WO2015188686A1 - Procédé de préparation de céritinib et de son intermédiaire - Google Patents

Procédé de préparation de céritinib et de son intermédiaire Download PDF

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Publication number
WO2015188686A1
WO2015188686A1 PCT/CN2015/079455 CN2015079455W WO2015188686A1 WO 2015188686 A1 WO2015188686 A1 WO 2015188686A1 CN 2015079455 W CN2015079455 W CN 2015079455W WO 2015188686 A1 WO2015188686 A1 WO 2015188686A1
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WO
WIPO (PCT)
Prior art keywords
isopropoxy
methyl
palladium
piperidin
reaction
Prior art date
Application number
PCT/CN2015/079455
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English (en)
Chinese (zh)
Inventor
许学农
Original Assignee
苏州明锐医药科技有限公司
哲人药业南京有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
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Application filed by 苏州明锐医药科技有限公司, 哲人药业南京有限公司 filed Critical 苏州明锐医药科技有限公司
Publication of WO2015188686A1 publication Critical patent/WO2015188686A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the technical field of organic synthesis route design and preparation technology of raw materials and intermediates, and particularly relates to a preparation method of Ceritinib and its intermediates.
  • Ceritinib (formerly LDK378) is an anaplastic lymphoma enzyme (ALK) tyrosine kinase inhibitor developed by Novartis, which was approved by the FDA for use in April 2014. Treatment with patients with metastatic NSCLC who have progressed or are intolerant after treatment with izozinib (Crizotinib) under the trade name Zykadia. Since the drug has not been officially listed in China and does not have a standard Chinese translation, the applicant hereby transliterates it as “serinibini”. Ceritinib is the second FDA-approved ALK inhibitor following crizotinib and is the second drug to be marketed via the four-pass special channel following Ibrutinib.
  • ALK anaplastic lymphoma enzyme
  • Serui erlotinib (Ceritinib, VIII), the chemical name 5-Chloro -N 2 - [2- isopropoxy-5-methyl-4- (piperidin-4-yl) - phenyl)] - N 4- [2-(Isopropylsulfonyl)-phenyl]-pyrimidine-2,4-diamine.
  • one of the objects of the present invention is to provide an intermediate required to prepare serritinib, 2-isopropoxy-5-methyl-4-(in accordance with the synthesis concept of green chemistry).
  • Piperidin-4-yl)halobenzene (I) and a preparation method thereof the preparation method is simple in process, mild in condition and less in side reaction, and is suitable for industrialization amplification.
  • the preparation of the intermediate comprises the following steps: using 4-(5-isopropoxy-2-methyl-4-nitrophenyl)pyridine (II) as a raw material, Catalytic hydrogenation to give 2-isopropoxy-5-methyl-4-(piperidin-4-yl)aniline (III), compound (III) is obtained by Sandmeyer reaction to obtain the 2-iso Propoxy-5-methyl-4-(piperidin-4-yl)halobenzene (I).
  • the halogen in the 2-isopropoxy-5-methyl-4-(piperidin-4-yl)halobenzene (I) is fluorine, chlorine, bromine or iodine, preferably bromine or iodine.
  • the catalyst for the catalytic hydrogenation reaction is palladium carbon, Raney nickel, ruthenium, rhodium, platinum, palladium chloride, rhodium chloride, ruthenium chloride, platinum chloride, aluminum oxide, palladium oxide, ruthenium oxide, platinum oxide, oxidation.
  • the halogenating agent of the Sandmeyer reaction is a potassium halide, a sodium halide, a cuprous halide, a copper halide or a trimethylhalosilane, preferably a copper halide or a trimethylhalosilane, more preferably copper bromide or trimethyliodide. Silane.
  • the second object of the present invention is to provide an application of the above-described seratinib intermediate (I) as a raw material in preparing serritinib (VIII), which has the same simple process, mild conditions and less side reactions. Suitable for industrial amplification requirements.
  • serritinib is known in English as Ceritinib, and its chemical name is 5-chloro-N 2 -[2-isopropoxy-5-methyl-4-(piperidin-4-yl)-phenyl)]- N 4 - [2- (isopropylsulfonyl) - phenyl] - pyrimidine-2,4-diamine, the following chemical structure:
  • the preparation method of the above serritinib comprises the following steps: 2-isopropoxy-5-methyl-4-(piperidin-4-yl)halobenzene (I) and 4-nitro-5-chloro- Substitution reaction of pyrimidine-2-amine (IV) (1) to 4-nitro 5-chloro-N-[2-isopropoxy-5-methyl-4-(piperidin-4-yl)-benzene yl)] - pyrimidin-2-amine (V); intermediate (V) by reduction reaction of 5-chloro -N 2 - [2- isopropoxy-5-methyl-4- (piperidin-4 Base)-phenyl)]-pyrimidine-2,4-diamine (VI); substitution reaction of intermediate (VI) with 2-bromo-(isopropylsulfonyl)benzene (VII) (2) generation of seri Tini (VIII).
  • the catalysts for the substitution reactions (a) and (ii) are copper, cuprous iodide, brominated ketone, cuprous chloride, palladium, palladium chloride, palladium acetate, tetrakis(triphenylphosphine)palladium, and Chlorobis(triphenylphosphine)palladium, (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride or (bisbenzylideneacetone)dipalladium, preferably cuprous iodide, tetra ( Triphenylphosphine) palladium or (bisbenzylideneacetone) dipalladium.
  • the basic cocatalysts of the substitution reactions (a) and (ii) are potassium t-butoxide, sodium t-butoxide, sodium amide, sodium bis(trimethylsilyl)amide, sodium hydride, potassium hydroxide, sodium hydroxide or Potassium carbonate, preferably potassium t-butoxide or sodium bis(trimethylsilyl)amide.
  • the solvent for the substitution reactions (a) and (ii) is xylene, dioxane, dimethyl sulfoxide, N,N-dimethylformamide or N,N-dimethylacetamide, preferably dimethyl Sulfoxide or N,N-dimethylformamide.
  • the temperature of the substitution reactions (1) and (2) is 50-150 °C.
  • the reducing agent for the reduction reaction is iron powder, tin powder, zinc powder, aluminum powder, hydrazine hydrate, insurance powder, hydrazine hydrate, stannous chloride, sodium sulfide or hydrogen, preferably iron powder, zinc powder or hydrogen.
  • the catalyst used is palladium carbon, platinum carbon, palladium hydroxide carbon or Raney nickel, preferably palladium carbon or platinum carbon.
  • the preparation method of the serritinib and the intermediate thereof according to the invention has the advantages of simple process, mild conditions and reduced side reaction, and is suitable for industrial amplification.
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • Embodiment 2 is a diagrammatic representation of Embodiment 1:
  • Embodiment 3 is a diagrammatic representation of Embodiment 3
  • Embodiment 4 is a diagrammatic representation of Embodiment 4:
  • Embodiment 5 is a diagrammatic representation of Embodiment 5:
  • reaction was carried out for 8 hours at ° C, and the reaction was terminated by TLC. Cool and filter to remove insolubles.
  • the mixture was dissolved in methylene chloride, washed successively with saturated aqueous sodium hydrogen carbonate solution, brine and purified water, and dried over anhydrous sodium sulfate.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

