WO2015054960A1 - Procédé de préparation du médicament antigoutteux lesinurad et intermédiaire de synthèse de lesinurad - Google Patents

Procédé de préparation du médicament antigoutteux lesinurad et intermédiaire de synthèse de lesinurad Download PDF

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Publication number
WO2015054960A1
WO2015054960A1 PCT/CN2013/090399 CN2013090399W WO2015054960A1 WO 2015054960 A1 WO2015054960 A1 WO 2015054960A1 CN 2013090399 W CN2013090399 W CN 2013090399W WO 2015054960 A1 WO2015054960 A1 WO 2015054960A1
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Prior art keywords
formula
compound
lesinurad
group
reaction
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PCT/CN2013/090399
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English (en)
Chinese (zh)
Inventor
王鹏
李丕旭
谷向永
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苏州鹏旭医药科技有限公司
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Publication of WO2015054960A1 publication Critical patent/WO2015054960A1/fr

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    • 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
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/40—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of thiourea or isothiourea groups further bound to other hetero atoms

Definitions

  • the invention relates to a preparation method of a gout therapeutic drug Lesmurad and a key intermediate thereof.
  • Gout is a crystal-associated joint disease caused by the deposition of sputum urate (MSU), which is directly related to hyperuricemia caused by a disorder of sputum metabolism and/or a decrease in uric acid excretion. More than 20 million patients worldwide have gout. Lesimirad (1« ⁇ 594) is an oral uric acid cistern that inhibits renal proximal uric acid transporter URAT. Exploratory studies in previous gout patients have shown that allopurinol (ALLO), combined with iesimirad treatment, is more effective in reducing serum uric acid (SUA) than ALLO alone.
  • ALLO allopurinol
  • Chinese patent CN102040546A starts from 4-cyclopropyl-1-naphthaldehyde and, after three steps, synthesizes an intermediate isothionitrite to avoid the use of sulfur phosgene.
  • the technical problem to be solved by the present invention is to overcome the deficiencies of the prior art, to provide a new type of Lesmumd intermediate, and to provide a more economical, more efficient, safer, more environmentally friendly, and suitable for large-scale industrial production of the preparation of Lesinurad. Process.
  • the present invention also provides a method of preparing a known Lesinurad intermediate and Lesmurad using the novel Lesmurad intermediate provided.
  • a Lesinurad intermediate is a compound represented by Formula I,
  • R represents H or COCH 3 ; or R represents CH 2 R f , wherein R 1 represents an ester group; CN; CH 2 OH; unsubstituted or selected from one of C r , . C 6 alkyl, or a plurality of substituted phenyl groups;
  • R 2 represents a cyclopropyl group; halogen; OTf.
  • R represents H
  • R 2 represents a cyclopropane group
  • the structural formula is as shown in Formula 13 -
  • the present invention also provides a Lesmurad intermediate which is a compound represented by the general formula II.
  • R 2 represents a cyclopropyl group; halogen; OTf.
  • R 2 represents a cyclopropenyl group
  • the structural formula of the Lesinurad intermediate is as shown in the formula 12:
  • Another technical solution of the present invention is: a method for preparing a Lesinurad intermediate represented by the formula ⁇ ,
  • R_ represents H or COCH 3 ; or R represents CHsR 1 , wherein: R 1 represents an ester group; CN: C3 ⁇ 4OH; unsubstituted or substituted by one or more selected from the group consisting of C ⁇ C 6 fluorenyl, halogen Phenyl-R 2 represents cyclopropenyl; halogen; OTf.
