Classifications

• • 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
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2/00—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms
  • C07C2/86—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms by condensation between a hydrocarbon and a non-hydrocarbon
  • C07C2/861—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms by condensation between a hydrocarbon and a non-hydrocarbon the non-hydrocarbon contains only halogen as hetero-atoms
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00781—Aspects relating to microreactors
  • B01J2219/00819—Materials of construction
  • B01J2219/00835—Comprising catalytically active material
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00781—Aspects relating to microreactors
  • B01J2219/00851—Additional features
  • B01J2219/00858—Aspects relating to the size of the reactor
  • B01J2219/0086—Dimensions of the flow channels
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00781—Aspects relating to microreactors
  • B01J2219/00851—Additional features
  • B01J2219/00858—Aspects relating to the size of the reactor
  • B01J2219/00862—Dimensions of the reaction cavity itself
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00781—Aspects relating to microreactors
  • B01J2219/00873—Heat exchange
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00781—Aspects relating to microreactors
  • B01J2219/00889—Mixing
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00781—Aspects relating to microreactors
  • B01J2219/00905—Separation
  • B01J2219/00916—Separation by chromatography
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2527/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
  • C07C2527/06—Halogens; Compounds thereof
  • C07C2527/122—Compounds comprising a halogen and copper
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2527/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
  • C07C2527/06—Halogens; Compounds thereof
  • C07C2527/128—Compounds comprising a halogen and an iron group metal or a platinum group metal
  • C07C2527/13—Platinum group metals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2531/00—Catalysts comprising hydrides, coordination complexes or organic compounds
  • C07C2531/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
  • C07C2531/04—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing carboxylic acids or their salts
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2531/00—Catalysts comprising hydrides, coordination complexes or organic compounds
  • C07C2531/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
  • C07C2531/22—Organic complexes

Definitions

• the present invention relates to a method for coupling organic compounds.
• the object of the present invention is therefore to provide a method for coupling organic compounds which avoids the disadvantages mentioned above.
• This process should in particular be able to be carried out in a simple, reproducible manner with increased safety for humans and the environment and with good yields, and the reaction conditions should be very easy to control.
• This object is surprisingly achieved by the process according to the invention for coupling organic compounds, in which at least one organic compound which has at least one leaving group is in liquid or dissolved form with at least one organic compound which has at least one vinyl or acetylenic hydrogen atom liquid or dissolved form in the presence of at least one catalyst in liquid or dissolved form is mixed in at least one microreactor, reacts during a residence time and the coupling product thus obtained is optionally isolated from the reaction mixture.
• At least one organic compound which has at least one leaving group is reacted with at least one organic compound which has at least one vinyl or acetylenic hydrogen atom, or the organic compound used simultaneously contains at least one leaving group and at least one vinyl or acetylenic hydrogen atom. It follows that both inter- and intramolecular coupling reactions are included in the sense of the present invention. It is also possible to use a mixture of two or more organic compounds with at least one leaving group and / or a mixture of two or more organic compounds with at least one vinyl or acetylenic
• hydrogen atom Preferably, only one organic compound with one leaving group and only one organic compound each with a vinyl or acetylenic hydrogen atom are used in the process according to the invention. If an organic compound has two or more leaving groups and / or two or more contains vinyl or acetylenic hydrogen atoms, these can be the same or different.
• a leaving group in the sense of the present invention is any group whose bond to a carbon atom of the organic compound is split in the course of the coupling reaction and which then emerges from this organic compound.
• a microreactor in the sense of the invention is a reactor with a volume ⁇ 1000 ⁇ l in which the liquids and / or solutions are intimately mixed at least once.
• the volume of the microreactor is preferably ⁇ 100 ⁇ l, particularly preferably ⁇ 50 ⁇ l.
• the microreactor is preferably produced from thin, interconnected silicon structures.
• the microreactor is preferably a miniaturized flow reactor, particularly preferably a static micromixer.
