer.
A mixture of duloxetine hydrochloride (0.75g, containing 3.4% R-enantiomer) in acetonitrile (5.5ml) was heated to reflux to obtain clear solution, followed by stirring at 25-30°C for 3 hours. The solid was filtered and dried in a vacuum oven to afford 0.48g of duloxetine hydrochloride having purity of 99.55% by HPLC containing 0.02% R-enantiomer.
Method E:
A mixture of duloxetine hydrochloride (l.0g, HPLC purity: 94.77% containing 6.4% R-enantiomer), methyl iso-butyl ketone(4.95ml) and acetonitrile (0.05ml) was heated to 90-95°C, followed by stirring at 25-30°C for 2 hours. The solid was filtered and dried in a vacuum oven, to afford 0.82g of duloxetine hydrochloride having purity of 98.51% by HPLC containing 3.35% R-enantiomer.
A mixture of Duloxetine hydrochloride (0.82g, containing 3.35% R-enantiomer) in acetonitrile (5.8ml) was heated to reflux to obtain clear solution, followed by stirring at 25-30°C for 1 hour. The solid was filtered and dried in a vacuum oven to afford 0.55g of duloxetine hydrochloride having purity of 99.55% by HPLC containing 0.02% R-enantiomer.
Method F:
A mixture of duloxetine hydrochloride (2.5g, HPLC purity: 94.77% containing 6.4% R-enantiomer), methyl iso-butyl ketone(9.5ml) and acetonitrile(0.5ml) was heated to 90-95°C, followed by stirring at 25-30°C for 2 hours. The solid was filtered and dried in a vacuum oven, to obtain 2.0g of duloxetine hydrochloride having purity of 99.60% of HPLC containing 4% R-enantiomer.
A mixture of duloxetine hydrochloride (l.Og, HPLC purity 99.60%containing 4% R-enantiomer), propionitrile (6 ml) was heated to reflux, followed by stirring at 25-30°C for 3 hours. The solid was filtered and dried in a vacuum oven, to obtain 0.65g of duloxetine hydrochloride containing 0.56% R-enantiomer.
Method G:
A mixture of duloxetine hydrochloride (l.Og, HPLC purity: 94.77% containing 6.4% R-enantiomer), ethyl acetate (4.75ml) and acetonitrile (0.25ml) was heated to reflux, followed by stirring at 25-30°C for 2 hours. The solid was filtered and dried in a vacuum oven, to obtain 0.6g of duloxetine hydrochloride having purity of 98.54% by HPLC containing 2.8% R-enantiomer.
A mixture of duloxetine hydrochloride (0.6g, containing 2.8% R-enantiomer) in acetonitrile (4.5ml) was heated to reflux to obtain clear solution, followed by stirring at 25-30°C for 3 hours. The solid was filtered and dried in a vacuum oven to afford 0.39g of duloxetine hydrochloride having purity of 99.59% by HPLC containing 0.04 % R-enantiomer.
Method H:
A mixture of duloxetine hydrochloride (3g, HPLC purity: 94.77% containing 6.4% R-enantiomer) in acetonitrile (21ml) was heated to reflux to obtain clear solution, followed by stirring at 25-30°C for 3 hours. The solid was filtered and dried in a vacuum oven to afford 1.8g of duloxetine hydrochloride having purity of 99.6% by HPLC containing 0.1% R enantiomer.
Example 02: Preparation of duloxetine hydrochioride
(I) Preparation of duloxetine oxalate
A solution of duloxetine free base (l0g, HPLC purity : 90.0% containing 7% R-enantiomer) in ethyl acetate (40ml) was added to a solution of oxalic acid (4.4g) in ethyl acetate (60ml), stirred for 1hour at 25-30°C. Filtered and dried the solid to obtain duloxetine oxalate (12.0g).
(II) Preparation of duloxetine hydrochloride
Duloxetine oxalate (lOg) and ammonium chloride (2.8g) in methanol (40ml) was refluxed for 5 hours, cooled to room temperature. Methanol was distilled off in vacuum. Water (40ml) and dichloromethane (80ml) was added to above solution and stirred for 30 minutes. The organic layer was separated, washed with water, and concentrated in vacuum to obtain l0g of the title compound having purity of 93.89% by HPLC.
(III) Purification of duloxetine hydrochloridc Method A:
A mixture of crude duloxetine hydrochloride (2.5g, HPLC purity: 93.89% containing 7% R-enantiomer), in ethyl acetate (12.5ml) was heated to 80°C for 30 minutes and then for one hour at 25-30°C. The solid was filtered and dried to obtain l.lg of duloxetine hydrochloride having purity of 98.70% by HPLC containing 4% R-enantiomer.
