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WO2004013068A1 - Procede de realisation de reactions chimiques en presence de composes absorbes sur des supports fluores par interactions fluor-fluor - Google Patents

Procede de realisation de reactions chimiques en presence de composes absorbes sur des supports fluores par interactions fluor-fluor Download PDF

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Publication number
WO2004013068A1
WO2004013068A1 PCT/EP2003/007592 EP0307592W WO2004013068A1 WO 2004013068 A1 WO2004013068 A1 WO 2004013068A1 EP 0307592 W EP0307592 W EP 0307592W WO 2004013068 A1 WO2004013068 A1 WO 2004013068A1
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Prior art keywords
compound
fluorinated
reaction
fluorine
adsorbed
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German (de)
English (en)
Inventor
Willi Bannwarth
Carl Christoph Tzschucke
Heiko Glatz
Dominik Schwinn
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Albert Ludwigs Universitaet Freiburg
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Albert Ludwigs Universitaet Freiburg
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Priority to AU2003250053A priority Critical patent/AU2003250053A1/en
Publication of WO2004013068A1 publication Critical patent/WO2004013068A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B43/00—Formation or introduction of functional groups containing nitrogen
    • C07B43/06—Formation or introduction of functional groups containing nitrogen of amide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
    • C07B37/04—Substitution
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures

Definitions

  • the present invention relates to a method for carrying out chemical reactions, in which a compound involved in the reaction is adsorbed on a fluorinated carrier material via fluorine-fluorine interactions.
  • the majority of combinatorial synthesis processes use solid support materials to immobilize the compounds involved in the reaction.
  • the synthesis robots which were developed for this automated, massively parallel reaction procedure, often have in common that they have two automated functions: pipetting liquids and suctioning liquids.
  • the synthesis robots often have a larger number of reaction compartments, into which a defined amount of solid support material is introduced before the reaction.
  • the reaction compartments are individually controlled by a pipetting arm and defined amounts of pure solvent or substances dissolved in a solvent are added, whereby chemical reactions can be initiated on the solid support material.
  • the solvents with the compounds dissolved therein are sucked off through a diaphragm, which prevents the solid support material from leaving the reaction compartment.
  • EP 857 180 discloses metal complexes which can be immobilized on supports containing aluminum or silicon.
  • solid phases are commercially available which have functional groups on their surface which are suitable for covalent linkage with the compounds to be immobilized.
  • glass particles controiled pore glass, CPG
  • the amino groups can be used to immobilize suitable compounds, such as carboxylic acids, on the glass particles via amide bonds.
  • the covalent linkage between the solid support materials (solid phases) and the compounds to be immobilized must meet the condition that the chemical bond which is formed in the immobilization step between the solid phase and the molecule to be immobilized under the reaction conditions of the subsequent reactions which are carried out on the Solid phase immobilized compound should be stable, so that there is no early splitting of the connection from the solid phase.
  • the chemical bond between the solid support material and the molecule to be immobilized should also be such that it can be selectively cleaved again after completion of the overall synthesis, so that the reaction product, which is initially still immobilized on the solid support material, can be detached therefrom, in particular if you are not interested in immobilized end products, but in free, soluble compounds.
  • the immobilization of compounds on solid support materials via covalent bonds has certain disadvantages. If, for example, a compound which contains a carboxylic acid function is immobilized on the amino groups of the aminopropyl-modified solid phase mentioned above, amide bonds are formed between the compound and the solid phase, via which the compound is covalently bound to the solid phase. Assuming the yield of the immobilization reaction is 95%, 5% of the amino groups of the solid phase are still free after the immobilization of the compound and are available for further reactions. The remaining 95% of the amino groups of the solid phase, however, are occupied with the immobilized compound via amide bonds.
  • the solid phase can have a favorable effect on the stability of the compound immobilized thereon (cf., for example, D. Seebach et al., Helv. Chim. Acta 2002, 85, 913-926).
  • the present invention relates to a method for carrying out a chemical reaction of a compound B with the participation of a compound A-F, the compound A-F being adsorbed on a fluorinated carrier material FT via fluorine-fluorine interactions as an adduct.
  • the adduct is suitable, for example, for use in combinatorial solid-phase synthesis.
  • the use of compounds which are adsorbed onto fluorinated carrier materials via fluorine-fluorine interactions is unknown in the prior art for carrying out chemical reactions.
