Form 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULE 2003
PROVISIONAL SPECIFICATION
[See section 10 and rule 131
1. TITLE OF THE INVENTION
"A process for the preparation of (S)-(+)-N-methyl-3-(l-naphthyloxy)-3-(2-
thienyl)propylamine hydrochloride"
2. APPLICANT
(a) NAME: USV LIMITED
(b) NATIONALITY: Indian Company incorporated under the
Companies ACT 1956
(c) ADDRESS: B.S.D. Marg, Govandi, Mumbai 400 088,
Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the nature of this invention and the
manner in which it is to be performed.
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A process for preparation of (S)-(+)-N-methyl-3-( l-naphthyloxy)-3-(2-thienyl)propylamine hydrochloride
TECHNICAL FIELD:
The present invention relates to an improved process for the preparation of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propylamine hydrochloride also known as Duloxetine hydrochloride having formula I.

BACKGROUND OF INVENTION:
Duloxetine HCl is a selective serotonin norepinephrine reuptake inhibitor indicated for the treatment of major depressive disorder. United State Patent US 5023269 describes a process for the preparation (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propylamine hydrochloride known as Duloxetine (I), by reacting 2-acetyl thiophene (2) with paraformaldehyde and dimethyl amine hydrochloride to obtain mannich base i.e. 3-dimethylamino-l-(2-thienyl)-l-propanone (3). The mannich base was then reduced with sodium borohydride to get racemic alcohol (4) which was further resolved using agents like dibenzoyl-d and -1-tartaric acids to (S)-(-)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)-propanamine (5). The compound (5) was then treated with metal hydride and fluoronaphthalenc in N,N-dimethylacetamide to obtain (S)-(+)-N,N-dimethyl-3-(l-
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naphthalenyloxy)-3-(2-thienyl)propanamine oxalate (6) which was demcthylatcd using phenyl chloroformate in toluene to obtain free base of Duloxetine (7). The pharmaceutical^ acceptable acid addition salts were then prepared by reacting free base with equimolar or excess amount of acid.
US 5362886 describes preparation of compound I, by reacting 2-acetyl thiophen (2) with dimethyl amine HCl and paraformaldehyde in isopropanol and the resulting keto compound (3) was reduced by sodium borohydride to get racemic compound oo-[2-(dimethylamino)ethyl]-2-thiophene methanol (4). which was resolved by (S)-(+)-Mandelic acid in ethanol and methyl tert butyl ether to get (S)-(-)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)-propanamine (5). The compound (5) was then condensed using 1-fluoronaphthalene in presence of sodium hydride and potassium benzoate in dimethylsulphoxide to obtain compound o\' formula (6). which was then demethylated using phenyl chloroformate and diisopropyl ethylamine in toluene and subsequently hydrolysed by alkali metal h\dioxides to yield Duloxetine base (7). Compound of formula (1) was prepared by the action o! concentrated HC1 on a solution of the Duloxetine base (7) in ethyl acetate. An inoculating crystal of the compound (I) was added to the reaction mixture and ethyl acetate was added for more dilution. The mixture was then concentrated to original volume after stirring for 30 minutes The reaction mixture was stirred at ambient temperature for 1 hr and at 0°C for another 1 hr. However, the process resulted in poor yield. When stirring was further prolonged, it resulted in the accumulation of impurities. (Scheme I).
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Scheme I



WO2006045255 by Zentiva describes the preparation of Duloxetine base by demethylating the compound of formula (6) with phenyl chloroformate and diisopropyl ethyl amine in toluene then hydrolyzing with alkali metal hydroxides to get Duloxetine base (7). Compound of formula (1) is prepared by treating Duloxetine Base (7) by heating it with weak base hydrochloride viz ammonium chloride. The crude yield is reported to about 55% before crystallization.
