DESC:The following specification particularly describes the invention and the manner in which it is to be performed:
PROCESS FOR THE PREPARATION OF LESINURAD OR ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF USING NOVEL INTERMEDIATES

INTRODUCTION
The present invention relates to a process for the preparation of lesinurad or its pharmaceutically acceptable salts thereof. The present invention further provides novel intermediates, process for their preparation and their use for the preparation of lesinurad or its pharmaceutically acceptable salts thereof.

Lesinurad is a selective uric acid re-absorption inhibitor (SURI). Lesinurad or its salt is used for reducing serum uric acid level and for the treatment of gout and hyperurecemia. Lesinurad is chemically known as 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid and has following structural formula (I):

(I) (Ia)
US8084483B2, US8173690B2 discloses a compound of formula I and a method for the preparation of compound of formula (I) as shown in scheme 1:

Scheme-1:

CN102040546A discloses the synthesis of isothiocyanate derivative as an intermediate in the preparation of lesinurad. The disclosed process starts from 4-cyclopropyl-1-naphthaldehyde and involves three steps, to get isothiocyanate derivative as an intermediate and thus avoiding the use of sulfur phosgene.

Keeping in view of the importance of lesinurad as a medicament, there remains a need to provide a novel process for the preparation of lesinurad of formula (I), its related compounds and its intermediates that are simple, economical and commercially viable.
SUMMARY
In the first embodiment, the present application relates to a process for the preparation of lesinurad of formula (I) or its pharmaceutically acceptable salts thereof comprising the steps of:
a) reaction of 4-cyclopropyl naphthalene-1-amine or its pharmaceutically acceptable salt of formula (II) with 1,2-diformyl hydrazine to form a compound of formula (III) or its pharmaceutically acceptable salt thereof;
b) bromination of triazole compound of formula (III) using suitable brominating agent in presence of a suitable solvent to form dibromo compound of formula (IV);
c) alkylation of dibromo compound of formula (IV) with alkyl thioglycolate in the presence of a suitable base and a suitable solvent to provide an ester compound of formula (V);
d) hydrolysis of an ester compound of formula (V) in the presence of a suitable base and a suitable solvent to provide lesinurad of formula (I);
e) optionally, isolating and purifying lesinurad of formula (I);
f) optionally, converting lesinurad of formula (I) to its pharmaceutically acceptable salts thereof.
In the second embodiment, the present application provides novel compound of formula (III) or its pharmaceutically acceptable salt and compound of formula (IV),

(III) (IV)
In the third embodiment, the present application provides a process for the preparation of lesinurad or its pharmaceutically acceptable salts thereof comprising involving the use of compound of formula (III) or its pharmaceutically acceptable salt and/or compound of formula (IV).
In the fourth embodiment of the present application provides pharmaceutical compositions comprising lesinurad of formula (I) or its pharmaceutically acceptable salts thereof prepared according to process of the present application together with one or more pharmaceutically acceptable excipient, carrier and diluents.

DETAILED DESCRIPTION
In the first embodiment, the present application relates to a process for the preparation of lesinurad of formula (I) or its pharmaceutically acceptable salts thereof comprising the steps of:
a) reaction of 4-cyclopropyl naphthalene-1-amine or its pharmaceutically acceptable salt of formula (II) with 1,2-diformyl hydrazine to form a compound of formula (III) or its pharmaceutically acceptable salt thereof;

b) bromination of triazole compound of formula (III) using suitable brominating agent in presence of a suitable solvent to form dibromo compound of formula (IV);

c) alkylation of dibromo compound of formula (IV) with alkyl thioglycolate in the presence of a suitable base and a suitable solvent to provide an ester compound of formula (V);

wherein R= C1-6 alkyl; preferably methyl, ethyl, isopropyl
d) hydrolysis of an ester compound of formula (V) in the presence of a suitable base and a suitable solvent to provide lesinurad of formula (I);
e) optionally, isolating and purifying lesinurad of formula (I);
f) optionally, converting lesinurad of formula (I) to pharmaceutically acceptable salts thereof.
Wherein M+ is pharmaceutically acceptable salt

