WO2020127887A1 - Procédé de préparation d'un produit intermédiaire d'ivosidénib - Google Patents

Procédé de préparation d'un produit intermédiaire d'ivosidénib Download PDF

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Publication number
WO2020127887A1
WO2020127887A1 PCT/EP2019/086549 EP2019086549W WO2020127887A1 WO 2020127887 A1 WO2020127887 A1 WO 2020127887A1 EP 2019086549 W EP2019086549 W EP 2019086549W WO 2020127887 A1 WO2020127887 A1 WO 2020127887A1
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WO
WIPO (PCT)
Prior art keywords
formula
isonitrile
uorocy
preparing
difluorocyclobutyl
Prior art date
Application number
PCT/EP2019/086549
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English (en)
Inventor
Sven Nerdinger
Miroslaw SZARMACH
Andrzej Manikowski
Original Assignee
Sandoz Ag
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
Publication date
Application filed by Sandoz Ag filed Critical Sandoz Ag
Publication of WO2020127887A1 publication Critical patent/WO2020127887A1/fr

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C291/00—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00
    • C07C291/10—Isocyanides
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C263/00—Preparation of derivatives of isocyanic acid

Definitions

  • the present invention is directed to a process for the preparation of (3,3-difluorocyclo- butyl)isonitrile, an intermediate product in the synthesis of ivosidenib.
  • the intermediate product (3,3-difluorocyclobutyl)isonitrile is prepared from A -(3 , 3 -di fl uorocy cl ob uty 1 )form a i de in dichloromethane using PPh3 and CCU and TEA (triethylamine) and is subsequently purified by filtration and column chromatography.
  • This process for preparing (3,3-difluorocyclobutyl)isonitrile has several disadvantages. Several byproducts are formed so that the (3,3-difluorocyclobutyl)isonitrile needs to be purified by filtration and column chromatography. However, purification by column chromatography is expensive, cumbersome, and not suitable for the purification of an intermediate product in large scale production. Furthermore, PPh3 and CCU are not environmentally friendly and their use causes significant regulatory burden. Furthermore, the use of PPI13 poses several problems. First, PPI13 needs to be added as a solid under N2 atmosphere. Second, PPh3 byproducts are difficult to remove during the purification process.
  • the present invention relates to the use of propylphosphonic acid anhydride (III) for preparing a compound according to formulae (2), (3) and/or (4).
  • the present invention relates to a process for preparing the compound of formula (3) comprising the steps
  • the present invention relates to a process for preparing ivosidenib according to formula (4) comprising the step
  • Aprotic solvents are usually solvents that do not readily donate H + ions under reaction conditions in the presence of the tertiary amine base, i.e. the pK a of the solvent is at least 20.
  • aprotic solvents comprise aliphatic, aromatic, ether, amide and ester solvents.
  • Non-limiting examples of aprotic solvents comprise pentane, hexane, benzene, toluene, chloroform, DCM (di chi orom ethane), diethyl ether, 1,2-dimethoxy ether, MTBE (methyl -/t V-butyl ether), 1,4-dioxane, THF (tetrahydrofuran), MTHF (methyl- tetrahydrofuran), EtOAc (ethyl acetate), acetonitrile, DMF (A) A-di methyl form amide), DMA (A) A -di m ethyl acetam i de), DMSO (dimethylsulfoxide), and mixtures thereof.
  • DCM di chi orom ethane
  • diethyl ether 1,2-dimethoxy ether
  • MTBE methyl -/t V-butyl ether
  • Tertiary amine bases usually are hindered amines that contain three substituents independently selected from alkyl and aryl substituents.
  • the term“tertiary amine” also refers to secondary cyclic amines and alkali metal acetate. These hindered amines act as a base, but do not act as nucleophiles due to steric hindrance.
  • Non-limiting examples of tertiary amines comprise triethylamine, tributyl- amine, DIPEA ( N , A -di -/.vo-propy 1 ethyl am i ne), DBU (l,8-diazabicyclo[5.4.0]undec-7- ene), TBD (l,5,7-triazabicyclo(4.4.0)dec-5-ene), MTBD (7-methyl-l,5,7-triazabi- cyclo(4.4.0)dec-5-ene), DBN (l,5-diazabicyclo[4.3.0]non-5-ene), TMP (2,2,6,6-tetra- methylpiperidine), DABCO (l,4-diazabicyclo[2.2.2]octane), quinuclidine, and mixtures thereof.
  • Propylphosphonic acid anhydride also called //-propylphosphonic anhydride
  • T3P ® is usually supplied as 50 vol-% solution in various aprotic solvents under the trade mark T3P ® .
  • step (b) comprises the steps of
  • step (b) comprises the steps of (bT) adding the propylphosphonic acid anhydride (III) to the A -(3 , 3 -di fl uorocy cl o- butyl)formamide according to formula (1) in an aprotic solvent (I) and subsequently,
