Field of the Invention:

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

Number of synthetic approach for the production of the active metabolite and monoesters of the phenolic hydroxy group of the active metabolite such as Fesoterodine has been disclosed in the literatures such as US 6,713,464, US 6,858,650, US 2006/0270738 and WO 2007/138440 Al.

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 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 an improved process for the preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl) phenol compound of formula-7 which comprises of the following steps:

a) Reacting the 2-oxo-4-phenylchroman-6-carboxylic acid compound of formula-2 with R-1-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-12,

b) reducing the compound of formula-12 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-13,

c) debenzylating the compound of formula-13 with a suitable debenzylating agent in a suitable solvent provides (R)-2-(3-amino-l-phenylpropyl)-4-(hydroxyl methyl) phenol compound of formula-14,

d) reacting the compound of formula-14 with isopropyl chloride in presence of a suitable base in a suitable solvent provides the compound of formula-7.

The second 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-7 which comprises of the following steps:

a) Reacting the (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-methylphenol compound of formula-15 with N-bromosuccinamide (NBS) or NCS or NIS in a suitable solvent provides its corresponding (R)-4-(halo-substiruted methyl)-2-(3-(diisopropylamino)-l-phenylpropyl)phenol derivative compound of formula-16,

b) reacting the compound of formula-16 with sodium or potassium acetate in a suitable solvent provides the (R)-3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxybenzylacetate compound of formula-17,

c) hydrolyzing the compound of formula-17 with a suitable base in a suitable solvent provides the compound of formula-7.

The third aspect of the present invention is to provide a novel process for the preparation of (R)-2-(3 -(diisopropylamino)-1 -phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate compound of formula-1 and its pharmaceutically acceptable salt compounds, which comprises of the following steps:

a) Reacting the 4-hydroxybenzoic acid with cinnamic acid in the presence of suitable acid in a suitable solvent provides 2-oxo-4-phenylchroman-6-carboxylic acid compound of formula-2,

b) reducing the compound of formula-2 with a suitable reducing agent in a suitable solvent to provide 2-hydroxy-4-phenylchroman-6-carboxylic acid compound of formula-3,

c) reacting the compound of formula-3 with diisopropylamine followed by treating with a suitable reducing agent in a suitable solvent provides 3-(3-(diisopropyl amino)-l-phenylpropyl)-4-hydroxybenzoic acid compound of formula-4,

d) esterifying the compound of formula-4 with methanol provides methyl 3-(3-(diisopropylamino)-1 -phenylpropyl)-4-hydroxybenzoate compound of formula-5,

e) reducing the compound of formula-5 with a suitable reducing agent in a suitable solvent provides 2-(3-(diisopropylamino)-1 -phenylpropyl)-4-(hydroxymethyl) phenol compound of formula-6,

f) resolving the compound of formula-6 with a suitable chiral acid in a suitable solvent provides the (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxy methyl) phenol compound of formula-7,

g) reacting the compound of formula-7 with isobutyryl chloride in a suitable solvent provides (R)-2-(3-(diisopropylamino)-1 -phenylpropyl)-4-(hydroxylmethyl) phenyl isobutyrate compound of formula-1.

The fourth 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-7 which comprises of the following steps:

a) Reacting the 2-hydroxy-4-phenylchroman-6-carboxylic acid compound of formula-3 with diisopropylamine followed by treating with a suitable reducing agent in a suitable solvent provides 3-(3-(diisopropylamino)-l-phenylpropyl)-4- hydroxy benzoic acid compound of formula-4,

b) resolving the compound of formula-4 with R-1-phenylethylamine provides (R)-3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxybenzoic acid compound of formula-8,

c) esterifying the compound of formula-8 with methanol provides (R)-methyl 3-(3-(diisopropylamino)-1 -phenylpropyl)-4-hydroxybenzoate compound of formula-9,

d) reducing the compound of formula-9 with a suitable reducing agent in a suitable solvent provides the compound of formula-7.

The fifth 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-7, which comprises of the following steps:

a) Reacting the 2-oxo-4-phenylchroman-6-carboxylic acid compound of formula-2 with diisopropylamine followed by treating with a suitable reducing agent in a suitable solvent provides 3-(3-(diisopropylamino)-3-oxo-l-phenylpropyl)-4-hydroxy benzoic acid compound of formula-10,

b) resolving the compound of formula-10 with a suitable chiral acid in a suitable solvent provides (R)-3-(3-(diisopropylamino)-3-oxo-l-phenylpropyl)-4-hydroxy benzoic acid compound of formula-11,

c) reducing the compound of formula-11 with a suitable reducing agent in a suitable solvent provides the compound of formula-7.

