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:
A PROCESS FOR PREPARING BRIMONIDINE OR SALTS THEREOF
2. APPLICANT (S)
(a) NAME: BABASAHEB PANDURANG BANDGAR,SANJAY SURESH
SAWANT,S.M.SALMAN JAWEED MUKARRAM
(b) NATIONALITY: INDIAN
(c) ADDRESS: SCHOOL OF CHEMICAL SCIENCES
SOLAPUR UNIVERSITY SOLAPUR, SOLAPUR - PUNE HIGHWAY,KEGAON SOLAPUR - 413255, MAHARASHTRA, INDIA.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a process for the preparation of Brimonidine or salts thereof.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION
The present invention provides a process for the preparation of Brimonidine or salts thereof. The present invention especially relates to methylation of 5-bromo-6-thioureidoquinoxaline with dimethyl sulfate provide S-methyl-5-bromo-6-thioureidoquinoxaline, which is cyclized in presence of ethylenediamine-p-toluene sulfonic to provide Brimonidine or salt thereof.
Brimonidine of Formula I is chemically known as 5-bromo-6-(2-imidazolidinylideneamino) quinoxaline.

Formula I
Tartrate salt of Brimonidine is a relatively selective alpha-2 adrenergic receptor agonist (topical intraocular pressure lowering agent) that is available as ophthalmic solution 0.1% or 0.15% sterile under the trade name ALPHAGAN® P.
Brimonidine tartarate is novel substituted derivative of quinoxaline. More particulary, which is useful as therapeutic agent, for example, to reduction in intraocular pressure, to increase renal fluid and to effect an alteration in the rate of fluid transport in the gastrointestinal teract. Brimonidine tartarate used for open angle glaucoma and eye hypertension, topical administration decreases intraocular pressure with minimal effect on cardiovascular parameters, reducing aqueous humor production and increasing uveoscleral outflow. Brimonidine is used to treat glaucoma or another condition in which pressure in the eye is too high (ocular hypertension). Topical administration of brimonidine decreases intraocular pressure (IOP) in humans. When used as directed, brimonidine ophthalmic solution reduces elevated IOP with minimal effect on

cardiovascular parameters. Brimonidine has a rapid onset of action, with the peak ocular hypotensive effect occurring at approximately 2 hours post-dosing. The duration of effect is 12 hours or greater.
U.S. Patent No. 3,890,319 discloses Brimonidine and its therapeutic indication with preparation, as regulators of the cardiovascular system and the treatment of hypertension. According to the US '319, Brimonidine was prepared by hydrobromide salt of 6 -amino-5-bromoquanoxaline in water treated with thiophosgene to get a compound 5-bromo-6-isothiocynatoquinoxaline. Furthermore treated with ethylenediamine in benzene with evolution of hydrogen sulphide to get Brimonidine. However, use of thiophosgene and evolution of toxic hydrogen sulphide gas is highly dangerous on large scale production.
US Patent no. 6,323,204 and EP patent No. 4,228,78 B1 disclose a process for Brimonidine, which involves treatment of 6-amino-5-bromoquinoxaiine with thiophosgene to get 6-isothiocynato quinoxaline, which is purified using column separation technique. Furthermore, it is cyclized with ethylenediamine to get 5- bromo-6-(N-2-aminoethyl) thiouredo quinoxaiine and finally, with evolution of hydrogen sulphide to get a title compound. However, the use of thiophosgene, evolution of toxic hydrogen sulphide gas and column purification may not provide industrial applicable process for large-scale production.
Russian patent no. 2,285,003 discloses a process for preparing Brimonidine base which involves reaction of immonium chloride ((CH3)2N+=CCI2CI) [prepared by chlorination of tetramethyl thioperoxydicarbonic diamide in CH2CI2at 20 °C] with 6-amino -5-bromo quinoxaiine followed by reaction with 1,2 ethanediamine of formed N,N-dimethyl-N1-(5-bromoquinoxalin-6-yl)- α -chloroformamidine, which is then cyclized to provide Brimonidine and then converted to its tartrate salt with 38.4% yield. However, yield is very low the number operations are more which is undesired for large scale preparation.
US patent no. 5,130,441 discloses a process for preparing Brimonidine, involves reaction of 6-amino-5- bromo quinoxaiine with imidazoline 2-sulphonic acid in isobutanol at 125 °C for 16 hours to obtain a 5-bromo 6-(2-imidazoline -2 yl amino)-quinoxaline, which is purified by column chromatography to obtain pure Brimonidine base. However,

