WO2025183111A1 - Dérivé d'aocn d'élément de réaction clic ou sel de celui-ci - Google Patents

Dérivé d'aocn d'élément de réaction clic ou sel de celui-ci

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Publication number
WO2025183111A1
WO2025183111A1 PCT/JP2025/006953 JP2025006953W WO2025183111A1 WO 2025183111 A1 WO2025183111 A1 WO 2025183111A1 JP 2025006953 W JP2025006953 W JP 2025006953W WO 2025183111 A1 WO2025183111 A1 WO 2025183111A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
less
aocn
reaction
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
PCT/JP2025/006953
Other languages
English (en)
Japanese (ja)
Inventor
克彦 友岡
和宣 井川
悠也 河崎
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kyushu University NUC
Kumamoto University NUC
Original Assignee
Kyushu University NUC
Kumamoto University NUC
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 Kyushu University NUC, Kumamoto University NUC filed Critical Kyushu University NUC
Publication of WO2025183111A1 publication Critical patent/WO2025183111A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms 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 a click reaction element, an AOCN derivative, or a salt thereof.
  • a typical click reaction is the cycloaddition reaction that occurs between a compound with an azide group and a compound with a terminal alkyne group.
  • Research is being conducted on cyclic alkynes such as 4,8-diazacyclononyne as reaction substrates that can undergo cycloaddition reactions without the use of a copper catalyst (for example, Patent Documents 1 and 2 and Non-Patent Document 1).
  • the object of the present invention is to provide a novel cyclic alkyne compound and a method for producing the same.
  • a compound represented by the following formula (I) or a salt thereof [In formula (I), n represents an integer of 1 to 10, and X represents an amino group or a hydroxy group.] [2] The compound or salt thereof according to [1], wherein n is 1. [3] The compound or salt thereof according to [1] or [2], wherein X is —NH 2 . [4] A compound represented by the following formula (IIa): [In formula (II), n represents an integer of 1 to 10.] [5] The compound according to [4], wherein n is 1.
  • the present invention provides novel cyclic alkyne compounds and methods for producing the same.
  • the compounds of the present invention have high solubility in water and organic solvents, high click reactivity, and are capable of linking to multiple molecules.
  • Compound or salt thereof is a compound represented by the following formula (I) (hereinafter also referred to as "compound (I)").
  • Compound (I) is a compound having a 4-aza-8-oxacyclononyne (AOCN) skeleton, and is capable of linking to a molecule containing an azide group via a triple bond, and also capable of linking to a molecule containing a functional group reactive with X via X, and is therefore also referred to as a multi-linked AOCN.
  • AOCN 4-aza-8-oxacyclononyne
  • n represents an integer of 1 to 10.
  • the upper limit of n may be 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less.
  • n is preferably 1 because it is easy to synthesize and has a low molecular weight.
  • X represents an amino group (—NH 2 ) or a hydroxy group (—OH).
  • Compound (I) is preferably compound (Ia) represented by the following formula (Ia) in which n is 1 and X is an amino group.
  • Salts of compound (I) include salts of compound (I) with inorganic or organic acids.
  • inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid.
  • organic acids include organic carboxylic acids and organic sulfonic acids.
  • organic carboxylic acids include acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, lactic acid, and trifluoroacetic acid.
  • organic sulfonic acids examples include methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and naphthalenesulfonic acid.
  • compound (I) contains a nine-membered cyclic alkyne structure, it can undergo a cycloaddition reaction with an azide compound without the use of a catalyst such as a copper catalyst. Because compound (I) contains a 4-aza-8-oxacyclononyne skeleton, it has higher click reactivity than nine-membered cyclic alkyne compounds containing a 4,8-diazacyclononyne skeleton.
  • Compound (I) is a compound having a 4-aza-8-oxacyclononyne skeleton, and therefore has superior solubility in water and organic solvents compared to nine-membered cyclic alkyne compounds having a 4,8-diazacyclononyne (DACN) skeleton and cyclic alkyne compounds containing two benzene rings, such as dibenzocyclooctyne (DBCO). Furthermore, compound (I) has improved thermal and chemical stability compared to dibenzocyclooctyne (DBCO), and is less susceptible to nonspecific adsorption to proteins, etc.
  • DBN 4,8-diazacyclononyne
  • DBCO dibenzocyclooctyne
  • Compound (I) and its salts have a reactive functional group, X, introduced into the 4-aza-8-oxacyclononyne skeleton, making it possible to link to other molecules via X.
  • the other molecule is not particularly limited, and various functional molecules can be used. Examples of functional molecules include fluorescent dyes.
