FIELD OF INVENTION
The present invention relates to an improved and industrial feasible intermediate process for the preparation of Lesinurad of formula 1
BACKGROUND OF THE INVENTION
Hyperuricaemia (i.e. elevated serum urate levels) associated with gout most commonly results from the insufficient renal excretion of uric acid. Urate—anion exchanger transporter 1 (URAT1) has been identified as the major transporter protein associated with the re-absorption of uric acid. Lesinurad is a selective uric acid re-absorption inhibitor was developed by Ardea Biosciences (a subsidiary of AstraZeneca acquired by the company in June 2012) for the treatment of hyperuricaemia associated with gout.
Lesinurad is chemically known as 2-(5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-tnazol-3-ylthio)acelic acid and has following structural formula-l. The active ingredient Lesinurad is marketed under trade name ZURAMPIC ™ in USA and Europe.

Compounds used in modulating blood uric acid level, were originally developed by Valeant (RDEA806) in 2006 and reported in a patent publication WO2006/026356, the general process as per WO'356 is depicted in the following Scheme-1
The process for preparation of Lesinurad & its analogues preparation is disclosed in WO2009/070740 (herein after WO'740). The general process as per WOJ740 is depicted in the following Scheme-2 & Scheme-3

In WO'740 reaction of l-cyclopropyl-4-isothiocyanatonaphthalene with amino guanidine hydrochloride was performed in presence of base like diisopropylethylamine and the product obtained with yield less than 50%. The time cycles for later reactions are approximately 24 h, which is not viable on commercial scale. Additionally end product required 2-3 purifications to get required quality, which is not economically viable at industrial level. Thus there is a need to develop an alternate process which can defeat the prior art issues.
Other reported process for the preparation of Lesiriurad is mentioned in WO2012/092395A1 (herein after WO'395). Process as per WO'395 is depicted in the following Scheme-4

Scheme-4
In WO2014/008295AI (herein after WO'295) disclosed a process for the preparation of Lesinurad, the process as per WO'295 is depicted in the following Scheme-5
acneme-3
In Chinese patent publication CN103524440 (herein after CN'440) disclosed a process for the preparation of Lesinurad, the process as per CN'440 is depicted in the following Scheme-6

In Chinese patent publication CN104710374 (herein after CN'374) disclosed a process for the preparation of Lesinurad, the process as per CN'374 is depicted in the following Scheme-7
In Chinese patent publication CN 1049873II (herein after CN'311) disclosed a process for the preparation of Lesinurad, the process as per CN'311 is depicted in the following Scheme-8

In Chinese patent publication CN105153056 (herein after CN'056) disclosed a process for the preparation of Lesinurad, the process as per CN'056 is depicted in the following Scheme-9
In Chinese patent publication CN105175348 (herein after CN'348) disclosed a process for the preparation of Lesinurad, the process as per CN'348 is depicted in the following scheme-10

In Chinese patent publication CN105906576 (herein after CN'576) disclosed a process for the preparation of Lesinurad, the process as per CN'576 is depicted in the following scheme-11
In Chinese patent publication CNI06632108 (herein after CN'108) disclosed a process for the preparation of Lesinurad, the process as per CN' 108 is depicted in the following scheme-12

Scheme-12
As per the scientist observations of the present invention, the process as per the WO2006/026356, the condensation of l-cyclopropyl-4-isothiocyanatonaphthalene with aminoguanidine hydrochloride in presence of base DIPEA and DMF solvent to get the desired product with yield less than 50%.
Hence, present invention fulfils the need of the art to provide an improved and industrially applicable pure Lesinurad process for the condensation of 1-cyclopropyl-4-isothipcyanatonaphthalene with aminoguanidine hydrochloride in suitable reaction conditions to get product with high yield, which makes the process economically viable.
OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide an improved, cost effective and commercially viable process for the preparation of Lesinurad intermediate of Formula 4.
!

