EP1102796A1 - Method for the stereoselective production of grignard compounds and use thereof - Google Patents

Method for the stereoselective production of grignard compounds and use thereof

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Publication number
EP1102796A1
EP1102796A1 EP99934559A EP99934559A EP1102796A1 EP 1102796 A1 EP1102796 A1 EP 1102796A1 EP 99934559 A EP99934559 A EP 99934559A EP 99934559 A EP99934559 A EP 99934559A EP 1102796 A1 EP1102796 A1 EP 1102796A1
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formula
alkyl
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German (de)
French (fr)
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Laure Boymond
Mario Rottländer
Gerard Cahiez
Paul Knochel
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BASF SE
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BASF SE
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    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • C40B40/16—Libraries containing metal-containing organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B49/00—Grignard reactions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/14—Preparation of carboxylic acid nitriles by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
    • C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
    • C07C29/40—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones with compounds containing carbon-to-metal bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/28—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic System
    • C07F3/02—Magnesium compounds
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
    • C40B50/14—Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/11—Compounds covalently bound to a solid support

Definitions

  • the invention relates to a process for the stereoselective preparation of Grignard compounds of the formula I.
  • the invention also relates to polymer-bound compounds of the formula Ia.
  • the invention further relates to the use of the process for the preparation of substance libraries and the use of the compounds of the formulas I and Ia in stereoselective chemical synthesis.
  • Grignard compounds are valuable intermediates in organic synthesis. They belong to the most important classes of compounds in organic synthetic chemistry. Their reaction with electrophilic substances allows the production of a wide variety of compounds. A variety of syntheses are known from the literature in which Grignard compounds are used (see: Handbook of Grignard-Reagents, Eds. G.S. Silverman, P.E. Rakita, Marcel Dekker, Inc., 1996). Grignard compounds have good reactivity with satisfactory chemoselectivity (see Posner GH Org. React., Vol. 22, 1975: 253, Lipshutz et al., Org. React., Vol. 41, 1992: 135, Luh T.-Y. Che Res., Vol 24, 1991: 257 or Tamao et al., J. Am. Chem. Soc., Vol, 94, 1972: 4374).
  • Alkenyl Grignard compounds are usually prepared by reacting an appropriate alkenyl halide with metallic magnesium or another magnesium source. Another method is based on acetylenes which are carbometalated with Grignard compounds in the presence of suitable promoters. The methods for this are known to the person skilled in the art and can be found, for example, in Houben-Weyl vol. XIII / 2a and the literature cited therein and in the Handbook of Grignard-Reagents, Eds. G.S. Silverman, P.E. Rakita, Marcel Dekker, Inc., 1996 or in J. Organomet. Chem. 1976, 113: 107 or in J. Fluorine Chem. 1982, 20, 699.
  • the residues Ri ', R' and R ' are only shown schematically as residues in Scheme I.
  • the object of the present invention was therefore to provide a process for the synthesis of vinyl Grignard compounds which enables stereoselective access to these compounds while maintaining the original E / Z geometry. Another task was to enable the further stereoselective reaction of these compounds with electrophiles. Furthermore, it was an object to provide a process which tolerates a large number of additional functional groups in the molecule in order to be able to produce synthetically and pharmacologically interesting compounds.
  • X halogen such as Cl or R 3
  • R 1 substituted or unsubstituted, branched or unbranched Ci-Cio-alkyl, C 3 -C 10 cycloalkyl, -C-C 4 alkylaryl, C ⁇ -C 4 alkylhetaryl, aryl or hetaryl,
  • R 2 hydrogen, -CH 2 -R 4
  • R 3 branched or unbranched Ci-Cio-alkyl-, C 3 -C ⁇ o ⁇ cyclo-alkyl,
  • R 4 hydrogen, substituted or unsubstituted, branched or unbranched -OCi-Cio-alkyl, -OC 3 -C ⁇ o-cyclo-alkyl, -OC ⁇ -C 4 -alkylaryl, -OC ⁇ -C 4 -alkylhetaryl, -OCNR ⁇ 5 , R 6
  • R 5 like R 1 ' but regardless of
  • R 6 a solid support.
  • R 1 in the compounds of the formulas I and II denotes substituted or unsubstituted, branched or unbranched Ci-Cio-alkyl-, C 3 -C ⁇ 0 -cycloalkyl-, C 1 -C 4 -alkylaryl-, -C-C 4 -alkyl- hetaryl, aryl, hetaryl or R 5 ,
  • alkyl radicals are substituted or unsubstituted branched or unbranched -CC-alkyl chains such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, n-pentyl , 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1, l-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl , 4-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 2-dimethylbutyl, 2,3-dimethylbutyl, 3, 3-dimethylbutyl, 1-ethylbutyl, 2-ethy
  • C 3 -C 10 cycloalkyl chains with 3 to 7 carbon atoms in the ring or ring system such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-methylcyclopropyl, 1-ethylcyclopropyl, 1-propylcyclopropyl, 1-butylcyclopropyl, 1-pentylcyclopropyl, 1 -Methyl-l-butylcyclopropyl, 1, 2-dimethylcyclypropyl, l-methyl-2-ethylcyclopropyl, cyclooctyl, cyclononyl or cyclodecyl.
  • the cycloalkyl radicals can also contain heteroatoms such as S, N and 0 in the ring.
  • the cycloalkyl radicals can contain branched or unbranched alkyl parts.
  • C 1 -C 4 alkylaryl substituted or unsubstituted branched or unbranched C 1 -C 4 alkylphenyl or C 1 -C 4 alkylnaphthyl radicals such as methylphenyl, ethylphenyl, propylphenyl, 1-methylethylphenyl, butylphenyl, 1-methylpropyl , 2-Methylpropylphenyl, 1, 1-Dimethylethylphenyl, Methylnaphthyl, Ethylnaphthyl, Propylnaphthyl, 1-Methylethylnaphthyl, Butylnaphthyl, 1-Methylpropylnaphthyl, 2-Methylpropylnaphthyl or 1, 1-Dimethylethylnaphthyl called.
  • Substituted or unsubstituted branched or unbranched C 1 -C 4 -alkylhetaryl radicals which contain one or more nitrogen, sulfur and / or oxygen atoms in the ring or ring system may be mentioned as alkylhetaryl radicals.
  • Aryl radicals which may be substituted or unsubstituted aryls such as, for example, phenyl, naphthyl or aromatic rings or ring systems with 6 to 18 carbon atoms in the ring system and up to 24 further C atoms which form further non-aromatic rings or ring systems with 3 to 8 C atoms in the ring can, for example.
  • aryls such as, for example, phenyl, naphthyl or aromatic rings or ring systems with 6 to 18 carbon atoms in the ring system and up to 24 further C atoms which form further non-aromatic rings or ring systems with 3 to 8 C atoms in the ring can, for example.
  • Optionally substituted phenyl or naphthyl are preferred.
  • Simple or fused aromatic ring systems with one or more heteroaromatic 3- to 7-membered rings which may contain one or more heteroatoms such as N, O or S may be mentioned as hetaryl radicals.
  • substituents for the radicals mentioned of R 1 for example one or more substituents such as halogen, such as fluorine, chlorine or bromine, cyano, nitro, amino, hydroxy, alkyl, cycloalkyl, aryl, alkoxy, Benzyloxy, phenyl or benzyl.
  • R 2 denotes hydrogen, in the formulas I and II, or -CH-R 4.
  • R 3 in the formula R 3 denotes MgX (III) branched or unbranched Ci-Cio-alkyl- or C 3 -C ⁇ o-cycloalkyl-.
  • alkyl radicals are substituted or unsubstituted branched or unbranched C ⁇ -C ⁇ o alkyl chains such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, n-pentyl , 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl , 4-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 2-dimethylbutyl, 2, 3-dimethylbutyl, 3, 3-dimethylbutyl, 1-ethylbutyl, 2-ethyl
  • cycloalkyl radicals in the formula III are substituted or unsubstituted branched or unbranched C 3 -C 10 -cycloalkyl chains having 3 to 7 carbon atoms in the ring or ring system, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-methylcyclopropyl, 1-ethylcyclopropyl, 1- Propyl-cyclopropyl, 1-butylcyclopropyl, 1-pentylcyclopropyl, 1-methyl-1-butylcyclopropyl, 1, 2-dimethylcyclypropyl, 1-methyl-2-ethylcyclopropyl, cyclooctyl, cyclononyl or cyclodecyl.
