WO2002000577A2 - Method for coupling organic compounds - Google Patents
Method for coupling organic compounds Download PDFInfo
- Publication number
- WO2002000577A2 WO2002000577A2 PCT/EP2001/005282 EP0105282W WO0200577A2 WO 2002000577 A2 WO2002000577 A2 WO 2002000577A2 EP 0105282 W EP0105282 W EP 0105282W WO 0200577 A2 WO0200577 A2 WO 0200577A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- vinyl
- microreactor
- sulfonate
- particularly preferably
- organic
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 73
- 150000002894 organic compounds Chemical class 0.000 title claims abstract description 55
- 238000005859 coupling reaction Methods 0.000 title claims abstract description 37
- 230000008878 coupling Effects 0.000 title claims abstract description 23
- 238000010168 coupling process Methods 0.000 title claims abstract description 23
- -1 heteroaryl halide Chemical class 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 22
- 229920002554 vinyl polymer Polymers 0.000 claims description 22
- 239000003054 catalyst Substances 0.000 claims description 21
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 17
- 239000007788 liquid Substances 0.000 claims description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 230000003647 oxidation Effects 0.000 claims description 7
- 238000007254 oxidation reaction Methods 0.000 claims description 7
- 239000011541 reaction mixture Substances 0.000 claims description 7
- 230000003068 static effect Effects 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000012298 atmosphere Substances 0.000 claims description 6
- 239000007789 gas Substances 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- 230000001681 protective effect Effects 0.000 claims description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 5
- 125000004122 cyclic group Chemical group 0.000 claims description 5
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 5
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 5
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 5
- 150000001503 aryl iodides Chemical class 0.000 claims description 4
- GHXZPUGJZVBLGC-UHFFFAOYSA-N iodoethene Chemical compound IC=C GHXZPUGJZVBLGC-UHFFFAOYSA-N 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 claims description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 4
- 230000001105 regulatory effect Effects 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 3
- 150000001502 aryl halides Chemical class 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 239000003446 ligand Substances 0.000 claims description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 3
- 239000007983 Tris buffer Substances 0.000 claims description 2
- 150000001345 alkine derivatives Chemical class 0.000 claims description 2
- 239000012300 argon atmosphere Substances 0.000 claims description 2
- 150000001499 aryl bromides Chemical class 0.000 claims description 2
- INLLPKCGLOXCIV-UHFFFAOYSA-N bromoethene Chemical compound BrC=C INLLPKCGLOXCIV-UHFFFAOYSA-N 0.000 claims description 2
- 238000004587 chromatography analysis Methods 0.000 claims description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 2
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- SZQVETPSXXBSDR-UHFFFAOYSA-N ethenyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)S(=O)(=O)OC=C SZQVETPSXXBSDR-UHFFFAOYSA-N 0.000 claims description 2
- VDDXQSUSMHZCLS-UHFFFAOYSA-N ethenyl trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)OC=C VDDXQSUSMHZCLS-UHFFFAOYSA-N 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 150000002941 palladium compounds Chemical class 0.000 claims description 2
- 239000005922 Phosphane Substances 0.000 claims 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims 1
- 150000002466 imines Chemical class 0.000 claims 1
- 229910000064 phosphane Inorganic materials 0.000 claims 1
- 239000000243 solution Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 7
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 6
- PJANXHGTPQOBST-VAWYXSNFSA-N trans-stilbene Chemical compound C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 3
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 239000004809 Teflon Substances 0.000 description 2
- 229920006362 Teflon® Polymers 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 2
- 238000004880 explosion Methods 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- PJANXHGTPQOBST-UHFFFAOYSA-N trans-Stilbene Natural products C=1C=CC=CC=1C=CC1=CC=CC=C1 PJANXHGTPQOBST-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- SOEIEEFOUUTYOM-UHFFFAOYSA-N benzyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)S(=O)(=O)OCC1=CC=CC=C1 SOEIEEFOUUTYOM-UHFFFAOYSA-N 0.000 description 1
- QHTRLHAGKRCHKW-UHFFFAOYSA-N benzyl trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)OCC1=CC=CC=C1 QHTRLHAGKRCHKW-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 231100000481 chemical toxicant Toxicity 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- WJTCGQSWYFHTAC-UHFFFAOYSA-N cyclooctane Chemical compound C1CCCCCCC1 WJTCGQSWYFHTAC-UHFFFAOYSA-N 0.000 description 1
- 239000004914 cyclooctane Substances 0.000 description 1
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 239000000383 hazardous chemical Substances 0.000 description 1
- 150000002390 heteroarenes Chemical class 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000011089 mechanical engineering Methods 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000003738 xylenes Chemical class 0.000 description 1
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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Abstract
Description
Verfahren zur Kupplung von organischen Verbindungen Process for coupling organic compounds
Die vorliegende Erfindung betrifft ein Verfahren zur Kupplung von organischen Verbindungen.The present invention relates to a method for coupling organic compounds.
