FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"IMPROVED PROCESS FOR MANUFACTURE OF RACTOPAMINE
HYDROCHLORIDE"
2. APPLICANT:
(a) NAME: ATRA PHARMACEUTICAL LIMITED
(b) NATIONALITY: Indian Company incorporated under the
Companies Act, 1956
(c) ADDRESS: H-19, MIDC, Waluj, Aurangabad 431133, Maharashtra,
India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be formed.

FIELD OF INVENTION:
The present invention relates to an improved, low cost, one pot commercially viable process for the manufacture of highly pure Ractopamine hydrochloride of formula (I) and pharmaceutically acceptable salts thereof, which is unique from the view point of ease of operation, scale-up and reduced processing time.

BACKGROUND AND DESCRIPTION OF PRIOR ART:
Ractopamine HC1, is chemically known as 4-[3-[[2-Hydroxy-2-(4-hydroxyphenyl) ethyl ] amino ] butyl] phenol and represented by the following Formula 1

Ractopamine is an feed additive generally employed for increasing the weight gain and improving the feed utilization and the quality of the carcass in swine, poultry, ruminants and other livestock which are raised for their meat. Pharmacologically, it is a beta-adrenoceptor agonist and has the property of repartitioning (i.e., the capability of altering muscle lean-to-fat ratios), most likely through some combination of stimulation of lypolysis, stimulation of protein synthesis, or down-regulation of lipogenesis. This results in reduction of fat, increased muscle mass, and improved feed utilization efficiency in

swine, cattle, and turkeys. Ractopamine promotes protein deposition with little effect on fat deposition in the pig . Ractopamine introduced through the diet decreases basal plasma insulin concentrations but has no effect on plasma glucose or non-esterified fatty acids.. It is the active ingredient in products known as Paylean for swine and Optaflexx for cattle for use in food animals for growth promotion.
Ractopamine has two chiral centers, and therefore can exist as four isomers. Commercially available ractopamine consist of a mixture of almost equal amount of two diasteriomeric racemates( Ratio RR/SS to RS/SR = 50 : 50 )
Ractopamine and its preparation thereof are first disclosed in US4690951. This patent discloses the process for synthesizing ractopamine and related compounds in two different ways, which are incorporated herein for reference. According to the first process dl-4-hydroxy mandelic acid is condensed with dl-methyphenyl)propylamine in the presence of DCC to yield racemic 1-(4-benzyloxyphenyl)-2-oxo-2-[ l-methyl-3(4-benzyloxyphenyl) propylaminoethanol, which is further deprotected to yield racemic 4-[3-[[2-Hydroxy-2-(4-hydroxyphenyl)ethyl Jamino] butyl] phenol.
Second process involves the reductive amination of methyl-2-(4-hydroxyphenyl) ethyl ketone and l-(4-hydroxyphenyl)-2-aminoethanol in ethanol employing five percent palladium on carbon as a catalyst.
The process disclosed above suffers from several drawbacks such as use of ethanol, incomplete reaction as well as isolation and purification of the product. When the process was carried out as reported in the patent '473 we have found that the reaction does not go to completion, furthermore the isolation results in the formation of dark brown colored sticky mass which was quite cumbersome for further purification. Moreover, we have found that pH is very critical for the reaction, thus when the reaction is conducted under alkaline conditions it results in the formation of impurities which adversely affects the purity and the yield of ractopamine.

