PROCESS FOR PREPARING ATOMOXETINE HYDROCHLORIDE FIELD OF INVENTION

The present invention relates to the process for preparing Atomoxetine hydrochloride. Atomoxetine HCl is marketed as STRATTERA ^® , which is a selective norepinephrine reuptake inhibitor. Atomoxetine HCl is chemically known as (-)-_¥■ Methyl-3-phenyl-3-(ø-tolyloxy)-propylamine hydrochloride and represented by below mentioned formula.

More particularly, the invention relates to crystalline form of N-methyl-3- phenyl-3-(o-tolyloxy) propylamine oxalate (here in after referred as "(±) Atomoxetine Oxalate"), which is an useful intermediate for the synthesis of Atomoxetine hydrochloride. BACKGROUND AND DESCRIPTION OF PRIOR ART

Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.

Atomoxetine HCl is marketed as STRATTERA ^® , which is a selective norepinephrine reuptake inhibitor. Atomoxetine HCl is chemically known as (-)-TV-

Methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride and represented by below mentioned formula I. The molecular formula is CnH ₂₁ NO-HCl, which corresponds to a molecular weight of 291.82. The chemical structure is:

I

STRATTERA ^® capsules are intended for oral administration only. Each capsule contains atomoxetine HCl equivalent to 10, 18, 25, 40, or 60 mg of atomoxetine. The l

capsules also contain pregelatinized starch and dimethicone. The capsule shells contain gelatin, sodium lauryl sulfate, and other inactive ingredients. The capsule shells also contain one or more of the following: FD&C Blue No. 2, synthetic yellow iron oxide, titanium dioxide. The capsules are imprinted with edible black ink. . U.S. Patent No. 4,314,081 describes 3 -Aryloxy-3 -phenyl polyamines, which possess central nervous system activity. Atomoxetine is a member of the above class of compounds, and is a useful drug for the treatment of depression. Atomoxetine was claimed in U.S. Patent No. 4,314,081 and the patent describes a process for the preparation of atomoxetine and related compounds in two different ways as depicted below as Scheme A and Scheme B, respectively.

Scheme A

Scheme B

Atomoxetine

The process illustrated in Scheme A involves the preparation of the atomoxetine using 3 -phenyl chloropropyl amine (Formula 5) as a starting material. The process involves bromination of said starting compound (Formula 5) by using N- bromosύccinimide. Further the bromo derivative is condensed with o-cresol to result in a compound of Formula 7, which is then subjected to animation using methylamine.

Though the process looks very simple, it involves the following disadvantages: (a) N-bromosuccinimide being a corrosive and sensitive chemical, its usage demands special care;

(b) the work up of the compound formula 7 involves high vacuum (0.03 torr) distillation at 135-145 ⁰ C ₅ which is a tedious and cumbersome process to carry out at the plant level. (c) the reaction conditions involved in some of the steps are harsh, for example the animation reaction is conducted at 14O ⁰ C. at pressures of 10 kg/cm ² for 12 hours in autoclave.

All the. above disadvantages make the process not viable for practicing on a commercial scale.

On the other hand, Scheme B describes the preparation of atomoxetine using β- dimethylaminopropiophenone produced by a Mannich reaction; which is reduced to the hydroxy derivative having Formula 9 using diborane; further the hydroxy compound (Formula 9) is converted to the corresponding chloro derivative of Formula 10 using dry HCI gas and thionyl chloride and is followed by condensation with o-cresol. The said reaction is carried out in methanol at reflux for a duration of five days to achieve the compound of formula 11 and is followed by demethylation using cyanogen bromide to end up with atomoxetine. As can be clearly understood the process is associated with the following problems: In scheme B, chloro compound (formula 10) treated with o-creosol condense to obtain compound (formula 11) then demethylation to obtain compound (formula 4) the several unite operation in as above process. One most disadvantage is that the using o- cresol commercial grade, o-cresol which contain phenol, p-cresol as impurity so in final

API more purification are required. The use of costly reagents such as diborane makes the process uneconomical;

The passage of dry HCI gas followed by thionyl chloride addition is very cumbersome and is not advisable in the plant.

