Hassan, et al, Brit. J. Clin. Pharmacol., 1985,19, 705 ; L. E. Dahl et al. , Acta Osychiatr.

Scand. , 1982,9, 66). US pat. No. 3,912, 743 delineates some of paroxetine's pharmacological properties.

BACKGROUND OF INVENTION For the first time, the ()-compound of formula-I was disclosed in the US patent No 3,912, 743. Subsequently it was also disclosed in the US patent no 4,007, 196. Process disclosed in these patents is based on a Grignard reaction in which arecoline and 4- fluorophenylmagnesium bromide are reacted.

The main disadvantage of this process is that arecoline is very irritant and harmful to the persons involved in the usage and is also not commercially available. The process

produces mixture of two stereoisomers in equal ratio. Therefore, it involves a resolution step and the unwanted isomer is of no use. Therefore, this process is not suitable for commercial preparation.

Subsequently, a number of processes for the preparation of ()-I were disclosed in various patents. Some of them include US Pat. No. 5,258, 517 ; US Pat. No. 4,902, 801; EP No. 374,675 ; EP No. 802,185 ; ES Patent No. 96 00,369 ; EP No. 812827 ; WO 98 53, 824 ; EP No. 812, 827; WO 00/026187 and WO 02/053537. Resolution of this mixture to get (-)-I leads to a loss of more than 50% of unwanted isomer which represents a severe disadvantage of the above processes.

Keeping in view of the disadvantages of the process leading to formation of ()-trans compound of formula-I a number of groups developed enantiospecific processes for the preparation of compound of the formula-I. Some of the processes that gave more than 70% of the required isomer of formula-I are given below.

In Tetrahedron Letters, 2001,7805, a process for the preparation compound of the formula-I is disclosed starting from 2-piperidone derivative. Key step in this process is the introduction of 4-fluorophenyl group via 1, 4-Michael addition to the compound of formula-VI in a stereospecific manner. Reduction of the compound of formula-VII gave the required compound of the formula-1.

Scheme-I The main disadvantage of the process is that it involves handling of a chiral reagent (R* shown in scheme) which is not commercially available and very expensive. Also, the process produces the required (-) -I isomer in 80%. Purification of this isomer to >99% requires a conventional resolution step which is not commercially attractive over the above mentioned process for the ()-trans-I.

In the US patent No 6,066, 737 a process for the preparation of compound of the formula- I is disclosed starting from pyridine-3-carboxaldehyde (Scheme-II). According to the process pyridine-3-carboxaldehyde is converted to an aminal using a chiral compound 1, 2-diarylethylenediamine derivative. 1,4-Reduction of pyridine ring gave the compound of the formula-X as major isomer. Liberation of the protecting group and reduction of the dihydropyridine ring gave the required compound of the formula-I.

Scheme-II

Disadvantages of this process are that it requires a costly and rarely available chiral amine (N, N'-dimethyl-2, 3-diphenylethylenediamine). Also, formation of piperidine ring requires a hydrogenation step which would lead to the formation of a desfluoro impurity in the process. Removal of this impurity from required compound of formula-I is very difficult.

Stereoselective synthesis of the compound of the formula-I is disclosed in US patent no 5,962, 689 using a starting material of formula-XIII where R is chiral auxiliary which controls the stereochemistry during 1,4-Michael addition of organometallic reagents (Scheme-III). Ratio of the required isomer formed in this process is only 80%. Remaining 20% of the unwanted isomer was removed by separation techniques such as column chromatography. F F tR t R 0--ll- XH ! N N R' R III R = chiral alcohol or amine XIV XV t\oH t \ X > F F I\ I\ N N" ,,,N OU O I I Scheme-III

Main drawback of this process is that the compound of formula-I is produced with 80% purity. Increasing the purity to required level needs a column chromatography which is not commercially viable.

Keeping in view of the difficulties in commercialization of the above mentioned processes we aimed to develop a versatile method that could control the stereochemistry at C-3 and C-4 of compound of the formula-I in more than 95%.

SUMMARY OF INVENTION Recently we developed a novel process (shown in Scheme-IV) for the preparation of ()- trans compound of formula-I which is the subject matter of our Indian patent application bearing no 830/MAS/2002. According to the process disclosed in the said patent application the compound of the formula-XVI is reacted with an acrylate ester and converted the hydroxy group present in the compound of the formula-XVII to a leaving group and treated with a strong base to get the piperidine derivative of the formula-XIX.

Reduction of the ester group present in compound of formula-XIX with a reducing agent gave the compound of formula-I.

Scheme-IV Piperidin ring formation in the above mentioned process is an intramolecular nucleophilic displacement reaction. If the stereochemistry of the leaving group OX in compound of formula-XVIII is fixed, the cyclized product of formula-XIX is also expected to be of stereospecific with opposite stereochemistry. Accordingly, to get the required compound of the formula-I (3S, 4R-isomer), starting compound of the formula- XVI should have the opposite stereochemistry, i. e. , S-configuration at the asymmetric center of the compound of formula-XVIII.

Accordingly, process for the preparation of the compound of the formula-I is as given below: F F F F Resolution with I I I chiral acid oc OH OH OH OH L L. - L * r*o R N Ph N Ph"NH N" ( ( XX XXI XXI XXIII F F F co 2R < sOX f CO2R C) * OH k . CO, R L J L. J ox OH ( XXIV (-)-XXV (-)-I

Scheme-V The amine compound of the formula-XX can be resolved into a chiral amine of the formula-XXI and debenzylated under hydrogenation conditions to get the secondary amine of formula-XXII. The secondary amine of formula-XXII can be reacted with acrylic acid esters to give the corresponding N-alkylated derivative of the formula-XXIII.

The hydroxy group present in the compound of the formula-XXIII can be converted to a leaving group OX (X = methanesulfonyl-, toluenesulfonyl-, benzenesulfonyl) to get a compound of the formula-XXIV.

