EP2013220A1 - Procédé de production d'acides boroniques portant des groupes cyanoalkyle, carboxyle et aminocarbonyle et leurs dérivés - Google Patents

Procédé de production d'acides boroniques portant des groupes cyanoalkyle, carboxyle et aminocarbonyle et leurs dérivés

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Publication number
EP2013220A1
EP2013220A1 EP07711737A EP07711737A EP2013220A1 EP 2013220 A1 EP2013220 A1 EP 2013220A1 EP 07711737 A EP07711737 A EP 07711737A EP 07711737 A EP07711737 A EP 07711737A EP 2013220 A1 EP2013220 A1 EP 2013220A1
Authority
EP
European Patent Office
Prior art keywords
formula
hydroxide
acid
boronic
iii
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.)
Withdrawn
Application number
EP07711737A
Other languages
German (de)
English (en)
Inventor
Andreas Meudt
Sven Nerdinger
Bernd Lehnemann
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.)
Euticals GmbH
Original Assignee
Archimica GmbH
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 Archimica GmbH filed Critical Archimica GmbH
Publication of EP2013220A1 publication Critical patent/EP2013220A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds

Definitions

  • the invention relates to a process for the preparation of boronic acids which carry at any point a cyano, carboxy or aminocarbonyl group, and their esters and salts.
  • an organic compound carrying at least one nitrile group is metallated (for example by halogen-metal exchange or deprotonation) and then converted with a trialkyl borate into the corresponding boronic acid or a boronic acid derivative, which may then optionally undergo partial hydrolysis to give the boronic acid functionality an aminocarbonyl group or converted by complete hydrolysis into a carboxyl group.
  • Aminocarbonylboronic acids are only available in small quantities and at such high prices that an application outside of drug discovery hardly makes sense. In particular, such heterocyclic and alkylboronic acids are virtually unavailable despite their great importance for biologically active substance classes.
  • nitrile-bearing boronic acids some syntheses have recently been published, for example, benzonitrile-derived arylboronic acids accessible by metalated bromine or iodobenzonitriles and the metalated intermediates - optionally in situ - are reacted with trialkyl borates (eg Li et al., J. Org. Chem. 2002, 67, 15, 5394).
  • Aminocarbonylboronic acids are only available in small quantities in the chemicals market. While derivates derived from tertiary and partly also from secondary amides can be prepared by the boronic acid function via organometallic intermediates (eg ortho-metalation or halogen-metal exchange, eg Liao et al., J. Med. Chem. 2000, 43, 517) introduced, primary amides are available in this way only through elaborate protecting group operations.
  • organometallic intermediates eg ortho-metalation or halogen-metal exchange, eg Liao et al., J. Med. Chem. 2000, 43, 51
  • Alkylboronic acids substituted with cyano, carboxy or aminocarbonyl groups are also scarcely available, general access to these classes of compounds is not described.
  • nitrile function in contrast to carboxy, aminocarbonyl and ester functionalities under suitable conditions, is compatible with the usual organometallic compounds used for boronic acid synthesis (L / et al., J. Org. Chem. 2002, 67, 15, 5394), so that cyanoboronic acids are much easier to access than other carboxylic acid derivatives.
  • organometallic compounds used for boronic acid synthesis L / et al., J. Org. Chem. 2002, 67, 15, 5394
  • cyanoboronic acids are much easier to access than other carboxylic acid derivatives.
  • there are other methods for introducing the nitrile function which are compatible with boronic acids or boronic acid esters or anhydrides, eg the Finkelstein exchange of halogens by cyanide (eg Miginiac et al., J. Organomet. Chem. 1971, 29, 349).
  • the present invention solves all three objects and relates to a process for the preparation of aminocarbonylboronic acids of the formula (IV) by reacting compounds of the formula (III) with a Bronsted base Y (OH) n in a solvent or solvent mixture
  • Z is an optionally substituted organic diradical structure, e.g. Aryl, heteroarylene, alkylene, heteroalkylene, alkylidene, heteroalkylidene, alkenylidene, heteroalkenylidene, alkynylidene, arylalkylene, heteroarylalkylene, arylheteroalkylene, heteroarylheteroalkylene, alkylheteroarylene, heteroalkylheteroarylene or alkylarylene radical,
  • Y means a cation of valence n
  • B is a boronic acid, a boronic ester, a borate or a boronic anhydride.
  • Z can be any substituents such as hydrogen, methyl, primary, secondary or tertiary, cyclic or acyclic alkyl radicals having 2 to 12 carbon atoms, in which one or more hydrogen atoms are optionally replaced by fluorine or chlorine, for example CF 3 , substituted cyclic or acyclic Alkyl groups, hydroxy, alkoxy, dialkylamino, alkylamino, arylamino, diarylamino, amino, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, thio, alkylthio, arylthio, diarylphosphino, dialkylphosphino, alkylarylphosphino, CO 2 " , hydroxyalkyl, alkoxyalkyl, fluorine, chlorine, Bromine, iodine, nitro, aryl or alkylsulfone, aryl or alkylsulfonyl, formyl, alkylcarbonyl
