Field of the Invention:

The present invention provides a process for the preparation of muscarinic antagonist receptor namely (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine represented by the structural formula-1 and its pharmaceutically acceptable salts thereof.

Formula-1 The present invention also provides novel intermediate compound for the preparation of (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine compound of formula-1 and its pharmaceutically acceptable salts.

Background of the Invention:

(R)-N,N-diisopropyl-3 -(2-hydroxy-5-methylphenyl)-3 -phenyl propanamine is commonly known as tolterodine. It is useful for treating urinary incontinence and other symptoms of bladder over activity. It is commercially available in products sold under the brand name DETROL™, containing tolterodine tartrate as the active ingredient. The major active metabolite of (R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenyl propanamine contributes significantly to the therapeutic effect of tolterodine. Tolterodine and analogues thereof, including the corresponding (S)-enantiomer, as well as processes for the preparation thereof are disclosed in US 5,382,600.

US 5,382,600 discloses a process for the preparation of (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine and its pharmaceutically acceptable salts along with pharmaceutical composition. The disclosed process involves the reaction of 6-methyl-4-phenyl-chroman-2-one with methyl iodide and potassium carbonate in refluxing acetone/methanol to give methyl 3-(2-methoxy-5-methylphenyl)-3-phenyl propionate. The ester thus obtained is reduced with lithium aluminum hydride to the corresponding propanol, which is reacted with tosyl chloride in presence of pyridine to yield the tosylate, which on condensation with diisopropylamine in hot acetonitrile is converted into the tertiary amine compound. The obtained tertiary amine compound is treated with boron tribromide in dichloromethane to give racemic tolterodine, which is resolved with L-(+) tartaric acid.

Long reaction time and low overall yields makes this process very expensive and less productive. Furthermore, the use of expensive and hazardous reagents like methyl iodide, lithium aluminum hydride and boron tribromide also renders this process unsuitable and hazardous on commercial scale.

US 5,922,914 provides an alternate method for the preparation of (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine tartrate. The process involves the cyclization of trans-cinnamic acid with p-cresol in hot sulfuric acid to give 6-methyl-4-phenyl-chroman-2-one, which is reduced with diisobutyl aluminium hydride (DIBAL) in toluene to yield 6-methyl-4-phenyl-chroman-2-ol. This on reducto-condensation with diisopropylamine, by means of hydrogen over palladium on charcoal in methanol, affords racemic tolterodine, which is resolved with L-(+)-tartaric acid.

This process is also not commercially feasible since it makes use of an expensive and hazardous reagent DIBAL. Although the number of steps are reduced, the cost incurred to produce tolterodine is high.

US 6,822,119 provides another method for the preparation of (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine. The process involves reacting 6-methyl-4-phenyl-chroman-2-one with dimethyl sulfate in the presence of sodium hydroxide, and a phase transfer catalyst to obtain methyl 3-(2-methoxy-5-methylphenyl)-3-phenyl propionate. Reducing the ester thus obtained with a reducing agent in the presence of a Lewis acid to obtain 3-(2-methoxy-5-methylphenyl)-3-phenyl propanol. Protecting the hydroxy group of the alcohol followed by aminating with diisopropylamine to give N,N-diisopropyl-3-(2-methoxy-5-methylphenyl)-3-phenyl propylamine and removing the hydroxy protecting group to obtain N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine.

This process involves a large number of steps and isolation of intermediates at each step, leading to poor yields.

US 7,355,077 B2 describes another process for the preparation of (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine. The disclosed process involves the reaction of 6-methyl-4-phenyl-chroman-2-one with benzyl bromide and potassium carbonate in acetone/methanol to give methyl 3-(2-benzyloxy-5-methylphenyl)-3-phenyl propionate, which is reduced with vitride to give 3-(2-benzyloxy-5-methylphenyi)-3-phenyl propanol. The propanol compound thus obtained upon treatment with alkyl or aryl
sulphonyl halide in presence of a base produces protected hydroxy compound, which is then treated with diisopropylamine followed by debenzylation produces N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine hydrochloride. The hydrochloride salt upon treating with a base followed by resolution with L(+)-tartaric acid provides (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine tartrate.