The compound of the formula-XXV can be prepared by the generation of an anion a to the ester carbon present in compound of the formula XXIV and. intramolecular cyclization through displacement of the leaving group OX. The ester group present in compound of the formula-XXV can be reduced with a number of reagents like sodium borohydride or lithium aluminum hydride to get the desired compound of the formula-I in more than 97% chiral purity.

DETAILED DESCRIPTION OF INVENTION In a preferred embodiment of the present invention, compound of the formula-XX can be resolved into its single isomers by treating it with a chiral acid and preferential crystallization of the required salt in a suitable solvent. The acid used in the resolution step is selected from (+)-Mandelic acid, (+) -camphorsulphonic acid, (+)-di-p- toluoyltartaric acid, (+) -tartaric acid, etc. , preferably (+) -Mandelic acid. The solvent used in the crystallization step is selected from alcoholic solvents such as methanol, ethanol, isopropanol, n-butanol, t-butanol, etc. , preferably methanol, ethanol, isopropanol, more preferably isopropanol. The solvent used for the recrystallization of the resolved amine salt is same as the solvent used for crystallization or different. The quantity of chiral acid used in the resolution step is at least one molar equivalent to the amine.

Chiral amine of the formula-XXI can be isolated from diastereomeric salt by neutralization with inorganic base and extraction of liberated amine with a solvent. The inorganic base used for neutralization of salt is selected from sodium or potassium carbonate, bicarbonate, hydroxide, preferably sodium hydroxide. The solvent used for extraction of liberated amine is selected from hydrocarbon solvents such as toluene, hexane, heptane, cyclohexane, etc, preferably toluene, or cyclohexane. Chiral purity of the amine by chiral HPLC was found to be more than 99.9%.

The resolved amine of formula-XXI can be hydrogenated in the presence of heterogeneous metal catalyst to get the secondary amine of formula-XXII. The hydrogenation can be done on free amine of formula-XXI or on its acid addition salt. The acids used for salt formation are selected from organic or mineral acids. The organic acids include, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, toluic acid, mandelic acid, tartaric acid, methanesulfonic acid, camphorsulfonic acid, etc. The mineral acids used can be such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphate, etc. The metal catalyst used in hydrogenation is selected from 2-10% palladium-on-carbon, Raney nickel.

The chiral amine of formula-XXII can be reacted with methyl or ethyl acrylate to get the 1,4-addition product of formula-XXIII. The reaction can be done in a number solvents such as toluene, xylene, cyclohexane, hexane, heptane, methylene chloride, THF, ether, diisopropyl ether, 1, 4-dioxane, acetonitrile, etc. , preferably toluene or heptane. The temperature of the reaction is in the range of 20-90°C, preferably 50-60°C. Compound of formula-XXIII can be isolated from the reaction mass by simple distillation of solvent and excess reagent.

Hydroxy group present in compound of formula-XXIII can be converted into a facile leaving group such as benzenesulfonate, methanesulfonate, toluenesulfonate, trifluoromethanesulfonate, etc. , preferably methanesulfonate or benzenesulfonate. The reaction can be done in various solvents such halogenated solvents (methylene chloride, dichloroethane, chloroform, et.), hydrocarbon solvents (toluene, cyclohexane, hexane, heptane) or ether solvents (diethyl ether, diisopropyl ether, dioxane, THF).

The sulfonate derivatives of the formula-XXIV can be reacted with a strong base (NaH, n-butyl lithium, potassium t-butoxide, lithium diisopropyl amide, etc. ) in a hydrocarbon/ether and/or dipolar aprotic solvent such as N, N-dimethylformamide, N, N- dimethylacetamide, dimethyl sulfoxide. The ether solvent used is such as tetrahydrofuran, dioxane, diisopropyl ether and the hydrocarbon solvent used is such as toluene, hexane, heptane, cyclohexane, xylene.

The cyclized compound of the formula-XXV can be reduced using sodium borohydride under various conditions (sodium borohydride/borontrifluoride-etherate, sodium borohydride/t-butanol/methanol, reflux; t-butanol/acetic acid, etc.), vitride, sodium/ethanol, lithium tris- (t-butoxy) aluminum hydride, lithium aluminum hydride, etc., to get the required compound of the formula-I. The medium of the reaction can be an alcoholic solvent (for sodium borohydride), hydrocarbon solvent for vitride, and an ether solvent for lithium reagents.

The invention provides novel chiral compound of the formula-XXI,

its isomer and the acid addition salts.

Accordingly the invention also provides a process for the preparation of chiral compound of the formula-XXI,

which comprises: (i) Reacting the compound of the formula-XX,

with a chiral acid in an organic solvent to get preferentially crystalline (S, S)- diastereomeric salt (ii) Recrystallizing the (S, S) -diastereomeric salt in a solvent to enhance the chiral purity to >99.5% (iii) Neutralizing the (S, S) -diastereomeric salt with an inorganic base (iv) Extracting the liberated chiral amine of the formula-XXI into an organic solvent (v) Removing the solvent by distillation to get the chiral amine of formula-XXI

The chiral acid used in resolution step (i) is selected from (+)-Mandelic acid, (+)- camphorsulfonic acid, (+) -tartaric acid, (+) -di-p-toluoyltartaric acid, etc. , preferably (+)- mandelic acid. The solvent used in step (i) and (ii) is selected from alcoholic solvent such c as methanol, ethanol, isopropanol, t-butanol, etc. , preferably methanol or isopropanol, or a combination of alcoholic solvent with ether solvent such as THF, dioxane, etc. , or a hydrocarbon solvent such as toluene, xylene, cyclohexane, heptane, etc.

The inorganic base used in neutralization step (iii) is selected from sodium or potassium hydroxide, carbonate, bicarbonate, etc. The solvent used for extraction of chiral amine in step (iv) is selected from hydrocarbon solvent such as toluene, xylene, hexane, heptane, cyclohexane, etc.; ester solvent such as ethyl acetate, isopropyl acetate; ether solvent such as diethyl ether, diisopropyl ether, methyl isobutyl ether, methyl t-butyl ether ; halogenated solvent such as methylene chloride, ethylene chloride, chloroform.