this process involves isolation of Brimonidine by column chromatography which is a tedious, costly and time consuming process for scale up preparation.
GB Patent no. 1,463,520 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. However, It has more number of operations for the preparation of title compound 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 Patent Application No. 2007MU01509 discloses a process for the preparation of Brimonidine, which involves 6-amino-5-bromo quinoxaline with N-acetyl ethylene urea in presence of phosphorus oxychloride to get Acetyl Brimonidine, which is further hydrolyzed in methanolic sodium hydroxide to afford Brimonidine free base, which is then converted to its tartrate salt.
Various other prior art references are DE. Patent No. 2, 322,880, DE. Patent No. 2, 505,664, DE. Patent No. 289, 376, DE. Patent No. 3, 610,407 EP. Patent No. 644,192, JP. Patent No. 7, 258,251, JP. Patent No. 7, 267,950, JP. Patent No. 8,176,150, US. Patent No. 3, 202,660, DE.Patent No. 19690820, JP. Patent .No. 48076870, DE, Patent No. 2,505,297, JP. Patent No.50154246, EP. Patent No. 19780430, EP. Patent No. 0422878, U.S.Patent No. 6,187,956, J.P.Patent No. 2004115437, Synthesis, 6563-6566, J.Med.Chem.1997, 40, 18-23, and Org.Proc.Rec.Dev. 1998, 2, 422-424.
The above prior art references faces one or the other problems, for example, yield of brimonidine or its intermediates, the use of number of steps, expensive column chromatography and use of hazardous chemicals. Therefore, the present inventors developed a novel process for preparing Brimonidine or its salt, which is an industrially applicable, commercially feasible and provides high yield. Further, the process avoids use of hazardous liquid bromine, flammable sodium hydride, pheyl cyanide during the development of Brimonidine or its salt.


which comprises:
i) methylation of 5- bromo-6-thioureidoquinoxaline of Formula II

to S-methyl-5-bromo-6-thioureidoquinoxaiine of Formula III with dimethyl sulfide in presence of solvent and base; and

In an aspect of the present invention provides a process for the preparation of Brimonidine of Formula I or salt thereof,
ii) cyclization of Formula II) with ethylenediamine-p-toluene sulfonic acid in presence of solvent to provide Brimonidine or salt thereof.
The methylation reaction may be performed at a temperature of about 25 °C to about reflux temperature as per the solvent used. Suitable sovlent for methylation includes but are not limited to alcohol such as methanol, ethanol, isopropyl alcohol, and the like; ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone and the like; hydrocarbon such as hexane, heptane, cyclohexane, toluene and the like. The metylation reaction may carried out for a period of about 15 minutes to 1 hour or more. Suitable base includes but are not limited to inorganic base such as sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, and potassium bicarbonate; orgnaic base such as triethyl amine, pyridine and the like,

The cyclization reaction may be performed at a temperature of about 25 °C to about reflux temperature. Suitable solvent may be selected from alcohol, ketone and the like. This reaction may be carried out for a period of about 45 minutes to 2 hours or more.
After completion of cyclization reaction, the separated solid of Brimonidine can be filtered by using suitable well known filtration techniques such as filtration under vacuum, suction filtration and the like. The obtained solid optionally dried for a period of about 30 minutes or more at a temperature of about 25 to 50 °C or more to meet the ICH guidelines.
The yield of Brimonidine obtained from the present invention is more than or equal to 90%.
The resultant Brimonidine converted to its salt by the reaction of Brimonidine with an acid such as tartric acid, succinic acid, hydrochloric acid, hydrobromic acid and the like.
In an embodiment of the present invention, there is provided a conversion of Brimonidine to its tartrate salt by using tartaric acid.
In another aspect of the present invention provides a process for the preparation of intermediate of Brimonidine, 5-bromo-6-thioureidoquinoxaline of Formula II, which comprises:
a) bromination of 6-aminoquanoxaline with N-bromosuccinimide in presence of reagnet and solvent to provide 5 - bromo- 6 - aminoquanoxaline; and
b) reaction of 5-bromo-6-aminoquanoxaline with ammonium thiocyanate in presence of benzoyl chloride and solvent followed by hydrolysis with base to provide 5-bromo-6-thioureidoquinoxaline.
The compound, 6-aminoquanoxaline, may be prepared as per the prior art, Russian Chemical Bulletin, 56(6), 1216-1226 or as per the example-1-2 of the present invention.