Chinese patent CN102070468 (A) discloses a process for synthesizing beta-suprarenal kinetin Ractopamine hydrochloride. The process describes the reaction of 4-hydroxyacetophenone with acyl chloride under alkali condition to obtain 4-acetyl phenyl acetate. This intermediate is brominated to yield benzoic acid (2-bromo-4'-hydoxyacetophenone)benzoic acid methyl ester which is reacted withl-methyl-3(4-hydroxyphenyl) propylamine to provide: benzoic acid[l-methyl-3-(4-hydroxyphenyl)-propylamino]-acetophenone ester. This ester is treated with the mixture of hydrochloric acid and alcohol to obtain hydrolysates; which is subjected to catalytic hydrogenation to obtain the ractopamine hydrochloride.
CN1174830 (A) relates to a method for synthesizing ractopamine hydrochloride by using p-hydroxyacetophenone and raspberry ketone as raw materials. The p-hydroxyacetophenone is processed by catalytic brominating reaction to obtain omega-bromo-p-hydroxyacetophenone. The raspberry ketone is processed by oximation and catalytic hydrogenation to obtain l-methyl-3-(4-hydroxyphenyl)-propylamine. The omega-bromo-p-hydroxyacetophenone and 1 -methyl-3-(4-hydroxyphenyl)-propylamine are added in two-phase system formed from alkaline aqueous solution and ethyl acetate, strenuously stirred and reacted, and the obtained reaction product is acidified by hydrochloric acid to obtain intermediate product hydrochloride of 1-(4-hydrophenyl)-2-GBP l-methyI-3-(4-hydrophenyl)-propyl!-ethylketone, the said intermediate product is further processed by catalytic hydrogenation reduction so as to obtain the ractopamine hydrochloride.
CN1116620 (A) discloses process for synthesizing Ractopamine Hydrochloride as feed additive which includes oximation and catalytic hydrogenation of Fructusrubi ketone to obtain l-methyI-3-(4-hydroxyl phenyl)-propylamine, reacting omega-bromo-p-hydoxylacetophenone, l-methyl-3~(4-hydroxylphenyl)-propylamine with triethylamine in tetrahydrofuran to obtain hydrochloric salt of 1-(4-hydroxylphenyl)-2- l-methyI-3(4-hydroxylphenyl) propylamino"-methylketone, followed by hydrogenation.
To the best of our knowledge no process for the manufacture of ractopamine has been reported employing hydrogenation catalysts like Raney Nickel, Urushibara catalyst etc.

The processes disclosed in the prior art are multi-step and complicated thereby increasing the cost of production. Thus, there remains a need to provide a process for the production of Ractopamine, which is simple, cost effective and industrially viable to give high yields as well as high purity.
OBJECTS OF INVENTION:
The principal object of the present invention is to overcome or ameliorate the disadvantages of the prior art.
Another object of the present embodiment is to provide commercially viable, improved, one pot process for the manufacture of Ractopamine and /or a pharmaceutically acceptable acid addition salts thereof in high yield.
Another object of the present embodiment is to provide an improved process for the manufacture of Ractopamine, wherein the synthesis is accomplished by reductive hydrogenation employing hydrogenation catalyst under moderate reaction conditions to achieve high yields and high purity.
Yet another object of the present embodiment is to provide an improved process for the manufacture of Ractopamine, wherein the synthesis is accomplished by reductive hydrogenation employing precious hydrogenation catalyst under moderate reaction conditions to achieve high yields and high purity.
Yet another object of the present embodiment is to provide an improved process for the manufacture of highly pure Ractopamine wherein the process includes the use of simple pressure reactor such as autoclave, thus rendering the process cost effective.
One another object of the present invention is to provide a process for the manufacture of highly pure Ractopamine, by controlling the formation of impurities.

SUMMARY OF INVENTION:
According to one of the embodiments of the present invention, provides an improved, efficient, one pot process for the manufacture of highly pure Ractopamine hydrochloride of Formula (I) and pharmaceutically acceptable salts thereof

which comprises of;
(a) reacting 4-(2-amino-l-hydroxy-ethyl)phenol Formula (II) with 4-(4-Hydroxyphenyl)butan-2-one Formula (111) dissolved in a solvent in an autoclave, adjusting the pH between 5.5-7.5 using a base

(b) subjecting the reaction mixture to reductive amination under hydrogen pressure in the range of 1.0-45 kg/cm2 in an autoclave, in presence of hydrogenation catalyst at a temperature in the range of 50 -120°C for 3.0 to 30 hours to obtain ractopamine base; and
(c) converting ractopamine to its pharmaceutically acceptable salts.

