Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF ENANTIOMERICALLY PURE 3-PHENYL-3-HYDROXYPROPYLAMINE

Abstract

The present invention provides an improved process for the synthesis of the enantiomerically pure 3-phenyl -3-hydroxypropylamine of formula-1. The present invention provides the process where styrene undergoes sharpless asymmetric dihydroxylation to give optically pure dihydroxy compound. The optically pure dihydroxy compound undergoes monotosylation of primary alcohol, then nucelophilic displacement by cyano group and subsequent reduction to amino group to furnish the desired enantiomerically pure 3-phenyl -3-hydroxypropylamine. This key intermediate is used in the synthesis of oxetine related anti-depressant drugs.

Full Text

` The present invention relates to an improved process for the synthesis of enantiomerically pure 3-phenyl-3-hydroxypropylamine. , (Formula Removed) More particularly the present invention relates to the said process using styrene. 3-Phenyl-3-hydroxypropylamine is an important intermediate for the synthesis of a variety of antidepressant drugs such as fluoxetine, tomoxetine and nisoxetine etc. Fluoxetine, tomoxetine and nisoxetine are among the most important pharmaceuticals for the treatment of psychiatric disorders (depression, anxiety, alcoholism) and also metabolic problems (obesity and bulimia) [(a) Zerbe, R. L.; Rowe, H.; Enas, G. G.; Wong, D.; Farid, N.; Lemberger, L. J. Pharmacol. Exp. Ther. 1985, 232, 139; (b) Stark, P.; Hardison, C. D. Clin. J. Psychiatry 1985, 46, 53; (c) Robertson, D. W.; Jones, N. D.; Swrtzendruber, J. K.; Yang, K. S.; Wang, D. T. J. Med. Chem. 1988, 31, 185; (d) Robertson, D. W.; Krushinski, J. H.; Fuller, R. W.; Leander, J. D. J. Med. Chem. 1988, 31, 1412]. In the prior-art the synthesis of 3-phenyl-3-hydroxypropylamine segment of fluoxetine and related analogues has been accomplished employing various synthetic strategies. A commonly used strategy for the synthesis of N-methyl-3-phenyl-3-hydroxypropylamine is to employ the the reduction of ethylbenzoylacetate with a metal hydride followed by amidation, (G. Magnone, EP 380924, 8 Aug. 1990; Kumar, A. et al Tetrahedron Lett 1991, 32, 1901; Kumar, A. et al Indian J. Chem 1992, 31B, 803; Chenevert, R. et al Tetrahedron 1992, 48, 6769), enzymatic reduction of ethyl benzoylacetate with a chiral ligand e.g. (-)-DIP-chloride (Hilborn, J. W. US 5936124, 1999). In another prior-art method, N-methyl-3-phenyl-3-hydroxypropylamine can be obtained from asymmetric reduction of ß-chloropropiophenone with BH3 and chiral oxazoborolidine and subsequent substitution with methyl amine (Corey, E. J. et al Tetrahedron Lett 1989, 30, 5207). In yet another prior-art method, N-methyl-3-phenyl-3-hydroxypropylamine was obtained by enzymatic resolution process of ß-chloropropiophenone and subsequent substitution with methylamine (Schneider, M. P. et al Tetrahedron Asymmetry 1992, 3, 525). In still another prior-art method, N-methyl-3-phenyl-3-hydroxypropylamine was obtained by asymmetric epoxidation of cinnamyl alcohol and regioselective reductive opening of epoxide with Red-Al (Sharpless K. B. et al J. Org. Chem. 1988, 53, 4081; Young, J. W. W092-US888,1992, US-91-793036, 1991). In another prior-art method, 3-phenyl-3-hydroxypropylamine was obtained by the reduction of 3-phenyl-3-hydroxypropanenitrile (Koenig, T. M. et al Tetrahedron Lett. 1994, 35, 1339; Mitchell D. et al Synth. Commun. 