FIELD OF THE INVENTION

[001] The present invention relates to a compound and a method for preparing the same, in which the compound is thio-l,2,4-triazole derivatives used in decreasing a level of uric acid, particularly relates to 2-(5-bromo-4-(4-substituent-4H-l,2,4-triazole-3-ylthio) acetic acid derivatives.

BACKGROUND OF THE INVENTION

[002] Uric acid is a result of an oxidation of xanthine. Disorders of uric acid metabolism include, but not limited to, polycythemia, myeloid metaplasia, gout, recurrent gout attacks, gouty arthritis, hyperuricaemia, hypertension, cardiovascular disease, coronary heart disease, Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, kidney disease, kidney stones, kidney failure, joint inflammation, arthritis, urolithiasis, plumbism, hyperparathyroidism, psoriasis or sarcoidosis.

[003] WO 2009070740 discloses a compound used in modulating blood uric acid level, and a formulation containing the compound as well as uses thereof, the compound comprises 2-(5-bromo-4-(4-substituent-4H-l,2,4-triazole-3-ylthio) acetic acid derivatives, shown as formula (I),

[004] Lesinurad,

2-((5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazo l-3-yl)thio)acetic acid, shown as formula (la), is a compound which promotes uric acid excretion through blocking transportation of uric acid, using in therapy of hyperuricemia and gout.

l

[005] WO 2009070740 discloses a compound

2-((5-bromo-4-(4-cyclopropylnaphthalen- 1 -yl)-4H- 1 ,2,4-triazol-3 -yl)thio)acetic acid method for preparing the same, shown as Scheme 1 :

8 la

Scheme 1.

[006] The scheme 1 provides a process for preparing a compound of bromo- triazole derivatives shown as formula (8) comprises: subjecting a compound of amino triazole derivatives shown as formula (7) to diazotization and bromination successively, in which the diazotization is performed in the presence of sodium nitrite having an excessive amount of 20 equivalent weights, during which an organic impurity of azo easily generates. The sodium nitrite and the organic impurity of the azo both are carcinogenic, which may bring a tremendous risk to a final product thereof. Moreover, the above process uses tribromomethane as a reacting solvent during the bromination, having a high toxicity, which is not suitable for industry scale.

SUMMARY OF THE INVENTION

[007] Embodiments of the present disclosure seek to solve at least one of the problems existing in the related art to at least some extent. [008] In a first aspect, there is provided a process for preparing a compound shown as formula (I)

comprising a step of:

contacting a compound shown as formula (II) or a salt thereof with a brominating agent,

wherein R ^h is OR ² or R ³ R ⁴ ;

R ² is C1-C6 alkyl or phenyl;

each R ³ , R ⁴ is independently H, C1-C6 alkyl or cycloalkyl,

wherein C1-C6 alkyl, cycloalkyl, or phenyl is optionally further substituted by F, CI, Br, CH ₃ or CF ₃ .

[009] In some embodiments, the process for preparing a compound shown as formula (I) further comprises contacting the compound shown as formula (II) or the salt thereof with the brominating agent in the presence of Ν,Ν'-thiocarbonyl diimidazole.

[010] In a second aspect, there is provided a process for preparing a compound shown as formula (II) comprising a step of:

contacting a compound shown as formula (V) with a compound shown as formula (VI), wherein

R^s O^ or R ;

LG is CI, Br, I, tosylate, mesylate, triflate or besylate, preferably LG is Br, more preferably

LG is CI.

[Oi l] In a third aspect, there is provided a process for preparing a compound shown as formula (V) comprising steps of:

contacting a compound shown as formula (III) with carbohydrazide in the presence of a third solvent at a temperature below about 35 degrees Celsius, to obtain a compound shown as formula (IV); and

subjecting the compound shown as formula (IV) to an intramolecular cyclization reaction in the presence of a fourth solvent, to obtain the compound shown as formula (V),

[012] In a fourth aspect, there is provided a process for preparing a compound shown as formula (III) comprising following steps of:

contacting 4-cyclopropylnaphthalen-l -amine with CS ₂ in the presence of a first alkaline solution, to form a first reaction solution;

adding 2,4,6-trichloro-l,3,5-triazine to the first reaction solution, to form a second reaction solution; and

adding a second alkaline solution to the second reaction solution, to obtain the compound shown as formula (III),

[013] In a fifth aspect, there is provided an intermediate compound as shown as formula

(Ila) or formula (lb),

[014] In a six aspect, there is provided a process for preparing a compound shown as formula (la). In some embodiments, the process may comprise: hydrolyzing a compound (I) in the presences of an alkaline solution, to obtain a compound shown as formula (Ic), wherein M is

a cation, (I), (i _c ).

[015] In some other embodiments, the compound shown as (Ic) may be subjected to a treatment of proton acid, to obtain a compound shown as formula (la),

[016] Additional aspects and advantages of embodiments of present disclosure will be given in part in the following descriptions, become apparent in part from the following descriptions, or be learned from the practice of the embodiments of the present disclosure.