• the microreactor is very particularly preferably a static micromixer, as described in the patent application with the international publication number WO
• Such a microreactor has small channels in which liquids and / or chemical compounds present in solutions are mixed with one another by the kinetic energy of the flowing liquids and / or solutions.
• the channels of the microreactor preferably have a diameter of 10 to 1000 ⁇ m, particularly preferably 20 to 800 ⁇ m and very particularly preferably 30 to 400 ⁇ m.
• the liquids and / or solutions are preferably pumped into the microreactor in such a way that they flow through them at a flow rate of 0.01 ⁇ l / min to 100 ml / min, particularly preferably 1 ⁇ l / min to 1 ml / min.
• the microreactor can preferably be tempered.
• the microreactor is preferably connected via an outlet to at least one retention zone, preferably a capillary, particularly preferably a temperature-controlled capillary.
• the liquids and / or solutions are passed into this residence zone or capillary after they have been mixed in the microreactor in order to extend their residence time.
• the residence time in the sense of the invention is the time between the mixing of the starting materials and the working up of the resulting ones. Reaction solution for analysis or isolation of the desired product (s).
• the required dwell time in the process according to the invention depends on various parameters, such as the temperature or the reactivity of the starting materials. It is possible for the person skilled in the art to adapt the dwell time to these parameters and thus to achieve an optimal course of the reaction.
• the residence time of the reaction solution in the system used comprising at least one microreactor and, if appropriate, a residence zone, can be selected by selecting the flow rate of the one used
• Liquids and / or solutions can be set.
• the reaction mixture is likewise preferably passed through two or more microreactors connected in series. This ensures that the residence time is increased even at an increased flow rate and used components of the coupling reaction are implemented so that an optimal product yield of the desired coupling product (s) is achieved.
• reaction mixture is passed through two or more microreactors arranged in parallel in order to increase the throughput.
• the number and the arrangement of the channels in one or more microreactor (s) are varied in such a way that the residence time is increased, so that here too, with an increased flow rate, an optimal yield of the desired coupling product (s) is achieved.
• the residence time of the reaction solution in the microreactor is preferably ⁇ 15 hours, preferably ⁇ 3 hours, particularly preferably ⁇ 1 hour.
• the inventive method can be carried out in a very wide temperature range, which is essentially by the
• the process according to the invention is preferably carried out at a temperature of from -100 to +250 ° C., preferably from -78 to + 150 ° C., particularly preferably from 0 to +40 ° C.
• the inventive method for coupling organic compounds can usually be carried out without using a protective gas atmosphere. But it is also possible to use the invention Carry out the process under a protective gas atmosphere. If the process according to the invention is carried out under a protective gas atmosphere, it can preferably be carried out under a nitrogen and / or argon atmosphere.
• the process according to the invention can be carried out either continuously or batchwise. It is preferably carried out continuously.
• the course of the reaction of the coupling reaction in the process according to the invention can be followed and optionally regulated using various analytical methods known to the person skilled in the art.
• the course of the reaction is preferably followed by chromatography, particularly preferably by high-pressure liquid chromatography, and, if necessary, regulated.
• the control of the reaction is significantly improved compared to known methods.
• the coupling product (s) formed is / are optionally isolated.
• the coupling product (s) formed is / are preferably isolated from the reaction mixture by extraction.
• organic compounds which have at least one leaving group all organic compounds with at least one leaving group known to the person skilled in the art as substrates of coupling reactions can be used in the process according to the invention.
• An aryl halide particularly preferably an aryl bromide or an aryl iodide, very particularly preferably an aryl iodide, a heteroaryl halide, particularly preferably a heteroaryl bromide or a heteroaryl iodide, very particularly preferably a heteroaryl iodide, a vinyl halide can be used as the organic compound with at least one leaving group in the process according to the invention.
• a vinyl bromide or a vinyl iodide very particularly preferably a vinyl iodide, or or a mixture of at least two of the abovementioned compounds.
