WO2023035571A1 - Procédés de synthèse de l'esaxérénone et de son intermédiaire - Google Patents

Procédés de synthèse de l'esaxérénone et de son intermédiaire Download PDF

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Publication number
WO2023035571A1
WO2023035571A1 PCT/CN2022/080532 CN2022080532W WO2023035571A1 WO 2023035571 A1 WO2023035571 A1 WO 2023035571A1 CN 2022080532 W CN2022080532 W CN 2022080532W WO 2023035571 A1 WO2023035571 A1 WO 2023035571A1
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solvent
compound formula
limited
synthetic method
base
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PCT/CN2022/080532
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English (en)
Chinese (zh)
Inventor
阮晶
张鑫鑫
严恭超
阮晓娜
张薇
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上海鼎雅药物化学科技有限公司
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Publication of WO2023035571A1 publication Critical patent/WO2023035571A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to the field of organic synthesis, in particular, to a synthetic method for an eschacillinone intermediate, and in addition to a synthetic method for eschacillinone.
  • ethacillinone is (5P)-1-(2-hydroxyethyl)-N-[4-(methylsulfonyl)phenyl]-4-methyl-5-[2-(trifluoromethyl ) phenyl]-1H-pyrrole-3-carboxamide, the structural formula is as follows:
  • MR mineralocorticoid receptor
  • the preparation method of key intermediate IV is also reported, such as patent documents CN102186817A and WO2021078135A1.
  • the preparation methods of key intermediate IV disclosed in the above patent documents are all prepared by Suzuki coupling reaction, and the palladium catalyst used in this reaction is expensive. The cost is high, and ligands need to be added, which is not conducive to purification and industrial production.
  • the cyclization step of this route uses hydrogen chloride gas as the reaction material, which is highly corrosive, and the palladium metal catalyst used in the chlorine group removal step is expensive and costly, which is not conducive to industrial scale-up production.
  • the present invention provides a synthetic method of an eschacillinone intermediate, which has the advantages of high yield, simple aftertreatment, low cost, and ease of industrialization, while making the product meet the purity required for registration of raw materials.
  • One of purpose of the present invention is to provide a kind of synthetic method of new eschacillinone intermediate, to solve the existing synthetic method of eschacillinone intermediate that preparation yield is low, cost is high, post-processing is complicated and inconvenient Conducive to the problem of industrialized production.
  • the first aspect of the present invention provides a kind of synthetic method of new oxacillinone intermediate compound formula IV, and this synthetic method comprises the following steps:
  • step (1) The amide compound formula II obtained in step (1) is prepared through a dehydration reaction in the presence of a dehydrating agent and an acid-binding agent to obtain an isonitrile compound formula III;
  • step (3) The isonitrile compound formula III obtained in step (2) is cyclized with ethyl 2-butynoate to form the pyrrole ring compound formula IV in the presence of a base and a metal catalyst;
  • the process route is as follows:
  • the inert solvent described in step (1) includes but not limited to one or more of the group consisting of halogenated hydrocarbons, benzene, toluene, ether, xylene, nitrobenzene, and acetonitrile; One or more of imidazole, pyridine, tetrabutylammonium fluoride, 2,6-lutidine, potassium carbonate, N,N-diisopropylethylamine, sodium carbonate, and triethylamine; 2
  • the molar ratio of -(trifluoromethyl)phenylacetic acid to base is 1:0.5 ⁇ 1; the molar ratio of 2-(trifluoromethyl)phenylacetic acid to ethyl chloroformate or isobutyl chloroformate is 1:1 ⁇ 1.5; the reaction temperature is 0° C. to room temperature; the reaction time is 12 hours to 36 hours.
  • the dehydrating agent described in step (2) is one or more of P 2 O 5 , PCl 3 , SOCl 2 , COCl 2 , ArSO 2 Cl, POCl 3 ;
  • the acid-binding agent is an organic base Or inorganic base, described inorganic base is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium tert-butoxide etc.;
  • Described organic base is triethylamine, diisopropylamine; Described solvent selects halogenated alkanes, two Chloromethane, dichloroethane.
  • the base in step (3) is Pr 3 N, pyridine, DBU, TEEDA; the metal catalyst is Cu 2 O, CuCl, CuI, CuBr, Cu(OMe) 2 , copper powder.
  • the second aspect of the present invention also provides the esacillinone intermediate compound formula IV, which is prepared by the above synthesis process.