The reaction is carried out in polar or a mixture of polar and non- polar solvents with or without water. Accordingly, the solvents are selected from a class of organic solvents consisting of C6-10 aromatic hydrocarbons such as benzene, toluene, or xylene, Cl-4 alcohols like methanol, ethanol, propanol, isopropanol, butanol; ketones like acetone, ethylmethyl ketone, polar aprotic solvents like l-methyl-2-pyrrolidinone ( NMP), N,N-Dimethylethylformamide ( DMF), dimethyl acetamide acetonitrile; esters like ethyl acetate, isopropyl acetate, ethers like diethyl ether, diisopropyl ether etc, preferably isopropanol.
The catalyst for the reductive amination is selected from hydrogenation catalyst selected from non-precious hydrogenation catalysts such as Raney nickel, Urushibara, and/or precious hydrogenation catalysts such as Pt, Pd, Ru, Rh etc. loaded on inert support.
In another aspect the process is carried out employing 1.0 to 50 % hydrogenation catalyst loading with respect to the substrate, more preferably 21 % catalyst loading for the non-precious catalyst.
In a preferred embodiment of the present invention the manufacturing process is carried out by employing 0.1 to 40 % precious catalyst loading with respect to the substrate, more preferably 9.1 % catalyst loading for the precious catalyst.
In yet another aspect, the reductive amination is carried out in an autoclave (pressure reactor) under hydrogen pressure of 1.0 to 45 kg/cm2, more preferably 1.0 to 15 Kg/cm2 hydrogen pressure.
In accordance with another aspect of the present invention in the process for the manufacturing of highly pure Ractopamine and /or a pharmaceutically acceptable acid salt thereof, the reductive amination reaction is carried out between 4.5 to 8.5 pH preferably between 5.5 to 7.5 pH.
In accordance with another aspect of the present invention in the process for the manufacturing highly pure ractopamine and /or a pharmaceutically acceptable acid salt thereof the reductive amination reaction is completed in about 3.0 to 30 hrs.

In yet another aspect of the present invention ractopamine base obtained can be directly treated with gaseous or aqueous inorganic acids to obtain pharmaceutically acceptable acid addition salts e.g hydrochloride, hydrosulphate, hydrobromide, nitrates etc; or can be directly treated with organic acids to obtain pharmaceutically acceptable acid addition salts e.g formate, oxalate, succinate, maleate, tartrate etc.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention is described herein after in more details substantiating various embodiments and conditions of reaction for better understanding/appreciation of the invention.
The present invention provides an efficient, improved, one pot process for the manufacture of highly pure Ractopamine and /or its pharmaceutically acceptable acid addition salt under the reaction conditions that is cost effective with improved yields which renders the process commercially viable.
In an embodiment, the present invention relates to an improved, efficient, one pot process for the synthesis of highly pure Ractopamine hydrochloride of Formula - (I)

which comprises,
(a) reacting 4-(2-amino-l-hydroxy-ethyl) phenol Formula (II) with 4-(4-Hydroxy phenyl) butan-2-one Formula - (III) in a solvent in an autoclave, adjusting the pH between 5.5-7.5 using a base;


Formula (III)
(b) subjecting the reaction mixture to reductive animation under hydrogen pressure in the range of 1.0-45 kg/cm2 in an autoclave, in presence of hydrogenation catalyst at a temperature in the range of 50 -120°C for 3.0 to 30 hours to obtain ractopamine base; and
(c) converting ractopamine base to its pharmaceutically acceptable salts.
According to the process, 4-(2-amino-l-hydroxy-ethyl)phenol HC1 is reacted with 4-(4-Hydroxyphenyl)butan-2-one dissolved in solvent in an autoclave to obtain the reaction mixture. The pH of the reaction is adjusted between 5.5 to 7.5 with the base. This is followed by addition of catalyst and subjected to hydrogen pressure in the range of 1.0 -45 kg/cm2 at a temperature in the range of 50-120°C for about 3.0 - 30 hours to obtain ractopamine base. This is further treated with aqueous or gaseous hydrochloric acid to obtain a slurry. The slurry is digested, preferably by stirring, for a sufficient time to obtain ractopamine hydrochloride, which is then filtered and dried to obtain the product.
The reductive amination reaction can be carried out between 4.5 - 8.5 pH, preferably between 5.5 to 7.5 pH.
The reaction is carried out in a suitable solvent selected from the group consisting of C6-' 10 aromatic hydrocarbons like benzene, toluene, or xylene, CI-4 alcohols like methanol, ethanol, propanol, isopropanol, butanol; ketones like acetone dimethyl ketone, polar aprotic solvents like l-methyl-2-pyrrolidinone (NMP), N,N-Dimethylethylformamide