The invention provides novel chiral compound of the formula-XXII,

XXII its isomer and acid addition salts.

Accordingly the invention also provides a process for the preparation of chiral compound of the formula-XXII,

XXII which comprises: (i) Resolution of the amine compound of formula-XX, With a chiral acid to get the resolved amine of formula-XXI,

XXI (ii) Hydrogenation of the acid addition salt of the resolved amine of formula-XXI using a metal catalyst under heterogeneous conditions to get the secondary amine of formula-XXII.

The invention provides novel compounds of formula-XXIII,

XXIII wherein R = Me or Et its isomer and acid addition salts.

Accordingly, the invention provides a process for the preparation of compounds of the formula-XXIII,

wherein R = Me or Et which comprises : (i) Resolution of the amine compound of formula-XX, xx With a chiral acid to get the resolved amine of formula-XXI,

XXI (ii) Hydrogenation of the acid addition salt of the resolved amine of formula-XXI using a metal catalyst under heterogeneous conditions to get the secondary amine of formula-XXII,

(iii) Reaction of the chiral amine offbrmuIa-XXIl with methyl or ethyl acrylate in the presence of a solvent at an elevated temperature to get the 1,4-addition product of the formula-XXIII.

The chiral acid used in resolution step (i) is selected from (+)-Mandelic acid, (+)- camphorsulfonic acid, (+) -tartaric acid, (+) -di-p-toluoyltartaric acid, etc., preferably (+)- mandelic acid. The acids used for salt formation during hydrogenation step (ii) are selected from organic or mineral acids. The organic acids include acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, toluic acid, mandelic acid, tartaric acid, methanesulfonic acid, camphorsulfonic acid, etc. The mineral acids used can be such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphate, etc. The metal catalyst used in hydrogenation is selected from 2-10% palladium-on-carbon, Raney nickel. The acid addition salt of the compound of formula-XXII thus obtained can be neutralized with a base and extracted into a suitable organic solvent.

The solvent used in step (iii) is selected from toluene, xylene, cyclohexane, hexane, heptane, methylene chloride, THF, ether, diisopropyl ether, 1,4-dioxane, acetonitrile, etc., preferably toluene or heptane. The temperature of the reaction in step (iii) is in the range of 20-90°C, preferably 50-60°C. Compound of formula-XXIII can be isolated from the reaction mass by simple distillation of solvent and excess reagent.

The invention provides novel compounds of formula-XXIV,

Wherein X = Ms, Bs, Ts, CF3SO2 ; R = Me or Et And its isomers The invention provides a process for the preparation of compound of formula-XXIV,

XXIV Wherein X = Ms, Bs, Ts, CF3SO2 ; R = Me or Et, Which comprises: (i) Resolution of the amine compound of formula-XX, xx With a chiral acid to get the resolved amine of formula-XXI,

XXI (ii) Hydrogenation of the acid addition salt of the resolved amine of formula-XXI using a metal catalyst under heterogeneous conditions to get the secondary amine of formula-XXII,

(iii) Reaction of the chiral amine of formula-XXII with methyl or ethyl acrylate in the presence of a solvent at an elevated temperature to get the, 1,4-addition product of the formula-XXIII,

XXIII (iv) Conversion of the hydroxy group present in the compound of the formula- XXIII into a leaving group OX with appropriate reagent in a solvent medium with or without a base at low temperature or elevated temperature to get the compound of formula-XXIV The invention provides an improved process for the preparation of compound of the formula-1,

(-)-I Which comprises: (i) Resolution of the amine compound of formula-XX,

XX With a chiral acid to get the resolved amine of formula-XXI, XXI (ii) Hydrogenation of the acid addition salt of the resolved amine of formula-XXI using a metal catalyst under heterogeneous conditions to get the secondary amine of formula-XXII, XXII (iii) Reaction of the chiral amine of formula-XXII with methyl or ethyl acrylate in the presence of a solvent at an elevated temperature to get the 1,4-addition product of the formula-XXIII,

XXIII (iv) Conversion of the hydroxy group present in the compound of the formula- XXIII into a leaving group OX with appropriate reagent in a solvent medium with or without a base at low temperature or elevated temperature to get the compound of formula-XXIV,

XXIV Wherein X = Ms, Bs, Ts, CF3SO2 ; R = Me or Et, (v) Reacting the compound of the formula-XXIV with a strong base in the presence in a hydrocarbon/ether and/or dipolar aprotic solvent at a temperature in the range of-20 to 40 °C to get the cyclized compound of formula-XXV,

Wherein R = Me or Et (vi) Reducing the ester group present in the compound of the formula-XXV with a reducing agent to get the compound of the formula-I.

The chiral acid used in resolution step (i) is selected from (+)-Mandelic acid, (+)- camphorsulfonic acid, (+) -tartaric acid, (+) -di-p-toluoyltartaric acid, etc., preferably (+)- mandelic acid.

The acids used for salt formation during hydrogenation step (ii) are selected from organic or mineral acids. The organic acids include acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, toluic acid, mandelic acid, tartaric acid, methanesulfonic acid, camphorsulfonic acid, etc. The mineral acids used can be such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphate, etc. The metal catalyst used in hydrogenation is selected from 2-10% palladium-on-carbon, Raney nickel. The acid addition salt. of the compound of formula-XXII thus obtained can be neutralized with a base and extracted into a suitable organic solvent.

The acrylate ester used in step (iii) is selected from methyl or ethyl acrylate and the like.

The solvent used in step (iii) is selected from toluene, xylene, cyclohexane, hexane, heptane, methylene chloride, THF, ether, diisopropyl ether, 1,4-dioxane, acetonitrile, etc., preferably toluene or heptane. The temperature of the reaction in step (iii) is in the range of 20-90°C, preferably 50-60°C.

borohydide/t-butanol/methanol, vitride, lithium aluminum hydride. The temperature of reaction in step (vi) is in the range of -50°C to 70°C, preferably -20°C to 20°C.