DETAILED DESCRIPTION OF THE INVENTION

DEFINITIONS AND GENERAL TERMINOLOGY

[017] The term "alkyl" or "alkyl group" used herein refers to a saturated linear or branched-chain monovalent hydrocarbon radical of 1 to 6 carbon atoms, in which the alkyl may be optionally substituted with one or more substituents described below independently. Unless otherwise specified, alkyl groups contain 1-6 carbon atoms. In some embodiments, alkyl groups contain 1-4 carbon atoms, and in other embodiments, alkyl groups contain 1-3 carbon atoms.

[018] In some non-limited examples, the alkyl group includes, but not limited to, methyl

(Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), 1 -propyl (n-Pr, n-propyl, -CH ₂ CH ₂ CH ₃ ), 2-propyl (i-Pr, i-propyl, -CH(CH ₃ ) ₂ ), 1 -butyl (n-Bu, n-butyl, -CH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-l-propyl (i-Bu, i-butyl, -CH ₂ CH(CH ₃ ) ₂ ), 2-butyl (s-Bu, s-butyl, -CH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH ₃ ) ₃ ), 1-pentyl (n-pentyl, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-l-butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-l-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), 1-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl

(-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ) and the like.

[019] The term "cycloalkyl" used herein refers to a monovalent or multivalent saturated ring having 3 to 12 carbon atoms as a monocyclic, bicyclic, or tricyclic ring system. In some embodiments, the cycloalkyl contains 3 to 10 carbon atoms. In still other embodiments, the cycloalkyl contains 3 to 8 carbon atoms, and in yet other embodiments, the cycloalkyl contains 3 to 6 carbon atoms. The cycloalkyl is optionally substituted with one or more substituents described herein independently. [020] The expression "reaction is complete" used herein refers that reactant is consumed to a certain extent of greater than about 90%, preferably greater than 95%. In some embodiments, whether or not the reaction is complete is monitored using a conventionally-used method in the art, such as thin layer chromatography (TLC), high performance liquid chromatography (HPLC), gas chromatography (GC), etc. In some specific examples, the reaction in the present disclosure may be monitored by HPLC, in which a reaction is deemed to be completed when a peak area of HPLC of reactant is less than 10%, preferably less than 5%, more preferably less than 1%.

[021] The expression "not require work up procedure" or the like used herein refers to reactant(s) may be directly added to the resulting product of a previous reaction, and the conventional purification process, such as filtration, extraction, washing, distillation (steam distillation, fractional distillation, distillation), recrystallization, acid treatment, alkali treatment, purification of the targeted intermediate compound or purification by chromatography or combinations thereof may be eliminated.

[022] The term "comprising" used herein refers to an open-ended expression, including the indicated components but not excluding other elements.

[023] The term "about" used herein generally means within 10%, suitably within 5% and particularly within 3% of a given value or range. Alternatively, the term "about" means within an acceptable standard error of the mean, when considered by one of the ordinary skill in the art. DETAILED DESCRIPTION

[024] Reference will be made in detail to embodiments of the present disclosure. The embodiments described herein with reference are explanatory, illustrative, and used to generally understand the present disclosure. The embodiments shall not be construed to limit the present disclosure. The same or similar elements and the elements having same or similar functions are denoted by like reference numerals throughout the descriptions.

[025] In a first aspect, there is provided a process for preparing a compound shown as formula (I) comprising a step of:

contacting a compound shown as formula (II) or a salt thereof with a brominating agent, wherein

R^s O^ or R ;

R ² is C1-C6 alkyl or phenyl;

each R ³ , R ⁴ is independently H, C1-C6 alkyl or cycloalkyl,

wherein C1-C6 alkyl, cycloalkyl, or phenyl is optionally further substituted by F, CI, Br, CH ₃ or CF ₃ .

[026] In some embodiments, R ² is methyl, ethyl, propyl, isopropyl or phenyl.

[027] In some embodiments, R ² is methyl or phenyl.

[028] In some embodiments, the brominating agent is N-bromosuccinimide ( BS), pyridinium tribromide, benzyl trimethyl ammonium tribromide, l,3-dibromo-5,5-dimethylhydantoin, l,3-dibromo-l,3,5-three triazine-2,4,6-trione, dibromo-barbituric acid, or a combination thereof. In some other embodiments, the brominating agent is N-bromosuccinimide (NBS), l,3-dibromo-5,5-dimethylhydantoin, or a combination thereof. In some embodiment, based on 1.0 equivalent weight of the compound shown as formula (II), an amount of the brominating agent is about 1.0 equivalent weight to about 5.0 equivalent weights. In some other embodiments, based on 1.0 equivalent weight of the compound shown as formula (II), the amount of the brominating agent is about 1.2 equivalent weights to about 2.5 equivalent weights. In still some other embodiments, the amount of the brominating agent is about 1.5 equivalent weights.

[029] In some embodiments, the process for preparing a compound shown as formula (I) further comprises contacting the compound shown as formula (II) or the salt thereof with the brominating agent in the presence of Ν,Ν'-thiocarbonyl diimidazole. In some embodiments, based on 1 mole of the compound shown as formula (II), an amount of N,N'-thiocarbonyl diimidazole is about 0.02 mole to about 0.1 mole. In some embodiments, based on 1 mole of the compound shown as formula (II), an amount of Ν,Ν'-thiocarbonyl diimidazole is about 0.05 mole.

