Process for the preparation of muscarinic receptor antagonist

Related Application:

This application claims the benefit of priority of our Indian patent application numbers 154/CHE/2011 filed on 17 ^th Jan. 2011 and 3555/CHE/2011 filed on 17 ^th Oct. 2011 which are incorporated herein by reference.

Field of invention:

The present invention relates to novel and improved processes for the preparation of (R)-2-(3 -(diisopropylamino)- 1 -phenylpropyl)-4-(hydroxymethyl)pheny lisobutyrate and its pharmaceutically acceptable salts. (R)-2-(3-(diisopropyl amino)- 1- phenylpropyl)-4-(hydroxylmethyl)phenylisobutyrate is commonly known as fesoterodine and is represented by the following structural formula- 1

Formula-1

Fesoterodine is a prodrug, which broken down into its active metabolite, 5- hydroxymethyl tolterodine, by plasma esterases. It is commercially available under the brand name of Toviaz® in the form of fumarate salt.

Background of the Invention:

Isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)-4-

(hydroxymethyl)phenyl ester (or) 2-[(lR)-3-[bis(l-methylethyl)amino]-l-phenylpropyl]-4- hydroxymethylphenyl isobutyrate is a new, potent and competitive muscarinic antagonist and useful in the potential treatment of urinary incontinence.

U.S. Patent No. 6,713,464 Bl 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, 2-[(lR)-3-[bis(l-methylethyl)amino]-l- phenylpropyl]-4-hydroxymethylphenyl isobutyrate, is a new, potent and competitive muscarinic antagonist and useful in the potential treatment of urinary incontinence.

Processes for the preparation of Isobutyric acid 2-((R)-3-diisopropylammonium-l- phenylpropyl)-4-(hydroxymethyl) phenyl ester and related compounds, and their pharmaceutically acceptable salts are disclosed in the U.S. Patent Nos. 6,713,464 Bl and 6,858,650 Bl ; U.S. Patent Application No. 2006/0270738 and PCT Publication No. WO 2007/138440 Al.

According to the U.S. Patent No. 6,713,464 Bl (herein after referred to as the '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 by 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-l-ol is then treated with p-toluenesulphonyl chloride in the presence of pyridine in dichloromethane to afford (±)-toluene-4-sulphonic acid 3-(2-benzyloxy-5- bromophenyl)-3-phenylpropyl ester. Reaction with Ν,Ν-diisopropylamine in acetonitrile at reflux temperature produces (±)-[3-(2-benzyloxy-5-bromophenyl)-3- phenylpropylj-diisopropylamine as a brown and viscous syrup, which by resolution produces (R)-[3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl]-diisoprop ylamine, which is then subjected to Grignard reaction with ethylbromide and magnesium in the presence of solid carbon dioxide in tetrahydrofuran to produce (R)-4-benzyloxy-3-(3- diisopropylamino-l-phenylpropyl)-benzoic acid hydrochloride. Esterification with methanol in the presence of sulphuric acid produces (R)-4-benzyloxy-3-(3- diisopropylamino-l-phenylpropyl)-benzoic acid methyl ester, which is then reduced with lithium aluminium hydride to produce (R)-[4-benzyloxy-3-(3-diisopropylamino-l- phenylpropyl)-phenyl] -methanol, which is then subjected to deprotection with Raney- Nickel to produce (R)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxymethylphe nol, followed by condensation with isobutyryl chloride in an inert solvent in the presence of a base to give Isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)-4- (hydroxymethyl) phenyl ester.

The usage of lithium aluminium hydride for the conversion of (±)-3-(2- benzyloxy-5-bromophenyl)-3-phenylpropionic acid methyl ester to (±)-3-(2-benzyloxy- 5-bromophenyl)-3-phenylpropan-l-ol and the usage of Raney-Nickel for the debenzylation were not suggestible in large scale synthesis.

In general, the reported processes for the preparation of fesoterodine and its pharmaceutically acceptable salt involves numerous steps including complex purification procedures, that results in time-delay, enhanced possibility of human error and thereby prohibiting optimal efficiency and cost-effectiveness.

Henceforth, there is a need in the art for the cost-effective process for the preparation of pure fesoterodine, which involves the usage of simple and cost-effective reagents through novel intermediates.

Brief description of the invention:

The first aspect of the present invention is to provide a novel process for the preparation of isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)-4- (hydroxymethyl) phenyl ester 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-ph enol 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) optionally, purifying the compound of formula-9 by converting it into its acid addition salt compound of general formula-39, further treating 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 the isobutyric acid 2-((R)-3-diisopropylammonium-l- phenylpropyl)-4-(hydroxymethyl)phenyl ester compound of formula- 1, d) converting the compound of formula- 1 into its fumarate salt compound of formula- la by treating it with fumaric acid in a suitable solvent.

The second aspect of the present invention is to provide a novel process for the preparation of isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)-4- (hydroxymethyl) phenyl ester compound of formula- 1, comprising of;

a) Reacting the (R)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxymethyl-ph enol compound of formula-8 with 2-halo-2-methylpropanoyl chloride in presence or absence of base in a suitable solvent to provide the (R)-2-(3-(diisopropylamino)-l- phenylpropyl)-4-(hydroxymethyl)phenyl-2-halo-2 -methyl propanoate compound of formula-37,

b) dehalogenating the compound of formula-37 by using a suitable metal catalyst in presence or absence of base in a suitable solvent to provide the isobutyric acid 2- ((R)-3-diisopropyl ammonium- l-phenylpropyl)-4-(hydroxymethyl) phenyl ester compound of formula- 1.

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

a) Reacting the (R)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxymethyl-ph enol compound of formula-8 with 3-halo-2-methylpropanoyl chloride in presence or absence of base in a suitable solvent to provide the 2-((R)-3-(diisopropylamino)-l- phenylpropyl)-4-(hydroxymethyl)phenyl-3-halo-2-methylpropano ate compound of formula-38,

b) dehalogenating the compound of formula-38 by using a suitable metal catalyst in presence or absence of base in a suitable solvent to provide the isobutyric acid 2- ((R)-3-diisopropyl ammonium- l-phenylpropyl)-4-(hydroxymethyl) phenyl ester compound of formula- 1.

The fourth aspect of the present invention is to provide a novel process for the preparation of isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)-4- (hydroxymethyl) phenyl ester compound of formula- 1, comprising of; a) Dehydrohalogenating the compound of formula-37 in presence of a suitable base in a suitable solvent to provide the compound of formula-9,

b) reducing the compound of formula-9 with a suitable reducing agent in a suitable solvent to provide the isobutyric acid 2-((R)-3-diisopropyl ammonium- 1- phenylpropyl)-4-(hydroxymethyl) phenyl ester compound of formula- 1.

The fifth aspect of the present invention is to provide an improved process for the preparation of 3-(2-benzyl0xy-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 in a suitable solvent.

The sixth aspect of the present invention is to provide a novel process for the preparation of isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)-4- (hydroxymethyl) phenyl ester compound of formula- 1 , comprising of;

a) Resolving 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 the chiral acid addition salt compound of general formula-5,

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

c) debenzylating the compound of formula-6 by treating with a suitable debenzylating agent in a suitable solvent to provide the (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-l-phenylpropyl)-4-hydroxymethyl- phenol compound of formula-8,

e) optionally, purifying the compound of formula-8 by converting it into its acid addition salt compound of general formula-43, further treating with a suitable base in a suitable solvent to provide pure compound of formula-8, f) reacting the compound of formula-8 with methacryloyl chloride in presence or absence of base in a suitable solvent to provide the (R)-2-(3-(diisopropylamino)-l- phenylpropyl)-4-(hydroxymethyl)phenyl methacrylate compound of formula-9, g) optionally, purifying the compound of formula-9 by converting it into its acid addition salt compound of general formula-39, further treating with a suitable base in a suitable solvent to provide pure compound of formula-9,

h) reducing the compound of formula-9 with a suitable reducing agent in a suitable solvent to provide the isobutyric acid 2-((R)-3-diisopropylammonium-l- phenylpropyl)-4-(hydroxymethyl) phenyl ester compound of formula- 1.

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

a) Reacting 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 corresponding 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 the (R)-methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l- phenylpropyl)benzoate compound of formula-6.

The eighth aspect of the present invention is to provide a process for the preparation of (R)-methyl 3-(3-(diisopropylamino)-l-phenylpropyl)-4-(methacryl oyloxy)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 base in a suitable solvent.

The ninth 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)-N,N-diisopropyl-3-(5-formyl-2-hydroxyphenyl)-3- phenyl propanamine compound of formula- 11,

b) reacting the compound of formula- 11 with methacryloyi 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 tenth aspect of the present invention is to provide a novel process for the preparation of isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)-4- (hydroxymethyl) phenyl ester compound of formula- 1, comprising of;

a) Reacting the racemic N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenyl propanamine compound of formula- 13 with magnesium and carbon dioxide in presence of ethylbromide 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 agent 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 methacryloyi 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 isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)- 4-(hydroxymethyl) phenyl ester compound of formula- 1.

The eleventh aspect of the present invention is to provide a novel process for the preparation of isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)-4- (hydroxymethyl) phenyl ester compound of formula- 1, comprising of;

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

b) reacting the compound of formula- 15 with magnesium and carbon dioxide in presence of ethylbromide 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 isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)- 4-(hydroxymethyl) phenyl ester compound of formula- 1.

The twelfth aspect of the present invention is to provide a novel process for the preparation of (R)-N,N-diisopropyl-3-(5-formyl-2-hydroxyphenyl)-3-phenyl propanamine compound of formula- 11, comprising of;

a) Reacting the N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenyl propanamine 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 agent 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)-N,N-diisopropyl-3-(5-formyl-2-hydroxyphenyl)-3- phenyl propanamine compound of formula- 1 1.

The thirteenth aspect of the present invention is to provide another novel process for the preparation of isobutyric acid 2-((R)-3-diisopropylammonium-l- phenylpropyl)-4-(hydroxymethyl) phenyl ester compound of formula- 1, comprising of; a) Reacting the racemic N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3 -phenyl propanamine compound of formula- 13 with magnesium and carbon dioxide in presence of ethylbromide 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 agent in a suitable solvent to provide (R)-3-(3-(diisopropylamino)-l-phenylpropyl)-4-(methacryl oyloxy)benzoic acid compound of formula- 18,

e) reducing the compound of formula- 18 with a suitable reducing agent in a suitable solvent to provide isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)-

4-(hydroxymethyl) phenyl ester compound of formula- 1.

The fourteenth aspect of the present invention is to provide a novel purification process for the preparation of isobutyric acid 2-((R)-3-diisopropylammonium-l- phenylpropyl)-4-(hydroxymethyl) phenyl ester compound of formula- 1, comprising of; a) Treating the isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)-4- (hydroxymethyl) phenyl ester compound of formula- 1 with (R)-(-)-acetoxy (phenyl)acetic acid in a suitable solvent to provide its (R)-(-)-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 isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)-4- (hydroxymethyl) phenyl ester compound of formula- 1.

The fifteenth 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 base in a suitable solvent.

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

a) Resolving 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)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenyl propanamine compound of formula- 15.

The seventeenth aspect of the present invention is to provide an improved process for the preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4- (hydroxymethyl) phenol compound of formula-8 which comprises of the following steps:

a) Reacting the 2-oxo-4-phenylchroman-6-carboxylic acid compound of formula-27 with R-l-phenylethylamine in a suitable solvent provides the 4-hydroxy-3-((R)-3- oxo- 1 -phenyl-3 -((R)- 1 -phenylethylamino)propyl)benzoic acid compound of formula-28,

b) reducing the compound of formula-28 with a suitable reducing agent in a suitable solvent provides 4-(hydroxymethyl)-2-((R)-l -phenyl-3 -((R)-l-phenylethyl amino) propyl)phenol compound of formula-29,

c) debenzylating the compound of formula-29 with a suitable debenzylating agent in a suitable solvent provides the (R)-2-(3-amino-l-phenylpropyl)-4-(hydroxyl methyl) phenol compound of formula-30,

d) reacting the compound of formula-30 with isopropyl chloride in presence of a suitable base in a suitable solvent provides the compound of formula-8.

The eighteenth aspect of the present invention is to provide an improved process for the preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl ) phenol compound of formula-8 which comprises of the following steps: a) Reacting the (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-methylphenol compound of formula-31 with N-bromosuccinamide (NBS) or NCS or NIS in a suitable solvent provides its corresponding (R)-4-(halo-substituted methyl)-2-(3- (diisopropylamino)-l-phenylpropyl)phenol derivative compound of formula-32, b) reacting the compound of formula-32 with sodium or potassium acetate in a suitable solvent provides (R)-3-(3-(diisopropylamino)- 1 -phenylpropyl)-4-hydroxybenzyl acetate compound of formula-33,

c) hydrolyzing the compound of formula-33 in presence of a suitable base in a suitable solvent provides the compound of formula-8.