This is a time-consuming process, involving a reaction which requires five days for its completion; and iv) use of cyanogen bromide, which is highly toxic, is not desirable.

Further, M. Srebnik et al., Journal of Organic Chemistry, Vol. 53, pages 2916- 2920 (1988); E. Corey et al., Tetrahedron Letters, Vol. 30, pages 5207-5210 (1989); U.S. Patent No. 4,868,344; Y. Gao et al., Journal of Organic Chemistry, Vol. 53, pages 4081-4084 (1988); J. Deeter et al., Tetrahedron Letters, Vol. 31, pages 7101-7104 (1990); and U.S. Patent No. 4,950,791 disclose stereospecifϊc methods for the preparation of 3-aryloxy-3-phenylpropylamines; the enantiomers of 3-hydroxy-3- phenylpropylamines are prepared by the stereospecifϊc reduction of the corresponding ketones. The thus obtained (S)-3-hydroxy-3 -phenyl propylamines are subjected to condensation with aryl alcohols using the Mitsunobo reaction as shown in below Scheme C:

Scheme C

Atomoxetine

The first critical step is an asymmetric reduction of the ketone to its corresponding alcohol. The second critical step involves the condensation of the obtained enantiomeric alcohol with the corresponding aryl alcohol. The process suffers from the following disadvantages:

(i) the reagent used for the asymmetric reduction of the ketone is highly expensive; (ii) the reagent diethyl azodicarboxylate ("DEAD") is expensive; (iii) the DEAD reagent is known to be highly carcinogenic, thus creating problems in handling; and the reaction involves the use of triphenylphosphine and DEAD and the resulting byproducts formed in the reaction, phoshineoxide and a hydrazine derivative, are very difficult to remove.

Therefore, commercial applicability of the said process is limited owing to the above noted disadvantages. WO 00/58262 relates to a stereospecific . process for the preparation of atomoxetine using nucleophilic aromatic displacement of an aromatic ring having a functional group, which can be converted to a methyl group. As can be seen, the process is very lengthy and involves many steps and is thus not commercially desirable.

U.S. Patent No. 5,847,214 describes the nucleophilic aromatic displacement reaction of 3-hydroxy-3-arylpropylammes with activated aryl halides, for example the reaction of N-methyl-3-phenyl-3-hydroxypropylamine with 4- triflouromethyl-1-cholro

benzene has been reported; the success of this reaction is mainly due to electron withdrawing group on benzene ring of the aryl halides.

U.S. Patent No. 6,541 ,668 describes a process for the preparation of atomoxetine and its pharmaceutically acceptable addition salts which comprises reacting an alkoxide of N-methyl-3-phenyl-3 -hydroxy propyl amine or an N protected derivative thereof, with 2-flouro toluene in the presence of 1 ,3-Dimethyl - 2- imidazolidinone ("DMI") or N-Methyl-3-pyrrolidinone ("NMP") as the solvent. The process disclosed in the said patent can be shown as Scheme D. Further, the process disclosed in the said patent restricts itself to the solvents DMI and NMP.

Scheme D

Atomoxetine

WO2006/037055 discloses the (±) atomoxetine oxalate having crystalline Form

II and a solid (±) atomoxetine free base are useful for preparing atomoxetine hydrochloride. The process disclosed in the said patent can be shown as Scheme E.

Scheme E

Oxalate

INaOH 3.(+)-Mandelic acid 2.Toluene 4. Eth l acetate/n-heptane

Mandelate

R-(-)-Atomoxetine Hydrochloride

The above patent discloses Form-I of Atomoxetine Oxalate as per the process in basic patent US 4,314,081 by condensation of o-creosol and compound (formula 10) as solvent ethyl acetate and recrystallization from ethyl acetate and methanol. WO 2006/037055 discloses only XRPD and no other characterization like DSC, IR are provided. This XRPD refers to Form-I of crude product of (±) Atomoxetine oxalate having melting range of 155-157 ⁰ C as disclosed in US 4,314,081.