Formula-4
Yet another object of the present invention is to provide an industrial feasible process for the preparation of Lesinurad of formula-l.
SUMMARY OF THE INVENTION
The present invention relates to an improved intermediate process for the preparation of Lesinurad of formula-l, comprising
NCS
Formula-2
a) treating i-cyclopropyl-4-isothiocyanatonaphthalene of formula-2 with
aminoguanidine hydrochloride in presence of suitable solvent in absence of base to get compound of formula 3
b) optionally isolating compound of formula-3, treated with base and solvent to get
compound of formula-4
10

Formula-4
c) treating compound of formula-4 with methyl 2-chloroacetate in presence of base and solvent to get compound of formula-6
d) using Sandmeyer reaction to get the compound of formula-7
e) hydrolysis of compound of formula-7} in suitable basic medium to get
Lesinurad of formula-1 or pharmaceutically acceptable salts thereof.

In step-a to step-e, the suitable solvent is selected from; polar aprotic solvents such as DMF, DMSO, DMAc, NMP, N-methylmorpholine, sulfolanc, pyridine; nitrile solvents such as ACN, propionitrile; ketone solvents such as acetone, methylethyl ketone, methylisobutyl ketone; ester solvents such as ethyl acetate, methyl acetate, isopropyl acetate, terl-buty\ acetate; chlorinated solvents such as dichloromethane, chloroform; hydrocarbon solvents such as toluene, xylene; alcoholic solvents such as methanol, ethanol, l-propanol, 2-propanol, l-butanol3 isobutanol, /ert-butanol etc, or water mixtures thereof;
In step- b & c, base is selected from organic and inorganic base. Organic base is selected from group but not limited to triethylamine, N,N-diethylisopropylamine, N,N-diisopropylethylamine (DIPEA), diethylamine, tripropylamine trioctylamine, pyridine, Imidazole, N-acetyl imidazole, Dimethylaminopyridine (DMAP), and dicyclohexylamine.
Inorganic bases selected from alkali metal or alkaline earth metal hydroxides, carbonates, bicarbonates such as sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, magnesium hydroxide, calcium hydroxide, strontium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate and calcium bicarbonate.
In step-d Sandmeyer reaction, conditions are used to synthesize aryl halides from aryl amine through its diazon'ium salts as per person skilled in the art.
In step-e, suitable medium for hydrolysis is selected from acid or base.

Acid medium includes but not limited to protic acid selected from HCI, H2S04 and acetic acid etc., Basic medium is selected from but not limited to NaOH , LiOH, and KOH etc.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is schematically represented as depicted in the following Scheme 13
The starting- material of compound of formula-2 is known in the art and can be produced by the methods known and recognized by US patent No. 8,003,681 which is included by reference herein in its entirety.
Another starting material aminoguanidine hydrochloride of the present invention is prepared as per the process reported in Acta Cryst. (1957), 10, 677.

In Formula-5, X is selected from halo and R is substituted or unsubstituted alkyl, phenyl, alkylphenyl.
Sandmeyer reaction, conditions are used to synthesize aryl halides from aryl amine through its diazonium salts as per person skilled in the art.
Purification of compound of formula-l, can be done by any of the person skilled in the art selected from recystrallization method, solvent & anti-solvent treatment, acid
base treatment, leaching or salification de-saltification method.
i
Purification of Lesinurad using salification & de-saltification is reported in CN104447589B, in which secondary amine salts are used t6 get pure Lesinurad as a final product.
EXAMPLES
In the following examples, the preferred embodiment of the present invention is described only by way of illustrating the processes of the invention. However, these are not intended to limit the scope of the invention in any way.
Example-1 Preparation of 5-Amino-4-(4-cyclopropylnaphthalen-l-yl)-4//-l, 2, 4-triazole-3-thiol
l-Cyclopropyl-4-isothiocyanatonaphthalene (5.0 g, 1.0 m. eq), aminoguanidine hydrochloride (4.9 g, 2.0 m. eq) and DMSO (15 mL) were taken and stirred for 2 h at 50-55°C. Then reaction mixture was cooled to 20-30°C. A 2.0 M aqueous solution of sodium hydroxide (46.0 mL) was added and the reaction mixture was heated to 60-65°C and stirred for 6-8 h. Further, the reaction mixture was cooled to 5-10°C and neutralized with 2.0 M hydrochloric acid. The reaction mass was filtered, washed with water and dried at 60-65°C to obtain 5-Amino-4-(4-cyclopropylnaphthalen-l-yl)-4//-l, 2, 4-triazole-3-thiol. Yield: 88.0%, HPLC purity: 9'9.0%

