FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the Invention:
A PROCESS FOR PRODUCTION OF 5-(4-BROMOPHENYL)-4,6-DICHLOROPYRIMIDINE
Applicant Name and Address: Megafine Pharma (P) Ltd
An Indian Company having registered address of
4th Floor, Sethna, 55, Maharshi Karve Road, Marine Lines,
Mumbai - 400 002,
Maharashtra,
India.
The following specification particularly describes the nature of this invention and the manner in which it is to be performed.

FIELD OF THE INVENTION:
The present invention relates to a method for the preparation of 5-(4-bromophenyl)-4,6-dichloropyrimidine (I).

Particularly, the present invention relates to an improved, commercially viable, production friendly and cost effective process for the preparation of 5-(4-bromophenyl)-4,6-dichloropyrimidine of formula (I), which is substantially free from impurities.
5-(4-bromophenyl)-4,6-dichloropyrimidine (I) can be further used as intermediate for the manufacturing of Macitentan by any method known in the art.
BACKGROUND OF THE INVENTION:
5-(4-bromophenyl)-4,6-dichloropyrimidine (I) is a central precursor of N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N-propylsulfamide (herein after referred as"Macitentan"). 5-(4-bromophenyl)-4,6-dichloropyrimidine (I) has a CAS number of 146533-41-7, and a molecular formula ofC10H5BrCl2N2.
US 7,868,012 describes a method for preparing 5-(4-bromophenyl)-4,6-dichloropyrimidine of formula (I), wherein dimethyl (4-bromophenyl)malonate (IV) is reacted with formamidine hydrochloride (V) in the presence of sodium methoxide

(CH3ONa) to give 5-(4-bromophenyl)pyrimidine-4,6-diol of formula (VI). Chlorination of 5-(4-bromophenyl) pyrimidine - 4,6 - diol of formula (VI) with phosphors oxychloride in the presence of N, N -dimethylaniline to give 5 -(4 -bromophenyl) - 4,6 - dichloropyrimidine of formula (I) as shown in scheme-1

US 8,324,232 describes the preparation of compound of 5 - (4 -bromophenyl) pyrimidine - 4,6 - diol formula (VI), wherein dimethyl (4 - bromophenyl) malonate is reacted with formamidine or its salt in isopropanol and tetra-n-butylammonium bromide (TBAB) as phase transfer catalyst.
However, the processes disclosed in the above mentioned prior art has the following observed limitations:
• This route of synthesis is costly and not feasible at industrial scale;

• This route involves the use of hazardous sodium hydride in the preparation of compound namely, dimethyl (4-bromophenyl)malonate of formula (IV);
• Conventional cyclisation of dimethyl (4-bromophenyl)malonate of formula (IV) uses formamidine hydrochloride of formula (V) to obtain compound of 5 -(4-bromophenyl) pyrimidine-4,6-diol of formula (VI), which is industrially not feasible because formamidine hydrochloride formula (V) is very costly. Further, the reaction time of cyclisation is approximately 24 hours Thus making the process lengthy, industrially disadvantageous and expensive; and
• The reported process for the preparation of formula (I) involves column chromatographic purification thereby making the process undesirable for large scale operations, and hence, economically unfeasible.
Hence, there is a need for providing process that overcomes the above stated limitations.
The present invention proposes a process for preparation of 5-(4-bromophenyl)-4,6-dichloropyrimidine (I), which is economic, efficient, eco-friendly and eliminates extensive laborious work-up.
OBJECTS OF THE PRESENT INVENTION
The primary object of the present invention is to provide a process for preparation of 5-(4-bromophenyl)-4,6-dichloropyrimidine (I).
Another object of the invention is to provide a process for preparation of 5-(4-bromophenyl)-4,6-dichloropyrimidine, wherein the process uses cyclising agent namely, formamide, which is easily available at cheaper cost and also reduces time for cyclisation, thereby making the process efficient and economic.