1995,25, 1231). In yet another prior-art method, 3-phenyl-3-hydroxypropylamine was obtained by asymmetric hydrogenation of ß-aminoketone catalyzed by cationic Rhodium (I) {AMPP} complex (Devocelle, M. et al Synlett 1997, 1307). In still another prior-art method, 3-phenyl-3-hydroxypropylamine was obtained by the asymmetric reduction of methyl-3-benzoylpropionate and subsequent conversion of product to amide and Hofman rearrangement (Hilborn, J. M. Tetrahedron Lett. 2001,42,8919). Tomoxetine has been prepared via reduction of phenyl haloalkyl ketones with diisopinocamphenyl haloboranes as key steps. The intermediate phenyl haloalkylketone was prepared in 75 % yield and 97 % ee (Brown, H. C. et. al US 4868344, 1989; J. Org. Chem. 1988, 53, 2916). The same intermediate was prepared by Baker's yeast reduction and was further used for the synthesis of (R)-fluoxetine and (R)- and (S)-fenfluramine (Fronza, G. et. al J. Org. Chem., 1991, 56, 6019). In another prior-art method, fluoxetine hydrochloride is manufactured catalytically by hydrogenating 2-benzoyl-N-benzyl-N-methylethylamine in ethylacetate under H pressure of 5 bar using Pt/C or Pd-Pt/C catalyst as key step (Kairisalo, P. J. FI81083, 1990). In yet another prior-art method, the (S)-3-amino-l-phenyl-propanol was prepared by the reaction of (S)-l-phthalimido-l-phenyl-propanol and anhydrous N2H4 in ethanol. This intermediate was subsequently used for the synthesis of fluoxetine derivatives (Fuller, R. W. et al EP 369685,1990). In still another prior-art method, the N-methyl-3-phenyl-3-hydroxypropylamine was prepared by the condensation of PhCH(OH)CH2CH2NMe2 with ClC02Et and subsequent hydrolysis (Schwartz, E. EP 529842,1993). In prior-art method, the optically active fluoxetine was prepared employing N- methyl-3-phenyl-3-hydroxypropionamide as a precursor which in turn was prepared by lipase catalyzed resolution of PhCH(OH)CH2COOEt (Yashida, N. Jpn. Kokai Tokkyo Koho JP 04005268, 1992). Fluoxetine and its analogs are prepared by the etherification of 1 -phenyl-3-(N- methylamino)-propan-l-ol with an arylating reagent (Agusti Cruz, A. ES 2120368, 1998; Arosio, R. US 5847214, 1998). In yet another prior-art method, N-methyl-3R-hydroxy-3-phenylpropylamine was prepared by resolving the racemic by 5-(+)-mandelic acid (Ratz, A. M. EP 909754, 1999). In still another prior-art method, 3-(methylamino)-l-phenyl-l-propanol was prepared by reaction of methylamine with 3-chloro-1-phenyl-1-propanol and subsequently converting into fluoxetine (Weber, B. WO 2000037425, 2000) or by converting chloropropiophenone into racemic alcohol and resolving it by the chiral separation (Gattuso, M. J. Jpn. Kokai Tokkyo Koho JP 2000290239,2000). Some of the major drawbacks of the methods known in the prior-art are such as (i) Multi-step synthesis (ii) High cost of materials involved (iii) Complicated reagents, longer reaction time and high reaction temperature (iv) Difficulties involved in work-up procedure (v) Difficulties involved in handling sophisticated reagents (vi) Overall low yield of the desired compound (vii) Poor enantio-selectivity (viii) Lack of reusability of expensive reagents In view of the abovementioned drawbacks and disadvantages of the prior-art procedure, it is desirable to develop an improved, efficient and enantioselective process for the synthesis of 3-phenyl-3-hydroxypropylamine. The main object of the present invention is to provide an improved, efficient process for the synthesis of enantiomerically pure 3-phenyl-3-hydroxy-propylamine, which overcomes the drawbacks of the prior-art processes employing the Sharpiess asymmetric dihydroxylation, selective monotosylation of primary alcohol and nucleophilic displacement by cyno and subsequent reduction to amino group. The significant feature of the present invention is: (i) The process relatively involves less number of steps (ii) The reaction involved in each step according to the present invention, could be carried out relatively at lower temperature or room temperature (iii) The process leads to high yields of the desired compound (iv) Both the enantiomers of 3-phenyl-3-hydroxypropylamine could be prepared using this process (v) The process gives high enantioselectivity of the product (vi) The chiral ligands used to induce chirality could be recovered The process of the present invention is described in details in schematic diagram herein below (Formula Removed) Accordingly the present invention provides an improved process for the preparation of enantiomerically pure 3-phenyl-3- hydroxy propyl amine, said process comprising the steps of: i. adding osmium tetraoxide to a mixture of potassium ferricyanide, potassium carbonate, chiral ligand as one of the the 1st or 2 nd generation mono or bi-dentate ligand selected from a group consisting of phthalazine, pyrimidine, phenanthryl, quinoxaline and p- chlorobenzoate , preferably phthalazine in an aqueous organic solvent, at a temperature in the range of 0 to 5° C; ii. stirring the mixture obtained in step (i) with styrene, at a temperature in the range of 0 to 5°C, for 12 to 24 hours and then quenching with solid sodium sulfite; iii. further stirring the contents of step (ii) for 30 minutes to 2 hours and extracting with ethyl acetate repeatedly; iv. washing the combined ethyl acetate extracts with brine, drying over anhydrous Na2SO4, filtering and concentrating to obtain a crude product; v. purifying the crude product obtained in step (iv) over silica-gel column using a proportionate mixture of petroleum ether and ethyl acetate to obtain pure chiral diol (R)-phenylethylene glycol compound of formula (2); (Formula Removed) vi. reacting chiral diol (R)-phenylethylene glycol of formula (2) with an activating reagent portion wise in presence of a base stirring it for a period in the range of 15 to 24 hours at a temperature range of -40.degree. C. to 35.degree. C. and then quenching to obtain monotosyl compound of formula (3); (Formula Removed) vii. reacting monotosyl compound of formula (3) obtained from step (vi) with a metal cyanide in an aqueous alcohol at a temperature of 25-35°C, for a period of 15 to 24 hours, concentrating it at a temperature range of 40-70°C, extracting with brine, drying over anhydrous Na2SO4, purifying it over silica gel column to obtain a pure chiral cyano compound (R)-3-phenyl-3-hydroxypropanenitrile of formula (4); (Formula Removed) viii. reducing the (R)-3-phenyl-3-hydroxypropanenitrile compound of formula (4) obtained from step (vii) with a reducing agent at -15 to 0°C, refluxing for a period of 1-3 hours, extracting the mixture with an organic solvent and then concentrating to obtain the desired product of formula-1. (Formula Removed) In a embodiment of the present invention the organic solvent used in step (i) is preferably toluene. In yet another embodiemnt the ratio of petroleum ether to ethyl acetate used in step (v) is ranges from 4:1 to 2:1. In yet another embodiemnt the ratio of activating agent to chiral diol (2) used in step (vi) is in the range of 1:5-5:1. In yet another embodiemnt the activating reagent used in step (vi) is at least one selected from a group consisting of acid chloride, anhydride,and sulfonyl chloride like p-toluene sulfonyl chloride and methane sulfonyl chloride preferably p-toluene sulfonyl chloride. In yet another embodiemnt the base used in step (vi) is at least one selected from a group consisting of triethylamine and pyridine. In yet another embodiemnt the quenching agent used in step (vi) is preferably water. In yet another embodiemnt the metal cyanide used in step (vii) is an alkali or alkaline earth metal cyanide, preferably sodium cyanide. In yet another embodiemnt the aqueous alcohol used in step (vii) is ethanol. In yet another embodiemnt the organic solvent used in step (viii) is dichloro methane. In yet another embodiemnt the reducing agent used in step (viii) is at least one selected from a group consisting of neat dimethyl sulfide complex or THF solution or hydride of alkali metals selected from the group consisting of sodium borohydride, lithium borohydride, lithium aluminum hydride, sodium cyanoborohydride and Raney Ni preferably borane-dimethyl sulfide complex / lithium aluminum hydride. The following examples are given by the way of illustration and therefore should not be construed