[030] In some embodiments, the step of contacting the compound shown as formula (II) or the salt thereof with the brominating agent is performed in the presence of a first solvent. In some embodiments, the first solvent is water, tetrahydrofuran (THF), acetonitrile, methyl tert-butyl ether (MTBE), chloroform, dichloromethane, carbon tetrachloride, acetic acid, sulfuric acid, ethyl acetate or a combination thereof. In some other embodiments, the first solvent is di chl or om ethane .

[031] In some embodiments, the step of contacting a compound shown as formula (II) or a salt thereof with a brominating agent is performed at a temperature from room temperature to reflux temperature. In one embodiment, the step of contacting a compound shown as formula (II) or a salt thereof with a brominating agent is performed at room temperature. In another embodiment, the step of contacting a compound shown as formula (II) or a salt thereof with a brominating agent is performed at reflux temperature.

[032] In some specific examples, phenyl

2-((5-bromo-4-(4-cyclopropylnaphthalen- 1 -yl)-4H- 1 ,2,4-triazol-3 -yl)thio)acetate shown as formula (lb) is prepared by the process above described,

(lb).

[033] In a second aspect, there is provided a process for preparing a compound shown as formula (II) comprising a step of:

contacting a compound shown as formula (V) with a compound shown as formula (VI), wherein

(Π),

R^s O^ or R ;

LG is a leaving a group, in some embodiment, LG is halogen (such as CI, Br or I), tosylate, mesylate, triflate, or besylate, in one embodiment, LG is Br, in another embodiment, LG is CI.

[034] In some embodiments, the step of contacting the compound shown as formula (V) with the compound shown as formula (VI) is performed in the presence of a first organic base and a second solvent.

[035] In some embodiments, the first organic base may be at least one selected from a group consisting of alkali carbonate, alkali bicarbonate and organic tertiary amine. In some embodiments, the alkali carbonate may be lithium carbonate, sodium carbonate or potassium carbonate. In some other embodiments, the alkali bicarbonate may be lithium hydrogencarbonate, sodium hydrogencarbonate or potassium hydrogencarbonate. In still some other embodiments, the organic tertiary amine may be triethylamine, diisopropylethylamine, DBU (1,8-diazabicyclo [5.4.0] undecene). In a specific example, the first organic base is organic tertiary amine triethylamine.

[036] In some embodiments, the second solvent may be at least one selected from a group consisting of water, toluene, xylene, 1,4-dioxane, methanol, ethanol, butanol, isopropanol, diethyl ether, hexane, pentane, heptane, ethyl acetate, dichloromethane, dichloroethane, 1,2-dichlorobenzene, acetonitrile, N-methylpyrrolidone, acetone, dimethylformamide (DMF), dimethylsulfoxide (DMSO). In one embodiment, the second solvent may be at least one selected from a group consisting of ethanol and isopropanol. In a specific example, the second solvent is acetone.

[037] In some embodiments, the second solvent and the first organic base are acetone/triethylamine. In some other embodiments, the second solvent and the first organic base are ethanol/triethylamine.

[038] In some embodiments, the step of contacting the compound shown as formula (V) with the compound shown as formula (VI) is performed at a temperature below about 35 degrees Celsius. In some other embodiments, the step of contacting the compound shown as formula (V) with the compound shown as formula (VI) is performed at a temperature below about 20 degrees Celsius.

[039] In some embodiments, the process for preparing the compound shown as formula

(II) may further comprises a step after the step of contacting the compound shown as formula (V) with the compound shown as formula (VI):

subjecting a resulting solution to a first filtration, to obtain a first filtrate and a first filter cake;

washing the first filter cake with the second solvent which is used in the step of contacting the compound shown as formula (V) with the compound shown as formula (VI);

slurrying the washed first filter cake with a purified water under a condition of stirring for about 1 hour after removing the first second solvent, to obtain a slurry;

subjecting the slurry to a vacuum filtration, to obtain a second filtrate and a second filter cake;

subjecting the second filter cake to a vacuum drying, to obtain the compound shown as formula (II) with high purity.

[040] In some embodiments, the compound shown as formula (VI) is bromo phenyl acetate or chloro phenyl acetate.

[041] In an embodiment, a compound of phenyl

2-((4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-y l)thio)acetate shown as formula (Ha), which is prepared by the second aspect of the present invention,

[042] The process provided herein avoids tedious work up procedure, and the HPLC purity of the product is more than 99%. The process also involves mild reaction conditions, the reaction can be carried out at room temperature.

