DESC:FORM 2
THE PATENT ACT, 1970
[39 OF 1970]
&
PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

AN INDUSTRIAL PROCESS FOR THE PREPARATION OF
5-BROMO-2-FLUOROBENZONITRILE

IND-SWIFT LABORATORIES LIMITED
S.C.O. NO. 850, SHIVALIK ENCLAVE,
NAC, MANIMAJRA,
CHANDIGARH-160101

The following application particularly describes the invention and the manner in which is to be performed

FIELD OF THE INVENTION
The present invention relates to an industrially advantageous process for the preparation of 5-bromo-2-fluorobenzonitrile of formula I, with high purity and high yield

Formula I
wherein compound of formula I is a precursor of key intermediate used in the synthesis of certain xanthine oxidase inhibitor compounds such as febuxostat.

BACKGROUND OF THE INVENTION
Febuxostat is a xanthine oxidase inhibitor which is used in the management of chronic hyperuricemia and it is sold by the brand name of Uloric. It is chemically known as 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid and is represented by the formula II.

Formula II

Febuxostat as a product is first described in US5,614,520 herein referred as US '520. US '520 discloses a process for the preparation of febuxostat, wherein 4-hydroxy-3-nitrobenzaldehyde is heated with hydroxylamine hydrochloride and sodium formate, in presence of formic acid to give 4-hydroxy-3-nitrobenzonitrile, which on reaction with thioacetamide in presence of hydrogen chloride in N,N-dimethylformamide yields 4-hydroxy-3-nitrobenzthioamide. The resulting compound is then reacted with ethyl 2-chloroacetoacetate to give ethyl 2-(4-hydroxy-3-nitrophenyl)-4-methyl-5-thiazolecarboxylate and converted into ethyl 2-[4-(2-methylpropoxy)-3-nitrophenyl]-4-methyl-5-thiazolecarboxylate by O-alkylation. The nitro group of resulting compound is reduced by using hydrogen in presence of Pd/C in mixed solvent of ethyl acetate and ethanol to give corresponding amino derivative. The amino derivative is diazotized and reacted with potassium cyanide in presence of cuprous cyanide, which after decomposition and work up, purified using silica gel column chromatography to give febuxostat ester derivative. The resulting febuxostat ester derivative on hydrolysis using sodium hydroxide gives febuxostat. The reaction sequence is as shown below:

The main drawback of this process is that it results in poor yield of intermediates and final product thereof. Therefore, said process is not industrially viable and it is not an attractive route for synthesizing febuxostat.

US patent publication US2011/0313169 discloses an alternative short step process for the preparation of febuxostat by using 5-bromo-2-isobutoxybenzonitrile as a key starting material, which in turn is prepared from 5-bromo-2-fluorobenzonitrile. Therefore, 5-bromo-2-fluorobenzonitrile is an important precursor of key intermediate 5-bromo-2-isobutoxybenzonitrile, used for the synthesis of febuxostat.
The said US publication is silent about the preparation of 5-bromo-2-fluorobenzonitrile and there is no disclosure found providing preparation of 5-bromo-2-fluorobenzonitrile. A PCT publication WO 9619458, describes the preparation of an isomer, 3-bromo-5-fluorobenzonitrile by the reaction of 1,3-dibromo-5-fluorobenzene with copper (I) cyanide.
A recently granted Chinese patent CN101898976B discloses a process for the preparation of 5-bromo-2-fluorobenzonitrile from 2-fluoroaniline through 2-fluorobenzonitrile. The process comprises of converting 2-fluoroaniline into 2-fluorobenzonitrile via diazotization, bromination and cyanation using suitable reagents. Thereafter 2-fluorobenzonitrile of formula III

Formula III

is converted to 5-bromo-2-fluorobenzonitrile using bromination agent such as N-bromosuccinimide or dibromohydantoin in the presence of an acid including concentrated sulfuric acid at room temperature for 2-18 hours. When the reaction is complete, then ice water is added to the reaction mixture and the resulting solid is isolated by filtration. The resulting compound is then crystallized with anhydrous ethanol to give 70-80% yield of 5-bromo-2-fluorobenzonitrile.

It has been observed that repetition of said process using specified reaction conditions; the bromination reaction of 2-fluorobenzonitrile does not go to completion within 2-18 hours. It is observed that the desired product 5-bromo-2-fluorobenzonitrile is only 28-30%, when the reaction mixture is performed for 2 hours. When same reaction is performed for extended hours upto 48, then the yield of desired product 5-bromo-2-fluorobenzonitrile was even reduced to 3.2% and corresponding amide impurity of formula IV starts forming.