  • Valence n with 0 ⁇ n ⁇ 5 and an aliphatic or aromatic ammonium cation Preference is given to the inexpensive and strong bases of the alkali metals and the
  • lithium hydroxide sodium hydroxide, potassium hydroxide,
  • At least 2 equivalents of hydroxide anions are required to achieve complete saponification of the cyano function to a carboxy function in anhydrous media (see below) and at least 1 equivalent relative to the compound of formula (III) to complete conversion of the cyano function to the aminocarbonyl function achieve.
  • aqueous media usually 1 equivalent is sufficient.
  • part of the base is reversibly bound by quaternizing the boronic acid or its ester used by addition of a hydroxide ion. It has been found that this does not require a full equivalent of hydroxide ions but requires a substoichiometric amount, e.g. 0.25 to 0.95 equivalents based on the compound of formula (III), completely sufficient.
  • the reaction is preferably carried out with 1 to 10 equivalents of hydroxide. Particularly preferred is the implementation with 1-4 equivalents.
  • Bronsted base Y (OH) n in situ, for example by using other bases such as carbonates, fluorides or amines or basic oxides in aqueous media.
  • Such preferred Bronsted bases are sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, magnesium hydroxide, aliphatic or aromatic amines or ammonia, if used in conjunction with water.
  • the hydrolysis reaction is preferably carried out in a solvent or solvent mixture.
  • Particularly suitable are polar aprotic and protic solvents and their mixtures, in which both the substrate and the base are sufficiently soluble at the reaction temperature to ensure a rapid reaction, but in turn, not or only partially participate in the reaction.
  • water Preferably, water, linear, branched or cyclic (C 1 -C 20 ) - alkyl alcohols, linear, branched or cyclic (CrC 2 o) -alkanediols, linear, branched or cyclic (CrC 2 o) -alkanetriols, DMPU (Dimethylpropylidenharnstoff), NMP (N-methylpyrrolidone), DMF (dimethylformamide), DMAc (dimethylacetamide), tetrahydrofuran, 2-methyltetrahydrofuran, glymes or PEG (polyethylene glycol) or a mixture of several of these solvents.
  • DMPU Dimethylpropylidenharnstoff
  • NMP N-methylpyrrolidone
  • DMF dimethylformamide
  • DMAc dimethylacetamide
  • tetrahydrofuran 2-methyltetrahydrofuran
  • glymes or PEG polyethylene glycol
  • tetrahydrofuran 2-methyltetrahydrofuran
  • water methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 1-pentanol, tert-butanol
  • ethylene glycol propylene glycol, glycerol, butylene glycol, di-, tri- and tetraethylene glycol as well as polyethylene glycols and their mixtures.
  • reaction temperature of the hydrolysis is preferably chosen so that the reaction proceeds at an acceptable rate and with the desired selectivity.
  • reaction temperatures between room temperature and 250 ° C are applicable, preferably temperatures between 65 and 200 0 C, more preferably the normal pressure boiling temperature of the solvent or solvent mixture used.
  • the concentration of the reactants is conveniently chosen so that at the reaction temperature as saturated as possible solution in the selected solvent or solvent mixture is present; However, the reaction can also be carried out in suspension or in higher dilution.
  • the preferred work-up variant is the hydrolysis of the reaction mixture, followed by precipitation of the resulting boronic acid by adjustment of the corresponding pH with a Bronsted acid and isolation by filtration or centrifugation.
  • Other refurbishments include the isolation of the As borate salt or boronic acid esters, as well as the in-situ reaction of the resulting basic product solution with other reagents, for example, the in-situ alkylation to obtain carboxylic acid esters or N-alkylaminocarbonyl boronic esters.
  • aminocarbonylboronic acid of formula (IV) formed is further hydrolyzed to the carboxyboronic acid of formula (V).
  • the present invention relates to a process for the preparation of cyano-functionalized boronic acids of the formula (III) by metallation of nitrile compounds of the formula (I) with a metallating MR and subsequent reaction of the metalated compound of the formula (II) with a trialkyl borate to the compound of formula (III).
  • MR means a metallating reagent B and Z and v ⁇ / have the abovementioned meaning.
  • boronic acid esters may be optionally mixed esters of simple alcohols such as methanol, ethanol, 1-propanol, isopropanol, etc., polyhydric alcohols such as ethylene glycol, propylene glycol, butylene glycol, pinacol, neopentyl glycol, etc. or amino alcohols such as N-methyl or Act N-phenyldiethanolamine. If borates are used, these radicals may also be present, as well as the hydroxide ion, if necessary mixed. Most are in situ prepared (cyanoorganyl) trimethylborate and (cyanoorganyl) triisopropylborate.
  • the CN radical is attached to an aliphatic group.
