DESC:
FORM 2
The Patent Act 1970
(39 of 1970)
&
The Patent Rules, 2005
COMPLETE SPECIFICATION
(SEE SECTION 10 AND RULE 13)

Title: PROCESS FOR THE PREPARATION OF RACTOPAMINE HYDROCHLORIDE VIA NOVEL INTERMEDIATES

Applicant Name : INCHEM LABORATORIES PVT. LTD
Nationality : INDIAN
Address : PLOT NO.52C, 52F, 52G, 52J, 53B, & 53C, KONDAPALLI, IBRAHIMPATNAM MANDAL, KRISHNA DISTRICT, ANDHRA PRADESH, INDIA.

The following specification particularly describes the invention and the manner in which it is to be performed.

TECHNICAL FIELD OF THE INVENTION
[001] The present invention relates generally to the field of organic synthesis. In particular, the present disclosure involves the advanced synthetic strategies to prepare Ractopamine hydrochoride, a feed additive via novel intermediate.
BACKGROUND OF THE INVENTION
[002] Background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
[003]Ractopamine belongs to the class of phenylethanolamines, which are also attributed to ß-adrenergic compounds. These compounds have extremely high physiological activity and medicinal value and play an important role in regulating the physiological processes of energy metabolism in animals. Methods and application areas have always received attention.
[004] Ractopamine hydrochloride is a feed additive to promote leanness in animals raised for their meat. It is known as ß adrenoreceptor agonist that stimulates ß1 and ß2 adrenergic receptors.Its IUPAC name is 4-[3-[[2-Hydroxy-2-(4-hydroxyphenyl)ethyl]aminobutyl]phenol HCl. It occurs in four stereoisomers (RR, SR, SS, RS). In that two sets of isomers RS,SR: 45-49%, and RR,SS:50-55% and individual isomers RR:23-27%, SR:23-27% SS:23-27%, RS: 23-27%. The chemical structural formula of Ractopamine hydrochloride is as follows:

[005] It belongs to ß-phenethanolamine family which are known to be found naturally in human body. Ractopamine Hydrochloride is a synthetic phenethanolamine prepared in laboratory.
[006] Much research work has been done in state of art for synthesis of Ractopamine hydrochloride. In the past decade, animal nutritionists and pharmacologists have conducted extensive research on the application and mechanism of use of Ractopamine hydrochloride as a feed additive for animals. Recent studies have shown that pharmacological experiments with Ractopamine hydrochloride have shown that the compound does not cause side effects in animals.
[007] Further, as a medicine, it is a cardio tonic medicine, can be used for treating congestive heart failure, and can also be used for treating obesity and muscle atrophy.
[008] Regarding the synthesis method of Ractopamine hydrochloride, thesteps of the method are complicated, and expensive chemical reagents and special chemical equipment are used in the reaction process, and the industrial preparation of Ractopamine hydrochloride is costly.
[009] Synthesis of Ractopamine hydrochloride from p-hydroxyphenylethanolamine and raspberry ketone disclosed incomplete reaction and many by-products, and the reaction conditions, separation and purification are quite difficult; and the raw materials are expensive, and the cost for preparing Ractopamine hydrochloride is also extremely high.
[0010] In the light of aforementioned discussion, there exists a need for methods to synthesize Ractopamine hydrochloride in a cost-effective manner for large scale production.The present invention discloses methods for synthesizing Ractopamine and its salts that are commercially viable and suitable for bulk production.
OBJECT OF THE INVENTION

[0011]The main objective of the present invention is to provide advanced synthetic strategies to prepare Ractopamine hydrochloride.
?[0012]The objective of the present invention uses common solvents that are less toxic.

[0013]Yet another embodiment of the present invention Nickel is used as the catalyst in the present disclosure that is easy to handle, cost effective and a recyclable material.

[0014]Yet another embodiment of the present invention is to provide novel intermediates of Ractopamine hydrochloride.

[0015]Another objective of the present invention needs less input in terms of solvent quantities but gives higher yields of Ractopamine hydrochloride with good purity and lesser impurity profile.

