DESC:PROCESS FOR THE PREPARATION OF LESINURAD AND ITS INTERMEDIATES

INTRODUCTION
The present invention relates to a process for the preparation of Lesinurad intermediate and their use in 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)
4-(4-Cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II) and (4-cyclopropylnaphthalen-1-yl) boronic acid of formula (V) are key intermediates useful in the preparation of Lesinurad (I).

(II) (V)
Process for the preparation of Lesinurad (I) and its intermediates have been disclosed in US8084483B2 and US8173690B2, which is 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 provides a process for the preparation of 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II), which comprises:
a) converting a compound of formula (III) to 4-cyclopropylnaphthalen-1-amine of formula (IV);

Wherein X is chloro, bromo, iodo, triflate and tosylate;
b) treating 4-cyclopropylnaphthalen-1-amine of formula (IV) with N'-((dialkylamino)methylene)-N,N-dimethylformohydrazonamide or its acid addition salt to form 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II);

c) optionally converting 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II) to its pharmaceutically acceptable salts;
d) optionally purifying 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II) or its pharmaceutically acceptable salts.
In the second embodiment, the present application provides a process for the preparation of Lesinurad of formula (I) or its pharmaceutically acceptable salts which comprises;
a) converting a compound of formula (III) to 4-cyclopropylnaphthalen-1-amine of formula (IV);

Wherein X is chloro, bromo, iodo, triflate and tosylate;
b) treating 4-cyclopropylnaphthalen-1-amine of formula (IV) with N'-((dialkylamino)methylene)-N,N-dimethylformohydrazonamide or its acid addition salt to form 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II);
c) optionally converting 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II) to its pharmaceutically acceptable salts;
d) optionally purifying 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II) or its pharmaceutically acceptable salts.
e) converting 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II) to Lesinurad of formula (I) or its pharmaceutically acceptable salts.
In the third embodiment, the present application provides a process for the preparation of (4-cyclopropylnaphthalen-1-yl) boronic acid of formula (V) which comprises:
a) reacting a compound of formula (III) with trialkyl borate to form (4-cyclopropylnaphthalen-1-yl) boronic acid of formula (V);

Wherein X is chloro, bromo, iodo, triflate and tosylate;
b) optionally purifying (4-cyclopropylnaphthalen-1-yl) boronic acid of formula (V).
In the fourth embodiment of the present application provides a process for the preparation of Lesinurad of formula (I) or its pharmaceutically acceptable salts which comprises;
a) reacting a compound of formula (III) with trialkyl borate to form (4-cyclopropylnaphthalen-1-yl) boronic acid of formula (V);

Wherein X is chloro, bromo, iodo, triflate and tosylate;
b) optionally purifying (4-cyclopropylnaphthalen-1-yl) boronic acid of formula (V);
c) converting (4-cyclopropylnaphthalen-1-yl) boronic acid of formula (V) to Lesinurad of formula (I) or its pharmaceutically acceptable salts.
In the fifth embodiment of the present application provides the use of 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II) and/or (4-cyclopropylnaphthalen-1-yl)boronic acid of formula (V) in the preparation of Lesinurad of formula (I) or its pharmaceutically acceptable salts.
In the sixth 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 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II), which comprises:
a) converting a compound of formula (III) to 4-cyclopropylnaphthalen-1-amine of formula (IV);

Wherein X is chloro, bromo, iodo, triflate and tosylate;
b) reaction of 4-cyclopropylnaphthalen-1-amine of formula (IV) with N'-((dialkylamino)methylene)-N,N-dimethylformohydrazonamide or its acid addition salt to form 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II);

c) optionally converting 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II) to its pharmaceutically acceptable salts;
d) optionally purifying 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II) or its pharmaceutically acceptable salts.
Conversion of a compound of formula (III) may be carried out in the presence of a suitable reagent and a base to provide a compound of formula (VI), which may be optionally isolated and followed by its conversion to provide 4-cyclopropylnaphthalen-1-amine of formula (IV);