The nineteenth aspect of the present invention is to provide a crystalline (R)-2- (3-(diisopropylamino)- 1 -phenylpropyl)-4-(hydroxylmethyl)phenyl methacrylate mandelate salt compound of formula-39a, which is characterized by its powder X-ray powder diffraction pattern showing characteristic peaks at 9.77, 10.24, 11.83,13.27,15.15, 15.94,18.94, 20.22, 21.60 and 25.83 ±0.2 degrees 2Θ. This crystalline form of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-

(hydroxylmethyl)phenyl methacrylate mandelate is hereinafter designated as crystalline form-M. The crystalline form-M of the present invention further characterized by its PXRD showing peaks at 5.12, 10.73, 13.95, 18.04, 18.31, 20.53, 21.06, 22.55 and 30.05 ± 0.2 degrees 2Θ. The PXRD of crystalline form-M is substantially similar to the PXRD pattern depicted in figure- 1.

The twentieth of the present invention provides a process for the preparation of crystalline (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxylmethy l)phenyl methacrylate mandelate salt compound of formula-39a, comprising of;

a) Dissolving (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4- (hydroxymethyl)phenyl methacrylate in a suitable solvent at 25-30°C,

b) heating the reaction mixture,

c) adding mandelic acid solution dissolved in a suitable solvent,

d) cool the reaction mixture to 0-5°C,

e) stirring the reaction mixture for 20-25 hours at same temperature,

f) filtering the precipitated solid and washing with a suitable solvent, g) optionally recrystallized from a suitable solvent

h) drying the obtained compound to get the crystalline (R)-2-(3-(diisopropylamino)- l-phenylpropyl)-4-(hydroxylmethyl)phenyl methacrylate mandelate salt.

The twenty- first of the present invention provides a novel acid addition salts of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl )phenyl methacrylate compound of formula-39.

The twenty-second aspect of the present invention provides a process for the preparation of isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)-4- (hydroxymethyl) phenyl ester hydrogen fumarate compound of formula- la, comprising of;

a) Reacting cinnamic acid with 4-halo phenol in conc.sulfuric acid provides 6- bromo-4-phenylchroman-2-one compound of formula-40,

b) reacting the 6-bromo-4-phenylchroman-2-one compound of formula-40 with benzyl chloride in the presence of sodium iodide and a suitable inorganic base in a suitable solvent to provide 3-phenylpropionate compound of formula-2, c) reducing the compound of formula-2 with a suitable reducing agent in a suitable solvent to provide 3 -phenyl propanol compound of formula-3,

d) reacting the compound of formula-3 with a Ci-Q-alkyl- or aryl-sulfonyl halide in the presence of an aliphatic organic base in a suitable solvent to provide the protected compound of formula-41,

wherein 'P' represents a Ci-C6-alkyl- or aryl-sulfonyl protecting group, e) aminating the compound of formula-41 with diisopropylamine in a suitable solvent at a temperature ranging from 70°C-140°C in an autoclave or closed condition to provide diisopropylamine compound of formula- 13,

f) resolving the compound of formula- 13 obtained in step-(e) with a suitable optically active acid in a suitable solvent to provide (R)-enantiomer of formula- 15,

g) reacting the (R)-enantiomer of formula- 15 with ethyl halide and magnesium in the 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 or its hydrochloride;

h) esterifying the compound obtained in step-(g) with methanol in the presence of a suitable catalyst to obtain methyl ester compound of formula-6,

i) reducing the compound of formula-6 with a suitable reducing agent in a suitable solvent to provide (R)-[4-benzyloxy-3-(3-diisopropylamino-l-phenylpropyl)- phenyl] -methanol of formula-42;

j) debenzylating the compound of formula-42 by treating with a suitable debenzylating agent in a suitable solvent to provide (R)-2-(3-diisopropylamino- l-phenylpropyl)-4-hydroxymethylphenol compound of formula-8.

k) condensing the compound of formula-8 with isobutyryl chloride in a suitable solvent, optionally in the presence of a suitable base, to provide substantially pure isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)-4- (hydroxymethyl) phenyl ester compound of formula- 1 and optionally converting the compound of formula- 1 into its pharmaceutically acceptable acid addition salts.

The twenty-third aspect of the present invention is to provide novel intermediate compounds for the synthesis of isobutyric acid 2-((R)-3-diisopropylammonium-l- phenylpropyl)-4-(hydroxymethyl) phenyl ester compound of formula- 1.

Brief description of drawings:

Figure-1: PXRD of the crystalline form-M of (R)-2-(3-(diisopropylamino)-l- phenylpropyl)-4-(hydroxylmethyl) phenyl methacrylate mandelate salt compound of formula-39a.

Detailed description of the Invention:

As used herein the present invention the term "suitable solvents" refers to solvents selected from "ester solvents" like ethyl acetate, methyl acetate, isopropyl acetate; "ether solvents" like tetrahydrofuran, diethyl ether, methyl tert-butyl ether; "hydrocarbon solvents" like toluene, hexane, heptane and cyclohexane; "polar aprotic solvents" like dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide; "ketone solvents" like acetone, methyl ethyl ketone, methyl isobutyl ketone; "alcoholic solvents" like methanol, ethanol, n-propanol, isopropanol, n-butanol and isobutanol; "chlorinated hydrocarbon solvents" like methylene chloride, chloroform and ethylene dichloride; "nitrile solvents" like acetonitrile and propionitrile; polar solvents like water; and/or their mixtures thereof.

As used herein the present invention the term "suitable base" refers to the bases selected from inorganic bases like alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal hydrides such as lithium hydride, sodium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide; alkali metal carbonates like lithium carbonate, sodium carbonate, potassium carbonate; alkali metal bicarbonates like sodium bicarbonate and potassium bicarbonate; and organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine, pyridine and their mixtures thereof.

As used herein the term "chiral agent" refer to chiral acid selected from S-(+) mandelic acid, R-(-) mandelic acid, L-(+)tartaric acid, D-(-)tartaric acid, L-malic acid, D-malic acid, D-maleic acid, (-)-naproxen, (+)-naproxen, (lR)-(-)-camphor sulfonic acid, (lS)-(+)-camphor sulfonic acid (lR)-(+)-bromocamphor- 10- sulfonic acid, (lS)-(- )-bromocamphor-10-sulfonic acid, (-)-Dibenzoyl-L-tartaric acid, (-)-Dibenzoyl-L- tartaricacid monohydrate, (+)-Dibenzoyl-D -tartaric acid, (+)-Dibenzoyl-D -tartaric acid monohydrate, (+)-dipara-tolyl-D-tataric acid, (-)-dipara-tolyl-L-tataricacid, L(-)- pyroglutamic acid, L(+)-pyroglutamic acid, (-)-lactic acid, L-lysine, D-lysine and mixtures thereof.

As used herein the term "acid" used to form the acid addition salts of fesoterodine compound of formula- 1 is selected from oxalic acid, succinic acid, fumaric acid, malonic acid, malic acid, maleic acid, d-tartaric acid, 1-tartaric acid, dl-tartaric acid, citric acid, methanesulfonic acid, paratoluene sulfonic acid, acetic acid, sulfuric acid, phosphoric acid or hydrobromic acid and hydrochloric acid.

As used herein the term "reducing agent" used is selected from vitride, sodium borohydride, Diisobutyl aluminium hydride (DIBAL), sodium cyanoborohydride, tetraalkyl ammonium borohydride, lithium aluminium hydride, Raney Ni, BF ₃ etherate/NaBH _4i borane dimethyl sulfide, Pd/C and the like;

In the present invention methacryloyl chloride can also be referred as 2-methyl- prop-2-enoyl chloride.

The first aspect of the present invention provides a novel process for the preparation of isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)-4- (hydroxymethyl) phenyl ester hydrogen fumarate salt compound of formula- la, comprising of;

a) Reacting the (R)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxymethyl -phenol compound of formula-8

Formula-8

with methacryloyl chloride in presence or absence of a suitable base in a suitable solvent provides (R)-2-(3 -(diisopropylamino)- 1 -phenylpropyl)-4-(hydroxymethyl) phenyl methacrylate compound of formula-9

Formula-9

b) optionally, purifying the compound of formula-9 by converting it into its acid addition salt compound of g

Formula-39 further treating 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 provides isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)- 4-(hydroxymethyl)phenyl ester a- 1,

Formula- 1

d) converting the compound of formula- 1 to its fumarate salt compound of formula- la by treating it with fumaric acid in a suitable solvent.

Formula- la

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

In step-a) & b) the suitable base is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal alkoxides and organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N- methyl morpholine, piperidine, pyridine etc.

In step-c) the suitable reducing agent is selected from Pd/C, vitride, sodium borohydride, sodium cyanoborohydride, tetraalkyl ammonium borohydride, lithium aluminium hydride, Raney Ni, BF ₃ etherate/NaBH _; borane dimethyl sulfide and the like; preferably Pd/C;

In step-b) the acid is selected from selected from hydrochloric acid,

hydrobromic acid, phosphoric acid, sulphuric acid, nitric acid, acetic acid, propionic acid, palmitic acid, stearic acid, maleic acid, fumaric acid, oxalic acid, succinic acid, DL-malic acid, L-(-)-malic acid, D-(+)-malic acid, DL-tartaric acid, L-(+) - tartaric acid, D-(-)-tartaric acid, diparatolyl tartaric acid, citric acid, L-aspartic acid, L-(+)-ascorbic acid, D-(+)-glucuronic acid, 2-oxopropionic acid (pyruvic acid), furan-2-carboxylic acid (mucic acid), benzoic acid, 4-hydroxybenzoic acid, salicyclic acid, vanillic acid, 4-hydroxycinammic acid, gallic acid, hippuric acid (N- benzoyl-glycine), aceturic acid (N-aectylglycine), phloretinic acid (3-(4- hydroxyphenyl)-propionic acid), phthalic acid, methanesulfonic acid, (S)-(+)- mandelic acid, (R)-(-)-mandelic acid, acetylmandelic acid or orotic acid

In a preferred embodiment of the present invention is to provide a novel process for the preparation of isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)- 4-(hydroxymethyl) phenyl ester hydrogen fumarate salt compound of formula- la, comprising of;

a)- Reacting^he ^~ (R)-2-(3 -diisopropylamino- 1 -phenylpropyl)-4-hydroxymethyl -phenol compound of formula-8 with methacryloyl chloride in chloroform provides (R)-2- (3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl) phenyl methacrylate compound of formula-9,

b) purifying the compound of formula-9 in-situ reacted with L(+)-mandelic acid in ethyl acetate to provide the (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-

(hydroxymethyl) phenyl methacrylate mandelate compound of formula-39a, further treating with sodium carbonate in water to provide pure compound of formula-9, c) reducing the compound of formula-9 with 10% Pd C in ethyl acetate provides isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester compound of formula- 1,

d) converting the compound of formula- 1 to its fumarate salt compound of formula- la by treating it with fumaric acid in methyl ethyl ketone.

The second aspect of the present invention is to provide a novel process for the preparation of isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)-4- (hydroxymethyl) phenyl ester compound of formula- 1, comprising of; c) Reacting the (R)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxymethyl-ph enol compound of formula-8 with 2-halo-2-methylpropanoyl chloride in presence or absence of base in a suitable solvent to provide the (R)-2-(3-(diisopropylamino)-l- phenylpropyl)-4-(hydroxymethyl)phenyl-2-halo-2-methyl propanoate compound of formula-37,

Formula-37

Wherein, X is halogen;

d) dehalogenating the compound of formula-37 by using a suitable metal catalyst in presence or absence of base in a suitable solvent to provide the isobutyric acid 2-

((R)-3-diisopropyl ammonium- l-phenylpropyl)-4-(hydroxymethyl) phenyl ester compound of formula- 1.

Wherein, the suitable base used in step-a) & b) is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal alkoxides and organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine, pyridine etc.

In step-(b) the suitable metal catalyst is selected from palladium on carbon or palladium salts such as palladium hydroxide, palladium hydroxide on carbon, and the like, Raney nickel, platinum, iridium, ruthenium, and the like; preferably, a palladium catalyst, or Raney nickel and most preferably, the metal catalyst is palladium on carbon.

In step-a) & b) the suitable solvent is as defined above;

In a preferred embodiment of the present invention is to provide a process for the preparation of isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)-4- (hydroxymethyl) phenyl ester compound of formula- 1, comprising of;

a) Reacting the compound of formula-8 with 2-bromo-2-methylpropanoyl chloride in presence aqueous sodium bicarbonate in dichloromethane to provide the (R)-2-(3 -(diisopropylamino)- 1 -phenylpropyl)-4-(hydroxymethyl)phenyl-2- halo-2-methyl propanoate compound of formula-37,

b) dehalogenating the compound of formula-37 by using sodium acetate with 10% Pd/C in a mixture of ethylacetate and water to provide the isobutyric acid 2- ((R)-3 -diisopropyl ammonium- 1 -phenylpropyl)-4-(hydroxymethyl) phenyl ester compound of formula- 1.