[043] In a third aspect, there is provided a process for preparing a compound shown as formula (V), which may comprise following steps of: contacting a compound shown as formula (III) with carbohydrazide in the presence of a third solvent at a temperature below about 35 degrees Celsius, to obtain a compound shown as formula (IV); and

subjecting the compound shown as formula (IV) to an intramolecular cyclization reaction in the presence of a fourth solvent and a base, to obtain the compound shown as formula (V),

[044] In some embodiments, the third solvent is at least one of an ether solvent or an ester solvent. In some embodiments, the ether solvent is at least one selected from a group consisting of tetrahydrofuran (THF), methyl tert-butyl ether (MTBE) and 1,4-dioxane. In some other embodiments, the ester solvent is at least one selected from a group consisting of ethyl acetate, iso-propyl acetate, n-butyl acetate and tert-butyl acetate. In still some embodiments, the third solvent is at least one selected from a group consisting of tetrahydrofuran (THF), methyl tert-butyl ether (MTBE) and ethyl acetate. In one embodiment, the third solvent is ethyl acetate.

[045] In some embodiments, the third solvent has a volume of about 6.0 ml to about 15.0 ml relative to 1 gram of the compound shown as formula (III)., In a specific embodiment, the third solvent has a volume of about 10.0 ml relative to 1 gram of the compound shown as formula (III).

[046] In some embodiments, the fourth solvent is at least one selected from a group consisting of dimethylformamide (DMF), water, acetone and tetrahydrofuran. In some other embodiments, the fourth solvent is dimethylformamide (DMF).; In certain embodiments, the fourth solvent is at least one of water and acetone. In other embodiments, the fourth solvent is a mixture of tetrahydrofuran and water.

[047] In some embodiments, the base is at least one selected from a group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, magnesium hydroxide and calcium hydroxide. In some other embodiments, the base is alkali hydroxide. In still some other embodiments, the base is tertiary organic amine, such as triethylamine, diisopropylethylamine or a combination thereof.

[048] In a fourth aspect, there is provided a process for preparing a compound shown as formula (III),

which may comprises following steps of:

contacting 4-cyclopropylnaphthalen-l -amine with CS ₂ in the presence of a first alkaline solution, to form a first reaction solution;

adding 2,4,6-trichloro-l,3,5-triazine to the first reaction solution, to form a second reaction solution; and

adding a second alkaline solution to the second reaction solution, to obtain the compound shown as formula (III),

[049] The step of contacting 4-cyclopropylnaphthalen-l -amine with CS ₂ in the presence of a first alkaline solution is complete when 4-cyclopropyl-l-naphthylamine is consumed to a certain extent, such as greater than about 90% of the reactant has been consumed, or greater than 95% of the reactant has been consumed; the step of adding 2,4,6-trichloro-l,3,5-triazine to the first reaction solution is complete when a product obtained in the step of contacting 4-cyclopropylnaphthalen-l -amine with CS ₂ in the presence of a first alkaline solution is consumed to a certain extent, such as greater than about 90% of the reactant has been consumed, or greater than 95% of the reactant has been consumed.

[050] In some embodiments, work up procedure or a step of separating the intermediate compound may be not required

[051] In some embodiments, the first alkaline solution comprises at least one selected from a group consisting of sodium hydroxide, potassium hydroxide, potassium carbonate and sodium carbonate.

[052] In some embodiments, the step of contacting 4-cyclopropylnaphthalen-l -amine with CS ₂ in the presence of a first alkaline solution is performed in a molar ratio from about 1 : 1 : 1 to about 1 :2:2, to form a first reaction solution. In a certain embodiment, the step of contacting 4-cyclopropylnaphthalen-l -amine with CS ₂ in the presence of a first alkaline solution is performed in a molar ratio of about 1 :2: 1. In an embodiment, the step of contacting 4-cyclopropylnaphthalen-l -amine with CS ₂ in the presence of a first alkaline solution is performed in a molar ratio of about 1 : 1.2:2.

[053] In some embodiments, the step of contacting 4-cyclopropylnaphthalen-l -amine with CS ₂ in the presence of a first alkaline solution is performed in the presence of a fifth solvent. In some embodiment the fifth solvent is water. In some other embodiment, the fifth solvent is a mixture of acetonitrile and water in a volume ratio of 1 :2 to 1 : 10. In still some other embodiment, the fifth solvent is a mixture of N, N-dimethylformamide (DMF) and water in a volume ratio of 1 :2 to 1 : 10. In yet some other embodiments, the fifth solvent is a mixture of dimethyl acetamide and water in a volume ratio of 1 :2 to 1 : 10. In some embodiments, the volume ratio of N, N-dimethylformamide to water is about 7: 1.

[054] In some embodiments, the step of contacting 4-cyclopropylnaphthalen-l -amine with CS ₂ in the presence of a first alkaline solution is performed at room temperature.

[055] In some embodiments, based on 1 equivalent weight of

4-cyclopropyl-l-naphthylamine, CS ₂ has an amount from about 1.2 equivalent weights to about 2.0 equivalent weights. In some embodiments, 2,4,6-trichloro-l,3,5-triazine having a concentration of about 0.5 mole to 1.0 mole is directly added to the first reaction solution without further processing in a stirring condition, to obtain a second reaction solution. In some embodiments, after stirring for 1 minute to 12 hours, the step of adding a second alkaline solution to the second reaction solution is performed at room temperature under the stirring condition, to obtain 4-cyclopropyl-l-isothiocyanato naphthalene.

