FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
&
The patent Rules, 2003
COMPLETE SPECIFICATION
A Process for Preparation of Ractopamine
SeQuent Scientific Limited
A Company Incorporated Under The Companies Act, 1956
Having Registered Office at
116 Vardhman Industrial Complex, L.B.S Marg,
Thane (W), Mumbai - 400601, India
The following specification particularly describes the nature of the invention and the manner in which it is to be performed:

FIELD OF INVENTION
The present invention relates to a novel, cost-effective process for the preparation of a beta-adrenoceptor agonist. Specifically, it relates to a process for the preparation of ractopamine.
BACKGROUND OF THE INVENTION
Ractopamine is used as a feed additive to promote leanness in pigs. Ractopamine is present as an active ingredient in products known as "Paylean" for swine and "Optaflexx" for cattle.
The chemical name of ractopamine is 4-[3-[[2-Hydroxy-2-(4-hydroxyphenyl)ethyl]amino]butyl]phenol hydrochloride represented by formula I.

There are number of literatures available which describe the
process for the preparation of compound of the formula (I). GB 2133986
patent describes a process for the preparation of ractopamine by treating
methyl 2-(4-hydroxyphenyl)ethyl ketone with l-(4-hydroxyphenyl)-2-
aminoethanol in ethanol containing 5% palladium on carbon. This patent also
describes an alternative process for the preparation of ractopamine by reacting
R-l-methyl-3-(4-benzyloxyphenyl)propylamine with R-2-(4-
benzyloxyphenyl)-2-hydroxyacetic acid in presence of N,N-dimethylformamide containing 1-hydroxybenzotriazole and N,N'-dicyclohexylcarbdiimide in dimethylformamide to form R,R-N-[2-(4-benzyloxyphenyl)-2-hydroxy-l-oxoethyl]-l-methyl-3-(4-benzyloxyphenyl) propylamine. R,R-N-[2-(4-benzyloxyphenyl)-2-hydroxy-1 -oxoethyl]-1 -

methy]-3-{4-benzyloxy phenyl)propylamine is treated with borane-dimethyl sulfide complex in tetrahydrofuran to obtain R,R-N-[2-(4-benzyIoxyphenyI)-2-hydroxyethyl]-l-methyl-3-(4-benzyloxyphenyl) propylamine. The amine obtained was further treated with ethereal hydrogen chloride to obtain R,R-N-[2-(4-benzyloxyphenyl)-2-hydroxyethyl]-l-methyl-3-(4-benzyloxyphenyl) propylaminium chloride and finally R,R-N-[2-(4-benzyloxyphenyl)-2-hydroxyethyl]-l-methyl-3-(4-benzyloxyphenyl) propylaminium chloride was debenzylated with raney nickel in ethanol and ethyl acetate to obtain ractopamine hydrochloride. The obtained ractopamine is crystallized from ethanol and diethyl ether. The drawback of this process is that it involves multiple steps and not desired on industrial scale manufacturing.
CN 1116620 describes a process for the preparation of ractopamine by oximation and catalytic hydrogenation of 4-(4-hydroxyphenyl)-2-butanone with hydroxylamine hydrochloride, sodium bicarbonate in presence of alcohol and Nickel catalyst to form l-methyl-3-(4-hydroxylphenyl)propylamine, further reacting with ω-bromo-p-hydoxyl acetophenone forms l-methyl-3-(4-hydroxylphenyl)propylamine, further reacting with triethylamine in tetrahydrofuran and hydrochloric acid to form hydrochloric salt of l-(4-hydroxylphenyl)-2- 1-methyl-3(4-hydroxylphenyl) propylamino -methylketone and finally hydrogenation using palladium and carbon forms ractopamine hydrochloride.
Chinese patent 1315318 describes a process for the preparation of ractopamine by reductive animation of 4-(4-hydroxyphenyl)-2-butanone with ammonia in an alcohol at 80-100°C for 2-3 h at hydrogen pressure 100-300 psi in the presence of raney nickel. The resulting 4-(3-aminobutyl)phenol is n-alkylated with 2-bromo-4'-hydroxyacetophenone in ethyl acetate in the presence of sodium carbonate and tetrabutylammonium bromide at room temperature. The obtained l-(4-hydroxyphenyl)-2-{[3-(4-hydroxyphenyl)-l-methylpropyl] amino}ethanone is further salificated with hydrogen chloride and hydrogenated in the presence of Palladium and carbon to form ractopamine hydrochloride.

