Field of the invention:

The present invention provides a novel process for the preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate represented by structural formula-1 and its pharmaceutically acceptable salts.

Background of the Invention:

US6713464B1 patent discloses a variety of 3,3-diphenylpropylamine derivatives, processes for their preparation, pharmaceutical compositions comprising the derivatives and methods of use thereof. These compounds are anti-muscarinic agents with superior pharmacokinetic properties compared to existing drugs such as oxybutynin and tolterodine which are useful in the treatment of urinary incontinence, gastrointestinal hyperactivity (irritable bowel syndrome) and other smooth muscle contractile conditions. Among them, (R)-2-(3-(diisopropylamino)-1 -phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate
commonly known as fesoterodine is a new, potent and competitive muscarinic antagonist and useful in the potential treatment of urinary incontinence.

Processes for the preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate and its related compounds are disclosed in the US6713464B1, US6858650B1, U.S. Patent Appl. No.2006/0270738, WO2007138440 Al.

According to US6,713,464 Bl (herein after referred as '464' patent), fesoterodine is prepared by the reaction of (±)-6-bromo-4-phenylchroman-2-one with benzyl chloride in the presence of sodium iodide and anhydrous potassium carbonate in methanol and acetone to give (±)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid methyl ester as a light yellow oil, which on reduction with lithium aluminium hydride in tetrahydrofuran at room temperature produces (±)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropan-l-ol. (±)-3-(2-Benzyloxy-5-bromophenyl)-3-phenyl propan-1-ol is then treated with p-toluenesulfonyl chloride in presence of pyridine in dichloromethane to afford (±)-toluene-4-sulphonic acid 3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl ester, which on reaction with N,N-diisopropylamine in acetonitrile at reflux temperature produces (±)-[3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl]-diisopropylamine as a brown and viscous syrup. Resolution of the amine compound produces (R)-[3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl]-diisopropylamine, which is then subjected to Grignard reaction with ethyl bromide and magnesium in the presence of solid carbon dioxide in tetrahydrofuran followed by treatment with aq.hydrochloric acid produces (R)-4-benzyloxy-3-(3-diisopropylamino-l-phenylpropyl)-benzoic acid hydrochloride. Esterification of the obtained acid with methanol in presence of sulfuric acid produces its methyl ester, which is then reduced with lithium aluminium hydride to produce (R)-[4-benzyloxy-3-(3-diisopropylamino-l-phenylpropyl)-phenyl]-methanol. Debenzylation of the resulting compound with Raney-Ni produces (R)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxymethylphenol which on further acylation with isobutyryl chloride in an inert solvent in the presence of a base gives (R)-2-(3-(diisopropylamino)-1 -phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate.

In the above process, the usage of lithium aluminium hydride for the reduction of (±)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid methyl ester is not suggestible on large scale.

Hence, there is a need in the art to develop an industrially applicable process for the preparation of (R)-2-(3-(diisopropylamino)-1 -phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate and its pharmaceutically acceptable salts using simple reagents.

The present invention overcomes the above said problems by adopting a novel process for the preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate and its pharmaceutically acceptable salts.

Brief description of the invention:

The first aspect of the present invention is to provide a novel process for the preparation of (R)-2-(3 -(diisopropylamino)-1 -phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1 and its fumarate salt compound of formula-la, comprising of;

a) Reacting the (R)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxymethyl-phenol compound of formula-8 with methacryloyl chloride in presence or absence of a suitable base in a suitable solvent to provide (R)-2-(3 -(diisopropylamino)- l-phenylpropyl)-4-(hydroxylmethyl)phenyl methacrylate compound of formula-9,

b) reducing the compound of formula-9 with a suitable reducing agent in a suitable solvent to provide the (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1,

c) converting the compound of formula-1 into its fumarate salt compound of formula-la by treating it with fumaric acid in a suitable solvent or mixture of solvents.

The second aspect of the present invention is to provide an improved process for the preparation of 3-(2-benzyloxy-5-bromophenyl)-3-phenyl propanol compound of formula-3 which comprises of reducing the methyl 3-(2-benzyloxy-5-bromophenyl)-3-phenyl propanoate compound of formula-2 with a suitable reducing agent such as vitride in a suitable solvent.

The third aspect of the present invention is to provide a novel process for the preparation of (R)-2-(3-(diisopropylamino)-l -phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1, comprising of;

a) Treating the methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzoate compound of formula-4 with a suitable chiral acid in a suitable solvent to provide its chiral acid addition salt compound of general formula-5,

b) treating the compound of general formula-5 with a suitable base in a suitable solvent to provide (R)-methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-1 -phenylpropyl)benzoate compound of formula-6,

c) debenzylating the compound of formula-6 with a suitable debenzylating agent in a suitable solvent to provide (R)-methyl 3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxybenzoate compound of formula-7,

d) reducing the compound of formula-7 with a suitable reducing agent in a suitable solvent to provide (R)-2-(3-diisopropylamino-1 -phenylpropyl)-4-hydroxymethyl-phenol compound of formula-8,

e) reacting the compound of formula-8 with methacryloyl chloride in presence or absence of a suitable base in a suitable solvent to provide (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxylmethyl)phenyl methacrylate compound of formula-9,

f) reducing the compound of formula-9 with a suitable reducing agent in a suitable solvent to provide the (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1.

The fourth aspect of the present invention is to provide a process for the preparation of (R)-methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzoate compound of formula-6, comprising of;

a) Treating the racemic methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzoate compound of formula-4 with a suitable chiral acid in a suitable solvent to provide its chiral acid addition salt compound of general formula-5,

b) treating the compound of general formula-5 with a suitable base in a suitable solvent to provide (R)-methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzoate compound of formula-6.

The fifth aspect of the present invention is to provide a process for the preparation of (R)-methyl3 -(3 -(diisopropylamino)-1 -phenylpropyl)-4-(methacryloyloxy)benzoate compound of formula-10, which comprises of reacting the (R)-methyl 3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxybenzoate compound of formula-7 with methacryloyl chloride in presence or absence of a base in a suitable solvent.

The sixth aspect of the present invention is to provide a process for the preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-formylphenyl methacrylate compound of formula-12, comprising of;

a) Reducing the (R)-methyl 3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxybenzoate compound of formula-7 with a suitable reducing agent in a suitable solvent to provide (R)-3-(3-(diisopropylamino)-1 -phenylpropyl)-4-hydroxybenzaldehyde compound of formula-11,

b) reacting the compound of formula-11 with methacryloyl chloride in presence or absence of base in a suitable solvent to provide (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-formylphenyl methacrylate compound of formula-12.

The seventh aspect of the present invention is to provide a novel process for the preparation of (R)-2-(3-(diisopropylamino)-1 -phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1, comprising of;

a) Reacting the racemic 3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3-phenylpropan-1-amine compound of formula-13 with ethyl bromide and magnesium in presence of solid carbon dioxide in a suitable solvent to provide 4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzoic acid compound of formula-14,

b) resolving the compound of formula-14 with a suitable chiral acid in a suitable solvent to provide (R)-4-(benzyloxy)-3-(3-(diisopropylamino)-1 -phenylpropyl)benzoic acid compound of formula-16,

c) debenzylating the compound of formula-16 by treating it with a suitable debenzylating agent in a suitable solvent to provide (R)-3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxy benzoic acid compound of formula-17,

d) reacting the compound of formula-17 with methacryloyl chloride in presence or absence of base in a suitable solvent to provide (R)-3-(3-(diisopropylamino)-l-phenylpropyl)-4-(methacryloyloxy)benzoic acid compound of formula-18,

e) reducing the compound of formula-18 with a suitable reducing agent in a suitable solvent to provide (R)-2-(3 -(diisopropylamino)-1 -phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1.

The eighth aspect of the present invention is to provide a novel process for the preparation of (R)-2-(3-(diisopropylamino)-1 -phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1, comprising of;

a) Resolving the racemic 3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3-phenylpropan-1-amine compound of formula-13 with a suitable chiral acid in a suitable solvent to provide (R)-3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3-phenylpropan-1-amine compound of formula-15,

b) reacting the compound of formula-15 with ethyl bromide and magnesium in presence of solid carbon dioxide in a suitable solvent to provide (R)-4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzoic acid compound of formula-16,

c) debenzylating the compound of formula-16 by treating it with a suitable debenzylating agent in a suitable solvent to provide (R)-3 -(3 -(diisopropylamino)- l-phenylpropyl)-4-hydroxy benzoic acid compound of formula-17,

d) reacting the compound of formula-17 with methacryloyl chloride in presence or absence of base in a suitable solvent to provide (R)-3-(3-(diisopropylamino)-l-phenylpropyl)-4-(methacryloyloxy)benzoic acid compound of formula-18,

e) reducing the compound of formula-18 with a suitable reducing agent in a suitable solvent to provide (R)-2-(3 -(diisopropylamino)-1 -phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1.

The ninth aspect of the present invention is to provide a novel process for the preparation of (R)-3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxybenzaldehyde compound of formula-11, comprising of;

a) Reacting the racemic 3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3-phenylpropan-1-amine compound of formula-13 with dimethyl formamide and n-butyl lithium in a suitable solvent to provide 4-(benzyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl) benzaldehyde compound of formula-19,

b) resolving the compound of formula-19 with a suitable chiral acid in a suitable solvent to provide (R)-4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzaldehyde compound of formula-20,
c) debenzylating the compound of formula-20 with a suitable debenzylating agent in a suitable solvent to provide (R)-3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxybenzaldehyde compound of formula-11.