  • radicals mentioned under R 3 could also carry substituents, but since these compounds would first have to be prepared in a complex manner and the radical R 3 is not contained in the products synthesized from the Grignard compounds, it is more sensible with the unsubstituted ones for economic reasons to work commercially available or easily synthesized compounds.
  • R 4 denotes hydrogen, substituted or unsubstituted, branched or unbranched -OC ⁇ -C ⁇ o-alkyl-, - ⁇ C 3 -C ⁇ 0 -cyclo- alkyl-, -OC x -C 4 -alkylaryl-, -OC ⁇ -C 4 -alkylhetaryl- , OCNR ⁇ -R 5 , R 6 .
  • Substituted or unsubstituted branched or unbranched -OC ⁇ -C ⁇ 0 alkyl chains may be mentioned as -O-alkyl radicals.
  • the C ⁇ -C ⁇ o alkyl chains have, for example, the following meaning: methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl-, 2-methylpropyl, 1, 1-dimethylethyl, n- Pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl
  • substituted or unsubstituted branched or unbranched branched or -branched -OC 3 -C ⁇ o-cycloalkyl chains with 3 to 7 carbon atoms in the ring or ring system may be mentioned as -O-cycloalkyl radicals in the R 4 radical, the C 3 in these -OC 3 -C ⁇ o-cycloalkyl chains being -C ⁇ o-cycloalkyl chains, for example, have the following meaning: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-methylcyclopropyl, 1-ethylcyclopropyl, 1-propylcyclopropyl, 1-butylcyclopropyl, 1-pentylcyclopropyl, 1-methyl-l-butylcyclopropyl, 1 , 2-dimethylcyclypropyl, l-methyl-2-ethylcyclopropyl, cyclo
  • C ⁇ -C4 alkyl-phenyl- or -CC 4 alkyl naphthyl residues such as methylphenyl, ethylphenyl, propylphenyl, 1-methylethylphenyl, butylphenyl, 1-methylpropylphenyl, 2-methylpropylphenyl, 1, 1-dimethylethylphenyl, methylnaphthyl, ethylnaphthyl, propylnaphthyl, 1- Methylethylnaphthyl, butylnaphthyl, 1-methylpropylnaphthyl, 2-methylpropylnaphthyl
  • Substituted and unsubstituted branched or unbranched -0-C 1 -C 4 -alkylhetaryl radicals which contain one or more nitrogen, sulfur and / or oxygen atoms in the ring or ring system may be mentioned as -O-alkylhetaryl radicals.
  • the heteroaromatic part can contain simple or condensed aromatic rings or ring systems with one or more heteroaromatic 3- to 7-membered rings.
  • substituents of the said radicals of R 4 for example one or more substituents, such as halogen, such as fluorine, chlorine or bromine, cyano, nitro, amino, hydroxy, alkyl, cycloalkyl, aryl, alkoxy, Benzyloxy, phenyl or benzyl.
  • substituents such as halogen, such as fluorine, chlorine or bromine, cyano, nitro, amino, hydroxy, alkyl, cycloalkyl, aryl, alkoxy, Benzyloxy, phenyl or benzyl.
  • THF tetrahydro
  • a reaction temperature of less than -20 ° C., preferably between -100 ° C. and -20 ° C., particularly preferably between -80 ° C. and -40 ° C. is advantageously selected .
  • a reaction temperature of less than +30 ° C, preferably between -40 ° C and +30 ° C, particularly preferably between -20 ° C and +30 ° C is entirely advantageous particularly preferably chosen between 0 ° C and +30 ° C.
  • all compounds of the formula R 3 MgX known to the person skilled in the art can be used to prepare the Grignard compound; diisopropylmagnesium or isopropylmagnesium chloride are preferably used.
  • reaction time is between 1 h and 18 h.
  • the following compounds of the general formula Ia can be prepared by using polymer-bound alcohols:
  • R 2 is -CH-R 4
  • R 4 is R 6 and R 6 is a solid support.
  • Usable carriers can, as far as they are compatible with the synthetic chemistry used, consist of a variety of materials.
  • the size, size distribution and shape of the straps can vary widely depending on the material. Spherical particles are preferred which are advantageously homogeneous in their size distribution.
  • Solid supports which are preferably suitable are, for example, functionalized crosslinked polystyrenes such as 4-hydroxybenzylpolystyrene.
  • connection of the compound to the support or polymeric support takes place via reactions known to the person skilled in the art, for example from the review by Balkenhohl et al. (Angew. Chem., Vol. 108, 1996: 2436) and the literature cited there.
  • the connection can be made via an ester, for example. After the synthesis has been completed, it can be split off from the resin with, for example, trifluoroacetic acid.
  • Exemplary here are his carotenoid, vitamin or active ingredient syntheses such as active ingredients in the pharmaceutical or crop protection sector.
  • Table I shows the results of analogous reactions with different electrophiles.
  • the starting compounds (Grignard compounds) were established within 7-28 h via an od-magnesium exchange.
  • the temperature of the reaction solutions were between -78 to + 25 ° C. Good sales were achieved at these temperatures.
  • Table II Preparation of Grignard compounds and reaction with electrophiles on a solid support.

Abstract

The invention relates to a method for the stereoselective production of grignard compounds of formula (I), to polymer-bonded compounds of formula (Ia), to the use of the method for producing libraries of substances and to the use of the compounds of formulae (I) and (Ia) in stereoselective chemical synthesis.

Description

Verfahren zur stereoselektiven Herstellung von Grignard- verbindungen und deren VerwendungProcess for the stereoselective production of Grignard compounds and their use
Beschreibungdescription
Die Erfindung betrifft ein Verfahren zur stereoselektiven Herstellung von Grignardverbindungen der Formel I. Die Erfindung betrifft außerdem polymergebundene Verbindungen der Formel la. Weiterhin betrifft die Erfindung die Verwendung des Verfahrens zur Herstellung von Substanzbibliotheken sowie die Verwendung der Verbindungen der Formeln I und la in der stereoselektiven chemischen Synthese.The invention relates to a process for the stereoselective preparation of Grignard compounds of the formula I. The invention also relates to polymer-bound compounds of the formula Ia. The invention further relates to the use of the process for the preparation of substance libraries and the use of the compounds of the formulas I and Ia in stereoselective chemical synthesis.
Grignardverbindungen sind wertvolle Zwischenstufen in der organischen Synthese. Sie gehören zu den wichtigsten Verbindungsklassen in der organischen Synthesechemie. Ihre Umsetzung mit elektrophilen Substanzen erlaubt die Herstellung der unterschiedlichsten Verbindungen. Aus der Literatur sind eine Vielzahl von Synthesen bekannt, in denen Grignardverbindungen verwendet werden (siehe: Handbook of Grignard-Reagents , Eds. G.S. Silverman, P.E. Rakita, Marcel Dekker, Inc., 1996). Grignardverbindungen besitzen eine gute Reaktivität bei befriedigender Chemoselektivität (siehe Posner G. H. Org. React., Vol. 22, 1975: 253, Lipshutz et al., Org. React., Vol. 41, 1992: 135, Luh T.-Y. Che . Res., Vol 24, 1991: 257 oder Tamao et al . , J. Am. Chem. Soc. , Vol, 94, 1972: 4374).Grignard compounds are valuable intermediates in organic synthesis. They belong to the most important classes of compounds in organic synthetic chemistry. Their reaction with electrophilic substances allows the production of a wide variety of compounds. A variety of syntheses are known from the literature in which Grignard compounds are used (see: Handbook of Grignard-Reagents, Eds. G.S. Silverman, P.E. Rakita, Marcel Dekker, Inc., 1996). Grignard compounds have good reactivity with satisfactory chemoselectivity (see Posner GH Org. React., Vol. 22, 1975: 253, Lipshutz et al., Org. React., Vol. 41, 1992: 135, Luh T.-Y. Che Res., Vol 24, 1991: 257 or Tamao et al., J. Am. Chem. Soc., Vol, 94, 1972: 4374).