Die Kupplung von organischen Verbindungen ist ein in der chemischen Industrie sehr häufig durchgeführtes Verfahren, dessen große Bedeutung sich auch in zahlreichen Veröffentlichungen zu diesem Thema widerspiegelt.The coupling of organic compounds is a very common process in the chemical industry, the great importance of which is also reflected in numerous publications on this subject.
Die Durchführung derartiger Kupplungsreaktionen im technischen Maßstab bringt jedoch Sicherheitsprobleme und Gefahren mit sich. Zum einen werden häufig größere Mengen hochgiftige chemische Substanzen eingesetzt, die für sich allein bereits ein erhebliches Risiko für Mensch und Umwelt darstellen und zum anderen verlaufen diese Reaktionen häufig sehr stark exotherm, so daß bei der Durchführung dieser Reaktionen im technischen Maßstab eine erhöhte Explosionsgefahr besteht. Die Erlangung einer behördlichen Genehmigung nach dem BimschG für das Betreiben von Anlagen zur Durchführung dieser Reaktionen im technischen Maßstab ist daher mit einem beträchtlichen Aufwand verbunden.However, carrying out such coupling reactions on an industrial scale entails safety problems and dangers. On the one hand, large amounts of highly toxic chemical substances are often used, which in themselves already represent a considerable risk to humans and the environment, and on the other hand, these reactions are often very exothermic, so that there is an increased risk of explosion when these reactions are carried out on an industrial scale. Obtaining official approval according to the BimschG for the operation of plants for the implementation of these reactions on a technical scale is therefore associated with considerable effort.
Aufgabe der vorliegenden Erfindung ist es daher, ein Verfahren zur Kupplung von organischen Verbindungen zur Verfügung zu stellen, das die oben genannten Nachteile vermeidet. Dieses Verfahren soll insbesondere in einfacher, reproduzierbarer Weise mit erhöhter Sicherheit für Mensch und Umwelt sowie mit guten Ausbeuten durchführbar sein und die Reaktionsbedingungen sollen sehr gut kontrollierbar sein. Die Lösung dieser Aufgabe gelingt überraschenderweise durch das erfindungsgemäße Verfahren zur Kupplung von organischen Verbindungen, bei dem wenigstens eine organische Verbindung, die wenigstens eine Austrittsgruppe aufweist, in flüssiger oder gelöster Form mit wenigstens einer organischen Verbindung, die wenigstens ein vinylisches oder acetylenisches Wasserstoffatom aufweist, in flüssiger oder gelöster Form in Gegenwart wenigstens eines Katalysators in flüssiger oder gelöster Form in wenigstens einem Mikroreaktor vermischt wird, während einer Verweilzeit reagiert und das so erhaltene Kupplungsprodukt gegebenenfalls aus dem Reaktionsgemisch isoliert wird.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.
Vorteilhafte Ausführungsformen des erfindungsgemäßen Verfahrens sind in den Unteransprüchen beschrieben.Advantageous embodiments of the method according to the invention are described in the subclaims.
Im Sinne der Erfindung wird wenigstens eine organische Verbindung, die wenigstens eine Austrittsgruppe aufweist, mit wenigstens einer organischen Verbindung, die wenigstens ein vinylisches oder acetylenisches Wasserstoffatom aufweist, umgesetzt oder die eingesetzte organische Verbindung enthält gleichzeitig wenigstens eine Austrittsgruppe und wenigstens ein vinylisches oder acetylenisches Wasserstoffatom. Daraus folgt, daß im Sinne der vorliegenden Erfindung sowohl inter- als auch intramolekulare Kupplungsreaktionen umfaßt sind. Es ist auch möglich, ein Gemisch aus zwei oder mehr organischen Verbindungen mit wenigstens einer Austrittsgruppe und/oder ein Gemisch aus zwei oder mehr organischen Verbindungen mit wenigstens einem vinylischen oder acetylenischenFor the purposes of the invention, 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
Wasserstoff atom einzusetzen. Vorzugsweise wird in dem erfindungsgemäßen Verfahren jeweils nur eine organische Verbindung mit einer Austrittsgruppe und jeweils nur eine organische Verbindung mit einem vinylischen oder acetylenischen Wasserstoffatom eingesetzt. Sofern eine organische Verbindung zwei oder mehr Austrittsgruppen und/oder zwei oder mehr vinylische oder acetylenische Wasserstoffatome enthält, können diese jeweils gleich oder verschieden sein.To use 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.
Eine Austrittsgruppe im Sinne der vorliegenden Erfindung ist jede Gruppe, deren Bindung zu einem Kohlenstoffatom der organischen Verbindung im Verlauf der Kupplungsreaktion gespalten wird und welche dann aus dieser organischen Verbindung austritt.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.
Ein Mikroreaktor im Sinne der Erfindung ist ein Reaktor mit einem Volumen < 1000 μl in dem die Flüssigkeiten und/oder Lösungen wenigstens einmal innig vermischt werden. Vorzugsweise beträgt das Volumen des Mikroreaktors < 100 μl, besonders bevorzugt < 50 μl.A microreactor in the sense of the invention is a reactor with a volume <1000 μl in which the liquids and / or solutions are intimately mixed at least once. The volume of the microreactor is preferably <100 μl, particularly preferably <50 μl.