The tenth aspect of the present invention is to provide another novel process for the preparation of (R)-2-(3-(diisopropylamino)-1 -phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1, comprising of;

a) Reacting the racemic 3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3-phenylpropan-1-amine compound of formula-13 with ethyl bromide and magnesium in presence of solid carbon dioxide in a suitable solvent to provide 4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzoic acid compound of formula-14,

b) debenzylating the compound of formula-14 by treating it with a suitable debenzylating agent in a suitable solvent to provide 3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxy benzoic acid compound of formula-21,

c) reacting the compound of formula-21 with methacryloyl chloride in presence or absence of base in a suitable solvent to provide 3-(3-(diisopropylamino)-l-phenylpropyl)-4-(methacryloyloxy)benzoic acid compound of formula-22,

d) resolving the compound of formula-22 with a suitable chiral acid in a suitable solvent to provide (R)-3 -(3 -(diisopropylamino)-1 -phenylpropyl)-4-(methacryloyloxy)benzoic acid compound of formula-18,

e) reducing the compound of formula-18 with a suitable reducing agent in a suitable solvent to provide (R)-2-(3-(diisopropylamino)-1 -phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1.

The eleventh aspect of the present invention is to provide a novel process for the purification of (R)-2-(3 -(diisopropylamino)-1 -phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1, comprising of;

a) Treating the compound of formula-1 with S(+)-acetoxy(phenyl)acetic acid in a suitable solvent to provide its S(+)-acetoxy(phenyl)acetic acid salt compound of formula-23,

b) treating the compound of formula-23 with a suitable base in a suitable solvent or mixture of solvents to provide pure (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1.

The twelfth aspect of the present invention is to provide a process for the preparation of (R)-4-cyano-2-(3-(diisopropylamino)-l-phenylpropyl)phenyl isobutyrate compound of formula-25, which comprises of reacting the (R)-3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxy benzonitrile compound of formula-24 with isobutyryl chloride in presence or absence of a base in a suitable solvent.

The thirteenth aspect of the present invention is to provide a process for the resolution of 3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3-phenylpropan-l-amine compound of formula-13, comprising of;

a) Treating the compound of formula-13 with D(-)-tartaric acid in a suitable solvent to provide its D(-)-tartrate salt compound of formula-26,

b) treating the compound of formula-26 with a suitable base in a suitable solvent to provide (R)-3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3-phenylpropan-l-amine compound of formula-15.

The fourteenth aspect of the present invention is to provide novel intermediate compounds for the synthesis of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1.

Brief description of the drawings:

Figure-1: Illustrates the PXRD pattern of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl)phenyl methacrylate mandelate salt (formula-28a).

Figure-2: Illustrates the PXRD pattern of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-
(hydroxymethyl)phenyl isobutyrate S(+)-acetoxy(phenyl)acetic acid salt (formula-23).

Figure-3: Illustrates the PXRD pattern of isobutyric acid 2-((R)-3-diisopropylammonium-l-
phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrogen fumarate (formula-la).

Detailed description of the invention:

The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethylether, diethylether, methyl tert-butyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, acetonitrile and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform and the like; "ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "alcoholic solvents" such as methanol, ethanol, isopropyl alcohol, n-butanol and the like; "polar solvents" such as water; and/or their mixtures thereof.

As used herein the present invention the term "suitable base" refers to "alkali metal carbonates" such as sodium carbonate, potassium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium tertbutoxide and the like; and organic bases like triethylamine, isopropylethyl amine, diisopropyl amine, diisopropylethyl amine, diisobutyl amine, pyridine, piperidine, N-methyl morpholine and/or their mixtures thereof.

The first aspect of the present invention provides a novel process for the preparation of (R)-2-(3-(diisopropylamino)-l -phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1 and its fumarate salt compound of formula-la, comprising of; a) Reacting the (R)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxymethyl-phenol compound of formula-8

wherein, 'i-pr' represents isopropyl group;

with methacryloyl chloride (2-methylprop-2-enoyl chloride) in presence or absence of a suitable base in a suitable solvent to provide (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxylmethyl)phenyl methacrylate compound of formula-9,

b) reducing the compound of formula-9 with a suitable reducing agent in a suitable solvent to provide (R)-2-(3-(diisopropylamino)-1 -phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1,

c) converting the compound of formula-1 into its fumarate salt compound of formula-la by treating it with fumaric acid in a suitable solvent or mixture of solvents.

Wherein, in step-a) to step-c) the suitable solvent is selected from hydrocarbon solvents, ketone solvents, alcoholic solvents, chloro solvents, ester solvents, ether solvents, polar aprotic solvents, nitrile solvents, polar solvents and/or their mixtures thereof;

In step-a) the suitable base is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal alkoxides and organic bases, preferably alkali metal carbonates;

In step-b) the suitable reducing agent is selected from Pd/C, Pt/C, Raney Ni in combination with hydrogen gas, vitride, sodium borohydride, sodium cyanoborohydride, tetraalkyl ammonium borohydride, lithium aluminium hydride, BF3-etherate/NaBH4> borane-dimethyl sulfide and the like; preferably Pd/C.

The (R)-2-(3 -(diisopropylamino)-1 -phenylpropyl)-4-(hydroxylmethyl)phenyl
methacrylate compound of formula-9 and (R)-2-(3 -(diisopropylamino)- l-phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1 obtained by the above process can be further purified by converting them into their acid-addition salts by treating with a suitable acid in a suitable solvent followed by treating the obtained salt with a suitable base in suitable solvent to provide pure compounds of formula-9 and formula-1 respectively.

Wherein, the suitable acid can be selected from but are not limited to hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, acetic acid, propionic acid, palmitic acid, maleic acid, fumaric acid, oxalic acid, succinic acid, malic acid, citric acid, benzoic acid, 4-hydroxybenzoic acid, salicyclic acid, 4-hydroxycinammic acid, phthalic acid, methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid, toluene sulfonic acid, L-(+)-tartaric acid, D-(-)-tartaric acid, L(+)-mandelic acid, D(-)-mandelic acid, S(+)-acetoxy(phenyl)acetic acid, R(-)-acetoxy(phenyl)acetic acid, 3-chloro mandelic acid, (-)-di-p-
toluoyl-L-tartaric acid, (+)-di-p-toluoyl-D-tartaric acid, (-)-dibenzoyl-L-tartaric acid, (+)-dibenzoyl-D-tartaric acid, S(+)-camphor sulfonic acid and hydrates thereof; and the suitable base is selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and organic bases.

A preferred embodiment of the present invention provides a process for the preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1 and its fumarate salt compound of formula-la, comprising of;

a) Reacting the (R)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxymethyl-phenol compound of formula-8 with methacryloyl chloride in presence of potassium carbonate in acetone to provide (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl) phenyl methacrylate compound of formula-9 and which can be further purified by converting it into its acid-addition salts compound of general formula-28; preferably mandelate salt compound of formula-28a by treating the compound of formula-9 with L(+) mandelic acid in a suitable ester solvent followed by treating the obtained salt compound of formula-28 a with aqueous alkali metal carbonate base in a suitable solvent provides pure compound of formula-9,

b) reducing the compound of formula-9 with Pd/C in ethyl acetate to provide (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1, and which can be further purified by converting it into its pharmaceutically acceptable acid-addition salts, preferably acetyl mandelate salt compound of formula-23 by treating the compound of formula-1 with S(+)-acetoxy(phenyl)acetic acid in a suitable ester solvent, followed by treating the obtained acid-addition salt compound of formula-23 with aqueous alkali metal carbonate in a suitable solvent provides pure compound of formula-1,

c) converting the compound of formula-1 into its fumarate salt compound of formula-la by treating it with fumaric acid in a mixture of methyl ethyl ketone and cyclohexane.

Further the present invention also provides a purification process for the acid-addition salts of compound of formula-1 and compound of formula-9 by recrystallizing them from a suitable solvent.

The second aspect of the present invention provides a process for the preparation of 3-(2-benzyloxy-5-bromophenyl)-3-phenyl propanol compound of formula-3 comprising of reducing the methyl 3-(2-benzyloxy-5-bromophenyl)-3-phenyl propanoate compound of formula-2 with a suitable reducing agent selected from vitride, tetraalkyl ammonium borohydric sodium borohydride, sodium cyanoborohydride, lithium aluminium hydride, Raney I NaBH4-BF3.etherate( borane-dimethyl sulfide and the like, preferably vitride in a suitat solvent selected from hydrocarbon solvents, ether solvents, ester solvents, ketone solven alcoholic solvents, chloro solvents, polar solvents and/or their mixtures; preferably in toluer
Methyl 3-(2-benzyloxy-5-bromophenyl)-3-phenyl propanoate compound of formula used in the above process can be prepared according to the process disclosed US5559269A.

The third aspect of the present invention provides a novel process for the preparatii of (R)-2-(3-(diisopropylamino)-1 -phenylpropyl)-4-(hydroxymethyl)phenyl isobutyn compound of formula-1, comprising of;

a) Treating the methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzo£ compound of formula-4 with a suitable chiral acid in a suitable solvent to provide its chiral acid addition salt compound of general formula-5,

b) treating the compound of general formula-5 with a suitable base in a suitable solvent to provide (R)-methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzoate compound of formula-6,

c) debenzylating the compound of formula-6 with a suitable debenzylating agent in a suitable solvent to provide (R)-methyl 3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxybenzoate compound of formula-7,

d) reducing the compound of formula-7 with a suitable reducing agent in a suitable solvent to provide (R)-2-(3-diisopropylamino-1 -phenylpropyl)-4-hydroxymethyl-phenol compound of formula-8,

e) reacting (R)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxymethyl-phenol compound of formula-8 with methacryloyl chloride in presence or absence of a suitable base in a suitable solvent to provide (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxylmethyl)phenyl methacrylate compound of formula-9,

f) reducing the compound of formula-9 with a suitable reducing agent in a suitable solvent to provide the (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1.

Wherein, the suitable solvent used in step-a) to step-f) is independently selected from hydrocarbon solvents, ketone solvents, alcoholic solvents, chloro solvents, ester solvents, ether solvents, polar-aprotic solvents, nitrile solvents, polar solvents and/or their mixtures thereof;

In step-a) the suitable chiral acid is selected from L(+)-tartaric acid, D(-)-tartaric acid, (-)-di-p-toluoyl-L-tartaric acid, (+)-di-p-toluoyl-D-tartaric acid, (-)-dibenzoyl-L-tartaric acid, (+)-dibenzoyl-D-tartaric acid, L(+)-mandelic acid, D(-)-mandelic acid, 3-chloro mandelic acid, abietic acid, S(+)-camphor sulfonic acid, S(+)-acetoxy(phenyl)acetic acid, R(-)-acetoxy(phenyl)acetic acid and their hydrates; preferably (-)-di-p-toluoyl-L-tartaric acid;

In step-b) and step-e) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and organic bases; preferably alkali metal carbonates.