The chiral purity of the (-) -trans isomeric compound of formula-XXV obtained from the reaction is in the range of 95-98%. Chiral purity can be raised to more than 99.8% after converting it to the required compound of the formula-I and crystallization of compound of formula-1. Alternatively, chiral purity of compound of formula-XXV can be raised to >99.8% by forming a diastereomeric salt with a chiral acid and neutralization of the diastereomeric salt with a base.

The details of the invention are given in the Examples given below which are provided to illustrate the invention only and therefore should not be construed to limit the scope of the present invention.

Example 1 Preparation of (+)-N-methyl-N- [3-hydroxy-3- (4-fluorophenyl)] propylamine (i) Preparation of (+)-N-benzyl-N-methyl-N- [3-hydroxy-3- (4-fluorophenyl)] propyl- amine (+)-mandelic acid salt Into a 2-L, three-necked RB flask was charged 200 g of ()-N-benzyl-N-methyl-N- [3- hydroxy-3- (4-fluorophenyl)] propyl-amine, 650 mL of isopropanol, and 110 g of (+)- mandelic acid. The reaction mass was heated to 50-55 °C and maintained for 1 hr to get a clear solution. The reaction mass was allowed to cool to 25-30 °C and filtered and the wet solid washed with 50 mL of isopropanol to get 140 g of (+)-N-benzyl-N-methyl-N- [3-hydroxy-3- (4-fluorophenyl)] propyl-amine (+)-mandelic, acid salt. Optical rotation is +54.44 (c=1, MeOH).

The above crude mandelate salt was taken into a 2-L, three-necked, RB flask and added 600 mL of isopropanol. After heating to 70 °C a clear solution formed. The resultant solution was allowed to cool to 25-30 °C and maintained for 1 hr. The reaction mass was filtered and the solid washed with 100 mL of isopropanol to get 125 g of pure mandelate

The reagents used in step (iv) for the conversion of the hydroxy group to OX is selected from methanesulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride, p- toluenesulfonyl chloride, acetyl chloride, benzoyl chloride, trifluoromethanesulfonyl chloride, etc. , preferably, methanesulfonyl chloride, benzenesulfonyl chloride.

The solvent used in step (iv) is selected from methylene chloride, ethylene dichloride, toluene, cylcohexane, heptane, THF, ether, diisopropyl ether etc. , preferably, methylene chloride, toluene or heptane and the reaction temperature is in the range of-20 to 25°C, preferably-5 to 15°C. The base used in step (iv) is selected from triethylamine, pyridine, lutidine, sodium or potassium carbonate, or bicarbonate, etc. , preferably, pyridine or triethylamine.

The strong base used in step (v) is selected from sodium hydride, butyl lithium, hexyl lithium, lithium diisopropylamide, sodium t-butoxide, potassium t-butoxide, sodium sec- amyloxide, sodium amide, lithium amide, sodium methoxide, and the like, preferably sodium hydride or lithium diisopropylamide.

The solvent used in step (v) is selected from N, N-dimethylformamide, N, N- dimethylacetamide, pyridine, dimethylsulfoxide, tetrahydrofuran, dioxane, toluene, xylene, diisopropyl ether, etc. , preferably N, N-dimethylformamide, dimethylsulfoxide, pyridine, tetrahydrofuran, more preferably N, N-dimethylformamide, tetrahydrofuran. The temperature of reaction in step (v) is between-10 and 45°C, preferably-5 to 25°C. The mole ratio of base to substrate in step (v) is in the range of 1: 1.1 to 1: 2.0, preferably 1: 1.25.

The reducing agent used in step (vi) is selected from sodium borohydride/t- butanol/methanol, sodium borohydride in the presence of an acid catalyst like boron trifluoride-etherate, sulfuric acid, etc.; vitride, lithium aluminum hydride, lithium tris- (t- butoxy) aluminum hydride, sodium/ethanol, and the like, preferably, sodium

salt. Optical rotation is +62. 7 (c = 1, MeOH). Melting point is l l0-111 °C. Chiral purity by HPLC is 100%.

(ii) Preparation of (+)-N-benzyl-N-mettyl-N- [3-hydroxy-3- (4-fluorophenyl)] propyl- amine Into a 1-L, three-necked, RB flask were charged 450 mL of isopropanol and 11.5 g of sodium hydroxide. After stirring the reaction mass for 20 min, 125 g of step (i) salt was added to the reaction mass and kept under stirring for 6 hr. The reaction mass was filtered and the cake washed with 100 mL of isopropanol and dried to get 40 g of sodium mandelate. The isopropanol filtrate was taken into a RB flask and distilled off solvent under vaccum. The residue was suspended in water (150 mL) and extracted with toluene (2 x 300 mL). The toluene layer was washed with water, dried and evaporated under vaccum to get 82 g of (+)-N-benzyl-N-methyl-N- [3-hydroxy-3- (4-fluorophenyl)] propyl- amine as liquid. Optical rotation is +22.36 (c = 1, MeOH).

(iii) (+)-N-methyl-N- [3-hydroxy-3- (4-ftuorophenyl)] propyIamine Into a 1-L stainless steel kettle are charged 50 g of above step (ii) compound, 500 mL of isopropanol, 11 g of acetic acid, and 2.5 g of 5% palladium-on-carbon (50% wet). After evacuating the kettle it was filled with hydrogen and shaken under hydrogen pressure of 40-60psi at room temperature. After maintaining under hydrogen pressure for 6 hr reaction mass was filtered and the filtrate distilled under vaccum to get 43 g of crude acetate salt of (+)-N-methyl-N- [3-hydroxy-3- (4-fluorophenyl)] propylamine. The crude salt was suspended in toluene (40 mL) and filtered to get 40 g of pure white crystalline acetate salt. Melting point is 127 °C. Optical rotation is +41.4 (c = 1, MeOH). Purity by HPLC is 99.3% and the des-fluoro impurity is 0.07%.