  • the method for linking compound (I) and its salts with other molecules is not particularly limited, and for example, methods utilizing amidation reaction, ureation reaction, and thioureation reaction can be used.
  • a condensing agent or the like can be used for linking, if necessary.
  • Compound (I) and its salts can be molecularly linked, for example, by reaction with an NHS ester, or a reaction in combination with a carboxylic acid and a condensing agent, or by reaction with an acid chloride to form an amidated product, or by reaction with an isocyanate to form a ureated product, or by reaction with a thioisocyanate to form a thioureated product, or by reaction with a sulfonamidated product, allowing the introduction of various fluorescent molecules, radioisotopes, biotin, physiologically active molecules, etc.
  • a specific example of molecular linkage using compound (Ia) is shown in the following formula.
  • the starting material used for the molecular linkage shown in the following formula is not limited to compound (Ia), and for example, a salt of compound (Ia) can also be used.
  • Compound (I) is, for example, a compound represented by the following formula (II): [In formula (II), n has the same meaning as n in formula (I), and Y represents an amino group protected by a protecting group or a hydroxy group protected by a protecting group.]
  • the compound can be produced by a method including a deprotection step of removing a protecting group in an intermediate compound represented by the following formula:
  • Protecting groups for amino groups include, for example, phthaloyl (Phth), tert-butoxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), and 2-nitrobenzenesulfonyl (Ns).
  • Protecting groups for hydroxy groups include, for example, methoxymethyl ether (MOM), tetrahydropyranyl (THP), trityl (Tr), tert-butyl (t-Bu), trialkylsilyl groups (e.g., TMS, TES, TIPS, TBS, and TBDPS), and acetyl.
  • the conditions for deprotecting the protecting group in the intermediate compound can be appropriately set depending on the type of protecting group, etc.
  • the intermediate compound is preferably a compound represented by the following formula (IIa) (hereinafter “compound (IIa)") in which Y is an amino group protected by a Phth group.
  • the deprotection step is preferably a step in which compound (IIa) is reacted with 1,3-propanediamine to obtain compound (I).
  • 1,3-propanediamine is used, the deprotection of the Phth group can suppress side reaction products (e.g., compounds in which the alkyne is reduced) compared to when hydrazine, which is commonly used, is used.
  • the amount (number of moles) of 1,3-propanediamine used is preferably 2.0 or more relative to the number of moles of the intermediate compound, and although there is no particular upper limit, it is, for example, 10.0 or less, or 5.0 or less.
  • the amount (number of moles) of 1,3-propanediamine used is not particularly limited relative to the number of moles of the intermediate compound, and is, for example, 2.0 or more and 10.0 or less, or 2.0 or more and 5.0 or less.
  • the reaction temperature in the deprotection step is not particularly limited, but is, for example, 40°C or higher, or 45°C or higher, and 60°C or lower, or 55°C or lower.
  • the reaction temperature in the deprotection step is not particularly limited, but is, for example, 40°C or higher and 60°C or lower, 40°C or higher and 55°C or lower, 45°C or higher and 60°C or lower, or 45°C or higher and 55°C or lower.
  • the time for which the reaction temperature is maintained is not particularly limited, but is, for example, 1 hour or higher, 5 hours or higher, or 10 hours or higher, and 30 hours or lower, or 20 hours or lower.
  • reaction time is not particularly limited, but is, for example, 1 hour or higher and 30 hours or lower, 1 hour or higher and 20 hours or lower, 5 hours or higher and 30 hours or lower, 5 hours or higher and 20 hours or lower, 10 hours or higher and 30 hours or lower, or 10 hours or higher and 20 hours or lower.
  • post-treatment After the reaction, it is preferable to carry out post-treatment as necessary.
  • post-treatment include filtration, washing with an organic solvent and removing the solvent, and purification using a silica gel column.
  • the intermediate compound can be prepared, for example, by a step (a-1) of reacting 2-butyne-1,4-diol with octacarbonyl dicobalt (Co 2 (CO ) 8 ) to obtain a reactant (a-1), and a step ( b ) of reacting the reactant (a-1) with a compound represented by formula (1): [In formula (1), n and Y have the same meanings as n and Y in formula (II)] and a step (a-3) of reacting the reactant (a-2) with ammonium cerium (IV) nitrate to obtain an intermediate compound.
  • step (a-1) 2-butyne-1,4-diol is reacted with Co 2 (CO) 8.
  • the reactant (a-1) obtained in step (a-1) contains a cobalt complex formed by the reaction of 2-butyne-1,4-diol with Co 2 (CO) 8 .
  • the ratio of the number of moles of Co 2 (CO) 8 to the number of moles of 1,4-butynediol is, for example, 0.8 or more, or 0.9 or more, or 1.2 or less, or 1.1 or less.