Yet another object of the invention is to provide a process for preparation of 5-(4-bromophenyl)-4,6-dichloropyrimidine, wherein the process avoids use of special apparatus / equipment including column chromatograph and also eliminates extensive laborious work-up thereby making the process efficient, eco-friendly and industrially viable.
Still another object of the invention is to provide a process for preparation of 5-(4-bromophenyl)-4,6-dichloropyrimidine, wherein the process results into high yield as well as purity and thus making the product substantially free from impurities.
DETAILED DESCRIPTION OF THE INVENTION
Before the present invention is described, it is to be understood that this invention is not limited to particular methodologies and materials described, as these may vary as per the person skilled in the art. It is also to be understood that the terminology used in the description is for the purpose of describing the particular embodiments only, and is not intended to limit the scope of the present invention.
Before the present invention is described, it is to be understood that unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Further, it is to be understood that the present invention is not limited to the methodologies and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described, as these may vary within the specification indicated. Unless stated to the contrary, any use of the words such as "including," "containing," "comprising," "having" and the like, means "including without limitation" and shall

not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims. Further the terms disclosed embodiments are merely exemplary methods of the invention, which may be embodied in various forms.
A term "reflux temperature" referred herein means the temperature at which the solvent or the solvent system refluxes or boils at atmospheric pressure.
According to the present invention, there is provided a process for the preparation of 5-(4-bromophenyl)-4,6-dichloropyrimidine of formula (I), wherein the said process comprises the steps of:
a) reacting 4-(bromophenyl) acetic acid of formula (II) with methanol in the presence of acid to produce methyl-(4-bromophenyl) acetate of formula (III);

b) condensing compound of formula (III) with dimethyl carbonate in a solvent and in presence of a base to obtain dimethyl-(4-bromophenyl) malonate of formula (IV);


c) cyclizing dimethyl-(4-bromophenyl) malonate of formula (IV) by using base and formamide of formula (Va) in a suitable solvent to obtain 5-(4-bromophenyl)pyrimidine-4,6-diol of formula (VI); and

d) chlorinating the compound (VI) to obtain 5-(4-bromophenyl)-4,6-dichloro pyrimidine of formula (I);

The solvent used in steps (b) and (c) may be either same or different and is selected from alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, ter-butanol, ethylene glycol, 2-ethyl hexanol, 2-methyl-l-butanol, 2-methyl-l-pentanol, 3-methyl-2-butanol, 2-pentanol, propylene glycol,

hexylene glycol, triethylene glycol, tripropylene glycol, and the like; ester such as ethyl acetate, methyl acetate, isopropyl acetate, hexyl acetate, butyl acetate, sec-butyl acetate, tert-butyl acetate, and the like; ether such as tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, methyl tert-butyl ether, ethyl tert-butyl ether, 1,4-dioxane, dimethoxy ethane, dimethoxy methane, diisopropyl ether, di-tert-butyl ether, and the like; hydrocarbon such as toluene, xylene, hexane, heptane, pentane, cyclohexane, cycloheptane, cyclopentane, cyclooctane and the like; polar aprotic solvents such as N,N-dimethyl acetamide, N,N-dimethyl formamide, dimethyl sulfoxide and the like; ketone such as acetone, methyl ethyl ketone/butanone, methyl isobutyl ketone, methyl isopropyl ketone and the like; halogenated hydrocarbons such as dichloro methane, chloroform, chlorobenzene, dichloro ethane, and the like; nitrile such as acetonitrile, propionitrile, butyronitrile and the like; nitro hydrocarbons such as nitro methane, nitro ethane, nitro benzene and the like; cyclic amides such as N-methylpyrrolidinone and the like; polar solvent such as water; and mixtures thereof.
The acid used in the step (a) is selected from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like; or organic acids such as trifluoroacetic acid, acetic acid, methane sulfonic acid, and the like.
The base used in step (b) of the present invention may be organic or inorganic base; organic bases selected from group consisting of primary amines such as methylamine, ethyl amine, propyl amine, 2-propyl amine, and butyl amine; secondary amines such as N,N-diisopropyl amine, dimethylamine, diethyl amine, N-methyl propyl amine, pyrrole, and methyl ethanolamine; tertiary amines such as triethylamine, N,N-dimethyl aniline, N,N-diisopropyl ethyl amine, trimethyl amine, pyridine, pyrimidine, and N,N-dimethylethyl amine; tetra alkyl ammonium and phosphonium hydroxides; inorganic bases selected from group consisting of alkali