Alkenyl-Grignardverbindungen werden üblicherweise hergestellt, in dem ein entsprechendes Alkenylhalogenid mit metallischem Magnesium oder einer anderen Magnesiumquelle umgesetzt wird. Eine weitere Methode geht von Acetylenen aus, die in Gegenwart geeigneter Promotoren mit Grignardverbindungen carbometalliert werden. Die Methoden hierzu sind dem Fachmann bekannt und können beispielsweise in Houben-Weyl Bd. XIII/2a und der darin zitierten Literatur und in Handbook of Grignard-Reagents, Eds. G.S. Silverman, P.E. Rakita, Marcel Dekker, Inc., 1996 oder in J. Organomet. Chem. 1976, 113: 107 oder in J. Fluorine Chem. 1982, 20, 699 nachgelesen werden.Alkenyl Grignard compounds are usually prepared by reacting an appropriate alkenyl halide with metallic magnesium or another magnesium source. Another method is based on acetylenes which are carbometalated with Grignard compounds in the presence of suitable promoters. The methods for this are known to the person skilled in the art and can be found, for example, in Houben-Weyl vol. XIII / 2a and the literature cited therein and in the Handbook of Grignard-Reagents, Eds. G.S. Silverman, P.E. Rakita, Marcel Dekker, Inc., 1996 or in J. Organomet. Chem. 1976, 113: 107 or in J. Fluorine Chem. 1982, 20, 699.
Die Darstellung vinylischer Grignardverbindungen nach diesen Methoden ist aber oftmals von Nebenreaktionen (z.B. Eliminierungen) begleitet und nicht auf alle Vinylhalogenide anwendbar. So reagieren z.B. endständige, vinylische Halogenide zumeist nur sehr schlecht zu der gewünschten Grignardverbindung. Unter den Reaktionsbedingungen wird auch oftmals eine Isomerisierung gemäß Schema I beobachtet. Schema I: Isomerisierung von GrignardverbindungenThe preparation of vinylic Grignard compounds by these methods is often accompanied by side reactions (eg eliminations) and is not applicable to all vinyl halides. For example, terminal vinylic halides usually react very poorly to the desired Grignard compound. Isomerization according to Scheme I is often observed under the reaction conditions. Scheme I: Isomerization of Grignard compounds
ElEl
Aus einem Z-Halogenid (bezogen auf Halogen und Ri') wird ein Gemisch der E/Z isomeren Grignardverbindungen, die dann auch in der Weiterreaktion mit dem Elektrophil (= El) ein E/Z-Gemisch der gewünschten Produkte liefern. Die Reste Ri', R ' und R ' sind in Schema I als Reste nur schematisch angeben.A Z-halide (based on halogen and Ri ') becomes a mixture of the E / Z isomeric Grignard compounds, which then also provide an E / Z mixture of the desired products in the further reaction with the electrophile (= El). The residues Ri ', R' and R 'are only shown schematically as residues in Scheme I.
Ein weiterer Nachteil der bisher zur Verfügung stehenden Methoden ist, daß sie es nicht erlauben Grignardverbindungen mit weiteren funktionellen Gruppen wie beispielsweise Estern, Nitrilen oder Amiden herzustellen, die mit einem Elektrophil reagieren würden, da derartige Gruppen bei der Herstellung der Grignardverbindung abreagieren würden.Another disadvantage of the methods available hitherto is that they do not allow Grignard compounds to be produced with other functional groups, such as esters, nitriles or amides, which would react with an electrophile, since such groups would react during the production of the Grignard compound.
Aufgabe der vorliegenden Erfindung war es deshalb, ein Verfahren zur Synthese von vinylischen Grignardverbindungen bereitzustellen, das einen stereoselektiven Zugang zu diesen Verbindungen unter Erhalt der ursprünglichen E/Z-Geometrie ermöglicht. Eine weitere Aufgabe war die weitere stereoselektive Umsetzung dieser Verbindungen mit Elektrophilen zu ermöglichen. Des Weiteren war Aufgabe ein Verfahren zur Verfügung zu stellen, daß eine Vielzahl zusätzlicher funktioneller Gruppen im Molekül toleriert, um so synthetisch und pharmakologisch interessante Verbindungen herstellen zu können.The object of the present invention was therefore to provide a process for the synthesis of vinyl Grignard compounds which enables stereoselective access to these compounds while maintaining the original E / Z geometry. Another task was to enable the further stereoselective reaction of these compounds with electrophiles. Furthermore, it was an object to provide a process which tolerates a large number of additional functional groups in the molecule in order to be able to produce synthetically and pharmacologically interesting compounds.
Diese Aufgabe wurde durch ein Verfahren zur Herstellung von Verbindungen der allgemeinen Formel I gelöstThis object was achieved by a process for the preparation of compounds of the general formula I.
dadurch gekennzeichnet, daß man Verbindungen der allgemeinen characterized in that compounds of general
Formel IIFormula II
mit Verbindungen der Formel R3MgX (III) bei Temperaturen von kleiner +30 °C stereoselektiv zu Verbindungen der Formel I umsetzt,reacted with compounds of the formula R 3 MgX (III) stereoselectively at temperatures of less than +30 ° C. to give compounds of the formula I,
wobei die Substituenten und Variablen in den Formeln I, II und III folgende Bedeutung haben:where the substituents and variables in the formulas I, II and III have the following meaning:
X = Halogen wie Cl oder R3 X = halogen such as Cl or R 3
R1 = substituiertes oder unsubstituiertes, verzweigtes oder unverzweigtes Ci-Cio-Alkyl-, C3-C10-Cycloalkyl-, Cι-C4-Alkylaryl-, Cι-C4-Alkylhetaryl-, Aryl oder Hetaryl,R 1 = substituted or unsubstituted, branched or unbranched Ci-Cio-alkyl, C 3 -C 10 cycloalkyl, -C-C 4 alkylaryl, Cι-C 4 alkylhetaryl, aryl or hetaryl,
R2 = Wasserstoff , -CH2-R4 R 2 = hydrogen, -CH 2 -R 4
R3 = verzweigtes oder unverzweigtes Ci-Cio-Alkyl-, C3-Cιo~Cyclo- alkyl ,R 3 = branched or unbranched Ci-Cio-alkyl-, C 3 -Cιo ~ cyclo-alkyl,
R4 = Wasserstoff, substituiertes oder unsubstituiertes, verzweigtes oder unverzweigtes -OCi-Cio-Alkyl, -OC3-Cιo-Cyclo- alkyl, -OCι-C4-Alkylaryl, -OCι-C4-Alkylhetaryl , -OCNR^5 , R6 R 4 = hydrogen, substituted or unsubstituted, branched or unbranched -OCi-Cio-alkyl, -OC 3 -Cιo-cyclo-alkyl, -OCι-C 4 -alkylaryl, -OCι-C 4 -alkylhetaryl, -OCNR ^ 5 , R 6
R5 = wie R1 ' jedoch unabhängig davon,R 5 = like R 1 ' but regardless of
R6 = ein fester Träger.R 6 = a solid support.