The above acetate salt was taken into a 1-L, three-necked RB flask and added a solution of aqueous sodium hydroxide (8 g of sodium hydroxide dissolved in 120 mL of water). After stirring for 30 min toluene (100 mL) was added to the reaction mass. Toluene layer was separated and the aqueous layer extracted with 50 mL of toluene. Combined toluene layer was washed with water, dried and distilled off solvent under vaccum to get 30 g

liquid (+)-N-methyl-N- [3-hydroxy-3- (4-fluorophenyl)] propylamine. Optical rotation is +32.3 (c = 1, MeOH). HPLC purity is 99. 9%.

Example 2 Preparation of (-)-N-methl-N-13-hydroxy-3-(4-fluorophenyl) l propylamine (i) Preparation of (-)-N-benzyl-N-methyl-N- [3-hydroxy-3- (4-fluorophenyl) lpropyl- amine (-)-mandelic acid salt Into a 2-L, tluee-necked RB flask was charged 200 g of ()-N-benzyl-N-methyl-N- [3- hydroxy-3- (4-fluorophenyl) propyl-amine, 650 mL of isopropanol, and 110 g of (-)- mandelic acid. The reaction mass was heated to 50-55 °C and maintained for 1 hr to get a clear solution. The reaction mass was allowed to cool to 25-30 °C and filtered and the wet solid washed with 100 mL of isopropanol to get 138 g of (-)-N-benzyl-N-methyl-N- [3-hydroxy-3- (4-fluorophenyl)] propyl-amine (-) -mandelic acid salt. Optical rotation is- 55.40 (c =1, MeOH).

The above crude mandelate salt was taken into a 2-L, three-neclced, RB flask and added 600 mL of isopropanol. After heating to 70 °C a clear solution formed. The resultant solution was allowed to cool to 25-30 °C and maintained for 1 hr. The reaction mass was filtered and the solid washed with 100 mL of isopropanol to get 120 g of pure mandelate salt. Optical rotation is-62.1 (c = 1, MeOH). Melting point is 110-111 °C. Chiral purity by HPLC is 99. 5%.

(ii) Preparation of (-)-N-benzyl-N-metliyl-N- [3-hydroxy-3- (4-fluorophenyl)] propyl- amine Into a 1-L, three-necked, RB flask were charged 450 mL of isopropanol and 11 g of sodium hydroxide. After stirring the reaction mass for 20 min, 120 g of step (i) salt was added to the reaction mass and kept under stirring for 6 hr. The reaction mass was filtered

and the cake washed with 100 mL of isopropanol and dried to get 40 g of sodium mandelate. The isopropanol nitrate was taken into a RB flask and distilled off solvent under vaccum. The residue was suspended in water (150 mL) and extracted with toluene (2 x 300 mL). The toluene layer was washed with water, dried and evaporated under vaccum to get 80 g of (-)-N-benzyl-N-methyl-N- [3-hydroxy-3- (4-fluorophenyl)] propyl- amine as liquid. Optical rotation is-22.1 (c = 1, MeOH).

(iii) (-)-N-methyl-N- [3-hydroxy-3- (4-fluorophenyl)] propylamine Into a 1-L stainless steel kettle are charged 50 g of above step (ii) compound, 500 mL of isopropanol, 11 g of acetic acid, and 2.5 g of 5% palladium-on-carbon (50% wet). After evacuating the kettle it was filled with hydrogen and shaken under hydrogen pressure of 40-60psi at room temperature. After maintaining under hydrogen pressure for 6 hr reaction mass was filtered and the filtrate distilled under vaccum to get 43 g of crude acetate salt of (-)-N-methyl-N- [3-hydroxy-3- (4-fluorophenyl)] propylamine. The crude salt was suspended in toluene (40 mL) and filtered to get 40 g of pure white crystalline acetate salt. Melting point is 127 °C. Optical rotation is-41.4 (c = 1, MeOH). Purity by HPLC is 99.4% and the des-fluoro impurity is 0.06%.

The above acetate salt was taken into a 1-L, three-necked RB flask and added a solution of aqueous sodium hydroxide (8 g of sodium hydroxide dissolved in 120 mL of water).

After stirring for 30 min toluene (100 mL) was added to the reaction mass. Toluene layer was separated and the aqueous layer extracted with 50 mL of toluene. Combined toluene layer was washed with water, dried and distilled off solvent under vaccum to get 30 g of (-)-N-methyl-N- [3-hydroxy-3- (4-fluorophenyl)] propylamineas colorless liquid. Optical rotation is-32.0 (c = 1, MeOH). HPLC purity is 99. 8%.

Example 3 Preparation of (3S, 4R)-trans-4- (4-fluorophenyt)-3-hydroxymethyl-l-methyl- piperidine of the formula-1

(i) Preparation of meth5l (+)-3- [N-methyl-N- (3-hydroxy-3- (4-fluorophenyl) propyl)]- aminopropionate Into a 1-L, three-necked, RB flask was charged 100 g of (+)-N-methyl-N- [3-hydroxy-3- (4-fluorophenyl) ] propylamine and 300 mL of toluene. Methyl acrylate (48 g) was added to the reaction mixture. The reaction mixture was slowly heated to 60-65 °C and maintained for 7 hr. The reaction mixture was cooled to 40 °C and toluene distilled off under vaccum. The residue was dissolved in hexane (150 mL), cooled to 0-5 °C, and filtered to give 140 g of white solid. Melting point is 43. 3 °C. Optical rotation is +23.5 (c = 1, MeOH).

