TECHNICAL FIELD OF THE INVENTION
The present invention relates to novel process for synthesis of duioxetine hydrochloride of formula (1) in chiral purity of greater than 99.9%.

BACK GROUND OF THE INVENTION
The chemical name of duioxetine hydrochloride is (S)-(+)-N-methyl-3-(l-naphthyloxy)-3-(2-
thienyl)propanamine (1).
Duioxetine was disclosed in patent US 4,956,388 and its acid addition salts in patent US
5,362,886. Duioxetine hydrochloride is useful for the treatment as an anti-depressant and also
for treatment of urinary incontinence. It is the active ingredient of drug "CYMBALTA".
Very little number of references is 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 duioxetine.
Numbers of documents are cited in the patent as well as academic literature for the synthesis of duioxetine and its enantiomerically pure intermediate compounds via an optical resolution of racemic duioxetine or racemic intermediates that are formed in the synthesis of duioxetine at different steps. These pathways are illustrated in the following synthetic scheme I.
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Most of the literature data indicate that the initial step of duloxetine synthesis is condensation of either racemic hydroxy compound i.e. (RS)-N.N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine or enantiomerically pure (S)-N.N-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 pyrophoric and reacts violently with water with evolution of hydrogen gas.
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The inventors of PCT application 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 phosphonium salts to facilitate the reaction. The use of phase transfer catalysts render the process economically non viable since they are much costlier.
The patent 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-methylpyrrolidinone as solvent. The alkoxides are very strong bases and therefore are hazardous that brings limitation on their use on large scale.
The PCT application 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 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 pyrophoric, 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(trimethylsilyl)amide.
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-tartaric acid, mandelic acid, camphor sulphonic acid, (S)-2-pyroIidine-2-one-5-
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carboxylic-acid and (-)-2,3,4,6-di-O-isopropylidine-2-keto-L-gulonic acid. However, very few
of them are directed towards resolution of racemic condensed compound (RS)-N.N-di mcthyl-
3-(l-naphthyloxy)-3-(2-thienyl)propanamine, which are discussed below.
According to the PCT application WO 2006/045255 the (S)-N,N-dimethyl-3-(rtaphthyioxy)-3-
(2-thienyl)propanamine-D-tartarate salt is obtained by using D-tartaric acid as resolving agent
in chiral purity up to 99.6% which was converted to duloxetine hydrochloride of chiral purity
99.6%.
The poor efficiency of dibenzoyl-L-tartaric acid and higher cost of chiral resolving agents such as (S)-2-pyrolidine-2-one-5-carboxylic-acid and (-)-2,3,4,6-di-O-isopropylidine-2-keto-L-gulonic acid is noted and mentioned in the PCT application WO 2006/027798, the inventors of which were able to overcome these drawbacks arising from use of dtbenzoyl tartaric acid by performing the optical resolution with di-p-toluoyl-L-tartaric acid as resolving agent. The inventors of the present invention have developed a process for optical resolution of racemic condensed compound (RS)-N.N-di methyl-3-(l-naphthyloxy)-3-(2-thienyl)propanamine with a novel resolving agent di-p-anisoyl-L-tarataric acid in a solvent selected from esters, ethers, ketones, lower alcohols. The desired product (S)-(t)-N.N-dimethyl-3-(l-naphthyIoxy)-3-(2-thienyl)propanamine dianisoyl tartarate salt was obtained in enantiomeric purity up to 99.8% after purification. The pure tartarate salt on subjecting lo subsequent steps was converted to duloxetine hydrochloride of chiral purity greater than 99.9%.
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
To provide a method for synthesis of duloxetine hydrochloride (1) of 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:
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(i) preparation of racemic condensed compound (RS)-N,N-di methyl-3-(l-naphthyloxy)-3-(2-thienyl)propanamine oxalate (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(trimethylsilyl)amide in polar aprotic solvent,
(ii) optical resolution of racemic condensed compound (5) with di-para-anisoyl-1.-tarataric acid (DATA) to obtain crude (S)-N.N-dimethyl-3-(l-naphthyloxy)-3-(2-thienyl)propanamine dianisoyl tartarate salt (6),
(iii) purification of crude tartarate salt (6) by crystallization and
(iv) raeemization of undesired (R)-N,N-di methyi-3-(l-naphthyloxy)-3-(2-thienyl)propanamine (7b) by treatment with base potassium bis(trimethylsilyl)amide to obtain racemic condensed compound (5).
