WO2014198241A1 - Dérivés de thio-1,2,4-triazole et leur procédé de préparation - Google Patents

Dérivés de thio-1,2,4-triazole et leur procédé de préparation Download PDF

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Publication number
WO2014198241A1
WO2014198241A1 PCT/CN2014/079975 CN2014079975W WO2014198241A1 WO 2014198241 A1 WO2014198241 A1 WO 2014198241A1 CN 2014079975 W CN2014079975 W CN 2014079975W WO 2014198241 A1 WO2014198241 A1 WO 2014198241A1
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formula
compound shown
solvent
contacting
reaction solution
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PCT/CN2014/079975
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English (en)
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Weiqiang Chen
Jian Luo
Lixue Liu
Yuping FAN
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Sunshine Lake Pharma Co., Ltd.
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Priority to CN201480029241.7A priority Critical patent/CN105263913B/zh
Publication of WO2014198241A1 publication Critical patent/WO2014198241A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C331/00—Derivatives of thiocyanic acid or of isothiocyanic acid
    • C07C331/16—Isothiocyanates
    • C07C331/28—Isothiocyanates having isothiocyanate groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • 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.
  • 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.
  • 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),
  • 2-((5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-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.
  • WO 2009070740 discloses a compound
  • 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.
  • the above process uses tribromomethane as a reacting solvent during the bromination, having a high toxicity, which is not suitable for industry scale.
  • 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)
  • 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
  • C1-C6 alkyl, cycloalkyl, or phenyl is optionally further substituted by F, CI, Br, CH 3 or CF 3 .
  • 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 ⁇ , ⁇ '-thiocarbonyl diimidazole.
  • LG is CI, Br, I, tosylate, mesylate, triflate or besylate, preferably LG is Br, more preferably
  • LG is CI.
  • 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
  • the compound shown as (Ic) may be subjected to a treatment of proton acid, to obtain a compound shown as formula (la),
  • 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.
  • the alkyl group includes, but not limited to, methyl
  • cycloalkyl 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%.
  • 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.
  • TLC thin layer chromatography
  • HPLC high performance liquid chromatography
  • GC gas chromatography
  • 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%.
  • R 2 is C1-C6 alkyl or phenyl
  • each R 3 , R 4 is independently H, C1-C6 alkyl or cycloalkyl
  • C1-C6 alkyl, cycloalkyl, or phenyl is optionally further substituted by F, CI, Br, CH 3 or CF 3 .
  • R 2 is methyl, ethyl, propyl, isopropyl or phenyl.
  • R 2 is methyl or phenyl.
  • 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.
  • the brominating agent is N-bromosuccinimide (NBS), l,3-dibromo-5,5-dimethylhydantoin, or a combination thereof.
  • 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.
  • 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 ⁇ , ⁇ '-thiocarbonyl diimidazole.
  • an amount of N,N'-thiocarbonyl diimidazole is about 0.02 mole to about 0.1 mole.
  • an amount of ⁇ , ⁇ '-thiocarbonyl diimidazole is about 0.05 mole.
  • 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.
  • 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.
  • the first solvent is di chl or om ethane .
  • 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.
  • 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.
  • halogen such as CI, Br or I
  • 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.
  • the first organic base may be at least one selected from a group consisting of alkali carbonate, alkali bicarbonate and organic tertiary amine.
  • the alkali carbonate may be lithium carbonate, sodium carbonate or potassium carbonate.