(DMF), acetonitrile ; esters like ethyl acetate, isopropyl acetate, ethers like diethyl ether, diisopropyl ether etc, preferably isopropanol.
The base used is most preferably sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium acetate, sodium acetate, ammonia and amines like monomethyl amine, diethylamine, triethyl amine ( TEA ), Tributyl amine (TBA) etc.
The catalyst for the reaction is selected from hydrogenation catalyst selected from non-precious hydrogenation catalysts such as Raney nickel, Urushibara, and/or precious hydrogenation catalysts such as Pt, Pd, Ru, Rh etc. loaded on inert support.
In a preferred aspect of the present invention, the process for manufacturing highly pure Ractopamine and /or a pharmaceutically acceptable acid salt thereof the reductive amination reaction is carried out employing Raney Nickel as the catalyst.
In accordance with yet another preferred aspect of the present invention, the process for manufacturing highly pure Ractopamine and /or a pharmaceutically acceptable acid salt thereof the reductive amination reaction is carried out employing Urushibara catalyst.
In accordance with an aspect of the present invention, the process for manufacturing highly pure Ractopamine and /or a pharmaceutically acceptable acid salts thereof is carried out by the reductive amination employing platinum on carbon ( Pt/C ) as the catalyst.
In accordance with another aspect of the present invention, the process for manufacturing highly pure Ractopamine and /or a pharmaceutically acceptable acid salt thereof the reductive amination reaction is carried out employing palladium on carbon (Pd/C ) as the catalyst.
In accordance with yet another aspect of the present invention, the process for manufacturing highly pure Ractopamine and /or a pharmaceutically acceptable acid salt

thereof the reductive amination reaction is carried out employing ruthenium on carbon (Ru/C ) as the catalyst.
In accordance with another aspect of the present invention, the process for manufacturing highly pure Ractopamine and /or a pharmaceutically acceptable acid salt thereof the reductive amination reaction is carried out employing rhodium on carbon ( Rh/C ) as the catalyst.
The precious metal catalyst may be provided on an inert support such as carbon, activated carbon, graphite, calcium carbonate, alumina and the like.
Preferably non-precious metal catalyst is 50% wet Raney Nickel.
Preferably precious metal catalyst is platinum on carbon (Pt/C) in the form of extrudate or powder or Pt(OAc)2 or Platinum chloride.
In another embodiment, the process is carried out employing 1 to 50 % hydrogenation catalyst loading with respect to the substrate, more preferably 21 % catalyst loading for the Raney Nickel.
In another embodiment, the process is carried out by employing 0.1 to 40 % precious hydrogenation catalyst loading with respect to the substrate, more preferably 9.1% catalyst loading for the precious hydrogenation catalyst.
In yet another embodiment, the reductive amination is carried out in an autoclave (pressure reactor) under hydrogen pressure of 1.0 to 45 kg/cm2, more preferably 15 Kg/cm hydrogen pressure.
The catalyst may be recovered by conventional means known to the skilled in art such as by evaporation or filtration.