Formula IV

The yield of corresponding amide impurity of formula IV has been increased with the course of reaction time.
Further, the process described uses alcoholic solvents, particularly ethanol, for the final crystallization of the product which leads to undesired yield loss of the compound. The required product has greater solubility in ethanol and so 15-20% of compound is lost during purification with ethanol.
The above observation is strengthened from the working examples of said Chinese patent, wherein yield of desired product 5-bromo-2-fluorobenzonitrile was reduced as timings for reaction of bromination increase. It is reported in said Chinese patent that the yield was 80% when the reaction proceeds for 2 hours and the yield was 70% when the reaction proceeds for 18 hours. Further, patent is silent about the purity of 5-bromo-2-fluorobenzonitrile. Although, reported percentage yield was not obtained, when said experiment was repeated.

Therefore, the major draw back of said Chinese patent application is that said process uses very corrosive and stringent reagent, which may result in high yield of amide impurity instead of desired product 5-bromo-2-fluorobenzonitrile and hence not attractive option for industrial production.
In view of above, there is an urgent need to develop an industrially viable process for the preparation of 5-bromo-2-fluorobenzonitrile, substantially free from corresponding amide impurity, in high purity and high yield.
Therefore, the present invention aims to fulfill the need in the art and provides an cost effective, less time consuming, industrially viable process for the preparation of 5-bromo-2-fluorobenzonitrile with high purity and high yield using moderate reaction condition.

OBJECT OF THE INVENTION
The main object of the present invention is to provide an industrially advantageous process for the preparation of 5-bromo-2-fluorobenzonitrile, a precursor of key intermediates, used in the synthesis of certain xanthine oxidase inhibitor compounds such as febuxostat.

Another object of the present invention is to provide a process for the preparation of pure 5-bromo-2-fluorobenzonitrile by using moderate reaction conditions.

Another object of the present invention is to provide a process for the purification of 5-bromo-2-fluorobenzonitrile to obtain pure 5-bromo-2-fluorobenzonitrile in high yield and purity.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides a process for the preparation of pure 5-bromo-2-fluorobenzonitrile compound of formula I, with high yield and purity comprises the step of:

Formula I
a) reacting 2-fluorobenzonitrile of formula III,

Formula III
with a suitable brominating agent in the presence of an acid catalyst, at least in the presence of water at a suitable temperature for sufficient time,
b) quenching the reaction mass;
c) isolating 5-bromo-2-fluorobenzonitrile of formula I;
d) optionally, recrystallizing 5-bromo-2-fluorobenzonitrile using a suitable organic solvent.
According to another embodiment, the present invention provides a process for the purification of 5-bromo-2-fluorobenzonitrile of formula I,

Formula I

by recrystallization of 5-bromo-2-fluorobenzonitrile with a suitable volatile solvents at suitable temperature for sufficient time for recrystallization.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an industrially advantageous process for the preparation of 5-bromo-2-fluorobenzonitrile, a precursor of key intermediates, used in the synthesis of certain xanthine oxidase inhibitor compounds such as febuxostat.
According to one embodiment, the present invention provides a process for the preparation of pure 5-bromo-2-fluorobenzonitrile of formula I with high yield and purity, under moderate reaction condition. The process involves reaction of 2-fluorobenzonitrile with a suitable brominating agent in the presence of an acid catalyst and water at room temperature for sufficient time.
As used herein ''pure 5-bromo-2-fluorobenzonitrile compound of formula I '' refers to 5-bromo-2-fluorobenzonitrile compound of formula I having purity greater than 99.0%, more preferably greater than 99.5%, and absence of amide impurity, checked by GC.
The suitable brominating agent includes but not limited to N-bromosuccinimide [NBS] N-bromoacetamide, dibromo hydantoins, 1,3-dibromo-5,5-dimethylhydantoin [DBH], N-bromophthalimide, N-bromosaccharin, bromo trichloromethane, bromine, boron tribromide, tetrabutylammonium tribromide, trimethylphenylammonium tribromide, bromodimethylsulfonium bromide, benzyl trimethylammonium tribromide, potassium tribromide, triphenylphosphine dibromide and the like. The brominating reagent and 2-fluorobenzonitrile can be taken in the ratio of 0.1-2:1.
The suitable acid catalyst used in the reaction can be selected from a group, which provides moderate reaction conditions for reaction such as sulfuric acid in water, acetic acid, trifluoromethanesulfonic acid, trifluoroacetic acid. Preferably, sulfuric acid in water or dilute sulfuric acid is used as a catalyst for bromination reaction. The optimal ratio of sulfuric acid to water can be 1:1 to 4:1, preferably from 1.5-2.5:1.
The bromination reaction can be carried out with or without solvent. The solvent can be selected from water, methanol, ethanol, isopropanol, tert-butanol, acetonitrile, tetrahydrofuran, carbon tetrachloride, 1,4-dioxane, methylene chloride, chloroform, polyethylene glycol, ethylene glycol, pentane, hexane, cyclohexane, heptane and petroleum ether and the like or mixture thereof.