  • the propylphosphonic acid anhydride (III) and the tertiary amine base (II) may be added in pure, undiluted form or as solution in a suitable aprotic solvent.
  • the tertiary amine base (II) is selected from triethylamine, DIPEA, DBU, DABCO, quinuclidine and mixtures thereof. In a preferred embodiment, the tertiary amine base (II) is selected from triethylamine, DIPEA and mixtures thereof.
  • the aprotic solvent (I) is a polar solvent.
  • the aprotic solvent (I) is selected from EtOAc, THF, acetonitrile, 1,4-dioxane, DMF, DMA and mixtures thereof.
  • the aprotic solvent is EtOAc.
  • the process may be performed at room temperature.
  • room temperature or ambient temperature is to be understood to encompass temperatures from 15°C to 30°C.
  • step (b) further comprises: adding the at least one tertiary amine base (II) and/or the propylphosphonic acid anhydride (III) to the A -(3 , 3 -di fl uorocy cl ob uty 1 )form am i de according to formula (1) at a temperature Ti selected from -78°C to 30°C and subsequently heating the mixture to T2 selected from above 30°C to 77°C.
  • step (b) further comprises: adding the at least one tertiary amine base (II) and/or the propylphosphonic acid anhydride (III) to the A -(3 , 3 -di fl uorocy cl ob uty 1 )form am i de according to formula (1) at a temperature Ti selected from 0°C to 30°C and subsequently heating the mixture to T2 selected from above 30°C to 77°C.
  • step (b) further comprises: adding the at least one tertiary amine base (II) and/or the propylphosphonic acid anhydride (III) to the A -(3 , 3 -di fl uorocy cl ob uty 1 )form a i de according to formula (1) at a temperature Ti selected from 0°C to 30°C and subsequently heating the mixture to the boiling temperature of the aprotic solvent (I).
  • temperature Ti is independently selected for the respective addition of the tertiary amine base (Ti a ) and the addition of the propylphosphonic acid anhydride (Tib).
  • the skilled person will know how to select an appropriate temperature T2 for the heating so that the reaction is run to completion. If the heating temperature T2 is above the boiling temperature of the respective solvent, the reaction is performed under pressure. It is, however, preferred that the process is performed at ambient pressure.
  • the process for preparing (3,3-difluorocyclo- butyl)isonitrile according to formula (2) comprises the steps:
  • the process for preparing ivosidenib according to formula (4) comprises the steps
  • This reaction can be referred to as a Ugi one-pot reaction.
  • This reaction is a four component reaction (U-4CR), wherein the components comprise an aldehyde/ketone (2- chlorobenzaldehyde), an amine (3-amino-5-fluoropyridine), a carboxylic acid (L-pyro glutamic acid) and an isonitrile functional group ((3,3-difluorocyclobutyl)isonitrile).
  • the purification in step (iii) comprises separating the diastereomers to obtain ivosidenib.
  • suitable techniques such as high-performance liquid column chromatography (HPLC) or recrystallization from suitable solvents, to obtain ivosidenib as the desired diastereomer.
  • the reaction in step (ii) with a compound selected from 2-bromo-4-cyano-pyridine, 4- cyano-2-fluoro-pyridine, 4-cyano-2-iodo-pyridine, and (4-cyano-2-pyridinyl)-trifluoro- methanesulfonate is a metal-catalyzed cross coupling reaction, e.g. a Buchwald- Hartwig coupling.
  • Suitable reaction conditions, base, ligand and metal catalyst are known to the person skilled in the art.
  • the metal catalyst is a palladium catalyst and that the ligand is a sterically hindered phosphine ligand, preferably a dialkylbiaryl phosphine, dppf (l, l'-bis(diphenylphosphino)ferrocene) or XantPhos ligand (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene). It is even more preferred that the metal catalyst is Pd 2 (dba) 3 and the ligand is XantPhos.
  • the process for preparing the compound of formula (3) and the process for preparing ivosidenib according to formula (4) comprises the steps
  • step (i) preparing (3,3-difluorocyclobutyl)isonitrile according to formula (2) by the process of the present invention and reacting the 3,3-difluorocyclobutyl)isonitrile according to formula (2) prepared in step (i) in-situ in step (ii) to obtain the compound of formula (3) in a one-pot process.
  • step (i) and step (ii) are performed in the same reaction vessel and only the additional reactants needed in step (ii) are further added to the reaction vessel or the 3,3-difluorocyclobutyl)isonitrile prepared in step (i) is obtained as a crude product by routine work-up and directly used in step (ii) without further purification by e.g. filtration or column chromatography.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Toxicology (AREA)