Ractopamine hydrochloride may be separated from the reaction mixture by techniques known in the art, such as filtration. The product may be washed with the solvents. The product may then be dried, preferably under reduced pressure.
The present invention also provides an animal feedstuff comprising ractopamine and/or its pharmaceutically acceptable addition salts together with a suitable carrier.
In an embodiment, the present invention provides a method of promoting growth and improving leanness and feed efficiency by administering an effective amount of a compound of formula (1) and its pharmaceutically acceptable salts to a warm-blooded animal that receives a nutritionally adequate diet.
The compound of formula (I) of the instant invention is administered orally, intramuscularly or intravenously. The amount to be administered to an animal is an amount that is effective in causing a promotion of growth or an improvement in the efficiency of utilization of food, or an improvement in carcass quality of the animal.
Having described the invention with reference to particular preferred embodiments and illustrative examples, those in the art may appreciate modifications to the inventions described and illustrated that do not depart from the spirit and scope of invention as disclosed in the specifications. The examples are set forth to aid understanding the invention but are not intended to, and should not be construed to limit the scope in anyway. The examples do not include detailed description of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in numerous publications. All reference mentioned herein are incorporated in their entity.
Example 1:
150 ml Isopropyl alcohol is charged into the round bottom flask followed by the addition of 47.41 (0. 25 mole ) 4-(2-amino-l-hydroxy-ethyl)phenol hydrochloride at 25 - 35° C. Reaction mixture is stirred for 30 minutes and pH of the reaction mixture is adjusted to the 5.5 to 7.5 pH with the saturated sodium bicarbonate solution. Reaction mixture is stirred for 1.0 hr and filtered through a hyflow bed. Reaction mixture is then transferred to the autoclave followed by the addition of 41.05 g (0.25mole) 4-(4-

Hydroxyphenyl)butan-2-one,19.9 g Raney Nickel ( 50% wet) and 130 ml isopropanol. The mass is heated to 115°C and a hydrogen pressure of 15 Kg/cm2 is applied and maintained for a period of 21 hours. Then the reaction mass is cooled to room temperature, filtered through a hyflow ( flux calcined diatomaceous earth) bed and washed with 48 ml isopropyl alcohol. The filtrate is distilled under vacuum to obtain a residue. DM water is added to the residue and stirred to dissolve. Ethyl acetate (45 ml) is added and stirred for 1.0 hr. The organic layer and aqueous layers are separated. Aqueous layer is cooled to 5 C and cone. Hydrochloric acid is gradually added over period of 2.0 hr under vigorous stirring. Then the reaction mixture was digested for 7 hr. The product is collected by filtration, washed with chilled DM water (50 ml) and dried at 60° C under reduced pressure for 12 hours to obtain the product. Yield 38.9% Purity by HPLC 98.2%.
Example 2:
110 ml THF is charged into the round bottom flask followed by the addition of 47.41 (0. 25 mole ) 4-(2-amino-l-hydroxy-ethyl)phenoI hydrochloride at 25 -35° C. Reaction mixture is stirred for 30 minutes and pH of the reaction mixture is adjusted between 5.5 to 7.5 with the saturated sodium bicarbonate solution. Reaction mixture is stirred for 1.0 hr and filtered through a Hyflow bed. Reaction mixture is then transferred to the autoclave followed by the addition of 41.05 g ( 0.25mole ) 4-(4-Hydroxyphenyl)butan-2-one, 19.9 g Raney Nickel ( 50% wet) and 125 ml THF. Reaction mass heated to 115°C and a hydrogen pressure of 15 Kg/cm2 is applied and maintained for a period of 23 hours. Then the reaction mass is cooled to room temperature, filtered through a hyflow (flux calcined diatomaceous earth) bed and washed with 45 ml THF. The filtrate is distilled under vacuum to obtain a residue. DM water is added to the residue and stirred to dissolve. Ethyl acetate ( 45 ml ) is added and stirred for 1.0 hr. The organic layer and aqueous layers are separated. Aqueous layer is cooled to 5° C and cone. Hydrochloric acid was gradually added over period of 2.0hr under vigorous stirring. Then the reaction mixture was maintained for 7 hr. The product is collected by filtration, washed with chilled DM water (30 ml ) and dried at 60° C under reduced pressure for 12 hours to obtain the product. Yield 37.3% Purity by HPLC 98.1%.