EP 1798215 Al discloses a new crystalline form of Atomoxetine Hydrochloride having purity degree higher than 95% and characterized by XRPD and unit cell parameters. Also disclosed is the process for the preparation of crystalline form by dissolving crude Atomoxetine HCl in a suitable solvent, at a suitable temperature, cooling, filtering, drying and optionally milling or micronizing the obtained crystals.

U.S. Patent Application 2006/0252836 Al claims a stable Atomoxetine HCl has a pH of at least about 4. Also claimed is the process for its preparation and analytical control for its stability. U.S. Patent Application 2006/0079581 Al discloses three crystalline forms of (R)-Atomoxetine HCl i.e. Form-A, Form-B and Form-C.

According to the disclosure Form-A is the prior art.

U.S. Patent Application 2006/0009490 Al claims enantiomerically pure (R)-(-)- Tomoxetine (S)-(+)-Mandelate, wherein the level of (S)-(+)-Tomoxetine (S)-(+)-

Mandelate enantiomer is about 0.1% or less. Also, the process for the preparation of

enantiomerically pure Atomoxetine HCl is claimed by using n-butyl acetate/water in presence of base.

WO 2007/006132 Al claims the Oxalate salt of compound of formula 11 herein above before the ethereal linkage. Thus, the oxalate salt of racemic Atomoxetine is out of the scope of WO '132 Al.

Thus, there is still a need for the process for the preparation of (R)-Atomoxetine Hydrochloride which uses less hazardous solvents, in minimum reaction time. The process can be easily applicable to large scale productions with high yield and purity. OBJECTS OF INVENTION It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.

The object of the present invention is to provide a process for preparing Atomoxetine hydrochloride.

Another object of the invention is to provide a crystalline form of (±)~ Atomoxetine oxalate.

Yet another object of the present invention to provide a process for preparing a crystalline form of (±)- Atomoxetine oxalate. SUMMARY OF INVENTION:

According to one of the aspect of the present invention, there is provided a process for preparing (R)-Atomoxetine hydrochloride of formula I

I

which comprises of:

(a) demethylating N,N-dimethyl-3-(o-methylphenoxy)-3-phenyl-propylamine of formula IV

IV

with phenylchloroformate in a suitable organic solvent in presence of organic or inorganic base to form (±)-Atomoxetine residue without isolating N-methyl-3[-(o- methylphenoxy)-3-phenylpropyl]-carbamic acid, phenyl ester;

(b) treating (±)-Atomoxetine residue with oxalic acid in a suitable organic solvent to form crude (±)-Atomoxetine oxalate salt of formula (V); and

V

(c) purifying crude (±)-Atomoxetine oxalate salt in suitable organic solvent or mixture therof to obtain (±)-Atomoxetine oxalate crystalline Form-I characterized by having atleast one of the following properties:

(i) a melting point in the range of about 167 ⁰ C to about 172 ⁰ C; and/or (ii) a powder x-ray diffraction (PXRD) pattern substantially in accordance with Figure I; and/or

(iii) a powder x-ray diffraction (PXRD) having characteristic peaks at 9.6, 14.6,

17.3, 19.2, 22.3 and 24.7 2θ±0.2° 2θ; and/or

(iv) differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure II and having endothermic peak at about 170.7 ⁰ C; and/or

(v) an Infrared (IR) spectrum substantially in accordance with Figure III.

According to second aspect of the present invention, there is provided a process for preparation of (R>(-)-atomoxetine hydrochloride of formula (I)

which comprises:

(a) treating crystalline Form-I of (±)-Atomoxetine oxalate salt with base to obtain (±)- Atomoxetine free base oil;

(b) resolving (±)-Atomoxetine free base oil with a chiral resolving agent to form (R)-(- )-Atomoxetine (S)-(+)-mandelate salt in a suitable organic solvent;

(c) hydrolyzing (R)-(-)-Atomoxetine (S)-(+)-mandelate salt with base in a suitable organic solvent to form (R)-(-)-Atomoxetine free base oil; and

(d) isolating (R)-(-)-Atomoxetine hydrochloride by treating (R)-(-)-Atomoxetine free base oil with alcoholic HCl or gaseous HCl or aqueous HCl in suitable organic solvent.