  • the third aspect of the present invention also provides a synthetic method of a new oxacillinone intermediate compound formula V, the synthetic method comprising the following steps: the above-mentioned pyrrole ring compound formula IV in a solvent, under the condition of the presence of a base, and Reaction preparation obtains compound formula V;
  • the structural formula of intermediate compound formula V is as follows:
  • the X is halogen, and the A is hydroxyl or halogen.
  • the solvent is an alcohol solvent, a halogenated hydrocarbon solvent, an aromatic hydrocarbon solvent, an ether solvent or an amide solvent;
  • the alcohol solvent includes but not limited to ethanol;
  • the halogenated hydrocarbon solvent includes but not limited to dichloromethane or chloroform;
  • the aromatic hydrocarbon solvents include but not limited to toluene, benzene, xylene or nitrobenzene;
  • the ether solvents include but not limited to tetrahydrofuran, 1,4-dioxane
  • the amide solvent includes but not limited to N,N-dimethylacetamide, N,N-dimethylformamide;
  • the alkali is sodium hydroxide, potassium hydroxide, lithium hydroxide, tert-butanol Sodium, potassium tert-butoxide, cesium carbonate, sodium hydride, potassium carbonate, sodium carbonate, 4-dimethylaminopyridine, N,N-diisopropylethylamine,
  • the fourth aspect of the present invention also provides the esacillinone intermediate compound formula V, which is prepared by the aforementioned synthesis process.
  • the fifth aspect of the present invention also provides a kind of synthetic method of new ethacillinone, adopts following technical scheme:
  • the condensing agent is 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole (HOBT), and the solvent is dry N,N-dimethylformamide (DMF), in addition to adding a certain amount of alkali, commonly used alkali is N,N-diisopropylethylamine (DIPEA), triethylamine, pyridine, hexafluorophosphoric acid Benzotriazol-1-yl-oxytripyrrolidinyl (PyBop), preferably N,N-diisopropylethylamine (DIPEA).
  • DIPEA N,N-diisopropylethylamine
  • PyBop Benzotriazol-1-yl-oxytripyrrolidinyl
  • DIPEA N,N-diisopropylethylamine
  • the sixth aspect of the present invention also provides a second new preparation method of ethacillinone, which adopts the following technical scheme: the above-mentioned ethacillinone intermediate compound formula V is reacted with a suitable acylating reagent to obtain the acid chloride compound formula VII, The acid chloride compound formula VII is acylated with 4-methanesulfonylanilide to obtain compound VI, wherein the structural formula of the acid chloride compound formula VII is as follows:
  • the acylating agent is oxalyl chloride, and the acylating reaction is preferably carried out in the presence of a base and a solvent, and the base is an organic base or an inorganic base, including but not limited to triethylamine, N , N-diisopropylethylamine;
  • the solvent is halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, ether solvent or amide solvent;
  • the halogenated hydrocarbon solvent includes but not limited to dichloromethane or chloroform ;
  • the aromatic hydrocarbon solvents include but not limited to toluene, benzene, xylene or nitrobenzene;
  • the ether solvents include but not limited to tetrahydrofuran, 1,4-dioxane or the amides
  • Solvents include, but are not limited to, N,N-dimethylacetamide, N,N-dimethylformamide.
  • the seventh aspect of the present invention also provides eschacillinone, which is prepared by any one of the aforementioned synthesis processes.
  • the existing synthetic methods of oxacillinone intermediates have the problems of low preparation yield, high cost, complicated post-processing and unfavorable industrial production.
  • the application provides a kind of synthetic method of new eschacillinone intermediate compound formula IV, and this synthetic method comprises the following steps:
  • step (1) The amide compound formula II obtained in step (1) is prepared through a dehydration reaction in the presence of a dehydrating agent and an acid-binding agent to obtain an isonitrile compound formula III;
  • step (3) The isonitrile compound formula III obtained in step (2) is cyclized with ethyl 2-butynoate to form pyrrole ring compound IV in the presence of a base and a metal catalyst;
  • the process route is as follows:
  • the inert solvent described in step (1) includes but not limited to one or more of the group consisting of halogenated hydrocarbons, benzene, toluene, ether, xylene, nitrobenzene, and acetonitrile; One or more of imidazole, pyridine, tetrabutylammonium fluoride, 2,6-lutidine, potassium carbonate, N,N-diisopropylethylamine, sodium carbonate, and triethylamine; 2
  • the molar ratio of -(trifluoromethyl)phenylacetic acid to base is 1:0.5 ⁇ 1; the molar ratio of 2-(trifluoromethyl)phenylacetic acid to ethyl chloroformate or isobutyl chloroformate is 1:1 ⁇ 1.5; the reaction temperature is 0° C. to room temperature; the reaction time is 12 hours to 36 hours.