The bromination reaction can be carried out at the temperature range of -10°C to 70oC, the preferred temperature range is 0-30oC, most preferred temperature range is 20-30oC, for few minutes to few hours or till the completion of reaction. It is advantageous to carry out the reaction at around ambient temperature as at higher temperature formation of undesired side-products are more and at low temperature, rate of reaction is slow and sometimes, reaction is incomplete and further putting burden of cooling on equipment.

After, competition of the reaction, the reaction is quenched by slow addition of demineralized water, since quenching of reaction is exothermic. Then reaction mixture is cooled at room temperature and kept at same temperature for upto 2 hours for complete precipitation. the solid thus, precipitated can be isolated by conventional techniques such as filtration or centrifugation. It is advantageous to use water with sulfuric acid or dilute sulfuric acid, since it avoids the formation of amide impurity of formula IV.

Formula IV
Even in crude 5-bromo-2-fluorobenzonitrile, prepared by using process of present invention, amide impurity is present in less than 0.5% by GC. The amide impurity of formula IV is characterized by 1H NMR (400 MHz, CDCl3): ? 8.19-8.16 (dd, J = 6.8, 2.6 Hz, 1 H), 7.56-7.52 (dd, J = 8.7, 4.5, 2.6 Hz, 1H), 7.01-6.96 (dd, J = 11.2, 8.7 Hz, 1H) 6.60 (bs, 1H), 6.21 (bs, 1H).
GC-MS: m/z, - 217.0 and 219.0 [calculated for C7H5BrFNO (M)+ 216.9 and 218.9]

The reaction monitoring results of bromination reaction using concentrated sulfuric acid is given below in Table 1

Table 1(GC-MS analytical result)
S.N. Time
(hours) 2-Fluoro
benzonitrile 5-Bromo-2-fluorobenzonitrile 5-Bromo-2-fluorobenzamide(Amide Impurity of formula IV)
1 1.0 58.1% 28.3% 13.6%
2 2.0 53.2% 28.8% 17.9%
3 4.0 47.0% 28.3% 24.7%
4 6.0 46.2% 26.4% 27.4%
5 24.0 14.2% 13.5% 72.3%
6 27.0 11.3% 11.9% 76.8%
7 31.0 8.9% 9.9% 81.3%
8 48.0 2.1% 3.2% 94.7%

From the above data, it is observed that using concentrated sulfuric acid, amide impurity of formula IV increases as reaction time increases and even after certain period of time, desired compound starts decomposing to amide impurity of formula IV due to strongly acidic conditions by use of corrosive concentrated sulfuric acid.

The reaction monitoring results of bromination reaction using sulfuric acid with water, according to reaction conditions used in present invention is given below in Tables 2 and 3.

Table 2 (GC-MS analytical result)
Sr.
No. Time
(hours) Reagent 2-Fluoro
benzonitrile 5-Bromo-2-fluorobenzonitrile Amide impurity of formula IV
1 4.5 NBS 18.3% 80.7% 1.0%
2 6.0 NBS 1.1% 94.7% 4.2%

Table 3 (GC-MS analytical result)
Sr.
No. Time
(hours) Reagent 2-Fluoro
benzonitrile 5-Bromo-2-fluorobenzonitrile Amide impurity of formula IV
1 4.5 DBH 17.8% 82.1% 1.1%
2 6.0 DBH 1.8% 95.1% 3.1%