The process for the preparation of starting material 4-cyclopropyl naphthalene-1-amine or its pharmaceutically acceptable salt of formula (II) may be performed by any suitable process disclosed in the prior references.
1,2-diformyl hydrazine can be prepared by condensing hydrazine hydrate with formic acid in presence of suitable solvent like ethanol, methanol and the like or it may also be performed by any suitable conventional methods known in the art. Alternatively, the said starting material may be procured from commercial sources to perform the present invention.
Step (b), step (c) and step (d) may be carried out in one or more suitable solvents. The suitable solvent that may be used in step (b), step (c) and step (d) include, but are not limited to ether solvents, such as, for example, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1, 4-dioxane, and the like; ketone solvents, such as, for example, acetone, methyl ethyl ketone and the like; aromatic hydrocarbon solvents, such as, for example, toluene, xylene, chlorobenzene, tetralin, and the like; nitrile solvents, such as, for example, acetonitrile, propionitrile, and the like; alcohol solvents, such as, for example, methanol, ethanol, isopropanol and the like; ester solvents, such as, for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, and the like or amide solvents, such as, for example, dimethylacetamide, dimethylformamide, N-methylpyrollidine and the like or acids such formic acid, acetic acid, propionic acid; water or mixtures thereof.
The selection of suitable solvent may be dependent on particular type of reaction in particular step that was used in the present invention.
Suitable brominating agent that may be used in step (b) include, but are not limited to such as for example phosphorus tribromide, aluminum tribromide, N-bromo succinimide (NBS) or liquid bromine and the like.
Step (c) and step (d) may be carried out in the presence of one or more suitable bases. Suitable base that may be used in step (c) and step (d) include, but are not limited to organic bases like pyridine, piperidine, pyrimidine, triethylamine, diethylamine, diisopropyl ethylamine, 1,1,3,3-tetramethylguanidine, DBU, DABCO and the like; or inorganic bases like metal carbonates such as sodium carbonate, potassium carbonate; metal bicarbonates such as sodium bicarbonate, potassium bicarbonate; metal hydroxide like sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide and the like.
Step (e) which involves the isolation and purification of lesinurad of formula (I) can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, crystallization, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phase-transfer chromatography, column chromatography, or by a combination of these procedures.
Step (f) involves the conversion of lesinurad of formula (I) into its pharmaceutically acceptable salt comprising the reaction with suitable base. Suitable base include but are not limited to, metal hydroxide like sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide and the like. In a preferred embodiment, the pharmaceutically acceptable salt in the present invention is sodium salt of compound of formula (I).
In an embodiment, lesinurad of formula (I) or its pharmaceutically acceptable salt obtained in the present invention may be further subjected to known purification techniques to get the required purity for qualifying ICH grade material.
The temperature at which the above steps may be carried out in between about 0°C and about 250°C, preferably at about 0°C and about 150°C, based on the solvent or mixture of solvent used in particular step.
In the second embodiment, the present application provides novel compound of formula (III) or its pharmaceutically acceptable salt and compound of formula (IV).

(III) (IV)
In an embodiment, the pharmaceutically acceptable salt of compound of formula (III) may be but not limited to, sodium, potassium, lithium, calcium or the like. The preparation of pharmaceutically acceptable salt of compound of formula (III) may followed by the procedures known in the art for example reacting freebase of compound of formula (III) with suitable base such as metal hydroxide like sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide and the like in a suitable solvent. In a preferred embodiment, the pharmaceutically acceptable salt in the present invention is sodium salt of compound of formula (III).

In the fourth embodiment, the present application provides a process for the preparation of lesinurad (I) or its pharmaceutically acceptable salts thereof involving the use of compounds of formula (III) ) or its pharmaceutically acceptable salt and/or compound of formula (IV).

In the fifth embodiment, the present application provides a pharmaceutical compositions comprising lesinurad of formula (I) or its pharmaceutically acceptable salts thereof prepared according to process of the present application together with one or more pharmaceutically acceptable excipient, carrier and diluents.

The process of the present invention is easy to handle, environment friendly, provides better yield and purity and it may also be practiced on industrial scale.

DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.

An “alcohol solvent” is an organic solvent containing a carbon bound to a hydroxyl group. “Alcoholic solvents” include, but are not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, C1-6 alcohols, or the like.
A “halogenated hydrocarbon solvent” is an organic solvent containing a carbon bound to a halogen. “Halogenated hydrocarbon solvents” include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.

A “ketone solvent” is an organic solvent containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “Ketone solvents” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, C3-6 ketones, 4-methyl-pentane-2-one or the like.

An “ether solvent” is an organic solvent containing an oxygen atom –O- bonded to two other carbon atoms. “Ether solvents” include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, C2-6 ethers, or the like.

The terms "about," "general, ‘generally," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

The term “optional” or “optionally” is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.

Lesinurad and its pharmaceutically acceptable salts thereof obtained by the process of the invention is in fact substantially pure, and in particular substantially free from the impurities. The expression "substantially pure'' means having a purity degree equal to or higher than 99%. The process for the preparation of lesinurad described in the present invention is demonstrated in the examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

EXAMPLES
EXAMPLE 1: Preparation of 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole (III)
4-Cyclopropyl naphthalen-1-amine hydrochloride (36 g, 0.195 moles) and 1,2-diformyl hydrazine (25.7 g, 0.293 moles) were charged at room temperature under nitrogen atmosphere. The temperature of the reaction was raised to 130-135oC and maintained for 24 hours. The progress of the reaction was monitored by TLC and upon completion of reaction; the reaction mass was cooled to room temperature. The reaction mass was diluted with dichloromethane (100 ml) and the crude compound obtained was purified by column chromatography (100-200 mesh silica gels) by eluting with 5% methanol-dichloromethane to give 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole (III) as on off white solid.
Yield: 35.21 g