According to another aspect of the present invention, there is provided a process for preparing (R)-Atomoxetine hydrochloride of formula I

which comprises the steps of

(a) reacting N,N-dimethyl-3-phenyl-3-chloropropylamine hydrochloride with o-cresol in presence of inorganic base to form N,N-dimethyl-3-(o-methylphenoxy)-3- phenyl-propylamine;

(b) demethylating N ₅ N-dimethyl-3-(o-methylphenoxy)-3 -phenyl-propylamine with phenyl- chloroformate in a suitable organic solvent in presence of organic or inorganic base to form (±)~Atomoxetine residue without isolating N-methyl-3[-(o- methylphenoxy)-3-phenylpropyl]-carbamic acid, phenyl ester.

(c) treating (±)-Atomoxetine with oxalic acid in a suitable organic solvent to form crude (±)-Atomoxetine oxalate salt;

(d) purifying crude (±)-Atomoxetine oxalate salt in suitable organic solvent or mixture therof to obtain (±)-Atomoxetine oxalate crystalline Form-I;

(e) treating crystalline Form-I of (±)-Atomoxetine oxalate salt with base to obtain (±)- Atomoxetine free base oil; (f) resolving (±)-Atomoxetine free base oil with a chiral resolving agent to form (R)-(-

)-Atomoxetine (S)-(+)-mandelate salt; (g) hydrolyzing (R)-(-)-Atomoxetine (S)-(+)-mandelate salt with base in a suitable organic solvent to form (R)-(-)-Atomoxetine free base oil; and

(h) isolating (R)-(-)-Atomoxetine hydrochloride by treating (R)-(-)-Atomoxetine .free base oil with alcoholic HCl or gaseous HCl or aqueous HCl in suitable organic solvent. BRIEF DESCRIPTION OF DRAWINGS

The above and other objects and features of the present invention will become apparent from the following description of the invention taken in conjunction with the following accompaying drawings, which respectively show:

FIG. I: X-ray diffraction pattern of (±)-Atomoxetine Oxalate crystalline Form-I. FIG. II: Differential Scanning Calorimetry analysis of (±)-Atomoxetine Oxalate crystalline Form-I.

FIG. Ill: Infrared spectra analysis of (±)-Atomoxetine Oxalate crystalline Form-I. DESCRIPTION OF THE INVENTION

According to the first embodiment of the present invention there is provided a process for the preparation of (±)-Atomoxetine Oxalate crystalline Form-I, an important intermediate for the preparation of (R)-(-)-Atomoxetine HCl characterized by having atleast one of the following properties: (i) a melting point in the range of about 167 ⁰ C to about 172 ⁰ C; and/or

(ii) a powder x-ray diffraction (PXRD) pattern substantially in accordance with Figure

I; and/or (iii)a powder x-ray diffraction (PXRD) having characteristic peaks at 9.6, 14.6, 17.3,

with Figure II and having endothermic peak at about 170.7 ⁰ C; and/or (v) an Infrared (IR) spectrum substantially in accordance with Figure III.

According to the preferred embodiment the demethylation of N,N-dimethyl-3- (o-methylphenoxy)-3 -phenyl-propylamine is performed by using phenylchloroformate

in suitable organic solvent selected from aromatic hydrocarbons like toluene, xylene, ethylbenzene and the like, halogenated hydrocarbon like methylene dichloride, chloroform and the like, esters like ethyl acetate, isopropyl acetate, tert-butyl acetate, butyl acetate and the like, preferably toluene. The demethylation is performed in presence of organic base like triethyl amine, diethyl amine, diisopropyl ethyl amine, isopropyl amine, pyridine, ammonia or inorganic base like alkali metal or alkaline earth metal hydroxides like sodium or potassium hydroxide; hydrides like sodium hydride, potassium hydride; alkoxide like potassium tert-butoxide and the like, preferably organic base like triethyl amine as an acid scavengers to form (±)-Atomoxetine residue without isolating N-methyl-3[-(o- methylphenoxy)-3-phenylpropyl]-carbamic acid, phenyl ester.