Example 3 :
85 ml methanol is charged into the round bottom flask followed by the addition of 47.41g (0. 25 mole) 4-(2-amino-l-hydroxy-ethyl)phenol hydrochloride at 25 -35° C. Reaction mixture is stirred for 30 minutes and pH of the reaction mixture is adjusted between 5.5 to 7.5 with the saturated sodium bicarbonate solution. Reaction mixture is stirred for 1.0 hr and filtered through a Hyflow bed. Reaction mixture is then transferred to the autoclave followed by the addition of 41.05 g (0.25 mole) 4-(4-Hydroxyphenyl) butan-2-one, 19.9 g Raney Nickel (50% wet) and 50 ml methanol. Reaction mass heated to 110°C and a hydrogen pressure of 15 Kg/cm2 is applied and maintained for a period of 18 hours. Then the reaction is cooled to room temperature, filtered through a hyflow (flux calcined diatomaceous earth) bed and washed with 30 ml methanol. The filtrate is distilled under vacuum to obtain a residue. DM water is added to the residue and stirred to dissolve. Ethyl acetate (45 ml is added and stirred for 1.0 hr. The organic layer and aqueous layers are separated. Aqueous layer is cooled to 5° C and cone. Hydrochloric acid was gradually added over period of 2.0 hr under vigorous stirring. Then the reaction mixture was digested for 7 hr. The product is collected by filtration, washed with chilled DM water (30 ml) and dried at 60° C under reduced pressure for 12 hours to obtain the product. Yield 38.6% Purity by HPLC 98.2%.
Example 4 :
94.83 g (0.50 mole) 4-(2-amino-l-hydroxy-ethyl)phenol hydrochloride and 300 ml isopropyl alcohol are charged into the round bottom flask and pH of the reaction mixture is adjusted between 5.5 - 7.5 with saturated sodium bicarabonate solution. Reaction mixture was stirred for 1.0 hr and filtered through a Hyflow bed. Reaction mixture was transferred to the autoclave followed by the addition of 98.52 g (0.60mole) 4-(4-Hydroxyphenyl)butan-2-one, 16 g Pt/C and 400 ml isopropyl alcohol 1. The mass is heated to 118 °C and a hydrogen pressure of 8.9 Kg/cm2 is applied and maintained for a period of 14 hours. Then the reaction is cooled to room temperature, filtered through a hyflow (flux calcined diatomaceous earth) bed and washed with 60 ml isopropyl alcohol. The filtrate is distilled under vacuum to obtain a residue. DM water is added to the residue and stirred to dissolve. Ethyl acetate (75 ml) is added and stirred for 1.0 hour. The organic layer and aqueous layers are separated. Aqueous layer was cooled to 5 C and cone, hydrochloric acid was gradually added over 2.0 hr under vigorous stirring. Then the