US 7,538,249 B2 patent describes process for the preparation of (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine, which involves the reduction of 6-methyl-4-phenyl-chroman-2-one with sodium borohydride to give 2-(3-hydroxy-1-phenylpropyl)-4-methyl phenol, which upon treating with anhydrous potassium carbonate and benzyl chloride provides 3-(2-benzyloxy-5-methylphenyl)-3-phenyl propanol. This compound upon treating with aryl sulfonyl halide in presence of a base followed by treating with diisopropylamine produces [3-(2-benzyloxy-5-methylphenyl)-3-phenylpropyl] diisopropylamine. The amino compound upon debenzylation followed by treating with a base provides racemic tolterodine, which upon resolution with L(+)-tartaric acid provides (R)-N,N-diisopropyl-3 -(2-hydroxy-5-methylphenyl)-3 -phenyl propanamine tartrate.

Brief Description of the Invention:

The first aspect of the present invention is to provide a process for the preparation of (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine tartrate compound of formula-la, comprising of;

a) Reacting the trans-cinnamic acid compound of formula-2 with p-cresol compound of formula-3 in presence of sulfuric acid to provide 6-methyl-4-phenyl-chroman-2-one compound of formula-4,

b) reacting the compound of formula-4 with p-chloro benzylbromide in presence of a suitable base in a suitable solvent to provide methyl 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propionate compound of formula-5,

c) reducing the compound of formula-5 with a suitable reducing agent in a suitable solvent to provide 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propanol compound of formula-6,

d) reacting the compound of formula-6 in-situ with alkyl or arylsulfonyl halide in presence of a suitable base in a suitable solvent to provide compound of general formula-7,

e) aminating the compound of general formula-7 in-situ with diisopropylamine in a suitable solvent to provide N,N-diisopropyl-3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propanamine compound of formula-8,

f) debenzylating the compound of formula-8 in-situ with a suitable debenzylating agent in a suitable solvent followed by treating with hydrochloric acid to provide N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine hydrochloride compound of formula-9,

g) reacting the compound of formula-9 with L(+)-tartaric acid in presence of a suitable base in a suitable solvent to provide (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine tartrate compound of formula-la,

h) optionally purifying the compound of formula-la from a suitable solvent or mixture of solvents to provide pure compound of formula-la.

The second aspect of the present invention is to provide a process for the preparation of (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine tartrate compound of formula-la, comprising of;

a) Reacting the trans-cinnamic acid compound of formula-2 with p-cresol compound of formula-3 in presence of sulfuric acid to provide 6-methyl-4-phenyl-chroman-2-one compound of formula-4,

b) reacting the compound of formula-4 with p-chloro benzylbromide in presence of a suitable base in a suitable solvent to provide methyl 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propionate compound of formula-5,

c) reducing the compound of formula-5 with a suitable reducing agent in a suitable solvent to provide 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propanol compound of formula-6,

d) reacting the compound of formula-6 in-situ with p-toluene sulfonyl chloride in presence of a suitable base in a suitable solvent to provide 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenylpropyl-4-rnethyl benzenesulfonate compound of formula-7c,

e) aminating the compound of formula-7c with diisopropylamine in a suitable solvent to provide N,N-diisopropyl-3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propanamine compound of formula-8,

f) debenzylating the compound of formula-8 with a suitable debenzylating agent in a suitable solvent followed by treating with hydrochloric acid to provide N,N-diisopropyl- 3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine hydrochloride compound of formula-9, g) reacting the compound of formula-9 with L(+)-tartaric acid in presence of a suitable base in a suitable solvent to provide (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3- phenyl propanamine tartrate compound of formula-la, h) optionally purifying the compound of formula-la from a suitable solvent or mixture of solvents to provide pure compound of formula-la.

The third aspect of the present invention is to provide a process for the preparation of methyl 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propionate compound of formula-5, comprising of reacting the 6-methyl-4-phenyl-chroman-2-one compound of formula-4 with p-chloro benzylbromide in presence of a suitable base in a suitable solvent.

The fourth aspect of the present invention is to provide a process for the preparation of 3-(2-(4-chlorobenzyloxy)-5-methyIphenyl)-3-phenyl propanol compound of formula-6 comprising of reducing the methyl 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propionate compound of formula-5 with a suitable reducing agent in a suitable solvent.