The bromination reaction of present invention involves reaction of 6-aminoquanoxaline, N-bromosuccinimide, (NBS) in presence of reagent like a radical initiator, for example, usually azo-bis-isobutyronitrile (AIBN) or benzoyl peroxide.
The suitable temperature for the bromination is about 25 to about 40 or room termperature. Suitable solvent includes but are not limited to halo solvents such as dichloromethane, carbon tetrachloride, chloroform, and chlorobenzene.
The step b) involves reaction between 5-bromo-6-aminoquanoxaline with ammonium thiocyanate in presence of solvent, includes but are not limited to, ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone. The suitable termperature is about 25 to about reflux temperature.
After completion of the reaction, the separated solid is subjected to hydrolysis to provide 5-bromo-6-thioureidoquinoxaline by using base such as inorganic base includes sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, and potassium bicarbonate.
The resultant 5-bromo-6-thioureidoquinoxaline may be utilized for further reaction to provide Brimonidine as per the process disclosed in the prior art or present invention.
In another aspect of the present invention provides an intermediate, S-methyl-5-bromo-6-thioureidoquinoxaline of Formula III

which is useful as a key intermediate for the preparation of Brimonidine or its salt.
The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

EXAMPLES
Example -1
Synthesis of 1,2, 3 -triaminobenzene diyhdrochloride

To a solution of 2,4-dinitroaniline (10 g, 0.055 mole) in methanol (30 ml) was added Pd/C (0.5 g ) in water (5 ml) and maintain reaction mixture under hydrogen pressure at 30-35 °C for 1 h. After completion of reaction, reaction mixture was cooled at room temperature and collects the Pd/C by filtration at suction. The organic layer was reacted with hydrochloric acid to give 1, 2, 3 -triaminobenzene diyhdrochloride.
Yield = 10.5 g, 98%
Mp = 250°C
IR cm"1 (KBr): 797.79, 843.68, 1335.24, 2901.98.
1H NMR (300 MHz, CDCI3): 57.5 (d, 1H, J = 8Hz), 7.32 (dd, 1H , J = 8 Hz, J - 2 Hz), 7.12 (d, 1H J = 2Hz), 5.32 (s2H).
Anal. Calcd for C6hvU2C\2: C 39.56 (39.50), H 6.04 (6.00), N 15.38 (15.30), C!2 39.01 (39.00).
Example - 2
Synthesis of 6 - aminoquanoxaline


To a solution of sodium bicarbonate (5.4 g, 0.051 mole) in water (40 ml) was added 2,1,3 -triaminobenzene diyhdrochloride (10.0 g , 0.051 mole ), glyoxal sodium bisulphate (15.4 g, 0.051 mole) and maintain reaction mixture at 40 - 45 oC for 1 h. After completion of reaction, product was extracted with ethyl acetate and concentrated to obtain 6-aminoquanoxaline.
Yield = 7.23 g, 98 %
Mp = 155-156°C
IR cm'1 (KBr): 52.16, 768.10, 817.34, 858.98, 928.21, 959.74, 1032.54, 1135.21, 1226.98, 1310.32, 1370.98, 1434.71, 1548.40, 1649.42, 1916.54, 2063.63, 2753.39, 3191.48,3395.58.
1H NMR (300 MHz, CDCI3): 6 7.5 (d, 1H, J = 8Hz), 7.32 (dd, 1H, J = 8 Hz, J = 2 Hz), 7.12 (d, 1H, J = 2Hz), 5.32 (s,2H).
Anal. Calcd for C8H7N3: C 66.20 (66.22), H 4.82 (4.85), N 28.96 (28.90).
Example - 3
Synthesis of 5 - bromo- 6 - aminoquanoxaline

To a solution of 6-aminoquanoxa!ine (10.0 g 0.069 mole) in methylene dichloride (100 ml) was added benzoyl peroxide (1.67 g 1 % mole), N-bromo -succinimide, (12.3 g , 0.069 mole) at room temperature. Reaction mixture was stirred for 2 h. After completion of reaction, mixture was filtered and washed with water (2 x 100 ml). The organic layer was concentrated to furnish 5-bromo-6- aminoquanoxaline.
Yield = 13.9 g, 90% MP = 157-158 °C