metal carbonates such as potassium carbonate, sodium carbonate, and cesium carbonate; alkali metal bicarbonates such as sodium bicarbonate, and potassium bicarbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide, and lithium hydroxide; metal hydrides such as sodium hydride, and potassium hydride; alkali metal alkoxides selected from sodium methoxide, sodium ethoxide, and potassium tert butoxide.
The cyclising agent used in step (c) is formamide.
The base used in the cyclisation step (c) is inorganic bases selected from group consisting of alkali metal carbonates such as but not limited to potassium carbonate, sodium carbonate and cesium carbonate; alkali metal bicarbonates such as but not limited to sodium bicarbonate and potassium bicarbonate; alkali metal hydroxides such as but not limited to sodium hydroxide, potassium hydroxide, barium hydroxide and lithium hydroxide; metal hydrides such as but not limited to sodium hydride and potassium hydride; alkali metal alkoxides such as but not limited to sodium methoxide, sodium ethoxide and potassium tert butoxide.
The chlorinating agent used in step (d) is selected from thionyl chloride, phosphorous trichloride, phosphorous pentachloride, phosphorus oxychloride, oxalyl chloride and the like.
In a preferred embodiment of the present invention, step (a) is carried out at temperature ranging from 35° C to 75° C; preferably at the temperature ranging from 60°C to 70°C.

In a preferred embodiment of the present invention, step (b) is carried out at temperature ranging from 0° C to 30° C, preferably at the temperature ranging from 0° C to 5° C.
In a preferred embodiment of the present invention, step (c) is carried out at the temperature ranging from 40° C to 75° C, preferably at a temperature ranging from 60° C to 70° C.
In a preferred embodiment of the present invention, step (d) is carried out at the temperature ranging from 40° C to 110° C, preferably at a temperature ranging from 80° C to 90° C.
According to another embodiment of the present invention, compound of formula (III) can be purified by using conventional methods known in the art like recrystalization, salt making and salt breaking or by other conventional purification process.
According to the present invention, isolation followed by purification of compound of the formula (III) from reaction mass of step (a) comprises the steps of: i. concentrating the reaction mixture of step (a) to obtain a residue; ii. suspending the obtained residue of step (i) in a mixture of solvent and water; iii. separating the organic layer followed by neutralizing the separated organic
layer with suitable aqueous base; and iv. concentrating the organic layer of step (iii) to obtain compound of formula (III).
The solvent used in the above step (ii) is selected from alcohols such as methanol, ethanol, isopropanol, n-butanol and the like; aromatic hydrocarbons such as toluene,

xylene, and the like; aliphatic hydrocarbons such as hexane, heptane and the like; halogenated hydrocarbon such as dichloromethane, dichloroethane and the like; formamide such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the like; cyclic amides such as N-methylpyrrolidinone and the like; nitriles such as acetonitrile and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, diisopropyl ether, methyl tert-butyl ether and the like; esters such as ethyl acetate, methyl acetate, isopropyl acetate and the like; or a mixture thereof.
The mixture of solvent and water used in step (ii) is in proportion of 60:40.
The base used in step (iii) is selected from aqueous solution of alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates.
According to the present invention, compound of the formula (IV) is isolated from reaction mass of step (b) and further purified it. The said isolation and purification of compound of the formula (IV) comprises the steps of: v. concentrating the reaction mixture of step (b) to obtain a residue; vi. suspending the obtained residue of step (v) in a mixture of solvent and water; vii. separating and concentrating organic layer of step (vi) to obtain a residue; viii. suspending the obtained residue of step (vii) in solvent and heating the suspension; ix. cooling and stirring the obtained suspension of step (viii); x. filtering the precipitate of step (ix) and washing the precipitate with organic
solvent; and xi. drying the obtained solid of step (x) to get solid compound of formula (IV).

