EP1102796A1 - Verfahren zur stereoselektiven herstellung von grignardverbindungen und deren verwendung - Google Patents
Verfahren zur stereoselektiven herstellung von grignardverbindungen und deren verwendungInfo
- Publication number
- EP1102796A1 EP1102796A1 EP99934559A EP99934559A EP1102796A1 EP 1102796 A1 EP1102796 A1 EP 1102796A1 EP 99934559 A EP99934559 A EP 99934559A EP 99934559 A EP99934559 A EP 99934559A EP 1102796 A1 EP1102796 A1 EP 1102796A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compounds
- formula
- alkyl
- unbranched
- branched
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 58
- 238000000034 method Methods 0.000 title claims abstract description 26
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 8
- 230000000707 stereoselective effect Effects 0.000 title abstract description 8
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 11
- 239000000126 substance Substances 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 239000007787 solid Substances 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical group 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000000010 aprotic solvent Substances 0.000 claims description 2
- 235000021466 carotenoid Nutrition 0.000 claims description 2
- 150000001747 carotenoids Chemical class 0.000 claims description 2
- 239000011782 vitamin Substances 0.000 claims description 2
- 229940088594 vitamin Drugs 0.000 claims description 2
- 229930003231 vitamin Natural products 0.000 claims description 2
- 235000013343 vitamin Nutrition 0.000 claims description 2
- 150000003722 vitamin derivatives Chemical class 0.000 claims description 2
- -1 alkenyl halide Chemical class 0.000 description 95
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 150000003254 radicals Chemical class 0.000 description 13
- 229920000642 polymer Polymers 0.000 description 11
- 239000012039 electrophile Substances 0.000 description 10
- 125000004122 cyclic group Chemical group 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000011777 magnesium Substances 0.000 description 6
- 229910052749 magnesium Inorganic materials 0.000 description 6
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 229910052717 sulfur Inorganic materials 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 125000005919 1,2,2-trimethylpropyl group Chemical group 0.000 description 3
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 3
- 125000006433 1-ethyl cyclopropyl group Chemical group [H]C([H])([H])C([H])([H])C1(*)C([H])([H])C1([H])[H] 0.000 description 3
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000006432 1-methyl cyclopropyl group Chemical group [H]C([H])([H])C1(*)C([H])([H])C1([H])[H] 0.000 description 3
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 3
- 125000005916 2-methylpentyl group Chemical group 0.000 description 3
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000005917 3-methylpentyl group Chemical group 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 3
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 3
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 3
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 229920002554 vinyl polymer Polymers 0.000 description 3
- JONIMGVUGJVFQD-UHFFFAOYSA-N (4-methylphenyl)sulfonylformonitrile Chemical compound CC1=CC=C(S(=O)(=O)C#N)C=C1 JONIMGVUGJVFQD-UHFFFAOYSA-N 0.000 description 2
- RMSGQZDGSZOJMU-UHFFFAOYSA-N 1-butyl-2-phenylbenzene Chemical group CCCCC1=CC=CC=C1C1=CC=CC=C1 RMSGQZDGSZOJMU-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- GUUVPOWQJOLRAS-UHFFFAOYSA-N Diphenyl disulfide Chemical compound C=1C=CC=CC=1SSC1=CC=CC=C1 GUUVPOWQJOLRAS-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000003875 Wang resin Substances 0.000 description 2
- NERFNHBZJXXFGY-UHFFFAOYSA-N [4-[(4-methylphenyl)methoxy]phenyl]methanol Chemical compound C1=CC(C)=CC=C1COC1=CC=C(CO)C=C1 NERFNHBZJXXFGY-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- APVKDJJWVLLAQJ-WYMLVPIESA-N ethyl 4-[[4-[(e)-1-iodoprop-1-en-2-yl]phenoxy]methyl]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1COC1=CC=C(C(\C)=C\I)C=C1 APVKDJJWVLLAQJ-WYMLVPIESA-N 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 238000006317 isomerization reaction Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000003944 tolyl group Chemical group 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 1
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- 125000003143 4-hydroxybenzyl group Chemical group [H]C([*])([H])C1=C([H])C([H])=C(O[H])C([H])=C1[H] 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000005840 aryl radicals Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000002534 ethynyl group Chemical class [H]C#C* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- DQZLQYHGCKLKGU-UHFFFAOYSA-N magnesium;propane Chemical compound [Mg+2].C[CH-]C.C[CH-]C DQZLQYHGCKLKGU-UHFFFAOYSA-N 0.000 description 1
- LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 239000012798 spherical particle Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 125000002348 vinylic group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B40/00—Libraries per se, e.g. arrays, mixtures
- C40B40/04—Libraries containing only organic compounds
- C40B40/16—Libraries containing metal-containing organic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B49/00—Grignard reactions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/14—Preparation of carboxylic acid nitriles by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
- C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
- C07C29/40—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones with compounds containing carbon-to-metal bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/28—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/02—Magnesium compounds
-
- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
- C40B50/14—Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/11—Compounds covalently bound to a solid support
Definitions
- the invention relates to a process for the stereoselective preparation of Grignard compounds of the formula I.