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

a) Reacting the (R)-2-(3 -diisopropylamino- l-phenylpropyl)-4-hydroxymethyl -phenol compound of formula-8 with 3-halo-2-methylpropanoyl chloride in presence or absence of base in a suitable solvent to provide the 2-((R)-3 -(diisopropylamino)- 1- phenylpropyl)-4-(hydroxymethyl)phenyl-3-halo-2 -methyl propanoate compound of formula-38,

Formula-38

Wherein, X is halogen;

e) dehalogenating the compound of formula-38 by using a suitable metal catalyst in presence or absence of base in a suitable solvent to provide the isobutyric acid 2-

((R)-3 -diisopropyl ammonium- l-phenylpropyl)-4-(hydroxymethyl) phenyl ester compound of formula- 1.

Wherein, the suitable base and the solvents used is as defined above;

In step-(b) the suitable metal catalyst is as defined above.

In a preferred embodiment of the present invention is to provide a novel process for the preparation of isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)- 4-(hydroxymethyl) phenyl ester compound of formula- 1, comprising of; a) Reacting the (R)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxymethyl -phenol compound of formula-8 with 3-bromo-2-methylpropanoyl chloride in presence of sodium bicarbonate in dichloromethane to provide the 2-((R)-3-(diisopropylamino)- 1 -phenylpropyl)-4-(hydroxymethyl)phenyl-3 -halo-2-methyl propanoate compound of formula-38,

b) dehalogenating the compound of formula-38 by using sodium acetate with 10% Pd/C in a mixture of ethylacetate and water to provide the isobutyric acid 2-((R)-3- diisopropyl ammonium- l-phenylpropyl)-4-(hydroxymethyl) phenyl ester compound of formula- 1.

The fourth aspect of the present invention is to provide a novel process for the preparation of isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)-4- (hydroxymethyl) phenyl ester compound of formula- 1, comprising of;

a) Dehydrohalogenating the compound of formula-37 in presence of a suitable base in a suitable solvent to provide the compound of formula-9,

b) reducing the compound of formula-9 with a suitable reducing agent in a suitable solvent to provide the isobutyric acid 2-((R)-3-diisopropyl ammonium- 1- phenylpropyl)-4-(hydroxymethyl) phenyl ester compound of formula- 1.

Wherein, the suitable base, solvent and reducing agent is as defined above.

The fifth aspect of the present invention provides an improved process for the preparation of 3-(2-benzyloxy-5-bromophenyl)-3-phenyl propanol compound of formula-3

Formula-3

comprising of reducing the methyl 3-(2-benzyloxy-5-bromophenyl)-3-phenyl propanoate compound of formula-2

Formula-2

with a suitable reducing agent in a suitable solvent.

Wherein, the suitable reducing agent used is as defined above, preferably vitride; and the suitable solvent is as defined above, preferably hydrocarbon solvents.

The starting material methyl 3-(2-benzyloxy-5-bromophenyl)-3-phenyl propanoate compound of formula-2 used in the present invention is prepared according to the process disclosed in US 5559269.

The sixth aspect of the present invention provides a novel process for the preparation.. - of isobutyric acid 2-((R)-3-diisopropylammonium- l -phenylpropyl)-4- ^~ (hydroxymethyl) phenyl ester compound of formula- 1, comprising of;

a) Resolving the methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l- phenylpropyl)benzoate compound of formula-4

Formula-4

with a suitable chiral agent in a suitable solvent provides the chiral acid addition salt compound of general formula-5,

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

Formula-6

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

Formula-7

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

optionally, purifying the compound of formula-8 by converting it into its acid addition salt compound of g

Formula-43

further treating with a suitable base in a suitable solvent to provide pure compound of formula-8, f) reacting the compound of formula-8 with methacryloyl chloride in presence or absence of base in a suitable solvent provides the (R)-2-(3-(diisopropylamino)-l- phenylpropyl)-4-(hydroxymethyl)phenyl methacrylate compound of formula-9, g) optionally, purifying the compound of formula-9 by converting it into its acid addition salt compound of general formula-39, further treating with a suitable base in a suitable solvent to provide pure compound of formula-9,

h) reducing the compound of formula-9 with a suitable reducing agent in a suitable solvent provides the isobutyric acid 2-((R)-3-diisopropylammonium-l- phenylpropyl)-4-(hydroxymethyl) phenyl ester compound of formula- 1.

Wherein, in step-a) the suitable chiral acid is selected from L(+)-tartaric acid, D(-)-tartaric acid, L-(-)-malic acid, D-(+)-malic acid, (-)-di-p-toluoyl-L-tartaric acid, (+)-di-p-toluoyl-D-tartaric acid, (-)-dibenzoyl-L-tartaric acid, (+)-dibenzoyl-D-tartaric acid, (S)-mandelic acid, 3-chloro mandelic acid, abietic acid, S(+)-camphor sulphonic acid, (R)-(-)-acetoxy(phenyl)acetic acid and hydrates thereof;

In step-b) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal hydrides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates, and organic bases and/or their mixtures thereof;

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

In step-d) and step-h) the suitable reducing agent is independently selected from Pd/C, vitride, tetraalkyl ammonium borohydride, sodium borohydride, sodium cyanoborohydride, lithium aluminium hydride, Raney Ni, BF ₃ etherate NaBH _4; borane dimethyl sulfide and the like;

In step e), f) & g) the suitable base is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal alkoxides and organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine, pyridine etc.

The suitable solvent selected from step-a) to step-h) is independently selected from hydrocarbon solvents, ketone solvents, alcoholic solvents, chlorinated hydrocarbons, ester solvents, ether solvents, polar aprotic solvents, nitrile solvents, polar solvents and/or their mixtures thereof;

In a preferred embodiment of the present invention is to provide a novel process for the preparation of isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)- 4-(hydroxymethyl) phenyl ester compound of formula- 1, comprising of;

a) Resolving the methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l- phenylpropyl)benzoate compound of formula-4 with (-)-di-p-toluoyl-L-tartaric acid in isopropyl alcohol provides the corresponding salt compound of formula- 5 a, b) treating the compound of formula-5a with aqueous sodium carbonate in water provides the (R)-methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l- phenylpropyl)benzoate compound of formula-6,

c) debenzylating the compound of formula-6 by treating with 5% Pd/C in ethylacetate provides the (R)-methyl 3-(3-(diisopropylamino)-l-phenylpropyl)-4- hydroxybenzoate compound of formula-7,

d) reducing the compound of formula-7 with vitride in tetrahydrofuran provides the (R)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxymethyl-ph enol compound of formula-8,

e) purifying the compound of formula-8 by converting into its mandelate salt compound of formula-43a by using mandelic acid in isopropyl alcohol, further treating with aqueous sodium carbonate in chloroform to provide compound of formula-8,

f) reacting the (R)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxymethyl-ph enol compound of formula-8 with methacryloyl chloride in chloroform provides (R)-2- (3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl) phenyl methacrylate compound of formula-9,

g) purifying the compound of formula-9 in-situ reacted with L(+)-mandelic acid in ethyl acetate to provide the (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4- (hydroxymethyl) phenyl methacrylate mandelate compound of formula-39a, further treating with sodium carbonate in water to provide pure compound of formula-9, h) reducing the compound of formula-9 with 10% Pd/C in ethyl acetate provides isobutyric acid 2-((R)-3-diisopropylammonium- 1 -phenylpropyl)-4-(hydroxymethyl) phenyl ester compound of formula- 1.

The methyl 4-(benzyloxy)-3-(3 -(diisopropylamino)- 1 -phenylpropyl)benzoate compound of formula-4 utilized in this process can be synthesized as follows;

The 3-(2-benzyloxy-5-bromophenyl)-3-phenyl propanol compound of formula- 3 is treated with p-toluene sulfonyl chloride in dichloromethane and pyridine to provide tosyl protected compound, which is then treated with Ν,Ν-diisopropylamine in acetonitrile at reflux temperature to provide N,N-diisopropyl-3-(2-benzyloxy-5- bromophenyl)-3-phenyl propanamine. The obtained compound was then treated with magnesium, ethyl bromide in presence of iodine in diethyl ether to provide N,N- diisopropyl-3-(2-benzyloxy-5-carboxyphenyl)-3-phenyl propanamine hydrochloride, which is then esterified with methanol in presence of cone, sulfuric acid to provide compound of formula-4.

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

a) Resolving the racemic methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l- phenylpropyl)benzoate compound of formula-4 using a suitable chiral acid in a suitable solvent to provide its corresponding 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 the (R)-methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l- phenylpropyl)benzoate compound of formula-6.

Wherein, in step-a) the suitable chiral acid used is as defined above;

In step-b) the suitable base used is as defined above;

The suitable solvent used in step-a) and step-b) is selected from hydrocarbon solvents, ketone solvents, alcoholic solvents, chlorinated hydrocarbons, ester solvents, ether solvents, polar aprotic solvents, nitrile solvents, polar solvents and/or their mixtures thereof. In a preferred embodiment of the present invention provides a resolution process for the preparation of (R)-methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l- phenylpropyl) benzoate compound of formula-6, comprising of;

i) Resolving the methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l- phenylpropyl)benzoate compound of formula-4 with (-)-di-p-toluoyl-L-tartaric acid in isopropyl alcohol provides the corresponding salt compound of formula-5a, j) treating the compound of formula-5a with aqueous sodium carbonate in water provides the (R)-methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l- phenylpropyl)benzoate compound of formula-6.

The eighth 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,

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.

Wherein, the suitable solvent and base are as defined above.

The compound of formula- 10 obtained in the present invention is purified by optionally converting it into its acid salts.

The ninth aspect of the present invention provides a process for the preparation of (R)-2-(3 -(diisopropylamino)- 1 -phenylpropyl)-4-formylphenylmethacrylate compound of formula- 12, comprising of;

a) Reducing the (R)-methyl-3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxy benzoate compound of formula-7 with a suitable reducing agent in a suitable solvent to provide (R)-N,N-diisopropyl-3-(5-formyl-2-hydroxyphenyl)-3-phenyl propanamine compound of formu - 11,

b) reacting the compound of formula- 1 1 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.

Formula- 12

Wherein, in step-a) the suitable reducing agent is Diisobutyl aluminium hydride (DIBAL); and suitable base and solvents are as defined above;

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

a) Reacting the racemic N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenyl propanamine compound of fo

Formula- 13

with magnesium and carbon dioxide in presence of ethylbromide in a suitable solvent provides 4-(benzyloxy)-3 -(3- (diisopropylamino)-l- phenylpropyl)benzoic acid compound of formula- 14,

Formula- 14

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

Formula- 16

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

Formula- 17

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

Formula- 18 e) reducing the compound of formula- 18 with a suitable reducing agent in a suitable solvent provides isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)- 4-(hydroxymethyl) phenyl ester compound of formula- 1.

Wherein, in step-b) the suitable chiral agent is as defined above;

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

In step-d) the suitable base as defined above;

In step-e) the suitable reducing agent is as defined above;

The suitable solvent used in step-a) to step-e) as defined above.

The compound of formula- 18 obtained in the present invention is purified by optionally converting it into its acid or base salts.

The eleventh aspect of the present invention is to provide a novel process for the preparation of isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)-4- (hydroxymethyl) phenyl ester compound of formula- 1 , comprising of;

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

Formula- 15

b) reacting of the compound of formula- 15 by treating it with magnesium and carbon dioxide in presence of ethylbromide 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 isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)- 4-(hydroxymethyl) phenyl ester compound of formula- 1.

Wherein, in step-a) the suitable chiral agent is selected from L(+)-tartaric and

D(-)-tartaric acid.

In step-c) the suitable debenzylating agent is as defined above;

In step-e) the suitable reducing agent is as defined above;

In step-a) to step-e) the suitable solvents is as defined above.

The twelfth aspect of the present invention is to provide a novel process for the preparation of (R)-N,N-diisopropyl-3 -(5-formyl -2 -hydroxyphenyl)-3 -phenyl propanamine compound of formula- 11, comprising of;

a) Reacting the N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenyl propanamine 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,

Formula- 19

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

Formula-20

c) debenzylating the compound of formula-20 with a suitable debenzylating agent in a suitable solvent to provide (R)-N,N-diisopropyl-3-(5-formyl-2-hydroxyphenyl)-3- phenyl propanamine compound of formula- 11.

Wherein, in step-b) the suitable chiral agent is as defined above;

In step-c) the suitable debenzylating agent is as defined above;

In step-a) to step-c) the suitable solvent is as defined above.

The thirteenth aspect of the present invention is to provide another novel process for the preparation of isobutyric acid 2-((R)-3-diisopropylammonium-l- phenylpropyl)-4-(hydroxymethyl) phenyl ester compound of formula- 1, comprising of; a) Reacting the racemic N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenyl propanamine compound of formula- 13 with magnesium and carbon dioxide in presence of ethylbromide 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 ageht in a suitable solvent to provide 3-(3-(diisopropylamino)-l- phenylpropyl)-4-hydroxy benzoic acid compound of formula-21,

Formula-21

:) 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,

Formula-22

d) resolving the compound of formula-22 with a suitable chiral agent 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 isobutyric acid 2-((R)-3-diisopropylammonium-l- phenylpropyl)-4-(hydroxymethyl) phenyl ester compound of formula- 1.