In view of the above, it is evident that process of present invention is robust, industrially efficient and avoids the formation of amide impurity of formula IV by using the milder conditions. Also, stirring or holding the reaction mass for longer periods of time, which is often unavoidable in industrial processes, does not lead to increase in the amide impurity or total amount of impurities in the product. The reaction mass, even after stirring for upto 25 to 30 hrs do not show an increase in the impurity formation. As shown in Example 3, Method A, using NBS as brominating agent and dilute sulfuric acid, even after extended reaction time to 23 hours, amide impurity of formula IV is 0.8% and desired compound is 96.4%. In Example 3, another Method B using DBH as brominating agent and dilute sulfuric acid, even after extended reaction time to 31 hours, amide impurity of formula IV is 0.4% and desired compound is 97.5%. From the above comparative data, it is clearly pointed out that even after stirring reaction mass for up to 25 to 30 hours, reaction do not show an increase in the formation of amide impurity of formula IV.
According to another embodiment, the present invention provides a process for the purification of 5-bromo-2-fluorobenzonitrile of formula I by recrystallization using a suitable volatile solvent at suitable temperature.
The solvent used for recrystallization can be selected from halogenated hydrocarbons, nitriles, ketones, aromatic hydrocarbons, esters, ethers, hydrocarbons, alicyclic hydrocarbons or mixtures thereof. Preferably solvent used for recrystallization can be selected from pentane, hexane, cyclohexane, n-heptane, acetonitrile, tetrahydrofuran, 1,4-dioxane, methylene chloride or mixtures thereof.
The temperature used for recrystallization can be in the range of ambient temperature to the reflux temperature of the solvent or till clear solution is formed. The resulting pure 5-bromo-2-fluorobenzonitrile obtained after recrystallization has a purity of greater than 99% ; having the amide impurity of formula IV in less than 0.1% by GC and having yield greater than 75%.
The progress of reaction completion and mass balance can be monitored by suitable techniques such as such as high performance liquid chromatography [HPLC], thin layer chromatography [TLC], gas chromatography [GC] or gas chromatography-mass spectrophotometer [GC-MS] ultra pressure liquid chromatography [UPLC] and the like.
The major advantage of present invention is that the bromination process of the present invention uses moderate conditions and thereby provides 5-bromo-2-fluorobenzonitrile in very high chemical purity with very less amount of amide impurity of formula IV and uses volatile solvent during recrystallization to avoid loss of yield.
Although, following examples illustrate practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of the invention.

EXAMPLES
Example 1: Preparation of 5-bromo-2-fluorobenzonitrile
Method A: To a mixture of sulfuric acid (400ml) and water (200ml), 2-fluorobenzonitrile (100g, 0.83 mol.) and N-bromosuccinimide (162g, 0.91 mol.) were added at room temperature and the reaction mixture was further stirred for 6 hours. After completion of the reaction, the reaction was quenched by slow addition of demineralized water (1400ml). Then reaction mixture was gradually cooled down to room temperature and stirred for further 30 minutes to precipitate the compound. The precipitated compound was filtered and washed with demineralized water (2000 ml). The resulting wet material was stirred again in demineralized water (2000ml) at room temperature for 30 minutes. Then filtered off the reaction mass and suck dried under vacuum. to give crude 5-bromo-2-fluorobenzonitrile. The resulting compound was recrystallized from n-heptane to obtain 127g (76.5%) of the title compound as a white crystalline powder, having purity of 99.5% measured by GC, amide impurity not detected.
m. p: 78-82 ?C.; 1H NMR (400 MHz, CDCl3): ? 7.72-7.77 (m, 2 H), 7.12-7.17 (t, J = 8.6 Hz, 1 H).; GC-MS: m/z :198.9. and 200.9.[ calcd. for C7H3BrFN (M)+ 198.9 and 200.9].
Method B: To a mixture of sulfuric acid (400ml) and water (200ml), 2-fluorobenzonitrile (100g, 0.83 mol.) and dibromohydantoin (142g, 0.5 mol.) were added at room temperature and the reaction mixture was stirred for 6 hours. After completion of the reaction, the reaction was quenched by slow addition of demineralized water (1400ml). Then reaction mixture was gradually cooled down to room temperature and stirred for 30 minutes to precipitate the compound. The precipitated compound was filtered, washed thoroughly with demineralized water (2x2000 ml). and suck dried under vacuum to give crude 5-bromo-2-fluorobenzonitrile. The resulting compound was recrystallized from n-heptane to obtain 140g (85%) of the title compound as a white crystalline powder, having purity of 99.4%; amide impurity not detected, measured by GC.
Example 2 Preparation of 5-bromo-2-fluorobenzonitrile
To a cooled solution of potable water (175L) and sulfuric acid (350L) at room temperature, 2-fluorobenzonitrile (35.0 Kg, 0.29 k. mol.) was added in 15 minutes and followed by addition of N-bromosuccinimide (56.56 Kg, 0.32 k. mol.) at a temperature of 0-5 ?C in 30 minutes under dark. Then temperature of the reaction mixture was slowly raised to room temperature by applying cool water circulation. Then the reaction mixture was maintained at room temperature for 6.0 hours. After completion of the reaction, the reaction mixture was quenched by slow addition of chilled potable water (1400 L) at 0-10 ?C and stirred the reaction mixture for 1.0 hours. Precipitate was filtered by centrifugation and spin dry for 30 minutes. The wet material was stirred in potable water (1400 L) at room temperature for 1.0 hour. Solid material was filtered by centrifugation and spin dry for 30 minutes. The wet material was treated with sodium bicarbonate solution (10%, 1050 L) at room temperature and stirred for 1.0 hour. Solid material was filtered and then stirred in potable water (1400 L) at room temperature for 1.0 hour. The resulting solid material was filtered and dried in vacuum tray dryer at 40-45 ?C for 8.0 hours. The resulting material was recrystallized from n-heptane, and spin dry for 30 min followed by vacuum drying at 40-45 ?C for 6.0 hours to obtain 44.7kg of title compound as a white crystalline powder (77.5%) and having purity 99.5%, amide impurity- not detected, by GC.