[056] In some embodiments, the process for preparing the compound shown as formula

(III) further comprises:

contacting 4-cyclopropylnaphthalen-l -amine having an amount of 1.0 equivalent weight with CS ₂ having an amount of 2.0 equivalent weight in the presence of potassium carbonate having an amount of 1.0 equivalent weight, DMF and water at room temperature (about 15 °C), to form the first reaction solution under a condition of stirring for about 30 minutes to 12 hours; adding 2,4,6-trichloro-l,3,5-triazine having an amount of 0.5 equivalent weight to the first reaction solution, to form the second reaction solution; and

adding sodium hydroxide to the second reaction solution at room temperature (about 16 °C) under a stirring condition, to obtain the compound shown as formula (III).

[057] In a fifth aspect, there is provided an intermediate compound as shown in formula

(Ila) or formula (lb),

[058] In a sixth aspect, there is provided a process for preparing a compound shown as formula (la). In some embodiments, the process comprises: hydrolyzing a compound (I) in the presences of an alkaline solution, to obtain a compound shown as formula (Ic), wherein M is a

cation, (I), (i _c ).

[059] In some other embodiments, the compound shown as (Ic) may be subjected to a treatment of proton acid, to obtain a compound shown as formula (la),

[060] In some embodiments, the step of hydrolyzing a compound (I) in the presences of an alkaline solution is to provide a compound shown as formula (Ic), in which M is a cation. In certain embodiments, M is selected from Na ⁺ , Li ⁺ , K ⁺ , Cs ⁺ , Ca ²⁺ , or any other suitable cations. In some embodiments, the alkaline solution is potassium hydroxide, sodium bicarbonate, potassium carbonate, potassium acetate, lithium hydroxide, sodium acetate, sodium benzoate, potassium bicarbonate, cesium hydroxide, sodium carbonate, sodium hydroxide, sodium silicate, trisodium phosphate, calcium hydroxide, potassium phosphate, or a combination thereof. In some embodiments, the alkaline solution is sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, calcium hydroxide, or a combination thereof. In some embodiments, the alkaline solution is potassium carbonate. In some other embodiments, the base is sodium bicarbonate.

[061] In some embodiments, the step of hydrolyzing a compound (I) in the presences of an alkaline solution is performed in a sixth solvent. In some embodiments, the sixth solvent is water, toluene, xylene, 1,4-dioxane, methanol, ethanol, butanol, isopropanol, diethyl ether, hexane, pentane, heptane, ethyl acetate, dichloromethane, 1,2-dichlorobenzene, acetonitrile, N-methylpyrrolidone, acetone, dimethylformamide (DMF), dimethylsulfoxide (DMSO), or a combination thereof. In some embodiments, the sixth solvent water. In some other embodiments, the sixth solvent is acetone. In an embodiment, the sixth solvent is a mixture of water and acetone.

[062] In some embodiments, the step of hydrolyzing a compound (I) in the presences of both acetone and a solution of sodium bicarbonate.

[063] In some embodiments, the step of hydrolyzing a compound (I) is performed at a reflux temperature.

[064] As disclosed herein, the compound shown as formula (I) is prepared by directly brominating the triazole ring, which avoids carcinogenic residual impurities caused by a diazotization reaction. The process of the present disclosure is simple but having a high yield, so the aforementioned process is suitable for industrial scale. Disclosed herein is a one-pot process for preparing l-cyclopropyl-4-isothiocyanatonaphthalene shown as formula (III), the process is performed in a vessel, a reactant and a reagent are successively to a reaction solution, without work-up procedure during the reaction process, the steps in the present disclosure involve reduced process steps, which is easy to operate an avoids using toxic and corrosive chemicals. The purity and overall yield of the product are improved without additional purifications.

EXAMPLES

[065] The present invention discloses a modulating Uric Acid compound that is thio-l,2,4-triazole derivatives and their preparation thereof. The skilled in the art can learn from the present invention and improve the process parameters appropriately. It should be noted that it can be readily apparent to those of ordinary skill in the art that certain modifications may be made thereto within the scope of the invention. Some embodiments of the invention are disclosed herein, obviously, a skilled artisan can make any alterations, changes or combinations thereof appropriately to implement and apply the present invention without departing from the content, spirit and scope of the present invention.

Example 1. 4-cyclopropyl-l-naphthylamine

[066] To a four necked flask that equipped with a mechanical stirrer, a reflux condenser and a thermometer added 4-bromo-l-naphthylamine (90 g, 40.5 mmol), cyclopropyl boronic acid (38.4 g, 44.6 mmol), anhydrous potassium phosphate (258 g, 122 mmol), toluene (800 mL) and water (30 mL) to form a mixture, stirred the mixture followed by adding cyclohexylphosphine (11.5 g, 4.1 mmol) and palladium acetate (3.65 g, 1.62 mmol) under nitrogen atmosphere to form a reaction mixture. The reaction mixture was heated to 110°C and stirred at 110°C for 3 hours, then was added with water (800 mL), separated the organic layer, extracted the aqueous phase with ethyl acetate (300 mL><2) and dried the combined organic phases with anhydrous sodium sulfate. After removing the desiccant, the filtrate was reduced under vacuum pressure to obtain 4-cyclopropyl-l-naphthylamine 80 g.