The solvent used is step (vi), (viii) and (x) is selected from alcohols such as methanol, ethanol, isopropanol, n-butanol and the like; aromatic hydrocarbons such as toluene, xylene, and the like; aliphatic hydrocarbons such as hexane, heptane and the like; halogenated hydrocarbon such as dichloromethane, dichloroethane and the like; formamide such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the like; cyclic amides such as N-methylpyrrolidinone and the like; cyclic amides such as N-methylpyrrolidinone and the like; nitriles such as acetonitrile and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, diisopropyl ether, methyl tert-butyl ether and the like; esters such as ethyl acetate, methyl acetate, isopropyl acetate and the like; or a mixture thereof.
The mixture of solvent and water used in step (vi) is in proportion of 33:67.
The suspension is heated in step (viii) in the range of 65°C to 75°C, preferably at 70° C.
The heated suspension is cooled in step (ix) in the range of 0°C to 5°C, preferably at 0°C.
According to the present invention, compound of the formula (VI) is isolated from
the reaction mass of step (c) followed by purifying it; said process of isolation and
purification comprises the steps of:
xii. concentrating the reaction mixture of step (c) to obtain a residue; xiii. suspending the obtained residue of step (xii) in a water; xiv. acidifying the solution of step (xiii) with hydrochloric acid and heating the reaction mixture to precipitate product;
xv. filtering the precipitate of step (xiv) and washing the precipitate with water;

xvi. neutralizing the solid obtained in step (xv); xvii. drying the obtained solid of step (xvi) to get a crude solid compound of
formula (VI); and xviii. crystallising the crude solid obtained in step (xvii) in a solvent followed by
drying it to obtain compound of formula (VI).
The solvent used in step (xviii) is selected from alcohols such as methanol, ethanol, isopropanol, n-butanol and the like; aromatic hydrocarbons such as toluene, xylene, and the like; aliphatic hydrocarbons such as hexane, heptane and the like; halogenated hydrocarbon such as dichloromethane, dichloroethane and the like; formamide such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the like; cyclic amides such as N-methylpyrrolidinone and the like; nitriles such as acetonitrile and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, diisopropyl ether, methyl tert-butyl ether and the like; esters such as ethyl acetate, methyl acetate, isopropyl acetate and the like; or a mixture thereof.
In step (xiv), the solution was acidified with hydrochloric acid to adjust the pH at around 2 to 2.5.
The neutralizing the solid in step (xvi) is carried out by washing the solid with water till the filtrate obtained has pH around 7-7.5.
The solid is dried in step (xvii) at 95°C to 100°C to get solid compound of formula (VI).

The solid is purified by crystallization in a solvent at temperature in the range of 60°C to 65 °C and subsequently cooled to obtain pure crystals of the compound of formula (VI).
According to the present invention, the compound of formula (I) is isolated from the reaction mass of step (d) and further purified it. The said process of isolation and purification comprises the steps of: xix. quenching the reaction mass of step (d) with ice water to precipitate a
compound of formula (I); xx. filtering and neutralizing the precipitate of step (xix); xxi. drying solid obtained in step (xx) to get a crude solid compound of formula
(I); and xxii. crystallizing the crude solid obtained in step (xxi) in a solvent followed by drying it to obtain compound of formula (I).
The crude solid is purified in the step (xxii) by crystallization wherein
the crude product is heated in a solvent at temperature in the range of 60° C
to 65 °C to get solution;
an activated carbon is added into the solution and maintained it at
temperature in the range of 60° C to 65 °C for 1 hour;
the reaction mixture is filtered;
the filtered mass is washed with hot methanol; and
the filtrate is combined with washings and cooled it to 0°C to obtain pure
crystals of the compound of formula (I).
The solvent used is step (xxii) is selected from alcohols such as methanol, ethanol, isopropanol, n-butanol and the like; aromatic hydrocarbons such as toluene, xylene, and the like; aliphatic hydrocarbons such as hexane, heptane and the like;