L'invention concerne un intermédiaire 2-isopropoxy-5-méthyl-4-(pipéridyl-4-yl) halogéno-benzène (I) qui peut être utilisé pour préparer du céritinib et un procédé de préparation de celui-ci. Le procédé de préparation comprend les étapes suivantes : mise en oeuvre d'une hydrogénation catalytique sur la matière première 4-(5-isopropoxy-2-méthyl-4-nitrophényle) pyridine (II) afin d'obtenir 2-isopropoxy-5-méthyl-4-(pipéridyl -4-yl) aniline (III); et mise en oeuvre d'une réaction de Sandmeyer sur le composé (III) pour obtenir l'intermédiaire (I). L'invention concerne également un procédé de préparation du céritinib. L'intermédiaire (I) qui est utilisé comme matière première est séquentiellement soumis à des réactions de substitution, de réduction et de substitution afin d'obtenir le céritinib (VIII). Le procédé de préparation présente les avantages d'une technique simple, de conditions douces et de réactions secondaires moindres, et est approprié pour l'amplification industrielle.
PCT/CN2015/079455 2014-06-12 2015-05-21 Procédé de préparation de céritinib et de son intermédiaire WO2015188686A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410259536.5 2014-06-12
CN201410259536.5A CN103992262B (zh) 2014-06-12 2014-06-12 塞瑞替尼及其中间体的制备方法