Example 2. 4 -cyclopropyl-l-isothiocyanate naphthalene

[067] To a flask added 4-cyclopropyl-l-naphthylamine prepared by example 1 (66 g),

K ₂ C0 ₃ (100 g), DMF (80 ml) and water (560 mL), the mixture was stirred at room temperature, then CS ₂ (44 mL) was drop wise added to the mixture in 5 min. After the addition was complete, the mixture was stirred for another 3.5 hours at room temperature (15°C). Then, the mixture was cooled to 0°C, and a solution of cyanuric chloride (33.6 g) in 250 mL of CH ₂ C1 ₂ was drop wise added. After the addition was complete, the mixture was stirred for another 1 hour to complete the conversion. The resulting mixture was added 6 N NaOH (300 mL) and was stirred for another 2 hours. To the resulting mixture added dichloromethane (400 mL) and water (200 mL), then the organic layer was separated and the aqueous layer was extracted with CH ₂ C1 ₂ (250 mL><2). The combined organic layers were dried over anhydrous Na ₂ S0 ₄ , filtered, and the solvent of filtrate was removed via distillation under atmospheric pressure to obtain a brown liquid. The brown liquid was further purified by a short silica gel column (cyclohexane as eluent), then 77.0 g (94%) of colorless liquid 4 -cyclopropyl-l-isothiocyanate naphthalene was obtained. GC-Ms: m/z (EI): 225, 1H MR (400 MHz, CDC1 ₃ ): δ 8.43 (m, 1H), 8.12 (m, 1H), 7.62 (m, 2H), 7.33 (d, J=8.0 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 2.31 (m, 1H), 1.10 (m, 2H), 0.77 (m, 2H).

Example 3. Preparation of 4-(4-cyclopropyl-naphthalen-l-yl)-l-formylamino-thiourea

[068] 4-cyclopropyl-l-isothiocyanate naphthalene (67.5 g, 300 mmol), formyl hydrazine

(18.0 g, 300 mmol), and ethyl acetate (400 mL) were placed into a flask to form a mixture, the mixture was heated to about 60°C, after stirred for 2 hours, the mixture was cooled to room temperature (about 23 °C ), then the mixture was filtered, the filter cake was washed with ethyl acetate, dried under vacuum at about 50°C to obtain 4-(4-cyclopropyl-naphthalen-l-yl)-l-formylamino-thiourea as a yellow solid 64.0 g, yield 75%. LC-Ms: m/z (ESI): 286 (M+H) ⁺ , 1H MR (400 MHz, acetone-d ₆ ): δ 8.46 (m, 1 H), 8.28 (s, 1 H), 8.02 (m, 1 H), 7.54 (m, 2 H), 7.40 (m, 1 H), 7.29 (m, 1 H), 2.40 (m, 1 H), 1.10 (m, 2 H), 0.75 (m, 2 H).

Example 4. Preparation of 4 - (4-cyclopropyl-naphthalen-l-yl)-l-formylamino-thiourea

[069] 4 -cyclopropyl-l-isothiocyanate naphthalene (49.4 g), formyl hydrazine (19.75 g), and ethyl acetate (500 mL) were placed into a lL-flask to form a mixture, the mixture was stirred at 20°C for 6 hours, then the mixture was cooled to 10°C, after stirred for another 2 hours, the mixture was filtered, the obtain solid was dried under vacuum for 12 hours to obtain the title compound, yield 85%.

Example 5. Preparation of 4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazole-3-thiol

[070] To a round bottom flask added 4-(4-cyclopropyl-naphthalen-l-yl)

-1-formylamino-thiourea (64.0 g, 225 mmol), DMF (300 mL) and 1 mol/L aqueous sodium hydroxide solution (225 mL) to form a mixture, the mixture was heated to about 30°C after stirred for about 16 hours, the mixture was cooled to room temperature (about 20°C). 1 mol/L hydrochloric acid (about 200 mL) was added into the mixture until the pH value of the mixture was about 6.0, then water (about 500 mL) was added. The mixture was stirred for about 15 minutes and filtered. The filter cake was washed with water, and the product was dried in vacuum at about 50°C for about 5 hours to obtain gray-green solid 4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazole-3 -thiol, 54.0 g, yield 90%. LC-Ms: m/z (ESI): 268(M+H) ⁺ , 1H MR (400 MHz, acetone-d ₆ ): δ 8.57 (d, J=8.0 Hz, 1 H), 8.37 (s, 1 H), 7.67 (m, 1 H), 7.60(m, 1 H), 7.5 l(d, J=8.0 Hz, 1 H), 7.48 (d, J=8.0 Hz, 1 H), 7.43 (d, J=8.0 Hz, 1 H), 2.50 (m, 1 H), 1.16 (m, 2 H), 0.84 (m, 2 H).