Der Mikroreaktor wird bevorzugt aus dünnen, miteinander verbundenen Siliziumstrukturen hergestellt.The microreactor is preferably produced from thin, interconnected silicon structures.
Vorzugsweise ist der Mikroreaktor ein miniaturisierter Durchflußreaktor, besonders bevorzugt ein statischer Mikromischer. Ganz besonders bevorzugt ist der Mikroreaktor ein statischer Mikromischer, wie er in der Patentanmeldung mit der internationalen Veröffentlichungsnummer WOThe 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
96/30113 beschrieben ist, die hiermit als Referenz eingeführt wird und als Teil der Offenbarung gilt. Ein solcher Mikroreaktor weist kleine Kanäle auf, in denen Flüssigkeiten und/oder in Lösungen vorliegende, chemische Verbindungen durch die kinetische Energie der strömenden Flüssigkeiten und/oder Lösungen miteinander vermischt werden.96/30113, which is hereby introduced as a reference and is considered part of the disclosure. 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.
Die Kanäle des Mikroreaktors weisen vorzugsweise einen Durchmesser von 10 bis 1000 μm, besonders bevorzugt von 20 bis 800 μm und ganz besonders bevorzugt von 30 bis 400 μm auf. Vorzugsweise werden die Flüssigkeiten und/oder Lösungen so in den Mikroreaktor gepumpt, daß sie diesen mit einer Durchflußgeschwindigkeit von 0,01 μl/min bis 100 ml/min, besonders bevorzugt 1 μl/min bis 1 ml/min durchströmen.The channels of the microreactor preferably have a diameter of 10 to 1000 μm, particularly preferably 20 to 800 μm and very particularly preferably 30 to 400 μm. 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 μl / min to 100 ml / min, particularly preferably 1 μl / min to 1 ml / min.
Der Mikroreaktor ist erfindungsgemäß vorzugsweise temperierbar.According to the invention, the microreactor can preferably be tempered.
Erfindungsgemäß ist der Mikroreaktor vorzugsweise über einen Auslaß mit wenigstens einer Verweilstrecke, vorzugsweise einer Kapillare, besonders bevorzugt einer temperierbaren Kapillare verbunden. In diese Verweilstrecke bzw. Kapillare werden die Flüssigkeiten und/oder Lösungen nach ihrer Durchmischung im Mikroreaktor zur Verlängerung ihrer Verweilzeit geführt.According to the invention, 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.
Die Verweilzeit im Sinne der Erfindung ist die Zeit zwischen der Durchmischung der Edukte und der Aufarbeitung der resultierenden. Reaktionslösung zur Analyse bzw. Isolierung der (des) gewünschten Produkte(s).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).
Die erforderliche Verweilzeit bei dem erfindungsgemäßen Verfahren hängt von verschiedenen Parametern ab, wie z.B. der Temperatur oder der Reaktivität der Edukte. Dem Fachmann ist es möglich, die Verweilzeit an diese Parameter anzupassen und so einen optimalen Reaktionsverlauf zu erzielen.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.
Die Verweilzeit der Reaktionslösung in dem zum Einsatz kommenden System aus wenigstens einem Mikroreaktor und gegebenenfalls einer Verweilstrecke kann durch die Wahl der Durchflußgeschwindigkeit der eingesetztenThe 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
Flüssigkeiten und/oder Lösungen eingestellt werden.Liquids and / or solutions can be set.
II
Ebenfalls bevorzugt wird das Reaktionsgemisch durch zwei oder mehr in Reihe geschaltete Mikroreaktoren geführt. Hierdurch wird erreicht, daß auch bei erhöhter Durchflußgeschwindigkeit die Verweilzeit verlängert wird und die eingesetzten Komponenten der Kupplungsreaktion so umgesetzt werden, daß eine optimale Produktausbeute des/der gewünschten Kupplungsprodukte(s) erreicht wird.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.
In einer weiteren bevorzugten Ausführungsform wird das Reaktionsgemisch durch zwei oder mehr parallel angeordnete Mikroreaktoren geleitet, um den Durchsatz zu erhöhen.In a further preferred embodiment, the reaction mixture is passed through two or more microreactors arranged in parallel in order to increase the throughput.
In einer anderen bevorzugten Ausführungsform des erfindungsgemäßen Verfahrens wird die Zahl und die Anordnung der Kanäle in einem oder mehreren Mikroreaktor(en) so variiert, daß die Verweilzeit verlängert wird, so daß auch hier bei erhöhter Durchflußgeschwindigkeit eine optimale Ausbeute an dem (den) gewünschten Kupplungsprodukt(en) erreicht wird.In another preferred embodiment of the process according to the invention, 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.
Vorzugsweise beträgt die Verweilzeit der Reaktionslösung im Mikroreaktor, gegebenfalls im Mikroreaktor und der Verweilstrecke < 15 Stunden, vorzugsweise < 3 Stunden, besonders bevorzugt < 1 Stunde.The residence time of the reaction solution in the microreactor, if appropriate in the microreactor and the residence zone, is preferably <15 hours, preferably <3 hours, particularly preferably <1 hour.