(ii) Preparation of methyl (+)-3- [N-methyl-N- (3-methanesulfonyloxy-3- (4-fluoro- phenyl) propyl) ] aminopropionate Into a 2-L, three-necked, RB flask was charged 850 mL of methylene chloride and 100 g of methyl (+)-3- [N-methyl-N- (3-hydroxy-3- (4-fluorophenyl) propyl) ] aminopropionate under nitrogen atmosphere. The reaction mixture was cooled to-5 to 0 °C and triethylamine (51 g) was added. A solution of methanesulfonyl chloride (51 g) in methylene chloride (100 mL) was added to the reaction mixture slowly over a period of 4-5 hr and kept under maintenance for additional 10 hr. The reaction mixture was poured into 450 mL of chilled water and extracted the product into methylene chloride. Aqueous layer was extracted with 2 x 150 mL of methylene chloride. Combined methylene chloride layer was washed with water and dried over sodium sulfate. Distillation of methylene chloride gave the crude compound (89 g) as syrup. This was found to be sufficiently pure enough for further conversion. Optical rotation is +60.0 (c = 1, MeOH).

(iii) Preparation of (3S, 4R)-trans-3-carbomethoxy-4- (4-fluorophenyl)-N-methyl- piperidine Into a 1-L, three-necked, RB flask were charged 400 mL of dry DMF and 89 g of compound obtained in step (ii) above under nitrogen atmosphere. The reaction mixture was cooled to-15 to-10 °C and added sodium hydride (14. 5 g, 55%) in lots over a period of 1 hr. The reaction mixture was maintained at same temperature for 3 hr and slowly allowed to reach 25-30 °C over a period of 5-6 hr. The reaction mixture was maintained

at 25-30 °C for 12-13 l1r and found to be over by TLC. The reaction mixture was cooled to 5-10 °C and quenched with methanol (20 mL). The reaction mixture was poured into 2.3L of chilled water. Toluene (600 mL) was added to the reaction mixture and stirred for 1 hr. Toluene layer was separated and the aqueous layer extracted with toluene (2 x 100 mL). The combined organic layer was washed with water and product extracted into 10% aqueous acetic acid (1 x 400 mL, 2 x 150 mL). Combined acetic acid layer was extracted with 100 mL of toluene. Aqueous acetic acid layer was treated with carbon and neutralized with sodium bicarbonate. The product thus obtained was extracted into toluene (1 x 400 mL, 2 x 150 mL). Toluene was distilled off from the organic layer to leave 47 g of crude compound as syrup. Optical rotation is-45.0 (c = 1, MeOH).

(iv) Preparation of (3S, 4R)-trans-4- (4-fluorophenyl)-3-hydroxymethyl-1-methyl- piperidine Into a 1-L, three-necked, RB flask was charged 47 g of the crude compound obtained in step (iii) above and t-butanol (300 mL). Sodium borohydride (10 g) was added to the reaction mixture and heated to reflux temperature. Methanol (50 mL) was added in lots to the reaction mixture over a period of 6 hr. After the last lot addition reaction mixture was maintained at reflux for 2 hr and checked the TLC. Reaction mixture was quenched with 5 mL of acetic acid. Solvent was removed from the reaction mixture under vaccum and water (200 mL) added to the reaction mass. pH of the reaction mass was adjusted to 8-9 with sodium bicarbonate Compound was extracted into toluene (2 x 100 mL). Toluene layer was dried and distilled under vaccum to get 37 g of the crude product. Optical rotation is-35.4 (c = 1, MeOH). Chiral purity by HPLC is 97.5%. The crude compound was crystallized from hexane/toluene to get the pure compound of the formula-I as off- white solid (30 g). Purity by HPLC is 98.5%. Melting point is 98-99 °C.

Example 4 Preparation of (3S, 4R)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methyl- piperidine of formula-I

(i) Preparation of (3S, 4R)-trans-3-carbomethoxy-4- (4-fluorophenyl)-N-methyl- piperidine (-)-mandelic acid salt Into a I-L, three-necked, RB flask was charged 100 g of crude (3S, 4R)-trans-3- carbomethoxy-4- (4-fluorophenyl)-N-methyl-piperidine obtained according to the procedure given in Example 3 step (iii), 450 mL of isopropanol, and 60 g of (-)-mandelic acid. The reaction mass was heated to 55-60 °C to get a clear solution. The reaction mass was slowly cooled to 25-30 °C and kept under stirring for 12-15 hr. The reaction mass was further cooled-to 5-10 °C and filtered the mass. The wet cake thus obtained was washed with 50 mL of isopropanol and dried to get 135 g of white solid. Melting point is 120 °C. Optical rotation is-69.4 (c = 1, MeOH).

(ii) Preparation of (3S, 4R)-trans-4- (4-fluorophenyl)-3-hydroxymethyl-1-methyl- piperidine Into a 2-L, three-necked RB flask were charged 500 mL of water, 200 mL of toluene, and 135 g of the compound obtained in step (i) above. Sodium bicarbonate (38 g) was slowly added to the reaction mass under stirring. Layers were separated and the aqueous layer extracted with 2 x 100 mL of toluene. Combined toluene layer was washed with water, dried and evaporated under vaccum to get 83 g of pure (3S, 4R)-trans-3-carbomethoxy-4- (4-fluorophenyl)-N-methyl-piperidine. Optical rotation is-49.5 (c = 1, MeOH).

Into a 1-L, three-necked RB flask was charged 300 mL of anhydrous THF under nitrogen atmosphere. Lithium aluminum hydride (7.5 g) was added to THF and cooled to-30 °C.

A solution of 50 g of above pure (3S, 4R)-trans-3-carbomethoxy-4- (4-fluorophenyl)-N- methyl-piperidine in 100 mL of anhydrous THF was slowly added to the reaction mass over a period of 1 hr keeping the temperature below-25°C. After stirring for 30 min reaction was found to be over by TLC. The reaction was quenched by adding 15 mL of water and stirred for Ihr at 25-30 °C. The inorganic solids were removed by filtration and washed the salts with 200 mL of ethyl acetate. Solvents were distilled off from the filtrate and the residue dissolved in 200 mL of toluene and washed with 100 mL of water.