  • the dehydrating agent described in step (2) is one or more of P 2 O 5 , PCl 3 , SOCl 2 , COCl 2 , ArSO 2 Cl, POCl 3 ;
  • the acid-binding agent is an organic base Or inorganic base, described inorganic base is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium tert-butoxide etc.;
  • Described organic base is triethylamine, diisopropylamine; Described solvent selects halogenated alkanes, two Chloromethane, dichloroethane.
  • the base in step (3) is Pr 3 N, pyridine, DBU, TEEDA; the metal catalyst is Cu 2 O, CuCl, CuI, CuBr, Cu(OMe) 2 , copper powder.
  • the raw material 2-(trifluoromethyl)phenylacetic acid (compound formula I) can be purchased.
  • the second aspect of the present invention also provides the esacillinone intermediate compound formula IV, which is prepared by the above synthesis process.
  • the third aspect of the present invention also provides a kind of synthetic method of new oxacillinone intermediate compound formula V, and this synthetic method is as follows:
  • the specific synthetic method comprises the following steps: the pyrrole ring compound formula IV obtained by the above synthesis is mixed with The compound formula V is prepared by reaction, wherein said X is halogen, and said A is hydroxyl or halogen.
  • the solvent is an alcohol solvent, a halogenated hydrocarbon solvent, an aromatic hydrocarbon solvent, an ether solvent or an amide solvent;
  • the alcohol solvent includes but not limited to ethanol;
  • the halogenated hydrocarbon solvent includes but not limited to dichloromethane or chloroform;
  • the aromatic hydrocarbon solvents include but not limited to toluene, benzene, xylene or nitrobenzene;
  • the ether solvents include but not limited to tetrahydrofuran, 1,4-dioxane
  • the amide solvent includes but not limited to N,N-dimethylacetamide, N,N-dimethylformamide;
  • the alkali is sodium hydroxide, potassium hydroxide, lithium hydroxide, tert-butanol Sodium, potassium tert-butoxide, cesium carbonate, sodium hydride, potassium carbonate, sodium carbonate, 4-dimethylaminopyridine, N,N-diisopropylethylamine,
  • the fourth aspect of the present invention also provides the esacillinone intermediate compound formula V, which is prepared by the aforementioned synthesis process.
  • the fifth aspect of the present invention also provides a new synthetic method of ixacillinone, the preparation method is as follows:
  • the specific synthesis method includes the following steps: condensing the above-mentioned oxacillinone intermediate compound formula V and 4-methanesulfonylaniline under the action of a condensing agent to obtain oxacillinone (compound formula VI).
  • the condensing agent is 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole (HOBT), and the solvent is dry N,N-dimethylformamide (DMF), in addition to adding a certain amount of alkali, commonly used alkali is N,N-diisopropylethylamine (DIPEA), triethylamine, pyridine, hexafluorophosphoric acid Benzotriazol-1-yl-oxytripyrrolidinyl (PyBop), preferably N,N-diisopropylethylamine (DIPEA).
  • DIPEA N,N-diisopropylethylamine
  • PyBop Benzotriazol-1-yl-oxytripyrrolidinyl
  • DIPEA N,N-diisopropylethylamine
  • the sixth aspect of the present invention also provides the second new synthetic method of ixacillinone, the synthetic method is as follows:
  • the specific preparation method includes the following steps: react the above-mentioned ethacillinone intermediate compound V with a suitable acylating agent to obtain the acyl chloride compound VII, and then acylate the acyl chloride compound VII with 4-methylsulfonylanilide to obtain the compound VI.
  • the acylating agent is oxalyl chloride, and the acylating reaction is preferably carried out in the presence of a base and a solvent, and the base is an organic base or an inorganic base, including but not limited to triethylamine, N , N-diisopropylethylamine;
  • the solvent is halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, ether solvent or amide solvent;
  • the halogenated hydrocarbon solvent includes but not limited to dichloromethane or chloroform ;
  • the aromatic hydrocarbon solvents include but not limited to toluene, benzene, xylene or nitrobenzene;
  • the ether solvents include but not limited to tetrahydrofuran, 1,4-dioxane or the amides
  • Solvents include, but are not limited to, N,N-dimethylacetamide, N,N-dimethylformamide.
  • the seventh aspect of the present invention also provides eschacillinone, which is prepared by any one of the aforementioned synthesis processes.
  • reaction solution was cooled to room temperature, and the pH was adjusted to 5-6 with 2N hydrochloric acid, and the layers were allowed to stand.
  • the aqueous phase was extracted twice with dichloromethane, and the organic phases were combined. , dried and concentrated to obtain 14.7 g of 1-(2-hydroxyethyl)4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylic acid with a yield of 94%.