Das erfindungsgemäße Verfahren kann in einem sehr breiten Temperaturbereich durchgeführt werden, der im wesentlichen durch dieThe inventive method can be carried out in a very wide temperature range, which is essentially by the
Temperaturbeständigkeit der zum Bau des Mikroreaktors, gegebenenfalls der Verweilstrecke, sowie weiterer Bestandteile, wie z.B. Anschlüsse und Dichtungen eingesetzten Materialien und durch die physikalischen Eigenschaften der eingesetzten Lösungen und/oder Flüssigkeiten beschränkt ist. Vorzugsweise wird das erfindungsgemäße Verfahren bei einer Temperatur von -100 bis +250 °C, vorzugsweise von -78 bis +150°C, besonders bevorzugt von 0 bis +40 °C durchgeführt.Temperature resistance of the microreactor, possibly the dwell, and other components such as Connections and seals used materials and is limited by the physical properties of the solutions and / or liquids used. 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.
Das erfindungsgemäße Verfahren zur Kupplung organischer Verbindungen kann üblicherweise ohne Verwendung einer Schutzgasatmosphäre durchgeführt werden. Es ist aber auch möglich, das erfindungsgemäße Verfahren unter einer Schutzgasatmosphäre durchzuführen. Sofern das erfindungsgemäße Verfahren unter einer Schutzgasatmosphäre durchgeführt wird, kann es bevorzugt unter einer Stickstoff- und/oder Argonatmosphäre durchgeführt werden.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.
Das erfindungsgemäße Verfahren kann sowohl kontinuierlich als auch diskontinuierlich durchgeführt werden. Vorzugsweise wird es kontinuierlich durchgeführt.The process according to the invention can be carried out either continuously or batchwise. It is preferably carried out continuously.
Für die Durchführung des erfindungsgemäßen Verfahrens zur Kupplung organischer Verbindungen ist es erforderlich, daß die Kupplungsreaktion möglichst in homogener flüssiger Phase, die keine oder nur sehr kleine Feststoffpartikel enthält, durchgeführt wird, da sonst die in den Mikroreaktoren vorhandenen Kanäle verstopft werden.To carry out the process according to the invention for coupling organic compounds, it is necessary that the coupling reaction be carried out as far as possible in a homogeneous liquid phase which contains no or only very small solid particles, since otherwise the channels present in the microreactors are blocked.
Der Reaktionsverlauf der Kupplungsreaktion bei dem erfindungsgemäßen Verfahren kann mit verschiedenen dem Fachmann bekannten analytischen Methoden verfolgt und gegebenenfalls geregelt werden. Vorzugsweise wird der Reaktionsverlauf chromatographisch, besonders bevorzugt durch Hochdruckflüssigkeitschromatographie verfolgt und gegebenenfalls geregelt. Die Kontrolle der Reaktion ist dabei im Vergleich zu bekannten Verfahren deutlich verbessert.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.
Nach der Reaktion wird/werden das/die gebildete(n) Kupplungsprodukt(e) gegebenenfalls isoliert. Vorzugsweise wird/werden das/die gebildete(n) Kupplungsprodukt(e) durch Extraktion aus dem Reaktionsgemisch isoliert.After the reaction, the coupling product (s) formed is / are optionally isolated. The coupling product (s) formed is / are preferably isolated from the reaction mixture by extraction.
Als organische Verbindungen, die wenigstens eine Austrittsgruppe aufweisen, können bei dem erfindungsgemäßen Verfahren alle dem Fachmann als Substrate von Kupplungsreaktionen bekannten organischen Verbindungen mit wenigstens einer Austrittsgruppe eingesetzt werden. Als organische Verbindung mit wenigstens einer Austrittsgruppe kann in dem erfindungsgemäßen Verfahren bevorzugt ein Arylhalogenid, besonders bevorzugt ein Arylbromid oder ein Aryljodid, ganz besonders bevorzugt ein Aryljodid, ein Heteroarylhalogenid, besonders bevorzugt ein Heteroarylbromid oder ein Heteroaryljodid, ganz besonders bevorzugt ein Heteroaryljodid, ein Vinylhalogenid, besonders bevorzugt ein Vinylbromid oder ein Vinyljodid, ganz besonders bevorzugt ein Vinyljodid, oder oder ein Gemisch aus wenigstens zwei der vorstehend genannten Verbindungen eingesetzt werden.As 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. particularly preferably 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.
Ebenfalls bevorzugt kann in dem erfindungsgemäßen Verfahren als Verbindung mit wenigstens einer Austrittsgruppe ein organisches Fluoralkylsulfonat, vorzugsweise ein Arylfluoralkylsulfonat, ein Heteroarylfluoralkylsulfonat oder ein Vinylfluoralkylsulfonat oder ein organisches Perfluoralkylsufonat, vorzugsweise ein Arylperfluoralkylsulfonat, ein Heteroarylperfluoralkylsulfonat oder ein Vinylperfluoralkylsulfonat oder ein Gemisch aus wenigstens zwei der vorstehend genannten Verbindungen eingesetzt werden.Also preferred in the process according to the invention as 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.