reaction mixture was maintained for 7 hr. The product is collected by filtration, washed with chilled DM water (50 ml) and dried at 60° C under reduced pressure for 12 hours to obtain the product. Yieid 55.6% Purity by HPLC 98.07%.
Example 5 :
94.83 g (0.50 mole) 4-(2-amino-l-hydroxy-ethyl) phenol hydrochloride and 300 ml isopropyl alcohol are charged into the round bottom flask and pH of the reaction mixture is adjusted to t 5.5 -7.5 pH with aqueous ammonia solution. Reaction mixture was stirred for 1.0 hr and filtered through a Hyflow bed. Reaction mixture was transferred to the autoclave followed by the addition of 98.52 g (0.60mole ) 4-(4-Hydroxyphenyl)butan-2-one, 8.9 g palladium on carbon ( 50% wet) and 300 ml isopropanol. The mass is heated to 106°C and a hydrogen pressure of 15 Kg/cm2 is applied and maintained for a period of 15 hours. Then the reaction is cooled to room temperature, filtered through a hyflow (flux calcined diatomaceous earth) bed and washed with 60 ml isopropyl alcohol. The filtrate is distilled under vacuum to obtain a residue. DM water is added to the residue and stirred to dissolve. Ethyl acetate ( 75 ml ) is added and stirred for 1.0 hr. The organic layer and aqueous layers are separated. Aqueous layer was cooled to 5° C and cone. Hydrochloric acid was gradually added over 2.0 hr under vigorous stirring. Then the reaction mixture was maintained for 7 hr. The product is collected by filtration, washed with chilled DM water (50 ml) and dried at 60° C under reduced pressure for 12 hours to obtain the product. Yield 58.6% Purity by HPLC 98.12%.
Example 6:
37.93 g (0.2mole) 4-(2-amino-l-hydroxy-ethyl)phenol HC1, 39.42 g (0.24mole) 4-(4-Hydroxyphenyl)butan-2-one was dissolved in 350 ml DMF and pH adjusted I between 5.5 - 7.5 with triethylamine and stirred for 1.0 hr. Reaction mass is charged into the autoclave, followed by the addition of 3.45 g Pt/C into the autoclave and subjected to the hydrogen pressure of 15 Kg/cm2. Reaction mixture was heated tol 15 °C and maintained over a period of 14 hours. Reaction mixture was cooled to RT, the catalyst was filtered and washed with DMF. The filtrate was collected, quenched in DM water and extracted with 3 x 150 ml methylene dichloride. Methylene dichloride layer is combined and washed with 125 ml brine solution, then distilled under vacuum to obtain a residue. DM water is added to the residue and stirred to dissolve. Ethyl acetate (35 ml) is added and

stirred for 1.0 hr. The organic layer and aqueous layers are separated. Aqueous layer was cooled to 5° C and cone. Hydrochloric acid was gradually added over 2.0 hr under vigorous stirring. Then the reaction mixture was maintained for 7 hr. The product is collected by filtration, washed with chilled DM water (50 ml ) and dried at 60° C under reduced pressure for 12 hours to obtain the product. Yield 44.7% Purity by HPLC 98.11%.

We claim,
1. An improved, efficient, one pot process for the synthesis of Ractopamine and/or its pharmaceutical ly acceptable salt of Formula - (I)

Formula (I) comprises,
(a) reacting 4-(2-amino-1 -hydroxy-ethy1)phenol Formula (II) with 4-(4-Hydroxy phenyl) butan-2-one Formula - (III) in a solvent in an autoclave, adjusting the pH between 5.5 - 7.5 using a base;

(b) subjecting the reaction mixture to reductive animation under hydrogen
pressure in the range of 1.0-45 kg/cm2 in an autoclave, in presence of
hydrogenation catalyst at a temperature in the range of 50-120°C for 3.0 to 30
hours to obtain ractopamine base; and
(c) converting ractopamine to its acid addition salt.
2. The process according to claim 1, wherein hydrogenation catalyst is selected from Raney Nickel, Urushibara Catalysts.

3. The process according to claim 1, wherein precious hydrogenation catalyst is selected from the group of platinum, palladium, ruthenium, rhodium etc on an inert support such as carbon, activated carbon, graphite, calcium carbonate or alumina.
4. The process according to claim 2, wherein 1 to 50 % hydrogenation catalyst is loaded with respect to the substrate.
5. The process according to claim 2, wherein 0.1 to 40 % precious hydrogenation catalyst is loaded with respect to the substrate.
6. The process according to claim 1, wherein solvent is selected from the group consisting of C6-10 aromatic hydrocarbons like benzene, toluene, or xylene, CI-4 alcohols like methanol, ethanol, propanol, isopropanol, butanol; ketones like acetone, methyl ketone, polar aprotic solvents like l-methyl-2-pyrrolidinone (NMP), N,N-Dmethylethylformamide ( DMF), acetonitrile; esters like ethyl acetate, isopropyl acetate, ethers like diethyl ether, diisopropyl ether.