[0016]The main objective of present invention is to synthesize Ractopamine hydrochloride using cost effective methods and environment friendly catalyst.
SUMMARY OF THE INVENTION

[0017]The following presents a simplified summary of the disclosure in order to provide a basic understanding to the reader. This summary is not an extensive overview of the disclosure and it does not identify key/critical elements of the invention or delineate the scope of the invention. Its sole purpose is to present some concepts disclosed herein in a simplified form as a prelude to the more detailed description that is presented later.
[0018]It is to be understood that the present disclosure is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the drawings. The present disclosure is capable of other embodiments and of being practiced or of being carried out in various ways. Also, it is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting.
[0019]The use of “including”, “comprising” or “having” and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items. The terms “a” and “an” herein do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. Further, the use of terms “first”, “second”, and “third”, and the like, herein do not denote any order, quantity, or importance, but rather are used to distinguish one element from another.
[0020] According to a non-limiting exemplary embodiment of the present disclosure, methods for synthesizing Ractopamine and its salts are disclosed.

[0021]Accordingly, the present invention provides a process for the preparation of Ractopamine hydrochloride of Formula (I)

(I)
Which comprises the following steps:
(a) 4-hydroxy benzaldehyde of Formula (II)

(II)
Undergoes condensation with acetone of Formula (III)

(III)
In presence of aqueous sodium hydroxide and hydrochloric acid to give compound of Formula (IV)
(IV)
(b) Compound of Formula (IV) undergoes condensation and hydrogenation with a compound of Formula (V) in presence of sodium bicarbonate,Pd/carbon/H2, using a solvent as methanol/ethanol to get compound of Formula (I).

(V)
Compound of Formula (I) purified in acetone/ethyl acetate to get pure compound of Formula (I).
[0022]In a preferred aspect, the present invention provides a process for the preparation of Ractopamine hydrochloride of Formula (I)

(I)
Which comprises the following steps:
(a) 4-hydroxy benzaldehyde of Formula (II)

(II)
Undergoes condensation with acetone of Formula (III)

(III)
In presence of aqueous sodium hydroxide and hydrochloric acid to give compound of Formula (IV)
(IV)
(b) Compound of Formula (IV) undergoes condensation and hydrogenation with a compound of Formula (V) in presence of sodium bicarbonate, RANEY Ni/H2, using a solvent as methanol/ethanol to get compound of Formula (I).
(V)

Compound of Formula (I) purified in acetone/ethyl acetate to get pure compound of Formula (I).
[0023]In another preferred aspect, the present invention provides a process for the preparation of Ractopamine hydrochloride of Formula (I)

(I)
Compound of Formula (VI)

(VI)
reacts with a compound of Formula (VII) in presence of sodium bi carbonate and Raney Nickel /H2 / Pd-Carbon/ H2, solvent methanol /ethanol to get a compound of Formula (I).

(VII)

Compound of Formula (I) is recrystallized in acetone/ethyl acetate to get pure compound of Formula (I).
[0024]The present invention uses common solvents like Methanol, Ethanol, Ethyl acetate and Water that are very less toxic. Raney Nickel used is 60% by weight and in other process Pd- Carbon used is 10% by weight. In hydrogenation process temperature used is below 500C and pressure is 10 kgs. At the time of hydrogenation process some impurities are formed, but product isolation in water and methanol mixture, all the impurities are removed by filtration. During the reaction process pH of reaction is 6.8-7.2 and base isolation process pH value is 9-10 and Ractopamine hydrochloride isolation process pH value is 3.0-4.0.
[0025]The main objective of present invention is to synthesize Ractopamine using cost effective methods and environment friendly catalyst.
[0026]Although the present disclosure has been described in terms of certain preferred embodiments and illustrations thereof, other embodiments and modifications to preferred embodiments may be possible that are within the principles and spirit of the invention. The above descriptions and figures are therefore to be regarded as illustrative and not restrictive.
[0027] Thus the scope of the present disclosure is defined by the appended claims and includes both combinations and sub combinations of the various features described herein above as well as variations and modifications thereof, which would occur to persons skilled in the art upon reading the foregoing description.