The sixth aspect of the present invention is to provide an improved process for the preparation of 3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxybenzoic acid compound of formula-4 which comprises of the following steps:

a) Reducing the 2-oxo-4-phenylchroman-6-carboxylic acid compound of formula-2 with a suitable reducing agent in a suitable solvent provides 4-hydroxy-3-(3-hydroxy-l-phenylpropyl)benzoic acid compound of formula-18,

b) reacting the compound of formula-18 with a suitable acid in a suitable solvent provides 4-hydroxy-3-(3-substituted-phenylpropyl)benzoic acid compound of formula-19,

c) reacting the compound of formula-19 with diisopropylamine followed by treating with a suitable reducing agent in a suitable solvent provides 3-(3-(diisopropyl amino)- l-phenylpropyl)-4-hydroxybenzoic acid compound of formula-4.

Detailed Description of the Invention:

Unless otherwise specified, as used herein the term "alcoholic solvents" refers to methanol, ethanol, n-propanol, isopropanol, n-butanol and isobutanol; "chloro solvents" refers to methylene chloride, chloroform, ethylene dichloride and carbon tetra chloride; "ketone solvents" refers to acetone, methyl ethyl ketone, methyl isobutyl ketone; "hydrocarbon solvents" refers to toluene, hexane, heptane and cyclohexane; "nitrile solvents" refers to acetonitrile; "ester solvents" refers to ethyl acetate, methyl acetate and isopropyl acetate; "ether solvents" refers to tetrahydrofuran, diethyl ether and methyl tert-butyl ether; "polar solvents" refers to water, "polar aprotic solvents" refers to dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide; and mixtures thereof.

As used herein the term "suitable base" refers to the bases selected from alkali metal hydroxides like sodium hydroxide, potassium hydroxide; alkali metal carbonates like sodium carbonate, potassium carbonate and alkali metal bicarbonates like sodium bicarbonate, potassium bicarbonate; ammonia or their aqueous solution; or the organic bases like methyl amine, ethyl amine, tert-butyl amine, triethyl amine, diisopropyl ethylamine, pyridine.

As used herein the term "chiral acid" refers to 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, (1S)-(+)-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, BF3 etherate/NaBH^borane dimethyl sulfide, Pd/C and the like;

The first aspect of the present invention is to provide an improved process for the preparation of compound of formula-7 which comprises of the following steps:

a) Reacting the 2-oxo-4-phenylchroman-6-carboxylic acid compound of formula-2 with R-1-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-12,

b) reducing the compound of formula-12 with a suitable reducing agent in a suitable solvent provides 4-(hydroxymethyl)-2-((R)-1 -phenyl-3-((R)-1 -phenylethylamino) propyl)phenol compound of formula-13,

c) debenzylating the compound of formula-13 with a suitable debenzylating agent in a suitable solvent provides (R)-2-(3-amino-l-phenylpropyl)-4-(hydroxyl methyl) phenol compound of formula-14,

d) reacting the compound of formula-14 with isopropyl chloride in presence of a suitable base in a suitable solvent provides the compound of formula-7.

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 BF3 etherate/NaBH^ vitride, sodium borohydride, sodium cyanoborohydride, tetraalkyl ammonium borohydride, lithium aluminium hydride, Raney Ni, borane dimethyl sulfide and the like; preferably BF3 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 and pyridine.

In a preferred embodiment of the present invention is to provide an improved process for the preparation of compound of formula-7 which comprises of the following steps:

a) Reacting the 2-oxo-4-phenylchroman-6-carboxylic acid compound of formula-2

with R-1-phenylethylamine in acetone provides the 4-hydroxy-3-((R)-3-oxo-l-phenyl-3-((R)-l-phenylethylamino)propyl)benzoic acid compound of formula-12,

b) reducing the compound of formula-12 with BF3.etherate in tetrahydrofuran provides the 4-(hydroxymethyl)-2-((R)-1 -phenyl-3-((R)-1 -phenylethylamino) propyl)phenol compound of formula-13,

c) debenzylating the compound of formula-13 with Pd/C in methanol provides the (R)-2-(3-amino-l-phenylpropyl)-4-(hydroxymethyl)phenol compound of formula-14,

d) reacting the compound of formula-14 with isopropyl chloride in presence of a suitable potassium carbonate in acetone provides the compound of formula-7.