to limit the scope of the invention. Example 1 To a mixture of K3Fe(CN)6, K2C03 and (DHQ)2PHAL in t-BuOH-H20) (1:1) cooled to 0°C was added OSO4 (0. IM solution in toluene). After stirring for 5 minutes at 0°C, styrene was added in one portion. The reaction mixture was stirred at 0°C, for 24hrs and then quenched with solid sodium sulfite. The stirring was continued for 1 hr and the solution was extracted with ethyl acetate. The combined organic phase was washed with brine, dried (Na2SO4) and concentrated. Silica gel column chromatography of crude product using petroleum ether: EtOAc (3.5:1.5) as eluent gave (R)-phenylethylene glycole as a white solid. To a mixture of (R) phenylethylene glycole, dry pyridine in dry dichloromethane cooled at -15°C was added portion wise p-toluenesulfonyl chloride over a period of lh. The reaction mixture was stirred at-15 C for 24 h and quenched by adding water. The solution was extracted with dichloromethane and then combined organic phase was washed with aqueous CuSO4, dried (Na2SO4) and concentrated. Silica gel column chromatography of crude product using petroleum ether: EtOAc (4 :1) as eluent gave monotosyl compound as a white solid. To stirring mixture of monotosyl compound in ethanol-H2O (4 : 1) at 0°C was added NaCN in one portion. The reaction mixture was stirred at room temperature for 24h. The reaction mixture was concentrated at 50°C on rotatory evaporator and extracted with ethyl acetate. The combined organic phases were washed with brine, dried (Na2S04) and concentrated. Silica gel column chromatography of crude product using petroleum ether : EtOAc (3 : 1) as eluent gave (#)-3-phenyl-3-hydroxypropanenitrile (4) as a colorless oil. To a THF solution of (R)-3-phenyl-3-hydroxypropanenitrile was slowly added borane dimethyl sulfide complex at room temperature. Methyl sulfide was then distilled from the reaction vessel and the resulting THF solution refluxed for 2.5h. After cooling to room temperature methanolic HC1 was added to the reaction mixture. Methanol and methyl borate were removed by distillation and the reaction mixture neutralized with sodium hydroxide (5N). Extraction of the mixture with dichloromethane followed by concentration provided the crystalline (R)-3-phenyl-3-hydroxypropylamine. Example 2 To a mixture of K3Fe(CN)6, K2C03 and (DHQ)2PHAL in t-BuOH-H20 (1:1) cooled to 0°C was added OsO4 (0.1 M solution in toluene). After stirring for 5 minutes at 0°C, styrene was added in one portion. The reaction mixture was stirred at 0°C for 24h and then quenched with solid sodium sulfite. The stirring was continued for lh and the solution was extracted with ethyl acetate. The combined organic phase was washed with brine, dried (Na2SO4) and concentrated. Silica gel column chromatography of crude product using petroleum ether: EtOAc (3.5: 1.5) as eluent gave (R)-phenylethylene glycol as a white solid. To a mixture of (R)-phenylethylene glycol, dry triethylamine in dry dichloromethane cooled at -15° C was added portion wise methanesulfonyl chloride over a period of lh. The reaction was stirred at -15° C for 24h and quenched by adding water. The solution was extracted with dichloromethane and then combined organic phase was washed with aqueous CuSO4, dried (Na2SO4) and concentrated. Silica gel column chromatography of crude product using petroleum ether: EtOAc (4 :1) as eluent gave monomesyl compound as a white solid. To stirring mixture of monomesyl compound in ethanol-H20 (4 : 1) at 0°C was added KCN in one portion. The reaction mixture was stirred at room temperature for 24h. The reaction mixture was concentrated at 50°C on rotatory evaporator and extracted with ethyl acetate. The combined organic phases were washed with brine, dried (Na2SO4) and concentrated. Silica gel column chromatography of crude product using petroleum ether EtOAc (3 :1) as eluent gave (R)-3-phenyl-3-hydroxypropanenitrile (4) as a colorless oil. To a THF solution of (i?)