FORM 2
THE PATENT ACT 1970
(39 of 1970)
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"Novel process for the preparation of Brimonidine"
2. APPLICANT (S)
(a) NAME: Centaur chemicals Pvt. ltd
(b) NATIONALITY: An Indian Company incorporated under the Indian Companies ACT 1956
(c) ADDRESS:Centaur chemicals Pvt. ltd.
Centaur House, shanti Nagar,Vakola, Santacruz (e) Mumbai 400055. Tel No. 66499144
Fax No. 66499108/112
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which il t is to be performed.

Novel process for the preparation of Brimonidine

Field of Invention:
This novel process mainly directed to the cost effective and commercially feasible for the preparation of compound formula (I); Brimonidine.

Background of Invention:
Brimonidine and its therapeutic indication with preparation firstly disclose by Danielewicz, et al in U.S. Pat. No. 3,890,319 as regulators of the cardiovascular system and the treatment of hypertension, having the following formula:

where the 2-imidazolin-2-ylamino group may be in any of the 5-, 6-, 7- or 8-position of the quinoxaline nucleus; X, Y and Z may be in any of the remaining 5-, 6-, 7- or 8-positions and may be selected from hydrogen, halogen, lower alkyl, lower alkoxy or trifluoromethyl; and R is an optional substituent in either the 2- or 3-position of the quinoxaline nucleus and may be hydrogen, lower alkyl or lower alkoxy. Gluchowski U.S. Pat. No. 5,021,416 discloses the use of similar quinoxaline derivatives to reduce or maintain the intraoccular pressure in a mammalian eye.
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According to Basic patent US 3,890,319, Brimonidine was prepared by hydrobromide salt of 6 -amino- 5- bromoquanoxaline in water treated with thiophosgene to get a compound 5 - bromo-6-isothiocynato quinoxaline. Furthermore treated with ethylenediamine in benzene with evolution of hydrogen sulphide to get the title compound.
The drawback of the process is that it is not environment friendly and industrially applicable due to the reactant use in this process is thiophosgene and evolution of toxic hydrogen sulphide gas which is heighly dangerous on large scale.
According to our preferred embodiment, the process is novel with a good yield, commercially feasible and environment friendly which does not use any hazardous chemical such as thiophosgene. Furthermore numbers of operations are less which makes the process more cost effective, which has been well depicted in example.
The preparation of Brimonidine disclosed in Patent no. US-6323204 , 6- amino -5- bromo quinoxaline treated with thiophosgene to get 6 isothiocynato quinoxaline which is purified using column separation technique . Furthermore cyclized with ethylenediamine to get 5- bromo -6-(N-2- aminoethyl) thiouredo quinoxaline and finally, with a evolution of hydrogen sulphide to get a title compound.
From the above preparation, as taking into account of industrial and commercial aspect use of thiophosgene along with evolution of hydrogen sulphide as well as column purification should be avoided on a large scale preparation.
In our preferred embodiment, 5- bromo- 6- aminoquinoxaline and phosphorous oxychloride condensed with N- acetyl ethylene urea at temp 55-60 °C to get a 5-bromo-N-(l-acetyl-4,5-dihydro-imidazole-2-yl) -6-quinoxalnamine (acetyl brimonidine). Furthermore hydrolysis with methanolic sodium hydroxide to obtain a 5-bromo-A^-(4,5-dihydro-l//-imidazol-2-yl)-6-quinoxalin-6-amine (Brimonidine base) with good yield and purity.
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In Russian patent no. RU-2285003, Brimonidine base was prepared by reaction of immonium chloride (II)[prepared by chlorination of tetramethyl thioperoxydicarbonic diamide in CH2C12 at 20 °C] with 6-amino -5-bromo quinoxaline (III) at reflux for 1 hour followed by reaction with 1,2 ethanediamine at 20 °C for 2 hrs. with 38.4% yield.
Scheme: I

//
(H3C)2—CN

CI,

(CH3)2N = CCI2CI

(IN)

(I)