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a novel process for synthesis of duloxetine hydrochloride (1) 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 -fiuronaphthalene (3) in aprotic polar organic solvent in
presence of a milder base to obtain (RS)-N.N-di methyl-3-(l-naphthyloxy)-3-(2-
thienyl)propanamine (4) (racemic condensed compound) isolated as oxalate salt, ii) conversion of oxalate salt (4) to free base (RS)-N.N-di methyl-3-(l-naphthyloxy)-3~
(2-thienyl)propanamine (5) by treatment with base, iii) .optical resolution of free base (5) of racemic condensed compound with di-p-
anisoyl-L-tartaric acid (DATA) in organic solvent to get crude tartarate salt of (S)-
isomer (6), iv) purification of crude tartarate salt of (S)-isomer (6) by crystallization from C1-C4
alcohol or aliphatic ester or mixtures thereof to get pure dianisoyl tartarate salt of
(S)-isomer (6), v) conversion of pure dianisoyl tartarate salt (6) to free base (S)-N.N-di methyl-3-( 1-
naphthyloxy)-3-(2-thienyl)propanamine (7a) by treatment with base, vi) demethylation of free base (7a) by treatment with phenyl chloroformate in presence
of diisopropylethyl amine in toluene to get carbamate intermediate (8) in situ, vii) hydrolysis of carbamate intermediate (8) with sodium hydroxide in dimethyl
sulfoxide solvent to give duloxetine base (9) and
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viii) conversion of duloxetine base (9) to duloxetine hydrochloride (1) in an organic
solvent or mixture of organic solvents.
The steps involved in the synthesis of duloxetine hydrochloride (1) according to the process of present invention is depicted in synthetic scheme II which is given below.

In one aspect, the present invention provides a safer and convenient method for condensation reaction of (rfc)-N, N-dimethyI-3-(2-thienyl)-3-hydroxypropanamine (2) (racemic hydroxy compound) with 1-naphthalene (3) to obtain (±)-N, N-dimethyl-3-(2-thienyl)-3-(l-naphthalenyloxy)propanamine oxalate salt (4) (racemic condensed compound). The reaction is carried out in presence of milder base selected from sodamide, potassium amide and potassium bis(trimethylsilyl)amide; the most preferred base is sodamide. The reaction is carried out with
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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 room temperature to 150°C, preferably at 70-100°C, most preferably at 80-90°C. The racemic condensed compound prepared according to the present invention as described above can be isolated as acid addition salts of acids 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 oxalate salt (4) is converted to free base racemic condensed compound (5) 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 (±)-N, N-dimethyl-3-(2-thienyl)-3-(l-naphthalenyloxy)-propanamine (5) with chiral acid as resolving agent such as di-p-anisoyl-L-tartaric acid (DATA) to obtain crude (S)-(+)-N, N-dimethyl-3-(2-thienyl)-3-(l-naphthalenyloxy)-propanamine (6). 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 is toluene, ethyl acetate, isopropyl acetate, acetone or mixtures thereof. The molar ratio of racemic free base (5) to DATA is varied from 1:0.5 to 1: 1.1, the preferred ratio is 1: 0.5. The resolution is carried out at room temperature or by heating the reaction mixture up to reflux temperature of the solvent.
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more preferably to 50-60°C and then allowing the solution to cool to room temperature and stirring for 5-20 hours, preferably 8-12 hours.