The compound of formula (VI) obtained in step a) of may be directly converted to formula (IV) without isolation or may be isolated as per the processes known in the art; and then converted to a compound of formula (IV).
Suitable reagent that may be used in step a) include, but are not limited to copper sulfate, copper acetate, copper stearate, copper triflate, copper Nitrate or any Cu(I) salts which can undergo oxidative coupling or can generate Cu(II) in situ under specific reaction conditions, ammonium acetate, ammonia, formamide, ammonium formate, ammonium chloride, ammonium hydroxide, ammonium carbonate or mixtures thereof.
Step a) may be carried out in the presence one or more suitable bases. Suitable base that may be used in step (a) include, but are not limited to sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, cesium hydroxide, sodium hydride, potassium hydride, sodium acetate, potassium acetate or mixtures thereof.
N'-((dialkylamino)methylene)-N,N-dimethylformohydrazonamide used in step b) include but not limited to N'-((dimethylamino)methylene)-N,N-dimethylformohydrazonamide, N'-((diethylamino)methylene)-N,N-dimethyl formohydrazonamide, N'-((dipropylamino)methylene)-N,N-dimethylformo hydrazonamide or acid addition salts comprising hydrochloride salt, hydrobromide salt, hydro iodide salt; preferably hydrochloride salt of N'-((dimethylamino)methylene)-N,N-dimethylformohydrazonamide.
Steps (a) and (b) may be carried out in one or more suitable solvents. Suitable solvent that may be used in step (a) and/or step (b) include, but are not limited to aromatic hydrocarbon solvents, such as, for example, toluene, xylene, chlorobenzene, tetralin, and the like; halogenated hydrocarbons such as dichloromethane, chloroform and the like; alcoholic solvents like methanol, ethanol, isopropyl alcohol and the like; aliphatic hydrocarbon solvents, such as n-pentane, n-hexane, n-heptane 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, or the like; 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.
Step (c) involves the conversion of 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II) into its pharmaceutically acceptable salt comprising acetic acid, lactic acid, citric acid, cinnamic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic acid, malic acid, oxalic acid, propionic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, glycolic acid, pyruvic acid, methane sulfonic acid, ethane sulfonic acid, toluene sulfonic acid, salicylic acid, benzoic acid, and similarly known acceptable acids.
Step (c) involves the conversion of 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II) 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.
Step (d) which involves the isolation and purification of 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II) or its pharmaceutically acceptable salt 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.
In another embodiment of the present application provides purification of 4-cyclopropylnaphthalen-1-amine of formula (IV). Purification of 4-cyclopropylnaphthalen-1-amine of formula (IV) may be carried out by treating 4-cyclopropylnaphthalen-1-amine of formula (IV) with a suitable pharmaceutically acceptable acid comprising acetic acid, lactic acid, citric acid, cinnamic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic acid, malic acid, oxalic acid, propionic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, glycolic acid, pyruvic acid, methane sulfonic acid, ethane sulfonic acid, toluene sulfonic acid, salicylic acid, benzoic acid, and similarly known acceptable acids. The pharmaceutically acceptable acid addition salt of formula (IV) may be neutralized with a suitable base in a suitable reaction conditions.
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 a process for the preparation of Lesinurad of formula (I) or its pharmaceutically acceptable salts which comprises;
a) converting a compound of formula (III) to 4-cyclopropylnaphthalen-1-amine of formula (IV);