(ID

N (CH3)2

Br VNHCH2CH2NH2

(-CH2NH2)2


Brimonidine In above patent preparation, yield is very inferior and the number operation is excess which is undesired for large scale preparation.
In our embodiment, raw materials used are commercially available such as phosphorus oxychloride, N-acetyl ethylene urea and less operations with good yield as well as purity.
According to patent no. US - 5130441, Brimonidine was prepared by reacting 6-amino-5- bromo quinoxaline and imidazoline 2- sulphonic acid in isobutanol at 125 °C for 16 hours to obtain a 5-
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bromo 6-(2-imidazoline -2 yl amino ) -quinoxaline which is purified by column chromatography to obtain pure Brimonidine base .
In above patent brimonidine base isolated by column chromatography which is a tedious, costly and time consuming process for scale up preparation. Furthermore a imidazoline -2- sulphonic acid is not commercially available and also use of MoO (molybdenum oxide) and immersion cooler for the preparation, which is not feasible for the large quantity .
In our embodiment, our process involve simple condensation of 6-amino-5- bromo quinoxaline and N- acetyl ethylene urea in phosphorous oxychloride at 55-60 °C to obtained acetyl brimonidine which on hydrolysis with methanolic sodium hydroxide to obtain brimonidine base with desired purity . Isolation process does not required column chromatography.
In patent no. GB-1463520 disclosed the preparation of 5- bromo- 6-[2- imidazoline -2yl amino] quinoxaline. According to this patent, 6-amino-5- bromo quinoxaline in acetone treated with benzoyl chloride and ammonium thiocynate to obtain 5- bromo-6-thiouredo quinoxaline furthermore treated with bromobenzene and ethylenediamine to get a title compound.
From above preparation the major disadvantage is, the number of operations required for the preparation of title compound and considering the cost and utility point of view is very tedious and time consuming. In this process hydrogen sulphide librated in finial stage which is toxic in a large scale preparation and use large volume bromobenzene at temperature 150-155 °C.
In our preferred embodiment, numbers of operations are less with major solvent recovery. Temperature of reaction is 55 -60 °C with no liberation of toxic hydrogen sulphide gas. This has been well illustrated in forgoing example.
Object of Invention:
The main object of present invention, to provide an industrially applicable and commercially feasible process along with a less number of operations in the preparation of brimonidine over the existing prior art.
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Summary of Invention:
This invention mainly directed to the novel, industrially applicable and commercially feasible process for the preparation of brimonidine. The invented process is carried out under mild condition and without isolation of intermediate substance and without use of highly toxic reagent.
This method further provides substantial benefits relative to previously used or suggested production methods. For example, the starting materials, intermediates, liquid media, and catalysts used are relatively easy to handle and to dispose off, if necessary. Importantly, the present method provides high yields of the desired product or products so that substantial process efficiencies are achieved.
According to present invention, the preparation of brimonidine involves the following steps:
Step-I
In step-I, Present process involves the insitu reaction of N-acetyl urea with phosphorus oxychloride and concomitant reaction with 6-amino-5- bromo quanoxaline at 55-60 °C to obtained N-acetyl brimonidine.
Step-II
In step-II acetyl brimonidine hydrolyzed in methanolic sodium hydroxide to get brimonidine base which is reacted with tartaric acid in methanol to obtained brimonidine tartrate in good yield and purity.
This invention encompasses a novel method of preparation of brimonidine with environment friendly process which has been well illustrated in example.
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Detail description of invention:
The novel method for the preparation of brimonidine involving the following steps.
Step-I


6 amino -5- bromoquinoxaline

\ / CH3
1-acetylimidazolidin-2-one

POCI,


5- bromo-N-(1-acetyl-4,5 -dihydro-imidazole-2-yl)-6 -quinoxaline
In step-I it covers the preparation of acetyl brimonidine in which condensation of 6-amino-5-bromoquinoxaline (0.22 mole) and N- acetyl ethylene urea (0.41 mole) by using phosphorus oxychloride (4.27 mole) at temperature 55-60 °C for 40 hours.
After completion of reaction excess phosphorus oxychloride distilled out under vacuum and reaction mass was diluted with organic solvent such as methylene dichloride, ethylene dichloride or toluene which was cooled to ambient temperature and further 15-20 °C, added ice cold water in reaction mass and further stirred for 8 hours. The sodium hydroxide solution was added in reaction mixture till pH 8-9 .The solid precipitated were filtered and suck dried to obtained acetyl brimonidine (0.083 mole).
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Step -II
Br

,NH M
(^

^
Hydrolysis
N'
0=^CH,
*N' ^ H
5- bromo-N-(1-acetyl-4,5 -dihydro-imidazole-2-yl)-6 -quinoxaline
5- bromo-N-(4,5 -dihydro-imidazole-2-yl)-6 -quinoxaline