  • R is COCH 3 or C3 ⁇ 4R ⁇
  • R 3 ⁇ 4 represents an ester group
  • CN CH 2 OH
  • R 2 represents a cyclopropane group.
  • the bromine source used in the bromination reaction may be liquid bromine, bromine water, N-bromosuccinimide or dibromohydantoin.
  • the bromination reaction can be carried out as follows: A bromination reaction occurs in the presence of an acid-binding agent with a compound of the formula I and a source of bromine in a solvent.
  • the preparation method of the Lewissrad intermediate represented by the formula III preferably further comprises the compound 13 RX in a solvent, a step-substituted compound of formula I reaction occurs in the presence of an acid-binding agent, wherein R is as defined above, in particular, R may be COC3 ⁇ 4 or CHbR 1, i Rj represents an ester group; CN; C3 ⁇ 4OH; not a phenyl group substituted or substituted with one or more selected from the group consisting of CC 6 fluorenyl, halogen; R 2 represents a cyclopropyl group; X represents a leaving group,
  • X is chlorine, bromine, iodine or OTf.
  • the method for preparing a Lesinurad intermediate represented by the formula HI preferably further comprises the step of reacting the compound 12 with a dimercapyl acetal in a solvent to form the compound 13,
  • the hydrazine, hydrazine-dimethylformamide dialkyl acetal may be N-dimethylformamide dimethyl acetal or hydrazine, hydrazine-dimethylformamide diethyl acetal.
  • the method for preparing the Lesimirad intermediate represented by the formula III further preferably comprises first reacting 4-cyclopropyl-1 naphthylamine, carbon disulfide with a base to form N-(4-cyclopropyl 1-naphthalene in a solvent. a salt of dithiocarbamic acid, followed by a step of reacting a salt of N-(4-cyclopropylphthalaphthalene)dithiocarbamic acid with hydrazine hydrate to form compound 12.
  • the base may be, for example, sodium hydroxide or potassium hydroxide or the like or a combination thereof.
  • a further technical solution adopted by the present invention is: a method for preparing Lesmnrad, which comprises the steps of Lesi Lesinurad represented by the formula: ⁇ :
  • R represents H or COCH 3 ; or R represents CH 2 R wherein R 3 ⁇ 4 represents an ester group; CN; CH 2 OH ; unsubstituted or substituted by one or more selected from the group consisting of Ci ⁇ C 6 alkyl, halogen Phenyl group;
  • R 2 represents a cyclopropane group; halogen; OTft
  • the method further comprises the step t of preparing the Lesmurad intermediate represented by Formula III by the above-described method of the present invention !
  • the present invention has the following advantages over the prior art:
  • the present invention provides a novel Lesimirad intermediate which provides a new synthetic route for the preparation of Lesinurad.
  • the novel Lesimirad intermediate provided by the present invention is used to synthesize Lesmurad, which has the advantage of T -
  • the total reaction yield can reach a level comparable to or higher than the prior art.
  • This invention relates to novel Lesiixurad intermediates and methods for preparing Lesimirad using these Lesiixurad intermediates.
  • the preparation method of Lesmimid can be expressed by the reaction equation as follows:
  • R may be any alkyl group, such as methyl or ethyl.
  • !1 is preferably COCH 3 or Ci-Wl 1 , wherein: 1 5 represents an ester group; CN; CH 2 OH ; is substituted or selected from one or more of: 6 alkyl, halogen Substituted phenyl (preferably phenyl).
  • R is CH2R 1 ' wherein R 1 is an ester group.
  • R is C3 ⁇ 4R, wherein R 1 is an ethyl ester group.