In step-c) the suitable debenzylating agent is selected from Pd/C, Raney Ni, palladium acetate, platinum oxide, platinum black, Rh/C, Ir, Ru and the like in combination with hydrogen gas;

In step-d) and step-f) the suitable reducing agent is independently selected from Pd/C, Raney Ni in combination with hydrogen gas, vitride, tetraalkyl ammonium borohydride, sodium borohydride, sodium cyanoborohydride, lithium aluminium hydride, BF3.etherate/NaBH4;borane-dimethyl sulfide and the like;
The racemic methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzoate compound of formula-4 utilized in the above process can be synthesized as per the process disclosed in US5559269A.
The fourth aspect of the present invention provides a process for the preparation of (R)-methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzoate compound of formula-6, comprising of;

a) Treating the racemic methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzoate compound of formula-4 with a suitable chiral acid in a suitable solvent to provide its chiral acid addition salt compound of general formula-5,

b) treating the compound of general formula-5 with a suitable base in a suitable solvent to provide (R)-methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzoate compound of formula-6.
Wherein, the suitable chiral acid used in step-a) is same as defined for step-a) of the third aspect of the present invention;

In step-b) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and organic bases; preferably alkali metal carbonates;

The suitable solvent used in step-a) and step-b) can be selected from hydrocarbon solvents, ketone solvents, alcoholic solvents, chloro solvents, ester solvents, ether solvents, polar-aprotic solvents, nitrile solvents, polar solvents and/or their mixtures thereof.

A preferred embodiment of the present invention provides a process for the preparation of (R)-methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzoate compound of formula-6, comprising of;

a) Treating the racemic methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzoate compound of formula-4 with (-)-di-p-toluoyl-L-tartaric acid in isopropyl alcohol to provide (R)-methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzoate (-)-di-p-toluoyl-L-tartaric acid salt compound of formula-5a,

b) treating the compound of formula-5a with sodium carbonate in water to provide (R)-methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzoate compound of formula-6.

The fifth aspect of the present invention provides a process for the preparation of (R)-methyl 3-(3-(diisopropylamino)-l-phenylpropyl)-4-(methacryloyloxy)benzoate compound of formula-10, which comprises of reacting the (R)-methyl 3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxy benzoate compound of formula-7 with methacryloyl chloride in presence or absence of a base in a suitable solvent.
Wherein, the suitable base is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal alkoxides and organic bases; and the suitable solvent is selected from hydrocarbon solvents, ketone solvents, alcoholic solvents, chloro solvents, ester solvents, ether solvents, polar-aprotic solvents, nitrile solvents, polar solvents and/or their rnixrures thereof.

The compound of formula-10 obtained in the present invention can be further purified by converting it into its acid-addition salts.

The sixth aspect of the present invention provides a process for the preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-formylphenyl methacrylate compound of fonnula-12, comprising of;

a) Reducing the (R)-methyl 3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxybenzoate compound of formula-7 with a suitable reducing agent in a suitable solvent to provide (R)-3-(3-(diisopropylamino)-1 -phenylpropyl)-4-hydroxybenzaldehyde of formula-11,

b) reacting the compound of formula-11 with methacryloyl chloride in presence or absence of a base in a suitable solvent to provide (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-formylphenyl methacrylate compound of formula-12.

Wherein, in step-a) the suitable reducing agent is selected from diisobutyl aluminium hydride (DIBAL), vitride, tetraalkyl ammonium borohydride, sodium borohydride, sodium cyanoborohydride, lithium aluminium hydride, Raney Ni, BF3.etherate/NaBH4, borane-dimethyl sulfide and the like; preferably DIBAL;

The suitable solvent used in step-a) and step-b) is selected from hydrocarbon solvents, ketone solvents, alcoholic solvents, chloro solvents, ester solvents, ether solvents, polar-aprotic solvents, nitrile solvents, polar solvents and/or their mixtures thereof;

The suitable base used in step b) is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal alkoxides and organic bases.

The compound of formula-12 obtained in the present invention can be further purified by converting it into its acid-addition salts.

The seventh aspect of the present invention provides a novel process for the preparation of (R)-2-(3-(diisopropylamino)-l -phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1, comprising of;

a) Reacting the racemic 3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3-phenylpropan-1-amine compound of formula-13 with ethyl bromide and magnesium in presence of solid carbon dioxide in a suitable solvent provides 4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzoic acid compound of formula-14,

b) resolving the compound of formula-14 with a suitable chiral acid in a suitable solvent provides (R)-4-(benzyloxy)-3 -(3 -(diisopropylamino)-1 -phenylpropyl)benzoic acid compound of formula-16,

c) debenzylating the compound of formula-16 with a suitable debenzylating agent in a suitable solvent provides (R)-3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxy benzoic acid compound of formula-17,
d) reacting the compound of formula-17 with methacryloyl chloride in presence or absence of a base in a suitable solvent provides (R)-3-(3-(diisopropylamino)-l-phenylpropyl)-4-(methacryloyloxy)benzoic acid compound of formula-18,

e) reducing the compound of formula-18 with a suitable reducing agent in a suitable solvent provides(R)-2-(3 -(diisopropylamino)-1 -phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1.
Wherein, the suitable solvent used in step-a) to step-e) is selected from hydrocarbon solvents, ketone solvents, alcoholic solvents, chloro solvents, ester solvents, ether solvents, polar-aprotic solvents, nitrile solvents, polar solvents and/or their mixtures thereof;

The suitable chiral acid used in step-b) is same as defined for step-a) of the third aspect of the present invention;

In step-c) the suitable debenzylating agent is same as defined in step c) of third aspect. In step-d) the suitable base is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal alkoxides and organic bases;

In step-e) the suitable reducing agent is selected from vitride, tetraalkyl ammonium borohydride, sodium borohydride, sodium cyanoborohydride, lithium aluminium hydride, Raney Ni,

BF3.etherate/NaBH4,borane-dimethyl sulfide and the like.

The compound of formula-18 obtained in the present invention can be further purified by converting it into its acid or base addition salts.

The eighth aspect of the present invention provides a novel process for the preparation of (R)-2-(3-(diisopropylamino)-1 -phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1, comprising of;

a) Resolving the racemic 3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3-phenylpropan-1-amine compound of formula-13 with a suitable chiral acid in a suitable solvent to provide (R)-3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3-phenylpropan-1-amine compound of formula-15,

b) treating the compound of formula-15 with ethyl bromide and magnesium in presence of solid carbon dioxide in a suitable solvent to provide (R)-4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzoic acid compound of formula-16,

c) debenzylating the compound of formula-16 by treating it with a suitable debenzylating agent in a suitable solvent to provide (R)-3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxy benzoic acid compound of formula-17,

d) reacting the compound of formula-17 with methacryloyl chloride in presence or absence of a base in a suitable solvent to provide (R)-3-(3-(diisopropylamino)-l-phenylpropyl)-4-(methacryloyloxy)benzoic acid compound of formula-18,

e) reducing the compound of formula-18 with a suitable reducing agent in a suitable solvent to provide (R)-2-(3-(diisopropylamino)-1 -phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1.

Wherein, the suitable solvent used in step-a) to step-e) wherever necessary is selected from hydrocarbon solvents, ketone solvents, alcoholic solvents, chloro solvents, ester solvents, ether solvents, polar-aprotic solvents, nitrile solvents, polar solvents and/or their mixtures thereof;

The suitable chiral acid used in step-a) is same as defined for step-a) of the third aspect of the present invention;

In step-c) the suitable debenzylating agent is same as defined in step c) of third aspect.

In step-d) the suitable base is selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and organic bases;

In step-e) the suitable reducing agent is selected from vitride, tetraalkyl ammonium borohydride, sodium borohydride, sodium cyanoborohydride, lithium aluminium hydride, Raney Ni, BFa.etherate/NaBH^ borane-dimethyl sulfide and the like.

The ninth aspect of the present invention provides a novel process for the preparation of (R)-3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxybenzaldehyde compound of formula-11, comprising of;

a) Reacting the racemic 3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3-phenylpropan-1-amine compound of formula-13 with dimethyl formamide and n-butyl lithium in a suitable solvent to provide 4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl) benzaldehyde compound of formula-19,

b) resolving the compound of formula-19 with a suitable chiral acid in a suitable solvent to provide (R)-4-(benzyloxy)-3 -(3 -(diisopropylamino)-1 -phenylpropyl)benzaldehyde compound of formula-20,

c) debenzylating the compound of formula-20 with a suitable debenzylating agent in a suitable solvent to provide (R)-3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxybenzaldehyde compound of formula-11.
Wherein, the suitable chiral acid used in step-b) is same as defined for step-a) of the third aspect of the present invention;

In step-c) the suitable debenzylating agent is same as defined in step c) of third aspect. The suitable solvent used in step-a) to step-c) is selected from hydrocarbon solvents, ketone solvents, alcoholic solvents, chloro solvents, ester solvents, ether solvents, polar-aprotic solvents, nitrile solvents, polar solvents and/or their mixtures thereof.

The tenth aspect of the present invention provides a novel process for the preparation of (R)-2-(3-(diisopropylamino)-1 -phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1, comprising of;

a) Reacting the racemic 3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3-phenylpropan-1-amine compound of formula-13 with ethyl bromide and magnesium in presence of solid carbon dioxide in a suitable solvent to provide 4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzoic acid compound of formula-14,

b) debenzylating the compound of formula-14 with a suitable debenzylating agent in a suitable solvent to provide 3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxy benzoic acid compound of formula-21, ruimuiii-z.1 c) reacting the compound of formula-21 with methacryloyl chloride in presence or absence of base in a suitable solvent to provide 3-(3-(diisopropylamino)-l-phenylpropyl)-4-(methacryloyloxy)benzoic acid compound of formula-22,

d) resolving the compound of formula-22 with a suitable chiral acid in a suitable solvent to provide (R)-3-(3-(diisopropylamino)-1 -phenylpropyl)-4-(methacryloyloxy)benzoic acid compound of formula-18,

e) reducing the compound of formula-18 with a suitable reducing agent in a suitable solvent
to provide (R)-2-(3-(diisopropylamino)-1 -phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1.