R1 bezeichnet in den Verbindungen der Formeln I und II substituiertes oder unsubstituiertes, verzweigtes oder unverzweigtes Ci-Cio-Alkyl-, C3-Cι0-Cycloalkyl-, C1-C4-Alkylaryl-, Cι-C4-Alkyl- hetaryl-, Aryl, Hetaryl oder R5,R 1 in the compounds of the formulas I and II denotes substituted or unsubstituted, branched or unbranched Ci-Cio-alkyl-, C 3 -Cι 0 -cycloalkyl-, C 1 -C 4 -alkylaryl-, -C-C 4 -alkyl- hetaryl, aryl, hetaryl or R 5 ,
Als Alkylreste seien substituierte oder unsubstituierte verzweigte oder unverzweigte Cι-Cιo-Alkylketten wie beispielsweise Methyl, Ethyl, n-Propyl, 1-Methylethyl, n-Butyl, 1-Methylpropyl-, 2-Methylpropyl, 1, 1-Dimethylethyl, n-Pentyl, 1-Methylbutyl, 2-Methylbutyl, 3-Methylbutyl, 2, 2-Dimethylpropyl, 1-Ethylpropyl, n-Hexyl, 1, l-Dimethylpropyl, 1, 2-Dimethylpropyl, 1-Methylpentyl, 2-Methylpentyl, 3-Methylpentyl, 4-Methylpentyl, 1, 1-Dimethyl- butyl, 1, 2-Dimethylbutyl, 1, 3-Dimethylbutyl, 2 , 2-Dimethylbutyl, 2,3-Dimethylbutyl, 3 , 3-Dimethylbutyl, 1-Ethylbutyl, 2-Ethylbutyl, 1, 1, 2-Trimethylpropyl, 1, 2 , 2-Trimethylpropyl, 1-Ethyl-l-methyl- propyl, l-Ethyl-2-methylpropyl, n-Heptyl, n-Octyl, n-Nonyl oder n-Decyl genannt .As alkyl radicals are substituted or unsubstituted branched or unbranched -CC-alkyl chains such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, n-pentyl , 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1, l-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl , 4-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 2-dimethylbutyl, 2,3-dimethylbutyl, 3, 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl , 1, 1, 2-trimethylpropyl, 1, 2, 2-trimethylpropyl, 1-ethyl-l-methyl called propyl, l-ethyl-2-methylpropyl, n-heptyl, n-octyl, n-nonyl or n-decyl.
Als Cycloalkylreste in der Formel seien beispielhaft substi- tuierte oder unsubstituierte verzweigte oder unverzweigteExamples of substituted or unsubstituted branched or unbranched cycloalkyl radicals in the formula
C3-C10-Cycloalkylketten mit 3 bis 7 Kohlenstoffatomen im Ring oder Ringsystem wie Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Cycloheptyl, 1-Methylcyclopropyl, 1-Ethylcyclopropyl, 1-Propyl- cyclopropyl, 1-Butylcyclopropyl, 1-Pentylcyclopropyl, 1-Methyl-l- Butylcyclopropyl, 1, 2-Dimethylcyclypropyl, l-Methyl-2-Ethylcyclo- propyl, Cyclooctyl, Cyclononyl oder Cyclodecyl genannt. Die Cycloalkylreste können auch Heteroatome wie S, N und 0 im Ring enthalten. Die Cycloalkylreste können verzweigte oder unverzweigte Alkylteile enthalten.C 3 -C 10 cycloalkyl chains with 3 to 7 carbon atoms in the ring or ring system such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-methylcyclopropyl, 1-ethylcyclopropyl, 1-propylcyclopropyl, 1-butylcyclopropyl, 1-pentylcyclopropyl, 1 -Methyl-l-butylcyclopropyl, 1, 2-dimethylcyclypropyl, l-methyl-2-ethylcyclopropyl, cyclooctyl, cyclononyl or cyclodecyl. The cycloalkyl radicals can also contain heteroatoms such as S, N and 0 in the ring. The cycloalkyl radicals can contain branched or unbranched alkyl parts.
Als Cι-C4-Alkylaryl seihen substituierte oder unsubstituierte verzweigtkettige oder unverzweigtkettige Cι-C4-Alkyl-phenyl- oder Cι-C4-Alkyl-naphthylreste wie Methylphenyl , Ethylphenyl, Propyl- phenyl, 1-Methylethylphenyl, Butylphenyl, 1-Methylpropylphenyl, 2-Methylpropylphenyl, 1, 1-Dimethylethylphenyl, Methylnaphthyl, Ethylnaphthyl , Propylnaphthyl , 1-Methylethylnaphthyl, Butyl- naphthyl, 1-Methylpropylnaphthyl, 2-Methylpropylnaphthyl oder 1, 1-Dimethylethylnaphthyl genannt.As C 1 -C 4 alkylaryl, substituted or unsubstituted branched or unbranched C 1 -C 4 alkylphenyl or C 1 -C 4 alkylnaphthyl radicals such as methylphenyl, ethylphenyl, propylphenyl, 1-methylethylphenyl, butylphenyl, 1-methylpropyl , 2-Methylpropylphenyl, 1, 1-Dimethylethylphenyl, Methylnaphthyl, Ethylnaphthyl, Propylnaphthyl, 1-Methylethylnaphthyl, Butylnaphthyl, 1-Methylpropylnaphthyl, 2-Methylpropylnaphthyl or 1, 1-Dimethylethylnaphthyl called.
Als Alkylhetarylreste seien substituierte oder unsubstituierte verzweigtkettige oder unverzweigtkettige Cι-C4-Alkylhetarylreste, die ein oder mehrere Stickstoff-, Schwefel- und/oder Sauerstoff- atome im Ring oder Ringsystem enthalten, genannt.Substituted or unsubstituted branched or unbranched C 1 -C 4 -alkylhetaryl radicals which contain one or more nitrogen, sulfur and / or oxygen atoms in the ring or ring system may be mentioned as alkylhetaryl radicals.
Als Arylreste seien substituierte oder unsubstituierte Aryle wie beispielsweise Phenyl, Naphthyl oder aromatische Ringe oder Ringsysteme mit 6 bis 18 Kohlenstoffatomen im Ringsystem sowie bis zu 24 weiteren C-Atomen, die weitere nicht aromatische Ringe oder Ringsysteme mit 3 bis 8 C-Atomen im Ring bilden können, beispiel- haft genannt. Bevorzugt sind ggf. substituiertes Phenyl oder Naphthyl .Aryl radicals which may be substituted or unsubstituted aryls such as, for example, phenyl, naphthyl or aromatic rings or ring systems with 6 to 18 carbon atoms in the ring system and up to 24 further C atoms which form further non-aromatic rings or ring systems with 3 to 8 C atoms in the ring can, for example. Optionally substituted phenyl or naphthyl are preferred.
Als Hetarylreste seien einfache oder kondensierte aromatische Ringsysteme mit einem oder mehreren heteroaromatischen 3- bis 7gliedrigen Ringen, die ein oder mehrere Heteroatome wie N, 0 oder S enthalten können genannt.Simple or fused aromatic ring systems with one or more heteroaromatic 3- to 7-membered rings which may contain one or more heteroatoms such as N, O or S may be mentioned as hetaryl radicals.
Als Substituenten der genannten Reste von R1 kommen prinzipiell bis auf Ketone oder Aldehyde alle denkbaren Substituenten in Frage beispielsweise ein oder mehrere Substituenten wie Halogen wie Fluor, Chlor oder Brom, Cyano, Nitro, Amino, Hydroxy, Alkyl, Cycloalkyl, Aryl, Alkoxy, Benzyloxy, Phenyl oder Benzyl . R2 bezeichnet in den Formeln I und II Wasserstoff oder -CH-R4.In principle, apart from ketones or aldehydes, all conceivable substituents are possible as substituents for the radicals mentioned of R 1 , for example one or more substituents such as halogen, such as fluorine, chlorine or bromine, cyano, nitro, amino, hydroxy, alkyl, cycloalkyl, aryl, alkoxy, Benzyloxy, phenyl or benzyl. R 2 denotes hydrogen, in the formulas I and II, or -CH-R 4.
R3 bezeichnet in der Formel R3MgX (III) verzweigtes oder unverzweigtes Ci-Cio-Alkyl- oder C3-Cιo-Cycloalkyl-.R 3 in the formula R 3 denotes MgX (III) branched or unbranched Ci-Cio-alkyl- or C 3 -Cιo-cycloalkyl-.