Als Perfluoralkylsulfonat kann in dem erfindungsgemäßen Verfahren besonders bevorzugt ein Aryltrifluormethansulfonat, ein Heteroaryltrifluormethansulfonat, ein Vinyltrifluormethansulfonat oder ein Gemisch aus wenigstens zwei der vorstehend genannten Verbindungen eingesetzt werden.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.
In einer weiteren besonders bevorzugten Ausführungsform des erfindungsgemäßen Verfahrens kann als Perfluoralkylsulfonat ein Arylnonafluorbutansulfonat, ein Heteroarylnonafluorbutansulfonat, ein Vinylnonafluorbutansulfonat oder ein Gemisch aus wenigstens zwei der vorstehend genannten Verbindungen eingesetzt werden.In a further particularly preferred embodiment of 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.
Unter Arylhalogeniden, Arylfluoralkylsulfonaten bzw. Arylperfluoralkylsulfonaten werden im Sinne der vorliegenden Erfindung auch solche aromatischen organischen Verbindungen umfaßt, in denen der Halogen-, Fluoralkylsulfonat- bzw. der Perfluoralkylsulfonat-Rest nicht direkt an den aromatischen Ring des Aryl-Restes, sondern z.B. über eine Alkylen- Gruppe an diesen gebunden ist, wie z.B. beim Benzylhalogenid, Benzyltrifluormethansulfonat oder beim Benzylnonafluorbutansulfonat.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.
Unter Heteroarylhalogeniden, Heteroarylfluoralkylsulfonaten bzw. Heteroarylperfluoralkylsulfonaten werden im Sinne der vorliegenden Erfindung auch solche heteroaromatischen organischen Verbindungen umfaßt, in denen der Halogen-, Fluoralkylsulfonat- bzw. der Perfluoralkylsulfonat-Rest nicht direkt an den heteroaromatischen Ring des Heteroaryl-Restes, sondern z.B. über eine Alkylen-Gruppe an diesen gebunden ist. Diese Heteroaryl-Reste weisen als Heteroatom bevorzugt wenigstens ein Sauerstoff- und/oder Stickstoff- und/oder Schwefelatom auf.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.
Als organische Verbindung mit wenigstens einem vinylischen oder acetylenischem Wasserstoffatom können bei dem erfindungsgemäßen Verfahren alle dem Fachmann bekannten organischen Verbindungen mit wenigstens einem vinylischen oder acetylenischen Wasserstoffatom eingesetzt werden, die sich als Substrate für Kupplungsreaktionen eignen. Vorzugsweise kann in dem erfindungsgemäßen Verfahren wenigstens ein unverzweigtes, verzweigtes, cyclisches, aromatisches oder heteroaromatisches Alken oder Alkin, besonders bevorzugt wenigstens ein un verzweigtes, verzweigtes, cyclisches, aromatisches oder heteroaromatisches Alken eingesetzt werden.As 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. Preferably, 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.
Unter aromatischen Verbindungen mit wenigstens einem vinylischen oder acetylenischem Wasserstoffatom werden im Sinne der vorliegenden Erfindung auch solche organische Verbindungen und/oder deren Derivate umfaßt, die ein monocyclisches und/oder polycyclisches homoaromatisches Grundgerüst oder eine entsprechende Teilstruktur, z.B. in Form von Substituenten sowie ein vinylisches oder acetylenisches Wasserstoffatom aufweisen.For the purposes of the present invention, 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.
Unter heteroaromatischen Verbindungen mit wenigstens einem vinylischen oder acetylenischen Wasserstoffatom werden im Sinne der vorliegenden Erfindung auch solche organischen Verbindungen und/oder deren Derivate umfaßt, die wenigstens ein monocyclisches und/oder polycyclisches heteroaromatisches Grundgerüst oder eine entsprechende Teilstruktur, z.B. in Form von Substituenten, sowie wenigstens ein vinylisches oder acetylenisches Wasserstoffatom aufweisen. Diese heteroaromatischen Grundgerüste oder Teilstrukturen umfassen besonders bevorzugt wenigstens ein Sauerstoff- und/oder Stickstoff- und/oder Schwefelatom.For the purposes of the present invention, 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.
Als Katalysatoren können bei dem erfindungsgemäßen Verfahren sämtliche, dem Fachmann bekannten, für Kupplungsreaktionen organischerIn the process according to the invention, all catalysts known to the person skilled in the art can be used as catalysts for coupling reactions
Verbindungen geeigneten Katalysatoren oder ein Gemisch aus mindestens zwei dieser Katalysatoren eingesetzt werden. Vorzugsweise wird jeweils nur ein Katalysator eingesetzt. Katalysatoren imCompounds 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
Sinne der Erfindung umfassen auch in-situ gebildete Katalysatoren, d.h.For the purposes of the invention also include catalysts formed in situ, i.e.