Wherein, the suitable solvent used in step-a) to step-e) is selected from hydrocarbon solvents, ketone solvents, alcoholic solvents, chloro solvents, ester solvents, ether solvents, polar-aprotic solvents, nitrile solvents, polar solvents and/or their mixtures thereof;

In step-b) the suitable debenzylating agent is same as defined in step c) of third aspect.

In step-c) the suitable base is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal alkoxides and organic bases;

In step-d) the suitable chiral acid is same as defined for step-a) of the third aspect of the present invention;

In step-e) the suitable reducing agent is selected from vitride, tetraalkyl ammonium borohydride, sodium borohydride, sodium cyanoborohydride, lithium aluminium hydride, Raney Ni, BF3 etherate/NaBH^borane dimethyl sulfide and the like.

The eleventh aspect of the present invention provides a novel process for the purification of (R)-2-(3-(diisopropylamino)-l -phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1, comprising of; a) Treating the compound of formula-1 with S(+)-acetoxy(phenyl)acetic acid in a suitable
solvent to provide its S(+)-acetoxy(phenyl)acetic acid salt compound of formula-23, b) treating the compound of formula-23 with a suitable base in a suitable solvent to provide pure (R)-2-(3-(diisopropylamino)-l -phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1.
Wherein, in step-a) and step-b) the suitable solvent is selected from hydrocarbon solvents, ketone solvents, alcoholic solvents, chloro solvents, ester solvents, ether solvents, polar-aprotic solvents, nitrile solvents, polar solvents and/or their mixtures thereof;

In step-b) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and organic bases.

A preferred embodiment of the present invention provides a novel process for the purification of (R)-2-(3-(diisopropylamino)-1 -phenylpropyi)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1, comprising of;

a) Treating the (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1 with S(+)-acetoxy(phenyl)acetic acid in ethyl acetate to provide its S(+)-acetoxy(phenyl)acetic acid salt compound of formula-23,

b) treating the compound of formula-23 with sodium carbonate in dichloromethane or in a mixture of dichloromethane and water to provide pure (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1.

The twelfth aspect of the present invention provides a process for the preparation of (R)-4-cyano-2-(3-(diisopropylamino)-l-phenylpropyl)phenyl isobutyrate compound of formula-25, comprising of reacting the (R)-3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxy benzonitrile compound of formula-24
with isobutyryl chloride in presence or absence of a base in a suitable solvent.

Wherein, the suitable base is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal alkoxides and organic bases; and the suitable solvent is selected from hydrocarbon solvents, ketone solvents, alcoholic solvents, chloro solvents, ester solvents, ether solvents, polar-aprotic solvents, nitrile solvents, polar solvents and/or their mixtures thereof.

The thirteenth aspect of the present invention provides a process for the resolution of 3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3-phenylpropan-l-amine compound of formula-13, comprising of;

a) Treating the 3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3-phenylpropan-l-amine compound of formula-13 with D(-)-tartaric acid in a suitable solvent to provide its D(-)-tartrate salt compound of formula-26,

b) treating the tartrate salt obtained in step-a) with a suitable base in a suitable solvent to provide (R)-3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3-phenylpropan-l-amine of formula-15.
Wherein, in step-a) and step-b) the suitable solvent is selected from hydrocarbon solvents, ketone solvents, alcoholic solvents, chloro solvents, ester solvents, ether solvents, polar-aprotic solvents, nitrile solvents, polar solvents and/or their mixtures thereof;

In step-b) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and organic bases.

A preferred embodiment of the present invention provides a process for the resolution of 3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3-phenylpropan-l-amine compound of formula-13, comprising of;

a) Treating the 3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3-phenylpropan-l-amine compound of formula-13 with D(-)-tartaric acid in isopropyl alcohol to provide its D(-)-tartrate salt compound of formula-26,

b) treating the compound of formula-26 with sodium hydroxide in a mixture of dichloromethane and water to provide (R)-3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3-phenylpropan-l-amine compound of formula-15.

The fourteenth aspect of the present invention provides novel intermediate compounds for the synthesis of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1, which are represented by the below mentioned structural formulae;

Throughout the specification of the present invention, the group 'i-pr' represents isopropyl group and 'OBn' represents benzyloxy group.

Isobutyric acid 2-((R)-3 -diisopropylammonium-1 -phenylpropyl)-4-(hydroxymethyl) phenyl ester hydrogen fumarate salt compound of formula-la of the present invention was analyzed by HPLC under the following conditions;

Apparatus: A liquid chromatographic system equipped with variable wavelength UV-detector and integrator; Column: Inert sustain CI8, 250x4.6 mm, 5um or equivalent; Flow rate: 1.2 mL/min; Wavelength: 220 nm; Column temperature: 45°C; Injection volume: 20uL; Run time: 55 min; Diluent: Buffer: Acetonitrile (60:40 v/v); Elution: Gradient; Buffer: 3 mL H3PO4 (85%) and 1.0 gm 1-octane sulfonic acid sodium salt anhydrous in 1000 mL of Milli Q water and adjust its pH to 7.2 with dil.KOH. Filter the solution through 0.22 urn Nylon membrane paper and sonicate to degas it. Mobile phase-A: Buffer: Acetonitrile (60:40 v/v); Mobile phase-B: Acetonitrile: water (90:10 v/v).

Chiral purity of the compound of formula-la of the present invention was analyzed by HPLC under the following conditions;

Apparatus: A liquid chromatographic system equipped with variable wavelength UV-detector; Column: Chiral pack 3-IC 250x4.6 mm, 3um or equivalent; Flow rate: 1.0 mL/min; Wavelength: 225 nm; Column temperature: 25°C; Injection volume: 20uL; Run time: 30 min; Diluent: n-hexane; Elution: Isocratic; Mobile phase: n-Hexane: Isopropyl alcohol: Diethyl amine (95:05:0.1) v/v.

The particle size distribution of isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrogen fumarate salt compound of formula-la of the present invention is measured using Malvern Mastersizer 2000 instrument.

Isobutyric acid 2-((R)-3 -diisopropylammonium-1 -phenylpropyl)-4-(hydroxymethyl) phenyl ester hydrogen fumarate salt compound of formula-la produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball mills, roller and hammer mills and jet mills. Milling or micronization may be performed before drying or after completion of drying of the product.

The PXRD analysis of the crystalline compounds of the present invention was carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A0 and continuous scan speed of 0.03°/min.

The best mode of carrying out the present invention is illustrated by the below mentioned examples.

These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention. Examples: Example-1: Preparation of 6-bromo-4-phenylchroman-2-one
A mixture of cinnamic acid (200 gm), 4-bromo phenol (234 gm) and conc.sulfuric acid (40 ml) was heated to 90-95°C and stirred for 12 hrs at the same temperature under N2 atmosphere. After completion of the reaction, toluene (2000 ml) followed by water (2000 ml) were added to the reaction mixture at 50-55°C and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was extracted with toluene. Both the organic layers were combined and washed with 10% sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure and then co-distilled with isopropyl alcohol. 600 ml of Isopropyl alcohol was added to the obtained residue, cooled the reaction mixture to 0-5°C and stirred for 2 hrs at the same temperature.

Filtered the precipitated solid, washed with chilled isopropyl alcohol and then dried to get the title compound; Yield: 309 gm; Purity by HPLC: 98.9%. Example-2: Preparation of methyl 3-(2-(benzyloxy)-5-bromophenyl)-3-phenyl propanoate (FormuIa-2)

Potassium carbonate (137.5 gm), sodium iodide (25 gm) followed by acetone (750 ml) were added to a mixture of 6-bromo-4-phenylchroman-2-one (250 gm) in methanol (750 ml) at 25-30°C. Cooled the reaction mixture to 15-20°C, benzyl chloride (112.5 ml) was added and stirred for 30 min at the same temperature. Heated the reaction mixture to reflux temperature and stirred for 5 hrs at the same temperature. After completion of the reaction, the solvent was completely distilled off from the reaction mixture under reduced pressure and co-distilled with acetone. Water (2500 ml) was added to the obtained residue at 25-30°C and stirred for 8 hrs at the same temperature. Filtered the precipitated solid and washed with water. Pet ether (1000 ml) was added to the obtained compound at 25-30°C and stirred for 30 min at the same temperature. Filtered the solid, washed with pet ether and then dried to get the title compound. Yield: 282 gm; Purity by HPLC: 98.5%.

Example-3: Preparation of 3-(2-benzyloxy-5-bromophenyl)-3-phenyl propanol (formuIa-3)
A solution of vitride in toluene (362.5 ml, 70% in toluene) was slowly added to a pre-cooled mixture of methyl 3-(2-(benzyloxy)-5-bromophenyl)-3-phenylpropanoate (280 gm) in toluene (3000 ml) at 0-5°C under nitrogen atmosphere and stirred for 4 hrs at the same temperature. After completion of the reaction, a solution of sodium potassium tartrate (465 gm) in water (1250 ml) was slowly added to the reaction mixture at 0-5°C. The temperature of the reaction mixture was raised to 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was extracted with toluene. Combined the organic layers and washed with 5% acetic acid solution, 5% aqueous sodium chloride solution followed by water. Distilled off the solvent completely from the organic layer under reduced pressure and then co-distilled with cyclohexane. Cyclohexane (1000 ml) was added to the obtained residue at 25-3 0°C and stirred for 4 hrs at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid, washed with cyclohexane and then dried to get the title compound. Yield: 224 gm; Purity by HPLC: 99.06%.