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

Abstract

L'invention concerne un nouveau procédé de synthèse d'un intermédiaire de l'ésaxérénone. Le procédé comprend les étapes suivantes consistant à : (1) Faire réagir de l'acide 2-(trifluorométhyl)phénylacétique en tant que matière première avec du chloroformiate d'éthyle ou du chloroformiate d'isobutyle dans un solvant inerte en présence d'un alcali pour produire un anhydride mixte, puis le faire réagir avec de l'ammoniac pour obtenir un composé amide correspondant de formule II ; (2) soumettre le composé amide de formule II obtenu à l'étape (1) à une réaction de déshydratation en présence d'un agent déshydratant et d'un agent de liaison à l'acide pour obtenir un composé isocyanure de formule III ; et (3) soumettre le composé isocyanure de formule III obtenu à l'étape (2) à une réaction de cyclisation avec du 2-butynonate d'éthyle en présence d'un alcali et d'un catalyseur métallique pour former un composé cyclique de pyrrole de formule IV ; et l'équation de réaction est représentée ci-dessous : Par rapport à l'état de la technique, la solution technique selon la présente invention a les avantages d'un rendement élevé, d'un post-traitement simple, de coûts faibles et d'une industrialisation facile, etc.
PCT/CN2022/080532 2021-09-10 2022-03-13 Procédés de synthèse de l'esaxérénone et de son intermédiaire WO2023035571A1 (fr)

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CN202111063792.3A CN115784961A (zh) 2021-09-10 2021-09-10 埃沙西林酮及其中间体的合成方法
CN202111063792.3 2021-09-10

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Citations (7)

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EP1844020A1 (fr) * 2005-01-10 2007-10-17 Exelixis, Inc. Composes carboxamides heterocycliques utilises ent ant qu'agents pharmaceutiques
CN101679243A (zh) * 2007-04-09 2010-03-24 第一三共株式会社 吡咯衍生物的阻转异构体
WO2010098286A1 (fr) * 2009-02-25 2010-09-02 第一三共株式会社 Préparation pharmaceutique contenant un antagoniste des récepteurs de minéralocorticoïdes
CN102186817A (zh) * 2008-10-08 2011-09-14 埃克塞利希斯股份有限公司 (羟烷基)吡咯衍生物的阻转异构体
CN105164105A (zh) * 2013-04-10 2015-12-16 第一三共株式会社 吡咯衍生物的结晶及其制备方法
CN105473552A (zh) * 2013-08-27 2016-04-06 第一三共株式会社 用于产生吡咯衍生物及其中间体的方法
CN112707854A (zh) * 2019-10-25 2021-04-27 广东东阳光药业有限公司 吡咯酰胺类化合物及其用途

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Publication number Priority date Publication date Assignee Title
EP1844020A1 (fr) * 2005-01-10 2007-10-17 Exelixis, Inc. Composes carboxamides heterocycliques utilises ent ant qu'agents pharmaceutiques
CN101679243A (zh) * 2007-04-09 2010-03-24 第一三共株式会社 吡咯衍生物的阻转异构体
CN102186817A (zh) * 2008-10-08 2011-09-14 埃克塞利希斯股份有限公司 (羟烷基)吡咯衍生物的阻转异构体
WO2010098286A1 (fr) * 2009-02-25 2010-09-02 第一三共株式会社 Préparation pharmaceutique contenant un antagoniste des récepteurs de minéralocorticoïdes
CN105164105A (zh) * 2013-04-10 2015-12-16 第一三共株式会社 吡咯衍生物的结晶及其制备方法
CN105473552A (zh) * 2013-08-27 2016-04-06 第一三共株式会社 用于产生吡咯衍生物及其中间体的方法
CN112707854A (zh) * 2019-10-25 2021-04-27 广东东阳光药业有限公司 吡咯酰胺类化合物及其用途

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