Als Alkylreste seien substituierte oder unsubstituierte verzweigte oder unverzweigte Cι-Cιo-Alkylketten wie beispielsweise Methyl, Ethyl, n-Propyl, 1-Methylethyl, n-Butyl, 1-Methylpropyl-, 2-Methylpropyl, 1, 1-Dimethylethyl, n-Pentyl, 1-Methylbutyl , 2-Methylbutyl, 3-Methylbutyl, 2, 2-Dimethylpropyl, 1-Ethylpropyl, n-Hexyl, 1, 1-Dimethylpropyl, 1, 2-Dimethylpropyl, 1-Methylpentyl, 2-Methylpentyl, 3-Methylpentyl, 4-Methylpentyl, 1, 1-Dimethyl- butyl, 1, 2-Dimethylbutyl, 1, 3-Dimethylbutyl, 2 , 2-Dimethylbutyl, 2, 3-Dimethylbutyl, 3 , 3-Dimethylbutyl, 1-Ethylbutyl, 2-Ethylbutyl, 1, 1, 2-Trimethylpropyl, 1, 2 , 2-Trimethylpropyl, 1-Ethyl-l-methyl- propyl, l-Ethyl-2-methylpropyl, n-Heptyl, n-Octyl, n-Nonyl oder n-Decyl genannt .As alkyl radicals are substituted or unsubstituted branched or unbranched Cι-Cιo alkyl chains such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, n-pentyl , 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl , 4-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 2-dimethylbutyl, 2, 3-dimethylbutyl, 3, 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl , 1, 1, 2-trimethylpropyl, 1, 2, 2-trimethylpropyl, 1-ethyl-l-methylpropyl, l-ethyl-2-methylpropyl, n-heptyl, n-octyl, n-nonyl or n-decyl called .
Als Cycloalkylreste in der Formel III seien beispielhaft substituierte oder unsubstituierte verzweigte oder unverzweigte C3-Cιo-Cycloalkylketten mit 3 bis 7 Kohlenstoffatomen im Ring oder Ringsystem wie Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Cycloheptyl, 1-Methylcyclopropyl, 1-Ethylcyclopropyl, 1-Propyl- cyclopropyl, 1-Butylcyclopropyl, 1-Pentylcyclopropyl, 1-Methyl-l- Butylcyclopropyl, 1, 2-Dimethylcyclypropyl, l-Methyl-2-Ethylcyclo- propyl, Cyclooctyl, Cyclononyl oder Cyclodecyl genannt.Examples of cycloalkyl radicals in the formula III are substituted or unsubstituted branched or unbranched C 3 -C 10 -cycloalkyl chains having 3 to 7 carbon atoms in the ring or ring system, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-methylcyclopropyl, 1-ethylcyclopropyl, 1- Propyl-cyclopropyl, 1-butylcyclopropyl, 1-pentylcyclopropyl, 1-methyl-1-butylcyclopropyl, 1, 2-dimethylcyclypropyl, 1-methyl-2-ethylcyclopropyl, cyclooctyl, cyclononyl or cyclodecyl.
Prinzipiell könnten die unter R3 genannten Reste auch Substituenten tragen, da diese Verbindungen jedoch erst aufwendig her- gestellt werden müßten und der Rest R3 in den aus den Grignardverbindungen synthetisierten Produkten nicht enthalten ist, ist es aus wirtschaftlichen Gründen sinnvoller mit den unsubstituier- ten kommerziell erhältlichen oder einfach synthetisierbaren Verbindungen zu arbeiten.In principle, the radicals mentioned under R 3 could also carry substituents, but since these compounds would first have to be prepared in a complex manner and the radical R 3 is not contained in the products synthesized from the Grignard compounds, it is more sensible with the unsubstituted ones for economic reasons to work commercially available or easily synthesized compounds.
R4 bezeichnet Wasserstoff, substituiertes oder unsubstituiertes, verzweigtes oder unverzweigtes -OCχ-Cιo-Alkyl-, -θC3-Cι0-Cyclo- alkyl-, -OCx-C4-Alkylaryl-, -OCι-C4-Alkylhetaryl-, OCNR^-R5, R6. 4-Hydroxybenzylpolystyrol .R 4 denotes hydrogen, substituted or unsubstituted, branched or unbranched -OCχ-Cιo-alkyl-, -θC 3 -Cι 0 -cyclo- alkyl-, -OC x -C 4 -alkylaryl-, -OCι-C 4 -alkylhetaryl- , OCNR ^ -R 5 , R 6 . 4-hydroxybenzyl polystyrene.
Als -O-Alkylreste seien substituierte oder unsubstituierte verzweigte oder unverzweigte -OCι-Cι0-Alkylketten genannt. In diesen -O-Alkylresten haben die Cι-Cιo-Alkylketten beispielhaft folgende Bedeutung: Methyl, Ethyl, n-Propyl, 1-Methylethyl, n-Butyl, 1-Methylpropyl-, 2-Methylpropyl, 1, 1-Dimethylethyl, n-Pentyl, 1-Methylbutyl, 2-Methylbutyl, 3-Methylbutyl, 2 , 2-Dimethylpropyl, 1-Ethylpropyl , n-Hexyl, 1 , 1-Dimethylpropyl , 1, 2-Dimethylpropyl, 1-Methylpentyl, 2-Methylpentyl, 3-Methylpentyl, 4-Methylpentyl, 1, 1-Dimethylbutyl, 1, 2-Dimethylbutyl, 1, 3-Dimethylbutyl, 2, 2-Dimethylbutyl, 2 , 3-Dimethylbutyl, 3 , 3-Dimethylbutyl, 1-Ethylbutyl, 2-Ethylbutyl, 1, 1, 2-Trimethylpropyl, 1, 2, 2-Trimethylpropyl, 1-Ethyl-l-methylpropyl, l-Ethyl-2-methylpropyl, n-Heptyl, n-Octyl, n-Nonyl oder n-Decyl.Substituted or unsubstituted branched or unbranched -OCι-Cι 0 alkyl chains may be mentioned as -O-alkyl radicals. In these -O-alkyl radicals, the Cι-Cιo alkyl chains have, for example, the following meaning: methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl-, 2-methylpropyl, 1, 1-dimethylethyl, n- Pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 2-dimethylbutyl, 2, 3-dimethylbutyl, 3, 3- Dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1, 1, 2-trimethylpropyl, 1, 2, 2-trimethylpropyl, 1-ethyl-l-methylpropyl, l-ethyl-2-methylpropyl, n-heptyl, n-octyl, n-nonyl or n-decyl.
Als -O-Cycloalkylreste im Rest R4 seien beispielhaft substituierte oder unsubstituierte verzweigte oder unverzweigte -θC3-Cιo-Cyclo- alkylketten mit 3 bis 7 Kohlenstoffatomen im Ring oder Ringsystem genannt, wobei in diesen -OC3-Cιo-Cycloalkylketten die C3-Cιo-Cycloalkylketten beispielsweise folgende Bedeutung haben: Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Cycloheptyl, 1-Methylcyclopropyl, 1-Ethylcyclopropyl, 1-Propylcyclopropyl, 1-Butylcyclopropyl, 1-Pentylcyclopropyl, 1-Methyl-l-Butylcyclo- propyl, 1, 2-Dimethylcyclypropyl, l-Methyl-2-Ethylcyclopropyl, Cyclooctyl, Cyclononyl oder Cyclodecyl. Die Cycloalkylreste können auch Heteroatome wie S, N und 0 im Ring enthalten. Die Cycloalkylreste können verzweigte oder unverzweigte Alkylteile enthalten.Examples of substituted or unsubstituted branched or unbranched branched or -branched -OC 3 -Cιo-cycloalkyl chains with 3 to 7 carbon atoms in the ring or ring system may be mentioned as -O-cycloalkyl radicals in the R 4 radical, the C 3 in these -OC 3 -Cιo-cycloalkyl chains being -Cιo-cycloalkyl chains, for example, have the following meaning: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-methylcyclopropyl, 1-ethylcyclopropyl, 1-propylcyclopropyl, 1-butylcyclopropyl, 1-pentylcyclopropyl, 1-methyl-l-butylcyclopropyl, 1 , 2-dimethylcyclypropyl, l-methyl-2-ethylcyclopropyl, cyclooctyl, cyclononyl or cyclodecyl. The cycloalkyl radicals can also contain heteroatoms such as S, N and 0 in the ring. The cycloalkyl radicals can contain branched or unbranched alkyl parts.