DETAILED DESCRIPTION OF THE INVENTION:

[0028]Accordingly, the present invention provides a process for preparing Ractopamine hydrochloride via novel intermediates.
[0029]In the preferred embodiment, compound of Formula (I) is Ractopamine hydrochloride, compound of Formula (II) is 4-hydroxybenzaldehyde, compound of formula (III) is acetone, compound of Formula (IV) is 4-(4-hydroxyphenyl)but-3-en-2-one, compound of formula (V) is 4-(2-amino-1-hydroxyethyl)phenol hydrochloride, compound of Formula (VI) is 4-(4-hydroxyphenyl)butan-2-one and compound of Formula (VII) is 2-amino-1-(4-hydroxyphenyl)ethannone hydrochloride.
[0030]According to the present embodiment of the present invention explains about the process of form 4-(4-hydroxyphenyl)-3-butene-2-one and Ractopamine hydrochloride and its preparation and experimental procedure.
Scheme -1 & 2

Brief process;
4- hydroxyl benzaldehyde is condensation with acetone in presence of aqua’s sodium hydroxide and hydrochloric acid to form 4-(4-hydroxyphenyl)-3-butene-2-one.
4- (4-hydroxyphenyl)-3-butene-2-one condensation and hydrogenation with 4-(2-amino-1-hydroxy ethyl) phenol hydrochloride.(Octopamine hydrochloride) in presence of sodium bi carbonate Pd/carbon/H2, Raney NI /H2 using solvent as methanol/ethanol to get Ractopamine hydrochloride .

Ractopamine hydrochloride is purified in acetone/ethyl acetate to get pure Ractopamine hydrochloride.
Experimental Procedure : 01
Preparation of 4-(4-hydroxyphenyl)-3-butene-2-one.
Ensure clean and dry the RB flask charge acetone 300 ml, charge 4-hydroxy benzaldehyde 100grams cool slowly added sodium hydroxide solution 60gram in 200 ml water during 2-3 hrs. After completion of addition, maintain for 8 hrs. Reaction mass conversation should be check by TLC absence of 4- hydroxyl benzaldehyde after completion of reaction mass charge water and adjust the pH with dil HCl up to 6-7 pHand filter the product and wash with water and to get 125gram product is light yellow solid having purity above 99%.

Preparation of Ractopamine hydrochloride

4-(2-amino-1-hydroxy ethyl) phenol hydrochloride (Octopamine hydrochloride) 100gram was dissolved in methanol 500 ml, charge Sodium bicarbonate 20gram added to the reaction mixture at room temperature, 4-(4-hydroxyphenyl)-3-butene-2-one. 90gram was added to above reaction mass and stir for 15 min at room temperature. 60gram Raney Nickel was taken in autoclave and washed with water and finally wash with methanol. The above reaction mass charged in autoclave and washed with methanol. Apply 6-8 kg H2 pressure and temperature maintain for 16-20hrs hrs. at below500C till reaction mass conversion should be above 85%. On HPLC, after completion of reaction then filter the reaction mass and separate the Raney nickel. Taken clear filtrate adjust the pH with 3- 4 pH with dil HCl and followed by distillation of methanol added water 500 ml further cool the reaction mass, followed by filtration to get Ractopamine hydrochloride. Further purification in Ethyl acetate /acetone to get pure Ractopamine hydrochloride having purity above 98.5%.

3. Experimental procedure;

4-(2-amino-1-hydroxy ethyl) phenol hydrochloride (Octopamine hydrochloride) 100gram was dissolved in methanol 500 ml , charge Sodium bicarbonate 20gram added to the reaction mixture at room temperature, 4-(4-hydroxyphenyl)-3-butene-2-one 90gram was added to above reaction mass and stir for 15 min at room temperature .10% Pd-carbon 10gramin autoclave. The above reaction mass charged in autoclave and washed with methanol. Apply 6-8 kg H2 pressure and temparature maintain for 20-24hrs hrs at below 500C till reaction mass conversion should be above 85%. On HPLC, after completion of reaction and filter the reaction mass and separate the Pd-Carbon. Taken clear filtrate adjust the pH with 3- 4 pH with dil HCl and followed by distillation of methanol added water 500 ml further cool the reaction mass, followed by filtration to get Ractopamine hydrochloride. Further it is purified in Ethyl acetate /acetone to get pure Ractopamine hydrochloride having purity 98.5% above.