Wherein X is chloro, bromo, iodo, triflate and tosylate;
b) reaction of 4-cyclopropylnaphthalen-1-amine of formula (IV) with N'-((dialkylamino)methylene)-N,N-dimethylformohydrazonamide or its acid addition salt to form 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II);
c) optionally converting 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II) to its pharmaceutically acceptable salts;
d) optionally purifying 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II) or its pharmaceutically acceptable salts;
e) converting 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II) to Lesinurad of formula (I) or its pharmaceutically acceptable salts.
The reagents and solvents for steps (a) to (d) may be selected from one or more suitable reagents and solvents as described in steps (a) to (d) of the first embodiment of the present invention.
The 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II) may be converted to Lesinurad of formula (I) or its pharmaceutically acceptable salts by the methods known in the literature.
The intermediates obtained in the present invention may be directly used for the next step with or without isolation or it may be further purified, if isolated, to improve the purity of the product.
The compound of formula (III) (wherein X is Br) may be prepared as per the processes disclosed in the literature. In one of the specific embodiment, the compound of formula (III) may be prepared by reacting 1-bromonaphthalene with cyclopropyl magnesium bromide in presence of (1,3-bis(diphenylphosphino propane)dichloronickel(II) under suitable conditions to produce 1-cyclopropylnaphthalene, followed by treating with N-bromosuccinimide under suitable conditions to produce a compound of formula (III) (wherein X is Br). Alternatively, the said starting material may be procured from commercial sources to perform the present invention.
N'-((dimethylamino)methylene)-N,N-dimethylformohydrazonamide dihydrochloride may be prepared by reacting thionyl chloride with hydrazine hydrate in presence of dimethyl formamide (DMF) or it may also be prepared 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.
In the third embodiment, the present application provides a process for the preparation of (4-cyclopropylnaphthalen-1-yl) boronic acid of formula (V) which comprises:
a) reaction of a compound of formula (III) with trialkyl borate to form (4-cyclopropylnaphthalen-1-yl) boronic acid of formula (V);

Wherein X is chloro, bromo, iodo, triflate and tosylate;
b) optionally purifying (4-cyclopropylnaphthalen-1-yl) boronic acid of formula (V);
Trialkyl borate used in step a) may be selected from trimethyl borate, triethyl borate, tripropyl borate, triisopropyl borate, hypodiboric acid, bispinacolato boron, tri-n-butyl borate, biscatecholato borane, bisneopentyl glycolato diboron, bis hexylene glycolato diboron and the like.
Step (a) may be carried out in one or more suitable solvents. Suitable solvent that may be used in step (a) include, but are not limited to aromatic hydrocarbon solvents, such as, for example, toluene, xylene, chlorobenzene, tetralin, and the like; halogenated hydrocarbons such as dichloromethane, chloroform and the like; 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; alcoholic solvents like methanol, ethanol, isopropyl alcohol and the like; aliphatic hydrocarbon solvents, such as n-pentane, n-hexane, n-heptane 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, or the like; water or mixtures thereof.
Step (b) which involves the isolation and purification of (4-cyclopropylnaphthalen-1-yl) boronic acid of formula (V) 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.
The temperature at which the above steps may be carried out in between about -100°C and about 100°C, preferably at about -100°C and about 80°C, based on the solvent or mixture of solvent used in particular step.
In the fourth embodiment of the present application provides a process for the preparation of Lesinurad of formula (I) or its pharmaceutically acceptable salts which comprises;
a) reaction of a compound of formula (III) with trialkyl borate to form (4-cyclopropylnaphthalen-1-yl) boronic acid of formula (V);

Wherein X is chloro, bromo, iodo, triflate and tosylate;
b) optionally purifying (4-cyclopropylnaphthalen-1-yl) boronic acid of formula (V);
c) converting (4-cyclopropylnaphthalen-1-yl) boronic acid of formula (V) to Lesinurad of formula (I) or its pharmaceutically acceptable salts.
The reagents and solvents for steps (a) to (b) may be selected from one or more suitable reagents and solvents as described in steps (a) to (b) of the third embodiment of the present invention.

The (4-cyclopropylnaphthalen-1-yl) boronic acid of formula (V) may be converted to Lesinurad of formula (I) or its pharmaceutically acceptable salts by the methods known in the literature. The intermediate obtained in the present invention may be isolated or used directly in the next step obtained as such from the reaction mass.