WO2006071868 by Teva describes formation of Duloxetine hydrochloride salt by taking Duloxetine base and HC1 in a solvent selected from the group of an aromatic hydrocarbon, a C1-4 ester other than ethyl acetate, a C2-8 ether, a C1-8 alcohol, acetonitrile and a ketone. The pH is then adjusted to about 1-5 to obtain Duloxetine Hydrochloride.
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WO2005019199 to Hetero Drugs discloses preparation of amorphous Duloxetine HCl. In WO2004056795 a process of preparation of (S) duloxetine or its acid addition salts from racemic duloxetine is described.
WO2005108386 discloses novel polymorphs of Duloxetine base.
WO2006126213 discloses a process for preparing Duloxetine, or its acid addition salt, comprising (i) condensation of (S)-(-)-N, N,N-dimethyl-3-(2-thienyl)-3-hydroxy propanamine with 1-fluoronaphthalene followed by demethylation or condensation of N, N-dimethyl-3-(2-thienyl)-3-hydroxy propanamine with 1-fluoronaphthalene followed by resolution and demethylation; and (ii) if desired, converting Duloxetine to its acid addition salt.
A process for the purification of duloxetine HCl, comprising crystallizing duloxetine HCl in water or a solvent selected from the group consisting of C3-8 ketones, C3-8 esters, C2-8 ethers, C2-8 alcohols, and mixtures thereof with water is described in US2006276660.
CN1676522 Describes the process for the preparation of (S)-N.N-dimethyl -3-( 1-naphthoxy-3-(2-thienyl)propylamine by treating (S)-(-)-N.N-dimeth\l-3-(2-thienyl)-3-hydroxypropylamine with 1-fluoronaphthalene in presence o\' sodium hydride at 30-80°C.
US2006270731 discloses preparation of highly pure Duloxetine hydrochloride (HCl), containing less than about 0.14 percent area by HPLC of the impurity (+)-N-methyl-3-( 1 -naphtalenyloxy)-3-(3-thienyl)propanamine.
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In WO2006071868 process for preparation of duloxetine hydrochloride is provided via preparation of N,N-Dimethyl-3- (l-naphthalenyloxy)-3-(2-thicnyl) propanamine from its oxalate salt using ammonium hydroxide in an organic solvent and converting it to Duloxetine base which is then converted into Duloxetine hydrochloride.
OBJECTIVES OF THE INVENTION:
An object of the present invention is to provide an improved process for the preparation of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propylamine hydrochloride (I), in high yield and high purity.
Another object of the invention is to provide a simple, economical and industrially feasible process for the preparation of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propylamine hydrochloride (I).
SUMMARY OF THE INVENTION:
The present invention provides an improved process for preparation of Duloxetine (I), comprising:
reacting 2-acetyl thiophene (2) with paraformaldehyde and dimethyl amine hydrochloride and further adding sodium borohydride in alcoholic solvent to provide racemic alcohol (4). Compound of formula(4) is resolved by methods reported in prior art into R (8) and S alcohols (5). The unwanted R alcohol (8) is recycled by racemizing the compound with dilute HC1 to form compound (4). Condensation of compound (5) with 1-fluoro naphthalene in presence of sodium hydride in DMSO provides the condensed product S-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine (6), which is then purified by forming organic acid salt in water and washing the aqueous layer by methyl tert
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butyl ether to get the pure organic acid salt of compound (6), which is basified with alkali and extracted with toluene. Compound of formula (6) is then demethylated using phenyl chloroformate in presence of diisopropyl ethylamine in
toluene to yield duloxetine (7). Duloxetine base thus obtained is then treated with reagents, preferably thionyl chloride or phosphorous oxychloride or phosphorous trichloride and C1-4 alcohols in ethyl acetate as a solvent provides Duloxetine HC1. Alternately Duloxetine hydrochloride is treated with concentrated HC1 in mixture of isopropanol and ethyl acetate to provide Duloxetine Hydrochloride. Duloxetine HC1 thus obtained is purified by crystallization in methylethylketone and ethyl acetate to yield pure Duloxetine hydrochloride (I).