Wherein, in step-b) the suitable debenzylating agent is as defined above;

In step-c) the suitable base is is as defined above;

In step-d) the suitable chiral agent is as defined above;

In step-e) the suitable reducing agent is as defined above, preferably vitride.

The fourteenth aspect of the present invention is to provide a novel purification process for the preparation of isobutyric acid 2-((R)-3-diisopropylammonium-l- phenylpropyl)-4-(hydroxymethyl) phenyl ester compound of formula- 1, comprising of; a) Treating the isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)-4- (hydroxymethyl) phenyl ester compound of formula- 1 with (R)-(-)-acetoxy (phenyl)acetic acid in a suitable solvent to provide its (R)-(-)-acetoxy (phenyl)acetic acid salt compound of formula-23,

Formula-23

b) treating the compound of formula-23 with a suitable base in a suitable solvent to provide pure isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)-4- (hydroxymethyl) phenyl ester compound of formula- 1. Wherein, in step-a) the solvent used is as defined above; preferably ethylacetate. In step-b) the suitable base is as defined above, preferably sodium carbonate.

The isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)-4- (hydroxyl methyl) phenyl ester compound of formula- 1 obtained by any of the above mentioned processes is further converted to its fumarate salt compound of formula- la by treating it with fumaric acid in a suitable solvent by any of the prior known methods.

The isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)-4- (hydroxymethyl) phenyl ester compound of formula- 1 obtained by any of the above said processes is further purified by converting it into its pharmaceutically acceptable acid addition salts.

The fifteenth 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,

Formula-25

which comprises of reacting the (R)-3-(3-(diisopropylamino)-l-phenylpropyl)-4- hydroxy benzonitrile compound of fo

Formula-24

with isobutyryl chloride in presence or absence of base in a suitable solvent.

Wherein, the suitable base and solvent are as defined above. The sixteenth aspect of the present invention is to provide a process for the resolution of N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenyl propanamine compound of formula- 13, comprising of;

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

D(-)-Tartaric acid

Formula-26

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

Wherein, in step-a) and step-b) the suitable solvent is as defined above; preferably alcoholic solvents, more preferably isopropyl alcohol.

In step-b) the suitable base is as defined above.

The seventeenth aspect of the present invention is to provide an improved process for the preparation of compound of formula-8 which comprises of the following steps:

a) Reacting the 2-oxo-4-phenylchroman-6-carboxylic acid compound of formula-27 with R-l-phenylethylamine in a suitable solvent provides the 4-hydroxy-3-((R)-3- oxo-l-phenyl-3-((R)-l-phenylethylamino)propyl)benzoic acid compound of formula-28,

Formula-28 b) reducing the compound of formula-28 with a suitable reducing agent in a suitable solvent provides 4-(hydroxymethyl)-2-((R)-l-phenyl-3-((R)-l-phenylethyl amino) propyl)phenol compound of formula-29,

Formula-29

c) debenzylating the compound of formula-29 with a suitable debenzylating agent in a suitable solvent provides the (R)-2-(3-amino-l-phenylpropyl)-4-(hydroxymethyl) phenol compound of formula-30,

Formula-30

d) reacting the compound of formula-30 with isopropyl chloride in presence of a

suitable base in a suitable solvent provides the compound of formula-8.

Wherein, in step-(a) the suitable solvent is selected from alcoholic solvent, ester solvents and keto solvents;

in step-(b) the suitable reducing agent is selected from BF ₃ etherate/NaBH _; vitride, sodium borohydride, sodium cyanoborohydride, tetraalkyl ammonium borohydride, lithium aluminium hydride, Raney Ni, borane dimethyl sulfide and the like; preferably BF ₃ etherate; and the suitable solvent is selected from tetrahydrofuran, diethyl ether and methyl tert-butyl ether; preferably tetrahydrofuran.

In step-(c) the suitable debenzylating agent is selected from Pd/C, palladium acetate, platinum oxide, platinum black, Rh/C, Ni, Ir, Ru and the like in combination with hydrogen; preferably Pd/C; and the suitable solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol and isobutanol; preferably methanol.

In step-(d) the suitable base is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates; or the organic bases like methyl amine, ethyl amine, tert-butyl amine, triethyl amine, diisopropyl ethylamine, pyridine.

In a preferred embodiment of the present invention is to provide an improved process for the preparation of compound of formula-8 which comprises of the following steps:

a) Reacting the 2-oxo-4-phenylchroman-6-carboxylic acid compound of formula-27 with R-l-phenylethylamine in acetone provides 4-hydroxy-3-((R)-3-oxo-l-phenyl- 3-((R)-l-phenylethylamino)propyl)benzoic acid compound of formula-28, b) reducing the compound of formula-28 with BF _3- etherate in tetrahydrofuran provides the 4-(hydroxymethyl)-2-((R)- 1 -phenyl-3 -((R)- 1 -phenylethyl amino) propyl)phenol compound of formula-29,

c) debenzylating the compound of formula-29 with Pd/C in methanol provides (R)-2- (3-amino-l-phenylpropyl)-4-(hydroxymethyl)phenol compound of formula-30, d) reacting the compound of formula-30 with isopropyl chloride in a suitable potassium carbonate in acetone provides the compound of formula-8.

The eighteenth aspect of the present invention is to provide an improved process for the preparation of compound of formula-8 which comprises of the following steps: a) Reacting the (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-methylphenol

compound of formula-31 ,

Formula-31 with N-bromosuccinamide (NBS) or NCS or NIS in a suitable solvent provides (R)-4-(halo-substitutedmethyl)-2-(3-(diisopropylamino)- 1 -phenylpropyl) phenol compound of formula-32,

Formula-32

reacting the compound of formula-32 with sodium or potassium acetate in a suitable solvent provides (R)-3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxy benzyl acetate compound of formula-33,

Formula-33

c) hydrolyzing the compound of formula-33 with a suitable base in a suitable solvent provides the compound of formula-8.

In a preferred embodiment of the present invention is to provide an improved process for the preparation of compound of formula-8 which comprises of the following steps:

a) Reacting the (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-methylphenol compound of formula-31 with N-bromosuccinamide (NBS) in chloroform provides the (R)-4-(bromomethyl)-2-(3-(diisopropylamino)-l -phenyl propyl) phenol compound of formula-32,

b) reacting the compound of formula-32 with sodium acetate in dimethylformamide provides (R)-3-(3-(diisopropylamino)- 1 -phenylpropyl)-4- hydroxybenzyl acetate compound of formula-33,

c) hydrolyzing the compound of formula-33 with lithium hydroxide in methanol provides the compound of formula-8.

i

The nineteenth aspect of the present invention is to provide a crystalline (R)-2- (3-(diisopropylamino)- 1 -phenylpropyl)-4-(hydroxylmethyl)phenyl methacrylate mandelate salt compound of formula-39a, which is characterized by its powder X-ray powder diffraction pattern showing characteristic peaks at 9.77, 10.24, 11.83,13.27,15.15, 15.94,18.94, 20.22, 21.60 and 25.83 ±0.2 degrees 2Θ. This crystalline form of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-

(hydroxylmethyl)phenyl methacrylate mandelate is hereinafter designated as crystalline form-M. The crystalline form-M of the present invention further characterized by its PXRD showing peaks at 5.12, 10.73, 13.95, 18.04, 18.31, 20.53, 21.06, 22.55 and 30.05 ± 0.2 degrees 2Θ. The PXRD of crystalline form-M is substantially similar to the PXRD pattern depicted in figure- 1.

The twentieth aspect of the present invention provides a process for the preparation of crystalline (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4- (hydroxylmethyl)phenyl methacrylate mandelate salt compound of formula-39a, comprising of;

a) Dissolving (R)-2-(3-(diisopropylamino)- 1 -phenylpropyl)-4-(hydroxymethyl) phenyl methacrylate in a suitable solvent at 25-30°C,

b) heating the reaction mixture,

c) adding mandelic acid solution dissolved in a suitable solvent,

d) cool the reaction mixture to 0-5 °C,

e) stirring the reaction mixture for 20-25 hours at same temperature,

f) filtering the precipitated solid and washing with a suitable solvent,

g) optionally recrystallized from a suitable solvent h) drying the obtained compound to get the crystalline (R)-2-(3- (diisopropylamino)- 1 -phenylpropyl)-4-(hydroxylmethyl)phenyl methacrylate mandelate salt.

The twenty-first aspect of the present invention provides a novel acid addition salts of (R)-2-(3-(diisopropylamino)- 1 -phenylpropyl)-4-(hydroxymethyl)phenyl methacrylate compound of formula-39.

Wherein the "Acid" is selected from hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, nitric acid, acetic acid, propionic acid, palmitic acid, stearic acid, maleic acid, fumaric acid, oxalic acid, succinic acid, DL-malic acid, L-(-)- malic acid, D-(+)-malic acid, DL-tartaric acid, L-(+) -tartaric acid, D-(-)-tartaric acid, diparatolyl tartaric acid, citric acid, L-aspartic acid, L-(+)-ascorbic acid, D-(+)- glucuronic acid, 2-oxopropionic acid (pyruvic acid), furan-2-carboxylic acid (mucic acid), benzoic acid, 4-hydroxybenzoic acid, salicyclic acid, vanillic acid, 4- hydroxycinammic acid, gallic acid, hippuric acid (N-benzoyl-glycine), aceturic acid (N- aectylglycine), phloretinic acid (3-(4-hydroxyphenyl)-propionic acid), phthalic acid, methanesulfonic acid, (S)-(+)-mandelic acid, (R)-(-)-mandelic acid, acetylmandelic acid or orotic acid.

The starting material compound of formula-8 can be prepared as follows, a) Reacting cinnamic acid with 4-bromo phenol in cone. sulfuric acid provides 6- bromo-4-phenylchroman-2-one compound of formula-40,

Formula-40

b) reacting the 6-bromo-4-phenylchroman-2-one compound of formula-40 with benzyl chloride in the presence of sodium iodide and a suitable inorganic base in a suitable solvent to provide 3-phenylpropionate compound of formula-2, c) reducing the compound of formula-2 with a suitable reducing agent in a suitable solvent to provide 3-phenyl propanol compound of formula-3, d) reacting the compound of formula-3 with a C Cg-alkyl- or aryl-sulfonyl halide in the presence of an organic base to provide the protected compound of formula-41,

Formula-41

wherein 'P' represents a Ci-Ce-alkyl- or aryl-sulfonyl protecting group, e) aminating the compound of formula-41 with diisopropylamine in a suitable solvent at a temperature ranging from 70°C-140°C in an autoclave or closed condition to provide diisopropylamine compound of formula- 13,

f) resolving the compound of formula- 13 obtained in step-(e) with a suitable optically active acid to provide (R)-enantiomer of formula- 15,

g) reacting the (R)-enantiomer of formula- 15 with ethyl halide and magnesium in the presence of solid carbon dioxide to provide (R)-4-benzyloxy-3-(3- diisopropylamino-l-phenylpropyl)-benzoic acid compound of formula- 16 or its hydrochloride;

h) esterifying the compound obtained in step-(g) with methanol in the presence of a suitable catalyst to obtain an ester compound of formula-6;

i) reducing the compound of formula-6 with a suitable reducing agent in a suitable solvent to provide (R)-[4-benzyloxy-3-(3-diisopropylamino-l-phenylpropyl)- phenylj-methanol of formul -42;

Formula-42

removing the benzyl protecting group of formula-42 to provide (R)-2- diisopropylamino- 1 -phenylpropyl)-4-hydroxymethylphenol of formula-8. Wherein in step b) the suitable base is selected from alkali metal carbonates and the suitable solvent is selected from alcohol solvents;

In step-c) the suitable reducing agent is vitride and the suitable solvent is selected from hydrocarbon solvents;

In step-d) the suitable organic base is triethylamine, DMAP and or mixtures thereof; and the suitable solvent is selected from chloro solvents;

In step-e) the suitable solvent is selected from nitrile solvents;

In step-f) the suitable optically active acid is D-(-)-tartaric acid and the suitable solvent is selected from alcohol solvents;

In step-g) the suitable solvent is selected from ether solvents;

In step-h) the suitable catalyst is selected from cone. sulfuric acid;

> In step-i) the suitable reducing agent is vitride and the suitable solvent is selected from ether solvents, hydrocarbon solvents and/or their mixtures thereof;

In step-j) the suitable debenzylating agent is selected from Rd/C, Raney Ni and the like; and the suitable solvent is selected from alcohol solvents.