Example-4: Preparation of 3-(2-benzyloxy-5-bromophenyl)-3-phenyI propanol (formula-3)
Potassium carbonate (137.5 gm), sodium iodide (25 gm) followed by acetone (750 ml) were added to a mixture of 6-bromo-4-phenylchroman-2-one (250 gm) in methanol (750 ml) at 25-30°C. Cooled the reaction mixture to 15-20°C, benzyl chloride (112.5 ml) was added and stirred for 30 min at the same temperature. Heated the reaction mixture to reflux temperature and stirred for 5 hrs at the same temperature. After completion of the reaction, the solvent was completely distilled off from the reaction mixture under reduced pressure and co-distilled with acetone. Water (2500 ml) was added to the obtained residue at 25-30°C and stirred for 8 hrs at the same temperature. Filtered the precipitated solid and washed with water. Pet ether (1000 ml) was added to the obtained compound at 25-30°C and stirred for 30 min at the same temperature. Filtered the solid and washed with pet ether. Toluene (3000 ml) was added to the obtained wet compound and separate water from the organic layer by azeotropic distillation. A solution of vitride in toluene (362.5 ml, 70% in toluene) was slowly added to the reaction mixture at 0-5°C under nitrogen atmosphere and stirred for 4 hrs at the same temperature. After completion of the reaction, a solution of sodium potassium tartrate (465 gm) in water (1250 ml) was slowly added to the reaction mixture at 0-5°C. The temperature of the reaction mixture was raised to 25-3 0°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was extracted with toluene. Combined the organic layers and washed with 5% acetic acid solution, 5% aqueous sodium chloride solution followed by water. Distilled off the solvent completely from the organic layer under reduced pressure and then co-distilled with cyclohexane. Cyclohexane (1000 ml) was added to the obtained residue at 25-30°C and stirred for 4 hrs at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid, washed with cyclohexane and then dried to get the title compound. Yield: 265 gm; Purity by HPLC: 99.06%. ExampIe-5: Preparation of 3-(2-(benzyloxy)-5-bromophenyl)-3-phenylpropyl-4-methylbenzenesulfonate 3-(2-Benzyloxy-5-bromophenyl)-3-phenyl propanol (300 gm) was dissolved in dichloromethane (1200 ml) at 25-30°C under nitrogen atmosphere and stirred for 15 min at the same temperature. Cooled the reaction mixture to 0-5°C and 4-dimethylamino pyridine (21 gm) followed by p-toluene sulfonyl chloride (203 gm) were added at the same temperature. Triethylamine (315 ml) was added drop wise to the resulting reaction mixture at 0-5°C and stirred for 2 hrs at the same temperature. After completion of the reaction, water was added to the reaction mixture and stirred for 15 min at 25-30°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Combined the organic layers and washed with 20% hydrochloric acid solution followed by water. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 425.0 gm; Purity by HPLC: 94.32%.

Example-6: Preparation of 3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (Formula-13)
3-(2-(benzyloxy)-5-bromophenyl)-3-phenylpropyl-4-methylbenzenesulfonate obtained in example-4, acetonitrile (450 ml) and N,N-diisopropylamine (529 ml) were charged into an autoclave vessel at 25-30°C under nitrogen atmosphere and stirred for 15 min at the same temperature. Heated the reaction mixture to 95-100°C and stirred for 32 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 10-15°C and stirred for 1 hr at the same temperature. Filtered the reaction mixture and washed the filtrate with acetonitrile. Distilled off the solvent completely from the filtrate under reduced pressure. Toluene (1500 ml) was added to the obtained residue and the reaction mixture was washed with aqueous sodium hydroxide solution followed by sodium chloride solution. Water was added to the organic layer and cooled the reaction mixture to 0-5°C. Acidifying the reaction mixture with ortho phosphoric acid at 0-5°C and raised the temperature of the reaction mixture to 25-3 0°C. Both the organic and aqueous layers were separated, basified the aqueous layer with aq.sodium hydroxide solution at 0-5°C. Dichloromethane was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with water. Distilled off the solvent completely from the organic layer under reduced pressure to get title compound. Yield: 260.0 gm.

Example-7: Preparation of (R)-3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3-phenylpropan-1-amine D(-)-tartrate salt (Formula-26)
D(-)-tartaric acid (94.7 gm) and isopropyl alcohol (2400 ml) were added to 3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3-phenylpropan-l-amine obtained in example-5 and at 30-35°C. Heated the reaction mixture to 50-55°C and stirred for 45 min at the same temperature. Slowly cooled the reaction mixture to 30-35°C and stirred for 6 hrs at the same temperature. Filtered the precipitated solid, washed with isopropyl alcohol and then dried to get the title compound. Yield: 186 gm; Purity by HPLC: 96.36%.

Example-8: Purification of (R)-3-(2-(benzyloxy)-5-bromophenyI)-N,N-diisopropyl-3-phenylpropan-1-amine D(-)-tartrate salt (Formula-26)

A mixture of (R)-3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3-phenylpropan-1-amine D(-)-tartrate salt (100 gm) and ethanol (300 ml) was heated to 50-55°C and stirred for 30 min at the same temperature. Slowly cooled the reaction mixture to 10-15°C and stirred for 1 hr at the same temperature. Filtered the precipitated solid, washed with chilled ethanol and then dried to get the title compound as a pure solid.

Yield: 75.0 gm; Purity by HPLC: 98.79%; Chiral purity by HPLC: 98.72%; S-isomer: 1.05%; SOR: (-)14.529° [C=5% in methanol]. Example-9: Preparation of (R)-3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (Formula-15)

A mixture of (R)-3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3-phenylpropan-1-amine D(-)-tartrate (500 gm), water (2500 ml) and dichloromethane (2500 ml) was stirred for 15 min at 0-5°C. Basifying the reaction mixture with aqueous sodium hydroxide solution at 5-10°C and stirred the reaction mixture for 10 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with water. Distilled off the solvent completely from the organic layer to get the title compound. Example-10: Preparation of (R)-4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenyl propyl)benzoic acid (Formula-16)

Magnesium turnings (100 gm), tetrahydrofuran (2000 ml) and iodine (0.5 gm) were added charged into a clean and dry RBF at 25-30°C under N2 atmosphere. Heated the reaction mixture to 35-40°C and slowly added a solution of ethyl bromide (60 ml) dissolved in tetrahydrofuran (250 ml). A mixture of (R)-3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3-phenylpropan-l-amine obtained in example-8, ethyl bromide (180 ml), tetrahydrofuran (1000 ml) and toluene (1000 ml) was slowly added to the reaction mixture at below 55°C. Heated the reaction mixture to 60-65°C and stirred for 1 hr at the same temperature. Cooled the reaction mixture to 25-30°C ad then further cooled to -30°C to -25°C under N2 atmosphere. 2.0 Kg/cm2 of CO2 gas was purged into the reaction mixture at -30 to -20°C. After completion of the reaction, the temperature of the reaction mixture was raised to -15°C to -10°C and quenched with aqueous ammonium chloride solution. Raised the temperature of the reaction mixture to 20-25°C and stirred for 45 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed with aqueous ammonium chloride solution. Both the organic and aqueous layers were separated and the aqueous layer was washed with toluene. Cooled the aqueous layer to 0-5 °C and acidified with aqueous hydrochloric acid at 0-5°C. The compound was extracted with dichloromethane at 25-30°C and water was added to the organic layer. Cooled the reaction mixture to 10-15°C and basifying with aqueous sodium bicarbonate solution. Both the organic and aqueous layers were separated and distilled off the solvent atmospherically from organic layer. Ethyl acetate (250 ml) was added to the obtained residue and stirred for 30 min at 25-30°C. Slowly added cyclohexane (1500 ml) to the reaction mixture at 25-30°C and stirred for 2 hrs at the same temperature. Further cooled the reaction mixture to 10-15°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid, washed with chilled cyclohexane and then dried to get the title compound; Yield: 240 gm; Purity by HPLC: 98.3%.

Example-11: Preparation of (R)-methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenyIpropyl)benzoate(Formula-6) Conc.sulfuric acid (60 ml) was added to a pre-cooled mixture of (R)-4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzoic acid (250 gm) in methanol (1250 ml) at 10-15°C. Heated the reaction mixture to reflux temperature and stirred for 8 hrs at the same temperature. After completion of the reaction, 70% of the solvent is distilled off under reduced pressure. Cooled the reaction mixture to 25-3 0°C, water and dichloromethane were added. Further cooled the reaction mixture to 5-10°C and basified with aqueous sodium carbonate solution. Raised the temperature of the reaction mixture to 25-3 0°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with water. Distilled of the solvent from the organic layer atmospherically to get the title compound.

Example-12: Preparation of (R)-methyl 4-(benzyloxy)-3-(3-(diisopropyIamino)-l-phenylpropyl)benzoate(Forimila-6)

A solution of (R)-4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzoic acid hydrochloride (280 gm) in methanol (2800 ml) was cooled 30 to 10-15°C and thionyl chloride (93 ml) was drop wise added. Heated the reaction mixture to 40-45°C and stirred for 5 hrs at the same temperature. After the completion of the reaction, distilled off the solvent completely from the reaction mixture under reduced pressure and then co-distilled with dichloromethane. Cooled the reaction mixture to 25-30°C, added dichloromethane (2800 ml) and then further cooled to 0-5°C. The pH of the reaction mixture was adjusted to 8.5 using 10% sodium bicarbonate solution (450 ml). Both the organic and aqueous layers were separated and the organic layer was washed with water. Distilled off the solvent completely from the organic layer at 40-45°C to get the title compound. Yield: 184 gm; Purity by HPLC: 85.58%.

Example-13: Preparation of (R)-(4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenyl propyl)phenyl)methanol (Formula-27)

Tetrahydrofuran (500 ml), toluene (1000 ml) were added to (R)-methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzoate obtained in example-10 under N2 atmosphere at 25-30°C and stirred for 15 min at the same temperature. Cooled the reaction mixture to 0-5°C, slowly added a solution of vitride in toluene (648 ml, 70% solution) and stirred for 2 hrs at the same temperature. After completion of the reaction, quenched the reaction mixture with aqueous sodium potassium tartrate solution at 0-5°C. Raised the temperature of the reaction mixture to 25-3 0°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound.