- the invention also relates to polymer-bound compounds of the formula Ia.
- the invention further relates to the use of the process for the preparation of substance libraries and the use of the compounds of the formulas I and Ia in stereoselective chemical synthesis.
- Grignard compounds are valuable intermediates in organic synthesis. They belong to the most important classes of compounds in organic synthetic chemistry. Their reaction with electrophilic substances allows the production of a wide variety of compounds. A variety of syntheses are known from the literature in which Grignard compounds are used (see: Handbook of Grignard-Reagents, Eds. G.S. Silverman, P.E. Rakita, Marcel Dekker, Inc., 1996). Grignard compounds have good reactivity with satisfactory chemoselectivity (see Posner GH Org. React., Vol. 22, 1975: 253, Lipshutz et al., Org. React., Vol. 41, 1992: 135, Luh T.-Y. Che Res., Vol 24, 1991: 257 or Tamao et al., J. Am. Chem. Soc., Vol, 94, 1972: 4374).
- Alkenyl Grignard compounds are usually prepared by reacting an appropriate alkenyl halide with metallic magnesium or another magnesium source. Another method is based on acetylenes which are carbometalated with Grignard compounds in the presence of suitable promoters. The methods for this are known to the person skilled in the art and can be found, for example, in Houben-Weyl vol. XIII / 2a and the literature cited therein and in the Handbook of Grignard-Reagents, Eds. G.S. Silverman, P.E. Rakita, Marcel Dekker, Inc., 1996 or in J. Organomet. Chem. 1976, 113: 107 or in J. Fluorine Chem. 1982, 20, 699.
- the residues Ri ', R' and R ' are only shown schematically as residues in Scheme I.
- the object of the present invention was therefore to provide a process for the synthesis of vinyl Grignard compounds which enables stereoselective access to these compounds while maintaining the original E / Z geometry. Another task was to enable the further stereoselective reaction of these compounds with electrophiles. Furthermore, it was an object to provide a process which tolerates a large number of additional functional groups in the molecule in order to be able to produce synthetically and pharmacologically interesting compounds.
- X halogen such as Cl or R 3
- R 1 substituted or unsubstituted, branched or unbranched Ci-Cio-alkyl, C 3 -C 10 cycloalkyl, -C-C 4 alkylaryl, C ⁇ -C 4 alkylhetaryl, aryl or hetaryl,
- R 2 hydrogen, -CH 2 -R 4
- R 3 branched or unbranched Ci-Cio-alkyl-, C 3 -C ⁇ o ⁇ cyclo-alkyl,
- R 4 hydrogen, substituted or unsubstituted, branched or unbranched -OCi-Cio-alkyl, -OC 3 -C ⁇ o-cyclo-alkyl, -OC ⁇ -C 4 -alkylaryl, -OC ⁇ -C 4 -alkylhetaryl, -OCNR ⁇ 5 , R 6
- R 5 like R 1 ' but regardless of
- R 6 a solid support.
- R 1 in the compounds of the formulas I and II denotes substituted or unsubstituted, branched or unbranched Ci-Cio-alkyl-, C 3 -C ⁇ 0 -cycloalkyl-, C 1 -C 4 -alkylaryl-, -C-C 4 -alkyl- hetaryl, aryl, hetaryl or R 5 ,
- alkyl radicals are substituted or unsubstituted branched or unbranched -CC-alkyl chains such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, n-pentyl , 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1, l-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl , 4-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 2-dimethylbutyl, 2,3-dimethylbutyl, 3, 3-dimethylbutyl, 1-ethylbutyl, 2-ethy
- C 3 -C 10 cycloalkyl chains with 3 to 7 carbon atoms in the ring or ring system such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-methylcyclopropyl, 1-ethylcyclopropyl, 1-propylcyclopropyl, 1-butylcyclopropyl, 1-pentylcyclopropyl, 1 -Methyl-l-butylcyclopropyl, 1, 2-dimethylcyclypropyl, l-methyl-2-ethylcyclopropyl, cyclooctyl, cyclononyl or cyclodecyl.