According to another preferred embodiment of the invention, (±)-Atomoxetine residue is converted to crude (±)-Atomoxetine oxalate by treating (±)-Atomoxetine residue with oxalic acid in a suitable organic solvent selected from the group consisting of C _1-4 alcohols like methanol, ethanol, propanol, isopropanol; ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone; esters like ethyl acetate, isopropyl acetate, ethers like diethyl ether, diisopropyl ether etc, preferably methanol.

The important aspect of the present invention is to prepare (±)-Atomoxetine oxalate in crystalline Form-I by purifying crude (±)-Atomoxetine oxalate is suitable organic solvent like C _1-4 alcohols like methanol, ethanol, propanol, isopropanol; ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone; esters like ethyl acetate, isopropyl acetate, ethers like diethyl ether, diisopropyl ether or mixture thereof, preferably mixture of methanol or mixture thereof with ethyl acetate.

Crystalline Form-I of (±)-Atomoxetine oxalate is characterized by X-ray powder diffraction (XRPD) pattern having characteristic peaks at 9.6, 14.6, 17.3, 19.2, 22.3 and 24.7 2θ±0.2° 20.

Crystalline Form-I of (±)-Atomoxetine oxalate is further characterized by X-ray powder diffraction (XRPD) pattern having peaks at 7.2, 9.6, 12.6, 14.6, 17.3, 18.4, 19.2, 20.5, 22.3, 24.7, 25.7, 27.1, 32.6, 35.8 and 37.5 2θ±0.2° 2θ Crystalline Form-I of (±)-Atomoxetine oxalate is further characterized by X-ray powder diffraction (XRPD) pattern substantially as depicted in FIG. I.

Crystalline Form-I of (±)-Atomoxetine oxalate is also characterized by differential scanning calorimetric (DSC) thermogram substantially as depicted in FIG. II and having endothermic peak at about 170.7 ⁰ C.

Crystalline Form-I of (±)-Atomoxetine oxalate is further characterized by Infrared (IR) spectrum substantially as depicted in FIG III.

Crystalline Form-I of (±)-Atomoxetine oxalate having atleast 90% crystallanity by XRD, preferably atleast 95% crystallanity by XRD.

In the preferred embodiment, the invention provides a process for preparation of

(R)-(-)-Atomoxetine hydrochloride by treating crystalline Form-I of (±)-Atomoxetine

Oxalate with a base selected from organic base like triethyl amine, diethyl amine, diisopropyl ethyl amine, isopropyl amine, pyridine, ammonia and the like, preferably ammonia in water.

The racemic atomoxetine free base oil is resolved with a chiral resolving agent like mandelic acid, camphor sulfonic acid, tartaric acid, p-ditolyltartaric acid, di- benzoyl tartaric acid and the like, preferably (S)-(+)-mandelic acid in a suitable organic solvent selected from aromatic hydrocarbons like toluene, xylene, ethylbenzene and the like, halogenated hydrocarbon like methylene dichloride, chloroform and the like, esters like ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate and the like, preferably n-butyl acetate to form pure (R)-(-)- Atomoxetine (S)-(+)-mandelate salt

According to another aspect of the present invention, the pure (R)-(-)-

Atomoxetine (S)-(+)-mandelate salt is hydrolyzed with a base selected from hydroxides, carbonates, bicarbonates, alkoxide, hydrides of alkali metal or alkaline earth metal. The suitable base can be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium tert-butoxide, preferably sodium or potassium carbonate, most preferably sodium carbonate. The (R)-(-)-Atomoxetine free base oil thus obtained can be converted to desired

(R)-(-)- Atomoxetine HCl by treating with alcoholic HCl like methanolic HCl, ethanolic

HCl, IPA HCl or gaseous HCl like HCl gas or aqueous HCl in suitable organic solvent selected from aromatic hydrocarbons like toluene, xylene, ethylbenzene and the like, halogenated hydrocarbon like methylene dichloride, chloroform and the like, esters like ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate and the like or mixture thereof preferably methylene dichloride or optionally mixture thereof with ethyl acetate.