Abstract

L'invention concerne un procédé de préparation de (3,3-difluorocyclobutyl)isonitrile de formule (2) comprenant les étapes consistant à mélanger du N-à (3,3-difluorocyclobutyl))formamide avec un solvant aprotique et à faire réagir le N-(3,3-difluorocyclobutyl)formamide avec de l'anhydride d'acide propylphosphonique en présence d'une base amine tertiaire. L'intermédiaire de formule (2) est utilisé pour la préparation d'ivosidénib de formule (4).
PCT/EP2019/086549 2018-12-21 2019-12-20 Procédé de préparation d'un produit intermédiaire d'ivosidénib WO2020127887A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP18215451.8 2018-12-21
EP18215451 2018-12-21

Publications (1)

Publication Number Publication Date
WO2020127887A1 true WO2020127887A1 (fr) 2020-06-25

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021026436A1 (fr) * 2019-08-08 2021-02-11 Agios Pharmaceuticals, Inc. Procédé de préparation d'ivosidenib et d'un intermédiaire de celui-ci
WO2022126947A1 (fr) * 2020-12-18 2022-06-23 新发药业有限公司 Procédé de préparation respectueux de l'environnement pour composé isonitrile substitué

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005070879A1 (fr) * 2004-01-26 2005-08-04 Clariant Produkte (Deutschland) Gmbh Procedes pour preparer des nitriles et des isonitriles par deshydratation avec des anhydrides d'acide propane-phosphonique
WO2013107405A1 (fr) * 2012-01-19 2013-07-25 Agios Pharmaceuticals, Inc. Composés thérapeutiquement actifs et leurs méthodes d'utilisation
WO2013107291A1 (fr) 2012-01-19 2013-07-25 Agios Pharmaceuticals, Inc. Composés thérapeutiquement actifs et leurs procédés d'utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005070879A1 (fr) * 2004-01-26 2005-08-04 Clariant Produkte (Deutschland) Gmbh Procedes pour preparer des nitriles et des isonitriles par deshydratation avec des anhydrides d'acide propane-phosphonique
WO2013107405A1 (fr) * 2012-01-19 2013-07-25 Agios Pharmaceuticals, Inc. Composés thérapeutiquement actifs et leurs méthodes d'utilisation
WO2013107291A1 (fr) 2012-01-19 2013-07-25 Agios Pharmaceuticals, Inc. Composés thérapeutiquement actifs et leurs procédés d'utilisation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JANETA POPOVICI-MULLER ET AL: "Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers", ACS MEDICINAL CHEMISTRY LETTERS, vol. 9, no. 4, 19 January 2018 (2018-01-19), pages 300 - 305, XP055543764, ISSN: 1948-5875, DOI: 10.1021/acsmedchemlett.7b00421 *
POPOVICI-MULLER, J. ET AL.: "Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers - Supporting Information", ACS MEDICINAL CHEMISTRY LETTERS, vol. 9, no. 4, 19 January 2018 (2018-01-19), pages 1 - 32, XP055543906, ISSN: 1948-5875, DOI: 10.1021/acsmedchemlett.7b00421 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021026436A1 (fr) * 2019-08-08 2021-02-11 Agios Pharmaceuticals, Inc. Procédé de préparation d'ivosidenib et d'un intermédiaire de celui-ci
WO2022126947A1 (fr) * 2020-12-18 2022-06-23 新发药业有限公司 Procédé de préparation respectueux de l'environnement pour composé isonitrile substitué

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