DETAILED DESCRIPTION OF THE INVENTION:
According to the invention process is provided for the preparation of Duloxetine OR (S)-(+)- N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine hydrochloride having formula I comprising:

(a) Reacting 2- acetyl thiophene with N, N- dimethyl amine hydrochloride, paraformaldehyde in presence of hydrochloric acid in ethanol and adding sodium borohydride in alochol viz. C1-4 alcohols and isolating 3-(dimethylamino)-l-(2-thienyl)-l-propanol (4).
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(b) Resolving the compound (4) with a resolving agent in solvents selected from ethers viz. methyl tertiary butyl ether or ketonic solvents like acetone. Recycling the unwanted R-isomer (8) by obtaining it from resolution mother liquor and treating it with hydrochloric acid to obtain racemic Duloxetine (4)

(c) Condensing the resolved alcohol (5) with 1-halo naphthalenes in presence of alkali metal hydrides in DMSO to get the crude compound (6). Treating the crude-compound with organic acids like formic acid, acetic acid, propanoic acid, methane sulphonic acid or para toluene sulphonic acid in water to get water soluble organic acid salt. Washing the aqueous layer with water immiscible solvents preferably methyl tert butyl ether, ethyl acetate, toluene, hexane or chlorinated solvents preferably MDC. Then basifying it and extracting it with water immiscible solvents to obtain the pure compound (6).
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(d) The compound of Formula (6) is further demethylating with phenyl chloroformate, and diisopropyl ethylamine in toluene and then isolating the compound of Formula (7).

(e) Treating compound of Formula (7) with alcohols selected from form C1-C4 and a reagent, preferably thionyl chloride, phosphorous oxychloride or phosphorous trichloride in ethylacetate as solvent to provide the compound of Formula I.
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(f) In another process compound 1 is also prepared by the action of concentrated HC1 in isopropanol in ethyl acetate as solvent.
The present invention relates to an improved process for the preparation of Duloxetine (I),comprising reacting 2- acetyl thiophene with N, N- dimethyl amine hydrochloride, paraformaldehyde in presence of hydrochloric acid in alcohols selected from C1-C4 and further adding sodium borohydride and isolating 3-(dimethylamino)-l-(2-thienyl)-l-propanol (4). After completion of reaction, alcoholic solvent is distilled out and water is added and extraction is done with an organic solvent selected from halogenated solvents or esters such as dichloromethane or ethyl acetate to obtain racemic 3-(dimethylamino)-l-(2-thienyl)-l-propanol (4).
Alternately after completion of reaction, alcoholic solvent is distilled out and water is added to precipitate the compound, filtered, washed with water and dried to get the 3-(dimethylamino)-l-(2-thienyl)-l-propanol (4).
The compound (4) is resolved using a resolving agent preferably S-(+)-Mandelic acid in methyl tert butyl ether and alcohol and crystallizing the resultant Mandellate salt to yield S- 3-(dimethylamino)-l-(2-thienyl)-l-propanol (5) and R-3-(dimethylamino)-l-(2-thienyl)-l-propanol (8).
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In another embodiment of the present invention, compound (4) is resolving by resolving agent preferably S-(+)- Mandelic acid in acetone into S- 3-
(dimethylamino)-l-(2-thienyl)-l-propanol (5) and R- 3-(dimethylamino)-l-(2-thienyl)-1-propanol (8). The advantage is the process avoids use of expensive methyl tert butyl ether (which is used in high volume) and alcohol. Single solvent acetone is used, which can be recycled.