  • the nuclear magnetic data of the product are as follows: i H NMR (400 MHz, DM SO) ⁇ 9.16 (s, IH), 8.43 (d, J- 7.8 Hz, IH), 7.98 ⁇ 7.89 (m, IH), 7.66-7.48 (m, 3H), 7.26 (d, J- 7.6 Hz, IH), 5,54 ⁇ 4.50 (m, IH), 2.46-2,34 (m, IH), 1.12 - 1.02 (m, 2H), 0.80 - 0.69 ( m, 2H).
  • the product nuclear magnetic data is as follows: Compound 13 (4 g, leq) was added to a single-necked flask, dissolved in solvent DMF (67 mL, 16.8 voi), stirred at room temperature, and added to K 2 C0 3 (2.272 g, l.leq). Compound 14 (1.74 mL, 1.05 eq) was added dropwise, and the dropping rate was controlled at 0.5 mL/min. After 2 hours at room temperature, the reaction was completed. The reaction solution was diluted with EA (ethyl acetate) and water, and extracted with EA three times. The saline solution was washed three times, and the anhydrous MgS0 4 was dried.
  • EA ethyl acetate
  • the reaction can be preferably carried out in a solvent such as THF, chloroform, carbon tetrachloride or 1,2-dichloroethane.
  • a solvent such as THF, chloroform, carbon tetrachloride or 1,2-dichloroethane.
  • the pH was adjusted to neutral with 0.5 hydrochloric acid, and the organic phase in the system was spun off, and the pH was adjusted to about 3 to 4 with a 0.5 N hydrochloric acid solution.
  • the resulting suspension was extracted with CH 2 Ci 2 and the organic phase was stirred to give the desired product, that is, Lesinurad, yield 99%.
  • Compound 23 can be obtained by a conventional hydrolysis reaction to obtain LesinuracL.
  • Compound 26 is oxidized to an acid by a conventional oxidation reaction to obtain LesimiracL.
  • Compound 31 is subjected to bromination, deprotection of thioacetyl group, hydrolysis after preparation of thioether derivative, and Lesimirac L is obtained.
  • the nuclear magnetic data of the product are as follows: l li NR (400 MHz, DMSO) ⁇ 14,09 (s, 1 ⁇ ), 8,72 (s, 1H), 8,29 (d, J::: 8.4 Hz, 1H), 8.09 (d, J::: 7.9 Hz, 1H), 7.81 ft, , /::::: 7.7 Hz, IH), 7.72 (t, J :: 7.6 Hz, 1H), 7.60 fd, J :: 7.9 Hz, IH), 7,44 (d, J::: 8.4 Hz, IH).
  • Compound 32-36 can be converted to a cyclopropyl group by a coupling reaction, and a target compound 8 can be obtained by a reaction similar to the route of the present application.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur un nouvel intermédiaire de synthèse de lesinurad, permettant un procédé de synthèse plus économique, plus efficace, plus sûr, plus respectueux de l'environnement et approprié pour une production industrielle à grande échelle pour la préparation de lesinurad. L'invention porte également sur un procédé pour la préparation de l'intermédiaire de synthèse de lesinurad connu et de lesinurad par l'intermédiaire du nouvel intermédiaire de synthèse de lesinurad selon l'invention. L'utilisation du nouvel intermédiaire de synthèse de lesinurad selon la présente invention pour synthétiser du lesinurad présente les avantages suivants : l'utilisation de matières premières nécessaires bon marché et facilement disponibles ; le fait d'éviter l'utilisation de métaux lourds et de solvants nocifs pour l'environnement ; la séparation et la purification faciles de l'intermédiaire du produit avec une opération simple ; le fait d'éviter l'utilisation du thiophosgène ayant une haute toxicité et étant difficile à manipuler ; et le fait de permettre au rendement total de la réaction d'atteindre un niveau supérieur ou égal à celui de l'état de la technique.
PCT/CN2013/090399 2013-10-15 2013-12-25 Procédé de préparation du médicament antigoutteux lesinurad et intermédiaire de synthèse de lesinurad WO2015054960A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201310482334.2A CN103524440B (zh) 2013-10-15 2013-10-15 痛风治疗药Lesinurad的制备方法及Lesinurad中间体
CN201310482334.2 2013-10-15