Further aspect of the present invention is the purification of crude (S)- (+)-N, N-dimethyl-3-(2~ thienyl)-3-(l-naphthalenyloxy)-propanamine dianisoyl tartarate salt (6) by crystallization to obtain pure (S)- (4)-N, N-dimethyl-3-(2-thienyl)-3-(l-naphthalenyloxy)-propanamine tartarate salt (6) having chiral 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 diisopropyl 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, most preferably 1:3 to 1:5. The ratio of substrate to solvent mixture is 1:1 to 1:30, preferably 1:5 to 1:15, most preferably 1:10 to 1:12. 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 pure (S)- (+)-N, N-dimethyl-3-(2-thienyl)-3-(l-naphthalenyloxy)-propanamine tartarate salt (6) is treated it with aqueous ammonia in mixture of dichloromethane and water, followed by separating the organic layer, drying and concentration under reduced pressure to obtain enantiomerically pure (S)-(+)-N, N-dimethyl-3-(2-thienyl)-3-(l-naphthalenyloxy)-propanamine (7a) (S-isomer of condensed compound) of chiral purity up to 99.8%.
The demethylation of (S)-(+)-N, N-dimethyl-3-(2-thienyl)-3-( 1 -naphthalenyloxy)-propanamine (7a) is achieved by treatment with phenyl chloroformate in presence of diisopropyl amine as base to obtain carbamate intermediate (8) in situ which is then subjected to hydrolysis with alkali such as sodium hydroxide or potassium hydroxide in polar aprotic solvent selected from dimethyl sulfoxidc, suifolane, dimethyl fonnamide, dimethyl acetamide, N-methyipyroiidine-2-onc, preferably in dimethyl sulfoxide to provide duloxetine base (9). 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 5,023,269. Duloxetine free base 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.
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In further embodiment, the present invention is characterized by the process for preparing duloxetine hydrochloride (1) that involves treatment of duloxetine base (9) with solution of about 20% hydrochloric acid in lower alkanol such as methanol, ethanol, propanol, isopropanol preferably isopropanol or ethyl acetate. The acidification is carried out in an organic solvent 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 diisopropyl ether, tert.-butyl methyl ether; acetonitrile or mixtures thereof the most preferred solvent is ethyl acetate or isopropyl acetate. The acidification is carried out up to pll in the range 2-3. The temperature is maintained in the range 0-50°C, preferably 10-20°C.
The present invention provides duloxetine hydrochloride (1) having chiral purity of greater than 99.9%. The powder X ray diffractogram of duloxetine hydrochloride (1) obtained by the process of the present invention showed it to be crystalline form A that is described in PCT application WO 2005/019,199.
In an alternative embodiment, the present invention provides process for racemization of undesired isomer (R)-(-)-N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine |(R)-isomer of condensed compound (7b)] with KHMDS as base to obtain racemic compound (RS)-N,N-di methyl-3-(l-naphthyloxy)-3-(2-thienyl)propanamine free base (5). The racemization is carried out in organic solvent selected from aromatic hydrocarbons such as benzene, toluene, xylene. cyclic and acyclic ethers such as diethyl ether, diisopropyl ether, 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 R-isomer 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-(l-naphthalenyloxy)-3-(2-thienyl)
propanamine oxalate salt (4).
50 g of N, N-dimethyl-3- (2-thienyl)-3-hydroxypropanamine (2, racemic hydroxy compound) was dissolved in 250 ml of dimethyl sulfoxide. To the clear solution 13.7 g of sodamide was
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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 43.4 g 1-fluoronaphthalene (3) 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 500 ml of cold-water. pH was adjusted to 5.5-6.0 with acetic acid. Aqueous reaction mass washed with cyclohexane followed by pH adjustment 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. Oily mass dissolved in 250 ml ethyl acetate and 30 g oxalic acid 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 75 g racemic N, N-dimethyl-3- (1- naphthalenyloxy)-3-(2-thienyl) propanamine oxalate (4) as white solid.
Example 2: Preparation of (±)-N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)
propanamine oxalate salt (4). 20 g Racemic hydroxy compound (2) was dissolved in 100 ml of N-methylpyrrolidinone to
get clear solution. To this solution was added 186.5 g of potassium bis(trimethylsilyl)amidc (15% solution in toluene) slowly within 10-15 minutes. Stirred for half an hour then 15.7 g 1-fluoronaphthalene (3) 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 500 ml of cold-water. 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 tol0.5-l 1.0 with caustic solution then extracted with cyclohexane. The organic layer was concentrated under reduced pressure to give thick oily mass, which was dissolved in 100 ml ethyl acetate. To this 12.15 g of oxalic acid 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 28 g racemic N, N-dimethyl-3- (1- naphthalenyloxy)-3-(2-thienyl) propanamine oxalate (4) as off white solid.