-3-phenyl-3-hydroxypropanenitrile was slowly added borane THF complex at room temperature and then the resulting solution was refluxed for 2.5 h. After cooling to room temperature methanolic HC1 was added to the reaction mixture. Methanol and methyl borate were removed by distillation and the reaction mixture neutralized with sodium hydroxide (5N). Extraction of the mixture with dichloromethane followed by concentration provided the crystalline (R)-3-phenyl-3-hydroxypropylamine. Example 3 To a mixture of K3Fe(CN)6, K2C03 and (DHQ)2PHAL in t-BuOH-H20 (1:1) cooled to 0°C was added Os04 (0.1 M solution in toluene). After stirring for 5 minutes at 0°C, styrene was added in one portion. The reaction mixture was stirred at 0°C for 24h and then quenched with solid sodium sulfite. The stirring was continued for lh and the solution was extracted with ethyl acetate. The combined organic phase was washed with brine, dried (Na2SO4) and concentrated. Silica gel column chromatography of crude product using petroleum ether: EtOAc (3.5: 1.5) as eluent gave (R)-phenylethylene glycol as a white solid. To a mixture of (R)-phenylethylene glycol, dry pyridine in dry dichloromethane cooled at -15° C was added portion wise p-toluenesulfonyl chloride over a period of lh. The reaction was stirred at -15° C for 24h and quenched by adding water. The solution was extracted with dichloromethane and then combined organic phase was washed with aqueous CuSO4, dried (Na2SO4) and concentrated. Silica gel column chromatography of crude product using petroleum ether: EtOAc (4 :1) as eluent gave monotosyl compound as a white solid. To stirring mixture of monotosyl compound in ethanol-H20 (4 : 1) at 0°C was added NaCN in one portion. The reaction mixture was stirred at room temperature for 24h. The reaction mixture was concentrated at 50°C on rotatory evaporator and extracted with ethyl acetate. The combined organic phases were washed with brine, dried (Na2SO4) and concentrated. Silica gel column chromatography of crude product using petroleum ether : EtOAc (3 :1) as eluent gave (R)-3-phenyl-3-hydroxypropanenitrile as a colorless oil. To a stirring suspension of lithium aluminum hydride in dry THF at 0°C was added a solution of (R)-3-phenyl-3-hydroxypropanenitrile in dry THF under nitrogen. The ice bath was removed and then the reaction mixture was refluxed for 2h. Excess lithium aluminium hydride was destroyed by adding H2O and EtOAc. The white precipitate obtained was filtered and washed with MeOH. The combined filtrate was concentrated 10 give (R)-3-phenyl-3-hydroxypropylamine. Example 4 To a mixture of K3Fe(CN)6, K2C03 and (DHQ)2PHAL in t-BuOH-H20 (1:1) cooled to 0°C was added Os04 (0.1 M solution in toluene). After stirring for 5 minutes at 0°C, styrene was added in one portion. The reaction mixture was stirred at 0°C for 24h and then quenched with solid sodium sulfite. The stirring was continued for lh and the solution was extracted with ethyl acetate. The combined organic phase was washed with brine, dried (Na2SO4) and concentrated. Silica gel column chromatography of crude product using petroleum ether: EtOAc (3.5: 1.5) as eluent gave (R)-phenylethylene glycol as a white solid. To a mixture of (R)-phenylethylene glycol, dry pyridine in dry dichloromethane cooled at -15° C was added portion wise p-toluenesulfonyl chloride over a period of lh. The reaction was stirred at -15° C for 24h and quenched by adding water. The solution was extracted with dichloromethane and then combined organic phase was washed with aqueous CuO4, dried (Na2SO4) and concentrated. Silica gel column chromatography of crude product using petroleum ether: EtOAc (4 :1) as eluent gave monotosyl compound as a white solid. To stirring mixture of monotosyl compound in ethanol-H20 (4 : 1) at 0°C was added KCN in one portion. The reaction mixture was stirred at room temperature for 24h. The reaction