Publications (1)

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WO2015188686A1 true WO2015188686A1 (fr) 2015-12-17

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CN (1) CN103992262B (fr)
WO (1) WO2015188686A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016098070A1 (fr) * 2014-12-19 2016-06-23 Novartis Ag Forme cristalline de la 5-chloro-n2-(2-isopropoxy-5-méthyl-4-pipéridin-4-yl-phényl)-n4-[2-(propane-2-sulfonyl)-phényl]-pyrimidine-2,4-diamine
AU2015385326B2 (en) * 2015-03-04 2019-04-18 Novartis Ag Chemical process for preparing pyrimidine derivatives and intermediates thereof
CN115057845A (zh) * 2022-06-14 2022-09-16 山东罗欣药业集团恒欣药业有限公司 一种阿贝西利的制备方法

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CN103992262B (zh) * 2014-06-12 2015-11-11 苏州明锐医药科技有限公司 塞瑞替尼及其中间体的制备方法
CN104356050B (zh) * 2014-09-30 2017-02-22 常州市勇毅生物药业有限公司 一种色瑞替尼中间体的制备方法
CN104447515B (zh) * 2014-11-07 2017-06-16 药源药物化学（上海）有限公司 制备色瑞替尼的新中间体及其制备方法
CN105777617B (zh) * 2014-12-26 2018-11-06 上海医药工业研究院 色瑞替尼的合成中间体及其制备方法
CN105777616B (zh) * 2014-12-26 2018-12-07 上海医药工业研究院 色瑞替尼的合成中间体及其制备方法
CN104803908A (zh) 2015-03-26 2015-07-29 药源药物化学（上海）有限公司 2-异丙氧基-5-甲基-4-(4-哌啶基)苯胺二盐酸盐的水合物、其制备方法及用途
WO2016199020A1 (fr) * 2015-06-08 2016-12-15 Dr. Reddy's Laboratories Limited Procédé de préparation de céritinib
CN106854200B (zh) * 2015-12-08 2019-05-21 上海复星星泰医药科技有限公司 色瑞替尼及其中间体的制备方法
CN105646452B (zh) * 2015-12-24 2018-05-01 北京康立生医药技术开发有限公司 一种蛋白激酶抑制剂的合成方法
WO2017152858A1 (fr) * 2016-03-11 2017-09-14 苏州晶云药物科技有限公司 Forme cristalline de céritinib et procédé pour sa préparation
JP2019196359A (ja) * 2019-06-17 2019-11-14 ノバルティス アーゲー ピリミジン誘導体およびそれらの中間体を調製する化学的方法
JP2021075535A (ja) * 2021-01-14 2021-05-20 ノバルティス アーゲー ピリミジン誘導体およびそれらの中間体を調製する化学的方法

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016098070A1 (fr) * 2014-12-19 2016-06-23 Novartis Ag Forme cristalline de la 5-chloro-n2-(2-isopropoxy-5-méthyl-4-pipéridin-4-yl-phényl)-n4-[2-(propane-2-sulfonyl)-phényl]-pyrimidine-2,4-diamine
AU2015385326B2 (en) * 2015-03-04 2019-04-18 Novartis Ag Chemical process for preparing pyrimidine derivatives and intermediates thereof
AU2019202552B2 (en) * 2015-03-04 2020-10-29 Novartis Ag Chemical process for preparing pyrimidine derivatives and intermediates thereof
CN115057845A (zh) * 2022-06-14 2022-09-16 山东罗欣药业集团恒欣药业有限公司 一种阿贝西利的制备方法

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CN103992262A (zh) 2014-08-20
CN103992262B (zh) 2015-11-11

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