Example-14: Preparation of (R)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxy methyl-phenol (Formula-8)

A mixture of Raney Ni (100 gm) in methanol (250 ml) was added to a solution of (R)-(4-(benzyloxy)-3-(3-(diisopropylamino)-l -phenylpropyl)phenyl)methanol obtained in example-13 in methanol (1000 ml) under N2 atmosphere at 25-30°C in an autoclave vessel. 4-5 kg/cm2 of hydrogen gas pressure was applied to the reaction mixture at 25-3 0°C and stirred for 6 hrs at the same temperature. After completion of the reaction, filtered the reaction mixture through hyfiow bed and washed with methanol. Distilled off the solvent completely from the filtrate under reduced pressure. Dichloromethane and water were added to the obtained residue at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with cyclohexane. Ethyl acetate (120 ml) and cyclohexane (480 ml) were added to the obtained residue at 30-35°C. Heated the reaction mixture to 65-70°C and stirred for 15 min at the same temperature. Cooled the reaction mixture to 25-3 0°C and stirred for 5 hrs at the same temperature. Further cooled the reaction mixture to 0-5°C and stirred for 2 hrs at the same temperature.

Filtered the precipitated solid, washed with a mixture of chilled ethyl acetate and cyclohexane and dried to get the title compound. Yield: 158 gm; Purity by HPLC: 97.63%; Chiral purity by HPLC: 99.12%. Example-15: Preparation of (R)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxy methyl-phenol (Formula-8)
(R)-(4-(benzyloxy)-3-(3-(diisopropylarnino)-l -phenylpropyl)phenyl)methanol (16 gm), methanol (160 ml) and 5% Pd/C (8 gm) were charged into an autoclave at 25-3 0°C under nitrogen atmosphere. 3-4 Kg/Cm2 hydrogen gas pressure was applied to the reaction mixture for 8 hrs at 25-30°C. After completion of the reaction, filtered the reaction mixture through hyfiow bed and washed with methanol. Distilled off the solvent completely form the filtrate under reduced pressure to get the title compound. Yield: 11.6 gm; Purity by HPLC: 93.75%.

Example-16: Preparation of (R)-methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzoate (-)-di-p-toluoyl-L-tartaric acid salt (Formula-5a) Methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzoate (10 gtn) and isopropyl alcohol (80 ml) were charged in a clean and dry RBF at 25-3 0°C. Heated the reaction mixture to 55-60°C and (-)-di-p-toluoyl-L-tartaric acid (7.5 gm) was added. Further heated the reaction mixture to 80-85°C and stirred for 1 hr at the same temperature. Cooled the reaction mixture to 40-45°C, filtered and washed with isopropyl alcohol. A mixture of isopropyl alcohol (85 ml) and water (9.5 ml) was added to the obtained compound, heated the reaction mixture to 80-85°C and stirred for 1 hr at the same temperature. Cooled the reaction mixture to 40-45°C, filtered the compound and washed with a mixture of isopropyl alcohol and water to get the title compound. Yield: 10.0 gm.

Example-17: Preparation of (R)-methyl 4-(benzyloxy)-3-(3-(diisopropyIamino)-l-phenylpropyl)benzoate (Formula-6)
(R)-methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzoate (-)-di-p-toluoyl-L-tartaric acid salt (10 gm) and water (50 ml) were charged into a clean and dry RBF at 25-30°C. Basifying the reaction mixture with 10% aqueous sodium carbonate solution. Extracted the reaction mixture with dichloromethane and the organic layer was washed with sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get title compound. Yield: 7.5 gm; Purity by HPLC: 99.6%.

Example-18: Preparation of (R)-methyl 3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxybenzoate (Formula-7)

(R)-methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzoate (50 gm), ethyl acetate (250 ml) and 5% Pd/C (10 gm) were charged into an autoclave at 25-30°C under nitrogen atmosphere. 3-4 Kg/Cm2 hydrogen gas pressure was applied to the reaction mixture for 18 hrs at 25-30°C. After completion of the reaction, filtered the reaction mixture through hyflow bed and washed with ethyl acetate. Distilled off the solvent completely under reduced pressure to get title compound. Yield: 30.0 gm.

Example-19: Preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl)phenol (Formula-8)

(R)-methyl 3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxybenzoate (35 gm) and tetrahydrofuran (180 ml) were charged into a clean and dry RBF at 25-30°C. Cooled the reaction mixture to 0-5°C and slowly added a solution of vitride in tetrahydrofuran (120 ml) under nitrogen atmosphere and stirred for 2 hrs at the same temperature. After completion of the reaction, quenched the reaction mixture with 20% sodium potassium tartrate solution at 0-5°C and raised the temperature to 25-30°C. Both the organic and aqueous layers were separated and the organic layer was washed with water. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 25.0 gm.

Example-20: Preparation of (R)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxy methyl phenol L(+)-mandelate salt A mixture of (R)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxymethyl-phenol (10 gm), isopropyl alcohol (40 ml) and L-(+)-mandelic acid (4.5 gm) was heated to reflux temperature and stirred for 30 min at the same temperature. Cooled the reaction mixture to 25°-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with isopropyl alcohol and then dried to get the title compound. Yield: 12.8 gm.

Example-21: Preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxyl methyl)phenol (Formula-8) 20% aqueous sodium carbonate solution (20 ml) was added to a pre-cooled mixture of (R)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxymethyl phenol L(+)-mandelate salt (20 gm), water (200 ml) and chloroform (200 ml) at 0-5°C and stirred the reaction mixture for 15 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with water. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 12.5 gm.

Example-22: Preparation of methacryloyl chloride

A mixture of methacrylic acid (40 ml), benzoyl chloride (100 ml) and butylated hydroxytoluene (100 mg) was heated to 95-100°C and stirred for 1 hr at the same temperature. Distilled the reaction mixture completely at below 105°C and the resulting crude compound is fractionally distilled at 90-95°C to get the title compound. Yield: 35.0 gm.

Example-23: Preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxyl methyl)phenyl methacrylate (Formula-9) Potassium carbonate (22.5 gm) was added to a solution of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl)phenol (50 gm) in acetone (150 ml) at 25-30°C and the reaction mixture was cooled to 0-5°C. A solution of methacryloyl chloride (15.7 ml) in acetone (50 ml) was added to the reaction mixture at 0-5°C and stirred for 30 min at the same temperature. After completion of the reaction, distilled off the solvent completely from the reaction mixture under reduced pressure. Water and ethyl acetate were added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with 5% aqueous sodium bicarbonate solution followed by with water. Distilled off the solvent
completely from the organic layer under reduced pressure to get the title compound. Yield: 65.0 gm; Purity by HPLC: 91.79%; dimer impurity: 4.78%.

Example-24: Preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxyl methyl)phenyl methacrylate (Formula-9)

The title compound is prepared as per the process disclosed in example-23 using chloroform as a solvent instead of acetone.

Example-25: Preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxyl methyl)phenyl methacrylate L(+)-mandelate salt (Formula-28a)

A mixture of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl)phenyl methacrylate obtained in example-23 and ethyl acetate (200 ml) was heated to 45-50°C and stirred for 10 min at the same temperature. L(+)-mandelic acid (26.6 gm) was added to the reaction mixture at 45-50°C and stirred for 30 min at the same temperature. Cooled the reaction mixture to 10-15°C and stirred for 60 min at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and then dried to get the title compound. The obtained solid was recrystallized from ethyl acetate; Yield: 50.0 gm; MR: 123-126°C; Purity by HPLC: 98.99 %; PXRD of the obtained compound is shown in figure-1. Example-26: Preparation of (R)-2-(3-(diisopropylamino)-l-phenyIpropyl)-4-(hydroxyl methyl)phenyl methacrylate mandelate salt (Formula-28a)

Acetone (150 ml) was added to (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl)phenol (50 gm) at 25-30°C and stirred for 15 min at the same temperature. Potassium carbonate (22.5 gm) was added to the reaction mixture at 25-30°C and cooled the reaction mixture to 0-5°C. A solution of methacryloyl chloride (15.7 ml) in acetone (50 ml) was added to the reaction mixture at 0-5°C and stirred for 30 min at the same temperature. After completion of the reaction, distilled off the solvent completely from the reaction mixture under reduced pressure. Water and ethyl acetate were added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with 5% aqueous sodium bicarbonate solution followed by with water. Distilled off the solvent completely from the organic layer. Ethyl acetate (200 ml) was added to the obtained residue and stirred for 15 min at the same temperature. Heated the reaction mixture to 45-50°C, L(+)-mandelic acid (26.6 gm) was added and stirred for 30 min at the same temperature. Cooled the reaction mixture to 10-15°C and stirred for 60 min at the same temperature. Filtered the solid, washed with chilled ethyl acetate and then dried to get the title compound. The obtained solid was recrystallized from ethyl acetate. The PXRD of the obtained compound is shown in fig-1. Yield: 50 gm; MR: 123-126°C; Purity by HPLC: 98.64 %;

Example-27: Preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxyl methyl)phenyl methacrylate (Formula-9)
Ethyl acetate (100 ml) was added to a pre-cooled solution of (R)-2-(3-(diisopropylamino)-1 -phenylpropyl)-4-(hydroxymethyl)phenyl methacrylate L(+)-mandelate (26 gm) in water (125 ml) at 10-15°C. Basifying the reaction mixture with 10% aqueous sodium carbonate solution at 10-15°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with water. Distilled off the solvent completely from the organic layer to get the pure title compound. Yield: 16.2 gm; Purity by HPLC: 99.6%.

Example-28: Preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxymethyI)phenyl isobutyrate (Formula-1) (R)-2-(3 -(diisopropylamino)-1 -phenylpropyl)-4-(hydroxymethyl)phenyl methacrylate (25 gm), ethyl cetate (250 ml) and 10% Pd/C (11.5 gm) were charged into an autoclave vessel at 25-30°C under nitrogen atmosphere. 3-4 Kg/Cm2 hydrogen gas pressure was applied to the reaction mixture at 25-30°C and stirred for 10 hrs at the same temperature. After completion of the reaction, filtered the reaction mixture through hyflow bed and washed with ethyl acetate. Distilled off the solvent completely from the filtrate under reduced pressure to get the title compound. Yield: 20.8 gm; Purity by HPLC: 98.1%; Diol impurity: 0.30%;

Example-29: Preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxy methyl)phenyl isobutyrate (S)-acetoxy(phenyl)acetic acid salt (formula-23) Ethyl acetate (50 ml) and (R)-2-(3 -(diisopropylamino)-1-phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate (20 gm) were charged into a clean and dry RBF at 25-30°C and stirred for 15 min at the same temperature. A solution of S(+)-acetoxy(phenyl)acetic acid (11.32 gm) in ethyl acetate (25 ml) was added to the reaction mixture at 25-30°C. Cooled the reaction mixture to 5-10°C and stirred for 90 min at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and then dried to get the title compound. Yield: 19.3 gm; Purity by HPLC: 99.55%.