Example 3: Preparation of (+)-N, N-dimethyl-3- (1- naphthalenyloxy)-3-(2-thienyl)
propanamine di-p-anisoyl-(L)-tartarate salt (6)
15 g of Racemic N, N-dimethyl-3- (1- naphthalenyloxy)-3-(2-thienyl) propanamine oxalate salt (4) was suspended in mixture of 100 ml of water and 50 ml cyclohexane. 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 10 gm of oily mass of (t )-N, N-dimethyl-3- (1- naphthalenyloxy)-3-(2-thienyl) propanamine free base(5, racemic condensed compound free base) .
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10 g of oily mass obtained above was dissolved in 80 ml ethyl acetate. Solution of 6.7 g of di-p-anisoyl- (L)-tartaric acid in 45 ml ethyl acetate 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), 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 (6)
10 g of racemic N, N-dimethyl-3- (1- naphthalenyloxy)-3-(2-thienyl) propanamine free base (5) was dissolved in 120 ml toluene or isopropyl acetate. Solution of 6.7 g di-p-anisoyl- (I.)-tartaric acid in 15 ml acetone 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 20 ml ethyl acetate and dried. Yield: 4.8 gm (off white solid), chiral purity: 94.2%
Example 5: Preparation of pure (S)-(+)-N, N-dimethyl-3- (1- naphthalenyloxy)-3-(2-thienyl)
propanamine tartarate salt (6)
25 g of Crude tartarate salt (6) obtained above was suspended in mixture of 275 ml ethyl acetate and 50 ml of methanol. 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 g, chiral purity: 99.8%
Example 6: Preparation of (S)- (+)-N-methyl-3- (1- naphthalenyloxy)-3-(2-thienyl)
propanamine (9, duloxetine free base)
100 g of pure (S)- N, N-dimethyl-3- (1- naphthalenyloxy)-3-(2-thienyl) propanamine dianisoyl tartarate salt (6) 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, dried (brine) and concentrated to get 44 g of thick oily mass of (S)- (+)-N,N-dimethyl-3- (1- naphthalenyloxy)-3-(2-thienyl) propanamine (7a).
The above oily mass of 7a was added to 220 ml of toluene. To the solution 21.9 g diisopropylethylamine was added and mixture was warmed to 45°C. To the mixture 33.2 g
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phenyl chloroformate was added dropwise and stirred for 2 hours at 55°C. Reaction mixture was cooled to room temperature and then basified with 220 ml of 2% NaHCO3 solution. Organic layer was separated, washed with water and concentrated to oily mass. The oily mass was added to 285 ml dimethyl sulfoxide followed by addition of solution of caustic lye (42.5 g 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 pi I 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 35 g of duloxetine free base as oily mass.
Example 7: Preparation of duloxetine hydrochloride salt (1)
35 g of Duloxetine free base (oily mass) was dissolved in 500 ml ethyl acetate and the resulting solution was cooled to 5-10°C. To this solution was added ethyl acetate-HCI solution (about 12%) dropwise in 10-15 minutes. Slowly white solid started to precipitate out. Addition of ethyl acetate-HCI 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 g, chemical purity: 99.8% (by HPLC) and chiral purity: 99.95%(by HPLC).
Example 8: Preparation of duloxetine hydrochloride salt (1)
10 g of Duloxetine free base (oily mass) was dissolved in 100 ml isopropyl acetate and cooled to 5-10°C. To this solution was added isopropyl alcohol-HCl solution (about 15%) dropwise till pH was between 2-3. The resulting thick slurry stirred at 15-20°C for two hours. Solid was filtered, washed with 20 ml isopropyl acetate, dried under reduced pressure at 45-50°C. Yield: 8.2 g, chemical purity: 99.8% (by HPLC) and chiral purity: 99.95% (by HPLC).