Example 3: Preparation of 5-bromo-2-fluorobenzonitrile
Method A: To a stirring mixture of sulfuric acid (40ml) and water (20ml) ,2-fluorobenzonitrile (10g, 0.082 mol.) and N-bromosuccinimide (16.2g, 0.091 mol.) were added at room temperature and the reaction mixture was further stirred for 23 hours. Reaction monitoring showed amide impurity of formula IV as 0.8% and desired compound 96.4%.After completion of the reaction, the reaction was quenched by slow addition of demineralized water (140ml). Then reaction mixture was gradually cooled down to room temperature and stirred for 30 minutes to precipitate the compound. The precipitated compound was filtered and washed with demineralized water (200ml). The resulting wet material was stirred again in demineralized water (200ml) at room temperature for 30 minutes. Then filtered off the reaction mass and suck dried under vacuum. to give crude 5-bromo-2-fluorobenzonitrile. The resulting compound was recrystallized from n-heptane to obtain 13g (78.7%) of the title compound as a white crystalline powder, having purity of 99.2%; amide impurity not detected, measured by GC.
Method B: To a stirring mixture of sulfuric acid (40ml) and water (20ml) , 2-fluorobenzonitrile (10g, 0.082 mol.) and dibromohydantoin (14.2g, 0.05 mol.) were added at room temperature and the reaction mixture was stirred for 31 hours. Reaction monitoring showed amide impurity of formula IV as 0.4% and desired compound 97.5%.After completion of the reaction, the reaction was quenched by slow addition of demineralized water (140ml). Then reaction mixture was gradually cooled down to room temperature and stirred for 30 minutes to precipitate the compound. The precipitated compound was filtered and washed with demineralized water (200 ml). The resulting wet material was stirred again in demineralized water (200ml) at room temperature for 30 minutes. Then filtered off the reaction mass and suck dried under vacuum. to give crude 5-bromo-2-fluorobenzonitrile. The resulting compound was recrystallized from n-heptane to obtain 12.8g (77.1%) of the title compound as a white crystalline powder, having purity of 99.7%; amide impurity not detected, measured by GC.
Reference Example 1: Preparation of 5-bromo-2-fluorobenzonitrile
To a mass of concentrated sulfuric acid (20ml) 2-fluorobenzonitrile (6.0g, 0.05 mol) and N-bromosuccinimide (8.85g, 0.05 mol) were added at room temperature and the reaction mixture was further stirred for 2 hours. Finally, the resulting reaction mixture was poured into ice cold water (100 ml) under stirring; the mass was stirred for another hour, a gummy mass obtained and solid did not form. GC analysis of residue: 16.28% of 5-bromo-2-fluoro benzonitrile, 42.7% of 2-fluorobenzonitrile and 37.54% of 5-bromo-2-fluorobenzamide [amide impurity of formula IV]