• a compound having at least one leaving group is an organic fluoroalkyl sulfonate, preferably an arylfluoroalkyl sulfonate, a heteroarylfluoroalkyl sulfonate or a vinyl fluoroalkyl sulfonate or an organic perfluoroalkyl sulfonate, preferably an aryl perfluoroalkyl sulfonate, a heteroaryonate or a mixture of at least one or two perfluoroalkyl compounds of at least one or of two or more be used.
• An aryl trifluoromethanesulfonate, a heteroaryl trifluoromethanesulfonate, a vinyl trifluoromethanesulfonate or a mixture of at least two of the abovementioned compounds can particularly preferably be used as the perfluoroalkyl sulfonate in the process according to the invention.
• an aryl nonafluorobutane sulfonate, a heteroaryl nonafluorobutane sulfonate can be used as the perfluoroalkyl sulfonate Vinyl nonafluorobutane sulfonate or a mixture of at least two of the aforementioned compounds can be used.
• Aryl halides, aryl fluoroalkyl sulfonates or aryl perfluoroalkyl sulfonates within the meaning of the present invention also include those aromatic organic compounds in which the halogen, fluoroalkyl sulfonate or perfluoroalkyl sulfonate residue does not directly on the aromatic ring of the aryl residue, but e.g. attached to it via an alkylene group, e.g. with benzyl halide, benzyl trifluoromethanesulfonate or with benzyl nonafluorobutanesulfonate.
• Heteroaryl halides, heteroarylfluoroalkylsulfonates or heteroarylperfluoroalkylsulfonates for the purposes of the present invention also include those heteroaromatic organic compounds in which the halogen, fluoroalkylsulfonate or perfluoroalkylsulfonate radical is not directly attached to the heteroaromatic ring of the heteroaryl radical, e.g. is bound to this via an alkylene group.
• These heteroaryl radicals preferably have at least one oxygen and / or nitrogen and / or sulfur atom as the hetero atom.
• organic compound with at least one vinyl or acetylenic hydrogen atom all organic compounds with at least one vinyl or acetylenic hydrogen atom known to the person skilled in the art which are suitable as substrates for coupling reactions can be used in the process according to the invention.
• at least one unbranched, branched, cyclic, aromatic or heteroaromatic alkene or alkyne can be used in the process according to the invention, particularly preferably at least one un branched, branched, cyclic, aromatic or heteroaromatic alkene can be used.
• aromatic compounds with at least one vinyl or acetylenic hydrogen atom also include those organic compounds and / or their derivatives which have a monocyclic and / or polycyclic homoaromatic backbone or a corresponding partial structure, e.g. in the form of substituents and a vinyl or acetylenic hydrogen atom.
• heteroaromatic compounds having at least one vinyl or acetylenic hydrogen atom also include those organic compounds and / or their derivatives which have at least one monocyclic and / or polycyclic heteroaromatic backbone or a corresponding partial structure, e.g. in the form of substituents and at least one vinyl or acetylenic hydrogen atom.
• These heteroaromatic basic structures or partial structures particularly preferably comprise at least one oxygen and / or nitrogen and / or sulfur atom.
• catalysts Compounds suitable catalysts or a mixture of at least two of these catalysts can be used. Preferably only one catalyst is used at a time. Catalysts in
• catalysts formed in situ i.e.
• Catalysts that are formed immediately before or during the coupling reaction.
• at least one compound which contains palladium in oxidation state 0 is used as the catalyst.
• Tris (dibenzylidene acetone) bispalladium can preferably be used as the compound which contains palladium in oxidation state 0.
• Palladium (II) chloride, palladium (II) acetate, bis (triphenylphosphine) palladium (II) dichloride or a mixture of at least two of these compounds can preferably be used as the palladium compound containing palladium in the oxidation stage (II) in the process according to the invention.
• An organic amine particularly preferably triethylamine, diethylamine or tri-n-butylamine, a nitrogen-containing, optionally aromatic heterocycle, particularly preferably pyridine or N-methylpyrrolidone or a mixture of at least two of the abovementioned compounds can preferably be used as the base.
• inorganic salts known to the person skilled in the art and suitable for coupling reactions of organic compounds can be used as the inorganic salt in the process according to the invention.