OH 0

5- bromo-N-(4,5 -dihydro-imidazole-2-yl)-6 -quinoxaline
tartaric acid

^
N'
^

Br

HO O NH w
N / ' II Y OH
H' O OH
Brimonidine Tartrate

In Step -II, acetyl brimonidine (0.083 mole) obtained from step -I hydrolyzed with methanolic sodium hydroxide to obtain a brimonidine base (0.075 mole).
The brimonidine base obtained from the above step was converted to brimonidine tartrate by reacting it with tartaric acid in methanol.
Following example is offered to provide the person skill in the art with sufficiently clear and complete explanation of this invention, but should not consider as a limitation to the essential aspect of the object thereof, as they have been explained in below.
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Example-1
Charged phosphorus oxychloride (400 ml) and 6-amino -5-bromo quinoxaline (50 gms) in a 1.0 Ltr. RB flask. Stirred the reaction mixture at room temperature for 15 min. Charged N-acetyl ethylene urea (53 gms) in two lots and stirred at room temperature for 15 min. Heated the reaction mixture to 55-60°C and stirred at same temperature for 40 hrs. At the end of the reaction (as indicated by TLC), phosphorus oxychloride was distilled out under vacuum at 55-60°C. The reaction mass was diluted with organic solvent such methylene dichloride, ethylene dichloride or toluene, cooled to room temperature and further to 15-20°C. Ice-cold water (250 ml) was added to the reaction mixture at temperature below 20°C and the reaction mass was stirred for 8 hrs. Sodium hydroxide solution was added till pH 8-9. The solids precipitated were filtered and suck dried. Acetyl brimonidine (28 gms) thus obtained was hydrolyzed in methanolic sodium hydroxide. The free base thus obtained (22.2 gms) was converted to tartrate salt by reacting it with tartaric acid in methanol.
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Claims:
1) A novel process for the preparation of brimonidine of a compound formula (I); namely 5-bromo-JV-(4, 5-dihydro-li/-imidazol-2-yl) 6-quinoxalinamine.

Formula (I)
a) A simple condensation of 6-amino-5-bromoquinoxaline (1 mole) in phosphorus oxychloride and N- acetyl ethylene urea (1.86 mole) at temperature 55-60 °C and furthermore reacting with water at 20°C to obtain a 5-bromo-N-(l -acetyl-4,5 dihydro -imidazole-2 yl)-6-quinoxalinamine (acetyl brimonidine).
b)Hydrolysis of N-(l-acetylimidazolidin-2-yl)-5-bromoquinoxaline-6-amine (acetyl brimonidine) in methanolic sodium hydroxide to obtain a 5-bromo-N-(l-acetyl-4,5 dihydro -imidazole-2 yl)-6-qunoxalinamine (Title compound) and concomitantly with tartaric acid in methanol to get brimonidine tartrate.
2) The process as in claimed in claim 1, condensation of 6-amino-5-bromoquinoxaline (1 mole) in phosphorus oxychloride and N- acetyl ethylene urea (1.86 mole) at temperature 55-60 °C and furthermore with water at 20°C at pH 8-9 by using sodium hydroxide to obtain a 5-bromo-N-(l-acetyl-4,5 dihydro -imidazole-2- yl )-6-quinoxalinamine (acetyl brimonidine) in a good yield along with purity.
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3) The process as claimed in claim 1, after the completion of condensation between 6-amino-5-bromoquinoxaline in phosphorus oxychloride and N- acetyl ethylene urea, excess phosphorus oxychloride distilled out at temperature 55-60 °C under vacuum and diluted with organic solvent such methylene dichloride, ethylene dichloride or toluene which is not extant to this limited solvent.
4) The Process as claimed in claim 1, wherein said ,charging mode of N- acetyl ethylene urea in a lot wise manner at ambient temperature in 15 minutes followed by maintaining at 55-60 °C to exert a good yield along with purity.
5) The Process as claimed in claim 1, wherein the molar ratio of said 6-amino-5-bromo-quinoxaline and N- acetyl ethylene urea is 1: 1.5 to 1: 2.
6) The process as claimed in claim 1, condensation between 6-amino-5-brmoquinoxaline and N-acetyl ethylene urea is carried out in presence of phosphorus oxychloride in a mole ratio 1: 3 to 1:5 against 6-amino-5-brmoquinoxaline.
7) The process as claimed in claim 1, hydrolysis of acetyl brimonidine is carried out in methanolic sodium hydroxide at temperature 20 °C in concomitant with tartaric acid in methanol to obtain a brimonidine tartrate.
8) The Process as claimed in claim 1 and 6 to 7 wherein said process is used to manufacture of brimonidine tartrate with a yield 60% and purity 99.8 %.
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9) A novel process for synthesis of brimonidine as substantially described herein with reference to the foregoing example-1.
Abbreviations:
• Acetyl Brimonidine: 5-bromo-N-(l-acetyl-4, 5 dihydro -imidazole-2 yl)-6-qunoxalinamine.
• Brimonidine Base: 5-bromo-iV-(4, 5-dihydro-l//-imidazol-2-yl)-6-quinoxalinamine.
• RT - Room temperature.
• RB Flask - Round bottom flask.
Dated this 06 Day of July '2007.

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Abstract:
The method for producing a 5-bromo-JV-(4, 5-dihydro-li/-imidazol-2-yl)- 6-quinoxalinamine (Brimonidine) formula (I) and it's tartrate salt having therapeutic indication as regulators of the cardiovascular system and, in particular, in the treatment of hypertension ;

Formula (I)
Comprises a contacting a 6-amino-5-brmquinoxaline with N- acetyl ethylene urea and furthermore hydrolysis with methanolic base to obtain brimonidine in concomitant with tartaric acid to get brimonidine tartrate.
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