1
Example-2 Preparation of 5-Amino-4-(4-cyclopropylnaphthalen-l-yl)-4/M, 2, 4-triazole-3-thiol
l-Cyclopropyl-4-isothiocyanato naphthalene (10 g) aminoguanidine hydrochloride (5.4 g) in DMSO (20 mL) was stirred at 50-55°C for 3-5 h. After completion of reaction, 10% aq.NaOH solution (75.0 mL) was added and the reaction mixture heated at 60-65°C for 3-5h. After completion of reaction, reaction mixture was neutralized with aq.HCI. The solid was filtered and washed with water. The wet solid was purified with acetone to obtain 5-amino-4-(4-cyclopropylnaphthalen-l-yl)-4//-l, 2, 4-triazole-3-thiol as solid (11.0 g; Yield: 87.8)
i
Example-3 Preparation of Methyl 2-((5-amino-4-(4-cyclopropylnaphthalen-l-yl)-
4//-1, 2, 4-triazol-3-yl) thio) acetate i
5-Amino-4-(4-cyclopropylnaphthalen-l-yl)-4H-l3 2,4-triazole-3-thiol (5.0 g) methyl chloroacetate (2.0 g), sodium carbonate (2.1 g) potassium iodide (0.6 g) and acetone (50 mL) were taken and stirred for 3-5 h at 20-30°C. Then, reaction mixture was cooled to 5-l0°C and 50 mL DM water was added. The reaction mixture was stirred for 30 minutes, then filtered and washed with DM water. The solid thus obtained was dried at 60-65°C to obtain methyl 2-((5-amino-4-(4-cyclopropylnaphthalen-l-yl)-4//-l,2,4-triazol-3-yl)thio) acetate. Yield: 80.0%, HPLC purity: 99.0%
Example-4 Preparation of Methyl 2-((5-amino-4-(4-cyclopropylnaphthalen-l-yl)-4/1-1, 2, 4-triazol-3-yl) thio) acetate
Methyl chloroacetate (3.84 g) was added to a suspension of 5-amino-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazole-3-thiol (10.0 g) and triethylamine (3.94 g) in methanol (20 mL) at 25-30°C. The reaction mixture was stirred for 2-4 h at room temperature. After reaction was completed, water was added to the reaction mass and filtered to obtain methyl-2-((5-amino-4-(4-cyclopropylnaphthalen-l-yl)-4//-l,2,4-triazol-3-yl)thio)acetate as solid (11.0 g; Yield: 87.6%).
1 r