In the preferred embodiment, the process for the preparation of atomoxetine hydrochloride comprises use of o-cresol as key starting material. In commercial grade

o-cresol, which contains phenol, p-cresol as impurity. To avoid the impurity in final compound more purification is required.

The process of the present invention provides (±)-Atomoxetine oxalate via intermediate N,N-dimethyl-3-(o-methylphenoxy)-3 -phenyl-propylamine treated with phenylchloroformate, potassium carbonate and triethylamine to form (±) atomoxetine free base which is further treated with oxalic acid in methanol to form crude (±)- Atomoxetine oxalate salt followed by its purification in methanol to get highly pure crystalline Form-I of (±) Atomoxetine oxalate.

The formation of (±)-Atomoxetine oxalate is according to US patent 4,314,081 which produces the form which is same as the from of crude (±)- Atomoxetine oxalate Form-I.

Further purification with methanol yields (±)-Atomoxetine oxalate in highly pure crystalline Form. Further, (±)-Atomoxetine oxalate is converted to (R)-(-)- Atomoxetine hydrochloride via the formation of (R)-(-)-Atomoxetine (S)-(+)- mandelate salt and (R)-(-)- Atomoxetine free base respectively. Finally, (R)-(-)- Atomoxetine free base is treated with methylene dichloride and ethyl acetate followed by treatment with IPA/HC1 to form (R)-(-)-Atomoxetine hydrochloride

The process ^' for preparing Atomoxetine hydrochloride according to the present invention is illustrated by below mentioned scheme:

(R)-(-)-Atomoxetine Hydrochloride

One of the aspect of present invention is also the one pot preparation of (±)- Atomoxetine oxalate of formula V in crystalline Form-I, an useful intermediate for preparing (R)- Atomoxetine HCl of formula I

V

(±)-Atomoxetine oxalate salt

which comprises of:

(a) demethylating N ₅ N-dimethyl-3 -(o-methylphenoxy)-3 -phenyl-propylamine of formula IV

with phenylchloroformate in a suitable organic solvent in presence of organic or inorganic base to form (±)-Atomoxetine residue without isolating N-methyl-3[-(o- methylphenoxy)-3-phenylpropyl]-carbamic acid, phenyl ester;

(b) treating (±)-Atomoxetine residue with oxalic acid in a suitable organic solvent to form crude (±)-Atomoxetine oxalate salt of formula (V); and

V

(c) purifying crude (±)-Atomoxetine oxalate salt in suitable organic solvent or mixture therof to obtain (±)-Atomoxetine oxalate crystalline Form-I characterized by having atleast one of the following properties:

(i) a melting point in the range of about 167 ⁰ C to about 172 ⁰ C; and/or (ii) a powder x-ray diffraction (PXRD) pattern substantially in accordance with

Figure I; and/or (iii) a powder x-ray diffraction (PXRD) having characteristic peaks at 9.6, 14.6,

17.3, 19.2, 22.3 and 24.7 2θ±0.2° 2θ; and/or

(iv) differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure II and having endothermic peak at about 170.7 ⁰ C; and/or (v) an Infrared (IR) spectrum substantially in accordance with Figure III.

Throughout the description and claims the word "comprise" and variations of the word are not intended to exclude other technical features, additives, components, or steps. The content of the abstract of the present application is incorporated herein as reference. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples are provided by way of illustration, and is not intended to be limiting of the present invention.