halogenated hydrocarbon such as dichloromethane, dichloroethane and the like; formamide such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the like; cyclic amides such as N-methylpyrrolidinone and the like; nitriles such as acetonitrile and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, diisopropyl ether, methyl tert-butyl ether and the like; esters such as ethyl acetate, methyl acetate, isopropyl acetate and the like; or a mixture thereof.
The reaction mass of step (d) is quenched with ice water in step (xix) at temperature below 15°C to precipitate compound of formula (I).
The precipitate is neutralized in step (xx) by washing the solid with water till the pH of filtrate adjusted to 6.5-7.0.
The solid obtained is dried in the step (xxi) at 60° C to 65° C to get a crude solid compound of formula (I).
The solid obtained in step (b), (c) and (d) may be dried using conventional methods such as Air tray drier (ATD), Vacuum Tray Drier (VTD), Fluidized bed drier (FBD), Spin Flash Drier (SFD), Flash Drier (FD), and the like.
According to the present invention, the obtained 5-(4-bromophenyl)-4,6-dichloropyrimidine of formula (I) can be further used for manufacturing of Macitentan by any method known in the art.

According to the invention, the overall yield of 5-(4-bromophenyl)-4,6-dichloropyrimidine of formula (I) as obtained by using the process of the present invention is at least about 70-80% with purity of at least about 99.0% by HPLC.
More particularly, the total purity of 5-(4-bromophenyl)-4,6-dichloropyrimidine of formula (I) as obtained according to the invention is at least about 99.70%) (by HPLC).
5-(4-bromophenyl)-4,6-dichloropyrimidine of formula (I) prepared according to the present invention, is substantially free from impurities generated either by carryover impurities from starting materials, side products, starting materials, reagents and solvents.
Thus, the present invention uses formamide, which is easily available at cheaper rate as compared to that of formamidine hydrochloride. Further, the cyclisation step of the present invention is carried out at reflux temperature and completes in an around 6 hours as the prior art carried out cyclization at 0°C followed to room temperature in about 24 hours. Thereby, reducing reaction time or production time and manufacturing cost of 5-(4-bromophenyl)-4,6-dichloropyrimidine of formula (I). The present invention avoids laborious workup and uses only simple crystallization or solvent treatment results into yield, of at least about 70-80% with purity of at least 99.7 % by HPLC. Thereby, making the process efficient, economic and industrially viable.

BEST MODE OR EXAMPLES FOR WORKING OF THE INVENTION
The present invention is described in the examples given below; further these are provided only to illustrate the invention and therefore should not be construed to limit the scope of the invention.
EXAMPLE 1
Preparation of methyl (4-bromophenvl) acetate (III)
4- bromophenyl acetic acid (100 gm) was charged in 300ml methanol under stirring. Addition of sulfuric acid (30 ml) was carried out under stirring in 1 hr. The temperature of the reaction mass was increased to 70° C and maintained the temperature until the completion of reaction by HPLC analysis. After completion of the reaction, excess methanol was distilled under vacuum below 70° C. In crude, methylene dichloride (300 ml) and water (200 ml) was charged, and the mixture was stirred for 15 minutes. The mixture was allowed to settle and separated the organic layer from aqueous layer. The organic layer was neutralized by adding 5 % aqueous solution of sodium bicarbonate into it. The organic layer so obtained was subjected to distillation under vacuum and the liquid product was collected. Methyl (4-bromophenyl) acetate as obtained is light brown colour liquid. [Yield: 101 gm, Purity by HPLC: 99%, Boiling Point: 265-270° C]
EXAMPLE 2:
Preparation dimethyl (4-bromophenvl) malonate (IV)
Sodium methoxide (95 gm) was added to the tetrahydrofuran (300 ml). The reaction mass was cooled-to 0° C. The solution of methyl-(4-bromophenyl) acetate (III) (100 gm) in 100 ml tetrahydrofuran was added into the reaction mass maintaining the temperature at 0° C in 2 hrs. After completion of addition, the reaction mass was maintained at 0° C in 1 hr. The dimethyl carbonate (DMC) (80 gm) was added