  • the compound of formula (III) is preferably generated in situ from the compound of formula (I) by metallation and subsequent reaction with a trialkyl borate.
  • M M represents a metal, optionally with further counterions and / or ligands, preferably an alkali metal or alkaline earth metal or zinc, particularly preferably lithium, magnesium and zinc.
  • MR metallation reagent
  • MR can be alkyl, vinyl and aryllithium compounds and Grignard and Diorganomagnesiumstatten and triorganylmagnesates and metallic zinc and organozinc compounds, optionally also organically substituted alkali and alkaline earth metal amides and silazides, in some cases, alcoholates.
  • MR may additionally include adjuvants that facilitate or accelerate metallation, such as lithium chloride or TMEDA.
  • the metallation is preferably carried out with a metallating reagent from the following group: lithium organyls, lithium organyls in the presence of complexing agents or alkali metal alcoholates, alkali metal amides and silazides, Grignard compounds, magnesium diorganyls, triorganylmagnesates, Magnesium dialkylamides and these reagents in the presence of alkali metal salts and / or complexing agents, metallic zinc.
  • a metallating reagent from the following group: lithium organyls, lithium organyls in the presence of complexing agents or alkali metal alcoholates, alkali metal amides and silazides, Grignard compounds, magnesium diorganyls, triorganylmagnesates, Magnesium dialkylamides and these reagents in the presence of alkali metal salts and / or complexing agents, metallic zinc.
  • At least one amount of metallating reagent sufficient for complete metallation is required.
  • metallating reagent sufficient for complete metallation.
  • alkali metal compounds, Grignard compounds and zinc this is at least 1 equivalent, in the case of dialkylmagnesium compounds at least 0.5 equivalents and in the case of triorganylmagnesates at least 0.34 equivalents.
  • full implementation requires the use of excess metallating agent. If acidic functions are present in the molecule against which the metalating agent acts as a base, a corresponding excess of the metalating agent must be used.
  • any boric triesters may be used, e.g. Trialkyl borates, triaryl borates, mixed alkylaryl borates or mixed boric acid esters of monohydric and polyhydric alcohols, e.g. Isopropyl pinacol borate or cyclohexyl pinacol borate.
  • the borating reagent may be added prior to metallation to achieve in situ scavenging of the metalated compound (II) or, after metalation, reacted with (II).
  • At least a quantity of boric acid triester sufficient to achieve complete conversion of the metalated cyano compound to the boronic acid derivative (III), ie. at least 1 equivalent. Often, it is necessary to work with excess boric acid triester to achieve complete conversion or to destroy excess metallating agent by borating.
  • the reaction temperature of the metallation and boration is preferably chosen so that the reaction proceeds with high selectivity and acceptable speed without side reactions occurring.
  • the boration itself is preferably carried out between -120 and +20 0 C, in particular at -100 to 0 ° C.
  • the preparation of the boronic acid of the formula (III) is preferably carried out in a solvent or solvent mixture.
  • open-chain and cyclic ethers and aromatic and aliphatic hydrocarbons in particular tetrahydrofuran, 2-methyltetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, dibutyl ether, toluene, xylene, hexane, heptane, isohexane or similar solvents and their mixtures.
  • Preferred compounds of formula (I) which can be converted to boronic acid by the process of the invention are e.g. Haloalkylnitriles, Haloalkylarylnitrile, Haloalkylheteroarylnitrile, Haloalkylvinylnitrile, Haloalkylalkinylnitrile (by halogen-metal exchange), alkynylnitriles, alkynylalkyl-aryl, -heteroarylnitrile (by deprotonation), which may be optionally substituted with further functional groups.
  • Haloalkylnitriles Haloalkylarylnitrile, Haloalkylheteroarylnitrile, Haloalkylvinylnitrile, Haloalkylalkinylnitrile (by halogen-metal exchange), alkynylnitriles, alkynylalkyl-aryl, -heteroarylnitrile (by depro
  • Preferred compounds of the formula (III) which can be hydrolyzed by the process according to the invention are, in addition to the cyanoalkyl-, vinyl- and alkynyl-substituted boronic acids derived from formula (I), also e.g.
  • Cyanophenylboronic acids cyanopyridinyl, -pyrimidinyl, -pyrazinyl, -pyridazinyl, -furanyl, -thiophenyl, -pyrrolyl, -naphthyl-, -biphenyl- and -quinolinylboronic acids as well as cyanoalkylaryl and cyanoheteroalkylaryl as well as cyanovinyl and cyanoalkynylboronic acids.
  • representatives of the compounds of formula (III) are, but are not limited to, the following compounds:
  • the workup of the reaction mixture of the borate is carried out in the usual manner, usually by hydrolysis with subsequent precipitation of the boronic acid.
  • the hydrolysis mixture can also be converted directly into the saponification step of the nitrile function without isolation of the boronic acid and further processed.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)