The second aspect of the present invention is to provide an improved process for the preparation of compound of formula-7 which comprises of the following steps:

a) Reacting the (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-methylphenol compound of formula-15,
OH .f

Formula-15 with N-bromosuccinamide (NBS) or NCS or NIS in a suitable solvent provides the (R)-4-(halo-substitutedmethyl)-2-(3 -(diisopropylamino)-1 -phenylpropyl) phenol compound of formula-16,


b) reacting the compound of formula-16 with sodium or potassium acetate in a suitable solvent provides (R)-3-(3-(diisopropylamino)-l-phenylpropyl)-4- hydroxybenzyl acetate compound of formula-17,

c) hydrolyzing the compound of formula-17 with a suitable base in a suitable solvent provides the compound of formula-7.

In a preferred embodiment of the present invention is to provide an improved process for the preparation of compound of formula-7 which comprises of the following steps:

a) Reacting the (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-methylphenol compound of formula-15 with N-bromosuccinamide (NBS) in chloroform provides (R)-4-(bromomethyl)-2-(3-(diisopropylamino)-l-phenyl propyl) phenol compound of formula-16,

a) reacting the compound of formula-16 with sodium acetate in dimethylformamide provides the (R)-3-(3-(diisopropylamino)-1 -phenylpropyl)-4-hydroxybenzyl acetate compound of formula-17,
b) hydrolyzing the compound of formula-17 with lithium hydroxide in methanol provides the compound of formula-7.

The compound of formula-15 can be prepared according to the process disclosed in the US 5382600 herein incorporated as reference.

The third aspect of the present invention is to provide a novel process for the preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl) phenyl isobutyrate compound of formula-1 and its pharmaceutically acceptable salt compounds, which comprises of the following steps:

a) Reacting the 4-hydroxybenzoic acid with cinnamic acid in the presence of a suitable acid in a suitable solvent provides 2-oxo-4-phenylchroman-6-carboxylic acid compound of formula-2,

b) reducing the compound of formula-2 with a suitable reducing agent in a suitable solvent provides 2-hydroxy-4-phenylchroman-6-carboxylic acid compound of formula-3,

c) reacting the compound of formula-3 with diisopropylamine followed by treating with a suitable reducing agent in a suitable solvent provides 3-(3- (diisopropylamino)-l-phenylpropyl)-4-hydroxybenzoic acid compound of formula-4,


d) esterifying the compound of formula-4 with methanol provides the methyl 3-(3-(diisopropylamino)-1 -phenylpropyl)-4-hydroxybenzoate compound of formula-5,

Formula-5

e) reducing the compound of formula-5 with a suitable reducing agent in a suitable solvent provides 2-(3-(diisopropylamino)-1 -phenylpropyl)-4-(hydroxylmethyl) phenol compound of formula-6,

Formula-6

f) resolving the compound of formula-6 with a suitable chiral acid in a suitable
solvent provides (R)-2-(3 -(diisopropylamino)-1 -phenylpropyl)-4-(hydroxyl
methyl)phenol compound of formula-7,


g) reacting the compound of formula-7 with isobutyryl chloride in a suitable solvent provides (R)-2-(3-(diisopropylamino)-1 -phenylpropyl)-4-(hydroxymethyl) phenyl isobutyrate compound of formula-1.

Fesoterodine compound of formula-1 prepared by the present invention can be further converted into acid addition salts by treating it with a suitable acid in a suitable solvent provides corresponding acid addition salt of fesoterodine.

The fourth aspect of the present invention is to provide an improved process for the preparation of compound of formula-7 which comprises of the following steps:

a) Reacting the 2-hydroxy-4-phenylchroman-6-carboxylic acid compound of formula-3 with diisopropylamine followed by treating with a suitable reducing agent in a suitable solvent provides 3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxy benzoic acid compound of formula-4,

b) resolving the compound of formula-4 with R-1-phenylethylamine provides the (R)-3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxybenzoic acid compound of formula-8,

c) esterifying the compound of formula-8 with suitable alcohol provides (R)-methyl 3 -(3 -(diisopropylamino)-1 -phenylpropyl)-4-hydroxybenzoate compound of formula-9,

d) reducing the compound of formula-9 with a suitable reducing agent in a suitable solvent provides the compound of formula-7.