  • the alkali bicarbonate may be lithium hydrogencarbonate, sodium hydrogencarbonate or potassium hydrogencarbonate.
  • the organic tertiary amine may be triethylamine, diisopropylethylamine, DBU (1,8-diazabicyclo [5.4.0] undecene).
  • the first organic base is organic tertiary amine triethylamine.
  • 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).
  • the second solvent may be at least one selected from a group consisting of ethanol and isopropanol.
  • the second solvent is acetone.
  • 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.
  • 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.
  • (II) may further comprises a step after the step of contacting the compound shown as formula (V) with the compound shown as formula (VI):
  • the compound shown as formula (VI) is bromo phenyl acetate or chloro phenyl acetate.
  • 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.
  • 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
  • the third solvent is at least one of an ether solvent or an ester solvent.
  • the ether solvent is at least one selected from a group consisting of tetrahydrofuran (THF), methyl tert-butyl ether (MTBE) and 1,4-dioxane.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • the base is alkali hydroxide.
  • the base is tertiary organic amine, such as triethylamine, diisopropylethylamine or a combination thereof.
  • 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.
  • work up procedure or a step of separating the intermediate compound may be not required
  • the first alkaline solution comprises at least one selected from a group consisting of sodium hydroxide, potassium hydroxide, potassium carbonate and sodium carbonate.
  • 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.
  • 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.
  • 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.
  • 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.
  • the fifth solvent is water.
  • the fifth solvent is a mixture of acetonitrile and water in a volume ratio of 1 :2 to 1 : 10.
  • the fifth solvent is a mixture of N, N-dimethylformamide (DMF) and water in a volume ratio of 1 :2 to 1 : 10.
  • the fifth solvent is a mixture of dimethyl acetamide and water in a volume ratio of 1 :2 to 1 : 10.
  • the volume ratio of N, N-dimethylformamide to water is about 7: 1.
  • the step of contacting 4-cyclopropylnaphthalen-l -amine with CS 2 in the presence of a first alkaline solution is performed at room temperature.
  • 4-cyclopropyl-l-naphthylamine, CS 2 has an amount from about 1.2 equivalent weights to about 2.0 equivalent weights.
  • 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.
  • 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.
  • (III) further comprises:
  • 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
  • the compound shown as (Ic) may be subjected to a treatment of proton acid, to obtain a compound shown as formula (la),
  • 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.
  • M is selected from Na + , Li + , K + , Cs + , Ca 2+ , or any other suitable cations.
  • 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.
  • the alkaline solution is sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, calcium hydroxide, or a combination thereof.
  • the alkaline solution is potassium carbonate.
  • the base is sodium bicarbonate.
  • the step of hydrolyzing a compound (I) in the presences of an alkaline solution is performed in a sixth solvent.
  • 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.
  • the sixth solvent water.
  • the sixth solvent is acetone.
  • the sixth solvent is a mixture of water and acetone.
  • the step of hydrolyzing a compound (I) in the presences of both acetone and a solution of sodium bicarbonate is a compound (I) in the presences of both acetone and a solution of sodium bicarbonate.
  • the step of hydrolyzing a compound (I) is performed at a reflux temperature.
  • 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.
  • 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.
  • 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.
  • 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)thio)acetate, yield 92%, the HPLC purity (area) 99.0%.
  • 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.
  • 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%.