In the fifth embodiment of the present application provides the use of 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II) and/or (4-cyclopropylnaphthalen-1-yl)boronic acid of formula (V) in the preparation of Lesinurad of formula (I) or its pharmaceutically acceptable salts.
In the sixth 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.
Lesinurad of formula (I) may be converted 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 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.

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.

EXAMPLES
EXAMPLE 1: Preparation of 1-cyclopropylnaphthalene.
1-Bromonaphthalene (5.0 g, 24.15 moles) and (1,3-bis(diphenylphosphino propane)dichloronickel(II) (2.62 g, 4.83 moles) were charged at room temperature under argon atmosphere and was cooled to -5°C to 0°C. Cyclopropylmagnesium bromide (0.5 M) solution in THF (17.54 g in 5 mL, 121 moles) was slowly added to the reaction mixture over a period of 30 minutes. The resultant reaction mixture was then stirred at room temperature for two hours. The temperature of the reaction mass was raised to 65-70°C and maintained for 24 hours. The progress of the reaction was monitored by TLC and upon completion of the reaction; the reaction mass was cooled to room temperature and concentrated at 45-50°C under vacuum. Ethyl acetate (100 mL) and water (50 mL) were added to the reaction mixture and stirred at room temperature for 10-15 minutes. The layers were separated and the organic layer was concentrated at 45-50°C under vacuum and the obtained crude compound was purified by column chromatography by using hexane (1000 mL) as eluting solvent to give the title compound.
Yield: 3.5 g

EXAMPLE 2: Preparation of 1-bromo-4-cyclopropylnaphthalene (III) (wherein X is Br).
1-Cyclopropylnaphthalene (3.0 g, 0.017 moles) and acetonitrile (30 mL) were charged at room temperature under nitrogen atmosphere and was cooled to -5°C to 0°C. N-Bromosuccinimide (3.33 g, 0.018 moles) was slowly added to the reaction mixture over a period of 20 minutes. The temperature of the reaction mass was raised to 25-30°C and maintained for 16-20 hours. Water (18 mL) and toluene (30 mL) were charged into the reaction mass and stirred for 10-15 minutes. The layers were separated and the organic layer was concentrated at 48-50°C under vacuum. Hexane (30 mL) was added to the obtained crude residue and stirred for 10-20 minutes. Filtered the reaction mass and the filtrate was concentrated under vacuum at 50°C. The obtained crude product was purified by column chromatography by using hexane (30 mL) to give the title compound.
Yield: 3.5 g

EXAMPLE 3: Preparation of 4-cyclopropylnaphthalen-1-amine (IV).
1-Bromo-4-cyclopropylnaphthalene (3.0 g, 0.012 moles), formamide (67.8 g) were charged at room temperature under nitrogen atmosphere. Coppersulphate pentahydrate (3.64 g, 0.014 moles) and potassium carbonate (4.19 g, 0.03 moles) were charged at room temperature and stirred for 5-10 minutes. The temperature of the reaction mass was raised to 155-160°C and maintained for 4 hours. The progress of the reaction was monitored by TLC and upon completion of the reaction; the reaction mass was cooled to room temperature. Water (30 mL), ethyl acetate (30 mL) were added to the reaction mixture and stirred at room temperature for 10-15 minutes. The layers were separated and the organic layer was concentrated at 45-50°C under vacuum and the obtained crude compound was purified by column chromatography by using mixture of hexane and ethyl acetate as eluting solvent to give N-(4-cyclopropylnaphthalen-1-yl)formamide (2.25 g).
The above obtained product, ethanol (250 mL) and sodium hydroxide solution (2.91 g in 50 mL water, 0.07 moles) were charged at room temperature under nitrogen atmosphere. The temperature of the reaction was raised to 75-85°C and maintained for 4 hours. The solvent was evaporated under vacuum at 60°C. Water (30 mL) and toluene (30 mL) were added to the obtained crude residue and stirred for 5 minutes. The reaction mass was acidified to pH 2 using 0.5 N hydrochloric acid (10 mL). The solid was filtered and washed with hexane (30 mL), dried under vacuum at room temperature to provide the title compound.
Yield: 1.6 g
Example-4: Preparation of 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole (II).
4-Cyclopropylnaphthalen-1-amine (1.0 g, 5.46 moles) and O-xylene (20 mL) were charged at room temperature under nitrogen atmosphere. N,N’-dimethylformamide azine dihydrochloride (DMAZ, 1.76 g, 8.19 moles) was added to the reaction mixture at room temperature. The temperature of the reaction mass was raised to 125-140°C and maintained for 15-24 hours. The progress of the reaction was monitored by TLC and upon completion of reaction; the reaction mass was cooled to room temperature. Water (20 mL) and hexane (10 mL) were charged into the reaction mass and stirred for 10 minutes. The layers were separated and the organic layer was concentrated at 55-60°C under vacuum and the obtained crude compound was purified by column chromatography by eluting with 5% methanol in ethyl acetate to give title compound.
Yield: 0.7 g