EXAMPLES:

Example: 1

Preparation of N,N-dimethyl-3-(o-methylphenoxy)-3-phenyl-propylamine

O-cresol (112 g 2.42 mole) was added to reaction vessel followed by addition of sodium hydroxide (40 g 2.35 mole) and methanol (1200 ml 12 vol) at 25-35 ⁰ C. The reaction mixture was stirred at 35-40 ⁰ C to get clear solution, the reaction mixture was cooled to 25-35 ⁰ C and N,N-dimethyl-3-chloro-3 -phenyl-propylamine (100 g 1.0 mole) was added. Reaction mixture was heated at 65-70 ⁰ C for 20-22 hrs. Methanol was distilled out. Then reaction mixture was cooled to 25-35 ⁰ C within 30 minutes and 20% Sodium hydroxide (500 ml) was added to the reaction mixture and stirred for 30 minutes. Then toluene (600 ml) was added to residue and cooled to 25-35 ⁰ C. The layers were separated and organic layer was washed with water (2 x 500 ml) and toluene was distilled out under vacuum at 70-80 ⁰ C to afford the title compound N, N-dimethyl-3-(o- methylphenoxy)-3-phenyl-propylamine.

% Yield = 85 %.

Example: 2

Preparation of (±)-Atomoxetine oxalate salt

N,N-dimethyl-3-(o-methylphenoxy)-3-phenyl-propylamme(100 g 1.0 mole) was added to reaction vessel followed by addition of toluene (100 mL) and triethylamine(18.8 g 0.50 mole) at 25-35 ⁰ C. Further, phenyl chloroformate (87.2 g 1.50 mole) was added to the reaction mixture with in 12 hrs and heated for 3 hrs at 40- 45°C.The reaction mixture was cooled to 25-35 ⁰ C, followed by addition of Potassium carbonate (30.8 g 0.60 mole) in water (900 ml) solution and stirred for 30 minutes at 25-35 ⁰ C. The layers were separated and organic layer was washed with water (2 x 25 mL). To the organic layer, toluene (400 mL) and potassium hydroxide (162 g 0.60 mole) was added and heated for 6 hrs at 105-110 ⁰ C. The reaction mixture was cooled to 25-35 ⁰ C followed by addition of water (1500 mL) and stirred for 30 minutes. The layers were separated and organic layer was distilled out under reduced pressure at 65- 7O ⁰ C, to afford the residue [(±) Atomoxetine free base]. To this oily residue, methanol (700 mL) and oxalic acid (39.83 g 0.85 mole) in methanol (300 mL) solution was added and stirred for 15 min. The reaction mixture was heated at 65-7O ⁰ C for 1 hr and further cooled to 25-35 ⁰ C and stirred for 1 hr. The product was filtered and washed with chilled methanol (2 x 100 mL) and dried under vacuum for 9 hrs at 40-50 ⁰ C to afford the title compound (±) Atomoxetine oxalate salt (67 gm). % Yield =52 %. HPLC Purity: 95%. 2-a) Preparation of (±)-Atomoxetine oxalate salt

(±) Atomoxetine oxalate crude (3.0 g) was added to the reaction vessel followed by addition of methanol (30 mL). The reaction mixture was heated to reflux temperature and heating was maintained for 15 min. After heating, ethyl acetate (90 mL) was added by dropping funnel and heated to reflux temperature for 30 min. The reaction mixture was cooled to 0-5 ⁰ C and stirred for 30 min. at the same temperature condition. The solid was filtered and washed with chilled ethyl acetate (10 mL) and dried in vacuum oven at 5O ⁰ C to afford the title compound (±) atomoxetine oxalate salt having highly crystalline form. DSC: Melting Point: 168-170 ⁰ C. 2-b) Preparation of (±)-Atomoxetine oxalate salt (Highly crystalline Form)

(±) Atomoxetine oxalate crude (50 g) was added to the reaction vessel followed by addition of methanol (500 mL). The reaction mixture was heated to reflux temperature and heating was maintained for 15 min. After heating, methanol was distilled out (to 225 mL methanol). The reaction mixture was cooled to 55 ⁰ C and maintained for 1 hr at the same temperature condition. The reaction mixture was cooled to 45 ⁰ C and maintained for 1 hr at the same temperature condition. The reaction mixture was further cooled to 30-35 ⁰ C and maintained for 1 hr at the same temperature condition. The solid was filtered and washed with methanol (2 x 25 mL) under chilled condition. The solid was dried in vacuum oven at 5O ⁰ C to afford the title compound (±) atomoxetine oxalate salt having highly crystalline form. DSC: Melting Point: 168-170 ⁰ C Example: 3 Preparation of (-) atomoxetine mandelate salt