  • fluorinated compounds have unique properties in which they differ from the non-fluorinated compounds: fluorine atoms have a particular affinity for one another, but on the other hand are neither pronouncedly lipophilic nor hydrophilic. Compounds which have several fluorine atoms are therefore usually not particularly readily soluble in water or in organic solvents. These properties are used in the so-called "fluorous biphase catalysis (FBC)". This method is based on the limited (temperature-dependent) miscibility of certain organic non-fluorinated solvents with perfluorinated solvents.
  • FBC fluorous biphase catalysis
  • the perfluorinated and the non-fluorinated solvent are immiscible at lower temperatures and form a two-phase system. However, if this two-phase system is heated, the mutual solubility increases, which allows the reaction to take place.
  • the concept of fluorine two-phase catalysis is based on the modification of a compound involved in a chemical reaction (catalyst, reactant or reagent) with a fluorinated side chain.
  • the other compounds involved in the reaction contain little or no fluorine atoms if possible.
  • the fluorinated side chain of the compound gives it the property that the compound with the fluorinated side chain essentially dissolves in the perfluorinated solvent, but not (or at least significantly worse) in the non-fluorinated solvent. If the two solvents are in the form of two phases at a lower temperature, the connection with the fluorinated side chain is therefore predominantly in the phase which is formed by the perfluorinated solvent.
  • the phase boundary can disappear and a homogeneous solution is available.
  • the compound with the fluorinated side chain can now undergo a chemical reaction (or, depending on the type of compound, catalyze the reaction of another compound). If the solvent mixture is cooled again after the chemical reaction has ended, two phases are formed again and the compound with the fluorinated side chain diffuses into the phase of the perfluorinated solvent as the only one of the substances involved in the reaction.
  • a separation can now be carried out in a simple manner, for example by separating the two solvent phases in a separating funnel.
  • fluorine two-phase catalysis the chemical reaction is carried out in a solvent system that dissolves both fluorinated and non-fluorinated compounds. These compounds can now react with each other in a homogeneous solution. After the reaction, the phase separation is not induced by cooling, as in the variant described above, but by the addition of a co-solvent.
  • Various fluorinated molecules are known in the prior art which are suitable as side chains for the modification of compounds which are used in fluorine two-phase catalysis.
  • Particularly suitable solvents and solvent mixtures for use in fluorine two-phase catalysis have also been developed. The concept is suitable for various chemical reactions in homogeneous solution and the subsequent separation via a liquid-liquid two-phase system.
  • fluorine atoms are also used in chromatography. If, for example, the stationary phase of a chromatography column with fluorinated side chains on its surface is modified, molecules which in turn also contain fluorinated side chains are retarded in contrast to non-fluorinated molecules. The choice of different fluorinated side chains for different molecules enables chromatographic separation on the stationary phase.
  • Suitable silica gel solid phases already fluorinated on their surface are in the Available commercially. It is also referred to as "fluorinated reversed phase silica gel (FRPSG)".
  • fluorine two-phase catalysis is only suitable to a limited extent, since most synthesis robots are aimed at solid-phase synthesis and thus the separation of the compounds involved in the chemical reaction via a solid and a liquid phase with the aid of a diaphragm.
  • the separation of a solvent phase from another solvent phase requires an incomparably higher expenditure on equipment, since either a precisely calculated volume, which corresponds to the phase of the one solvent in the two-phase system, must be removed from the reaction compartment, or the phase boundary must be detected using a suitable system (e.g. optical meniscus detection, conductivity measurement, etc.) so that the two liquid phases can be separated quantitatively.
  • a suitable system e.g. optical meniscus detection, conductivity measurement, etc.
  • the present invention relates to a method for carrying out a chemical reaction of a compound B with the participation of a compound AF, the compound AF being adsorbed on a carrier material FT via fluorine-fluorine interactions to form an adduct (AF) :( FT), characterized in that that the adduct (AF) :( FT) is suspended in a suitable solvent which contains the compound B, whereby the compound B reacts with the participation of the adsorbed compound AF to the reaction product B '.
  • the present invention also relates to the use of a compound A-F, which is adsorbed on a fluorinated carrier material FT via fluorine-fluorine interactions, for carrying out a chemical reaction.
  • the compound A-F contains a radical A and a fluorinated side chain F.