Synthesis of (S)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine (6) is achieved by coupling of compound (5) with 1- halonaphthalenes with sodium hydride in solvents like Dimethyl sulphoxide, N,N-dimethyl acetamide etc. After completion of reaction quenching is done with water and extracting the crude compound with water immiscible solvent. The crude compound is then treated with organic acids preferably formic acid, acetic acid, propanoic acid, methane sulphonic acid or PTSA more preferably with acetic acid in water to form the water soluble organic acid salt. Then washing the aqueous Layer with water immiscible solvents like methyl tert butyl ether, ethyl acetate, toluene or chlorinated solvents like MDC. Then basifying the aqueous layer and extracting
with water immiscible solvents to get the pure compound (6). An advantage of this process is that there is no preparation of oxalate salt. Further the yield of the product obtained is higher than the product obtained via the oxalate salt preparation.
Demethylation of Compound (6) by treating it with phenyl chloroformate in toluene in presence of diisopropyl ethylamine at 65-70° Cto ield the carbamate which is isolated and hydrolyzed in Dimethyl sulphoxide and aqueous sodium hydroxide solution to obtain crude Duloxetine base (7). The crude base is further purified by converting into itscorresponding acetate salt in aq. Acetic acid and washing the aqueous layer by methyl tert butyl ether to remove the organic
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impurities then basifying the aq layer by alkali solution and finally extracting the pure Duloxetine base in ethyl acetate.
Duloxetine base may be converted into its hydrochloride salt by reacting it with reagents preferably thionyl chloride or phosphorous oxychloride or phosphorous trichloride more preferably thionyl chloride and alcohols selected from C1-C4 alcohols in ethyl acetate as solvent. In another embodiment Duloxetine Hydrochloride is prepared by treated the duloxetine base with concentrated HC1 in mixture of isopropanol & ethyl acetate as a solvent. The advantage of these processes is that the product is obtained in good yield.
Example 1:
3-(dimethylamino)-l-(2-thienyl)-l-propanoI (4)
A mixture of 2-acetyl thiophene (250g, 1.98mol), Dimethyl amine hydrochloride (210 g, 2.57 mol), paraformaldehyde (78.44 g, 0.871 mol) and concentrated HCl (3.97 ml) in ethanol (317 ml) was refluxed for 4 h The reaction mixture was cooled to the room temperature and water (700 ml) was added, followed by methanol (1.6 L) was added at room temperature. The reaction mixture was cooled to 0-5° C and basified with aqueous sodium hydroxide solution to adjust pH 7-8. Then sodium borohydride (81 g, 2.18 mol) was added in small lots at 0-5" C. After completion of addition of sodium borohydride, reaction mixture was stirred for 30 minutes at 0-5° C. Then it was stirred at room temperature for 12-15 h The reaction mixture was concentrated to obtain oily residue. This residue was diluted with water (3.75 L) and stirred at room temperature for 2 h. The solid was obtained, filtered and washed with water. The compound was dried at 45-50" C under vaccum. Yield 180g, (49%).
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Example 2:
(S)- 3-(dimethylamino)-l-(2-thienyI)-l-propanol (5)
A mixture of 2-acetyl thiophene (250g, 1.98mol), dimethyl amine hydrochloride
(210 g, 2.57 mol), paraformaldehyde (78.44 g, 0.871 mol) and concentrated HCl (3.97 ml) in ethanol (317 ml) was refluxed for 4 h. The reaction mixture was cooled to the room temperature and water (700 ml) was added, followed by methanol (1.6 Lit) was added at room temperature. The reaction mixture was cooled to 0-5° C and basified with aqueous sodium hydroxide solution to adjust pH 7-8. Then sodium borohydride (81 g, 2.18 mol) was added in small lots at 0-5° C. After completion of addition of sodium borohydride, reaction mixture was stirred for 30 minutes at 0-5° C. Then it was stirred at room temperature for 12-15 h. The reaction mixture was concentrated to obtain an oily residue. The residue was treated with ethyl acetate (3.0 Lit) and washed with water (3x500 ml) and brine solution (500 ml). The ethyl acetate layer was separated, dried over sodium sulphate, concentrated to obtain an oil, which solidified on standing to white solid (210 g). This solid was taken in mehyl tert butyl ether (3.15 L) and heated to 45-50° C and a solution of S-(+)-Mandelic acid (86.27 g. 0.567 mol) in ethanol (250 ml.) added in a dropwise manner. The reaction mixture was stirred for 45 minutes at 45-50° C and cooled to room temperature. The solid obtained, filtered and washed with methyl tert butyl ether to obtain mandelate salt (112 g). This salt was crystallized in acetone to get pure mandelate salt (96 g). The madelate salt was basified with sodium hydroxide and extracted with dichloromethane to obtain (S)-3-(dimethylamino)-l-(2-thienyl)-l-propanol as an oil, which was solidified on standing. Yield 50g.