Example-5: Preparation of Methyl 2-((5-bromo-4-(4-cyclopropylnaphtha1en-l-yl)-4/T-j, 2,4-triazol-3-yl) thio) acetate
Methyl 2-((5-amino-4-(4-cyclopropylnaphthalen-l-yl)-4H-l3 2, 4-triazol-3-yl) thio) acetate (5.0 g) and MDC (50 ml) were taken and cooled to 0-5°C. 47% aqueous hydro bromic acid (20 mL) was added followed by a solution of NaN02 (5.84 g) in DM water at 0-5°C. After the addition, the mixture' was stirred for 1 h. Benzyltriethylammonium bromide was added to the reaction mixture and stirred for 2-4 h. Further, DM water (25 mL) was added to the reaction mixture, the aqueous layer was separated out. The organic layer was washed with 10% sodium chloride solution and concentrated under vacuum to get Methyl 2-((5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4//-l,2, 4-triazol-3-yl) thio)acetate residue. The residue was purified to obtain Methyl 2-((5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l, 2, 4-triazol-3-yl) thio)acetate.
Example-6: Preparation of Methyl 2-((5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4//-l, 2, 4-triazol-3-yl) thio) acetate
Aq.Hydrobromic acid (48%) (85.5 g) was added to a solution of methyl-2-((5-amino-
4-(4-cyclopropylnaphthalen-l-yl)-4//-l,2,4-triazol-3-yl)thio)acetate (10 g)in MDC
(50 mL) at 20-25°C. Solution of sodium nitrite (24.1 g) in water (50 mL) was slowly
added into the reaction mass at -5 to 5°C. Reaction mass was stirred for 3 h at -5 to
5°C. After reaction was completed, 25% aq.sodium metabisulphate was added
followed by layer separation. Organic layer was washed with water and distilled out
to obtained methyl-2-((5-bromo-4-(4-cyclopropylnaphthalen-1 -yl)-4//-1,2,4-triazol-
3-yl)thio)acetate as oily mass. I
Example-7: Preparation of 2-((5-Bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l, 2, 4-triazol-3-yl)thio)acetic acid

I N aqueous sodium hydroxide solution (30 mL) was added to a cooled mixture of Methyl 2-((5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-], 2, 4-triazol-3-yl) thio) acetate (10 g) and ethanol (90 mL). The mixture was stirred at 25-30°C for 4-6 h. Then reaction mixture was filtered and filtrate was concentrated under vacuum. DM water (6.0 mL) was added and the reaction mass cooled to 0-5°C. Reaction mass was stirred for 6-7 h and filtered. The resulting cake was washed with pre cooled water. The wet cake was suspended in DM water (50 mL) was stirred for 30 minutes at 25-30°C. The reaction mixture was filtered through micron filter. 48% aqueous hydrobromic acid (1.8 g) and DM water (1.3 mL) mixture was added into above filtrate at 10-I5°C. Ethyl acetate (80.0 mL) was added to the reaction mass and organic layer was separated. The organic layer was washed with DM water and concentrated under vacuum. The reaction mixture was stirred for 10-12 h at 0-5°C, then filtered, washed with pre cooled ethyl acetate (10 mL) and n-heptane (10 mL). The solid thus obtained was dried at 50-55°C under vacuum to obtained Lesinurad crystalline form.
Example-8: Preparation of 2-((5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4/f-l,2,4-triazol-3-yl)thio)acetic acid
48% of aq.HBr (85.5 g) was added to a solution of methyl-2-((5-amino-4-(4-cyclopropylnaphthalen-l-yl)-4//-lf2?4-triazol-3-yl)thio)acetate (10.0 g) in MDC (50 mL) at 20-25°C. Dissolved NaN02 (24.1 g, 349.9 mmol) in water (50 mL) and resulting solution was slowly added into the reaction mass at -5 to 5°C. After completion of reaction, 25% aq.sodium metabisulphate was,added followed by layer separation. Organic layer was washed with water and distilled out to obtained methyl-2-((5-bromo-4-(4-cyclopropylnaphthalen-1 -yl)-4//-1,2,4-triazol-3-yl)thio)acetate as oily mass.
NaOH solution (3.0 g in 60 mL water) was added to the above oily mass at 25-30°C and stirred for 4h. After completion of reaction, ethyl acetate was added and pH was