  • the method according to the invention comprises the step of bringing the compound AF into contact with the fluorinated carrier material FT, as a result of which the compound AF is adsorbed on the fluorinated carrier material FT.
  • the fluorinated surface on which the adsorption of the compound A-F takes place is provided by a fluorinated carrier material FT.
  • adsorbate the compound A-F can therefore be referred to as "adsorbate", and the fluorinated carrier material FT as "adsorbent”.
  • Adsorbate and adsorbent give the adduct (A-F) :( FT). The fluorine-fluorine interaction is indicated in this notation by the colon between the two letters F.
  • the process according to the invention has the advantage that the use of fluorinated and perfluorinated solvents can be dispensed with.
  • the compounds AF can be adsorbed in high yields on the fluorinated carrier materials FT without a covalent bond being formed in the process. Capp / ng steps of any unreacted functional groups on the surface of the fluorinated carrier material FT are therefore omitted.
  • the chemical nature of the fluorine-fluorine interaction which is responsible for the adsorption of the compounds AF on the fluorinated carrier material FT, is inert to most chemical reactions (while the conventionally used covalent linkers are not chemically inert), so that after the termination of the chemical reactions involving the adsorbed compounds AF do not detach them from their adducts (AF) :( FT) and thus detach them from the fluorinated carrier material FT. This is particularly important for the synthesis of substances which are to be tested in biological Screen / '/ IG method for activity. If the adsorbed compound AF is, for example, a catalyst which contains transition metals, as little as possible of the transition metal should get into the reaction product B ', since this transition metal could interfere with enzymatic tests.
  • the process according to the invention combines most of the advantages known from solid-phase synthesis with covalently bound compounds.
  • the yields of the chemical reactions under the heterogeneous reaction conditions on the solid phase are comparable to the yields of the analogous reactions, but carried out in a homogeneous solution.
  • a multiplicity of solid (optionally modified) support materials are suitable as the fluorinated support material FT. If it is a solid carrier material which initially does not yet have any fluorine atoms on the surface, these solid carrier materials are modified by the introduction of fluorine atoms. It is only through this modification that the non-fluorinated carrier materials become fluorinated carrier materials FT according to the invention.
  • suitable carrier materials are silica gels, aluminoxides, aluminosilicates, zeolites, glasses, but also polysaccharides, such as e.g. modified cellulose, and plastics such as polystyrene, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylonitrile, polyesters, polyamides, polyethers, polyether ether ketones or their mixtures and copolymers.
  • polysaccharides such as e.g. modified cellulose
  • plastics such as polystyrene, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylonitrile, polyesters, polyamides, polyethers, polyether ether ketones or their mixtures and copolymers.
  • plastics such as polystyrene, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylonitrile, polyesters, polyamides, polyethers, polyether ether ketones or their mixtures and cop
  • these carrier materials can be used as fluorinated carrier materials FT if they have at least on their surface fluorine atoms which are covalently bonded to the carrier material.
  • These fluorine atoms can have been present since the production of the fluorinated carrier materials or can only be introduced afterwards.
  • the carrier material FT is already fluorinated.
  • silica gel If, on the other hand, ordinary, non-fluorinated silica gel is to be used as the carrier material, then this must first be fluorinated in a suitable manner on the surface so that it can be used as a fluorinated carrier material FT in the sense of the invention.
  • a Modification of silica gel with fluorine atoms on the surface can be done, for example, by reacting the silica gel with molecules of the type
  • the modification of silica gel with fluorine atoms on the surface can also be carried out by reacting the silica gel with molecules of the type
  • a and b have the same meaning as above and X is halogen, preferably chlorine or bromine.
  • the fluorinated carrier material FT is covalently linked on its surface to substituents of the general formula I:
  • the present invention relates to silica gels which are modified on their surface with certain (per) fluorinated side chains, so that these fluorinated carrier materials (FRPSG) are suitable for use in the process according to the invention for carrying out chemical reactions.
  • FRPSG fluorinated carrier materials
  • silica gels which contain the following structural elements on their surface are particularly suitable: wherein e, g and h are each independently 0 to 8, preferably 0 to 4, in particular 2 and f and i are each independently 1 to 30, preferably 3 to 12, in particular 6 or 8.