The preferred embodiment of the present invention provides a process for the preparation of (R)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxymethylphe nol of formula-8,

a) Reacting cinnamic acid with 4-bromo phenol in cone, sulfuric acid provides 6- bromo-4-phenylchroman-2-one compound of formula-40,

b) reacting the 6-bromo-4-phenylchroman-2-one compound of formula-40 with benzyl chloride in the presence of sodium iodide and potassium carbonate in methanol to provide 3-phenylpropionate compound of formula-2,

c) reducing the compound of formula-2 with vitride in toluene to provide 3 -phenyl propanol compound of formula-3,

d) reacting the compound of formula-3 with p-toluene sulfonyl chloride in the presence of triethylamine and dimethylaminopyridine in dichloromethane to provide the tosyl protected compound of formula-41 a,

e) aminating the compound of formula-4 la with diisopropylamine in acetonitrile at a temperature ranging from 70°C-140°C in an autoclave or closed condition to provide diisopropylamine compound of formula- 13 ,

f) resolving the compound of formula- 13 obtained in step-(e) with D-(-)-tartaric acid in isopropyl alcohol to provide (R)-enantiomer compound of formula- 15, g) reacting the (R)-enantiomer compound of formula- 15 with ethyl bromide and magnesium in the presence of solid carbon dioxide in tetrahydrofuran to provide (R)-4-benzyloxy-3-(3-diisopropylamino- 1 -phenylpropyl)-benzoic acid compound of formula- 16 or its hydrochloride;

h) esterifying the compound obtained in step-(g) with methanol in the presence of sulfuric acid to provide methyl ester compound of formula-6,

i) reducing the compound of formula-6 with vitride in tetrahydrofuran to provide (R)-[4-benzyloxy-3-(3-diisopropylamino- 1 -phenylpropyl)-phenyl]-methanol of formula-42;

j) debenzylating the compound of formula-42 by treating with 5% Pd/C in methanol to provide (R)-2-(3-diisopropylamino-l-phenylpropyl)-4- hydroxymethylphenol compound of formula-8.

The twenty-second aspect of the present invention provides a process for the preparation of isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)-4- (hydroxymethyl) phenyl ester hydrogen fumarate compound of formula- la, comprising of;

a) Reacting cinnamic acid with 4-halo phenol in cone. sulfuric acid provides 6- bromo-4-phenylchroman-2-one compound of formula-40,

b) reacting the 6-bromo-4-phenylchroman-2-one compound of formula-40 with benzyl chloride in the presence of sodium iodide and a suitable inorganic base in a suitable solvent to provide 3-phenylpropionate compound of formula-2, c) reducing the compound of formula-2 with a suitable reducing agent in a suitable solvent to provide 3 -phenyl propanol compound of formula-3,

d) reacting the compound of formula-3 with a CrQ-alkyl- or aryl-sulfonyl halide in the presence of an aliphatic organic base in a suitable solvent to provide the protected compound of formula-41,

wherein 'P' represents a Ci-C6-alkyl- or aryl-sulfonyl protecting group, e) aminating the compound of formula-41 with diisopropylamine in a suitable solvent at a temperature ranging from 70°C-140°C in an autoclave or closed condition to provide diisopropylamine compound of formula- 13,

f) resolving the compound of formula- 13 obtained in step-(e) with a suitable optically active acid in a suitable solvent to provide (R)-enantiomer of formula- 15,

g) reacting the (R)-enantiomer of formula- 15 with ethyl halide and magnesium in the 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 or its hydrochloride;

h) esterifying the compound obtained in step-(g) with methanol in the presence of a suitable catalyst to obtain methyl ester compound of formula-6,

i) reducing the compound of formula-6 with a suitable reducing agent in a suitable

phenyl] -methanol of formula-42;

j) debenzylating the compound of formula-42 by treating with a suitable debenzylating agent in a suitable solvent to provide (R)-2-(3-diisopropylamino- l-phenylpropyl)-4-hydroxymethylphenol compound of formula-8.

k) condensing the compound of formula-8 with isobutyryl chloride in a suitable solvent, optionally in the presence of a suitable base, to provide substantially pure isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)-4- (hydroxymethyl) phenyl ester compound of formula- 1 and optionally converting the compound of formula- 1 into its pharmaceutically acceptable acid addition salts.

Wherein in step-b) the suitable base is selected from alkali metal carbonates and the suitable solvent is selected from alcohol solvents;

In step-c) the suitable reducing agent is vitride and the suitable solvent is selected from hydrocarbon solvents;

In step-d) the suitable organic base is triethylamine and dimethylaminopyridine and the suitable solvent is selected from chloro solvents;

In step-e) the suitable solvent is selected from nitrile solvents; In step-f) the suitable optically active acid is D-(-)-tartaric acid and the suitable solvent is selected from alcohol solvents;

In step-g) the suitable solvent is selected from ether solvents;

In step-h) the suitable catalyst is selected from conc.sulfuric acid;

In step-i) the suitable reducing agent is vitride and the suitable solvent is selected from ether solvents, hydrocarbon solvents and/or their mixtures thereof;

In step-j) the suitable debenzylating agent is selected from Pd/C, Raney Ni and the like; and the suitable solvent is selected from alcohol solvents.

In step-k) the suitable base is selected from carbonates and bicarbonates of alkali metals; and the suitable solvent is selected from chloro solvents.

The preferred embodiment of the present invention provides a process for the preparation of isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)-4- (hydroxymethyl) phenyl ester hydrogen fumarate compound of formula- la, comprising of;

a) Reacting cinnamic acid with 4-bromo phenol in conc.sulfuric acid provides 6- bromo-4-phenylchroman-2-one compound of formula-40,

b) reacting the 6-bromo-4-phenylchroman-2-one compound of formula-40 with benzyl chloride in the presence of sodium iodide and potassium carbonate in methanol to provide 3-phenylpropionate compound of formula-2,

c) reducing the compound of formula-2 with vitride in toluene to provide 3 -phenyl propanol compound of formula-3,

d) reacting the compound of formula-3 with p-toluene sulfonyl chloride in the presence of triethylamine and dimethylaminopyridine in dichloromethane to provide the protected compound of formula-41a,

e) aminating the compound of formula-41a with diisopropylamine in acetonitrile at a temperature ranging from 70°C-140°C in an autoclave or closed condition to provide diisopropylamine compound of formula- 13,

f) resolving the compound of formula- 13 obtained in step-(e) with D-(-)-tartaric acid in isopropyl alcohol to provide (R)-enantiomer of formula- 15,

g) reacting the (R)-enantiomer of formula- 15 with ethyl bromide and magnesium in the presence of solid carbon dioxide in tetrahydrofuran to provide (R)-4- benzyloxy-3-(3-diisopropylamino-l-phenylpropyl)-benzoic acid compound of formula- 16 or its hydrochloride salt;

h) esterifying the compound obtained in step-(g) with methanol in the presence of sulfuric acid to provide methyl ester compound of formula-6,

i) reducing the compound of formula-6 with vitride in a mixture of tetrahydrofuran and toluene to provide (R)-[4-benzyloxy-3-(3- diisopropylamino- 1 -phenylpropyl)-phenyl]-methanol of formula-42;

j) debenzylating the compound of formula-42 by treating with 5% Pd/C in methanol to provide (R)-2-(3-diisopropylamino-l-phenylpropyl)-4- hydroxymethylphenol compound of formula-8,

k) condensing the compound of formula-8 with isobutyryl chloride in presence of sodium bicarbonate in dichloromethane to provide substantially pure isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)-4-(hydroxymethy l) phenyl ester compound of formula- 1 and converting the compound of formula- 1 into its fumarate salt compound of formula- la by treating with fumaric acid in methyl ethyl ketone.

The twenty-third aspect of the present invention is to provide novel intermediate compounds for the synthesis of isobutyric acid 2-((R)-3-diisopropylammonium-l- phenylpropyl)-4-(hydroxymethyl) phenyl ester compound of formula- 1, which are represented by the below mentioned structural formulae;

The present invention is schematically represented as follows.

Scheme-1:

FormuIa-4 Formula-5 Formula-6 lation

Formula-8 Formula-7

Formula-la

Fesoterodine Fesoterodine fumarate

Scheme-II:

Scheme-Ill:

Scheme-IV:

Formula-13 Formula-19 Formula-20 Formula-11

Scheme-V:

Formula-14 Formula-16 Formula-17

Scheme- VI: Scheme- VII:

Scheme- VIII:

Formula-8 Formula-33

The following are the possible impurities which are observed in the preparation erodine and its pharmaceutically acceptable salts.

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration, only and therefore should not be construed as limitation of the scope of the invention. Examples:

Example-l: Preparation of 6-bromo-4-phenylchroman-2-one

Cinnamic acid (100 gm), 4-bromo phenol (122 gm) and conc.sulfuric acid (13 ml) were charged into a clean and dry RBF at 25-30°C. Heated the reaction mixture to 120-125°C and stirred for 12 hrs at the same temperature. After the completion of the reaction, the temperature of the reaction mixture was reduced to 50-60°C and toluene (300 ml) followed by water (200 ml) were added to the reaction mixture at 50-60°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. The total organic layer was w hedj ith jO%_sodium chloride solution. The solvent was completely distilled off under reduced pressure. Isopropyl alcohol (150 ml) was added to the obtained residue and was completely distilled off under reduced pressure. To the obtained residue, isopropyl alcohol (300 ml) was added and the reaction mixture was cooled to 0-5°C and stirred for 2 hrs at the same temperature. Filtered the precipitate, washed with chilled isopropyl alcohol and then dried to get the title compound.

Yield: 136 gm; Purity by HPLC: 98.9%.

Example-2: Preparation of methyl 3-(2-(benzyloxy)-5-bromophenyI)-3-phenyl propanoate

Potassium carbonate (165 gm), sodium iodide (29 gm) followed by acetone (870 ml) were added to a mixture of 6-bromo-4-phenylchroman-2-one (290 gm) and methanol (870 ml) at 25-30°C. Cooled the reaction mixture to 15-20°C and benzyl chloride (132 ml) was added and stirred for 30 min at the same temperature. Heated the reaction mixture to reflux and stirred for 5 hrs at the same temperature. After the completion of the reaction, the solvent was completely distilled off under reduced pressure. The temperature of the reaction mixture was reduced to 30-35°C and acetone (870 ml) was added. Cooled the reaction mixture to 25-30°C and stirred for 30 min at the same temperature. The obtained compound was filtered and washed with acetone. The solvent was completely distilled off from the reaction mixture under reduced pressure at 45-50°C. The obtained residue was cooled to 25-35°C, added dichloromethane (1160 ml) and stirred for 15 min at the same temperature. Added 10% sodium chloride solution (580 ml) to the reaction mixture at 25-35°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 10% sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure at 35-40°C. Cooled the residue to 25-30°C and pet ether (580 ml) was added. Distilled off the solvent completely under reduced pressure at 35-40°C. Pet ether (1 160 ml) was added to the obtained residue at 25-30°C and stirred for 5 hrs at the same temperature. Cooled the reaction mixture to 0-5 °C and stirred for 2 hrs at the same temperature. Filtered the compound, washed with chilled pet ether and then dried to get the title compound. Yield: 327 gm; Purity by HPLC: 98.13%.

Example-3: Preparation of 3-(2-(benzyIoxy)-5-bromophenyl)-3-phenylpropan-l-ol (formula-3)

A solution of methyl 3-(2-(benzyloxy)-5-bromophenyl)-3-phenylpropanoate compound of formula-2 (75 gm) in toluene (225 ml) was slowly added to a pre-cooled mixture of toluene (75 ml) and vitride (77 ml, 70% in toluene) at 5-10°C under nitrogen atmosphere and stirred for 4 hrs at the same temperature. After the completion of the reaction, a solution of sodium potassium tartrate (100 gm) in water (250 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. The combined organic layer was washed with a solution of acetic acid in water followed by 5% sodium chloride solution. The resulting organic layer was washed with water and then both the organic and aqueous layers were separated. Distilled off the solvent completely from the organic layer under reduced pressure. The obtained residue was cooled to 30-35°C and cyclohexane (150 ml) was added. Distilled off the solvent completely under reduced pressure at 50-60°C and the residue was cooled to 25-30°C. Cyclohexane (300 ml) was added to the residue at 25-30°C and the reaction mixture was 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 compound, washed with chilled cyclohexane and then dried to get the title compound.

Yield: 50 gm; Purity by HPLC: 99.06%.

Example-4: Preparation of 3-(2-(benzyloxy)-5-bromophenyI)-3-phenylpropyl-4- methylbenzenesulfonate

3-(2-(benzyloxy)-5-bromophenyl)-3-phenylpropan- l-ol (325 gm) and dichloromethane (1300 ml) were charged into a clean and dry RBF 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 (22.5 gm) followed by p- toluene sulfonyl chloride (220 gm) were added at the same temperature. Triethylamine (341 ml) was drop wise added to the resulting reaction mixture at 0-5°C and stirred for 2 hrs at the same temperature. After the completion of the reaction, water (1725 ml) was added to the reaction mixture and stirred for 15 min. 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. The solvent was completely distilled off from the organic layer under reduced pressure to get the title compound.

Yield: 450 gm; Purity by HPLC: 94.32%.