Toluene was distilled off under vaccum to get 41 g of residue which was crystallized using hexane/toluene (9: 1) to get 37 g of pure (3S, 4R)-trans-4- (4-fluorophenyl)-3-

hydroxymethyl-l-methyl-pipericline as white solid. Melting point is 99.5 °C. Optical rotation is-38.1 (c = 1, Merl-1). Chiral purity by HPLC is 100%. Chemical purity by HPLC is 99.7%.

Example 5 Preparation of (3S, 4It)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methyl- piperidine of formula-I (i) Preparation of ethyl (+)-3- [N-methyl-N- (3-hydroxy-3- (4-fluorophenyl) propyl)]- aminopropionate Into a 1-L, three-necked, RB flask was charged 63 g of (+)-N-methyl-N- [3-hydroxy-3- (4- fluorophenyl) ] propylamine and 200 mL of toluene. Ethyl acrylate (35 g) was added to the reaction mixture. The reaction mixture was slowly heated to. 60-65 °C and maintained for 7 hr. The reaction mixture was cooled to 40 °C and toluene distilled off under vaccum to leave the title compound (93 g) as syrup. Optical rotation is +19. 4 (c = 1, MeOH).

(ii) Preparation of ethyl (+)-3- [N-methyl-N- (3-methanesulfonyloxy-3- (4-fluoro- phenyl) propyl) aminopropionate Into a 2-L, three-necked, RB flask was charged 700 mL of methylene chloride and 81 g of ethyl (+)-3- [N-methyl-N- (3-hydroxy-3- (4-fluorophenyl) propyl) ] aminopropionate under nitrogen atmosphere. The reaction mixture was cooled to-5 to 0 °C and triethylamine (38.2 g) was added. A solution of methanesulfonyl chloride (38 g) in methylene chloride (100 mL) was added to the reaction'mixture slowly over a period of 4-5 hr and kept under maintenance for additional 10 hr. The reaction mixture was poured into 400 mL of chilled water and extracted the product into methylene chloride. Aqueous layer was extracted with 2 x 150 mL of methylene chloride. Combined methylene chloride layer was washed with water and dried over sodium sulfate. Distillation of methylene chloride gave the crude compound (70 g) as syrup. This was found to be sufficiently pure enough for further conversion. Optical rotation is +54.3 (c = 1, MeOH).

(iii) Preparation of (3S, 41R)-trans-3-carboethoxy-4- (4-fluorophenyl)-N- methylpipcridine Into a 1-L, three-necked, RB flask were charged 350 mL of dry DMF and 63 g of compound obtained in step (ii) above under nitrogen atmosphere. The reaction mixture was cooled to-15 to-10 °C and added sodium hydride (11 g, 55%) in lots over a period of 1 hr. The reaction mixture was maintained at same temperature for 3 hr and slowly allowed to reach 25-30 °C over a period of 5-6 hr. The reaction mixture was maintained at 25-30 °C for 12-13 hr and found to be over by TLC. The reaction mixture was cooled to 5-10 °C and quenched with ethanol (20 mL). The reaction mixture was poured into 700 mL of chilled water. Toluene (500 mL) was added to the reaction mixture and stirred for 1 hr. Toluene layer was separated and the aqueous layer extracted with toluene (2 x 100 mL). The combined organic layer was washed with water and product extracted into 5% aqueous acetic acid (1 x 300 mL,-2 x 100 mL). Combined acetic acid layer was extracted with 100 mL of toluene. Aqueous acetic acid layer was treated with carbon and neutralized with sodium bicarbonate. The product thus obtained was extracted into toluene (1 x 500 mL, 2 x 100 mol). Toluene was distilled off from the organic layer to leave 32 g of crude compound as syrup. Optical rotation is-45.3 (c = 1, MeOH).

Into a 500-mL, three-necked, RB flask were charged 30 g of above crude compound, 150 mL of isopropanol, and 18 g of (-) -mandelic acid. The reaction mixture was heated 55-60 °C and maintained for 1 hr. The resultant solution was slowly allowed to cool to 25-30 °C and maintained for 15 hr. The reaction mixture was cooled to 5-10 °C and filtered the salt. Washed the salt with 50 mL of isoporpanol and dried at 40-50 °C to get 43 g of white solid. Melting point is 117-118 °C. Optical rotation is-65.3 (c = 1, MeOH).

Into a 1-L, three-necked RB flask were charged 40 g of above salt, 250 mL of water and 250 mL of toluene. Sodium bicarbonate (15 g) was added to the reaction mixture./ Toluene layer was separated and the aqueous layer extracted with 2 x 100 mL of toluene.

Combined toluene layer was dried, and evaporated to get 26 g of pure compound as syrup. Optical rotation is-47. 1 (c = 1, MeOH).

(iv) Preparation of (3S, =tl2)-trans-4- (4-fluoroplienyl)-3-hydroxymethyl-1-methyl- piperidine Into a 1-L, three-necked, RB itask were charged 10 g of the above step (iii) compound and 70 mL oft-butanot. Sodium borohydride (2 g) was added to the reaction mixture and heated to reflux temperature. Methanol (20 mL) was added in lots to the reaction mixture over a period of 6 hr. After the last lot addition reaction mixture was maintained at reflux for 2 hr and checked the TLC. Reaction mixture was quenched with 2 mL of acetic acid.

Solvent was removed from the reaction mixture under vaccum and added water (100 mL) to the residue. pH of the reaction mass was adjusted to 8-9 with sodium bicarbonate and the product extracted into toluene (2 x 75 mL). Toluene layer was dried and distilled under vaccum to get 7 g of the crude product. Optical rotation is-37.8 (c = 1, MeOH).

Chiral purity by HPLC is 99.5%.