The fifth aspect of the present invention is to provide a novel intermediate compound for the preparation of (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine tartrate compound of formula-la.

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 iso-butanol; "chloro solvents" like methylene chloride, chloroform and ethylene dichloride; "nitrile solvents" like acetonitrile and propionitrile; "polar solvents" like water; and/or 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, diisopropylamine, diisopropylethylamine, N-methyl morpholine, piperidine, pyridine and their mixtures thereof.

The first aspect of the present invention provides a process for the preparation of (R)-N,N-diisopropyl-3 -(2-hydroxy-5-methylphenyl)-3 -phenyl propanamine tartrate compound of formula-la, comprising of the following steps; a) Reacting the trans-cinnamic acid compound of formula-2 Formula-2 with p-cresol compound of formula-3 Formula-3 in presence of sulfuric acid provides 6-methyl-4-phenyl-chroman-2-one compound of formula-4, Formula-4 b) reacting the compound of formula-4 with p-chlorobenzyl bromide in presence of a suitable base in a suitable solvent provides methyl 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propionate compound of formula-5, Formula-5 c) reducing the compound of formula-5 with a suitable reducing agent in a suitable solvent provides 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propanol compound of formula-6, Formula-6 d) reacting the compound of formula-6 in-situ with alkyl or aryl sulfonyl halide in presence of a suitable base in a suitable solvent provides compound of general formula-7, Formula-7 wherein, X is a leaving group selected from alkyl or aryl sulfonyloxy group, e) animating the compound of general formula-7 in-situ with diisopropylamine in a suitable solvent provides N,N-diisopropyl-3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propanamine compound of formula-8, Formula-8

f) debenzylating the compound of formula-8 in-situ with a suitable debenzylating agent in a suitable solvent followed by treating with hydrochloric acid provides N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine hydrochloride of formula-9,

Formula-9 g) reacting the compound of formula-9 with L(+)-tartaric acid in presence of a suitable base in a suitable solvent provides (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine tartrate compound of formula-la,

Formula-la h) optionally purifying the compound of formula-la from a suitable solvent or mixture of solvents provides pure compound of formula-la.

Wherein, in step-b) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and organic bases; the suitable solvent is selected from alcoholic solvents, ketone solvents, ether solvents, hydrocarbon solvents, ester solvents and/or their mixtures thereof;

In step-c) the suitable reducing agent is selected from vitride, L1AIH4, NaBtU, DIBAL, L-selectride and the like; and the suitable solvent is selected from hydrocarbon solvents, alcoholic solvents, ether solvents, ester solvents, ketone solvents and/or their mixtures thereof.

In step-d) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and organic bases; and the suitable solvent is selected from chloro solvents, hydrocarbon solvents, ester solvents, alcoholic solvents, ketone solvents, ether solvents, nitrile solvents and/or their mixtures thereof; and the suitable alkyl sulfonyl halide is methane sulfonyl chloride and the suitable aryl sulfonyl halide is selected from benzene sulfonyl chloride and toluene sulfonyl chloride.

In step-e) the suitable solvent is selected from hydrocarbon solvents, ester solvents, alcoholic solvents, ketone solvents, ether solvents, chloro solvents, nitrile solvents and/or their mixtures thereof.

In step-f) the suitable debenzylating agent is selected from Raney Ni, Pd/C, Pt, Ir, Ru Rh/C and the like in combination with hydrogen; and the suitable solvent is selected from alcoholic solvents, hydrocarbon solvents, polar solvents, chloro solvents, ester solvents, ether solvents, ketone solvents and/or their mixtures thereof.

In step-g) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates, organic bases; the suitable solvent is selected from ketone solvents, alcoholic solvents, chloro solvents, hydrocarbon solvents, ester solvents, ether solvents, nitrile solvents and/or their mixtures thereof.

In step-h) the suitable solvent can be selected from alcoholic solvents, ketone solvents, nitrile solvents and/or their mixtures thereof.