Example-5: Preparation of (4-cyclopropylnaphthalen-1-yl)boronic acid (V).
1-Bromo-4-cyclopropylnaphthalene (0.5 g, 2.023 moles) and THF (5 mL) were charged at room temperature under nitrogen atmosphere. The temperature of the reaction mixture was cooled to -78°C. n-butyl lithium (1.5 mL) was slowly added to the reaction mixture at -78°C. Trimethylborate (0.315 g, 3.03 moles) and THF (1 mL) were slowly added to the reaction mixture at -78°C. The temperature of the reaction mixture was raised to 25°C and maintained for 18-20 hours. 10% Hydrochloric acid (3 mL) was added to the reaction mass at 26°C. The solvent was evaporated under vacuum at 35°C and MTBE (5 mL) was added to the obtained crude residue at 35°C. The layers were separated and the organic layer was concentrated at 28-30°C under vacuum. 10% sodium hydroxide solution (3 ML) was added to the reaction mass and it was washed with MTBE (5 mL). The reaction mass was acidified to pH 2 using 10% hydrochloric acid (3 mL). The solid was filtered and dried under vacuum at 40°C to provide the title compound.
Yield: 70 mg.

Example-6: Preparation of (4-cyclopropylnaphthalen-1-yl)boronic acid (V).
1-Bromo-4-cyclopropylnaphthalene (2 g, 8.09 moles), heptane (10 mL) and THF (2 mL) were charged at room temperature under nitrogen atmosphere. The temperature of the reaction mixture was cooled to -78°C. n-butyl lithium (0.622 g, 9.71 moles) was slowly added to the reaction mixture at -78°C. Triisopropylborate (2.283 g, 12.14 moles) was slowly added to the reaction mixture at -78°C. The temperature of the reaction mixture was raised to 25°C and maintained for 18-20 hours. 10% Hydrochloric acid (10 mL) was added to the reaction mass at 26°C. The solvent was evaporated under vacuum at 35°C and MTBE (10 mL) was added to the obtained crude residue at 35°C. The layers were separated and the organic layer was concentrated at 28-30°C under vacuum. 10% sodium hydroxide solution (12 ML) was added to the reaction mass and it was washed with MTBE (10 mL). The reaction mass was acidified to pH 2 using 10% hydrochloric acid (10 mL). The solid was filtered and dried under vacuum at 40°C to provide the title compound.
Yield: 1.2 g.
,CLAIMS:1) A process for the preparation of 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II), which comprises:
a) converting a compound of formula (III) to 4-cyclopropylnaphthalen-1-amine of formula (IV);