EXAMPLE 2: Preparation of 3,5-dibromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole (IV)
4-(4-Cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole (III) (5.0 g, 0.021 moles) and acetonitrile (50 mL) were charged under nitrogen atmosphere at 25-30oC. N-bromo succinimide (11.3 g, 0.063 moles) was added portion wise to the reaction mixture at room temperature and stirred for 16 hours. The progress of the reaction was monitored by TLC and upon completion of reaction; the reaction mixture was poured into ice cold water (50 mL) and extracted with ethyl acetate (3X25 mL). The combined organic layer was washed with brine (50 mL) and dried over anhydrous sodium sulphate. The organic layer was concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by column chromatography (100-200 mesh silica gels) by eluting with 25-30% ethylacetate-hexane to give 3,5-dibromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole (IV) as pale yellow solid.
Yield: 6.5 g

EXAMPLE 3: Preparation of methyl 2-((5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetate (V)
3,5-Dibromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole (IV) (900 mg, 0.0022 moles) and dimethyl formamide (8.0 mL) were charged at room temperature under nitrogen atmosphere. Potassium carbonate (474 mg, 0.0034 moles) and methyl thioglycolate (231 mg, 0.0024 moles) were added to the reaction mixture at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 25-30oC for 24 hours. The progress of the reaction was monitored by TLC and upon completion of reaction; the reaction mass was quenched with water and extracted with ethyl acetate (3X25 mL). The combined organic layer was washed with water (3X30 mL), brine (50 mL) and dried over anhydrous sodium sulphate. The organic layer was concentrated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography (100-200 mesh silica gels) by eluting with 30% ethylacetate-hexane to give methyl 2-((5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetate (V) as a brown colour solid.
Yield: 310 mg

EXAMPLE 4: Preparation of Lesinurad Sodium salt
Methyl 2-((5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetate (V) (300 mg, 0.0007 moles) and ethanol (2.7 mL) were charged at room temperature under nitrogen atmosphere. The reaction was cooled to 0oC. Sodium hydroxide (350 mg, 0.00089 moles) dissolved in water (1 mL) was added to the reaction mixture at 0oC and stirred for another 30 min. The reaction mixture was warmed to room temperature and stirred for 3 hours. The progress of the reaction was monitored by TLC and upon completion of reaction; the reaction mass was concentrated under reduced pressure to give the crude compound. The crude solid was triturated with methyl tert-butyl ether. Filtered the solid, washed with cold methyl tert-butyl ether and dried under vacuum to get lesinurad sodium salt (Ia) as brown solid.
Yield: 210 mg
,CLAIMS:WE CLAIM:

1) A process for the preparation of lesinurad of formula (I) or its pharmaceutically acceptable salts thereof comprising the steps of:
a) reaction of 4-cyclopropyl naphthalene-1-amine or its pharmaceutically acceptable salt of formula (II) with 1,2-diformyl hydrazine to form a compound of formula (III) or its pharmaceutically acceptable salt thereof;

b) bromination of triazole compound of formula (III) using a suitable brominating agent in presence of a suitable solvent to form dibromo compound of formula (IV);

c) alkylation of dibromo compound of formula (IV) with alkyl thioglycolate in the presence of a suitable base and a suitable solvent to provide an ester compound of formula (V);

wherein R= C1-6 alkyl; preferably methyl, ethyl, isopropyl
d) hydrolysis of an ester compound of formula (V) in the presence of a suitable base and a suitable solvent to provide lesinurad of formula (I);
e) optionally isolating and purifying lesinurad of formula (I);
f) optionally converting lesinurad of formula (I) to pharmaceutically acceptable salts thereof.
wherein M+ is pharmaceutically acceptable salt.

2) The process as claimed in claim 1, wherein the brominating agent used in step b) is selected from phosphorus tribromide, aluminum tribromide, N-bromo succinimide (NBS) or liquid bromine and the like.

3) The process as claimed in claim 1, wherein the base used in step c) is selected from pyridine, piperidine, pyrimidine, triethylamine, diethylamine, diisopropyl ethylamine, 1,1,3,3- tetramethylguanidine, DBU, DABCO, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide and the like.

4) The process as claimed in claim 1, wherein the base used in step d) is selected from pyridine, piperidine, pyrimidine, triethylamine, diethylamine, diisopropyl ethylamine, 1,1,3,3- tetramethylguanidine, DBU, DABCO, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide and the like.

5) The process as claimed in claim 1, wherein the solvent used in step b), step c) and step d) is selected from diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2- ethoxyethanol, anisole, 1, 4-dioxane, acetone, methyl ethyl ketone, toluene, xylene, acetonitrile, propionitrile, methanol, ethanol, isopropanol ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, dimethylacetamide, dimethylformamide, N-methylpyrollidine, formic acid, acetic acid, propionic acid, water and the like.

6) A novel compound of formula (III) or its pharmaceutically acceptable salt thereof.

(III)

7) A novel compound of formula (IV).

(IV)
8) The use of novel compounds as claimed in claim 6 and claim 7 for the preparation of lesinurad or its intermediates.