Example 6 Preparation of (3R, 4S)-trans-4- (4-fluorophenyl)-3-hydroxymethyl-1-methyl- piperidine (i) Preparation of methyl (-)-3- [N-methyl-N- (3-hydroxy-3- (4-fluorophenyl) propyl)]- aminopropionate Into a 1-L, three-necked, RB flask were charged 100 g of (-)-N-methyl-N- [3-hydroxy-3- (4-fluorophenyl)] propylamine obtained as per the procedure given in Example 2 and 300 mL of toluene. Methyl acrylate (48 g) was added to the reaction mixture. The reaction mixture was slowly heated to 60-65 °C and maintained for 7 hr. Toluene was distilled off from the reaction mixture under vaccum. The residue was dissolved in hexane (150 mL), cooled to 0-5 °C, and filtered to give 138 g of white solid. Melting point is 43 °C. Optical rotation is-23.3 (c = 1, MeOH).

(ii) Preparation of methyl (-)-3- [N-methyl-N- (3-methanesulfonyloxy-3- (4-fluoro- phenyl) propyl) aminopropionate of the formula-XXII Into a 2-L, three-necked, RB flask was charged 850 mL of methylene chloride and 100 g of methyl (-)-3- [N-methyl-N- (3-hydroxy-3- (4-fluorophenyl) propyl) ] aminopropionate under nitrogen atmosphere. The reaction mixture was cooled to-5 to 0 °C and

triethylamine (51 g) was added. A solution of methanesulfonyl chloride (51 g) in methylene chloride (100 mL) was added to the reaction mixture slowly over a period of 4-5 hr and kept under maintenance for additional 10 hr. The reaction mixture was poured into 450 mL of chilled water and extracted the product into methylene chloride. Aqueous layer was extracted with 2 x 150 mL of methylene chloride. Combined methylene chloride layer was washed with water and dried over sodium sulfate. Distillation of methylene chloride gave the crude compound (86 g) as syrup. This was found to be sufficiently pure enough for further conversion. Optical rotation is-59.5 (c = 1, MeOH).

(iii) Preparation of (3R, 4S)-trans-3-carbomethoxy-4- (4-fluorophenyl)-N-methyl- piperidine Into a 1-L, three-necked, RB flask were charged 400 mL of dry DMF and 85 g of compound obtained in step (ii) above under nitrogen atmosphere. The reaction mixture was cooled to-15 to-10 °C and added sodium hydride (14.5 g, 55%) in lots over a period of 1 hr. The reaction mixture was maintained at same temperature for 3 hr and slowly allowed to reach 25-30 °C over a period of 5-6 hr. The reaction mixture was maintained at 25-30 °C for 12-13 hr and found to be over by TLC. The reaction mixture was cooled to 5-10 °C and quenched with methanol (20 mL). The reaction mixture was poured into 2.3L of chilled water. Toluene (500 mL) was added to the reaction mixture and stirred for 1 hr. Toluene layer was separated and the aqueous layer extracted with toluene (2 x 100 mL). The combined organic layer was washed with water and product extracted into 10% aqueous acetic acid (1 x 400 mL, 2 x 150 mL). Combined acetic acid layer was extracted with 100 mL of toluene. Aqueous acetic acid layer was treated with carbon and neutralized with sodium bicarbonate. The product thus obtained was extracted into toluene (1 x 400 mL, 2 x 150 mL). Toluene was distilled off from the organic layer to leave 45 g of crude compound as syrup. Optical rotation is +44.7 (c = 1, MeOH).

Into a 500-mL, three-necked, RB flask were charged 45 g of above crude compound, 200 mL of isopropanol, and 27 g of (+)-mandelic acid. The reaction mixture was heated 55-60 °C and maintained for 1 hr. The resultant solution was slowly allowed to cool to 25-30 °C and maintained for 15 hr. The reaction mixture was cooled to 5-10 °C and filtered the

salt : Washed the salt with 50 mL of isoporpanol and dried at 40-50 °C to get 62 g of white solid. Melting point is 116-118 °C. Optical rotation is +69.0 (c = 1, MeOH).

Into a 1-L, three-necked RB flask were charged 60 g of above salt, 400 mL of water and 300 mL of toluene. Sodium bicarbonate (25 g) was added to the reaction mixture.

Toluene layer was separated and the aqueous layer extracted with 2 x 100 mL of toluene.

Combined toluene layer was dried, and evaporated to get 36 g of pure compound as syrup. Optical rotation is +49.2 (c = 1, MeOH).

(iv) Preparation of (3R, 4S)-trans-4- (4-fluorophenyl)-3-hydroxymethyl-1-methyl- piperidine Into a 1-L, three-necked RB flask was charged 200 mL of anhydrous THF under nitrogen atmosphere. Lithium aluminum hydride (4.5 g) was added to THF and cooled to-30 °C.

A solution of 30 g of above pure (3R, 4S)-trans-3-carbomethoxy-4- (4-fluorophenyl)-N- methyl-piperidine in 100 mL of anhydrous THF was slowly added to the reaction mass over a period of 1 hr keeping the temperature below-25°C. After stirring for 30 min reaction was found to be over by TLC. The reaction was quenched by adding 15 mL of water and stirred for 1hr at 25-30 °C. The inorganic solids were removed by filtration and washed the salts with 100 mL of ethyl acetate. Solvents were distilled off from the filtrate and the residue dissolved in 100 mL of toluene and washed with 100 mL of water.

Toluene was distilled off under vaccum to get 24 g of residue which was crystallized using hexane/toluene (9: 1) to get 21 g of pure (3R, 4S)-trans-4- (4-fluorophenyl)-3- hydroxymethyl-1-methyl-piperidine as white solid. Melting point is 97.5 °C. Optical rotation is +38.0 (c = 1, MeOH).

Advantages of the Invention (i) The compound of formula-I is formed with >95% enantiospecificity.

(ii) No resolution of compound of formula-I is required hence no wastage.

(iii) No costly chiral reagents are used in building the compound of formula-I in a stereospecific manner.

(iv) Process is economically viable and commercially feasible.

(v) The raw materials employed are cheap and readily available.