Example-5: Preparation of 3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3- phenylpropan-l-amine (Formula-13)

3-(2-(Benzyloxy)-5-bromophenyl)-3-phenylpropyl-4-methylbenze nesulfonate (385 gm), acetonitrile (385 ml) and diisopropylamine (490 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 the completion of the reaction, cooled the reaction mixture to 25-30°C and stirred for 1 hr at the same temperature. Filtered the reaction mixture and washed with acetonitrile. Distilled off the solvent completely from the filtrate at 50- 60°C and the obtained residue was cooled to 35-40°C. Water (385 ml) followed by dichloromethane (770 ml) were added to the residue at 35-40°C and then cooled the reaction mixture to 10-15°C. The pH of the reaction mixture was adjusted to 9.5 by adding a mixture of hydrochloric acid (80 ml) and water (80 ml) at 10-15°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Both the organic layers were combined and water (385 ml) was added to the combined organic layer and the reaction mixture was cooled to 10-15°C. The pH of the reaction mixture was adjusted to 7.5 using ammonia solution (50 ml) at 10-15°C. Both the organic and aqueous layers were separated and the organic layer was washed with water. The solvent was completely distilled off from the organic layer under reduced pressure to get the title compound. Yield: 340.0 gm.

Example-6: Preparation of (R)-3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl- 3-phenylpropan-l-amine-D-tartrate salt (formula-26)

3-(2-(Benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3-phenylprop an-l-amine compound of formula- 13 (340 gm) and isopropyl alcohol (385 ml) were charged into a clean and dry RBF at 30-35°C and stirred for 30 min at the same temperature. Distilled off the solvent completely under vacuum and isopropyl alcohol (3080 ml) was added to the obtained residue at 40-45°C and stirred for 30 min at the same temperature. Heated the reaction mixture to 50-55°C and D(-)-tartaric acid (106 gm) was added. The reaction mixture was cooled to 40-45°C and then seeded with (R)-3-(2-(benzyloxy)-5- bromophenyl)-N,N-diisopropyl-3-phenylpropan-l-amine-D-tartra te salt. The reaction mixture was further cooled to 30-35°C and stirred for 16 hrs at the same temperature. Filtered the precipitated compound, washed with isopropyl alcohol and then dried to get the title compound. Yield: 130 gm; Purity by HPLC: 96.36%.

Example-7: Purification of (R)-3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl- 3-phenylpropan-l-amine-D-tartrate salt (formula-26)

(R)-3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3-phenyl propan-l- amine-D-tartrate (100 gm) and ethanol (300 ml) were charged into a clean and dry RBF at 25-30°C. Heated the reaction mixture 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 compound, 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°.

Example-8: Preparation of (R)-4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenyl propyl)benzoic acid hydrochloride salt A mixture of (R)-3-(2-(benzyloxy)-5-bromophenyl)-N,N-diisopropyl-3- phenylpropan-l-amine-D-tartrate (180 gm), water (900 ml) and dichloromethane (900 ml) was cooled to 10-15°C and stirred for 15 min at the same temperature. The pH of the reaction mixture was adjusted to 11.5 using aqueous sodium hydroxide solution (sodium hydroxide (22.5 gm) in water (135 ml) at 10-20°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 at 45-50°C and the obtained residue was cooled to 25-30°C under nitrogen atmosphere. Tetrahydrofuran (900 ml) was added to the residue at 25-30°C under nitrogen atmosphere and stirred for 15 min at the same temperature. Ethyl bromide (81 ml) was added to the reaction mixture and the obtained reaction mixture was added to a mixture of magnesium turnings (34.2 gm), tetrahydrofuran (900 ml), iodine (0.18 gm) and ethyl bromide (28 ml) at 35-40°C in another RBF. Heated the reaction mixture to 50-55°C and stirred for 4 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and then further cooled to -70°C under nitrogen atmosphere. Dry ice (720 gm) was slowly added to the reaction mixture at -60 to -70°C under nitrogen atmosphere and stirred for 90 min at the same temperature. After the completion of the reaction, the temperature of the reaction mixture was raised to -10°C and quenched with a solution of ammonium chloride in water. 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 a solution of ammonium chloride in water. Both the organic and aqueous layers were separated and ethyl acetate (1350 ml) was added to the aqueous layer at 0-5°C. The pH of the reaction mixture was adjusted to 1.5 at 0-5°C using a solution of hydrochloric acid (45 ml) in water (432 ml). Both the organic and aqueous layers were separated and the solvent was completely distilled off from the organic layer under reduced pressure to get the title compound. Yield: 135.0 gm; Purity by HPLC: 91.5%. Example-9: Preparation of (R)-methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l- phenylpropyl)benzoate (Formula-6)

A solution of (R)-4-(benzyloxy)-3-(3-(diisopropylamino)-l- phenylpropyl)benzoic acid hydrochloride (280 gm) in methanol (2800 ml) was cooled 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-10: Preparation of (R)-[4-(benzyloxy)-3-(3-(diisopropylamino)-l- phenylpropyl)phenyl] methanol

A solution of vitride in toluene (15 ml, 70% w/w) was drop wise added to a pre- cooled solution of (R)-methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l- phenylpropyl)benzoate (5 gm) in toluene (25 ml) at 0-5°C under nitrogen atmosphere and stirred for 4 hrs at the same temperature. After the completion of the reaction, a solution of sodium potassium tartrate (6.14 gm) in water (15 ml) was drop wise added to the reaction mixture 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: 3.4 gm; Purity by HPLC: 97.45%.

Example-11: Preparation of (R)-2-(3-(diisopropylamino)-l-phenyIpropyl)-4- (hydroxymethyl)phenol (FormuIa-8)

(R)-[4-(benzyloxy)-3 -(3 -(diisopropylamino)- 1 -phenylpropyl)phenyl]methanol (16 gm), methanol (160 ml) and 5% Pd/C (8 gm) were charged into an autoclave at 25- 30°C under nitrogen atmosphere. 3-4 Kg/Cm ² hydrogen gas pressure was applied to the reaction mixture for 8 hrs at 25-30°C. After the completion of the reaction, filtered the reaction mixture through hyflow bed and washed with methanol. Distilled off the solvent completely form the filtrate under reduced pressure to get the title compound. Yield: 1 1.6 gm; Purity by HPLC: 93.75%.

Example-12: Preparation of isobutyric acid 2-((R)-3-diisopropylanimonium-l- phenylpropyl)-4-(hydroxymethyl) phenyl ester (Formula-1) 75.0 gm of (R)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxymethyl- phenol (formula-8) and dichloromethane (2250 ml) were charged into a clean and dry RBF at 25-30°C under nitrogen atmosphere. Cooled the reaction mixture to 0-5°C and a solution of sodium bicarbonate (9 gm) in water (375 ml) was added. Isobutyryl chloride (26 ml) was drop wise added to the reaction mixture at 0-5°C and stirred for 30 min at the same temperature. After the completion of the reaction, separated the organic and aqueous layers and the organic layer was washed with 5% sodium bicarbonate solution followed by water. Distilled off the solvent completely from the organic layer under reduced pressure and then co-distilled with ethyl acetate. The obtained compound is purified by column chromatography to get the title compound. Yield: 60.0 gm.

Example-13: Preparation of isobutyric acid 2-((R)-3-diisopropylammonium-l- phenyIpropyl)-4-(hydroxy methyl)phenyl ester (R)-acetoxy(phenyl)acetate salt (Formula-23)

To 10 gms of isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)- 4-(hydroxy methyl)phenyl ester added 60 ml of ethyl acetate and 4.75 gms of (R)- acetoxy(phenyl)acetic acid. Heated the reaction mixture 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 ethyl acetate and the dried to get the title compound. Yield: 12.5 gms

Example-14: Preparation of isobutyric acid 2-((R)-3-diisopropylammonium-l- phenyIpropyl)-4-(hydroxymethyl) phenyl ester hydrogen fumarate salt (Formula- la)

Isobutyric acid 2-((R)-3-diisopropylammonium- 1 -phenylpropyl)-4-(hydroxyl methyl) phenyl ester (R)-acetoxy(phenyl)acetate salt (86 gm) and water (430 ml) were charged into a clean and dry RBF at 25-30°C and cooled the reaction mixture to 0-5°C. The pH of the reaction mixture was adjusted to 11.5 by adding drop wise a 20% solution of sodium carbonate at 0-5°C. Dichloromethane (860 ml) was added to the reaction mixture 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 and the obtained residue was dissolved in ethyl methyl ketone (189 ml). Fumaric acid (17.7 gm) was added to the reaction mixture at 25-30°C and then heated to 40-45°C and stirred for 1 hr at the same temperature. Cooled the reaction mixture to 20-25°C, seeded with isobutyric acid 2-((R)-3-diisopropyl ammonium- l-phenylpropyl)-4-(hydroxyl methyl)phenyl ester hydrogen fumarate (0.1 gm) and stirred for 2 hrs at the same temperature. Cyclohexane (344 ml) was drop wise added to the reaction mixture at 20- 30°C and stirred for 14 hrs at 25-35°C. Filtered the precipitated compound, washed with cyclohexane and then dried under vacuum at 25-35°C to get the title compound. Yield: 73.0 gm; Purity by HPLC: 99.7%.

Example-15: Preparation of (R)-methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l- pheny!propyl)benzoate (-)-di-p-toluoyl-L-tartaric acid salt (Formula-5a)

Methyl 4-(benzyloxy)-3 -(3 -(diisopropylamino)- 1 -phenylpropyl)benzoate compound of formula-4 (10 gm) and isopropyl alcohol (80 ml) were charged in a clean and dry RBF at 25-30°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 gms

Example-16: Preparation of (R)-methyl 4-(benzyloxy)-3-(3-(diisopropylamino)-l- phenylpropyl)benzoate (Formula-6)

(R)-methyl 4-(benzyloxy)-3 -(3 -(diisopropylamino)- 1 -phenylpropyl)benzoate (- )-di-p-toluoyl-L-tartaric acid salt compound of formula-5a (10 gm) and water (50 ml) were charged into a clean and dry RBF at 25-30°C. The pH of the reaction mixture was adjusted to 9.5 using 10% sodium carbonate solution. Extracted the reaction mixture with dichloromethane and washed with sodium chloride solution. Dried the organic layer over sodium sulfate and distilled off the solvent completely under reduced pressure to get the title compound. Yield: 7.5 gm; Purity by HPLC: 99.6%.

Example-17: Preparation of (R)-methyl 3-(3-(diisopropylamino)-l-phenyIpropyl)- 4-hydroxybenzoate (Formula-7) (R)-methyl 4-(benzyloxy)-3 -(3 -(diisopropylamino)- 1 -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/Cm ² hydrogen gas pressure was applied to the reaction mixture for 18 hrs at 25-30°C. After the 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-18: Preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4- (hydroxymethyl)phenol (Formula-8)

(R)-methyl 3 -(3 -(diisopropylamino)- 1 -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 a solution of vitride in tetrahydrofuran (120 ml) was drop wise added to the reaction mixture at 0-5°C under nitrogen atmosphere and stirred for 2 hrs at the same temperature. After the 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-19: Preparation of (R)-2-(3-diisopropylamino-l-phenylpropyl)-4- hydroxymethyl phenol mandelate salt

To 10 gms of (R)-2-(3 -diisopropylamino- l-phenylpropyl)-4-hydroxyrnethyl- phenol compound of formula-8 added 40 ml of isopropyl alcohol and 4.5 gms of L-(+)- mandelic acid. Heated the reaction mixture 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 gms.

ExampIe-20: Preparation of methacryloyl chloride

Methacrylic acid (40 ml), benzoyl chloride (100 ml) and butylated hydroxytoluene (100 mg) were charged into a clean and dry RBF at 25-30°C. Heated the reaction mixture to 90-100°C and stirred for 1 hr at the same temperature. Distilled the product completely at below 105°C and the resulting crude compound is fractionally distilled at 95-96°C to get the title compound. Yield: 35.0 gm.