maintaining temperature of the reaction mass 0°C in 2 hrs. The mass was maintained at RT until the completion of reaction by HPLC analysis. After completion of reaction, excess tetrahydrofuran from the reaction mass was distilled off under vacuum at 45° C to obtain crude product. In the crude product, mixture of methylene dichloride (250 ml) and water (500 ml) was added and the mixture was stirred for 30 minutes. The mixture was allowed to settle to separate two phases. The organic layer was separated from the aqueous layer. The excess methylene dichloride was distilled off from the organic layer under vacuum at-45° C to obtain the crude product. In crude product, isopropyl alcohol (200 ml) was charged and raised the temperature of the mixture to 70° C and maintained it for 1 hr. The mass was cooled, chilled to 0° C and filtered. The obtained solid was washed with chilled isopropyl alcohol and dried to get off white solid powder. [Yield: 80gm, Purity by HPLC: 99%, Melting Point: 70 -74° C]
EXAMPLE 3:
Preparation of 5 - (4 - bromophenvl) pyrimidine - 4, 6 - diol (VI)
The dimethyl (4-bromophenyl) malonate (IV) (lOOgm) was added to methanol (400ml) under stirring. Formamide (30 gm) was added to the reaction mass. Sodium methoxide (30 gm) was added to the reaction mass. The temperature of the reaction mass was raised to 70 °C and maintained it until completion of reaction by HPLC analysis. After completion of the reaction, excess methanol was distilled off from the reaction mass under vacuum below 70° C to obtain crude product. In the crude product, water (2000 ml) was charged and stirred the mixture for 30 minutes. The pH of the mixture was adjusted to 2 to 2.5 by adding 30 % hydrochloric acid to the mixture. The reaction mixture was filtered to obtain crude product and washed it with water till pH of filtrate was 7-7.5. The product was suck dried and followed by drying in an oven at 100°C to obtain crude solid powder of 5-(4-bromophenyl)pyrimidine-4,6-diol. In crude material, methanol (500 ml) was charged

and temperature of the mixture was raised to 65°C maintained for 1 hr. The reaction
mass was cooled to RT and the mass was filtered to obtain solid product. The solid
product so obtained was washed with methanol and it was dried to get cream solid
powder.
[Yield: 70gm, Purity by HPLC: 99.5 %, melting point above 300°C]
EXAMPLE 4:
Preparation of 5-(4-bromophenvl)-4,6-dichloropyrimidine (I) :
The 5-(4-bromophenyl) pyrimidine-4,6-diol (VI) (100 gm) was added to phosphorous oxychloride (300 ml) under stirring. The temperature of the reaction mixture was raised to 90° C and maintained the temperature of the reaction until completion of reaction by HPLC analysis. The reaction mass was quenched into ice-water mixture below 15°C. The product was filtered and pH of filtrate was adjusted to 6.5-7.0. The material was suck dried and further dried it in an oven at 65° C to obtain off white crude solid. In crude product, methanol (400 ml) was charged and the temperature of the mixture was increased to 65° C for dissolving the product. In a solution, 10.0 gm activated carbon was charged and maintained the temperature of the solution to 65 °C for 1 hr. The reaction mass was filtered and the filtered mass was washed with hot methanol (50 ml). The filtrate was combined with washings and cooled it and subsequently chilled it to 0°C, maintaining for 2 hrs at 0° C to obtain pure crystals. The pure crystals was filtered to obtain solid which was washed with chilled methanol and dried to get white solid powder of 5-(4-bromophenyl)-4,6-dichloropyrimidine. [Yield: 90gm, Purity by HPLC: 99.7 %, melting point: 94 - 97°C]

We Claim:
1. A process for the preparation of 5-(4-bromophenyl)-4,6- dichloropyrimidine of formula (I), wherein the said process comprising;
a) reacting 4-(bromophenyl) acetic acid of formula (II) with methanol in the presence of acid to obtain Methyl-(4-bromophenyl) acetate of formula (III);

b) condensing compound of formula (III) with dimethyl carbonate in a solvent and in presence of a base to obtain dimethyl-(4-bromophenyl) malonate of formula (IV);

c) cyclizing dimethyl (4 - bromophenyl) malonate of formula (IV) by using base and formamide of formula (Va) in a solvent to obtain 5-(4-bromophenyl) pyrimidine-4,6-diol of formula (VI); and


d) chlorinating the compound of formula (VI) to obtain 5-(4-bromophenyl)-4,6-dichloropyrimidine of formula (I);