Katalysatoren, die unmittelbar vor oder während der Kupplungsreaktion gebildet werden. In einer weiteren bevorzugten Ausführungsform der vorliegenden Erfindung wird als Katalysator wenigstens eine Verbindung eingesetzt, die Palladium in der Oxidationsstufe 0 enthält. Vorzugsweise kann als Verbindung, die Palladium in der Oxidationsstufe 0 enthält, Tris(dibenzylidenaceton)- bispalladium eingesetzt werden.Catalysts that are formed immediately before or during the coupling reaction. In a further preferred embodiment of the present invention, 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.
Ebenfalls bevorzugt wird in dem erfindungsgemäßen Verfahren als Katalysator wenigstens eine Verbindung, die Palladium in der Oxidationsstufe (+11) enthält, in Gegenwart wenigstens einer Base, ggf. wenigstens eines anorganischen Salzes und ggf. wenigstens eines Liganden eingesetzt.In the process according to the invention, preference is likewise given to using at least one compound which contains palladium in the oxidation state (+11) in the presence of at least one base, if appropriate at least one inorganic salt and if appropriate at least one ligand.
Als Palladiumverbindung enthaltend Palladium in der Oxidationsstufe (II) kann in dem erfindungsgemäßen Verfahren vorzugsweise Palladium(ll)chlorid, Palladium(ll)acetat, Bis(triphenylphosphin)-palladium(ll)-dichlorid oder ein Gemisch aus wenigstens zwei dieser Verbindungen eingesetzt werden.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.
Als Base können bei dem erfindungsgemäßen Verfahren alle dem Fachmann bekannten, für Kupplungsreaktionen organischer Verbindungen geeigneten Basen eingesetzt werden. Vorzugsweise kann als Base ein organisches Amin, besonders bevorzugt Triethylamin, Diethylamin oder Tri-n-Butylamin, ein Stickstoff-haltiger, ggf. aromatischer Heterocyclus, besonders bevorzugt Pyridin oder N-Methylpyrrolidon oder ein Gemisch aus wenigstens zwei der vorstehend gennanten Verbindungen eingesetzt werden.All bases known to the person skilled in the art and suitable for coupling reactions of organic compounds can be used as the base 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.
Als anorganisches Salz können bei dem erfindungsgemäßen Verfahren alle dem Fachmann bekannten, für Kupplungsreaktionen organischer Verbindungen geeigneten anorganischen Salze eingesetzt werden. Vorzugsweise wird als anorganisches Salz Kupfer(l)-jodid eingesetzt.All of the 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.
In einer weiteren bevorzugten Ausführungsform des erfindungsgemäßen Verfahrens werden 0,01 bis 110 Mol-%, vorzugsweise 0,01 bis 50 Mol-%, besonders bevorzugt 0,01 bis 1 Mol-% des (der) Katalysators (Katalysatoren), bezogen auf die eingesetzte(n) organische(n) Verbindung(en) mit wenigstens einer Austrittsgruppe, eingesetzt.In a further preferred embodiment of the process according to the invention, 0.01 to 110 mol%, preferably 0.01 to 50 mol%, particularly preferably 0.01 to 1 mol% of the catalyst (s), based on the organic compound (s) used with at least one leaving group.
Vorzugsweise werden die organische Verbindung mit wenigstens einer Austrittsgruppe und die organische Verbindung mit wenigstens einem vinylischen oder acetylenischen Wasserstoffatom bei dem erfindungsgemäßen Verfahren in einem äquimolaren Verhältnis eingesetzt. In einer anderen bevorzugten Ausführungsform des erfindungsgemäßen Verfahrens wird die organische Verbindung mit wenigstens einem vinylischen oder acetylenischem Wasserstoffatom in einem 1 ,05fachen bis 2fachen molaren Überschuß, besonders bevorzugt in einem 1 ,1 fachen bis 1 ,6fachen, ganz besonders bevorzugt in einem 1 ,2fachen bis 1 ,5fachen Überschuß, bezogen auf die organische Verbindung mit wenigstens einer Austrittsgruppe, eingesetzt.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. In another preferred embodiment of 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.
Die Selektivität der Reaktion selbst hängt außer von der Konzentration der eingesetzten Reagenzien von einer Reihe weiterer Parameter, wie z.B. der Temperatur, der Art der Austrittsgruppe, der Art des Katalysators oder der Verweilzeit, ab. Dem Fachmann ist es möglich, die verschiedenen Parameter auf die jeweilige Reaktion so abzustimmen, daß das (die) gewünschte(n) Kupplungsprodukt(e) erhalten wird (werden).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.