  • the ratio of the number of moles of Co 2 (CO) 8 to the number of moles of 1,4-butynediol is, for example, 0.8 or more and 1.2 or less, 0.8 or more and 1.1 or less, 0.9 or more and 1.2 or less, or 0.9 or more and 1.1 or less.
  • Step (a-1) is preferably carried out in the presence of an organic solvent.
  • organic solvents include dichloromethane.
  • Step (a-1) can be carried out with stirring.
  • the reaction temperature in step (a-1) is not particularly limited, but is, for example, 20 to 40°C or 25 to 35°C.
  • the time for which the reaction temperature is maintained is not particularly limited, but is, for example, 10 minutes or more, 20 minutes or more, or 30 minutes or more, and 60 minutes or less.
  • the time for which the reaction temperature is maintained is not particularly limited, but is, for example, 10 minutes or more and 60 minutes or less, 20 minutes or more and 60 minutes or less, or 30 minutes or more and 60 minutes or less.
  • step (a-2) reactant (a-1) is reacted with compound (1) in the presence of BF 3 ⁇ OEt 2.
  • step (a-2) reactant (a-2) containing a 9-membered cyclic alkyne cobalt complex is obtained.
  • the amount (number of moles) of compound (1) used relative to the number of moles of 1,4-butynediol or the number of moles of CO 2 (CO) 8 is not particularly limited, but is, for example, 0.8 or more, or 0.9 or more, and 1.2 or less, or 1.1 or less.
  • the amount (number of moles) of compound (1) used relative to the number of moles of 1,4-butynediol or the number of moles of CO 2 (CO) 8 is not particularly limited, but is, for example, 0.8 or more and 1.2 or less, 0.8 or more and 1.1 or less, 0.9 or more and 1.2 or less, or 0.9 or more and 1.1 or less.
  • the amount (number of moles) of BF 3 ⁇ OEt 2 used relative to the number of moles of 1,4-butynediol or the number of moles of Co 2 (CO) 8 is, for example, preferably 1.0 or more, 1.5 or more, 2.0 or more, or 2.3 or more, and is preferably less than 3.0, 2.8 or less, or 2.6 or less.
  • the amount (number of moles) of BF3.OEt2 used relative to the number of moles of 1,4-butynediol or the number of moles of Co2 (CO) 8 is preferably, for example, 1.0 or more and less than 3.0, 1.0 or more and less than 2.8, 1.0 or more and less than 2.6, 1.5 or more and less than 3.0, 1.5 or more and less than 2.8, 1.5 or more and less than 2.6, 2.0 or more and less than 3.0, 2.0 or more and less than 2.8, 2.0 or more and less than 2.6, 2.3 or more and less than 3.0, 2.3 or more and less than 2.8 , or 2.3 or more and less than 2.6.
  • the amount (number of moles) of BF3.OEt2 used is within the above-mentioned numerical range, the generation of by-products is easily suppressed.
  • Step (a-2) can be carried out after step (a-1) without performing operations such as separating and purifying the target product in the reaction product (a-1).
  • step (a-3) reactant (a-2) is reacted with ammonium cerium (IV) nitrate.
  • step (a-3) the cobalt in the nine-membered cyclic alkyne cobalt complex in reactant (a-2) is removed.
  • Step (a-3) is preferably carried out in the presence of silica gel.
  • Step (a-3) can be carried out after step (a-2) without performing operations such as separating and purifying the target product in the reaction product (a-2).
  • the amount (number of moles) of ammonium cerium (IV) nitrate used relative to the number of moles of 1,4-butynediol or the number of moles of CO 2 (CO) 8 is not particularly limited, but is, for example, 2.0 or more and 10.0 or less, 2.0 or more and 5.0 or less, 2.5 or more and 10.0 or less, 2.5 or more and 5.0 or less, 3.0 or more and 10.0 or less, or 3.0 or more and 5.0 or less.
  • the intermediate compound can be obtained, for example, by mixing and stirring aminopropylated silica gel and pyridine after treatment with ammonium cerium (IV) nitrate, then washing the solid obtained by filtration, and then performing operations such as purification using a silica gel column.
  • the present invention will now be described in more detail with reference to the following examples. However, the present invention is not limited to the following examples.
  • the nuclear magnetic resonance spectra (NMR) of the obtained compounds were measured by placing the compounds dissolved in a heavy solvent in a sample tube with an outer diameter of 5 mm and using a spectrometer (manufactured by JEOL, product name: ECX500) at room temperature.
  • Multi-linked AOCN reacts with acid anhydrides to give amides, which allows molecular linkage.
  • acid anhydrides to give amides, which allows molecular linkage.
  • acetic anhydride is an example of the reaction with acetic anhydride.
  • Multi-linked AOCN reacts with thioisocyanate to give thiourea, which allows molecular linkage.
  • thioisocyanate reacts with fluorescein isothioisocyanate.
  • hydrochloride salt of poly-linked AOCN reacts with sulfonyl chloride in the presence of a base to give sulfonamide, which allows molecular linkage.
  • a base to give sulfonamide, which allows molecular linkage.
  • dansyl chloride is shown below.