Als -0-Cι-C4-Alkylaryl seihen substituierte und unsubstituierte verzweigtkettige oder unverzweigtkettige -0-Cι-C4-Alkylarylreste genannt, wobei die Cι-C4-Alkylarylketten beispielsweise folgende Bedeutung haben: Cι-C4-Alkyl-phenyl- oder Cι-C4-Alkyl-naphthyl- reste wie Methylphenyl , Ethylphenyl, Propylphenyl, 1-Methylethyl- phenyl, Butylphenyl, 1-Methylpropylphenyl, 2-Methylpropylphenyl, 1, 1-Dimethylethylphenyl, Methylnaphthyl, Ethylnaphthyl , Propyl- naphthyl, 1-Methylethylnaphthyl, Butylnaphthyl, 1-Methylpropyl- naphthyl, 2-Methylpropylnaphthyl oder 1, 1-Dimethylethylnaphthyl .As -0-Cι-C substituted strain 4 alkylaryl and unsubstituted branched or unbranched Cι-C -0-called 4 -alkylaryl, wherein said Cι-C have 4 -Alkylarylketten example, the following meaning: Cι-C4 alkyl-phenyl- or -CC 4 alkyl naphthyl residues such as methylphenyl, ethylphenyl, propylphenyl, 1-methylethylphenyl, butylphenyl, 1-methylpropylphenyl, 2-methylpropylphenyl, 1, 1-dimethylethylphenyl, methylnaphthyl, ethylnaphthyl, propylnaphthyl, 1- Methylethylnaphthyl, butylnaphthyl, 1-methylpropylnaphthyl, 2-methylpropylnaphthyl or 1, 1-dimethylethylnaphthyl.
Als -O-Alkylhetarylreste seien substituierte und unsubstituierte verzweigtkettige oder unverzweigtkettige -0-Cι_-C4-Alkylhetaryl- reste, die ein oder mehrere Stickstoff-, Schwefel- und/oder Sauerstoffatome im Ring oder Ringsystem enthalten, genannt. Der Heteroaromaten teil kann einfache oder kondensierte aromatischen Ringe oder Ringsystemen mit einem oder mehreren heteroaromatischen 3- bis 7gliedrigen Ringen enthalten.Substituted and unsubstituted branched or unbranched -0-C 1 -C 4 -alkylhetaryl radicals which contain one or more nitrogen, sulfur and / or oxygen atoms in the ring or ring system may be mentioned as -O-alkylhetaryl radicals. The heteroaromatic part can contain simple or condensed aromatic rings or ring systems with one or more heteroaromatic 3- to 7-membered rings.
Alle vorstehend genannten Reste des Substituenten R4 sind über den Sauerstoff gebunden.All of the above-mentioned residues of the substituent R 4 are bonded via the oxygen.
R4 kann auch ein Polymer (= fester Träger) R6 sein (Definition des Trägers siehe unten) . Vorteilhaft wird als Polymer 4-Hydroxy- benzylpolysytrol verwendet. Als OCNR3^5 seien Carbamate genannt, in denen R1 und R5 unabhängig voneinander die oben genannte Bedeutung haben.R 4 can also be a polymer (= solid support) R 6 (definition of the support see below). 4-Hydroxybenzylpolysytrol is advantageously used as the polymer. Carbamates in which R 1 and R 5 independently of one another have the abovementioned meaning are mentioned as OCNR 3 ^ 5 .
Als Substituenten der genannten Reste von R4 kommen prinzipiell bis auf Ketone oder Aldehyde alle denkbaren Substituenten in Frage beispielsweise ein oder mehrere Substituenten wie Halogen wie Fluor, Chlor oder Brom, Cyano, Nitro, Amino, Hydroxy, Alkyl, Cycloalkyl, Aryl, Alkoxy, Benzyloxy, Phenyl oder Benzyl .In principle, apart from ketones or aldehydes, all conceivable substituents come into question as substituents of the said radicals of R 4 , for example one or more substituents, such as halogen, such as fluorine, chlorine or bromine, cyano, nitro, amino, hydroxy, alkyl, cycloalkyl, aryl, alkoxy, Benzyloxy, phenyl or benzyl.
Das erfindungsgemäße Verfahren wird in der Reaktion vorteilhafterweise so durchgeführt, daß die Verbindungen der Formel II vorteilhaft in einem inertem, aprotischen Lösungsmittel beispielsweise Ether wie Tetrahydrofuran (= THF) , Diethylether, Dioxan, Dirnethoxyethan oder Methyl-tert. -butylether (= MTB) bei Temperaturen von kleiner 30 °C, bevorzugt zwischen -100 °C und +30 °C, besonders bevorzugt zwischen -90 °C und +30 °C, ganz besonders bevorzugt zwischen -80 °C und +25 °C mit einer Verbindung der allgemeinen Formel R3MgX (III) zu Verbindung der Formel I umgesetzt werden. Für Verbindungen bei denen der Rest R4 über ein Sauerstoffatom gebunden ist, wird vorteilhaft eine Reaktionstemperatur von kleiner -20 °C, bevorzugt zwischen -100 °C und -20 °C, besonders bevorzugt zwischen -80 °C und -40 °C gewählt. Für Verbindungen bei denen der Rest R4 über eine Kohlenstoffatom gebunden ist, wird vorteilhaft eine Reaktionstemperatur von kleiner +30 °C, bevorzugt zwischen -40 °C und +30 °C, besonders bevorzugt zwischen -20 °C und +30 °C, ganz besonders bevorzugt zwischen 0 °C und +30 °C gewählt. Prinzipiell können alle dem Fachmann bekannten Verbindungen der Formel R3MgX zur Herstellung der Grignardverbindung verwendet werden, bevorzugt werden Diiso- propylmagnesium oder Isopropylmagnesiumchlorid verwendet.The process according to the invention is advantageously carried out in the reaction in such a way that the compounds of the formula II are advantageously in an inert, aprotic solvent, for example ethers such as tetrahydrofuran (= THF), diethyl ether, dioxane, dirthoxyethane or methyl tert. -butyl ether (= MTB) at temperatures below 30 ° C, preferably between -100 ° C and +30 ° C, particularly preferably between -90 ° C and +30 ° C, very particularly preferably between -80 ° C and +25 ° C are reacted with a compound of the general formula R 3 MgX (III) to give the compound of the formula I. For compounds in which the radical R 4 is bonded via an oxygen atom, a reaction temperature of less than -20 ° C., preferably between -100 ° C. and -20 ° C., particularly preferably between -80 ° C. and -40 ° C., is advantageously selected . For compounds in which the radical R4 is bonded via a carbon atom, a reaction temperature of less than +30 ° C, preferably between -40 ° C and +30 ° C, particularly preferably between -20 ° C and +30 ° C, is entirely advantageous particularly preferably chosen between 0 ° C and +30 ° C. In principle, all compounds of the formula R 3 MgX known to the person skilled in the art can be used to prepare the Grignard compound; diisopropylmagnesium or isopropylmagnesium chloride are preferably used.
Unter diesem milden Bedingungen erfolgt der Halogen-Magnesium- Austausch ohne, daß die gebildeten Grignardverbindungen der Formel I (siehe oben) mit den weiteren im Molekül enthaltenden funktionellen Gruppen reagieren. Die Verbindungen reagieren nur in der gewünschten Weise, stereoselektiv mit dem Elektrophil (siehe Beispiele in der Tabelle I) . Es werden E/Z-Verhältnisse von größer 85:15, bevorzugt von 90:10, besonders bevorzugt von 98:2 erreicht.Under these mild conditions, the halogen-magnesium exchange takes place without the Grignard compounds of formula I (see above) formed reacting with the other functional groups contained in the molecule. The compounds only react in the desired manner, stereoselectively with the electrophile (see examples in Table I). E / Z ratios of greater than 85:15, preferably 90:10, particularly preferably 98: 2 are achieved.
Die Reaktionszeit liegt je nach eingesetztem Vinylhalogenid zwischen 1 h und 18 h.Depending on the vinyl halide used, the reaction time is between 1 h and 18 h.
Ein besonderer Vorteil dieses Verfahrens ist, daß auch polymer gebundene Alkohole (= R4 = R6 = Polymer, fester Träger) in der gewünschten Weise den Halogen-Magnesiumaustausch eingehen. Diese Alkohole dienen ebenso wie die freien Alkohole als Ausgangsver- bindungen zur Synthese der Verbindungen der Formel II. Über die Verwendung von polymer gebundenen Alkoholen lassen sich die folgenden Verbindungen der allgemeinen Formel la darstellen:A particular advantage of this process is that polymer-bound alcohols (= R 4 = R 6 = polymer, solid carrier) also enter into the halogen-magnesium exchange in the desired manner. Like the free alcohols, these alcohols serve as starting materials. Bonds for the synthesis of the compounds of the formula II. The following compounds of the general formula Ia can be prepared by using polymer-bound alcohols:
In der der Rest R2 -CH-R4 bedeutet, R4 gleich R6 ist und R6 ein fester Träger ist.In which the radical R 2 is -CH-R 4 , R 4 is R 6 and R 6 is a solid support.