Für das erfindungsgemäße Verfahren ist es wesentlich, daß die eingesetzten organischen Verbindungen und der Katalysator entweder selbst flüssig sind oder in gelöster Form vorliegen. Sofern eine der eingesetzten Reaktionskomponenten oder der Katalysator selbst flüssig ist, kann diese(r) ggf. auch als Lösungsmittel für die anderen Reaktionskomponenten bzw. den Katalysator eingesetzt werden. Sofern diese nicht schon selbst in flüssiger Form vorliegen, müssen sie vor der Durchführung des erfindungsgemäßen Verfahrens in einem geeigneten Lösungsmittel gelöst werden. Als Lösungsmittel werden bevorzugt halogenierte Lösungsmittel, besonders bevorzugt Dichlormethan, Chloroform, 1,2-Dichlorethan oder 1,1 ,2,2- Tetrachlorethan, geradkettige, verzweigte oder cyclische Paraffine, besonders bevorzugt Pentan, Hexan, Heptan, Octan, Cyclopentan, Cyclohexan, Cycloheptan oder Cyclooctan oder geradkettige, verzweigte oder cyclische Ether, besonders bevorzugt Diethylether, Methyl-tert.-butylether, Tetrahydrofuran oder Dioxan, aromatische Lösungsmittel, besonders bevorzugt Toluol, Xylole, Ligroin oder Phenylether, N-haltige heterocyclische Lösungsmittel, besonders bevorzugt Pyridin oder N-Methylpyrrolidon, oder ein Gemisch aus wenigstens zwei der vorstehend genannten Lösungsmittel eingesetzt.It is essential for the process according to the invention that 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.
Bei dem erfindungsgemäßen Verfahren ist die Gefahr für Mensch und Umwelt durch austretende Chemikalien erheblich verringert und führt somit zu einer erhöhten Sicherheit beim Umgang mit Gefahrstoffen. Die Kupplung von organischen Verbindungen nach dem erfindungsgemäßen Verfahren ermöglicht ferner eine bessere Kontrolle der Reaktionsbedingungen, wie z.B. Reaktionsdauer und Reaktionstemperatur, als dies in den herkömmlichen Verfahren möglich ist. Weiterhin ist bei dem erfindungsgemäßen Verfahren die Gefahr von Explosionen bei sehr stark exothermen Kupplungsreaktionen deutlich vermindert. Die Temperatur kann in jedem Volumenelement des Systems individuell gewählt und konstant gehalten werden. DerIn the method according to the invention, 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. Furthermore, 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
Reaktionsverlauf der Kupplungsreaktionen ist bei dem erfindungsgemäßen Verfahren sehr schnell und genau regelbar. Die gewünschten Kupplungsprodukte lassen sich so in sehr guten und reproduzierbaren Ausbeuten erhalten. Das erfindungsgemäße Verfahren hat weiterhin den Vorteil, daß oxidationsempfindliche organische Verbindungen undThe 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
Katalysatoren, die üblicherweise unter Schutzgasatmosphäre gehandhabt werden müssen, bei dem erfindungsgemäßen Verfahren ohne Schutzgasatmosphäre eingesetzt werden können.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.
Besonders vorteilhaft ist auch, daß das erfindungsgemäße Verfahren kontinuierlich durchgeführt werden kann. Hierdurch ist es im Vergleich zu herkömmlichen Verfahren schneller und kostengünstiger und es ist ohne großen Meß- und Regelungsaufwand möglich, beliebige Mengen der gewünschten Kupplungsprodukte herzustellen.It is also particularly advantageous that the process according to the invention can be carried out continuously. This makes it compared to conventional methods faster and cheaper and it is possible to produce any quantities of the desired coupling products without great measurement and control effort.
Im folgenden wird die Erfindung anhand eines Beispiels erläutert. Dieses Beispiel dient lediglich der Erläuterung der Erfindung und schränkt den allgemeinen Erfindungsgedanken nicht ein.The invention is explained below using an example. This example only serves to explain the invention and does not limit the general idea of the invention.
Beispielexample
Kupplung von Phenyliodid und Styrol zu trans-StilbenCoupling of phenyl iodide and styrene to trans-stilbene
Die Kupplung von Phenyljodid und Styrol zu trans-Stilben in Gegenwart von Palladium(ll)acetat, Triphenylphosphin und Th-n-butylamin erfolgte in einem statischen Mikromischer (Technische Universität Ilmenau, FakultätThe coupling of phenyl iodide and styrene to trans-stilbene in the presence of palladium (II) acetate, triphenylphosphine and Th-n-butylamine was carried out in a static micromixer (Ilmenau University of Technology, Faculty
Maschinenbau, Dr.-Ing. Norbert Schwesinger, Postfach 100565, D-98684, Ilmenau) mit einer Baugröße von 40 mm x 25 mm x 1 mm, der insgesamt 11 Mischstufen mit einem Volumen von jeweils 0,125 μl aufwies. Der Gesamtdruckverlust betrug circa 1000 Pa.Mechanical engineering, Dr.-Ing. Norbert Schwesinger, PO Box 100565, D-98684, Ilmenau) with a size of 40 mm x 25 mm x 1 mm, which had a total of 11 mixing stages with a volume of 0.125 μl each. The total pressure loss was approximately 1000 Pa.