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

Abstract

La présente invention concerne un composé représenté par la formule (I) ou un sel de celui-ci. [Dans la formule (I), n est un nombre entier de 1 à 10, et X est un groupe amino ou un groupe hydroxy.]
PCT/JP2025/006953 2024-03-01 2025-02-27 Dérivé d'aocn d'élément de réaction clic ou sel de celui-ci Pending WO2025183111A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2024031528A JP2025133522A (ja) 2024-03-01 2024-03-01 クリック反応素子ａｏｃｎ誘導体又はその塩
JP2024-031528 2024-03-01

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WO2025183111A1 true WO2025183111A1 (fr) 2025-09-04

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018039773A (ja) * 2016-09-09 2018-03-15 克彦 友岡 含窒素９員環アルキン
JP2020026476A (ja) * 2018-08-10 2020-02-20 国立大学法人九州大学 化合物、高分子化合物及び高分子化合物の製造方法
WO2024043341A1 (fr) * 2022-08-26 2024-02-29 ペプチドリーム株式会社 Dérivé de cycloalcyne

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018039773A (ja) * 2016-09-09 2018-03-15 克彦 友岡 含窒素９員環アルキン
JP2020026476A (ja) * 2018-08-10 2020-02-20 国立大学法人九州大学 化合物、高分子化合物及び高分子化合物の製造方法
WO2024043341A1 (fr) * 2022-08-26 2024-02-29 ペプチドリーム株式会社 Dérivé de cycloalcyne

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NI, RUNYAN ET AL.: "Heteroatom-embedded Medium-Sized Cycloalkynes: Concise Synthesis, Structural Analysis, and Reactions", ANGEWANDTE CHEMIE, vol. 54, no. 4, 2 December 2014 (2014-12-02), pages 1190 - 1194, XP055630910, DOI: 10.1002/anie.201409910 *

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