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Example 3:
(S)- 3-(dimethylamino)-l-(2-thienyl)-l-propanol (5)
A mixture of 2-acetyl thiophene (100 g, 0.793 mol), dimethyl amine hydrochloride (81.5 g, 1 mol), paraformaldehyde (35.5 g, 0.394 mol) and concentrated HCl (4.0 ml) in ethanol (250 ml) was refluxed for 5 h. The reaction mixture was cooled at room temperature and diluted with ethanol (250 ml.). The reaction mixture was cooled to 5-10° C and basified with ethanolic sodium hydroxide solution (32 g, NaOH in 450 ml ethanol) to pH 8-10. The sodium borohydride (35 g. 0.92mol) was added portionwise into the reaction mixture at 5-10°C for 30 min. The reaction mixture was stirred at room temperature for 6 h. Then was added glacial acetic acid (165 ml) into it to adjust pH 5-6 . The white solid was formed, filtered and washed with ethanol (300 ml). The filtrate was basified with 20% aqueous NaOH (140 ml) to pH 7.5-8 and concentrated to obtain oily residue (112 g). The residue was disssolved in acetone (700 ml) at 45-50°C and a solution of S-(+)-mandelic acid (47 g, 0.31 mol) in acetone (100 ml) was added in a dropwise manner at 45-50°C for 30 min. The reaction mixture was stirred for 45 min at 45-50° C and cooled to room temperature. The solid obtained, filtered and washed with acetone to obtain mandellate salt (43 g). [The mother liquor was concentrated, basified and extracted with ethyl acetate to get the oily residue, which solidified on standing. It contained unwanted isomer (8)]. The mandellate salt was basified with sodium hydroxide and extracted with dichloromethane to obtain (S)- 3-(dimethylamino)-l-(2-thienyl)-l-propanol as an oil, which was solidified on standing. Yield 22g.
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Example 4:
3-(dimethylamino)-l-(2-thienyl)-l-propanol (4)
A solution of the solid obtained from the resolution mother liquor {contained
unwanted isomer (8), (55 g)} in a toluene (450 ml) and 1.5 M solution of hydrochloric acid (890 ml) was added at 20-25°C. The reaction mixture was stirred for 8 hrs at 20-25°C. The reaction mixture was basified with aqueous NaOH to pH 9-10 and extracted with ethyl acetate. The ethyl acetate layer was washed with water till neutral pH, dried over sodium sulphate and concentrated under reduced pressure to get 3-(dimethylamino)-l-(2-thienyl)-l-propanol (4) as an oil, which was solidified on standing. Yield: 35 g
Example 5:
(S)-(+)-N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine(8):-
A solution of (S)-(-)-3-(dimethylamino)-l-(2-thienyl)-l-propanol (175 g, 0.945 mol) in dimethyl sulphoxide (750 ml) was added lot wise to a mixture of 60% sodium hydride (47.3 g, 1.18 mol) in dimethyl sulphoxide (475 ml) at 30-35°C. This mixture was stirred for 30 minutes. Then raised temperature to 60-65° C and 1- fluoronaphthalene (152 g, 1.04 mol) was added drop wise. Reaction mixture was stirred for 6-8 hrs. After cooling to room temp water (4.9 L) was added to the reaction mass and extracted with ethyl acetate. The combined organic extracts
were washed with water and dried over sodium sulphate. The organic layer was concentrated under reduced pressure to get an oil (298 g). An 8 % aqueous solution of acetic acid (1.49 L) was added to this oil and stirred the mixture for 30 mins. Then washed the aqueous mixture with methyl tert butyl ether (3x1.49 L). Aqeous layer was basified with 5 % aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water, dried over
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sodium sulphate and concentrated under reduced pressure to get (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine as an oil. Yield: 192 g (65%).