Example-21: Preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4- (hydroxylmethyl)phenyl methacrylate mandelate salt (FormuIa-39a)

(R)-2-(3-diisopropylamino- 1 -phenylpropyl)-4-hydroxymethyl phenol mandelate salt (20 gm), water (200 ml) and chloroform (200 ml) were charged to another RBF at 25-30°C and cooled the reaction mixture to 0-5°C. 20% Sodium carbonate solution (20 ml) was added to the reaction mixture at 0-5°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. Dried the organic layer over sodium sulfate and then cooled to -45 to -35°C. A solution of methacryloyl chloride (4.6 gm) and potassium carbonate (2.8 gm) in chloroform (50 ml) was added to the reaction mixture at -45 to -35°C and stirred for 45 min at the same temperature. After the completion of the reaction, water (200 ml) was added to the reaction mixture and stirred for 15 min. Both the organic and aqueous layers were separated and the organic layer was washed with 5% sodium bicarbonate solution followed by water. Distilled off the solvent completely under reduced pressure and then co-distilled with ethyl acetate. Ethyl acetate (40 ml) was added at 25-30°C and stirred for 15 min at the same temperature. Heated the reaction mixture to 45-50°C and then a solution of L(+)-mandelic acid (7.4 gm) in ethyl acetate (60 ml) at 45-50°C was added to the reaction mixture at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 24 hrs at the same temperature. Filtered the reaction mixture, washed with chilled ethyl acetate and then dried to get the title compound. The obtained solid was recrystallized from ethyl acetate. Purity by HPLC: 98.99 %; Diol impurity: 0.01 %; dimer impurity: 0.09%;

Yield: 4.0 gm; MR: 121-123°C; PXRD of the obtained compound is shown in figure- 1. Example-22: Preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4- (hydroxylmethyl)phenyl methacrylate (Formula-9)

(R)-2-(3 -(diisopropylamino)- 1 -phenylpropyl)-4-(hydroxylmethyl)phenyl methacrylate mandelate (10 gm) and water (50 ml) were charged into a clean and dry RBF at 25-30°C. The pH of the reaction mixture was adjusted to 9.5 using 10% sodium carbonate solution. Extracted the solution with dichloromethane and washed with sodium chloride solution. Dried the organic layer and distilled off the solvent under reduced pressure to get the title compound. Yield: 7.5 gm; Purity by HPLC: 99.6%. Example-23: Preparation of isobutyric acid 2-((R)-3-diisopropylammonium-l- phenylpropyl)-4-(hydroxymethyl) phenyl ester (Formula-1)

(R)-2-(3 -(diisopropylamino)- 1 -phenylpropyl)-4-(hydroxymethyl)phenyl methacrylate (20 gm), ethyl acetate (200 ml) and 10% Pd/C (4 gm) were charged into an autoclave at 25-30°C under nitrogen atmosphere. 3-4 Kg/Cm ² hydrogen gas pressure was applied to the reaction mixture for 6 hrs at 25-30°C. After the completion of the reaction, filtered the reaction mixture through hyflow bed and washed with ethyl acetate. Distilled off the solvent completely form the filtrate under reduced pressure to get the title compound. Yield: 18 gm.

ExampIe-24: Preparation of (R)-N,N-diisopropyl-3-(5-formyl-2-hydroxyphenyl)-3- phenyl propanamine compound of formula-11.

To a solution of (R)-methyl 3-(3-(diisopropylamino)-l-phenylpropyl)-4- hydroxybenzoate compound of formula-7 (5 gm) dissolved in toluene (40 ml) and cooled the reaction mass to -78°C under nitrogen atmosphere. Diisobutyl aluminium hydride solution (9 ml) was added to the reaction mixture at -78°C and stirred for 1 hour the same temperature. After completion of the reaction, the reaction mixture was quenched with 20% potassium tartarate solution. Separated the both aqueous and organic layers and organic layer was washed with a solution of 10.0% acetic acid followed by brine solution. Distilled off the solvent completely from the organic layer to get the title compound.

Yield: 2.8 gm

Example-25:Preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4- formylphenyl methacrylate compound of formula-12

A solution of methacryloyl chloride (1.5 gm) in chloroform (15 ml) was added to the solution of (R)-N,N-diisopropyl-3-(5-formyl-2-hydroxyphenyl)-3 -phenyl propanamine (5 gms) dissolved in chloroform(50 ml) at -45 to -35°C and stirred for 45 min at the same temperature. After the completion of the reaction, water (50 ml) was added to the reaction mixture and stirred for 15 min. Both the organic and aqueous layers were separated and the organic layer was washed with 5% sodium bicarbonate solution followed by water. Distilled off the solvent completely under reduced pressure and then co-distilled with ethyl acetate to get the title compound. Yield: 4.0 gms

Example-26: Preparation of 4-(benzyIoxy)-3-(3-(diisopropylamino)-l- phenylpropyl)benzoic acid compound of formuIa-14.

Tetrahydrofuran (300 ml) was added to the N,N-diisopropyl-3-(2-benzyloxy-5- bromophenyl)-3 -phenyl propanamine compound of formula- 13 (50 gm) at 25-30°C under nitrogen atmosphere and stirred for 15 min at the same temperature. Ethyl bromide (30 ml) was added to the organic layer and the obtained reaction mixture was added to a mixture of magnesium turnings (13 gm), tetrahydrofuran (300 ml), iodine (0.1 gm) and ethyl bromide (10 ml) at 35-40°C in another RBF. Heated the reaction mixture to 50-55°C and stirred for 4 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and then further cooled to -70°C under nitrogen atmosphere. Dry ice (280 gm) was slowly added to the reaction mixture at -60 to -70°C under nitrogen atmosphere and stirred for 90 min at the same temperature. After the completion of the reaction, the temperature of the reaction mixture was raised to -10°C and quenched with a solution of ammonium chloride in water. 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 a solution of ammonium chloride in water. Both the organic and aqueous layers were separated and ethyl acetate (500 ml) was added to the aqueous layer at 0-5°C. The pH of the reaction mixture was adjusted to 1.5 at 0-5°C using aqueous hydrochloric acid. Both the organic and aqueous layers were separated and the solvent was completely distilled off from the organic layer under reduced pressure to get the title compound. Yield: 45.0 gm; Purity by HPLC: 91.5%.

Example-27:Preparation of (R)-4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenyl propyl)benzoic acid compound of formula-16

4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzoic acid (20 gm) and isopropyl alcohol (200 ml) were charged into a clean and dry RBF at 40-45°C and stirred for 30 min at the same temperature. Heated the reaction mixture to 50-55°C and D(-)-tartaric acid (6.1 gm) was added. The reaction mixture was cooled to 30-35°C and stirred for 16 hrs at the same temperature. Filtered the precipitated solid, washed with isopropyl alcohol. To the obtained solid water (150 ml) and methylene chloride (150 ml) were added and the reaction mixture was cooled to 10- 15°C. The pH of the reaction mixture was basified using aqueous sodium hydroxide solution at 10-15°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 to get the title compound. Yield: 8 gm;

Example-28:Preparation of (R)-3-(3-(diisopropylamino)-l-phenylpropyl)-4- hydroxy benzoic acid compound of formula-17

(R)-4-(benzyloxy)-3-(3-(diisopropylamino)- 1 -phenylpropyl)benzoic acid (15 gm), methanol (150 ml) and 5% Pd/C (7.5 gm) were charged into an autoclave at 25- 30°C under nitrogen atmosphere. 3-4 Kg/Cm ² hydrogen gas pressure was applied to the reaction mixture for 8 hrs at 25-30°C. After the completion of the reaction, filtered the reaction mixture through hyflow bed and washed with methanol. Distilled off the solvent completely form the filtrate under reduced pressure to get the title compound. Yield: 10 gm;

Example-29: Preparation of (R)-3-(3-(diisopropylamino)-l-phenylpropyl)-4- (methacryloyloxy)benzoic acid compound of formula-18

A solution of methacryloyl chloride (1.6 gm) in chloroform (15 ml) was added to the solution of (R)-3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxy benzoic acid compound of formula-17 (5 gms) dissolved in chloroform(50 ml) at -45 to -35°C and stirred for 45 min at the same temperature. After the completion of the reaction, water (50 ml) was added to the reaction mixture and stirred for 15 min. Both the organic and aqueous layers were separated and the organic layer was washed with 5% sodium bicarbonate solution followed by water. Distilled off the solvent completely under reduced pressure and then co-distilled with ethyl acetate to get the title compound. Yield: 3.5 gms

Example-30: Preparation of Fesoterodine:

(R)-3 -(3 -(diisopropylamino)- 1 -phenylpropyl)-4-(methacryloyloxy)benzoic acid (20 gm), ethyl acetate (200 ml) and 10% Pd/C (4 gm) were charged into an autoclave at 25-30°C under nitrogen atmosphere. 3-4 Kg/Cm hydrogen gas pressure was applied to the reaction mixture for 6 hrs at 25-30°C. After the completion of the reaction, filtered the reaction mixture through hyflow bed and washed with ethyl acetate. Distilled off the solvent completely form the filtrate under reduced pressure. The obtained residue added tetrahydrofuran (50 ml) and distilled off the solvent completely under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (80 ml) and the solution was added to the 0-5°C pre-cooled reaction mixture containing sodium borohydride (2.15 gm) and tetrahydrofuran(40 ml) at same temperature. Stirred the reaction mixture for 60 min. at 0-5°C. BF ₃ -etharate (10.70 gm) was added to the reaction mixture at 0-5°C and stirred for 1.5 hrs at the same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred the reaction mixture for 6 hours at the same temperature. Cooled the reaction mixture to 0-5 °C and quenched the reaction mixture using aqueous hydrochloric acid at same temperature. Raised the temperature of the reaction mixture to 25°-30°C and ethyl acetate was added to it. Separated the both aqueous and organic layers and the organic layer was washed with water. Distilled off the solvent completely to get the title compound. Yield: 12 gm; Example-31: Preparation of 4-(benzyloxy)-3-(3-(diisopropylamino)-l- phenylpropyl) benzaldehyde compound of formuIa-19

Tetrahydrofuran (70 ml) was added to the N,N-diisopropyl-3-(2-benzyloxy-5- bromophenyl)-3-phenyl propanamine (10 gm) and the reaction mixture was cooled to - 55 to -65°C. n-Butyl lithium (20 ml) was added to the reaction mixture at -60° to -65°C and further N,N-Dimethylformamide (5 ml) was added to it at the same temperature. Stirred the reaction mixture for 45 minutes at -60 to -65°C. Raised the temperature of the reaction mixture to 25-30°C and quenched with aqueous ammonium chloride solution. Ethyl acetate (50 ml) was added to the reaction mixture and separated the both aqueous and organic layers. Organic layer was washed with 10% sodium chloride solution. Distilled off the solvent completely from organic layer under reduced pressure to get the title compound. Yield: 6.2 gm.

Example-32: Preparation of (R)-4-(benzyloxy)-3-(3-(diisopropylamino)-l- phenylpropyl) benzaldehyde compound of formula-20

4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl) benzaldehyde (10 gm) and isopropyl alcohol (100 ml) were charged into a clean and dry RBF at 40-45°C and stirred for 30 min at the same temperature. Heated the reaction mixture to 50-55°C and D(-)-tartaric acid (3.5 gm) was added. The reaction mixture was cooled to 30-35°C and stirred for 16 hrs at the same temperature. Filtered the precipitated solid, washed with isopropyl alcohol. To the obtained solid water (75 ml) and methylene chloride (75 ml) were added and the reaction mixture was cooled to 10-15°C. The pH of the reaction mixture was basified using aqueous sodium hydroxide solution at 10-15°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 to get the title compound. Yield: 4 gm;

Example-33: Preparation of (R)-N,N-diisopropyl-3-(5-formyl-2-hydroxyphenyl)-3- phenyl propanamine compound of formula-ll

(R)-4-(benzyloxy)-3 -(3 -(diisopropylamino)- 1 -phenylpropyl) benzaldehyde (20 gm), methanol (200 ml) and 5% Pd/C (10 gm) were charged into an autoclave at 25- 30°C under nitrogen atmosphere. 3-4 Kg/Cm ² hydrogen gas pressure was applied to the reaction mixture for 8 hrs at 25-30°C. After the completion of the reaction, filtered the reaction mixture through hyflow bed and washed with methanol. Distilled off the solvent completely form the filtrate under reduced pressure to get the title compound. Yield: 14 gm;

ExampIe-34: Preparation of 3-(3-(diisopropyIamino)-l-phenylpropyl)-4-hydroxy benzoic acid compound of formula-21

4-(benzyloxy)-3-(3-(diisopropylamino)-l-phenylpropyl)benzoic acid (15 gm), methanol (150 ml) and 5% Pd/C (7.5 gm) were charged into an autoclave at 25-30°C under nitrogen atmosphere. 3-4 Kg/Cm hydrogen gas pressure was applied to the reaction mixture for 8 hrs at 25-30°C. After the completion of the reaction, filtered the reaction mixture through hyflow bed and washed with methanol. Distilled off the solvent completely form the filtrate under reduced pressure to get the title compound. Yield: 9.8 gm;

Example-35: Preparation of 3-(3-(diisopropylamino)-l-phenyIpropyI)-4- (methacryloyloxy)benzoic acid compound of formula-22

A solution of methacryloyl chloride (1.6 gm) in chloroform (15 ml) was added to the solution of 3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxy benzoic acid compound of formula-21 (5 gms) dissolved in chloroform(50 ml) at -45 to -35°C and stirred for 45 min at the same temperature. After the completion of the reaction, water (50 ml) was added to the reaction mixture and stirred for 15 min. Both the organic and aqueous layers were separated and the organic layer was washed with 5% sodium bicarbonate solution followed by water. Distilled off the solvent completely under reduced pressure and then co-distilled with ethyl acetate to get the title compound. Yield: 3.7 gms

Example-36: Preparation of (R)-3-(3-(diisopropylamino)-l-phenylpropyl)-4- (methacryloyloxy)benzoic acid compound of formula-18

3-(3-(diisopropylamino)- 1 -phenylpropyl)-4-(methacryloyloxy)benzoic acid (20 gm) and isopropyl alcohol (200 ml) were charged into a clean and dry RBF at 40-45°C and stirred for 30 min at the same temperature. Heated the reaction mixture to 50-55°C and D(-)-tartaric acid (7.0 gm) was added. The reaction mixture was cooled to 30-35°C and stirred for 16 hrs at the same temperature. Filtered the precipitated solid, washed with isopropyl alcohol. To the obtained solid water (200 ml) and methylene chloride (200 ml) were added and the reaction mixture was cooled to 10-15°C. The pH of the reaction mixture was basified using aqueous sodium hydroxide solution at 10-15°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 to get the title compound. Yield: 8 gm;

Example-37: Preparation of 2-oxo-4-phenylchroman-6-carboxylic acid compound of formula-27:

A mixture of 4-hydroxybenzoic acid (108 grams), cinnamic acid (100 grams), acetic acid (80 ml) was heated to 100°C. 96% sulfuric acid (80 ml) was added to the resulting clear solution and stirred for 16 hours. The reaction mixture was cooled to ambient temperature and diluted with water. The precipitated solid was filtered off, washed with diethylether and the dried to get the title compound. Yield: 142 grams. Example-38 : Preparation of 4-hydroxy-3-((R)-3-oxo-l-phenyl-3-((R)-l- phenylethyl amino)propyl)benzoic acid (formula-28)

To a solution of 2-oxo-4-phenylchroman-6-carboxylic acid compound of formula-27 (25 g ) in acetone (200 ml), R-l-phenylethylamine (12 grams) was added drop wise at 25-35°C and stirred for 2 hours. Filtered the precipitated product and dried under reduced pressure to get title compound. Yield: 30.0grams.

