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WO2018137679A1 - Procédé de préparation de (10r) -7- (2-aminoacétyl) amino-12-fluoro-2, 10, 16-triméthyl-15-oxo-10, 15, 16, 17-tétrahydro-2h-8, 4- (metheno) pyrazolo [4, 3-h] [2, 5, 11] -benzoxadiazacyclotétradécine-3-carbonitrile - Google Patents

Procédé de préparation de (10r) -7- (2-aminoacétyl) amino-12-fluoro-2, 10, 16-triméthyl-15-oxo-10, 15, 16, 17-tétrahydro-2h-8, 4- (metheno) pyrazolo [4, 3-h] [2, 5, 11] -benzoxadiazacyclotétradécine-3-carbonitrile Download PDF

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Publication number
WO2018137679A1
WO2018137679A1 PCT/CN2018/074097 CN2018074097W WO2018137679A1 WO 2018137679 A1 WO2018137679 A1 WO 2018137679A1 CN 2018074097 W CN2018074097 W CN 2018074097W WO 2018137679 A1 WO2018137679 A1 WO 2018137679A1
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WIPO (PCT)
Prior art keywords
compound
water
dcm
dioxane
coupling reagent
Prior art date
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Ceased
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PCT/CN2018/074097
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English (en)
Inventor
Dawei Zhang
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TELIGENE Ltd
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TELIGENE Ltd
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Filing date
Publication date
Application filed by TELIGENE Ltd filed Critical TELIGENE Ltd
Publication of WO2018137679A1 publication Critical patent/WO2018137679A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • 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
    • 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 (10R) -7- (2-aminoacetyl) amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15, 16, 17-tetrahydro-2H-8, 4- (metheno) pyrazolo [4, 3-h] [2, 5, 11] -benzoxadiazacyclotetradecine-3-carbonitrile, to processes for its preparation.
  • the invention provides a process for the preparation of (10R) -7- (2-aminoacetyl) amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15, 16, 17-tetrahydro-2H-8, 4- (metheno) pyrazolo [4, 3-h] [2, 5, 11] -benzoxadiazacyclotetradecine-3-carbonitrile (Compound 7 in Formula (I) ) , which is characterized by using Compound 5 with Boc protecting group as Scheme 1:
  • the invention provides the key intermediates for the preparing Compound 7:
  • the invention provides a process for the preparation of (10R) -7- (2-aminoacetyl) amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15, 16, 17-tetrahydro-2H-8, 4- (metheno) pyrazolo [4, 3-h] [2, 5, 11] -benzoxadiazacyclotetradecine-3-carbonitrile (Compound 7 in Formula (I) ) , which is characterized by using Compound 5 with Boc protecting group shown in Scheme 1:
  • the invention provided a process of preparing Compound 7, the ester group of Compound 1 is hydrolyzed with NaOH in THF/Water or MeOH/Water or acetone/Water or acetonitrile/water or isopropanol/Water or EtOH/Water into Compound 2 in the Step (1) , and more preferably, in THF/Water or MeOH/Water.
  • the invention provided a process of preparing Compound 7, the amide formation of Compound 2 and 3 optionally with a coupling reagent and in a non-reactive solvent, afforded Compound 4 in the Step (2) ;
  • the coupling reagent is selected from HATU, EDC, DCC, BOP, T 3 P, or HOBt, and with DIEA or DIPEA;
  • the non-reactive solvent is selected from DCM, DMF, or dioxane;
  • the coupling reagent is HATU, EDC, or DCC, and with DIEA or DIPEA;
  • the non-reactive solvent is selected from DCM, DMF, or dioxane.
  • the invention provided a process of preparing Compound 7, Compoud 4 is reacted with Boc-Glycine optionally in the present of a coupling reagent and in a non-reactive solvent to afford Compound 5 in the Step (3) ; more preferably, the coupling reagent is selected from HATU, EDC, DCC, BOP, T 3 P, or HOBt, and with DIEA or DIPEA; the non-reactive solvent is selected from DCM, DMF, or dioxane; most preferably, the coupling reagent is HATU, EDC, or DCC, and with DIEA or DIPEA; the non-reactive solvent is selected from DCM, DMF, or dioxane.
  • the coupling reagent is selected from HATU, EDC, or DCC, and with DIEA or DIPEA
  • the non-reactive solvent is selected from DCM, DMF, or dioxane.
  • the invention provided a process of preparing Compound 7, Compound 5 is intramolecularly cyclized into Compound 6 under palladium catalyzed condition in the Step (4) , more preferably, in the present of Pd (OAc) 2 , cataxiuma and KOAc, and in t-AmOH.
  • the invention provided a process of preparing Compound 7, Compound 6 is deprotected under acidic condition such as HCl in MeOH or dioxane in the Step (5) .
  • the invention provided a process of preparing Compound 7 in the Scheme 3:
  • the invention provides the key intermediates for the preparing Compound 7:
  • DMF means N, N-dimethylformamide.
  • DCM dichloromethane
  • HATU means 1- [Bis (dimethylamino) methylene] -1H-1, 2, 3-triazolo [4, 5-b] pyridinium 3-oxid hexafluorophosphate
  • DIPEA or DIEA means diisopropyl ethylamine.
  • DCC means Dicyclohexylcarbodiimide.
  • EDC means N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride.
  • THF means tetrahydrofuran
  • EA means ethyl acetate.
  • HOBt means hydroxybenzotriazole
  • m-CPBA meta-Chloroperoxybenzoic acid.
  • Boc-Gly-OH means N- (tert-Butoxycarbonyl) glycine.
  • BOP means (Benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate.
  • Pd (dppf) Cl 2 means [1, 1′-Bis (diphenylphosphino) ferrocene] dichloropalladium.
  • T 3 P means n-propylphosphonoic anhydride
  • Et 3 N means triethyl amine
  • Fmoc Fluorenylmethyloxycarbonyl
  • cataXium A means Di (1-adamantyl) -n-butylphosphine
  • Pd (OAc) 2 means palladium acetate