The major drawback in the above stated prior arts is the formation of oxime intermediate which is very unstable and very difficult to isolate. Moreover, the prior art process requires anhydrous condition, high pressure and high temperature for amination, which makes it very difficult to handle at industrial scale. Thus there is a need to develop a process which is economically viable and easy to handle on industrial scale.
The present inventors have developed a very cost effective and robust process for preparation of ractopamine which overcomes most of the above drawback.
SUMMARY OF THE INVENTION
Accordingly, the main aspect of the invention is to provide a process for the preparation of 4-(3-aminobutyl) phenol of formula III, which comprises amination of 4-(4-hydroxyphenyl)butan-2-one of formula V in presence of aqueous ammonium and a reducing agent at a temperature in the range of 40 to 60°C and hydrogen pressure of 45 to 65 psi to form 4-(3-aminobutyl)phenol of formula III.
The above process may be illustrated by the below reaction scheme - 1:

Another aspect of the invention is to provide a process for the preparation of 4-[3-[[2-Hydroxy-2-(4-hydroxyphenyl) ethyljamino] butyl]phenol of formula I, which comprises:

a) condensation of 4-(3-aminobutyl)phenol of formula III and 2-bromo-l-(4-hydroxyphenyl)ethanone of formula IV using base and acid in presence of a solvent to form l-(4-hydroxyphenyl)-2-{[3-(4-hydroxyphenyl)-l-methylpropyl] amino}ethanone hydrochloride of formula II;
b) reduction of l-(4-hydroxyphenyl)-2-{[3-(4-hydroxyphenyl)-l-methylpropyl] amino }ethanone hydrochloride of formula II using a reducing agent in presence of an alcohol to form 4-[3-[[2-Hydroxy-2-(4-hydroxyphenyl) ethyl] amino] butyljphenol hydrochloride of formula I; and
c) isolation of 4-[3-[[2-Hydroxy-2-(4-hydroxyphenyl) ethyljamino] butyl]phenol of formula I using ethyl acetate and acetone.
The above process may be illustrated by the below reaction scheme - 2:

DETAIL DESCRIPTION OF THE INVENTION
Accordingly in an embodiment of the invention, aqueous ammonia used for amination of 4-(4-hydroxyphenyl)butan-2-one of formula V is

preferably 10-30% solution more preferably 21% solution and the reducing agent is selected from palladium on carbon, Sodium borohydride, sodium cyanoborohydride and raney nickel, preferably raney nickel. The amination is carried out at hydrogen pressure of 45 to 65 psi preferably 57 psi and at temperature in the range 40-60°C preferably 50°C.
In another embodiment of the invention, condensation of 4-(3-aminobutyI)phenol of formula III with 2-bromo-l-(4-hydroxyphenyl)ethanone of formula IV is carried out using an aqueous solution of a base selected from potassium hydroxide, sodium hydroxide, sodium carbonate and potassium carbonate preferably sodium carbonate and an acid preferably hydrochloric acid in presence of solvent selected from the group water, methanol, ethanol, isopropyl alcohol, ethyl acetate and the like, preferably ethyl acetate at a temperature in the range of 0°C to reflux temperature to obtain l-(4-hydroxyphenyl)-2- {[3-(4-hydroxyphenyl)-1 -methylpropyl] amino} ethanone hydrochloride of formula II.
In another embodiment of the invention, reduction of l-(4-hydroxyphenyl)-2- {[3-(4-hydroxyphenyl)- 1 -methylpropyl] amino} ethanone hydrochloride of formula II is carried out using a reducing agent selected from palladium on carbon, raney nickel, palladium acetate, platinum preferably palladium on carbon in presence of an alcoholic solvent preferably methanol to form ractopamine hydrochloride of formula I.
In another embodiment of the invention, ractopamine hydrochloride obtained in step b) is extracted and isolated by treating it with ethyl acetate and acetone. The obtained product may be further crystallized using water, or methanol and water mixture,
Some of the noteworthy advantages of the process of the present invention are as given below:
a. The isolation of imine in the preparation of 4-(3-amino) butyl
phenol is avoided resulting to a single step reaction.
b. The reaction condition for amination is very mild. It is carried
out at very low temperature 50°C and pressure 57 psi as