Wherein X is chloro, bromo, iodo, triflate and tosylate;
b) treating 4-cyclopropylnaphthalen-1-amine of formula (IV) with N'-((dialkylamino)methylene)-N,N-dimethylformohydrazonamide or its acid addition salt to form 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II);

c) optionally converting 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II) to its pharmaceutically acceptable salts;
d) optionally purifying 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II) or its pharmaceutically acceptable salts.
2) The process as claimed in claim 1, wherein the reagent used in step a) is selected from copper sulfate, copper acetate, copper stearate, copper triflate, copper Nitrate, Cu(I) salts, ammonium acetate, ammonia, formamide, ammonium formate, ammonium chloride, ammonium hydroxide, ammonium carbonate or mixtures thereof.
3) The process as claimed in claim 1, wherein the based used in the step a) is selected from sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, cesium hydroxide, sodium hydride, potassium hydride, sodium acetate, potassium acetate or mixtures thereof.
4) The process as claimed in claim 1, wherein N'-((dialkylamino)methylene)-N,N-dimethylformohydrazonamide is selected from N'-((dimethylamino)methylene)-N,N-dimethylformohydrazonamide, N'-((diethylamino)methylene)-N,N-dimethyl formohydrazonamide, N'-((dipropylamino)methylene)-N,N-dimethylformo hydrazonamide or mixtures thereof.
5) The process as claimed in claim 1, wherein the solvent used in step a) and step b) is selected from toluene, xylene, chlorobenzene, tetralin, dichloromethane, chloroform, methanol, ethanol, isopropyl alcohol, n-pentane, n-hexane, n-heptane, ethyl formate methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, water and the like.
6) A process for the preparation of Lesinurad of formula (I) or its pharmaceutically acceptable salts which comprises;
a) converting a compound of formula (III) to 4-cyclopropylnaphthalen-1-amine of formula (IV);

Wherein X is chloro, bromo, iodo, triflate and tosylate;
b) treating 4-cyclopropylnaphthalen-1-amine of formula (IV) with N'-((dialkylamino)methylene)-N,N-dimethylformohydrazonamide or its acid addition salt to form 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II);
c) optionally converting 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II) to its pharmaceutically acceptable salts;
d) optionally purifying 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II) or its pharmaceutically acceptable salts.
e) converting 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II) to Lesinurad of formula (I) or its pharmaceutically acceptable salts.
7) A process for the preparation of (4-cyclopropylnaphthalen-1-yl) boronic acid of formula (V) which comprises:
a) reacting a compound of formula (III) with trialkyl borate to form (4-cyclopropylnaphthalen-1-yl) boronic acid of formula (V);

Wherein X is chloro, bromo, iodo, triflate and tosylate;
b) optionally purifying (4-cyclopropylnaphthalen-1-yl) boronic acid of formula (V).
8) The process as claimed in claim 1, wherein trialkyl borate is selected from trimethyl borate, triethyl borate, tripropyl borate, triisopropyl borate, hypodiboric acid, bispinacolato boron, tri-n-butyl borate, biscatecholato borane, bisneopentyl glycolato diboron, bis hexylene glycolato diboron or mixtures thereof.
9) A process for the preparation of Lesinurad of formula (I) or its pharmaceutically acceptable salts which comprises;
a) reacting a compound of formula (III) with trialkyl borate to form (4-cyclopropylnaphthalen-1-yl) boronic acid of formula (V);

Wherein X is chloro, bromo, iodo, triflate and tosylate;
b) optionally purifying (4-cyclopropylnaphthalen-1-yl) boronic acid of formula (V);
c) converting (4-cyclopropylnaphthalen-1-yl) boronic acid of formula (V) to Lesinurad of formula (I) or its pharmaceutically acceptable salts.
10) The use of 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole of formula (II) and/or (4-cyclopropylnaphthalen-1-yl)boronic acid of formula (V) in the preparation of Lesinurad of formula (I) or its pharmaceutically acceptable salts.