The fifth aspect of the present invention is to provide an improved process for the preparation of compound of formula-7 which comprises of the following steps:

a) Reacting the 2-oxo-4-phenylchroman-6-carboxylic acid compound of formula-2 with diisopropylamine followed by treating with a suitable reducing agent in a suitable solvent provides the 3-(3-(diisopropylamino)-3-oxo-l-phenylpropyl)-4- hydroxybenzoic acid compound of formula-10,

Formula-10

b) resolving the compound of formula-10 with a suitable chiral acid in a suitable solvent provides (R)-3-(3 -(diisopropylamino)-3 -oxo-1 -phenylpropyl)-4- hydroxybenzoic acid compound of formula-11,

c) reducing the compound of formula-11 with a suitable reducing agent in a suitable solvent provides the compound of formula-7.

The sixth aspect of the present invention is to provide an improved process for the preparation of 3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxy benzoic acid compound of formula-4 which comprises of the following steps:

a) Reducing the 2-oxo-4-phenylchroman-6-carboxylic acid compound of formula-2 with a suitable reducing agent in a suitable solvent provides 4-hydroxy-3-(3- hydroxy-l-phenylpropyl)benzoic acid compound of formula-18,

b) reacting the compound of formula-18 with a suitable acid in a suitable solvent provides the 4-hydroxy-3-(3-substituted-phenylpropyl)benzoic acid compound of formula-19,

Formula-19

Wherein, 'L' is a leaving group selected from Cl, Br, I and tosylate etc.

c) reacting the compound of formula-19 with diisopropylamine followed by treating with a suitable reducing agent in a suitable solvent provides 3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxybenzoic acid compound of formula-4.

The novelty of the present invention emphasizes the improved process, through the formation of novel intermediates to synthesize (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl)phenyl isobutyrate. Though there are several patents and patent applications are available on process for the preparation of said compound.

The following are the novel intermediate compounds of the present invention, which are useful for the preparation of fesoterodine and its pharmaceutically acceptable salts.

The following are the possible impurities which are observed in the preparation of fesoterodine 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-1: Preparation of 2-oxo-4-phenylchroman-6-carboxylic acid compound of formula-2:

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-2 : Preparation of 4-hydroxy-3-((R)-3-oxo-l-phenyl-3-((R)-l-phenylethyl amino)propyl)benzoic acid (formula-12)

To a solution of 2-oxo-4-phenylchroman-6-carboxylic acid compound of formula-2 (25 g ) in acetone (200 ml), R-1-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-3: Preparation of 4-(hydroxymethyl)-2-((R)-l-phenyl-3-((R)-l-phenylethyl amino)propyl)phenol compound of formula-13

To a solution of 4-hydroxy-3-((R)-3-oxo-l-phenyl-3-((R)-l-phenylethyl amino)propyl)benzoic acid compound of formula-12 (25 grams) in THF (250 ml) was cooled to -20°C. 10% BF3_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-4: Preparation of (R)-2-(3-amino-l-phenylpropyl)-4-(hydroxymethyl) phenol (formula-14)
4-(hydroxymethyl)-2-((R)-1 -phenyl-3 -((R)-1 -phenylethylamino)propyl)phenol compound of formula-13 (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/Cm2 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-5: Preparation of (R)-4-(bromomethyl)-2-(3-(diisopropylamino)-l-phenyl propyl) phenol (formula-16)

To a solution of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-methylphenol compound of formula-15 (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-6: Preparation of (R)-3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxy benzyl acetate (formula-17)

Dirnethylformamide (100 ml) was added to ((R)-4-(bromomethyl)-2-(3-(diisopropylamino)-l-phenyl propyl) phenol compound of formula-16 (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-7: Preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl) phenol (formula-7)

To a solution of (R)-3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxybenzyl acetate compound of formula-17 (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-8: Preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl) phenol compound of formula-7

To a solution of (R)-2-(3-amino-l-phenylpropyl)-4-(hydroxymethyl)phenol compound of formula-14 (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-9: Alternative process for preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl)phenol compound of formula-7

The title compound is prepared according to example-1, using dimethylformamide as a solvent instead of acetone at 100-120°C. Yield: 23.22 grams

Example-10: Alternative process for preparation of (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-(hydroxymethyl)phenol compound of formula-7

The title compound is prepared according to example-1, using acetonitrile as a solvent instead of acetone at a temperature of 80-90°C. Yield: 23.00 grams

We Claim:

1. An improved process for the preparation of compound of formula-7 which comprises of the following steps:

a) Reacting the 2-oxo-4-phenylchroman-6-carboxylic acid compound of formula-2 with R-1-phenylethylamine in a suitable solvent provides 4-hydroxy-3-((R)-3-oxo-1 -phenyl-3 -((R)-1 -phenylethylamino)propyl)benzoic acid compound of formula-12,

b) reducing the compound of formula-12 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-13,

c) debenzylating the compound of formula-13 with a suitable debenzylating agent in
a suitable solvent provides (R)-2-(3-amino-l-phenylpropyl)-4-(hydroxyl methyl)
phenol compound of formula-14,


d) reacting the compound of formula-14 with isopropyl chloride in presence of a suitable base in a suitable solvent provides the compound of formula-7.