Der statische Mikromischer war über einen Auslaß und eine Omnifit Mitteldruck-HPLC-Verbindungskomponente (Omnifit, Großbritannien) an eine Teflon-Kapillare mit einem Innendurchmesser von 0,49 mm und einer Länge von 1 ,0 m verbunden. Die Reaktion wurde bei 80, 100, 130 und 160 °C durchgeführt. Der statische Mikromischer und die Teflon-Kapillare wurden dazu in einem thermostatisierten Doppelmantelgefäß auf die jeweilige Temperatur temperiert.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.
Es wurde eine 2 ml Einweginjektionsspritze mit einem Teil einer Lösung aus 650 mg (6,25 mmol) Styrol und 1 ,2 g (6,25 mmol) Tri-n-Butylamin in 40 ml N- Methyl-Pyrrolidon und eine weitere 2 ml Einwegspritze mit einem Teil einer Lösung von 1 g (5 mmol) Phenyljodid, 100 mg (0,4 mmol) Triphenylphosphin und 20 mg (0,1 mmol) Palladium(ll)acetat in 40 ml N-Methyl-Pyrrolidon gefüllt. Anschließend wurde der Inhalt beider Spritzen mit einer Dosierpumpe (Harvard Apparatus Inc., Pump 22, South Natick, Massachussets, USA) in den statischen Mikromischer überführt.There was a 2 ml disposable injection syringe with part of a solution of 650 mg (6.25 mmol) of styrene and 1.2 g (6.25 mmol) of tri-n-butylamine in 40 ml of N-methyl-pyrrolidone and a further 2 ml Disposable syringe with part of one Solution of 1 g (5 mmol) phenyl iodide, 100 mg (0.4 mmol) triphenylphosphine and 20 mg (0.1 mmol) palladium (II) acetate in 40 ml N-methyl-pyrrolidone. The contents of both syringes were then transferred to the static micromixer using a metering pump (Harvard Apparatus Inc., Pump 22, South Natick, Massachussets, USA).
Die Versuchsanordnung wurde vor der Durchführung der Reaktion in Bezug auf die Abhängigkeit der Verweilzeit von der Pumpenflußrate kalibriert. Die Verweilzeit wurde auf 3,5; 7,5; 15; 30 60 und 120 Minuten eingestellt. Die Reaktion wurde mit Hilfe eines Merck Hitachi LaChrom HPLC-Instruments verfolgt. Auch das der jeweiligen Verweilzeit entsprechende Verhältnis der Edukte zu Produkt wurde mittels HPLC auf dem vorstehend genannten Instrument bestimmt. 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.
Claims
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2001283818A AU2001283818A1 (en) | 2000-06-28 | 2001-05-09 | Method for coupling organic compounds |
| JP2002505328A JP2004505895A (en) | 2000-06-28 | 2001-05-09 | Method for coupling organic compounds |
| EP01962682A EP1294660A2 (en) | 2000-06-28 | 2001-05-09 | Method for coupling organic compounds |
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| DE10031381.7 | 2000-06-28 | ||
| DE2000131381 DE10031381A1 (en) | 2000-06-28 | 2000-06-28 | Process for coupling organic compounds |
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| WO2002000577A3 WO2002000577A3 (en) | 2002-05-02 |
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| PCT/EP2001/005282 WO2002000577A2 (en) | 2000-06-28 | 2001-05-09 | Method for coupling organic compounds |
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| EP (1) | EP1294660A2 (en) |
| JP (1) | JP2004505895A (en) |
| AU (1) | AU2001283818A1 (en) |
| DE (1) | DE10031381A1 (en) |
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| JP2008081450A (en) * | 2006-09-28 | 2008-04-10 | Dainippon Ink & Chem Inc | Method for producing phenol dimer |
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| CA2189783A1 (en) * | 1994-05-09 | 1995-11-16 | Klaus Schubert | Method and device for performing chemical reactions with the aid of microstructure mixing |
| GB9723260D0 (en) * | 1997-11-05 | 1998-01-07 | British Nuclear Fuels Plc | A method of performing a chemical reaction |
| GB9723262D0 (en) * | 1997-11-05 | 1998-01-07 | British Nuclear Fuels Plc | Reactions of aromatic compounds |
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2000
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2001
- 2001-05-09 EP EP01962682A patent/EP1294660A2/en not_active Withdrawn
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| AT501927A1 (en) * | 2005-05-23 | 2006-12-15 | Dsm Fine Chem Austria Gmbh | METHOD FOR CARRYING OUT REACTIONS INVOLVED IN CARBOKATIONS |
| AT501927B1 (en) * | 2005-05-23 | 2007-06-15 | Dsm Fine Chem Austria Gmbh | IMPROVED METHOD FOR THE PERFORMANCE OF KNIGHT REACTIONS, ELECTROPHILIC ADDITIONS TO ALKENIC OR FRIEDEL CRAFTS ALKYLATION |
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| JP2004505895A (en) | 2004-02-26 |
| AU2001283818A1 (en) | 2002-01-08 |
| DE10031381A1 (en) | 2002-01-10 |
| EP1294660A2 (en) | 2003-03-26 |
| WO2002000577A3 (en) | 2002-05-02 |
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