A mixture of duloxetine hydrochloride, (l.lg), obtained above, in acetonitrile (5.5ml) was heated to 80°C for 30 minutes and then for one hour at 25-30°C. The solid was filtered and dried to obtain 0.7g of title compound having purity of 99.52% by HPLC containing 0.08% R-enantiomer.
Method B:
A mixture of 5g of Duloxetine hydrochloride (containing 7% R-enantiomer) in acetonitrile (35ml) was heated to reflux to clear solution, followed by stirring at 25-30°C for 3 hours. The solid was filtered and dried in a vacuum oven to afford 3.1g of duloxetine hydrochloride having purity of 99.7% by HPLC containing 0.11% R-enantiomer.
Example 03: Preparation of duloxetine hydrochloride
(I) Preparation of duloxetine oxalatc
Duloxetine free base (2.5 g, HPLC purity: 90.00%) was dissolved in ethyl acetate (10ml) and then solution of oxalic acid (l.lg) in ethyl acetate (15ml) was added. Stirred for 1hour at 25-30°C. Filtered and dried the solid to obtain 3g of duloxetine oxalate.
(II) Preparation of duloxetine hydrochloride
A solution of duloxetine oxalate (3g) and pyridine hydrochloride (2g) in methanol (10ml) was refluxed for 5 hours and cooled to room temperature. Methanol was distilled off in vacuum. Water (9ml) and dichloromethane (20ml) were added to the
above solution and stirred for 30 minutes. The organic layer was separated, washed with water, and concentrated in vacuum to obtain 2.2g of title compound having purity of 96.80% by HPLC containing 7% R-enantiomer. (Ill) Purification of duloxetine hydrochloride
A mixture of 2g of duloxetine hydrochloride (containing 7 % R-enantiomer) in acetonitrile (12ml) was heated to reflux to clear solution, followed by stirring at 25-30°C for 3 hours. The solid was filtered and dried in a vacuum oven to afford 1.3g of duloxetine hydrochloride having purity of 99.7% by HPLC containing 0.10% R-enantiomer.
Example 04: Preparation of Duloxetine hydrochloride (I) Preparation of duloxetine fumarate:
Duloxetine free base (23.0 g, HPLC purity: 90.12%) was dissolved in ethanol (46ml)
and then a solution of fumaric acid (9.0g) in ethanol (69ml) was added. Stirred for
1hour at 25-30°C, filtered and dried the solid to obtain 25.0 g of duloxetine fumarate
having purity of 98.5% by HPLC.
(H)Preparation of duloxetine hydrochloride:
A mixture of duloxetine fumarate (25.0 g), prepared above, in water (27ml), 2N
hydrochloric acid (54ml) and dichloromethane (135ml) was stirred for half hour. The
organic layer was separated and washed with brine (saturated aqueous sodium
chloride solution).Organic layer was concentrated in vacuum to obtain 18.0 g of
crude title compound having purity of 99.0% by HPLC containing 7.58% R-
enantiomer.
(IH)Purification of duloxetine hydrochloride
A mixture of duloxetine hydrochloride (6g, containing 7.58% R-enantiomer) in
acetonitrile (35ml) was heated to reflux to obtain clear solution, followed by stirring
at 25-30°C for 3 hours. The solid was filtered and dried in a vacuum oven to afford
3.9g of duloxetine hydrochloride having purity of 99.7% by HPLC containing 0.13%
R-enantiomer.
Example 05: Purification of duloxetine hydrochloride
A mixture of duloxetine hydrochloride (18.5g containing 2.95% R-enantiomer) in acetonitrile (129ml) was heated to reflux to obtain clear solution, followed by stirring at 25-30°C for 3 hours. Then solid was filtered and dried in a vacuum oven, to obtain 13.0g of duloxetine hydrochloride having purity of 99.86% by HPLC containing 0.03% R-enantiomer.
Example 06: Purification of duloxetine hydrochloride
A mixture of crude duloxetine hydrochloride (23.0g, HPLC purity: 93.17% and containing 7% R-enantiomer), in ethyl acetate (125ml) was heated to 80°C for 30 minutes and then for one hour at 25-30°C. The solid was filtered and dried to obtain 19.0g of duloxetine hydrochloride having purity of 98.49% by HPLC containing 4.92% R-enantiomer.
The duloxetine hydrochloride obtained above (3.9g) was heated in acetonitrile (27ml) to reflux to obtain clear solution, followed by stirring at 25-30°C for 3 hours. The solid was filtered and dried in a vacuum oven to obtain 2.9g of title compound having purity of 99.70% by HPLC containing 0.11% R-enantiomer.