Die Bindung der Verbindungen der Formel la kann dabei vorteilhaft über einen festen Träger (= R5) , wie sie aus der Festphasen- Peptidsynthese bekannt sind, erfolgen. Nutzbare Träger können, soweit sie mit der verwendeten Synthesechemie kompatibel sind aus einer Vielzahl von Materialien bestehen. Wobei die Größe, Größenverteilung und Form der Träger je nach Material in weitem Rahmen variieren kann. Bevorzugt werden sphärische Partikel, die vorteilhafterweise in ihrer Größenverteilung homogen sind.The compounds of the formula Ia can advantageously be bound via a solid support (= R 5 ), as are known from solid-phase peptide synthesis. Usable carriers can, as far as they are compatible with the synthetic chemistry used, consist of a variety of materials. The size, size distribution and shape of the straps can vary widely depending on the material. Spherical particles are preferred which are advantageously homogeneous in their size distribution.
Bevorzugt geeignete feste Träger sind beispielsweise funktionali- sierte cruervernetzte Polystyrole wie 4-Hydroxybenzylpolystyrol .Solid supports which are preferably suitable are, for example, functionalized crosslinked polystyrenes such as 4-hydroxybenzylpolystyrene.
Die Anbindung der Verbindung an den Träger bzw. polymeren Träger erfolgt über dem Fachmann bekannte Reaktionen, die beispielsweise aus dem Review von Balkenhohl et al . (Angew. Chem., Vol. 108, 1996: 2436) und der dort zitierten Literatur zu entnehmen ist. Im Falle von Wang-Harz kann die Anbindung beispielsweise über einen Ester erfolgen. Dieser kann nach abgeschlossener Synthese mit beispielsweise Trifluoressigsäure vom Harz abgespalten werden.The connection of the compound to the support or polymeric support takes place via reactions known to the person skilled in the art, for example from the review by Balkenhohl et al. (Angew. Chem., Vol. 108, 1996: 2436) and the literature cited there. In the case of Wang resin, the connection can be made via an ester, for example. After the synthesis has been completed, it can be split off from the resin with, for example, trifluoroacetic acid.
Auf diese Weise lassen sich die Vorteile der Festphasensynthese, nämlich die automatische Durchführung und Aufarbeitung der Reaktion durch einfaches Waschen und Filtern, nutzen. Unter Ver- wendung des erfindungsgemäßen Verfahrens lassen sich so leicht Substanzbibliotheken herstellen.In this way, the advantages of solid-phase synthesis, namely the automatic execution and processing of the reaction by simple washing and filtering, can be used. Using the method according to the invention, substance libraries can be easily produced.
Damit ist diese Reaktion sehr gut geeignet, um nach den Prinzipien der Kombinationischen Chemie bzw. des HSA Substanz- bibliotheken zu erzeugen (Angew. Chem., Vol. 108, 1996: 2436), in dem zuerst der Halogen-Magnesiumaustausch an einem Polymer gebundenen Edukt durchgeführt wird und dieses dann mit einer Vielzahl von Elektrophilen (in einem Gefäß zur Erzeugung von Mischungen) umgesetzt wird. Nach Waschen und Filtern werden die Zielprodukte dann unter Bedingung, die zur Spaltung der Linker-Bindung geeignet sind, von Polymer abgelöst.This reaction is therefore very well suited to generate substance libraries according to the principles of combination chemistry or the HSA (Angew. Chem., Vol. 108, 1996: 2436), in which the halogen-magnesium exchange is first bound to a polymer Educt is carried out and this is then reacted with a variety of electrophiles (in a vessel to produce mixtures). After washing and filtering, the target products are then detached from the polymer under conditions which are suitable for breaking the linker bond.
Die erfindungsgemäßen Verbindungen der Formeln I oder la (= R4 = Rδ = fester Träger bevorzugt polymerer Träger) lassen sich vorteilhaft als Ausgangs- bzw. Zwischenprodukte, die sich in vielfältigen Folgereaktionen einsetzen lassen, in der chemischen Synthese verwenden. Beispielhaft seinen hier Carotinoid-, Vitamin- oder Wirkstoffsynthesen wie Wirkstoffe im Pharma- oder Pflanzenschutzbereich.The compounds of the formulas I or Ia (= R 4 = R δ = solid support, preferably polymeric support) according to the invention can advantageously be used in chemical synthesis as starting or intermediate products which can be used in a variety of subsequent reactions. Exemplary here are his carotenoid, vitamin or active ingredient syntheses such as active ingredients in the pharmaceutical or crop protection sector.
Die folgenden Beispiele sollen das Verfahren veranschaulichen ohne eine Einschränkung der Methode zu bedeuten:The following examples are intended to illustrate the process without restricting the method:
BeispieleExamples
A. Darstellung von (E) -4 (4-carbethoxybenzyloxy) -2-phenyl-1- iodopropenA. Preparation of (E) -4 (4-carbethoxybenzyloxy) -2-phenyl-1-iodopropene
Eine Lösung von 700 mg (1.66 mmol) (E) -4 (4-carbethoxybenzy- loxy) 2-phenyl-l-iodopropen in 4 ml THF wurde auf -85 °C abgekühlt und 3.9 ml (3.32 mmol) einer Lösung von Diisopropyl agnesium in THF (0.85 M) wurden zugegeben. Nach 16 h h bei -70 °C wurden 0.48 ml (4.65 mmol) Benzaldehyd zugegeben. Nach 3 h wurde die Reaktionsmischung hydrolysiert und die org. Phase eingeengt. Chromatographie des Rohproduktes mit CHC1 /Ether 95:5 4/1 ergab 528 mg (79 %) des Alkohols.A solution of 700 mg (1.66 mmol) of (E) -4 (4-carbethoxybenzyloxy) 2-phenyl-l-iodopropene in 4 ml of THF was cooled to -85 ° C. and 3.9 ml (3.32 mmol) of a solution of diisopropyl agnes in THF (0.85 M) were added. After 16 h at -70 ° C, 0.48 ml (4.65 mmol) of benzaldehyde was added. After 3 h the reaction mixture was hydrolyzed and the org. Phase concentrated. Chromatography of the crude product with CHC1 / ether 95: 5 4/1 gave 528 mg (79%) of the alcohol.
Tabelle I gibt die Ergebnisse analoger Umsetzungen mit verschiedenen Elektrophilen wieder.Table I shows the results of analogous reactions with different electrophiles.
Die AusgangsVerbindungen (Grignardverbindungen) wurden innerhalb von 7-28 h Stunde über einen od-Magnesiumaustausch hergestellt. Die Temperatur der Reaktionslösungen lagen dabei zwischen -78 bis + 25°C. Bei diesen Temperaturen konnten gute Umsätze erzielt werden.The starting compounds (Grignard compounds) were established within 7-28 h via an od-magnesium exchange. The temperature of the reaction solutions were between -78 to + 25 ° C. Good sales were achieved at these temperatures.
Die in Tabelle I angegebenen Umsätze beziehen sich auf chemisch reines Endprodukt. Tabelle I: Herstellung von Grignardverbindungen und- Umsetzung mit ElektrophilenThe sales listed in Table I relate to chemically pure end product. Table I: Preparation of Grignard compounds and reaction with electrophiles
Die in Tabelle I wiedergegebenen Produkte wurden mit einem E/Z- bzw. Z/E-Verhältnis in jedem Fall von größer 98:2 erhalten.The products shown in Table I were obtained with an E / Z or Z / E ratio of greater than 98: 2 in each case.
B. Herstellung von Grignardverbindungen am Polymeren Träger und Umsetzung mit Elektrophilen.B. Production of Grignard compounds on the polymer carrier and reaction with electrophiles.