A preferred embodiment of the present invention provides a process for the preparation of (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine tartrate compound of formula-la, comprising of the following steps;

a) Reacting the trans-cinnamic acid compound of formula-2 with p-cresol compound of formula-3 in presence of sulfuric acid to provide 6-methyl-4-phenyl-chroman-2-one compound of formula-4,

b) reacting the compound of formula-4 with p-chlorobenzyl bromide in presence of potassium carbonate in a mixture of acetone and methanol to provide methyl 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propionate compound of formula-5,

c) reducing the compound of formula-5 with vitride in toluene to provide 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propanol compound of formula-6,

d) reacting the compound of formula-6 in-situ with p-toluene sulfonyl chloride in presence of triethylamine in dichloromethane to provide 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenylpropyl-4-methyl benzenesulfonate compound of formula-7c,

Formula-7c

e) aminating the compound of formula-7c in-situ with diisopropylamine in acetonitrile to provide N,N-diisopropyl-3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propanamine compound of formula-8,

f) debenzylating the compound of formula-8 in-situ with Raney Ni in a mixture of methanol and water followed by treating with hydrochloric acid to provide N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine hydrochloride compound of formula-9,

g) reacting the compound of formula-9 with L(+)-tartaric acid in presence of sodium hydroxide in a mixture of acetone and methanol to provide (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine tartrate compound of formula-la,

h) purifying the compound of formula-la by recrystallizing it from methanol to provide pure compound of formula-la.

The second aspect of the present invention provides a process for the preparation of (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine tartrate compound of formula-la, comprising of the following steps;

a) Reacting the trans-cinnamic acid compound of formula-2 with p-cresol compound of formula-3 in presence of sulfuric acid provides 6-methyl-4-phenyl-chroman-2-one compound of formula-4,

b) reacting the compound of formula-4 with p-chloro benzylbromide in presence of potassium carbonate in a mixture of acetone and methanol provides methyl 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propionate compound of formula-5,

c) reducing the compound of formula-5 with vitride in toluene provides 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propanol compound of formula-6,

d) reacting the compound of formula-6 in-situ with p-toluene sulfonyl chloride in presence of triethylamine in dichloromethane provides 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenylpropyl-4-methyl benzenesulfonate compound of formula-7c,

e) aminating the compound of formula-7c with diisopropylamine in acetonitrile provides N,N-diisopropyl-3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propanamine compound of formula-8,

f) debenzylating the compound of formula-8 with Raney Ni in a mixture of methanol and water followed by treating with hydrochloric acid provides N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine hydrochloride of formula-9,

g) reacting the compound of formula-9 with L(+)-tartaric acid in presence of sodium hydroxide in a mixture of acetone and methanol provides (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine tartrate compound of formula-la,

h) purifying the compound of formula-la by recrystallizing it from methanol to provide pure compound of formula-1 a.

The third aspect of the present invention provides a process for the preparation of methyl 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propionate compound of formula-5, comprising of reacting the 6-methyl-4-phenyl-chroman-2-one compound of formula-4 with p-chloro benzylbromide in presence of a suitable base selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and organic bases in a suitable solvent selected from alcoholic solvents, ketone solvents, ether solvents, hydrocarbon solvents, ester solvents and/or their mixtures thereof.

A preferred embodiment of the present invention provides a process for the preparation of methyl 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propionate compound of formula-5, comprising of reacting the 6-methyl-4-phenyl-chroman-2-one compound of formula-4 with p-chloro benzylbromide in presence of potassium carbonate in a mixture of acetone and methanol.

The fourth aspect of the present invention provides a process for the preparation of 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propanol compound of formula-6 comprising of reducing the methyl 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propionate compound of formula-5 with a suitable reducing agent selected from vitride, LiAlH4, NaBH4, DIBAL, L-selectride and the like in a suitable solvent selected from alcoholic solvents, ether solvents, hydrocarbon solvents, ester solvents, ketone solvents and/or their mixtures thereof.

A preferred embodiment of the present invention provides a process for the preparation of 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propanol compound of formula-6 comprising of reducing the methyl 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propionate compound of formula-5 with vitride in toluene.

The fifth aspect of the present invention provides a novel compound of formula-5, which is an useful intermediate in the synthesis of (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine tartrate compound of formula-la.

Formula-5 The present invention is schematically represented as follows. Synthetic scheme:

The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.