- the cycloalkyl radicals can also contain heteroatoms such as S, N and 0 in the ring.
- the cycloalkyl radicals can contain branched or unbranched alkyl parts.
- C 1 -C 4 alkylaryl substituted or unsubstituted branched or unbranched C 1 -C 4 alkylphenyl or C 1 -C 4 alkylnaphthyl radicals such as methylphenyl, ethylphenyl, propylphenyl, 1-methylethylphenyl, butylphenyl, 1-methylpropyl , 2-Methylpropylphenyl, 1, 1-Dimethylethylphenyl, Methylnaphthyl, Ethylnaphthyl, Propylnaphthyl, 1-Methylethylnaphthyl, Butylnaphthyl, 1-Methylpropylnaphthyl, 2-Methylpropylnaphthyl or 1, 1-Dimethylethylnaphthyl called.
- Substituted or unsubstituted branched or unbranched C 1 -C 4 -alkylhetaryl radicals which contain one or more nitrogen, sulfur and / or oxygen atoms in the ring or ring system may be mentioned as alkylhetaryl radicals.
- Aryl radicals which may be substituted or unsubstituted aryls such as, for example, phenyl, naphthyl or aromatic rings or ring systems with 6 to 18 carbon atoms in the ring system and up to 24 further C atoms which form further non-aromatic rings or ring systems with 3 to 8 C atoms in the ring can, for example.
- aryls such as, for example, phenyl, naphthyl or aromatic rings or ring systems with 6 to 18 carbon atoms in the ring system and up to 24 further C atoms which form further non-aromatic rings or ring systems with 3 to 8 C atoms in the ring can, for example.
- Optionally substituted phenyl or naphthyl are preferred.
- Simple or fused aromatic ring systems with one or more heteroaromatic 3- to 7-membered rings which may contain one or more heteroatoms such as N, O or S may be mentioned as hetaryl radicals.
- substituents for the radicals mentioned of R 1 for example one or more substituents such as halogen, such as fluorine, chlorine or bromine, cyano, nitro, amino, hydroxy, alkyl, cycloalkyl, aryl, alkoxy, Benzyloxy, phenyl or benzyl.
- R 2 denotes hydrogen, in the formulas I and II, or -CH-R 4.
- R 3 in the formula R 3 denotes MgX (III) branched or unbranched Ci-Cio-alkyl- or C 3 -C ⁇ o-cycloalkyl-.
- alkyl radicals are substituted or unsubstituted branched or unbranched C ⁇ -C ⁇ o alkyl chains such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, n-pentyl , 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl , 4-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 2-dimethylbutyl, 2, 3-dimethylbutyl, 3, 3-dimethylbutyl, 1-ethylbutyl, 2-ethyl
- cycloalkyl radicals in the formula III are substituted or unsubstituted branched or unbranched C 3 -C 10 -cycloalkyl chains having 3 to 7 carbon atoms in the ring or ring system, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-methylcyclopropyl, 1-ethylcyclopropyl, 1- Propyl-cyclopropyl, 1-butylcyclopropyl, 1-pentylcyclopropyl, 1-methyl-1-butylcyclopropyl, 1, 2-dimethylcyclypropyl, 1-methyl-2-ethylcyclopropyl, cyclooctyl, cyclononyl or cyclodecyl.
- radicals mentioned under R 3 could also carry substituents, but since these compounds would first have to be prepared in a complex manner and the radical R 3 is not contained in the products synthesized from the Grignard compounds, it is more sensible with the unsubstituted ones for economic reasons to work commercially available or easily synthesized compounds.
- R 4 denotes hydrogen, substituted or unsubstituted, branched or unbranched -OC ⁇ -C ⁇ o-alkyl-, - ⁇ C 3 -C ⁇ 0 -cyclo- alkyl-, -OC x -C 4 -alkylaryl-, -OC ⁇ -C 4 -alkylhetaryl- , OCNR ⁇ -R 5 , R 6 .
- Substituted or unsubstituted branched or unbranched -OC ⁇ -C ⁇ 0 alkyl chains may be mentioned as -O-alkyl radicals.