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation de (10R) -7- (2-aminoacétyl) amino-12-fluoro-2, 10, 16-triméthyl-15-oxo-10, 15, 16, 17-tétrahydro-2H-8, 4- (metheno) pyrazolo [4, 3-h] [2, 5, 11] -benzoxadiazacyclotétradécine-3-carbonitrile, caractérisé en ce qu'il utilise le composé 5 avec un groupe protecteur Boc, qui est plus approprié pour une production industrielle.
PCT/CN2018/074097 2017-01-25 2018-01-25 Procédé de préparation de (10r) -7- (2-aminoacétyl) amino-12-fluoro-2, 10, 16-triméthyl-15-oxo-10, 15, 16, 17-tétrahydro-2h-8, 4- (metheno) pyrazolo [4, 3-h] [2, 5, 11] -benzoxadiazacyclotétradécine-3-carbonitrile Ceased WO2018137679A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201762499395P 2017-01-25 2017-01-25
US62/499,395 2017-01-25

Publications (1)

Publication Number Publication Date
WO2018137679A1 true WO2018137679A1 (fr) 2018-08-02

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PCT/CN2018/074097 Ceased WO2018137679A1 (fr) 2017-01-25 2018-01-25 Procédé de préparation de (10r) -7- (2-aminoacétyl) amino-12-fluoro-2, 10, 16-triméthyl-15-oxo-10, 15, 16, 17-tétrahydro-2h-8, 4- (metheno) pyrazolo [4, 3-h] [2, 5, 11] -benzoxadiazacyclotétradécine-3-carbonitrile