Examples:

Example-1: Preparation of 6-methyl-4-phenyl-chroman-2-one (Formula-4)

A mixture of trans-cinnamic acid (100 gm), p-cresol (80 gm) and conc. sulfuric acid (14 ml) was heated to 120-125°C and stirred for 10 hrs at the same temperature. After the completion of the reaction, cooled the reaction mixture to 25-35°C, toluene (400 ml) was added and stirred for 20 min at the same temperature. Separated the acid layer from the reaction mixture and water (1000 ml) was added to the organic layer at 25-35°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated, toluene (100 ml) was added to the aqueous layer and stirred for 15 min. Both the organic and aqueous layers were separated and the combined organic layer was washed with sodium carbonate solution followed by water. Distilled off the solvent from the organic layer, isopropyl alcohol (400 ml) was added at 50-60°C and stirred for 45 min at the same temperature. Cooled the reaction mixture to 0-5 °C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid, washed with chilled isopropyl alcohol and dried to get the title compound. Yield: 135.0 gm.

Example-2: Preparation of methyl 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propionate (Formula-5)

A solution of 6-methyl-4-phenyl-chroman-2-one (100 gm), acetone (300 ml), potassium carbonate (76 gm), methanol (300 ml) and p-chloro benzylbromide (95 gm) was stirred for 15 min at 25-35°C. Heated the reaction mixture to reflux and stirred for 4 hrs at the same temperature. After the completion of the reaction, distilled off the solvent completely from the reaction mixture under reduced pressure. Water (1000 ml) and toluene (500 ml) were added to the obtained residue and stirred for 15 min. Both the organic and aqueous layers were separated and the aqueous layer was extracted with toluene. The combined organic layer was washed with water. Distilled off the solvent completely from the organic layer under reduced pressure and methanol (300 ml) was added to the obtained residue at 50-60°C. Cooled the reaction mixture to 0-5°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get the title compound. Yield: 130.0 gm.

Example-3: Preparation of 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propanol (Formula-6)

A solution of methyl 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propionate (100 gm) in toluene (400 ml) was stirred for 15 min at 25-35°C. Vitride (110 gm) was slowly added to the reaction mixture at below 40°C and stirred for 30 min at the same temperature. After the completion of the reaction, aq.hydrochloric acid was added to the reaction mixture at 10-15°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with toluene. The combined organic layer was washed with water followed by sodium carbonate solution. Distilled off the solvent completely from the organic layer under reduced pressure and the product was obtained as a residue.

Example-4: Preparation of 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenylpropyl-4-methyl benzenesulfonate (Formula-7c)

Triethylamine (92 gm) and dichloromethane (240 ml) were added to the residue obtained in example-3 at 25-35°C. A solution of p-toluene sulfonyl chloride (50.5 gm) in dichloromethane (160 ml) was added to the reaction mixture at 25-35°C and stirred for 8 hrs at the same temperature. After the completion of the reaction, hydrochloric acid (40 ml) and water (360 ml) were added to the reaction mixture at 25-35°C and stirred for 20 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 at atmosphere pressure and the product was obtained as a residue.

Example-5: Preparation of N, N-diisopropyl-3-(2-(4-chlorobenzyloxy)-5-methyIphenyl)-3-phenyl propanamine (Formula-8)

Acetonitrile (590 ml) was added to the residue obtained in example-4 at 25-35°C. Diisopropylamine (160 ml) was added to the obtained solution at 25-35°C in an autoclave vessel. Heated the reaction mixture to 110-115°C and stirred for 10 hrs under 2-3 kg/cm2 of pressure. After the completion of the reaction, cooled the reaction mixture to 25-35°C and the solvent was completely distilled off under reduced pressure. Toluene (590 ml) was added to the obtained residue at 40-50°C and cooled the reaction mixture to 25-35°C. Water (360 ml) and hydrochloric acid (12 ml) were added 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 sodium hydroxide solution followed by water. Distilled off the solvent completely from the organic layer under reduced pressure and the product was obtained as a residue.