Example-30: Preparation of (R)-2-(3-(diisopropyIamino)-l-phenylpropyl)-4-(hydroxy methyl)phenyl isobutyrate (S)-acetoxy(phenyl)acetic acid salt (formula-23) Ethyl acetate (100 ml) was added to a pre-cooled solution of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl)phenyl methacrylate mandelate (26 gm) in water (125 ml) at 10-15°C. Basifying the reaction mixture with 10% aqueous sodium carbonate solution at 10-15°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with water. The resulting organic layer and 10% Pd/C (7.5 gm) were charged into an autoclave vessel at 25-30°C under nitrogen atmosphere. 3-4 Kg/Cm2 hydrogen gas pressure was applied to the reaction mixture at 25-30°C and stirred for 10 hrs at the same temperature. Filtered the reaction mixture through hyflow bed and washed with ethyl acetate. Distilled off the solvent completely from the filtrate under reduced pressure. Ethyl acetate (28 ml) was added to the obtained residue at 25-30°C. A solution of (S)-acetoxy(phenyl)acetic acid (11.37 gm) in ethyl acetate (25 ml) was added to the reaction mixture at 25-30°C. Cooled the reaction mixture to 5-10°C and stirred for 90 min at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and then dried to get the title compound. The PXRD of the obtained compound is shown in figure-2. Yield: 13.5 gm; Purity by HPLC: 99.93%.

Example-31: Preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxy methyl)phenyl isobutyrate (Formula-1) (R)-2-(3 -(diisopropylamino)-1 -phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate (S)-acetoxy(phenyl)acetic acid salt (10 gm), dichloromethane (60 ml) and water (50 ml) were charged into a clean and dry RBF at 25-30°C and cooled the reaction mixture to 0-5°C. Basifying the reaction mixture with aqueous sodium carbonate solution at 0-5°C and stirred for 30 minutes at the same temperature. Raised the temperature of the reaction mixture to 25-30°C. Both the organic and aqueous layers were separated, and the organic layer was washed with aqueous sodium carbonate solution followed by with water. Distilled off the solvent completely from the organic layer to get the title compound. Yield: 9.0 gm; Purity by HPLC: 99.82%; Diol impurity: 0.01%;

Example-32: Preparation of isobutyric acid 2-((R)-3-diisopropylammonium-l-phenyl propyl)-4-(hydroxymethyl)phenyl ester hydrogen fumarate salt (Formula-la) (R)-2-(3 -(diisopropylamino)-1 -phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate (S)-acetoxy(phenyl)acetic acid salt (100 gm), dichloromethane (600 ml) and water (500 ml) were charged into a clean and dry RBF at 25-30°C and cooled the reaction mixture to 0-5°C. Basifying the reaction mixture with aqueous sodium carbonate solution at 0-5°C and stirred for 30 minutes at the same temperature. The temperature of the reaction mixture was raised to 25-30°C. Both the organic and aqueous layers were separated, and the organic layer was washed with aqueous sodium carbonate solution followed by with water. Distilled off the solvent completely from the organic layer and co-distilled with cyclohexane. Methyl ethyl ketone (250 ml) was added to the obtained residue at 25-30°C and stirred for 15 min at the same temperature. Fumaric acid (18.5 gm) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 40-45°C and stirred for 1 hr at the same temperature. Filtered the reaction mixture at 40-45°C and then slowly cooled the filtrate to 20-25°C. The reaction mixture was seeded with isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrogen fumarate (0.1 gm) at 20-25°C and stirred for 2 hrs at the same temperature. Cyclohexane (440 ml) was added to the reaction mixture at 20-25°C and stirred for 14 hrs at 25-3 0°C. Filtered the precipitated solid, washed with cyclohexane and then dried to get the title compound. The PXRD of the obtained compound is shown in figure-3. Yield: 76.0 gm; M R: 103°C; Purity by HPLC: 99.82%; Diol impurity: 0.01%; Particle size distribution: D(0.1): 20.92 um; D(0.5): 75.34 um; D(0.9): 169.12 urn. After Micronization: D(0.1): 9.89 um; D(0.5): 21.59 um; D(0.9): 43.38 um Example-33: Preparation of isobutyric acid 2-((R)-3-diisopropylammonium-l-phenyl propyl)-4-(hydroxymethyl)phenyl ester hydrogen fumarate salt (Formula-la) (R)-2-(3 -(diisopropylamino)-1 -phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate (S)-acetoxy(phenyl)acetic acid salt (100 gm), dichloromethane (600 ml) and water (500 ml) were charged into a clean and dry RBF at 25-30°C and cooled the reaction mixture to 0-5°C. Basifying the reaction mixture with aqueous sodium carbonate solution at 0-5°C and stirred for 30 minutes at the same temperature. The temperature of the reaction mixture was raised to 25-30°C. Both the organic and aqueous layers were separated, and the organic layer was washed with aqueous sodium carbonate solution followed by with water. Distilled off the solvent completely from the organic layer and co-distilled with cyclohexane. Methyl ethyl ketone (250 ml) was added to the obtained residue at 25-30°C and stirred for 15 min at the same temperature. Fumaric acid (18.5 gm) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 40-45°C and stirred for 1 hr at the same temperature. Filtered the reaction mixture at 40-45°C and then slowly cooled to 20-25°C. Cyclohexane (440 ml) was added to the reaction mixture at 25-3 0°C and stirred for 14 hrs at the same temperature. Filtered the precipitated solid, washed with cyclohexane and then dried to get the title compound. The PXRD of the obtained compound is shown in figure-3. Yield: 76.0 gm; M R: 103°C; Purity by HPLC: 99.88%.

We Claim:

1. Novel process for the preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1 and its fumarate salt compound of formula-la, comprising of;

a) Reacting the (R)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxymethyl-phenol compound of formula-8 with methacryloyl chloride in presence or absence of a suitable base in a suitable solvent to provide (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxyl methyl)phenyl methacrylate compound of formula-9,

b) optionally purifying the compound of formula-9 by converting it into its acid-addition salt compound of general formula-28 by treating compound of formula-9 with a suitable acid in a suitable solvent,
followed by treating the obtained salt with a suitable base in a suitable solvent to provide pure compound of formula-9,

c) reducing the compound of formula-9 with a suitable reducing agent in a suitable solvent to provide (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1,

d) optionally purifying the compound of formula-1 by converting it into its acid-addition salt by treating with a suitable acid in a suitable solvent, followed by treating the obtained acid-addition salt with a suitable base in a suitable solvent to provide pure compound of formula-1, e) converting the compound of formula-1 into its fumarate salt compound of formula-la by treating it with fumaric acid in a suitable solvent or mixture of solvents.

2. The process according to claim 1, wherein

the suitable solvent used in step-a) to step-e) is selected from hydrocarbon solvents, ketone solvents, alcoholic solvents, chloro solvents, ester solvents, ether solvents, polar-aprotic solvents, nitrile solvents, polar solvents and/or their mixtures;

the suitable base used in step-a), step-b) and step-d) is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal alkoxides and organic bases, preferably alkali metal carbonates;

the suitable reducing agent in step-c) is selected from Pd/C, Pt/C, Raney Ni in combination with hydrogen, vitride, sodium borohydride, sodium cyanoborohydride, tetraalkyl ammonium borohydride, lithium aluminium hydride, BFs-etherate/NaBH^ borane-dimethyl sulfide and the like; preferably Pd/C.
In step-c & step-d) the suitable acid is selected from hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, acetic acid, propionic acid, palmitic acid, maleic acid, fumaric acid, oxalic acid, succinic acid, malic acid, L-(+)-tartaric acid, D-(-)-tartaric acid, L(+)-mandelic acid, D(-)-mandelic acid, (-)-di-p-toluoyl-L-tartaric acid, (H-)-di-p-toluoyl-D-tartaric acid, (-)-dibenzoyl-L-tartaric acid, (+)-dibenzoyl-D-tartaric acid, S(+)-acetoxy(phenyl)acetic acid, R(-)-acetoxy(phenyl)acetic acid, citric acid, benzoic acid, 4-hydroxybenzoic acid, salicyclic acid, 4-hydroxycinammic acid, phthalic acid, methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid, toluene sulfonic acid;

3. Novel process for the preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4- (hydroxymethyl)phenyl isobutyrate compound of formula-1 and its fumarate salt
compound of formula-la, comprising of;

a) Reacting the (R)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxymethyl-phenol compound of formula-8 with methacryloyl chloride in presence of potassium carbonate in acetone to provide (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl)phenyl methacrylate compound of formula-9, b) purifying the compound of formula-9 by converting it into its mandelate salt of formula-28a followed by treating it with sodium carbonate in a mixture of ethyl acetate and water to provide pure compound of formula-9,

c) reducing the compound of formula-9 with Pd/C in ethyl acetate to provide (R)-2-(3-diisopropylamino)-l -phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1,

d) purifying the compound of formula-1 by converting it into its acetyl mandelate salt compound of formula-23

followed by treating it with sodium carbonate in a mixture of dichloromethane and water to provide pure compound of formula-1, e) converting the compound of formula-1 into its fumarate salt compound of formula-la by treating it with fumaric acid in a mixture of methyl ethyl ketone and cyclohexane.

4. A process for the preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl)phenyl methacrylate compound of formula-9 comprising of contacting the (R)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxymethyl-phenol compound of formula-8 with methacryloyl chloride (2-methylprop-2-enoyl chloride) to provide (R)-2-(3 -(diisopropylamino)-1 -phenylpropyl)-4-(hydroxymethyl)phenyl methacrylate compound of formula-9.