Example 9: Process for racemization of (R)-(-) - N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine (7b) to obtain racemic (RS)-N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine (5)
The ethyl acetate solution (mother liquor from resolution step, examples 3 and 4) that is enriched with R isomer, (R)-(-)-N, N-dimethyi-3- (l-naphthalenyloxy)-3-(2-thienyl) propanamine (7b) was concentrated under reduced pressure to obtain thick oily mass. Thick oily mass was dissolved in 120 ml toluene. To the solution 60 ml water was added and pll of biphasic system was adjusted to 10.0 -10.5 with caustic lye solution. Toluene layer was separated, washed with water and concentrated to afford 30 g of oily residue.
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The oily residue was again dissolved in 150 ml toluene having m/c less than 0,2% and to this solution75 ml of DMSO was added. To this mixture solution of 63.8 g potassium bis(trimethylsilyl)amide (15% solution in toluene) 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 250 ml water was added. Stirred for 15 minutes and separated the organic layer. Organic layer was washed with water and concentrated under reduced pressure to get 30 g of racemic condensed compound (5) as an oily mass.
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We claim:
1. A novel process for synthesis of duloxetine hydrochloride (1) comprising:
i) reaction of (RS)-N.N-di methyl-3-hydroxy-3-(2-thienyl)propanaminc (2.
racemic hydroxy compound) with I-fluronaphthalene (3) in aprotic polar
organic solvent in presence of a milder base to obtain (RS)-N.N-di methyl-
3-(l-naphthyloxy)-3-(2-thienyl)propanamine (4) (racemic condensed
compound) isolated as oxalate salt, ii) conversion of oxalate salt (4) to free base (RS)-N.N-di methyl-3-(l-
naphthyloxy)-3-(2-thienyl)propanamine (5) by treatment with base, iii) optical resolution of of racemic condensed compound free base (5) with di-
p-anisoyl-L-tartaric acid (DATA) in organic solvent to get crude (S)-isomer
tartarate salt, iv) purification of crude (S)-isomer tartarate salt by crystallization from C|-Ct
alcohol or aliphatic ester or mixtures thereof to get pure dianisoyl tartarate
salt of (S)-isomer (6), v) conversion of pure dianisoyl tartarate salt (6) to free base (S)-N.N-di
methyl-3-(l-naphthyloxy)-3-(2-thienyl)propanamine (7a) by treatment with
base, vi) dcmethylation of free base (7a) by treatment with phenyl chloroformate in
presence of diisopropyiethyl amine in toluene to get earbamate intermediate
(8) in situ, vii) hydrolysis of earbamate intermediate (8) with sodium hydroxide in polar
aprotic solvent to give duloxetine base (9) and viii) conversion of duloxetine base (9) to duloxetine hydrochloride (1) in an
organic solvent or mixture of organic solvents.
2. A process according to claim 1, wherein the aprotic solvent used in step (i) is selected
from dimethyl sulfoxide, sulfolane, dimethyl formamide, dimethyl acetamide, N-
methylpyrolidine-2-one, preferably dimethyl sulfoxide.
3. A process according to claim 1, wherein the reaction of step (i) is carried out at
temperature room temperature to 150°C, preferably at 70-100°C, most preferably at 80-
90°C.
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4. A process according to claim 1, wherein the reaction of step (i) is carried out in
presence of milder base such as sodamide, potassium amide, potassium
bis(trimethylsilyl)amide, preferably sodamide.
5. A process according to claim 1, wherein the reaction of step (i) 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.
6. A process according to claim 1, wherein the product of step (i) the racemic condensed
compound is isolated as salt of acids such as hydrochloric acid, sulfuric acid,
phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, oxalic acid, maleic acid,
succinic acid benzoic acid and acetic acid, preferably of oxalic acid.
7. A process according to claim 1, wherein the step (iii) is carried out by treating the salt
obtained from step ii) with aqueous ammonia in mixture of cyclohexane and water.