adjusted to 2.0-2.5 with dilute HCI Organic layer was separated and washed with water Distilled out ethyl acetate to obtained Lesinurad as an oily mass. To the above oily mass, ethanol (50 mL) and dicyclohexylamine (6.8 g) was added. Reaction mass was stirred for Ih at reflux temperature, cooled to 0-5°C, the solid was filtered and washed with ethanol to obtain- Lesinurad DCHA salt. The wet solid was added into 10% aq.ethanol stirred for 1 h at reflux temperuture. Reaction mass was cooled to 0-5°C and stirred for I h at 0-5°C. The crystallised solids were filtered and washed with 10% aq.ethanol to get pure Lesinurad DCHA salt. Further, Lesinurad DCHA salt (10.0 g) was added into ethyl acetate and water at 25-30°C. The pH of the reaction mass was adjusted to 2.0-2.5 at 25-30°C with 1:1 dilut HCI. Ethyl acetate layer was seperated and washed with water. Ethyl acetate layer was treated with activated carbon for decolorization and ethyl acetate was distilled out and co-distilled with cyclohexane. Cyclohexane was added into above reaction mass, stirred for I h at 25-30°C, filtered and wash with cyclohexane to obtain 2-((5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4//-l)2.4-triazol-3-yl)thio)acetic acid (6.1 g, Yield: 88.4%).
i
i

We Claim:
I. A process for the preparation of Lesinurad Intermediate of formula-4, comprising,
Formula-4
a) treating compound of formula-2
Formula-2
with aminoguanidine hydrochloride in presence of suitable solvent in absence of base to get compound of formula-3
Formula-3
b) optionally isolating compound of formula-3, treated with base and to get compound of formula-4.

2. The process according to claim-], solvents are selected from water; polar aprotic solvents such as DMF, DMSO, DMA, N-methylmorpholine, pyridine; nitrile solvents such as ACN, propionitrile; ketone solvents such as acetone, methyiethyl ketone, methylisobutyl ketone; ester solvents such as ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate; chlorinated solvents such as dichloromethane, chloroform; hydrocarbon solvents such as toluene, xylene; alcoholic solvents such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, isobutanol, tert-butanol etc, sulfolane or mixtures thereof;
3. The process according to claim-1, base is selected from base is selected from organic and inorganic base; organic base is selected from triethylamine, N,N-diethylisopropylamine, N,N-diisopropylethylamine (DIPEA), diethylamine, tripropylamine trioctylamine, pyridine, Imidazole, N-acetyl imidazole, Dimethylaminopyridine (DMAP), dicyclohexylamine., Inorganic bases selected from sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, magnesium hydroxide, calcium hydroxide, strontium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate and calcium bicarbonate.
A. The process according to claim-2, suitable solvent is selected from polar aprotic solvent.
5. The process according to claim-3, suitable base is selected from inorganic base.
6. The process for the preparation of Lesinurad Intermediate of formula-4, comprises,

a) treating compound of formula-2
Formula-2
with aminoguanidine hydrochloride in presence of polar aprotic solvent in absence of base to get compound of formula-3
b) optionally isolating compound of formula-3, treated with inorganic base and to get compound of formula-4.
7. The process according to claim-6, polar aprotic solvents selected from DMSO, DMF, DMA, NMP, more preferably DMSO or DMF.
8. The process according to claim-6, inorganic bases selected from sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, magnesium hydroxide,

calcium hydroxide, strontium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate and calcium bicarbonate, more preferably sodium hydroxide or potassium hydroxide.
9. The process according to claim-1, further comprises j
a) treating l-cyclopropyl-4-isothiocyanatonaphthalene with aminoguanidine
hydrochloride in presence of DMSO in absence of base to get compound of formula-3
b) treating compound of formula-3 with NaOH an solvent to get compound of formula-4
Formula-4
c) treating compound of formula-4 with methyl 2-chloroacetate in presence of base and solvent to get compound of formula-6.

formula o
d) using Sandmeyer reaction to get the compound of formula-7
Formula 7
e) hydrolysis of compound of formula-7, in basic medium to get Lesinurad of
forrnula-1.