mixture was concentrated at 50°C on rotatory evaporator and extracted with ethyl acetate. The combined organic phases were washed with brine, dried (Na2SO4) and concentrated. Silica gel column chromatography of crude product using petroleum ether : EtOAc (3 :1) as eluent gave (R)-3-phenyl-hydroxypropanenitrile as a colorless oil. To a THF solution of (R)-S-phenyl-S-hydroxypropanenitrile was slowly added borane dimethyl sulfide complex at room temperature. Methyl sulfide was then distilled from the reaction vessel and the resulting THF solution refluxed for 2.5h. After cooling to room temperature methanolic HC1 was added to the reaction mixture. Methanol and methyl borate were removed by distillation and the reaction mixture neutralized with sodium hydroxide (5N). Extraction of the mixture with dichloromethane followed by concentration provided the crystalline (R)-3-phenyl-3-hydroxypropylamine. Example 5 To a mixture of K3Fe(CN)6, K2C03 and (DHQD)2PHAL in t-BuOH-H20 (1:1) cooled to 0°C was added OSO4 (0.1 M solution in toluene). After stirring for 5 minutes at 0°C, styrene was added in one portion. The reaction mixture was stirred at 0°C for 24h and then quenched with solid sodium sulfite. The stirring was continued for lh and the solution was extracted with ethyl acetate. The combined organic phase was washed with brine, dried (Na2SO4) and concentrated. Silica gel column chromatography of crude product using petroleum ether: EtOAc (3.5: 1.5) as eluent gave (S)-phenylethylene glycol as a white solid. To a mixture of (5)-phenylethylene glycol, dry triethylamine in dry dichloromethane cooled at -15° C was added portion wise p-toluenesulfonyl chloride over a period of lh. The reaction was stirred at -15° C for 24h and quenched by adding water. The solution was extracted with dichloromethane and then combined organic phase was washed with aqueous CuSO4, dried (Na2SO4) and concentrated. Silica gel column chromatography of crude product using petroleum ether: EtOAc (4 :1) as eluent gave monotosyl compound as a white solid. To stirring mixture of monotosyl compound in ethanol-H2O (4 : 1) at 0°C was added NaCN in one portion. The reaction mixture was stirred at room temperature for 24h. The reaction mixture was concentrated at 50°C on rotatory evaporator and extracted with ethyl acetate. The combined organic phases were washed with brine, dried (Na2S04) and concentrated. Silica gel column chromatography of crude product using petroleum ether : EtOAc (3 :1) as eluent gave (S)-3-phenyl-hydroxypropanenitrile as a colorless oil. To a THF solution of (S)-3-phenyl-3-hydroxypropanenitrile was slowly added THF solution of borane dimethyl sulfide complex at room temperature. Methyl sulfide was then distilled from the reaction vessel and the resulting THF solution refluxed for 2.5h. After cooling to room temperature methanolic HC1 was added to the reaction mixture. Methanol and methyl borate were removed by distillation and the reaction mixture neutralized with sodium hydroxide (5N). Extraction of the mixture with dichloromethane followed by concentration provided the crystalline (S)-3-phenyl-3-hydroxypropylamine. The advantages of the present invention are as follows: (i) The process relatively involves less number of steps . (ii) The reactions involved in each step, according to the present invention, could be carried out lower temperature or room temperature, (iii) The process leads to high yields of the desired products, (iv) Both the enantiomers of the 3-phenyl-3-hydroxypropylamine could be prepared using this process. (v) The process gives high enantioselectivity of the product, (vi) The chiral ligands used to induce chirality could be recovered. We Claim 1.An improved process for the preparation of enantiomerically pure 3-phenyl-3-hydroxy propyl amine, said process comprising the steps of: i. adding osmium tetraoxide to a mixture of potassium ferricyanide, potassium