Example 6. Preparation of 4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazole-3-thiol

[071] To a round bottom flask added 4-

(4-cyclopropyl-naphthalen-l-yl)- 1-formylamino-thiourea (285 mg, 1.0 mmol), THF (about 4 mL) and 1 mol/L aqueous potassium hydroxide solution to form a mixture. The mixture was heated to about 30°C, after stirred for about 2 hours, the mixture was cooled to room temperature (about 19°C), then 1 mol/L hydrochloric acid was added to the mixture till the pH of the mixture was about 5.0. The mixture was extracted with ethyl acetate, the combined organic layer was dried with anhydrous sodium sulfate and filtered, reduced under pressure to obtain 4-(4-cyclopropyl-l-yl)-4H-l, 2,4-triazole-3-thiophenol, yellow solid 250 mg, yield 94%.

Example 7. Preparation of 4-(4-cyclopropyl-l-yl)-4H-l, 2,4- triazole-3-thiophenol

[072] To a round bottom flask added 4-(4-cyclopropyl-naphthalen-l-yl)

-1-formylamino-thiourea (23 g), sodium bicarbonate (8.1 g), acetone (115 mL) and water (29 mL) to form a mixture, the mixture was heated to about 70°C, after stirred for about 2 hours, 1 mole hydrochloric acid was added to the mixture until the pH of the mixture was about 5.0, then added water (about 1000 mL), stirred for about 15 minutes and filtered, the filter cake was dried in vacuum at about 60°C for about 12 hours to obtain 4-(4-cyclopropyl-l-yl)-4H-l,2,4-triazole-3-thiophenol, yield 87%.

Example 8. Preparation of methyl

2-((4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-y l)thio)acetate

[073] To a round bottom flask added 4-(4-cyclopropyl-l-yl)-4H-l,

2,4-triazole-3-thiophenol (54.0 g), acetone/water (500 mL/25 mL), methyl chloroacetate (17.8 mL) and potassium carbonate (33.5 g) to form a mixture, the mixture was heated to about 40°C, after stirred for about 6 hours, the mixture was cooled to room temperature (about 19°C), then was added water (about 400 mL), stirred for about 5 minutes followed by removing acetone, filtered, the filter cake was washed with water and dried in vacuum at about 50°C for about 12 hours to obtain methyl 2-((4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-yl)t hio)acetate 65.0 g, yield 90%. LC-Ms: m/z (ESI): 402 (M+H) ⁺ , 1H MR (400 MHz, CDC13): δ 8.54 (d, J=8.0 Hz, 1 H), 8.32 (s, 1 H), 7.66 (m, 1 H), 7.54 (m, 1 H), 7.34-7.41 (m, 5 H), 7.23 (m, 1 H), 7.10 (m, 2H), 4.30 (dd, J=8.0, 12 Hz, 2 H), 2.43 (m, 1 H), 1.17 (m, 2 H), 0.86 (m, 2 H).

Example 9. Preparation of phenyl

2-((4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-y l)thio)acetate

[074] To a round bottom flask was added 4-(4-cyclopropyl-l-yl)-4H-l,

2,4-triazole-3-thiophenol (40.0 g), isopropanol (620 mL) and triethylamine (16.6 g) to form a mixture at room temperature, after stirred for 20 min, the mixture was cooled to 0°C, then was added drop wise a solution of phenyl bromoacetate in isopropanol (33.8 g of phenyl bromoacetate was dissolved in 200 mL of isopropanol), during the addiction the mixture was maintained at about 0°C, after the addition, the mixture was warm to 20°C, after stirred for about 2 hours, the reaction was complete, filtered, the filter cake was washed with isopropanol (100 mL). The filter cake was added purified water (700 mL) to give a slurry, the slurry was stirred for 1 hour, then the purified water was removed by vacuum filtration, the filter case was dried under vacuum at about 50°C for about 24 hours to obtain phenyl 2-((4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-yl)t hio)acetate, yield 92%, the HPLC purity (area) 99.0%.

Example 10. Preparation of phenyl

2-((4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-y l)thio)acetate

[075] To a round bottom flask added

4-(4-cyclopropyl-l-yl)-4H-l,2,4-triazole-3-thiophenol (40.0 g), acetone (600 mL) and triethylamine (16.6 g) to form a mixture at room temperature, after stirred for 20 min, the mixture was cooled to 0°C, then was added drop wise a solution of phenyl chloroacetate in isopropanol (33.8 g of phenyl chloroacetate was dissolved in 200 mL of acetone), during the addiction the mixture was maintained at about 0°C, after the addition, the mixture was warm to 20°C, after stirred for about 2 hours, the reaction was complete, filtered, and the filter cake was washed with acetone (100 mL), after filtration, the filter cake was added purified water (700 mL) to give a slurry, the slurry was stirred for 1 hour, then the purified water was removed by vacuum filtration, the filter cake was dried in vacuum at about 50°C for about 24 hours to obtain phenyl 2-((4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-yl)t hio)acetate, yield 90% the HPLC purity(area) 99.2%.