Example-6: Preparation of N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine hydrochloride (Formula-9)

Methanol (390 ml) was added to the residue obtained in example-5, heated the reaction mixture to 40-45°C and stirred for 20 min at the same temperature. Raney Ni (11.5 ml) and water (35 ml) were added to the reaction mixture in an autoclave vessel at 25-35°C and stirred for 10 hrs under 5.0-5.5 kg of hydrogen gas pressure. After the completion of the reaction, filtered the reaction mixture through hyflow bed and washed the filtrate with methanol. Distilled off the solvent completely from the filtrate, ethyl acetate (390 ml) was added at 25-35°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated, distilled off ethyl acetate completely from the organic layer under reduced pressure. Ethyl acetate (325 ml) was added to the obtained compound and cooled the reaction mixture to 10-15°C. Adjusted the pH of the reaction mixture to 1.0 using aq.hydrochloric acid at 25-35°C and stirred for 15 min at the same temperature. Cooled the reaction mixture to 10-15°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound. Yield: 11.0 gm.

Example-7: Preparation of Preparation of N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine hydrochloride (Formula-9)

Vitride (110 gm) was slowly added to a solution of methyl 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propionate (100 gm) in toluene (400 ml) at below 40°C and stirred for 30 min at the same temperature. After the completion of the reaction, hydrochloric acid (200 ml) in water (200 ml) was added to the reaction mixture at 10-15°C. Both the organic and aqueous layers were separated and extracted the aqueous layer with toluene. The combined organic layer was washed with water followed by sodium carbonate solution and distilled off the solvent completely under reduced pressure. Triethylamine (92 gm) and dichloromethane (240 ml) were added to the obtained residue at 25-3 5°C and stirred for 15 min. A solution of p-toluene sulfonyl chloride (51 gm) in dichloromethane (160 ml) was added to the reaction mixture at 25-35°C and stirred for 8 hrs at the same temperature. After the completion of the reaction, hydrochloric acid (40 ml) and water (360 ml) were added to the reaction mixture at 25-35°C and stirred for 20 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 at atmosphere pressure and acetonitrile (590 ml) followed by diisopropylamine (160 ml) were added to the obtained residue at 25-35°C in an autoclave vessel. Heated the reaction mixture to 110-115°C and stirred for 10 hrs under 2-3 kg/cm2 of pressure at the same temperature. After the completion of the reaction, cooled the reaction mixture to 25-35°C and distilled off the solvent completely under reduced pressure. Toluene (590 ml) followed by aq.hydrochloric acid (12 ml) were added 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 sodium hydroxide solution followed by water. Distilled off the solvent completely from the organic layer under reduced pressure and methanol (390 ml) was added to the obtained residue at 25-35°C. Heated the reaction mixture to 40-45°C and stirred for 20 min at the same temperature. Raney Ni (11.5 ml) and water (35 ml) were added to the reaction mixture in an autoclave vessel at 25-35°C and stirred for 10 hrs under 5.0-5.5 kg of hydrogen gas pressure. After the completion of the reaction, filtered the reaction mixture through hyflow bed and washed with methanol. Distilled off the solvent completely from the filtrate, ethyl acetate (390 ml) was added to the obtained compound at 25-35°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated, distilled off ethyl acetate completely from the organic layer under reduced pressure. Ethyl acetate (325 ml) was added to the obtained compound and cooled the reaction mixture to 10-15°C. Adjusted the pH of the reaction mixture to 1.0 using aq.hydrochloric acid at 25-35°C and stirred for 15 min at the same temperature. Cooled the reaction mixture to 10-15°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound. Yield: 11.5gm.

Example-8: Preparation of (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine tartrate (Formula-la)

A solution of N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine hydrochloride (10 gm) in water (25 ml) and dichloromethane (30 ml) was stirred for 20 min at 25-35°C. Adjusted the pH of the reaction mixture to 12.0 using aq.sodium hydroxide solution at 20-30°C and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated, washed the organic layer with water and distilled off the solvent completely from the organic layer under reduced pressure. Acetone (10 ml) was added to the obtained residue at 35-45°C, stirred the reaction mixture for 15 min and the solvent was distilled off completely under reduced pressure. Acetone (40 ml) was added to the obtained residue at 25-35°C and the reaction mixture was stirred for 20 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed with acetone. A solution of L(+)-tartaric acid (4.2 gm) in methanol (35 ml) was added to the filtrate at 25-35°C and stirred for 45 min at the same temperature. Heated the reaction mixture to 50-55°C, stirred for 2 hrs and then cooled to 35-40°C. Filtered the precipitated solid, washed with acetone and dried to get the title compound. Yield: 5.0 gm.