  • Fluorinated carrier materials FT which are particularly preferred according to the invention are silica gels (silica gels) in which e, g and h are each 2 and f and i are each 6:
  • the fluorinated carrier material FT can be present in various spatial structures, for example in the form of beads, powders, grains, foils, surfaces of vessels, etc. Tentagele and dendrimers are also suitable.
  • Particles of FRPSG which preferably have an average diameter of 30 to 300 ⁇ m, are preferred according to the invention.
  • the chemical nature of the compound AF is such that it remains adsorbed with sufficient binding strength on the surface of the fluorinated solid phase under the reaction conditions of the chemical reaction to be carried out.
  • the adsorption on surfaces can be done via adsorption isotherms according to Langmuir or Describe Brunauer Emmet and Teller (BET). Since the adsorption generally decreases with increasing temperature, increased demands are placed on the compound AF for chemical reactions which are carried out at elevated temperatures, so that the adsorbed molecules are not detached from the fluorinated carrier material FT at these temperatures. Other external factors can also influence the adsorption.
  • the compound A-F contains, for example, palladium
  • this can be used in the eluate e.g. can be quantified by ICP-MS.
  • ICP-MS is a very sensitive method for quantifying metals (see Jose A.C. Broekaert; Analytical Atomic Spectometry with Flames and Plasmas; Wiley-VCH, Weinheim 2002, pp. 254-275).
  • the compound AF contains a radical A and a fluorinated side chain F.
  • the compound AF can be a contain one or more, preferably 1, 2 or 3 fluorinated side chains F.
  • the use of a fluorinated side chain F has the advantage that the same fluorinated side chain can often be used for different chemical reactions which are to be carried out with adsorbed compounds, only the remainder A has to be adapted to the conditions of the chemical reaction.
  • Fluorinated side chain F in the sense of the invention is any molecular structure which has at least 5 fluorine atoms.
  • a fluorinated side chain F which is derived from a linear, branched or cyclic aliphatic hydrocarbon in which more than 20%, more preferably more than 50% and in particular more than 80% of the hydrogen atoms are replaced by fluorine atoms.
  • the fluorinated side chain F preferably contains at least 5 carbon atoms, more preferably at least 12, more preferably at least 17, in particular at least 25 carbon atoms.
  • the fluorinated side chain F preferably contains at least 11 fluorine atoms, more preferably at least 25, more preferably at least 35, in particular at least 45 fluorine atoms.
  • the fluorinated side chain F can be replaced by 1 to 24, preferably 1 to 5 heteroatoms, e.g. N, O, S and P. Because of the electron-withdrawing effect of the fluorine atoms, it can be advantageous if there are 1 to 5 methylene groups between the fluorine-substituted carbon atoms of the side chain F and the radical A of the compound A-F.
  • the fluorinated side chain F comprises a structure of the general formula II:
  • the structure of the general formula II is bonded to the radical A of the compound AF via a phenyl ring.
  • the fluorinated side chain F can contain the structure of the general formula II once, but it is also possible that several structures of the general formula II are contained in the fluorinated side chain F. Three structures of the general formula II are preferably contained in the fluorinated side chain F. It is preferred if the compound A-F contains a branched fluorinated side chain F, in which each molecular chain branching off from the branching comprises a structure of the general formula II.
  • the fluorinated side chain F can be covalently bound to the radical A in the compound A-F.
  • ionic bonds or coordinative bonds are also possible.
  • the fluorinated side chain F contains a structure of the general formula III:
  • the method according to the invention can in principle be carried out with any solvents.
  • solvents for example, not only conventional organic solvents such as diethyl ether, THF, acetone, DMF, DMSO, methanol, ethanol, pentane, pyridine and acetonitrile are suitable, but also water and solvent mixtures.
  • the compound A-F which is adsorbed on the fluorinated carrier material FT, can be involved in the chemical reaction of the compound B to the reaction product B 'in various ways.
  • the involvement of compound A-F can either
  • the catalyst A-F is by definition not used due to its catalyst properties in the course of the chemical reaction. It is therefore not absolutely necessary for catalyst A-F to be used in stoichiometric amounts with respect to compound B. In this case, the catalyst A-F is preferably used in a molar deficit relative to the compound B.
  • compound B can be reacted with a compound C in the chemical reaction so that compound BC is formed by linking compound B to compound C with catalysis by the adsorbed catalyst A-F:
  • the support material FT with the catalyst AF immobilized thereon by adsorption can again be used as the catalyst in the form of the adduct (AF) :( FT) a chemical reaction.