5. A process according to claim 1, the process further comprises the preparation of (R)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxymethyl-phenol compound of formula-8 comprising of;

a) Treating the 3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3-phenylpropan-l-amine compound of formula-13 with a suitable chiral acid selected from L(+)-tartaric acid, D(-)-tartaric acid, (-)-di-p-toluoyl-L-tartaric acid, (+)-di-p-toluoyl-D-tartaric acid, (-)-dibenzoyl-L-tartaric acid, (+)-dibenzoyl-D-tartaric acid, L(+)-mandelic acid, D(-)-mandelic acid in a suitable solvent selected from alcoholic solvents, ester solvents, ether solvents, ketone solvents, polar solvents, chloro solvents or their mixtures to provide corresponding chiral acid addition salt,

b) treating the acid-addition salt obtained in step-a) with a suitable base selected from hydroxides, alkoxides, carbonates and bicarbonates of alkali metals and organic bases in a suitable solvent selected form polar solvents, chloro solvents, alcoholic solvents, ester solvents, ether solvents or their mixtures to provide (R)-3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3-phenylpropan-l -amine compound of formula-15,

c) treating the compound of formula-15 with ethyl bromide and magnesium in presence of solid carbon dioxide in a suitable solvent selected from hydrocarbon solvents, ether solvents, ester solvents or their mixtures to provide (R)-4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzoic acid compound of formula-16,

d) esterification of compound of formula-16 with methanol in presence of a suitable catalyst such as conc.sulfuric acid, thionyl chloride, methane sulfonic acid to provide (R)-methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzoate compound of formula-6,

e) reducing the compound of formula-6 with a suitable reducing agent selected from vitride, lithium aluminium hydride, sodium borohydride, sodium cyanoborohydride in a suitable solvent selected from hydrocarbon solvents, ether solvents, ester solvents, alcoholic solvents, polar solvents, chloro solvents or their mixtures to provide (R)-(4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)phenyl)methanol compound of formula-27,formula-1

f) debenzylation of compound of formula-27 with a suitable debenzylating agent selected from Pd/C, Raney Ni, palladium acetate, platinum oxide, platinum black, Rh/C in a suitable solvent selected from alcoholic solvents, chloro solvents, ester solvents, polar solvents, ether solvents to provide (R)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxymethyl-phenol compound of formula-8. 6. A process according to claim-1, the process further comprises the preparation of (R)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxymethyl-phenol compound of formula-8, comprising of;

a) Treating the 3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3-phenylpropan-l-amine compound of formula-13 with D(-)-tartaric acid in isopropyl alcohol to provide its D(-)-tartrate salt compound of formula-26,

b) treating the compound of formula-26 with sodium hydroxide in a mixture of dichloromethane and water to provide (R)-3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3-phenylpropan-l-amine compound of formula-15,

c) treating the compound of formula-15 with ethyl bromide and magnesium in presence of solid carbon dioxide in a mixture of tetrahydrofuran and toluene to provide (R)-4-(benzyloxy)-3-(3-diisopropylamino)-l-phenylpropyl)benzoic acid compound of formula-16,

d) esterification of compound of formula-16 with methanol in presence of conc.sulfuric acid to provide (R)-methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl) benzoate compound of formula-6,

e) reducing the compound of formula-6 with vitride in a mixture of toluene and tetrahydrofuran to provide (R)-(4-(benzyloxy)-3-(3-(diisopropylamino)-l -phenyl propyl)phenyl)methanol compound of formula-27,

f) debenzylation of compound of formula-27 with Raney Ni in methanol to provide (R)-2-(3 -diisopropylamino-1 -phenylpropyl)-4-hydroxymethyl-phenol compound of formula-8.

7. A process for the preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1, comprising of; a) Treating the methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzoate compound of formula-4
with a suitable chiral acid selected from L(+)-tartaric acid, D(-)-tartaric acid, (-)-di-p-toluoyl-L-tartaric acid, (+)-di-p-toluoyl-D-tartaric acid, (-)-dibenzoyl-L-tartaric acid, (+)-dibenzoyl-D-tartaric acid, L(+)-mandelic acid, D(-)-mandelic acid, 3-chloro mandelic acid, S(+)-camphor sulfonic acid, S(+)-acetoxy(phenyl)acetic acid ,R(-)-acetoxy(phenyl)acetic acid and their hydrates in a suitable solvent selected form alcoholic solvents, ester solvents, ether solvents, ketone solvents, polar solvents, chloro solvents or their mixtures to provide corresponding chiral acid addition salt compound of general formula-5,

b) treating the compound of general formula-5 with a suitable base selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and organic bases in a suitable solvent selected form alcoholic solvents, ester solvents, ether solvents, ketone solvents, polar solvents or their mixtures to provide (R)-methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzoate compound of formula-6,

c) debenzylating the compound of formula-6 with a suitable debenzylating agent selected from Pd/C, Raney Ni, palladium acetate, platinum oxide, platinum black and the like in a suitable solvent selected from alcoholic solvents, ester solvents, chloro solvents, hydrocarbon solvents or their mixtures to provide (R)-methyl 3-(3-(diisopropylamino)-1 -phenylpropyl)-4-hydroxybenzoate compound of formula-7,

d) reducing the compound of formula-7 with a suitable reducing agent selected from Pd/C, vitride, tetraalkyl ammonium borohydride, sodium borohydride, sodium cyanoborohydride, lithium aluminium hydride, Raney Ni, BF3.etherate/NaBH4; borane-dimethyl sulfide in a suitable solvent selected from alcoholic solvents, ester solvents, chloro solvents, hydrocarbon solvents, ether solvent or their mixtures to provide (R)-2-(3 -diisopropylamino-1 -phenylpropyl)-4-hydroxymethyl-phenol compound of formula-8,

e) optionally purifying the compound of formula-8 by converting it into its acid-addition salt followed by treating the obtained salt with a suitable base selected from suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and organic bases in a suitable solvent polar solvents, ester solvents, chloro solvents or their mixtures to provide pure compound of formula-8,

f) converting the compound of formula-8 into compound of formula-1 as per the process described in claim-1.

8. A process for the preparation of 3 -(2-benzyloxy-5-bromophenyl)-3 -phenyl propanol compound of formula-3 comprising of reducing the methyl 3-(2-benzyloxy-5-bromophenyl)-3-phenyl propanoate compound of formula-2 with vitride in a suitable solvent selected from hydrocarbon solvents, ether solvents, ester solvents ketone solvents, alcoholic solvents, chloro solvents, polar solvents and/or their mixtures, preferably in toluene.

9. Process for the purification of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-
(hydroxymethyl)phenyl isobutyrate compound of formula-1, comprising of;

a) Treating the compound of formula-1 with S(+)-acetoxy(phenyl)acetic acid in a suitable solvent selected from hydrocarbon solvents, ketone solvents, alcoholic solvents, chloro solvents, ester solvents, ether solvents, polar aprotic solvents, nitrile solvents, polar solvents or their mixtures to provide its S(+)-acetoxy(phenyl)acetic acid salt compound of formula-23,

b) treating the compound of formula-23 with a suitable base selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and organic bases in a suitable solvent to provide pure (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1.

10. Process for the purification of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxyl methyl)phenyl methacrylate compound of formula-9, comprising of;

a) Converting the compound of formula-9 into its acid addition salt compound of general formula-28 by treating the free base compound with a suitable acid selected from hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, acetic acid, propionic acid, palmitic acid, maleic acid, fumaric acid, oxalic acid, succinic acid, malic acid, L-(+)-tartaric acid, D-(-)-tartaric acid, L(+)-mandelic acid, D(-)-mandelic acid, (-)-di-p-toluoyl-L-tartaric acid, (+)-di-p-toluoyl-D-tartaric acid, (-)-dibenzoyl-L-tartaric acid, (+)-dibenzoyl-D-tartaric acid, S(+)-acetoxy(phenyl)acetic acid, R(-)-acetoxy(phenyl)acetic acid, citric acid, benzoic acid, 4-hydroxybenzoic acid, salicyclic acid, 4-hydroxycinammic acid, phthalic acid, methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid, toluene sulfonic acid; in a suitable solvent selected from alcoholic solvents, ester solvents, ketone solvents, ether solvents, hydrocarbon solvents, chloro solvents, polar solvents and/or their mixtures thereof,

b) treating the acid addition salt obtained in step-a) with a suitable base selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and organic bases in a suitable solvent as defined in step a) to provide pure (R)-2-(3-(diisopropylamino)-1 -phenylpropyl)-4-(hydroxymethyl)phenyl methacrylate compound of formula-9.

11. Acid addition salts of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl) phenyl methacrylate compound of formula-9, wherein the "acid" is selected from hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, acetic acid, propionic acid, palmitic acid, maleic acid, fumaric acid, oxalic acid, succinic acid, malic acid, L-(+)-tartaric acid, D-(-)-tartaric acid, L(+) or D(-)-mandelic acid, S(+)-acetoxy(phenyl)acetic acid, R(-)-acetoxy(phenyl)acetic acid, (-)-di-p-toluoyl-L-tartaric acid, (+)-di-p-toluoyl-D-tartaric acid, (-)-dibenzoyl-L-tartaric acid, (+)-dibenzoyl-D-tartaric acid, citric acid, benzoic acid, 4-hydroxybenzoic acid, salicyclic acid, 4-hydroxycinammic acid, phthalic acid, methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid, toluene sulfonic acid and the like.

12. Crystalline (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl)phenyl methacrylate mandelate salt characterized by its X-ray powder diffraction pattern having peaks at 9.7, 10.2, 11.8, 13.2, 15.1, 15.9, 18.9, 20.2, 21.6, 25.8 ± 0.2 degrees of 29 which is further characterized by its X-ray powder diffraction pattern having additional peaks at 5.1, 10.7, 13.9, 18.0, 18.3, 20.5,21.0, 22.5, 30.0 ± 0.2 degrees of 29.

13. Compounds having the following structural formulae;