Example-39: Preparation of 4-(hydroxymethyl)-2-((R)-l-phenyl-3-((R)-l- phenylethyl amino)propyl)phenol compound of formula-29

To a solution of 4-hydroxy-3-((R)-3-oxo-l-phenyl-3-((R)-l- phenylethylamino)propyl)benzoic acid compound of formula-28 (25 grams) in THF (250 ml) was cooled to -20°C. 10% BF _3- etharate solution (100 ml) was added drop wise under inert atmosphere at -20°C. The reaction mixture was stirred for 1 hour at -20°C. After completion of the reaction, the reaction mixture was quenched with water and filtered the reaction mixture. Product was extracted with methylene chloride from the filtrate and methylene chloride layer was concentrated under reduced pressure to get title compound as light yellow colored residue. Yield: 20 grams.

Example-40: Preparation of (R)-2-(3-amino-l-phenyIpropyl)-4-(hydroxymethyI) phenol (formula-30)

4-(hydroxymethyl)-2-((R)- 1 -phenyl-3 -((R)- 1 -phenyl ethylamino)propyl) phenol compound of formula-29 (50 grams) was dissolved in methanol (250 ml) and 5.0 Pd/C (10 grams) was added to it in an autoclave vessel. The reaction mixture was hydrogenated at 25-35°C at a pressure of 4 Kg/Cm ² over a period of 18 hours. After completion of the reaction, the reaction mixture was filtered through ceilite bed and the filtrate was evaporated under reduced pressure to get title compound. Yield: 30 grams.

Example-41: Preparation of (R)-4-(bromomethyl)-2-(3-(diisopropylamino)-l- phenyl propyl) phenol (formula-32)

To a solution of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4- methylphenol compound of formula-31 (25 grams) in chloroform (250 ml), N-bromo succinamide (23 grams) and dibenzyl peroxide (2 grams) were added and the reaction mixture was heated to reflux. The reaction mixture was stirred for about 8 hours at the same temperature. After completion of the reaction, the reaction mixture was filtered and washed with saturated vacuum salt solution. Distilled off the solvent completely from the filtrate to get the title compound as a light red colored residue. Yield: 24 grams. Example-42: Preparation of (R)-3-(3-(diisopropylamino)-l-phenylpropyl)-4- hydroxy benzyl acetate (formula-33)

Dimethylformamide (100 ml) was added to ((R)-4-(bromomethyl)-2-(3- (diisopropylamino)-l -phenyl propyl) phenol compound of formula-32 (20 grams) under inert atmosphere and followed by sodium acetate (12 grams). The reaction mixture was heated to 80-85°C and stirred for 12 hours at 80-85°C. After completion of the reaction, water was added to the reaction mixture and the reaction mixture was extracted with methylene chloride. Both the organic and aqueous layers were separated and the organic layer was washed twice with water. Distilled off the solvent completely from the organic layer under reduced pressure to get title compound as a thick residue. Yield: 15.0 grams

Example-43: Preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4- (hydroxymethyl) phenol (formula-8)

To a solution of (R)-3-(3-(diisopropylamino)-l-phenylpropyl)-4- hydroxybenzyl acetate compound of formula-33 (20 grams) in water (80 ml), methanol (20 ml) was added followed by lithium hydroxide (2 grams) and the reaction mixture was stirred for 4 hours at 25-35°C. After completion of the reaction, the reaction mixture was extracted into methylene dichloride. Both organic and aqueous layers were separated and the organic layer was concentrated under reduced pressure followed by crystallization in ethyl acetate provides the title compound as white crystalline solid. Yield: 15 grams

Example-44: Preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4- (hydroxymethyl) phenol compound of formula-8

To a solution of (R)-2-(3-amino-l-phenylpropyl)-4-(hydroxymethyl)phenol compound of formula-30 (25.0 grams) in acetone (250 ml), potassium carbonate (67.13 grams) was added followed by isopropyl chloride (44.19 ml) and the reaction mixture was heated to reflux temperature. The reaction mixture was stirred for 6 hours at the same temperature. After completion of the reaction, the reaction mixture was quenched with water and the product was extracted into dichloromethane. The dichloromethane layer was separated from aqueous layer and concentrated under reduced pressure to get the title compound. Yield: 22.00 grams Example-45: Alternative process for preparation of (R)-2-(3-(diisopropylamino)-l- phenylpropyl)-4-(hydroxymethyl)phenol compound of formula-8

The title compound is prepared according to example-44, using dimethylformamide as a solvent instead of acetone at 100-120°C. Yield: 23.22 grams Example-46: Alternative process for preparation of (R)-2-(3-(diisopropylamino)-l- phenylpropyl)-4-(hydroxymethyl)phenoI compound of formula-8

The title compound is prepared according to example-44, using acetonitrile as a solvent instead of acetone at a temperature of 80-90°C. Yield: 23.00 grams

Example-47: Preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4- (hydroxymethyl)phenyl-2-bromo-2-methyl propanoate (Formula-37)

5.0 gm of (R)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxymethyl -phenol (formula-8) and dichloromethane (150 ml) were charged into a clean and dry RBF at 25-30°C under nitrogen atmosphere. Cooled the reaction mixture to 0-5°C and a solution of sodium bicarbonate (0.6 gm) in water (25 ml) was added. 2-Bromo-2- methyl propanoyl chloride (1.8 ml) was drop wise added to the reaction mixture at 0- 5°C and stirred for 30 min at the same temperature. After the completion of the reaction, separated the organic and aqueous layers and the organic layer was washed with 5% sodium bicarbonate solution followed by water. Distilled off the solvent completely from the organic layer under reduced pressure and then co-distilled with ethyl acetate. The obtained compound is purified by column chromatography to get the title compound. Yield: 1.2 gm.

ExampIe-48: Preparation of 2-((R)-3-(diisopropylamino)-l-phenylpropyl)-4- (hydroxymethyi)phenyl-3-bromo-2-methyl propanoate (Formula-38)

5.0 gm of (R)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxymethyl-ph enol (formula-8) and dichloromethane (150 ml) were charged into a clean and dry RBF at 25-30°C under nitrogen atmosphere. Cooled the reaction mixture to 0-5°C and a solution of sodium bicarbonate (0.6 gm) in water (25 ml) was added. 3-Bromo-2- methyl propanoyl chloride (1.8 ml) was drop wise added to the reaction mixture at 0- 5°C and stirred for 30 min at the same temperature. After the completion of the reaction, separated the organic and aqueous layers and the organic layer was washed with 5% sodium bicarbonate solution followed by water. Distilled off the solvent completely from the organic layer under reduced pressure and then co-distilled with ethyl acetate. The obtained compound is purified by column chromatography to get the

i

title compound. Yield: 1.0 gm.

Example-49: Preparation of isobutyric acid 2-((R)-3-diisopropylammonium-l- phertyIpropyl)-4-(hydroxymethyi) phenyl ester (Formula-1)

5.0 gm of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl ) phenyl-2-bromo-2 -methyl propanoate, ethyl acetate (40 ml) and water (5 ml) were charged into an autoclave at 25-30°C and stirred for 15 min at the same temperature. Sodium acetate (2.5 gm) was added to the reaction mixture at 25-30°C and stirred for 30 min at the same temperature. 10% Pd/C (0.1 gm) was added to the reaction mixture _t at 25-30°C under 3.0-4.0 kg/cm2 of hydrogen gas pressure and stirred for 12 hrs at the same temperature. After the completion of the reaction, filtered the reaction mixture through hyflow bed and washed with ethyl acetate. Water (25 ml) and sodium carbonate (1.5 gm) were added^o the filtrate at 25-30°C and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated and washed the organic layer water. Added activated charcoal (0.25 gm) to the reaction mixture at 25- 30°C and stirred for 30 min at the same temperature. Filtered the reaction mixture through hyflow bed and distilled off the solvent completely under reduced pressure to get the title compound. Yield: 2.0 gm.

Example-50: Preparation of isobutyric acid 2-((R)-3-diisopropylammonium-l- phenylpropyl)-4-(hydroxymethyl) phenyl ester (Formula-1)

Compound of formula-1 can also be prepared from the 2-((R)-3- (diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl)phenyl-3 -bromo-2-methyl propanoate compound of formula-38 by repeating the process as described in example- 49. Yield: 1.5 gm.

Example-51: Preparation of (R)-2-(3-(diisopropylamino)-l-phenyIpropyl)-4- (hydroxylmethyl)phenyl methacrylate (Formula-9).

(R)-2-(3-diisopropyl amino- l-phenylpropyl)-4-hydroxymethyl phenol compound of formula-8 (13 gm) was taken in chloroform (130 ml) and cooled to -45 to -35°C. A solution of methacryloyl chloride (4.6 gm) in chloroform (50 ml) was added to the reaction mixture at -45 to -35°C and stirred for 45 min at the same temperature. After completion of the reaction, water (200 ml) was added to the reaction mixture and stirred for 15 min. Both the organic and aqueous layers were separated and the organic layer was washed with 5% sodium bicarbonate solution followed by water. Distilled off the solvent completely under reduced pressure and then co-distilled with ethyl acetate. Ethyl acetate (40 ml) was added to the obtained residue at 25-30°C and stirred for 15 min at the same temperature. Heated the reaction mixture to 45-50°C and then a solution of L(+)-mandelic acid (7.4 gm) in ethyl acetate (60 ml) at 45-50°C was added to the reaction mixture at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 24 hrs at the same temperature. Filtered the reaction mixture, washed with chilled ethyl acetate. Water (20 ml) was added to the obtained wet material at 25- 30°C. The pH of the reaction mixture was adjusted to 9.5 using 10% sodium carbonate solution. Extracted the solution with dichloromethane and washed with sodium chloride solution. Dried the organic layer and distilled off the solvent under reduced pressure to get the title compound. Yield: 3 gm.

Example-52: Preparation of isobutyric acid 2-((R)-3-diisopropylammonium-l- phenyIpropyl)-4-(hydroxymethyl) phenyl ester fumarate salt (Formula-la)

Isobutyric acid 2-((R)-3-diisopropylammonium-l-phenylpropyl)-4- (hydroxymethyl) phenyl ester compound of formula- 1 (5 gm) was dissolved in methyl ethyl ketone (24 ml). Fumaric acid (2.26 gm) was added to the reaction mixture at 25- 30°C and then heated to 40-45°C and stirred for 1 hr at the same temperature. Cooled the reaction mixture to 20-25°C, seeded with isobutyric acid 2-((R)-3- diisopropylammonium-l-phenylpropyl)-4-(hydroxymethyl) phenyl ester hydrogen fumarate and stirred for 2 hrs at the same temperature. Cyclohexane (44 ml) was drop wise added to the reaction mixture at 20-30°C and stirred for 14 hrs at 25-35°C. Filtered the precipitated compound, washed with cyclohexane and then dried under vacuum at 25-35°C to get the title compound. Yield: 4 gm.

Example-53: Preparation of (R)-2-(3-diisopropylamino-l-phenylpropyI)-4- hydroxymethyl phenol mandelate salt

To 20 gms of 2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxymethyl-phenol added 80 ml of isopropyl alcohol and 9.0 gms of L-(+)-mandelic acid. Heated the reaction mixture 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: 26 gms.