2. A process according to claim-1, 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 BF3 etherate optionally in presence of NaBH^ vitride, sodium borohydride, sodium cyanoborohydride, tetraalkyl ammonium borohydride, lithium aluminium hydride, Raney Ni, borane dimethyl sulfide and the like; preferably BF3 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 and pyridine.

3. An improved process for the preparation of compound of formula-7 which comprises of the following steps:

a) Reacting the 2-oxo-4-phenylchroman-6-carboxylic acid compound of formula-2 with R-1-phenylethylamine in acetone provides 4-hydroxy-3-((R)-3-oxo-l-phenyl-3-((R)-l-phenylethylamino)propyl)benzoic acid compound of formula-12,

b) reducing the compound of formula-12 with BF3.etherate in tetrahydrofuran provides 4-(hydroxymethyl)-2-((R)-1 -phenyl-3 -((R)-1 -phenylethylamino) propyl) phenol compound of formula-13,

c) debenzylating the compound of formula-13 with Pd/C in methanol provides the (R)-2-(3-amino-l-phenylpropyl)-4-(hydroxymethyl)phenol compound of formula-14,

d) reacting the compound of formula-14 with isopropyl chloride in presence of a suitable potassium carbonate in a suitable acetone provides the compound of formula-7.

4. An improved process for the preparation of compound of formula-7 which comprises of the following steps:

a) Reacting the (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-methylphenol
compound of formula-15, with N-bromosuccinamide (NBS) or N-chlorosuccinimide (NCS) or N-iodosuccinimide (NIS) in a suitable solvent provides the (R)-4-(halo-substituted methyl)-2-(3-(diisopropylamino)-l-phenylpropyl) phenol compound of formula-16,

Wherein, X is halogen

b) reacting the compound of formula-16 with sodium or potassium acetate in a suitable solvent provides (R)-3-(3-(diisopropylamino)-l-phenylpropyl)-4- hydroxybenzyl acetate compound of formula-17,

c) hydrolyzing the compound of formula-17 with a suitable base in a suitable solvent provides the compound of formula-7.

5. A process according to claim-4, wherein, in step-(a) the suitable halogenating agent is selected from N-bromosuccinimide (NBS) or N-chlorosuccinimide (NCS) or N-iodosuccinimide (NIS), preferably N-bromosuccinimide (NBS).

6. A process according to claim-4, wherein, the salt used in step-(b) is sodium or potassium acetate, preferably sodium acetate.

7. The compounds having the following structures:

8. An improved process for the preparation of compound of formula-7 which comprises of the following steps:

a) Reacting the (R)-2-(3-(diisopropylamino)-l-phenylpropyl)-4-methylphenol compound of formula-15 with N-bromosuccinamide (NBS) in chloroform provides the (R)-4-(bromomethyl)-2-(3-(diisopropylamino)-l-phenyl propyl) phenol compound of formula-16,

c) reacting the compound of formula-16 with sodium acetate in dimethylformamide provides the (R)-3-(3-(diisopropylamino)-1 -phenylpropyl)-4-hydroxybenzyl acetate compound of formula-17,

d) reacting the compound of formula-17 with lithium hydroxide in methanol provides the compound of formula-7.

9. An improved process for the preparation of 4-(hydroxymethyl)-2-((R)-l-phenyl-3-((R)-l-phenylethylamino)propyl)phenol compound of formula-13 which comprises of reducing the 4-hydroxy-3-((R)-3-oxo-l-phenyl-3-((R)-l-phenylethylamino) propyl) benzoic acid compound of formula-12 with a suitable reducing agent in a suitable solvent provides the compound of formula-13.

10. An improved process for the preparation of compound of 4-(hydroxymethyl)-2-((R)-l-phenyl-3-((R)-l-phenylethylamino)propyl)phenol compound of formula-13 which comprises of reducing the 4-hydroxy-3-((R)-3-oxo-l-phenyl-3-((R)-l-phenylethyl amino)propyl)benzoic acid compound of formula-12 with BF3.etherate in tetrahydrofuran provides the compound of formula-13.