• Copper (I) iodide is preferably used as the inorganic salt.
• the organic compound having at least one leaving group and the organic compound having at least one vinyl or acetylenic hydrogen atom are preferably used in an equimolar ratio in the process according to the invention.
• the organic compound having at least one vinyl or acetylenic hydrogen atom is in a 1.05 to 2-fold molar excess, particularly preferably in a 1.1-fold to 1.6-fold, very particularly preferably in a 1.2-fold up to 1.5 times excess, based on the organic compound with at least one leaving group.
• the selectivity of the reaction itself depends on a number of other parameters, e.g. the concentration of the reagents used, e.g. the temperature, the type of leaving group, the type of catalyst or the residence time. It is possible for the person skilled in the art to adapt the various parameters to the respective reaction in such a way that the desired coupling product (s) is (are) obtained.
• the organic compounds used and the catalyst are either themselves liquid or are in dissolved form. If one of the reaction components used or the catalyst itself is liquid, this (r) can optionally also be used as a solvent for the other reaction components or the catalyst. If these are not already in liquid form themselves, they must be dissolved in a suitable solvent before the process according to the invention is carried out.
• Halogenated solvents are preferred as solvents, particularly preferably dichloromethane, chloroform, 1,2-dichloroethane or 1,1,2,2- Tetrachloroethane, straight-chain, branched or cyclic paraffins, particularly preferably pentane, hexane, heptane, octane, cyclopentane, cyclohexane, cycloheptane or cyclooctane or straight-chain, branched or cyclic ethers, particularly preferably diethyl ether, methyl tert-butyl ether, tetrahydrofuran or dioxane Solvents, particularly preferably toluene, xylenes, ligroin or phenyl ether, N-containing heterocyclic solvents, particularly preferably pyridine or N-methylpyrrolidone, or a mixture of at least two of the abovementioned solvents.
• solvents particularly preferably
• the risk to humans and the environment from escaping chemicals is considerably reduced and thus leads to increased safety when handling hazardous substances.
• the coupling of organic compounds by the process according to the invention also enables better control of the reaction conditions, e.g. Reaction time and temperature than is possible in the conventional processes.
• the risk of explosions in very strongly exothermic coupling reactions is significantly reduced in the process according to the invention.
• the temperature can be individually selected and kept constant in each volume element of the system.
• the course of the reaction of the coupling reactions can be regulated very quickly and precisely in the process according to the invention.
• the desired coupling products can be obtained in very good and reproducible yields.
• the process according to the invention also has the advantage that oxidation-sensitive organic compounds and
• Catalysts which usually have to be handled under a protective gas atmosphere, can be used in the process according to the invention without a protective gas atmosphere.
• the static micromixer was connected via an outlet and an Omnifit medium pressure HPLC connection component (Omnifit, Great Britain) to a Teflon capillary with an inner diameter of 0.49 mm and a length of 1.0 m.
• the reaction was carried out at 80, 100, 130 and 160 ° C.
• the static micromixer and the Teflon capillary were tempered to the respective temperature in a thermostatted double-jacket vessel.
• the experimental set-up was calibrated for the dependence of the residence time on the pump flow rate before the reaction was carried out.
• the residence time was increased to 3.5; 7.5; 15; 30 60 and 120 minutes set.
• the reaction was followed using a Merck Hitachi LaChrom HPLC instrument.
• the ratio of the starting materials to the product corresponding to the respective residence time was also determined by means of HPLC on the above-mentioned instrument.

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• 2000
  • 2000-06-28 DE DE2000131381 patent/DE10031381A1/de not_active Withdrawn
• 2001
  • 2001-05-09 JP JP2002505328A patent/JP2004505895A/ja active Pending
  • 2001-05-09 WO PCT/EP2001/005282 patent/WO2002000577A2/de not_active Application Discontinuation
  • 2001-05-09 AU AU2001283818A patent/AU2001283818A1/en not_active Abandoned
  • 2001-05-09 EP EP01962682A patent/EP1294660A2/de not_active Withdrawn
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