IRcnr1 (KBr): 515.53, 527.17, 554.18, 642.16, 675.16, 743.51, 792.85, 828.71,863.69, 957.44, 1046.15, 1143.42, 1184.12, 1225.56, 1273.79, 1340.22, 1376.56, 1464.40, 1498.65, 1540.16, 1621.71, 1922.63, 2732.53, 3185.97, 3304.33, 3459.92.
1H NMR (300 MHz), CDCI3): 08.8 (brs, 1H, J = 8Hz), 8.6 (s, 1H ), 7.85 (d, 1H, J = 8Hz), 4.7 (brs , 2H).
Anal. Calcd for C3H6N3 Br: C 42.85 (42.80), H 2.67 (2.60), N 18.75 (18.80) , Br 35.71 (35.70).
Example - 4
Synthesis of 5- bromo-6-thioureidoquinoxaline

To a solution of ammonium thiocyanate (3.4 g, 0.044 mole), in acetone (100 ml) was added benzoyl chloride (6.25 g, 0.044 mole ) at room temperature with continuous stirring. To a solution of the 5-bromo-6-aminoquanoxaline (10 g, 0.044 mole) in acetone (100 ml) was added and the stirring was continued at reflux temperature for 30 min. The reaction mixture was filtered and solid was hydrolyzed with dilute sodium hydroxide solution 5% (100 ml) and stirring was continued for further 30 min at room temperature.After completion of reaction, mixture was neutralized with dilute hydrochloric acid 5% (100 ml). The reaction mixture was filtered at suction to obtain 5-bromo-6-thioureidoquinoxaline.
Yield = 12 g, 95%
MP = 175°C
IRcm-1 (KBr): 515.53, 527.17, 554.18, 642.16, 675.16, 743.51, 792,85, 828.71, 863.69, 957.44, 1046.15, 1143.42, 1184.12, 1225.56, 1273.79, 1340.22, 1376.56, 1464.40, 1498.65, 1540.16, 1621.71, 1922.63, 2732.53, 3185.97, 3304.33.

Anal. Calcd for C9H7N3Br S: C 40.10 (40.11), H 2.60 (2.62), N 15.61 (15.60), Br 29.73
(29.70), S 11.89(11.90).
Example - 5
Synthesis of S-methyl - 5- bromo-6-thioureidoquinoxaline

To a solution of 5- bromo-6-thioureidoquinoxaline (10 g 0.035 mole) in methanol (100 ml) was added sodium bicarbonate (2.3 g, 0.035 mole), dimethyl sulphate (4.45 g 0.035 mole) with continuous stirring at room temperature. The resulting solution was refluxed for 1 h. After completion of reaction, the mixture was concentrated and was water (150 ml) added with continuous stirring at room temperature, the precipitated product was filtered at suction to yield S-methyl-5- bromo-6-thioureidoquinoxaline.
Yield = 9.4 g, 90 %
MP = 120-122 °C
IRcrrr1(KBr): 515.53, 527.17, 554.18, 642.16, 875.16, 743.51, 792.85, 828.71, 863.69, 957.44, 1046.15, 1143.42, 1184.12, 1225.56, 1273.79, 1340.22, 1376.56, 1464.40, 1498.65, 1540.16, 1621.71, 1922.63, 2732.53, 3185.97,3304.33.
1H NMR (300 MHz), CDCI3): 6 8.9(s, 1H), 8.8(s, 1H ), 7.95 (d, 1H, J = 8 Hz ), 7.45 (d, 1H, J = 8 Hz ), 6.45 (brs ,2H ), 2.5 (s, 2H ).
Anal. Calcd for C10H9N3 BrS: C 48.97 (48.99), H 3.67 (3.70), N 17.14 (17.10), Br 32.65 (30.82), S 13.06(13.10).
Example - 6:
Synthesis of Brimonidine base