- the C ⁇ -C ⁇ o alkyl chains have, for example, the following meaning: methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl-, 2-methylpropyl, 1, 1-dimethylethyl, n- Pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl
- substituted or unsubstituted branched or unbranched branched or -branched -OC 3 -C ⁇ o-cycloalkyl chains with 3 to 7 carbon atoms in the ring or ring system may be mentioned as -O-cycloalkyl radicals in the R 4 radical, the C 3 in these -OC 3 -C ⁇ o-cycloalkyl chains being -C ⁇ o-cycloalkyl chains, for example, have the following meaning: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-methylcyclopropyl, 1-ethylcyclopropyl, 1-propylcyclopropyl, 1-butylcyclopropyl, 1-pentylcyclopropyl, 1-methyl-l-butylcyclopropyl, 1 , 2-dimethylcyclypropyl, l-methyl-2-ethylcyclopropyl, cyclo
- C ⁇ -C4 alkyl-phenyl- or -CC 4 alkyl naphthyl residues such as methylphenyl, ethylphenyl, propylphenyl, 1-methylethylphenyl, butylphenyl, 1-methylpropylphenyl, 2-methylpropylphenyl, 1, 1-dimethylethylphenyl, methylnaphthyl, ethylnaphthyl, propylnaphthyl, 1- Methylethylnaphthyl, butylnaphthyl, 1-methylpropylnaphthyl, 2-methylpropylnaphthyl
- Substituted and unsubstituted branched or unbranched -0-C 1 -C 4 -alkylhetaryl radicals which contain one or more nitrogen, sulfur and / or oxygen atoms in the ring or ring system may be mentioned as -O-alkylhetaryl radicals.
- the heteroaromatic part can contain simple or condensed aromatic rings or ring systems with one or more heteroaromatic 3- to 7-membered rings.
- substituents of the said radicals of R 4 for example one or more substituents, such as halogen, such as fluorine, chlorine or bromine, cyano, nitro, amino, hydroxy, alkyl, cycloalkyl, aryl, alkoxy, Benzyloxy, phenyl or benzyl.
- substituents such as halogen, such as fluorine, chlorine or bromine, cyano, nitro, amino, hydroxy, alkyl, cycloalkyl, aryl, alkoxy, Benzyloxy, phenyl or benzyl.
- THF tetrahydro
- a reaction temperature of less than -20 ° C., preferably between -100 ° C. and -20 ° C., particularly preferably between -80 ° C. and -40 ° C. is advantageously selected .
- a reaction temperature of less than +30 ° C, preferably between -40 ° C and +30 ° C, particularly preferably between -20 ° C and +30 ° C is entirely advantageous particularly preferably chosen between 0 ° C and +30 ° C.
- all compounds of the formula R 3 MgX known to the person skilled in the art can be used to prepare the Grignard compound; diisopropylmagnesium or isopropylmagnesium chloride are preferably used.
- reaction time is between 1 h and 18 h.
- the following compounds of the general formula Ia can be prepared by using polymer-bound alcohols:
- R 2 is -CH-R 4
- R 4 is R 6 and R 6 is a solid support.
- Usable carriers can, as far as they are compatible with the synthetic chemistry used, consist of a variety of materials.
- the size, size distribution and shape of the straps can vary widely depending on the material. Spherical particles are preferred which are advantageously homogeneous in their size distribution.
- Solid supports which are preferably suitable are, for example, functionalized crosslinked polystyrenes such as 4-hydroxybenzylpolystyrene.
- connection of the compound to the support or polymeric support takes place via reactions known to the person skilled in the art, for example from the review by Balkenhohl et al. (Angew. Chem., Vol. 108, 1996: 2436) and the literature cited there.
- the connection can be made via an ester, for example. After the synthesis has been completed, it can be split off from the resin with, for example, trifluoroacetic acid.
- Exemplary here are his carotenoid, vitamin or active ingredient syntheses such as active ingredients in the pharmaceutical or crop protection sector.
- Table I shows the results of analogous reactions with different electrophiles.
- the starting compounds (Grignard compounds) were established within 7-28 h via an od-magnesium exchange.
- the temperature of the reaction solutions were between -78 to + 25 ° C. Good sales were achieved at these temperatures.