Example 07: Purification of duloxetine hydrochloride
A mixture of duloxetine hydrochloride (3.2g, HPLC purity: 91.32% containing 7.2% R-enantiomer) in acetonitrile (22ml) was heated to reflux to obtain clear solution, followed by stirring at 25-30°C for 3 hours. The solid was filtered and dried in a vacuum oven to obtain 2.4g of duloxetine hydrochloride having purity of 99.60% by HPLC containing 0.12% R-enantiomer.
Example 08: Purification of duloxetine hydrochloride
The mother liquor of examples 05, 06 and 07 was concentrated to afford impure duloxetine hydrochloride containing 22% R-enantiomer. A mixture of this impure duloxetine hydrochloride (6.0g), in acetonitrile (24ml) was heated to reflux to obtain

clear solution, followed by stirring at 25-30°C for 3 hours. Then solid was filtered and dried in a vacuum to obtain 1.8g of duloxetine hydrochloride having purity of 99.02% by HPLC containing 0.7% R-enantiomer.
Example 09: Purification of duloxetine hydrochloride
A mixture of duloxetine hydrochloride (0.5g, containing 21% R-enantiomer, synthetically prepared by adding racemic duloxetine hydrochloride) in acetonitrile (2ml) was heated to reflux, followed by stirring at 25-30°C for 3 hours. The solid was filtered, washed with acetonitrile (0.5ml), and dried in a vacuum oven, to obtain 0.2g of duloxetine hydrochloride (containing 0.35 % R-enantiomer).

WE CLAIM:
1. A process for the preparation of highly pure duloxetine hydrochloride of formula I,
FORMULA 1 (Formula Removed)
comprising:
a) treating duloxetine with suitable acid to prepare duloxetine acid addition salt,
b) converting duloxetine acid addition salt to duloxetine hydrochloride, and
c) purifying duloxetine hydrochloride.
2. The process according to claim 1, wherein in step a) suitable acid is selected
from organic acid like C1-10 aliphatic carboxylic acid, aryl carboxylic acid,
hetero-aryl carboxylic acid, aryl alkyl carboxylic acid, oxalic acid, citric acid,
maleic acid, formic acid, fumaric acid, acetic acid; inorganic acid like
hydrobromic acid, hydroiodic acid.
3. The process according to claim 1, wherein in step b) duloxetine acid addition
salt is converted to duloxetine hydrochloride by treating duloxetine acid addition
salt with hydrochloride salt of base, wherein base is selected from ammonia,
N,N-dimethylamine, pyridine and the like in the presence of a protic solvent
selected from water, C|-6alcohol like methanol, ethanol, the like.
4. The process according to claim 1, wherein in step b) duloxetine acid addition
salt is converted to duloxetine hydrochloride by treating duloxetine acid
addition salt with hydrochloric acid.
5. The process according to claim 1, wherein step c) duloxetine hydrochloride is
purified using a nitrile solvent or a mixture of nitrile solvent with other suitable
organic solvent.
6. The process according to claim 5, wherein the nitrile solvent is selected from
C1-5 alkylnitrile preferably acetonitrile and suitable organic solvent is selected
from a C2-8 ether, a C5-8 aliphatic or C6-12 aromatic hydrocarbon, C1-8 ester C3-10
ketone and halogenated hydrocarbons, straight chain or branched C1-8 aliphatic
alcohol, tetrahydrofuran, dimethylsulfoxide, dimethylforamide, N-
methylpyrrolidine, sulfolane.
7. A process for the purification of duloxetine hydrochloride of formula I
comprising:

a) heating crude duloxetine hydrochloride containing R-enantiomer in a nitrile
solvent or in a mixture of nitrile solvent with other suitable organic solvent to
obtain clear solution;
b) cooling the reaction mixture,
c) isolating pure duloxetine hydrochloride by filtration.

8. The process according to claim 7, wherein the nitrile solvent is selected from
C1-5 alkylnitrile.
9. The process according to claim 7, where nitrile solvent is acetonitrile.
10. The process according to claim 7, wherein the suitable organic solvent is selected from a C2-8 ether, a C5-8 aliphatic or C6-12 aromatic hydrocarbon, C1-8 ester C3-10 ketone and halogenated hydrocarbons, straight chain or branched C1-8 aliphatic alcohol, tetrahydrofuran, dimethylsulfoxide, dimethylforamide, N-methylpyrrolidine, and sulfolane.