Example-9: Purification of (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine tartrate (Formula-la)

(R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine tartrate (10 gm) and methanol (60 ml) were charged into a clean and dry RBF at 25-35°C and stirred the reaction mixture for 10 min at the same temperature. Heated the reaction mixture to reflux and stirred for 2 hrs at the same temperature. Cooled the reaction mixture to 5-10°C and stirred for 3 hrs at the same temperature. Filtered the precipitated solid, washed with chilled methanol and dried to get the pure title compound. Yield: 8.5 gm.

We Claim:

1. A process for the preparation of (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine tartrate compound of formula-la, comprising of the following steps; a) Reacting the trans-cinnamic acid compound of formula-2

Formula-2 with p-cresol compound of formula-3

Formula-3 in presence of sulfuric acid to provide 6-methyl-4-phenyl-chroman-2-one compound offormula-4,

Formula-4 b) reacting the compound of formula-4 with p-chlorobenzyl bromide in presence of a suitable base in a suitable solvent to provide methyl 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propionate compound of formula-5, Formula-5

c) reducing the compound of formula-5 with a suitable reducing agent in a suitable solvent to provide 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propanol compound of formula-6,

Formula-6 d) reacting the compound of formula-6 in-situ with alkyl or aryl sulfonyl halide in presence of a suitable base in a suitable solvent to provide compound of general formula-7,

Formula-7 wherein, X is a leaving group selected from alkyl or aryl sulfonyloxy group, e) aminating the compound of general formula-7 in-situ with diisopropylamine in a suitable solvent to provide N,N-diisopropyl-3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propanamine compound of formula-8,
Formula-8 f) reacting the compound of formula-8 in-situ with a suitable debenzylating agent in a suitable solvent followed by treating with hydrochloric acid to provide N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine hydrochloride compound of formula-9,

Formula-9 g) reacting the compound of formula-9 with L(+)-tartaric acid in presence of a suitable base in a suitable solvent to provide (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine tartrate compound of formula-la,

Formula-la h) optionally purifying the compound of formula-la from a suitable solvent or mixture of solvents to provide pure compound of formula-1 a.

2. A process according to claim 1, wherein,

in step-b) the suitable base is selected from hydroxides, alkoxides, carbonates and bicarbonates of alkali metals and organic bases; the suitable solvent is selected from alcoholic solvents, ketone solvents, ether solvents and/or their mixtures thereof;

in step-c) the suitable reducing agent can be vitride, UAIH4, NaBHU, diisobutylaluminium hydride (DIBAL), L-selectride and the like; the suitable solvent is selected from hydrocarbon solvents, alcoholic solvents, ether solvents, ester solvents, ketone solvents and/or their mixtures thereof;

in step-d) the suitable solvent is selected from chloro solvents, hydrocarbon solvents, ester solvents, alcoholic solvents, ketone solvents, ether solvents, nitrile solvents and/or their mixtures thereof; the suitable base is selected from hydroxides, alkoxides, carbonates, bicarbonates of alkali metals and organic bases; the suitable alkyl sulfonyl halide is methane sulfonyl chloride and the suitable aryl sulfonyl halide is benzene sulfonyl chloride or toluene sulfonyl chloride;

in step-e) the suitable solvent is selected from nitrile solvents, hydrocarbon solvents, ester solvents, alcoholic solvents, ketone solvents, ether solvents and/or their mixtures thereof;

in step-f) the suitable debenzylating agent is selected from Raney Ni, Pd, Pt and the like in combination with hydrogen; and the suitable solvent is selected from alcoholic solvents, hydrocarbon solvents polar solvents, chloro solvents, ester solvents, ketone solvents and/or their mixtures thereof;

in step-g) the suitable base is selected from hydroxides, alkoxides, carbonates and bicarbonates of alkali metals, organic bases; and the suitable solvent is selected from ketone solvents, alcoholic solvents, chloro solvents, hydrocarbon solvents, ester solvents, ether solvents, nitrile solvents and/or their mixtures thereof.

in step-h) the suitable solvent can be selected from alcoholic solvents, ketone solvents, nitrile solvents and/or their mixtures thereof.