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Abstract

Cette invention concerne un procédé de préparation d'un composé représenté par la formule (I), comprenant une étape de mise en contact d'un composé représenté par la formule (II) ou un sel de celui-ci avec un agent de bromation, où R1 est OR2 ou NR3R4; R2 est un alkyle C1-C6 ou un phényle; chaque R3, R4 est indépendamment H, un alkyle C1-C6 ou un cycloalkyle, l'alkyle C1-C6, le cycloalkyle, ou le phényle étant en outre éventuellement substitué par F, Cl, Br, CH3 ou CF3. Un procédé de préparation d'un composé représenté par la formule (II), un procédé de préparation d'un composé représenté par la formule (V), un procédé de préparation d'un composé représenté par la formule (III), et un composé intermédiaire représenté par la formule (IIa) ou la formule (Ib) sont en outre décrits.
PCT/CN2014/079975 2013-06-14 2014-06-16 Dérivés de thio-1,2,4-triazole et leur procédé de préparation WO2014198241A1 (fr)

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CN105175348A (zh) * 2015-10-16 2015-12-23 北京康立生医药技术开发有限公司 一种乐司尼达的制备方法
WO2016155653A1 (fr) * 2015-04-03 2016-10-06 南京明德新药研发股份有限公司 Isomères à chiralité axiale, leurs procédés de préparation et leurs utilisations pharmaceutiques
EP3281941A1 (fr) 2016-08-11 2018-02-14 Zentiva K.S. Procédé de préparation d'acide 2-(5-bromo-4-(1-cyclopropylnaphtalén-4-yl)-4h-1,2,4-triazol-3-ythio) acétique
EP3315494A1 (fr) 2017-04-19 2018-05-02 Química Sintética, S.A. Forme amorphe de lésinurad et ses procédés de préparation
CZ307277B6 (cs) * 2016-09-30 2018-05-09 Zentiva, K.S. Způsob výroby 2-(5-brom-4-(1-cyklopropylnaftalen-4-yl)-4H-1,2,4-triazol-3-ylthio)octové kyseliny - lesinuradu
EP3498697A1 (fr) 2017-12-12 2019-06-19 Química Sintética, S.A. Nouveaux sels et polymorphes de lesinurad
US10351537B2 (en) 2017-03-10 2019-07-16 Apotex Inc. Processes for the preparation of lesinurad and intermediates thereof

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CN106187927B (zh) * 2016-07-26 2020-02-04 山东川成医药股份有限公司 一种Lesinurad中间体的制备方法
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CN109970668B (zh) * 2017-12-28 2021-12-07 普济生物科技（台州）有限公司 一种制备3-硫代-1,2,4-三氮唑类化合物的方法
CN111116501B (zh) * 2019-12-30 2021-03-12 北京鑫开元医药科技有限公司海南分公司 一种有效降低杂质含量的雷西纳德中间体的合成方法
CN111116500B (zh) * 2019-12-30 2021-06-08 北京鑫开元医药科技有限公司海南分公司 一种雷西纳德关键中间体的纯化方法
WO2021249468A1 (fr) * 2020-06-11 2021-12-16 南京明德新药研发有限公司 Procédé de préparation d'un composé chloré

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WO2007050087A1 (fr) * 2004-08-25 2007-05-03 Ardea Biosciences, Inc. Acides N[S(4-aryltriazol-3-yl)α-mercaptoacétyl]-p-aminobenzoïques EN TANT QU'INHIBITEURS DE TRANSCRIPTASE INVERSE DE VIH
WO2009070740A2 (fr) * 2007-11-27 2009-06-04 Ardea Biosciences Inc. Nouveaux composés et nouvelles compositions et leurs procédés d'utilisation

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WO2016155653A1 (fr) * 2015-04-03 2016-10-06 南京明德新药研发股份有限公司 Isomères à chiralité axiale, leurs procédés de préparation et leurs utilisations pharmaceutiques
US10183915B2 (en) 2015-04-03 2019-01-22 Medshine Discovery Inc. Axially chiral isomers, and preparation methods therefor and pharmaceutical uses thereof
CN105175348A (zh) * 2015-10-16 2015-12-23 北京康立生医药技术开发有限公司 一种乐司尼达的制备方法
EP3281941A1 (fr) 2016-08-11 2018-02-14 Zentiva K.S. Procédé de préparation d'acide 2-(5-bromo-4-(1-cyclopropylnaphtalén-4-yl)-4h-1,2,4-triazol-3-ythio) acétique
CZ307277B6 (cs) * 2016-09-30 2018-05-09 Zentiva, K.S. Způsob výroby 2-(5-brom-4-(1-cyklopropylnaftalen-4-yl)-4H-1,2,4-triazol-3-ylthio)octové kyseliny - lesinuradu
US10351537B2 (en) 2017-03-10 2019-07-16 Apotex Inc. Processes for the preparation of lesinurad and intermediates thereof
EP3315494A1 (fr) 2017-04-19 2018-05-02 Química Sintética, S.A. Forme amorphe de lésinurad et ses procédés de préparation
EP3498697A1 (fr) 2017-12-12 2019-06-19 Química Sintética, S.A. Nouveaux sels et polymorphes de lesinurad

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