(+/-) Atomoxetine oxalate salt (100 g 1.0 mole) was added to the reaction vessel followed by addition of water (1000 mL) and Liq. Ammonia (100 g 1.0 mole) with in 30 minutes at 25-35 ⁰ C. To the reaction mixture n-Butyl acetate (250 mL) was added and stirred for 30 minutes at 25-35 ⁰ C. The layers were separated and aqueous layer was extracted with n-butyl acetate (2 x 100 mL). To the organic layer L(+)mandelic acid (22 g 0.50 mole) in n-butyl acetate (300 mL) solution was added with in 1 hr and stirred for 4-5 hrs at 25-35°C.The reaction mixture was cooled to 0-5 ⁰ C with in 30 min, stirred for 2 hrs. The product was filtered and washed with chilled n-butyl acetate (2 x 50 mL) and solid was dried in vacuum for 4 hrs at 45-55 ⁰ C to afford the title compound (-) Atomoxetine mandelate salt. The title compound was further treated two times with n- butyl acetate for purification, The tile compound (-) Atomoxetine mandelate salt (28 g). % Yield = 62%. Example: 4 Preparation of (-) Atomoxetine hydrochloride

Water (1200 mL) and (-) Atomoxetine mandelate salt (100 g 1.0 mole) was added to the reaction vessel followed by addition of sodium carbonate (52 g 2.0 mole) solution and stirred for 30 min at 25-35 ⁰ C. The reaction mixture extracted with MDC (500 mL) and stirred for 30 minutes at 25-35 ⁰ C. The layer was separated and aqueous layer was extracted with MDC (2 x 200 mL) and stirred for 30 minutes. The MDC was distilled out from organic layer at 40-50 ⁰ C. To the oily residue [(-)Atomoxetine free base](58.90 g) MDC (58.90 mL) and Ethyl acetate (176 mL) was added and reaction

mixture was cooled to 0-5 ⁰ C followed by addition of IPA/HCl (15%) (110.50 g, 1.85 mole) with in 2 hr at 0-5 ⁰ C and stirred for 1 hr. The product was filtered and washed with chilled ethyl acetate (2 x 50 mL) at 0-5°C to afford the title compound (-) Atomoxetine hydrochloride. The title compound was further treated with MDC and Ethyl acetate for purification to obtain (-) Atomoxetine hydrochloride (51.0 g). % Yield = 71%. Advantages of the inventions:

1. The present invention provides one pot process for the preparation of (±)- Atomoxetine Oxalate without isolating N-methyl-3[-(o-methylphenoxy)-3- phenylpropylj-carbamic acid, phenyl ester after demethylation of N,N-dimethyl-3-

(o-methylphenoxy)-3 -phenyl-propylamine with phenylchloroformate.

2. The present invention also provides a process for the preparation of (R)- Atomόxetine Hydrochloride via (±)-Atomoxetine Oxalate without isolating (R)- Atomoxetine free base. 3. The present invention provides crystalline Form-I of (±)- Atomoxetine Oxalate characterized by XRD, DSC and IR.

4. The present invention provides crystalline Form-I of (±)-Atomoxetine Oxalate having atleast about 90% crystallanity, preferably atleast about 95% crystallanity.

5. The present invention is very cost effective using o-cresol instead of o-methyl halobenzene for ethereal linkage.

6. The present invention also provides pure intermediate (±)-Atomoxetine Oxalate, purified by using methanol or mixture thereof with ethyl acetate to control the impurities generated due to presence of phenol or p-cresol in commercial grade o- cresol. 7. The present invention is environment friendly and applicable to large scale production.