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017147270A1 (fr) * 2016-02-24 2017-08-31 Ardea Biosciences, Inc. Atropisomères de dérivé triazole
WO2017215589A1 (fr) * 2016-06-17 2017-12-21 南京明德新药研发股份有限公司 Composé halogéné et son isomère chiral axial
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
US10351537B2 (en) 2017-03-10 2019-07-16 Apotex Inc. Processes for the preparation of lesinurad and intermediates thereof

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CN104292123B (zh) * 2014-09-27 2015-12-02 张远强 苯基萘环的丁二酸酰胺衍生物、其制备方法及用途
CN109053608A (zh) * 2015-02-17 2018-12-21 华润赛科药业有限责任公司 一种旋光纯的硫代乙酸类化合物、其药物组合物和用途
CN105622531A (zh) * 2015-04-03 2016-06-01 南京明德新药研发股份有限公司 轴手性异构体及其制备方法和制药用途
CN105017169A (zh) * 2015-06-30 2015-11-04 安徽万邦医药科技有限公司 一种4-（4-环丙基萘-1-基）-5-硫代-[1,2,4]***烷-3-酮的制备方法及其中间体（4-环丙基萘-1-基）-氨基甲酸乙酯
CN104987311A (zh) * 2015-06-30 2015-10-21 安徽万邦医药科技有限公司 一种[4-(4-环丙基萘-1-基)-5-硝基- 4h-[1,2,4]***-3-基硫烷基]-乙酸乙酯的制备方法及其中间体(5-硝基-4h-[1,2,4]***-3-基硫基)-乙酸乙酯
CN105153056A (zh) * 2015-07-01 2015-12-16 安徽万邦医药科技有限公司 一种[5-溴-4-(4-环丙基萘-1-基)-4h-[1,2,4]***-3-基硫烷基]-乙酸甲酯的新制备方法
CN105017168A (zh) * 2015-07-01 2015-11-04 安徽万邦医药科技有限公司 一种[5-溴-4-(4-环丙基萘-1-基)-4h-[1,2,4]***-3-基硫烷基]-乙酸甲酯的新制备方法
CN106478531B (zh) * 2015-08-25 2019-06-28 南京华威医药科技集团有限公司 2-(5-溴-4-(4-环丙基萘-1-基)-4h-1，2，4-***-3-基硫基)乙酸中间体
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
CN105906576B (zh) * 2016-06-12 2018-04-17 成都百裕制药股份有限公司 一种来司诺雷中间体的制备方法
CN108014108A (zh) * 2016-11-03 2018-05-11 江苏万邦生化医药股份有限公司 lesinurad或其医药上可接受的盐在制备治疗或预防库欣综合征的药物中的应用
CN108164471B (zh) * 2016-12-07 2019-09-13 浙江京新药业股份有限公司 Lesinurad衍生物及其制备方法和用途
CN106916115B (zh) * 2017-03-22 2018-03-06 北京新领先医药科技发展有限公司 一种季铵盐催化及应用
CN106866560B (zh) * 2017-03-30 2023-05-30 浙江美诺华药物化学有限公司 一种Lesinurad的合成方法
CN108947919B (zh) 2017-05-17 2023-05-02 上海奥博生物医药股份有限公司 一种抗痛风药Lesinurad的新型制备方法及其关键中间体
CN108047148A (zh) * 2017-12-28 2018-05-18 北京沃邦医药科技有限公司 一种雷西纳德杂质的制备方法
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
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
JP2023528976A (ja) * 2020-06-11 2023-07-06 ジアンスー カニョン ファーマシューティカル カンパニー リミテッド 塩素化化合物の製造方法

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Publication number Priority date Publication date Assignee Title
WO2017147270A1 (fr) * 2016-02-24 2017-08-31 Ardea Biosciences, Inc. Atropisomères de dérivé triazole
WO2017215589A1 (fr) * 2016-06-17 2017-12-21 南京明德新药研发股份有限公司 Composé halogéné et son isomère chiral axial
US10633351B2 (en) 2016-06-17 2020-04-28 Medshine Discovery Inc. Halogenated compound and axially chiral isomer thereof
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
US10351537B2 (en) 2017-03-10 2019-07-16 Apotex Inc. Processes for the preparation of lesinurad and intermediates thereof

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