8. A process according to claim 1, wherein the solvent employed in step (iii) of 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 diisopropyl ether, tert.-butyl methyl
ether; acetonitrile or mixtures thereof, preferably toluene, ethyl acetate, isopropyl
acetate, acetone and mixtures thereof.
9. A process according to claim 1, wherein the step (iii) is carried out with approximately
equimolar quantities of racemic condensed compound and the resolving agent DATA,
preferably DATA is used 0.5 mole equivalent.
10. A process according to claim 1, wherein the step (iii) is carried out at room temperature
or by heating the reaction mixture up to reflux temperature of the solvent, more
preferably to 50-60°C.
11. A process according to claim 1, wherein the step (iv) of purification 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 diisopropyl ether.
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tert-butyl methyl ether; acetonitrile or mixtures thereof, preferably mixture of methanol and ethyl acetate.
12. A process according to claim 1, wherein the step (iv) of purification 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, most preferably from 1:10 to 1:12.
13. A process according to claim 1, wherein the step (v) is carried out by treating the
tartarate salt obtained from step 4 with aqueous ammonia in mixture of
diehloromethane and water.
14. A process according to claim 1, wherein the step (vi) is carried out by treatment of pure
(S)-isomer (7a) with phenyl chloroformate in presence of diisopropyl amine base in
toluene as solvent.
15. A process according to claim 1, wherein the step (vii) is carried out with sodium
hydroxide in polar aprotic solvent selected from dimethyl sulfoxide, sulfolane, dimethyl
formamide, dimethyl acetamide, N-methyipyrolidine-2-one, preferably in dimethyl
sulfoxide.
16. A process according to claim 1, wherein the step (viii) is carried out with solution of
about 20% hydrochloric acid in methanol, ethanol, propanol, isopropanol, ethyl acetate.
isopropyl acetate, preferably isopropanol or ethyl acetate.
17. A process according to claim 1, wherein the step (viii) is carried out an organic solvent
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 diisopropyl ether, tert.-butyl methyl ether; acetonitrile or mixtures thereof, the
most preferred solvent is ethyl acetate and isopropyl acetate.
18. A process according to claim 1, wherein the step (viii) is carried out at pH 2-3.
19. A process according to claim 1, wherein the step (viii) is carried out at 0-50°C.
preferably at 10-20°C.
20. A process for preparation of (RS)-N.N-di methyl-3-(l-naphthyloxy)-3-(2-
thieny!)propanamine oxalate (4, racemic condensed compound) by reaction of (RS)~
17

N.N-di methyi-3-hydroxy-3-(2-thienyl)propanamine (2, racemic hydroxy compound) with 1-fluronaphthaIene (3) in aprotic polar organic solvent in presence of sodamide or potassium bis(trimcthylsilyl)amide as a base to obtain isolated as oxalate salt.
21. A process according to claim 20, wherein the aprotic solvent is selected from dimethyl
sulfoxide, sulfolane, dimethyl formamide, dimethyl acetamide, N-methylpyrolidine-2-
one, preferably dimethyl sulfoxide.
22. A process according to claim 20, wherein the reaction is carried out at temperature
room temperature to 150°C. preferably at 70-100°C, most preferably at 80-90°C.
23. A process according to claim 20, wherein the reaction is carried out in presence of base
sodamide, potassium amide, potassium bis(trimethylsilyl)amide, preferably sodamide.
24. A process according to claim 20, wherein 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.
25. A process according to claim 20, wherein the racemic condensed compound is isolated
as salt of 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, preferably of oxalic acid.
26. A process optical resolution of racemic condensed compound (5) with di-para-anisoyl-
L-tarataric acid (DATA) to obtain crude (S)-N.N-dimethyl-3-(l-naphthyloxy)-3-(2-
thienyl)propanamine dianisoyl tartarate salt (6).
27. A process according to claim 26 wherein the solvent 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 ketonc,
diethyl ketone; aliphatic esters such as ethyl acetate, propyl acetate, isopropyl acetate;
ethers such as diisopropyl ether, tert.-butyi methyl ether; acetonitrile or mixtures
thereof, preferably toluene, ethyl acetate, isopropyl acetate, acetone and mixtures
thereof.