Reference Example 2: Preparation of 5-bromo-2-fluorobenzonitrile
To a mass of concentrated sulfuric acid (20ml) 2-fluorobenzonitrile (6.0g, 0.05 mol) and N-bromosuccinimide (8.85g, 0.05 mol) were added at 0oC temperature and the reaction mixture was further stirred for 18 hours at 0-5 oC. Finally, the resulting reaction mixture was poured into ice cold water (100 ml) under stirring; the mass was stirred for another hour, a gummy mass obtained and solid did not form. GC analysis of residue : 15.1% of 5-bromo-2-fluoro benzonitrile, 28.5% of 2-fluorobenzonitrile and 56.2% of 5-bromo-2-fluorobenzamide [amide impurity of formula IV]
Reference Example 3: Preparation of 5-bromo-2-fluorobenzonitrile
To a mass of concentrated sulfuric acid (100ml) 2-fluorobenzonitrile (30.25g, 0.25 mol) and N-bromosuccinimide (44.25g, 0.248 mol) were added at room temperature and the reaction mixture was further stirred for 48 hours. The reaction was monitored by GC-MS and the reaction results were 3.2% of 5-bromo-2-fluoro benzonitrile, 2.1% of 2-fluorobenzonitrile and 94.7% of 5-bromo-2-fluorobenzamide [amide impurity of formula IV]. Finally, the resulting reaction mixture was poured into ice cold water under stirring and then separates out solid was filtered and dried to give 39g of impure title compound, having less than 1% of desired compound 5-bromo-2-fluorobenzonitrile. ,CLAIMS:WE CLAIM:
1. A process for the preparation of pure 5-bromo-2-fluorobenzonitrile compound of formula I,

Formula I
with high yield and purity comprises the step of:
a) reacting 2-fluorobenzonitrile of formula III,

Formula III
with a suitable brominating agent in the presence of an acid catalyst, at least in the presence of water at suitable temperature for sufficient time,
b) quenching the reaction mass;
c) isolating 5-bromo-2-fluorobenzonitrile of formula I;
d) optionally, recrystallizing 5-bromo-2-fluorobenzonitrile using a suitable organic solvent.
2. The process as claimed in claim 1, wherein in step a) brominating agent is selected from N-bromosuccinimide [NBS] N-bromoacetamide, dibromo hydantoins, 1,3-dibromo-5,5-dimethylhydantoin [DBH], N-bromophthalimide, N-bromosaccharin, bromotrichloromethane, bromine, boron tribromide, tetrabutyl ammonium tribromide, trimethylphenylammonium tribromide, bromodimethyl sulfonium bromide, benzyltrimethylammonium tribromide, potassium tribromide, and triphenylphosphine dibromide.
3. The process as claimed in claim 1, wherein in step a) ratio of brominating reagent to 2-fluorobenzonitrile is 0.1-2 : 1.
4. The process as claimed in claim 1, wherein in step a) acid catalyst is selected from sulfuric acid in water, water or dilute sulfuric acid, acetic acid, trifluoromethanesulfonic acid and trifluoroacetic acid.
5. The process as claimed in claim 1, wherein in step a) acid catalyst is sulfuric acid in water or dilute sulfuric acid and ratio of sulfuric acid to water is 1:1 to 4:1, preferably from 1.5-2.5 : 1.
6. The process as claimed in claim 1, wherein in step a) solvent is selected from water, methanol, ethanol, isopropanol, tert-butanol, acetonitrile, tetrahydrofuran, carbon tetrachloride, 1,4-dioxane, methylene chloride, chloroform, polyethylene glycol, ethylene glycol, pentane, hexane, cyclohexane, heptane and petroleum ether and or mixture thereof.
7. The process as claimed in claim 1, wherein in step a) temperature of the reaction is -10°C to 70oC and preferred temperature range is 0°C to 30oC.
8. The process as claimed in claim 1, wherein in step c) crude 5-bromo-2-fluorobenzonitrile compound of formula I having less than 0.5% amide impurity by GC.
9. The process as claimed in claim 1, wherein in step d) solvent used for recrystallization is selected from halogenated hydrocarbons, nitriles, ketones, aromatic hydrocarbons, esters, ethers, hydrocarbons such as pentane, hexane, cyclohexane, n-heptane; alicyclic hydrocarbons or mixtures thereof.
10. Pure 5-bromo-2-fluorobenzonitrile compound of formula I, prepared as claimed in claim 1, is used for preparing febuxostat.

Dated this 13th day of March, 2014

....................
(Dr. Asha Aggarwal)
Head-IPM Department
Ind-Swift Laboratories limited