Abstract

Procédé de production d'acides aminocarbonylboroniques de formule (IV) par conversion de composés de formule (III) avec une base de Bronsted Y(OH)n dans un solvant ou un mélange de solvants, dans laquelle Z désigne un radical aryle, hétéroaryle, alkyle, hétéroalkyle, alkylidène, hétéroalkylidène, alcénylidène, hétéroalcénylidène, alcinylidène, arylalkylène, hétéroarylalkylène, arylhétéroalkylène, hétéroarylhétéroalkylène, alkylhétéroarylène, hétéroalkylhétéroarylène ou alkylarylène éventuellement substitués, Y désigne un cation métallique ou ammonium présentant une valeur n avec 0 < n < 5 et B désigne un acide boronique, un acide boronique ester ou un borate ou un anhydride boronique. L'acide aminocarbonylboronique de formule (IV) peut en outre être hydrolysé en acide carboxyboronique de formule (V).
EP07711737A 2006-04-21 2007-03-01 Procédé de production d'acides boroniques portant des groupes cyanoalkyle, carboxyle et aminocarbonyle et leurs dérivés Withdrawn EP2013220A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102006018524 2006-04-21
PCT/EP2007/001764 WO2007121805A1 (fr) 2006-04-21 2007-03-01 Procédé de production d'acides boroniques portant des groupes cyanoalkyle, carboxyle et aminocarbonyle et leurs dérivés

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EP2013220A1 true EP2013220A1 (fr) 2009-01-14

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US (1) US20090286995A1 (fr)
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CN105153208B (zh) * 2015-06-12 2017-01-25 沧州普瑞东方科技有限公司 一种合成5‑羧基呋喃/噻吩‑2‑硼酸的方法
CN111313092B (zh) * 2020-03-04 2022-08-12 多氟多新能源科技有限公司 一种可改善正负极成膜的锂离子电池电解液

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DE19917979A1 (de) * 1999-04-21 2000-10-26 Clariant Gmbh Verfahren zur Herstellung von substituierten Phenyl-boronsäuren
DE102004029812A1 (de) 2004-06-19 2006-05-24 Clariant Gmbh Verfahren zur Herstellung von Nitrilen aus Aldehydoximen durch Umsetzung mit Alkylphosphonsäureanhydriden
US20080000331A1 (en) * 2005-06-22 2008-01-03 Min-Chi Yu Vehicle Lube Filter Unfastening Fixture

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