Example 11. Preparation of methyl

2-((5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-tri azol-3-yl)thio)acetate

[076] To a flask added methyl

2-((4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-y l)thio)acetate (4.0 g, 11.8 mmol), l,3-Dibromo-5,5-dimethylhydantoin (11.8 mmol) and ethyl acetate (100 mL) to form a mixture, the mixture was heated to reflux, after the reaction was complete, the mixture was cooled to room temperature, then worked up to obtain phenyl

2-((5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-tri azol-3-yl)thio)acetate as a yellow solid 4.9 g, yield 99%, LC-Ms: m/z (ESI): 418,420 (M+H) ⁺ , 1H NMR (400 MHz, CDC1 ₃ ): δ 8.57 (d, J=8.0 Hz, 1 H), 7.69 (m, 1 H), 7.61 (m, 1 H), 7.39 (s, 2 H), 7.26 (d, J=8.4 Hz, 1 H), 4.07 (dd, J=16.0, 25.6 Hz, 2 H), 3.75 (s, 3 H), 2.46 (m, 1 H), 1.20 (m, 2 H), 0.91 (m, 2 H).

Example 12. Preparation of phenyl

2-((5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-tri azol-3-yl)thio)acetate

[077] To a flask added 2-[4-(4-cyclopropyl-l-yl)-4H-l,2,4-triazol-3-ylthio] phenyl acetate

(20.0 g) and CH ₂ CI ₂ (300 mL), the mixture was stirred to form a clear solution, to the solution was added Ι,Γ-Thiocarbonyldiimidazole (TCDI) (0.44 g), after stirred for 15 min at room temperature, N-bromobutanimide (13.2 g) was added, after the reaction was complete, the resulted solution was cooled to 0°C, followed by adding 150 mL purified water. After stirred for 30 min, the organic phase was separated and was cooled to 0°C, then was added 150 mL 10% of Na ₂ S0 ₃ solution. After the addiction was complete, the mixture was stirred at room temperature for 30 min, then the DCM layer was separated, washed with 150 mL purified water, then DCM was removed under reduced pressure to obtain a concentration mass. To the concentration mass added 80 mL methanol, stirred to give a solution, then the solution was added drop wise to 500 mL brine. After stirred for one hour, precipitate was separated, washed with pure water (100 mL), then the obtained solid was dried in vacuum to obtain the title compound 22. Og, yield 92%. LC-Ms: m/z (ESI): 481 (M+H) ⁺ , 1H NMR (400 MHz, CDC1 ₃ ): δ 8.57 (d, J=4.0 Hz, 1 H), 7.69 (m, 1 H), 7.57 (m, 1 H), 7.39-7.41 (m, 4 H), 7.25-7.28 (m, 2 H), 7.13 (m, 2H), 4.30 (dd, J=8.0, 12 Hz, 2 H), 2.47 (m, 1 H), 1.20 (m, 2 H), 0.91 (m, 2 H).

Example 13. Preparation of 2-(5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol -3-ylthio)acetate

[078] Methyl

2-((5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazo l-3-yl)thio)acetate (7.0 g), methanol (28 mL) and 1 mole sodium hydroxide solution (20 mL) were placed in a flask, the mixture was stirred at room temperature (16°C) for 20 min, then was added water (50 mL), and 0.5 mol/L of dilute hydrochloric acid was added to the reaction mixture till pH value was 2.5, after the addiction was complete, the mixture was extracted with CH ₂ CI ₂ , the organic phase was combined and CH ₂ CI ₂ was removed under reduce pressure to obtain yellow solid 2-(5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol -3-ylthio)acetate 6.0 g, yield 90%, LC-Ms: m/z (ESI): 404,406(M+H) ⁺ , 1H MR (400 MHz,CDCl ₃ ): δ 8.58 (d, J=8.0 Hz, 1 H), 7.71 (m, 1 H), 7.62 (m, 1 H), 7.40 (s, 2 H), 7.24 (d, J=8.4 Hz, 1 H), 4.00 (dd, J=16.0, 25.6 Hz, 2 H), 2.46 (m, 1 H), 1.21 (m, 2 H), 0.9 l(m, 2 H).

Example 14. Preparation of 2-((5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazo l-3-yl)thio)acetic acid

[079] Phenyl

2-((5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazo l-3-yl)thio)acetate (23.9g), and acetone (250 mL) were placed in a flask to form a mixture, after the mixture was stirred to a clear solution, the solution was added 1 mole NaHC0 ₃ solution to obtain a suspension, then the suspension was heated to 65°C. After refluxed for 12 hours, the reaction mixture was cooled to room temperature, distilled the acetone to obtain a solution, to the solution added 80 mL ethyl acetate. Adjusted the pH value of the solution to about 3.0 with 1 mole NaHS0 ₄ solution, stirred for 30 min at room temperature, then separated the organic phase, extracted the water layer with 80 mL ethyl acetate, and combined the organic phase. The organic phase was stirred at room temperature for 12 hours, then precipitate was filtered. The obtained solid was dried in vacuum to obtain 2-(5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol -3-ylthio)acetate, yield 93%.