150 mg z-Iodallylether-funktionalisiertes Wang-Harz wurde mit 2 ml THF versetzt und auf -40 °C abgekühlt. Es wurden 1.25 ml (0.9 mmol) einer 0.72 M Lösung von Isopropylmagnesiumbromid in THF zugetropft und nach 4 h 0.2 ml (1.88 mmol) Benzaldehyd zugegeben. Nach 1 h Inkubation wurde abfiltriert, mit THF, MeOH gewaschen und mit 4 ml 95 % Trifluoressigsäure das Produkt vom Polymer abgespalten.150 mg z-iodoallyl ether functionalized Wang resin was mixed with 2 ml THF and cooled to -40 ° C. 1.25 ml (0.9 mmol) of a 0.72 M solution of isopropyl magnesium bromide in THF were added dropwise and after 4 h 0.2 ml (1.88 mmol) of benzaldehyde was added. After 1 h of incubation, the mixture was filtered off, washed with THF, MeOH and the product was cleaved from the polymer with 4 ml of 95% trifluoroacetic acid.
Filtration und Eindampfen lieferte die entsprechenden Produkte.Filtration and evaporation provided the corresponding products.
Analog wurden die in Tabelle II aufgeführten Substanzen her- gestellt. Die Ausbeute an freiem Produkt betrug in der Regel 90 % oder mehr (siehe Angaben in der Tabelle, Spalte 5) . Tabelle II : Herstellung von Grignardverbindungen und Umsetzung mit Elektrophilen an festem Träger.The substances listed in Table II were prepared analogously. The yield of free product was generally 90% or more (see information in the table, column 5). Table II: Preparation of Grignard compounds and reaction with electrophiles on a solid support.
* nach saurer Abspaltung vom Polymer tritt hierbei spontane Cyclisierung zum Dihydrofuran ein * After acidic cleavage from the polymer, spontaneous cyclization to the dihydrofuran occurs
Die Abkürzungen der Elektrophile in den Tabellen I und II haben folgende Bedeutung PhCHO = Benzaldehyd, TsCN = Tosylcyanid und PhsSPh = Diphenyldisulfid. The abbreviations of the electrophiles in Tables I and II have the following meaning PhCHO = benzaldehyde, TsCN = tosyl cyanide and PhsSPh = diphenyl disulfide.

Claims

Patentansprüche claims
1. Verfahren zur Herstellung von Verbindungen der allgemeinen Formel I1. Process for the preparation of compounds of general formula I.
dadurch gekennzeichnet, daß man Verbindungen der allgemeinen Formel IIcharacterized in that compounds of the general formula II
mit Verbindungen der Formel R3MgX (III) bei Temperaturen von kleiner +30 °C stereoselektiv zu Verbindungen der Formel I umsetzt,reacted with compounds of the formula R 3 MgX (III) stereoselectively at temperatures of less than +30 ° C. to give compounds of the formula I,
wobei die Substituenten und Variablen in den Formeln I, II und III folgende Bedeutung haben:where the substituents and variables in the formulas I, II and III have the following meaning:
X = Halogen wie Cl oder R3 X = halogen such as Cl or R 3
R1 = substituiertes oder unsubstituiertes, verzweigtes oder unverzweigtes Ci-Cio-Alkyl-, C3-Cι0-Cycloalkyl-, Cι-C4-Alkylaryl-, Cι-C4-Alkylhetaryl-, Aryl oder Hetaryl,R 1 = substituted or unsubstituted, branched or unbranched Ci-Cio-alkyl-, C 3 -Cι 0 -cycloalkyl-, -C-C 4 -alkylaryl-, -Cι-C4-alkylhetaryl, aryl or hetaryl,
R2 = Wasserstoff, -CH-R4 R 2 = hydrogen, -CH-R 4
R3 = verzweigtes oder unverzweigtes Ci-Cio-Alkyl-, C3-Cι0-Cycloalkyl,R 3 = branched or unbranched Ci-Cio-alkyl-, C 3 -Cι 0 -cycloalkyl,
R4 = Wasserstoff, substituiertes oder unsubstituiertes, verzweigtes oder unverzweigtes -OCι-Cι0-Alkyl,R 4 = hydrogen, substituted or unsubstituted, branched or unbranched -OCι-Cι 0 alkyl,
-OC3-Cι0-Cycloalkyl, -OC1-C4-Alkylaryl, -OC!-C4-Alkyl- hetary^-OCNRiR5, R6 -OC 3 -Cι 0 -cycloalkyl, -OC 1 -C 4 -alkylaryl, -OC ! -C 4 alkyl hetary ^ -OCNR i R 5 , R 6
R5 = wie R1 ' jedoch unabhängig davon,R 5 = like R 1 ' but regardless of
R6 = ein fester Träger. R 6 = a solid support.
2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß das Verfahren in einem inertem aprotischen Lösungsmittel durchgeführt wird.2. The method according to claim 1, characterized in that the method is carried out in an inert aprotic solvent.
3. Verfahren nach Anspruch 1 oder 2, dadurch gekennzeichnet, daß das Verfahren bei Temperaturen zwischen -100 °C und +30 °C durchgeführt wird.3. The method according to claim 1 or 2, characterized in that the method is carried out at temperatures between -100 ° C and +30 ° C.
4. Verfahren nach den Ansprüchen 1 bis 3, dadurch gekennzeich- net, daß die Umsetzung zu Verbindungen der Formel I nach4. The method according to claims 1 to 3, characterized in that the reaction to compounds of formula I after
Anspruch 1 innerhalb 18 Stunden beendet ist.Claim 1 has ended within 18 hours.
5. Verfahren nach den Ansprüchen 1 bis 4, dadurch gekennzeichnet, daß das Verfahren an einem festen Träger (= R6) durch- geführt wird.5. Process according to claims 1 to 4, characterized in that the process is carried out on a solid support (= R 6 ).
6. Verbindungen der Formel la6. Compounds of formula la
in der die Variablen und Substituenten die in Anspruch 1 genannte Bedeutung haben und R2 -CH-R4 bedeutet und R4 gleich R6 ist und R6 ein fester Träger ist.in which the variables and substituents have the meaning given in claim 1 and R 2 is -CH-R 4 and R 4 is R 6 and R 6 is a solid support.
7. Verwendung eines Verf hrens gemäß den Ansprüchen 1 bis 5 zur Herstellung von Substanzbibliotheken.7. Use of a method according to claims 1 to 5 for the production of substance libraries.
8. Verwendung von Verbindungen der Formel I oder Formel la gemäß Anspruch 1 oder Anspruch 7 für chemische Synthesen.8. Use of compounds of formula I or formula la according to claim 1 or claim 7 for chemical syntheses.
9. Verwendung nach Anspruch 8 für Carotinoid-, Vitamin- oder WirkstoffSynthesen . 9. Use according to claim 8 for carotenoid, vitamin or active ingredient syntheses.
EP99934559A 1998-07-09 1999-07-02 Method for the stereoselective production of grignard compounds and use thereof Withdrawn EP1102796A1 (en)

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CH455766A (en) 1961-07-19 1968-05-15 Gen Electric Process for the preparation of Grignard reagent
US3428616A (en) * 1966-05-09 1969-02-18 Ritter Pfaudler Corp Regenerative polymeric grignard compositions
US3856867A (en) 1972-03-06 1974-12-24 Rhodia Process for the preparation of grignard reagents and their utilization in organic syntheses
US4293497A (en) * 1977-12-29 1981-10-06 Scm Corporation Coupling reaction involving a grignard and allylic halide
US5073659A (en) * 1989-08-22 1991-12-17 Eisai Co., Ltd. Process for the preparation of terpenes
US5286726A (en) * 1990-04-12 1994-02-15 The Regents Of The University Of Michigan Difluoroglutamic acid conjugates with folates and anti-folates for the treatment of neoplastic diseases
US5665720A (en) * 1992-08-07 1997-09-09 Merck & Co., Inc. Benzoxazinones as inhibitors of HIV reverse transcriptase
DE19628159A1 (en) 1996-07-12 1998-01-15 Studiengesellschaft Kohle Mbh Process for the synthesis of Grignard compounds using catalysts
DE60001433T2 (en) * 1999-05-27 2003-10-30 Givaudan Sa Alpha, beta unsaturated ketones

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