  • the adduct (A-F) :( FT) is first worked up (e.g. by rinsing the carrier material with a suitable solvent) before it is reused.
  • catalytic hydrogenations e.g. hydrogenation under catalysis by chelated rhodium
  • catalyzed oxidations e.g. S? A / ess epoxidations or epoxidations with Salen complexes according to Jacobsen
  • transition metal-catalyzed CC linkages Sr / V / e -Coupling, St / to / ⁇ coupling, So / 7o ⁇ ; as / 7 / ra coupling
  • catalyzed metathesis reactions reactions with catalysis by immobilized enzymes, etc.
  • the present invention relates to a process for carrying out a catalyzed chemical reaction of a compound B under catalysis by a catalyst AF, the catalyst AF containing a radical A and a fluorinated side chain F, and the catalyst AF on a fluorinated support material FT as Adduct (AF) :( FT) is adsorbed, the adduct (AF) .- (FT) being suspended in a suitable solvent containing compound B, whereby compound B is catalysed by the adsorbed catalyst AF to form the reaction product B 'reacts.
  • the catalyst AF is a metal complex in which the metal is preferably a transition metal, preferably an element of atomic numbers 40-48, in particular palladium.
  • the catalyst AF is one of the three compounds 1a-c, which are preferably adsorbed on FRPSG:
  • catalysts are suitable, for example, for the catalysis of the Suzu / c / ' reaction or the Sonogas / i / ra reaction.
  • the catalysts 1a-c can also be referred to as "pre-catalysts".
  • the term “catalyst” also includes “pre-catalysts”.
  • the reaction partner A-F is reacted with the compound B in the chemical reaction and thus consumed.
  • a stoichiometric amount of the reactant A-F based on the compound B is required.
  • the compound B is preferably added in molar excess in order to shift the yield of the reaction of the reactant A-F to the highest possible values.
  • the chemical reaction of the reactant A-F and the compound B can give rise to a new compound AB-F.
  • This compound AB-F formed by the reaction preferably contains a radical AB, which has arisen from the linkage of the radical A of the reactant A-F with the compound B, and a fluorinated side chain F, which originates from the reactant A-F. Because of the adsorption of the fluorinated side chain F on the fluorinated carrier material, the compound AB-F formed by the reaction is also adsorbed on the solid phase and thus immobilized.
  • the chemical reaction results from the adduct (A-F) :( FT) into the adduct (AB-F) :( FT):
  • the compound AB-F corresponds to the reaction product B '
  • Examples of this type of reaction are basically all chemical reactions in which a covalent bond is formed between two reaction partners (addition reactions, condensation reactions). It is preferably a condensation reaction in which water or hydrogen chloride are eliminated.
  • FIG. 1 of the description in which three reactions of this type are shown: formation of the chloroformate 4, reaction with the anthranilic acid derivative to form the carbamates 5a-d and formation of the amides 6a-p by adding the primary amines.
  • reaction of the reactant AF and the compound B can also deliberately split off the fluorinated side chain F from the reaction partner AF, so that the reaction between the reactant AF and the compound B produces a compound AB and the side chain F in a separated form remains adsorbed on the fluorinated carrier material.
  • the compounds AB and F correspond to the reaction product B ", the compound F remaining adsorbed and immobilized on the fluorinated carrier material FT.
  • the compound AB-F or F adsorbed on the fluorinated carrier material FT after the chemical reaction has ended can be separated off from the solvent (for example by filtration).
  • the adsorbed compound AB-F can also be cleaved from the fluorinated carrier material FT by an intramolecular cyclization with cleavage of the fluorinated side chain F.
  • reaction sequence depicted in FIG. 1 can be represented schematically as follows: BCD NEt 3
  • compound B is the diphosgene and compound BA-F is chloroformate 4; Compound C the anthranilic acid derivative and Compound CBA-F the carbamate 5a-d; Compound D the primary amine and Compound DCBA-F the amide 6a-p; Finally, compound DCB is the quinazoline-2,4-dione 7a-p, which is generated by the intramolecular cyclization induced with NEt 3 .
  • the present invention relates to a method for carrying out a chemical reaction between a compound B and a reaction partner AF, the reaction partner AF containing a radical A and a fluorinated side chain F, and the reaction partner AF on a fluorinated carrier material FT as an adduct ( AF) :( FT) is adsorbed, the adduct (AF) :( FT) being suspended in a suitable solvent which contains the compound B, as a result of which the compound B reacts with the adsorbed reaction partner AF to give the reaction product B '.