- Table II Preparation of Grignard compounds and reaction with electrophiles on a solid support.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Toxicology (AREA)
- Engineering & Computer Science (AREA)
- Structural Engineering (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Polyoxymethylene Polymers And Polymers With Carbon-To-Carbon Bonds (AREA)
- Polymers With Sulfur, Phosphorus Or Metals In The Main Chain (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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DE19830599 | 1998-07-09 | ||
DE19830599A DE19830599A1 (de) | 1998-07-09 | 1998-07-09 | Verfahren zur stereoselektiven Herstellung von Grignardverbindungen und deren Verwendung |
PCT/EP1999/004593 WO2000002928A1 (de) | 1998-07-09 | 1999-07-02 | Verfahren zur stereoselektiven herstellung von grignardverbindungen und deren verwendung |
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EP1102796A1 true EP1102796A1 (de) | 2001-05-30 |
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EP99934559A Withdrawn EP1102796A1 (de) | 1998-07-09 | 1999-07-02 | Verfahren zur stereoselektiven herstellung von grignardverbindungen und deren verwendung |
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US (1) | US6432326B1 (de) |
EP (1) | EP1102796A1 (de) |
JP (1) | JP2002520339A (de) |
KR (1) | KR20010053425A (de) |
CN (1) | CN1308643A (de) |
AU (1) | AU754539B2 (de) |
BR (1) | BR9911929A (de) |
CA (1) | CA2337043A1 (de) |
DE (1) | DE19830599A1 (de) |
HU (1) | HUP0104930A2 (de) |
IL (1) | IL140400A0 (de) |
NO (1) | NO20010122L (de) |
WO (1) | WO2000002928A1 (de) |
ZA (1) | ZA200101090B (de) |
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CH455766A (de) | 1961-07-19 | 1968-05-15 | Gen Electric | Verfahren zur Herstellung von Grignardreagens |
US3428616A (en) | 1966-05-09 | 1969-02-18 | Ritter Pfaudler Corp | Regenerative polymeric grignard compositions |
US3856867A (en) | 1972-03-06 | 1974-12-24 | Rhodia | Process for the preparation of grignard reagents and their utilization in organic syntheses |
US4293497A (en) | 1977-12-29 | 1981-10-06 | Scm Corporation | Coupling reaction involving a grignard and allylic halide |
US5073659A (en) | 1989-08-22 | 1991-12-17 | Eisai Co., Ltd. | Process for the preparation of terpenes |
US5286726A (en) * | 1990-04-12 | 1994-02-15 | The Regents Of The University Of Michigan | Difluoroglutamic acid conjugates with folates and anti-folates for the treatment of neoplastic diseases |
US5665720A (en) * | 1992-08-07 | 1997-09-09 | Merck & Co., Inc. | Benzoxazinones as inhibitors of HIV reverse transcriptase |
DE19628159A1 (de) | 1996-07-12 | 1998-01-15 | Studiengesellschaft Kohle Mbh | Verfahren zur Synthese von Grignard-Verbindungen unter Einsatz von Katalysatoren |
ATE232847T1 (de) * | 1999-05-27 | 2003-03-15 | Givaudan Sa | Alpha, beta-ungesättigte ketone |
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1998
- 1998-07-09 DE DE19830599A patent/DE19830599A1/de not_active Withdrawn
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1999
- 1999-07-02 EP EP99934559A patent/EP1102796A1/de not_active Withdrawn
- 1999-07-02 CA CA002337043A patent/CA2337043A1/en not_active Abandoned
- 1999-07-02 AU AU50302/99A patent/AU754539B2/en not_active Ceased
- 1999-07-02 IL IL14040099A patent/IL140400A0/xx unknown
- 1999-07-02 WO PCT/EP1999/004593 patent/WO2000002928A1/de not_active Application Discontinuation
- 1999-07-02 US US09/720,883 patent/US6432326B1/en not_active Expired - Fee Related
- 1999-07-02 KR KR1020017000264A patent/KR20010053425A/ko not_active Application Discontinuation
- 1999-07-02 JP JP2000559157A patent/JP2002520339A/ja not_active Withdrawn
- 1999-07-02 HU HU0104930A patent/HUP0104930A2/hu unknown
- 1999-07-02 CN CN99808447A patent/CN1308643A/zh active Pending
- 1999-07-02 BR BR9911929-3A patent/BR9911929A/pt not_active Application Discontinuation
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CN1308643A (zh) | 2001-08-15 |
BR9911929A (pt) | 2001-03-27 |
ZA200101090B (en) | 2002-05-22 |
WO2000002928A1 (de) | 2000-01-20 |
IL140400A0 (en) | 2002-02-10 |
NO20010122D0 (no) | 2001-01-08 |
US6432326B1 (en) | 2002-08-13 |
KR20010053425A (ko) | 2001-06-25 |
CA2337043A1 (en) | 2000-01-20 |
AU5030299A (en) | 2000-02-01 |
AU754539B2 (en) | 2002-11-21 |
NO20010122L (no) | 2001-01-08 |
JP2002520339A (ja) | 2002-07-09 |
HUP0104930A2 (hu) | 2002-04-29 |
DE19830599A1 (de) | 2000-01-13 |
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