2. The process as claimed in claim 1, wherein the solvent used in step (b) and (c) is selected from alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, ter-butanol, ethylene glycol, 2-ethyl hexanol, 2-methyl-1-butanol, 2-methyl-l-pentanol, 3-methyl-2-butanol, 2-pentanol, propylene glycol, hexylene glycol, triethylene glycol or tripropylene glycol; hydrocarbon such as toluene, xylene, hexane, heptane, pentane, cyclohexane, cycloheptane, cyclopentane or cyclooctane; halogenated hydrocarbon such as dichloromethane, chloroform, chlorobenzene or dichloro ethane; polar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide or dimethylsulfoxide; nitrile such as acetonitrile, propionitrile or butyronitrile; nitro hydrocarbons such as nitro methane, nitro ethane or nitro benzene; cyclic amides such as N-methylpyrrolidinone; ketones such as acetone, methyl ethyl ketone/butanone, methyl isobutyl ketone or methyl isopropyl ketone; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, diisopropyl ether,

methyl tert-butyl ether, ethyl tert-butyl ether, 1,4- dioxane, dimethoxy ethane, dimethoxy methane or di-tert-butyl ether; esters such as ethyl acetate, methyl acetate, isopropyl acetate, hexyl acetate, butyl acetate, sec-butyl acetate or tert-butyl acetate; polar solvent such as water or a mixture thereof.
3. The process as claimed in claim 1, wherein the acid used in the condensation step (a) is selected from inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid; or organic acids such as trifluoroacetic acid, acetic acid or methane sulfonic acid.
4. The process as claimed in claim 1,wherein the base used in step (b) may be organic or inorganic base; organic bases selected from group consisting of primary amines like methylamine, ethanolamine aniline, propyl amine, 2-propyl amine and butyl amine; secondary amines such as N,N-diisopropyl amine, dimethylamine, diethyl amine, N-methyl propyl amine, pyrrole and methyl ethanolamine; tertiary amines such as triethylamine, N,N-dimethyl aniline, N,N-diisopropyl ethyl amine, trimethyl amine, pyridine, pyrimidine and N,N-dimethylethyl amine; tetra alkyl ammonium and phosphonium hydroxides; inorganic bases selected from group consisting of alkali metal carbonates such as potassium carbonate, sodium carbonate and cesium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide and lithium hydroxide; metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides selected from sodium methoxide, sodium ethoxide and potassium tert butoxide.
5. The process as claimed in claim 1,wherein the base used in step (c) is inorganic bases selected from group consisting of alkali metal carbonates such as potassium

carbonate, sodium carbonate and cesium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide and lithium hydroxide; metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert butoxide.
6. The process as claimed in claim 1, wherein the chlorinating agent used in step (d) is selected from thionyl chloride, phosphorous trichloride, phosphorous pentachloride, phosphorous oxychloride and oxalyl chloride.
7. The process as claimed in claim 1, wherein the compound of the formula (III) is isolated from reaction mass of step (a) followed by purification by
i. concentrating the reaction mixture of step (a) to obtain a residue; ii. suspending the obtained residue of step (i) in a mixture of solvent and
water; iii. separating the organic layer followed by neutralizing the separated
organic layer with suitable aqueous base; and iv. concentrating the organic layer of step (iii) to obtain compound of
formula (III).
8. The process of claim 7, wherein the solvent used in step (ii) is selected from
alcohols such as methanol, ethanol, isopropanol or n-butanol; aromatic
hydrocarbons such as toluene or xylene; aliphatic hydrocarbons such as hexane or
heptane; halogenated hydrocarbon such as dichloromethane or dichloroethane;
formamide such as N,N-dimethylformamide or N,N-dimethylacetamide;
sulfoxides such as dimethylsulfoxide; cyclic amides such as N-
Methylpyrrolidinone; nitriles such as acetonitrile; ketones such as acetone or