3. A process for the preparation of (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine tartrate compound of formula-la, comprising of;

a) Reacting the trans-cinnamic acid compound of formula-2 with p-cresol compound of formula-3 in presence of sulfuric acid to provide 6-methyl-4-phenyl-chroman-2-one compound of formula-4,

b) reacting the compound of formula-4 with p-chlorobenzyl bromide in presence of potassium carbonate in a mixture of acetone and methanol to provide methyl 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propionate compound of formula-5,

c) reducing the compound of formula-5 with vitride in toluene to provide 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propanol compound of formula-6,

d) reacting the compound of formula-6 in-situ with p-toluene sulfonyl chloride in presence of triethylamine in dichloromethane to provide 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenylpropyl-4-methyl benzenesulfonate compound of formula-7c, Formula-7c

e) aminating the compound of formula-7c in-situ with diisopropylamine in acetonitrile to provide N,N-diisopropyl-3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propanamine compound of formula-8,

f) reacting the compound of formula-8 in-situ with Raney Ni in a mixture of methanol and water followed by treating with hydrochloric acid to provide N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3 -phenyl propanamine hydrochloride compound of formula-9,

g) reacting the compound of formula-9 with L(+)-tartaric acid in presence of sodium hydroxide in a mixture of acetone and methanol to provide (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3 -phenyl propanamine tartrate compound of formula-la,

h) purifying the compound of formula-la by recrystallizing it from methanol to provide pure compound of formula-la.

4. A process for the preparation of (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine tartrate compound of formula-la, comprising of;

a) Reacting the trans-cinnamic acid compound of formula-2 with p-cresol compound of formula-3 in presence of sulfuric acid to provide 6-methyl-4-phenyl-chroman-2-one compound of formula-4,

b) reacting the compound of formula-4 with p-chloro benzylbromide in presence of potassium carbonate in a mixture of acetone and methanol to provide methyl 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propionate compound of formula-5,

c) reducing the compound of formula-5 with vitride in toluene to provide 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propanol compound of formula-6,

d) reacting the compound of formula-6 in-situ with p-toluene sulfonyl chloride in presence of triethylamine in dichloromethane to provide 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenylpropyl-4-methyl benzenesulfonate compound of formula-7c,

e) aminating the compound of formula-7c with diisopropylamine in acetonitrile to provide N,N-diisopropyl-3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propanamine compound of formula-8,

f) reacting the compound of formula-8 with Raney Ni in a mixture of methanol and water followed by treating with hydrochloric acid to provide N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine hydrochloride compound of formula-9,

g) reacting the compound of formula-9 with L(+)-tartaric acid in presence of sodium hydroxide in a mixture of acetone and methanol to provide (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine tartrate compound of formula-la,

h) purifying the compound of formula-la by recrystallizing it from methanol to provide pure compound of formula-la.

5. A process for the preparation of methyl 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propionate compound of formula-5, comprising of reacting the 6-methyl-4-phenyl-chroman-2-one compound of formula-4 with p-chloro benzylbromide in presence of a suitable base selected from hydroxides, alkoxides, carbonates and bicarbonates of alkali metals and organic bases in a suitable solvent selected from alcoholic solvents, ketone solvents, ether solvents, hydrocarbon solvents, ester solvents and/or their mixtures thereof.

6. A process for the preparation of methyl 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propionate compound of formula-5, comprising of reacting the 6-methyl-4-phenyl-chroman-2-one compound of formula-4 with p-chloro benzylbromide in presence of potassium carbonate in a mixture of acetone and methanol.

7. A process for the preparation of 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propanol compound of formula-6, comprising of reducing the methyl 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propionate compound of formula-5 with a suitable reducing agent selected from vitride, LiAlH4, NaBELj, DIBAL and L-selectride in a suitable solvent selected from alcoholic solvents, hydrocarbon solvents, ether solvents, ester solvents, ketone solvents and/or their mixtures thereof.

8. A process for the preparation of 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propanol compound of formula-6, comprising of reducing the methyl 3-(2-(4-chlorobenzyloxy)-5-methylphenyI)-3-phenyl propionate compound of formula-5 with vitride in toluene.

9. Diaryl compound having the following structural formula;

10. Use of methyl 3-(2-(4-chlorobenzyloxy)-5-methylphenyl)-3-phenyl propionate in the synthesis of (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propanamine and its pharmaceutically acceptable salts.