  • the reaction of the reactant AF and the compound B selectively cleaves the bond of the fluorinated side chain F to the radical A, so that the reaction between the reactant AF and the compound B means that it is no longer adsorbed on the fluorinated carrier material FT Connection AB is formed and the side chain F remains adsorbed on the fluorinated carrier material in a separated form.
  • the adsorbed reaction partner AF is first reacted sequentially with various compounds, the intermediates which are initially also immobilized on the fluorinated carrier material FT via the fluorinated side chain F of the reaction partner AF.
  • the covalent bond between the fluorinated side chain F and the sequentially formed reaction product is selectively split, whereby the sequentially formed reaction product is detached from the fluorinated carrier material FT.
  • This sequential process can preferably be used for the synthesis of heterocyclic compounds.
  • the compound A-F contains a structure of the general formula IV
  • the compound A-F is a reagent A-F, which is consumed in the reaction of the compound B to the reaction product B ', the chemical reaction of the compound B with the reagent A-F results in a new compound B *.
  • the reagent A-F is converted into the used form by the chemical reaction, shown below as reagent A * -F.
  • reaction product B corresponds to the chemical reaction of the compound B * and the used reagent A * -F. Since the compound B * is in the solvent, the spent reagent A * -F in the form of the adduct (A * -F) :( FT) on the fluorinated carrier material FT, both reaction products can be separated from one another by decanting or filtration.
  • the compound AF is either a catalyst AF or a reaction partner AF.
  • One aspect of the invention relates to a fluorinated carrier material FT, which structural elements of one of the two following formulas
  • Such a fluorinated carrier material FT or such an adduct (A-F): FT) can be used particularly advantageously in the process according to the invention.
  • FIG. 1 shows a reaction sequence for the synthesis of quinazoline-2,4-diones.
  • This reaction sequence is a reaction sequence according to the invention in which the intermediates are adsorbed on fluorinated carrier material (FRPSG).
  • FRPSG fluorinated carrier material
  • the three palladium complexes 1a-c were synthesized as compounds A-F in accordance with a known synthesis instruction (cf. S. Schneider et al., Angew. Chem. 2000, 1 12, 4293- 4296).
  • FRPSG from Example 1 was added to a solution of the respective complex 1 a-c in diethyl ether or in a diethyl ether-hexafluorobenzene mixture. The solvent was evaporated in vacuo. The immobilized catalysts were in the form of an air-stable, free-flowing powder.
  • a 50 ml Schlenk vessel was loaded with 100 mg pre-catalyst and filled with FRPSG and evacuated three times and filled with argon.
  • Stock solutions of aryl halide 0.3 M in dimethoxyethane (DME), 1.0 ml, 0.3 mmol
  • boronic acid (0.33 M in DME [methanol was used instead with 4-methoxyphenylboronic acid]
  • 1.0 ml, 0.33 mmol 1.0 ml, 0.33 mmol
  • Na 2 CO 3 (2M in water, 1.0 ml, 2.0 mmol
  • the FRPSG was washed with DME (twice with 2 ml each), water (twice with 2 ml each) and DME (twice with 2 ml each).
  • the combined liquid phases were diluted with water (40 ml) and brine (20 ml) and three times with 20 ml of tert. Butyl methyl ether extracted.
  • the combined extracts were concentrated in vacuo, the residue was taken up in 2 ml of diethyl ether, added to neutral aluminum oxide (3 ml, activity 2-3) and eluted with diethyl ether (approx. 14 ml). Evaporation of the solvent provided the coupling product.
  • the immobilized catalyst was used as such for further experiments.
  • the catalyst 1 a was tested for its catalytic activity in the Sonogas ⁇ / ra coupling of phenylacetylene and para-nitrobromobenzene:
  • the method according to the invention was used to synthesize a library of quinazoline-2,4-diones.
  • benzyl alcohol was linked to a fluorinated side chain (see DP Curran et al., J. Org. Chem. 1997, 62, 6714; S. Kainz et al., Synthesis 1998, 1425) and to FRPSG through fluorine-fluorine interactions adsorbed.
  • FIG. 1 A general overview of the synthesis is shown in FIG. 1.