Scheme-3
[0031]Ractopamine hydrochloride
Experimental procedure ;

Brief process;

4-(4-hydroxylphenyl)butan-2-one reacted with2-amino-1-(4-hydroxyphenyl)ethanone hydrochloride in presence of base and Raney Nickel /H2 / Pd-Carbon/ H2, solvent methanol /ethanol to get Ractopamine hydrochloride.

Ractopamine hydrochloride is recrystalized in acetone /ethyl acetate to get pure Ractopamine hydrochloride.

Experimental procedure ;
2-amino-1-(4-hydroxyphenyl) ethanone hydrochloride 100gram was dissolved in methanol 500 ml and charge Sodium bicarbonate 10gram added to the reaction mixture at room temperature 4-( 4- hydroxyl phenyl )butan-2-one 90gram was added to above reaction mass at room temperature .Charge 50gram of Raney nickel in autoclave. The above reaction mass charged in autoclave and washed with methanol. Wash with H2 pressure and apply 6-8 kg H2 pressure and temperature maintain for 20-24 hrs at below 500C till reaction mass conversion should be above 85%. On HPLC, after completion filter the reaction mass and separate the Catalyst and taken clear filtrate adjust the pH with 3-4 pH with dil HCl after followed by distillation of Methanol added water 500 ml further cool mass followed by filtration to get 135gram Ractopamine hydrochloride. Further purification is done in Ethyl acetate / acetone to get pure Ractopamine hydrochloride 125gram having purity 98%.

Experimental procedure;

2-amino-1-(4-hydroxyphenyl) ethanone hydrochloride 100gram was dissolved in methanol 500 ml and charge Sodium bicarbonate 10gram added to the reaction mixture at room temperature 4-( 4- hydroxyl phenyl )butan-2-one and 90gram was added to above reaction mass at room temperature and charge 10% Pd carbon 10gram in autoclave. The above reaction mass charged in autoclave and washed with methanol. Wash with H2 pressure and apply 6-8 kg H2 pressure and temperature maintain for 20-24 hrs at below 500C till reaction mass conversion should be above 85%. Further on HPLC, after completion filter the reaction mass and separate the Catalyst and taken clear filtrate adjust the pH with 3-4 pH with dil HCl and followed by distillation of Methanol added water 500 ml further cool mass followed by filtration to get 135gram Ractopamine hydrochloride. Further purification is done in Ethyl acetate / Acetone to get pure Ractopamine hydrochloride 125gram having purity 98.5%. ,CLAIMS:CLAIMS:
We claim:
A process for the preparation of Ractopamine hydrochloride of Formula (I) via novel intermediates

(I)
comprises the following steps :
(a) 4-hydroxy benzaldehyde of Formula (II)

(II)
undergoes condensation with acetone of Formula (III)

(III)
in presence of aqueous sodium hydroxide and hydrochloric acid to give compound of Formula (IV)
(IV)
(b) Compound of Formula (IV) undergoes condensation and hydrogenation with a compound of Formula (V) in presence of sodium bicarbonate, Pd/carbon/H2, RANEY Ni/H2, using solvent to get compound of Formula (I); compound of formula (I) purified to get pure compound of Formula (I).

(V)

The process as claimed in claim 1, wherein solvents used are methanol/ethanol.
The process as claimed in claim 1, wherein compound of Formula (I) purified in acetone/ethyl acetate.
The process as claimed in claim 1, wherein hydrogenation process used Pd/carbon/H2 and temperature is below 500 C and pressure 10kgs.

A process for the preparation of Ractopamine hydrochloride of Formula (I) via novel intermediates
(I)
Comprises the following steps :
Compound of Formula (VI)

(VI)
reacts with a compound of Formula (VII) in presence of sodium bi carbonate and Raney Nickel / H2 / Pd-Carbon/ H2, solvent to get a compound of Formula (I);

(VII)

Compound of Formula (I) is recrystallized to get pure compound of Formula (I).

The process as claimed in claim 5, wherein solvent used are methanol/ethanol.

The process as claimed in claim 5, wherein compound of Formula (I) recrystallized in acetone/ethyl acetate.