28. A process according to claim 26 wherein the molar ratio of racemic free base (5) to
DATA is varied from 1:0.5 to 1: 1.1, the preferred ratio is 1: 0.5.
18

29. A process according to claim 26 wherein the resolution is carried out at room
temperature or by heating the reaction mixture up to reflux temperature of the solvent,
more preferably to 50-60°C.
30. A process purification of crude (S)-(+)-N, N-dimethyl-3- (1- naphthaleny!oxy)-3-(2-
thienyl) propanamine di-p-anisoyl-(L)-tartarate salt (6) by crystallization 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 diisopropyl ether, tert.-
butyl methyl ether; acetonitrile or mixtures thereof, preferably mixture of methanol and
ethyl acetate.
31. A process according to claim 30, wherein the ratio of substrate to solvent is in the range
from 1:1 to 1:30, preferably from 1:5 to 1:15, most preferably from 1:10 to 1:12.
32. A process according to claim 30, 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.
33. A process for conversion of duloxetine base (9) to duloxetine hydrochloride (1) is
carried out with solution of about 20% hydrochloric acid in methanol, ethanoi.
propanol, isopropanol, ethyl acetate, isopropyl acetate, preferably isopropanol or ethyl
acetate.
34. A process according to claim 33, wherein the reaction is carried out an organic solvent
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 diisopropyl ether, tert.-butyl methyl ether; acetonitrile or mixtures thereof, the
most preferred solvent is ethyl acetate and isopropyl acetate.
35. A process according to claim 33, wherein the pH is maintained at 2-3.
36. A process according to claim 33, wherein the reaction is carried out at 0-50°C.
preferably at 10-20°C.
37. A process for racemization of undesired isomer (R)-(-)-N, N-dimethyl-3-(l-
naphthalenyloxy)-3-(2-thienyl) propanamine [(R)-isomer of condensed compound (7b) |
19

with potassium bis(trimethylsilyl)amide as base to obtain racemic compound (RS)-N,N-di methyl-3-(l-naphthyloxy)-3-(2-thienyl)propanamine free base (5).
38. A process according to claim 37, wherein the racemization is carried out in organic-
solvent selected from aromatic hydrocarbons such as benzene, toluene, xylene, cyclic
and acyclic ethers such as diethyl ether, diisopropyl ether, methyl tert. butyl ether,
tetrahydrofuran, dioxane, esters such as ethyl acetate, isopropyl acetate, nitriles such as
acetonitrile, propionitrile, dimethyl sulfoxide, sulfolane or mixtures thereof, most
preferably mixture of toluene and dimethyl sulfoxide.
39. A process according to claim 37, wherein the racemization is performed at temperature
varying from 0-1 10 °C. preferably at room temperature to 80 °C, most preferably at 50-
60 °C.
40. (S)-(+)-N,N-DimethyI-3-( 1 -naphthylenyloxy)-3-(2-thienyl)-propanamine di-para-
anisoyl-L-tartaric acid salt of formula
20


The present invention provides an improved, safer and easy to operate on plant scale process for synthesis of duloxetine hydrochloride (1) that is characterized by: (i) preparation of racemic condensed compound (RS)-N,N-di methyl-3-(l-naphthyloxy)-3-(2-thienyl)propanamine oxalate (4) by reaction of racemic hydroxy compound (2) with 1-tluronaphthalene (3) in presence of sodamide or potassium bis(trimethylsilyl)amide as base in polar aprotic solvent, (ii) optical resolution of racemic condensed compound (5) with di-p-anisoyl-L-tarataric acid (DATA) to obtain crude (S)-N.N-dimethyl-3-(l-naphthyloxy)-3-(2-thienyl)propanamine dianisoyl tartarate salt (6), (iii) purification of crude tartarate salt (6) by crystallization and (iv) racemization of undesired (R)-N,N-di methyl-3-(l-naphthyloxy)-3-(2-thienyl)propanamine (7b) by treatment with base KHDMS to obtain racemic condensed compound (5).
The duloxetine hydrochloride (1) obtained by the process of present invention has chiral purity of greater than 99.9%.