  • the chloroformate 4 was divided into 4 equal parts and each part was reacted with a different anthranilic acid derivative in the presence of the Hunig base to form the carbamates 5a-d.
  • Each of these carbamates 5a-d was in turn also divided into 4 equal parts and each of these parts was reacted with one of 4 primary amines with TBTU as the coupling reagent, whereby the amides 6a-p were formed (see R. Knorr et al., Tetrahedron Lett. 1989, 30, 1927).
  • the Cyclization of the amides was induced with NEt 3 and led to the desired end compounds 7a-p.

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Abstract

L'invention concerne un procédé de réalisation d'une réaction chimique d'un composé (B) en présence d'un composé (A-F), ce composé (A-F) étant absorbé sur un support fluoré (FT) par interactions fluor-fluor jusqu'à la formation d'un adduit (A-F):(FT). Ledit procédé se caractérise en ce que cet adduit (A-F):(FT) est tenu en suspension dans un solvant approprié contenant ledit composé (B), lequel composé (B) réagit alors, en présence du composé absorbé (A-F), de façon à former le produit de la réaction (B').
PCT/EP2003/007592 2002-08-01 2003-07-14 Procede de realisation de reactions chimiques en presence de composes absorbes sur des supports fluores par interactions fluor-fluor Ceased WO2004013068A1 (fr)

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DE2002135225 DE10235225B3 (de) 2002-08-01 2002-08-01 Verfahren zur Durchführung chemischer Reaktionen unter Beteiligung von an fluorierten Trägermaterialien über Fluor-Fluor-Wechselwirkungen adsorbierten Verbindungen, fluoriertes Trägermaterial sowie die Verwendung des Trägermaterials
DE10235225.9 2002-08-01

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Cited By (6)

* Cited by examiner, † Cited by third party
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FR2900928A1 (fr) * 2006-05-12 2007-11-16 Saint Gobain Compose hydrophobe, couche et vitrage obtenus a partir de ce compose
WO2015169999A1 (fr) 2014-05-09 2015-11-12 Orion Corporation Dérivés de quinazolinedione pharmacologiquement actifs
JP2018515559A (ja) * 2015-05-20 2018-06-14 グアンドン ジョンシェン ファーマシューティカル カンパニー リミテッド ヒドロキシプリン類化合物及びその応用
TWI690526B (zh) * 2015-05-20 2020-04-11 大陸商廣東衆生睿創生物科技有限公司 羥基嘌呤類化合物及其應用
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Cited By (11)

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Publication number Priority date Publication date Assignee Title
WO2006094194A3 (fr) * 2005-03-03 2007-03-01 Univ Iowa State Res Found Inc Microreseaux a base fluoritique
FR2900928A1 (fr) * 2006-05-12 2007-11-16 Saint Gobain Compose hydrophobe, couche et vitrage obtenus a partir de ce compose
WO2007135315A1 (fr) * 2006-05-12 2007-11-29 Saint-Gobain Glass France Compose hydrophobe, couche et vitrage obtenus a partir de ce compose
WO2015169999A1 (fr) 2014-05-09 2015-11-12 Orion Corporation Dérivés de quinazolinedione pharmacologiquement actifs
CN106414430A (zh) * 2014-05-09 2017-02-15 奥赖恩公司 药理学活性喹唑啉二酮衍生物
US20170137387A1 (en) * 2014-05-09 2017-05-18 Orion Corporation Pharmacologically active quinazolinedione derivatives
JP2018515559A (ja) * 2015-05-20 2018-06-14 グアンドン ジョンシェン ファーマシューティカル カンパニー リミテッド ヒドロキシプリン類化合物及びその応用
EP3299371A4 (fr) * 2015-05-20 2018-06-20 Guangdong Zhongsheng Pharmaceutical Co., Ltd Composés d'hydroxyle et purine et leur utilisation
US10278973B2 (en) 2015-05-20 2019-05-07 Guangdong Raynovent Biotech Co., Ltd. Hydroxyl purine compounds and use thereof
TWI690526B (zh) * 2015-05-20 2020-04-11 大陸商廣東衆生睿創生物科技有限公司 羥基嘌呤類化合物及其應用
US10618898B2 (en) 2015-05-20 2020-04-14 Guangdong Raynovent Biotech Co., Ltd. Hydroxyl purine compounds and use thereof

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