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WO (1) WO2018137679A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109651398A (zh) * 2019-01-25 2019-04-19 安庆多辉生物科技有限公司 一种合成劳拉替尼的溴代物中间体及催化合成劳拉替尼的方法
WO2020108522A1 (fr) * 2018-11-28 2020-06-04 深圳市塔吉瑞生物医药有限公司 Procédé de préparation d'un composé macrocyclique deutéré
CN111362967A (zh) * 2020-04-28 2020-07-03 南京雷正医药科技有限公司 苯并氧杂二氮杂十四碳烯衍生物及其用途
WO2020228747A1 (fr) 2019-05-14 2020-11-19 Teligene Ltd Macrocycles substitués utiles en tant qu'inhibiteurs de kinase
CN112321604A (zh) * 2019-08-05 2021-02-05 华东理工大学 大环类jak2抑制剂及其应用

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CN101654473A (zh) * 2009-08-13 2010-02-24 上海力智生化科技有限公司 一种氨基保护甘氨酸二肽衍生物的合成方法
US20140135339A1 (en) * 2012-03-06 2014-05-15 Pfizer Inc. Macrocyclic derivatives for the treatment of diseases
WO2016026423A1 (fr) * 2014-08-20 2016-02-25 Teligene Ltd Macrocycles substitués utilisés comme inhibiteurs des kinases et leurs méthodes d'utilisation
CN106146614A (zh) * 2015-05-14 2016-11-23 沈阳科海医药科技有限公司 一种rgd三肽的制备方法

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Publication number Priority date Publication date Assignee Title
CN101654473A (zh) * 2009-08-13 2010-02-24 上海力智生化科技有限公司 一种氨基保护甘氨酸二肽衍生物的合成方法
US20140135339A1 (en) * 2012-03-06 2014-05-15 Pfizer Inc. Macrocyclic derivatives for the treatment of diseases
WO2016026423A1 (fr) * 2014-08-20 2016-02-25 Teligene Ltd Macrocycles substitués utilisés comme inhibiteurs des kinases et leurs méthodes d'utilisation
CN106146614A (zh) * 2015-05-14 2016-11-23 沈阳科海医药科技有限公司 一种rgd三肽的制备方法

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP7347852B2 (ja) 2018-11-28 2023-09-20 深▲チェン▼市塔吉瑞生物医薬有限公司 重水素化大環状化合物の調製方法
WO2020108522A1 (fr) * 2018-11-28 2020-06-04 深圳市塔吉瑞生物医药有限公司 Procédé de préparation d'un composé macrocyclique deutéré
CN111233833A (zh) * 2018-11-28 2020-06-05 深圳市塔吉瑞生物医药有限公司 一种氘代大环化合物的制备方法
US12077528B2 (en) 2018-11-28 2024-09-03 Shenzhen Targetrx, Inc. Preparation method for deuterated macrocyclic compound
JP2022513151A (ja) * 2018-11-28 2022-02-07 深▲チェン▼市塔吉瑞生物医薬有限公司 重水素化大環状化合物の調製方法
CN109651398A (zh) * 2019-01-25 2019-04-19 安庆多辉生物科技有限公司 一种合成劳拉替尼的溴代物中间体及催化合成劳拉替尼的方法
WO2020228747A1 (fr) 2019-05-14 2020-11-19 Teligene Ltd Macrocycles substitués utiles en tant qu'inhibiteurs de kinase
EP3844166A4 (fr) * 2019-05-14 2021-12-15 Teligene Ltd. Macrocycles substitués utiles en tant qu'inhibiteurs de kinase
JP2022504578A (ja) * 2019-05-14 2022-01-13 テリジーン リミテッド キナーゼ阻害剤として有用な置換大員環類
JP7345901B2 (ja) 2019-05-14 2023-09-19 テリジーン リミテッド キナーゼ阻害剤として有用な置換大員環類
CN112321604A (zh) * 2019-08-05 2021-02-05 华东理工大学 大环类jak2抑制剂及其应用
CN111362967A (zh) * 2020-04-28 2020-07-03 南京雷正医药科技有限公司 苯并氧杂二氮杂十四碳烯衍生物及其用途
CN111362967B (zh) * 2020-04-28 2021-09-07 南京雷正医药科技有限公司 苯并氧杂二氮杂十四碳烯衍生物及其用途

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