methyl isobutyl ketone; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, diisopropyl ether or methyl tert-butyl ether; esters such as ethyl acetate, methyl acetate or isopropyl acetate; or a mixture thereof.
9. The process of claim 7, wherein the base used in step (iii) is selected from aqueous
solution of alkali metal hydroxides, alkali metal carbonates and alkali metal
bicarbonates.
10. The process as claimed in claim 1, wherein the compound of the formula (IV) is
isolated from reaction mass of step (b) followed by purification by
v. concentrating the reaction mixture of step (b) to obtain a residue; vi. suspending the obtained residue of step (v) in a mixture of solvent and
water; vii. separating and concentrating the organic layer of step (vi) to obtain a
residue; viii. suspending the obtained residue of step (vii) in solvent and heating the
suspension; ix. cooling and stirring the obtained suspension of step (viii); x. filtering the precipitate of step (ix) and washing the precipitate with
organic solvent; and xi. drying the obtained solid of step (x) to get solid compound of formula
(IV).
11. The process of claim 10, wherein the solvent used is step (vi), (viii) and (x) is .
selected from alcohols such as methanol, ethanol, isopropanol or n-butanol;
aromatic hydrocarbons such as toluene or xylene; aliphatic hydrocarbons such as
hexane- or heptane; halogenated hydrocarbon such as dichloromethane or
dichloroethane; formamide such as N,N-dimethylformamide or N,N-

dimethylacetamide; sulfoxides such as dimethylsulfoxide; cyclic amides such as N-methylpyrrolidinone; nitriles such as acetonitrile; ketones such as acetone or methyl isobutyl ketone; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, diisopropyl ether or methyl tert-butyl ether; esters such as ethyl acetate, methyl acetate or isopropyl acetate; or a mixture thereof.
12. The process as claimed in claim 1, wherein the compound of formula (VI) is
isolated from the reaction mass of step (c) followed by purifying it by
xii. concentrating the reaction mixture of step (c) to obtain a residue; xiii. suspending the obtained residue of step (xii) in a water; xiv. acidifying the solution of step (xiii) with hydrochloric acid and heating
the reaction mixture to precipitate product; xv. filtering the precipitate of step (xiv) and washing the precipitate with
water; xvi. neutralizing the solid obtained in step (xv); xvii. drying solid of step (xvi) to get a crude solid compound of formula (VI);
and xviii. crystallising the crude solid obtained in step (xvii) in a solvent followed
by drying it to obtain compound of formula (VI).
13. The process of claim 12, wherein the solvent used is step (xviii) is selected from
alcohols such as methanol, ethanol, isopropanol or n-butanol; aromatic
hydrocarbons such as toluene or xylene; aliphatic hydrocarbons such as hexane
or heptane; halogenated hydrocarbon such as dichloromethane or dichloroethane;
formamide such as N,N-dimethylformamide or N,N-dimethylacetamide;
sulfoxides such as dimethylsulfoxide; cyclic amides such as N-
methylpyrrolidinone; nitriles such as acetonitrile; ketones such as acetone or
methyl isobutyl ketone; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran,

diisopropyl ether or methyl tert-butyl ether; esters such as ethyl acetate, methyl acetate or isopropyl acetate; or a mixture thereof.
14. The process as claimed in claim 1, wherein the compound of the formula (I) is
isolated from the reaction mass of step (d) followed by purifying it by
xix. quenching the reaction mass of step (d) with ice water to precipitate
compound of formula (I); xx. filtering and neutralizing the precipitate of step (xix); xxi. drying the solid obtained in step (xx) to get a crude solid compound of
formula (I); and xxii. crystallizing the crude solid obtained in step (xxi) in a solvent followed
by drying it to obtain compound of formula (I).
15. The process of claim 14, wherein the solvent used is step (xxii) is selected from
alcohols such as methanol, ethanol, isopropanol or n-butanol; aromatic
hydrocarbons such as toluene, xylene; aliphatic hydrocarbons such as hexane or
heptane; halogenated hydrocarbon such as dichloromethane or dichloroethane;
formamide such as N,N-dimethylformamide or N,N-dimethylacetamide;
sulfoxides such as dimethylsulfoxide; cyclic amides such as N-
methylpyrrolidinone; nitriles such as acetonitrile; ketones such as acetone or
methyl isobutyl ketone; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran,
diisopropyl ether or methyl tert-butyl ether; esters such as ethyl acetate, methyl
acetate or isopropyl acetate; or a mixture thereof.
16. The process as claimed in any of the preceding claims, wherein the 5-(4-
bromophenyl)-4,6-dichloropyrimidine of formula (I) obtained has at least
99.70% purity.