Example 6:
(S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine (7)
(S)-(+)-N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine (90 g, 0.0289 mol) was taken in Toluene (540 ml) and Diisopropyl ethyl amine (56 g, 0.434 mol) was added to the mixture at room temperature. To this solution phenyl chloroformate (68 g, 0.434 mol) in 90 ml Toluene was added dropwise. Then heated the reaction mixture to 65-70° C for 7 hr. Then cooled the reaction mass to 30° C and quenched it with 5% aqueous sodium hydroxide solution. Stirred the mass for 15 minutes and separated the layers. The orgnic layer was further washed with water (3x700 ml) then with 1 N Hydrochloric acid solution and finally with water. The organic layer was concentrated under reduced pressure to get crude carbamate (137 g). This oil was taken in dimethyl sulphoxide (675 ml) and a solution of sodium hydroxide (48 g) in water (290 ml) was added. Resulting solution was heated to 70-75° C for 7-8 hr. The reaction mixture was cooled, diluted with water (2.7 L) then extracted with ethyl acetate (3xlL). The organic layer was washed with water, dried over sodium sulphate and finally concentrated under vacuum to obtain an oil (122 g). To this oily compound 10% aqueous solution of acetic acid (1220 ml) was added and the mixture was stirred for 30 minutes. This aqueous solution was washed with Methyl tert butyl ether (4x600 ml). The washed aqueous layer was basified with 5% aqueous sodium hydroxide solution and extracted with ethyl acetate (3x600 ml). The combined organic layer
was washed with water till neutral pH, dried over sodium sulphate and concentrated under reduced pressure to get (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine as an oil. Yield : 59 g (68%).
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Example 7:
(S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thlenyl)propanamine hydrochloride (1 ):-
(S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine (20 g 0.0673 mol) was taken in ethyl acetate (200 ml) and concentrated HCl (7.2 ml) in 2-propanol (40 ml) was slowly added to the mixture. The precipitated reaction mass
was stirred for 1 hr at room temperature, then chilled to 0-5° and further stirred for 1 hr. Then filtered under reduced pressure, washed with ethyl acetate and dried
to get the title compound. Yield: 12.5 g (55%).
Example 8:
(S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine hydrochloride (1 ):-
(S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine (5 g 0.0168 mol) was taken in ethyl acetate (35 ml) and ethanol (1.2 ml, 0.02mol) was added to it. Then the reaction mixture was chilled to -5 to 0° C and thionyl chloride (2.45 g, 0.02 moles) was slowly added to the mixture at -5-0°C. The precipitated reaction mass was stirred for 1 hr at -5-0°C. Then filtered under reduced pressure, washed with ethyl acetate and dried to get the title compound. Yield : 4 g (71%). This compound was recrystallized in Methyl ethyl Ketone and ethyl acetate to get the pure compound.
Dated this the 31st day of January, 2007

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Abstract: The present invention provides an improved process for making Duloxtine hydrochloride of formula I from Duloxetine base (7) by treating it with reagents like thionyl chloride and alcohols. Invention also provides an improved process for the preparation of µ-[2-(dimethylamino)ethyl]-2-thiophene methanol (4) an intermediate in the preparation of Duloxetine.
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