carbonate, chiral ligand as one of the the 1st or 2 nd generation mono or bi-dentate ligand selected from a group consisting of phthalazine, pyrimidine, phenanthryl, quinoxaline and p-chlorobenzoate , preferably phthalazine in an aqueous organic solvent, at a temperature in the range of 0 to 5° C; ii. stirring the mixture obtained in step (i) with styrene, at a temperature in the range of 0 to 5°C, for 12 to 24 hours and then quenching with solid sodium sulfite; iii. further stirring the contents of step (ii) for 30 minutes to 2 hours and extracting with ethyl acetate repeatedly; iv. washing the combined ethyl acetate extracts with brine, drying over anhydrous Na2SO4, filtering and concentrating to obtain a crude product; v. purifying the crude product obtained in step (iv) over silica-gel column using a proportionate mixture of petroleum ether and ethyl acetate to obtain pure chiral diol (R)-phenylethylene glycol compound of formula (2); (Formula Removed) vi. reacting chiral diol (R)-phenylethylene glycol of formula (2) with an activating reagent portion wise in presence of a base stirring it for a period in the range of 15 to 24 hours at a temperature range of -40.degree. C. to 35.degree. C. and then quenching to obtain monotosyl compound of formula (3); (Formula Removed) vii. reacting monotosyl compound of formula (3) obtained from step (vi) with a metal cyanide in an aqueous alcohol at a temperature of 25-35°C, for a period of 15 to 24 hours, concentrating it at a temperature range of 40-70°C, extracting with brine, drying over anhydrous Na2SO4, purifying it over silica gel column to obtain a pure chiral cyano compound (R)-3-phenyl-3- hydroxypropanenitrile of formula (4); (Formula Removed) viii. reducing the (R)-3-phenyl-3-hydroxypropanenitrile compound of formula (4) obtained from step (vii) with a reducing agent at -15 to 0°C, refluxing for a period of 1-3 hours, extracting the mixture with an organic solvent and then concentrating to obtain the desired product of formula-1. (Formula Removed) 2. A process as claimed in claim 1, wherein the organic solvent used in step (i) is preferably toluene. 3. A process as claimed in claim 1, wherein the ratio of petroleum ether to ethyl acetate used in step (v) is ranges from 4:1 to 2:1. 4. A process as claimed in claim 1, wherein the ratio of activating agent to chiral diol (2) used in step (vi) is in the range of 1:5-5:1. 5. A process as claimed in claim 1, wherein the activating reagent used in step (vi) is at least one selected from a group consisting of acid chloride, anhydride, and sulfonyl chloride like p-toluene sulfonyl chloride and methane sulfonyl chloride preferably p-toluene sulfonyl chloride. 6. A process as claimed in claim 1, wherein the base used in step (vi) is at least one selected from a group consisting of triethylamine and pyridine. 7. A process as claimed in claim 1, wherein the quenching agent used in step (vi) is preferably water. 8. A process as claimed in claim 1, wherein the metal cyanide used in step (vii) is an alkali or alkaline earth metal cyanide, preferably sodium cyanide. 9. A process as claimed in claim 1, wherein the aqueous alcohol used in step (vii) is ethanol. 10. A process as claimed in claim 1, wherein the organic solvent used in step (viii) is dichloromethane. 11. A process as claimed in claim 1, wherein the reducing agent used in step (viii) is at least one selected from a group consisting of neat dimethyl sulfide complex or THF solution or hydride of alkali metals selected from the group consisting of sodium borohydride, lithium borohydride, lithium aluminum hydride, sodium cyanoborohydride and Raney Ni preferably borane-dimethyl sulfide complex / lithium aluminum hydride. 12.An improved process for the preparation of enantiomerically pure 3-phenyl-3-hydroxypropylamineas fully described herein with reference to examples.

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