compared to reported temperature of 80 to 100°C and pressure 100 to 300 psi.
c. The amination is carried out using aqueous ammonia which
results to a very low net volume of solvent requirement,
moreover the aqueous ammonia is very easy to handle at large
scale as compared to anhydrous alcoholic ammonia.
d. The obtained 4-(3-aminobutyl)phenol is pure & white in colour
and the reaction is fast even at low temperature and pressure.
e. The present process avoids the use of volatile solvent diethyl
ether and regulated solvent ethanol for the crystallization of
Ractopamine hydrochloride.
The present invention is illustrated by the following examples, which are not to limit the scope of the invention.
Example:
a) Preparation of 4-(3-aminobutyl) phenol:
4-(4-hydroxyphenyl)butan-2-one and methanol were treated with 21% aqueous ammonia in an autoclave. To the above reaction mass raney nickel was added and 4 kg/cm of hydrogen pressure was applied. The reaction mass was heated to 50 °C for 2-3 hours. After completion of reaction, the catalyst was filtered and methanol was distilled.
Yield: 92%
b) Preparation of l-(4-hydroxyphenyl)-2-{[3-(4-hydroxyphenyl)-l-
mcthylpropyl] amino}ethanone hydrochloride:
Ethyl acetate and 4-(3-aminobutyl) phenol were charged into sodium Carbonate solution in DM water at 25-30°C, stirred to become slurry and cool to 0-5°C. A solution 2-Bromo-p-hydroxyacetophenone in ethyl acetate was added slowly to the above reaction mass at 0-5°C and stirred for 6-8 hours at 25-30°C.The obtained solids were separated by filtration, washed with DM water, and suck dried. The obtained solid was heated in DM water and

concentrated Hydrochloric acid was added, and further crystallized to obtain the title compound.
Yield: 70%
c) Preparation of 4-[3-[[2-Hydroxy-2-(4-hydrOxyphenyl) ethyl]amino] butyl]phenol hydrochloride:
1 -(4-hydroxyphenyl)-2- {[3 -(4-hydroxyphenyl)-1 -methylpropyl] amino}ethanone hydrochloride and Palladium on carbon(5%) were charged into an autoclave at 25-30°C under nitrogen atmosphere. Methanol was added to the above reaction mass and nitrogen was purged. Hydrogen pressure 6 kg/cm2 was applied at 25 to 30°C, maintained at 30±2°C for 8 hours. After completion of reaction, the Reaction mixture was filtered and catalyst was washed with methanol under nitrogen. The filtrate was again filtered through hyflow bed and methanol was distilled out completely under vacuum below 65°C. At the end of the distillation ethyl acetate was added and stirred for 30 minutes. The reaction mass was cooled to 0 - 5°C, stirred for 2 hours. The precipitate was filtered, washed with ethyl acetate and suck dried.
Above solid material in acetone was heated to 50-55°C and maintained for 30 minutes. The RM was cooled to 0-5°C and maintained for one hour, filtered under nitrogen, washed with chilled acetone and suck dried. The material was dried at 50-55°C under vacuum.
Yield: 70%
Purity : More than 96.5%
(d) Recrystallization of Ractopamine
Ractopamine hydrochloride (50 g) was dissolved in water (200 ml) and heated to form a clear solution. The solution was treated with carbon (2.5g) and cooled slowly to 5-10°C to obtain pure Ractopamine hydrochloride with purity more than 99.0%.

We claim:
1. A process for the preparation of 4-(3-aminobutyl) phenol, which comprises amination of 4-(4-hydroxyphenyl)butan-2-one in presence of aqueous ammonium and a reducing agent.
2. A process according to claim 1, wherein the amination is carried out at a temperature in the range of 40 to 60°C and hydrogen pressure of 45 to 65 psi,
3. A process according to claim 1, wherein the reducing agent for amination is raney nickel.
4. A process for the preparation of 4-[3-[[2-Hydroxy-2-(4-hydroxyphenyl) ethyl]amino] butyl]phenol of formula I, which comprises:

a) condensation of 4-(3-aminobutyl)phenol of formula III and 2-bromo-l-(4-hydroxyphenyl)ethanone of formula IV using base and acid in presence of a solvent to form l-(4-hydroxyphenyl)-2-{[3-(4-hydroxyphenyl)-l-methylpropyl] amino}ethanone hydrochloride of formula II;

b) reduction of l-(4-hydroxyphenyl)-2-{[3-(4-hydroxyphenyl)-l-methylpropyl] amino}ethanone hydrochloride of formula II using a reducing agent in presence of an alcohol to form 4-[3-[[2-Hydroxy-2-

(4-hydroxyphenyl) ethyl]amino] butyl]phenol hydrochloride of formula I; and
c) isolation of 4-[3-[[2-Hydroxy-2-(4-hydroxyphenyl)ethyl]amino] butyl]phenol of formula I using ethyl acetate and acetone.
5. A process according to claim 4, wherein the solvent for condensation in step a) is selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, ethyl acetate and the like.
6. A process according to claim 4, wherein the solvent for condensation in step a) is ethyl acetate.
7. A process according to claim 4, wherein the base for condensation in step a) is selected from potassium hydroxide, sodium hydroxide, sodium carbonate and potassium carbonate and the acid is hydrochloric acid
8. A process according to claim 4, wherein the reducing agent in step b) is selected from the group consisting of palladium on carbon, raney nickel, palladium acetate, platinum and the solvent alcohol is methanol.
9. A process according to claim 4, wherein the ractopamine obtained is further crystallized by water or water and methanol mixture.