Example - 6:
Synthesis of Brimonidine base

To a solution of s-methyl 5- bromo-6-thioureidoquinoxaline (10 g, 0.033 mole) in isopropyl alcohol (100 ml) was added ethylenediamine-p-toluene sulfonic acid (7.8 g, 0.033 mole) with continuous stirring at room temperature. The resulted reaction mixture was heated under reflux for 1 h. After completion of reaction, reaction mixture was filtered and washed with water (175 ml), to give Brimonidine.
Yield = 9.0 g, 92 %
Mp = 252 °C
IR cm-1(KBr): 489.86, 544.44, 703.58, 805.58, 836.12, 958.01, 1041.08, 1101.07, 1136.71, 1197.82, 1247.70, 1283.09, 1326.40, 1360.28, 1409.28, 1482.45, 1541.50, 1595.04, 1907.42, 3223.07.
1H NMR (300 MHz), CDCI3): 5 brs, 1H), 5 (d, 1H, J = 2Hz ), 8.74 (d, 1H, J = 2), 8.73 (d, 1H, J = 8 Hz), 7.99 (d 2H, J = 8 Hz), 6.65-7.00 (brs, 2H).
13CNMR (75MHz,CDCI3): 6 41.93, 76.02, 76.46, 76.69, 114.17, 127.47, 128.63, 139.36, 141.61, 144.43, 151.49, 151.35, 154.06.
Anal. Calcd for C11H10N5Br; C 45.20 (45.25), H 3.42 (3.45), N 23.97 (23.90), Br 27.39 (27.40).

Example- 7:
Synthesis of Brimonidine tartarate

To a solution of brimonidine base (10 g, 0.034 mole ) in water (50 ml) was added tartaric acid (5.11 g, 0.034 mole) with continuous stirring at room temperature. After completion of reaction, reaction mixture was added acetone (250 ml) at room temperature and filter at suction to furnish Brimonidine tartarate.
Yield = 14.8 g, 98%
MP = 87-90 °C
IRcm"1(KBr): 485.67, 683.28, 789.75, 843.08, 894.44, 937.82, 959.57,
990.24, 1077.56, 1123.41, 1265.05, 1407.21, 1593.60, 1732.26, 3268.07.
1H NMR (300 MHz), CDCI3): 5 1H), 10.5 (s, 2H), (d, 1H, J = 2Hz ), 8.74 (d, 1H, J = 2), 8.73 (d, 1H , J = 8 Hz), 7.99 (d 2H, J = 8 Hz), 6.65-7.00 (brs,2H), 5.23 (s,2H), 4.78 (s,2H).
13CNMR (75MHz,CDCI3) :544.41, 74.25, 126.06, 129.72, 130.25, 137.75, 140.25,141.44, 147.05, 147.40, 159.33, 177.70.
Anal. Calcd for C15H16N5Br06: C 40.72 (40.70), H 3.61 (3.60),
Br 18.09 (18.10), 0 18.09(18.11).

We Claim:
1. A process for the preparation of Brimonidine of Formula I or salt thereof

which comprises:
i) methylation of 5- bromo-6-thioureidoquinoxaline of Formula II

to provide S-methyl-5-bromo-6-thioureidoquinoxaline of Formula III with dimethyl sulfide in presence of methanol and base; and

ii) cyclization of Formula III with ethylenediamine-p-toluene sulfonic acid in presence of solvent to provide Brimonidine or salt thereof.
2. The process of claim 1, wherein said base of ste i) is selected from inorganic, organic base or mixture thereof.
3. The process of claim 1, wherein said solvent of step ii) is selected from alcohol.
4. A process for the preparation of intermediate of Brimonidine, 5- bromo-6-thioureidoquinoxaline of Formula II,


which comprises:
a) bromination of 6-aminoquanoxaline with N-bromosuccinimide in presence of reagnet and solvent to provide 5 - bromo- 6 - aminoquanoxaline; and
b) reaction of 5-bromo-6-aminoquanoxaline with ammonium thiocyanate in presence of benzoyl chloride and solvent followed by treatment with base to provide 5- bromo-6-thioureidoquinoxaline.
10. The compound of claim 9, which is converted to Brimonidine or its salt.
5. The process of claim 4, wherein said reagent is selected from azo-bis-isobutyronitrile (AIBN) and benzoyl peroxide.
6. The process of claim 4, wherein said solvent of step a) is selected from halo solvents such as dichloromethane, carbon tetrachloride, chloroform, and chlorobenzene.
7. The .process of claim 4, wherein said solvent of step b) is selected from ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone.
8. The process of claim 4, wherein said base of step b) is selected from inorganic base such as sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, and potassium bicarbonate.
9. A compound, S-methyl-5-bromo-6-thioureidoquinoxaline of Formula III