EP1309531A1 - Derivatives of 4-(trifluoromethyl)-phenol and 4-(trifluoromethylphenyl)-2-(tetrahydropyranyl) ether and method for producing the same - Google Patents
Derivatives of 4-(trifluoromethyl)-phenol and 4-(trifluoromethylphenyl)-2-(tetrahydropyranyl) ether and method for producing the sameInfo
- Publication number
- EP1309531A1 EP1309531A1 EP01962929A EP01962929A EP1309531A1 EP 1309531 A1 EP1309531 A1 EP 1309531A1 EP 01962929 A EP01962929 A EP 01962929A EP 01962929 A EP01962929 A EP 01962929A EP 1309531 A1 EP1309531 A1 EP 1309531A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- aryl
- trifluoromethyl
- ether
- tetrahydropyranyl
- derivatives
- 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- Withdrawn
Links
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 title claims abstract description 39
- BAYGVMXZJBFEMB-UHFFFAOYSA-N 4-(trifluoromethyl)phenol Chemical class OC1=CC=C(C(F)(F)F)C=C1 BAYGVMXZJBFEMB-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 238000004519 manufacturing process Methods 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- 239000012039 electrophile Substances 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 23
- -1 trifluoromethylphenyl Chemical group 0.000 claims description 54
- 125000003118 aryl group Chemical group 0.000 claims description 48
- 238000002360 preparation method Methods 0.000 claims description 31
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 229910052801 chlorine Inorganic materials 0.000 claims description 14
- 229910052794 bromium Inorganic materials 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 229910052740 iodine Inorganic materials 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 150000001412 amines Chemical class 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- 229910052744 lithium Inorganic materials 0.000 claims description 6
- 229910052796 boron Inorganic materials 0.000 claims description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 28
- 230000015572 biosynthetic process Effects 0.000 description 16
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- 238000003786 synthesis reaction Methods 0.000 description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 14
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 11
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000000460 chlorine Substances 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 9
- 239000002585 base Substances 0.000 description 8
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000001569 carbon dioxide Substances 0.000 description 5
- 229910002092 carbon dioxide Inorganic materials 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 231100000331 toxic Toxicity 0.000 description 4
- 230000002588 toxic effect Effects 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- BXQPCQLNANMZFL-UHFFFAOYSA-N 2-hydroxy-5-(trifluoromethyl)benzaldehyde Chemical compound OC1=CC=C(C(F)(F)F)C=C1C=O BXQPCQLNANMZFL-UHFFFAOYSA-N 0.000 description 3
- YQDOJQUHDQGQPH-UHFFFAOYSA-N 2-hydroxy-5-(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=CC(C(F)(F)F)=CC=C1O YQDOJQUHDQGQPH-UHFFFAOYSA-N 0.000 description 3
- RZFLJQHPAGLLPF-UHFFFAOYSA-N 4-(trifluoromethyl)benzene-1,2-diol Chemical compound OC1=CC=C(C(F)(F)F)C=C1O RZFLJQHPAGLLPF-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 238000011097 chromatography purification Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 3
- 239000000155 melt Substances 0.000 description 3
- 125000006239 protecting group Chemical group 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
- 238000006467 substitution reaction Methods 0.000 description 3
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 3
- HNRMPXKDFBEGFZ-UHFFFAOYSA-N 2,2-dimethylbutane Chemical compound CCC(C)(C)C HNRMPXKDFBEGFZ-UHFFFAOYSA-N 0.000 description 2
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 2
- RFHPVPXRWIJXKP-UHFFFAOYSA-N 2-[2-chloro-4-(trifluoromethyl)phenoxy]oxane Chemical compound ClC1=CC(C(F)(F)F)=CC=C1OC1OCCCC1 RFHPVPXRWIJXKP-UHFFFAOYSA-N 0.000 description 2
- YNWKEXMSQQUMEL-UHFFFAOYSA-N 2-chloro-4-(trifluoromethyl)phenol Chemical compound OC1=CC=C(C(F)(F)F)C=C1Cl YNWKEXMSQQUMEL-UHFFFAOYSA-N 0.000 description 2
- FGLWZZOKMAMVSE-UHFFFAOYSA-N 2-hydroxy-5-(trifluoromethyl)benzonitrile Chemical compound OC1=CC=C(C(F)(F)F)C=C1C#N FGLWZZOKMAMVSE-UHFFFAOYSA-N 0.000 description 2
- PFEOZHBOMNWTJB-UHFFFAOYSA-N 3-methylpentane Chemical compound CCC(C)CC PFEOZHBOMNWTJB-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-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
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 150000004985 diamines Chemical group 0.000 description 2
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 235000013847 iso-butane Nutrition 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- OFCCYDUUBNUJIB-UHFFFAOYSA-N n,n-diethylcarbamoyl chloride Chemical compound CCN(CC)C(Cl)=O OFCCYDUUBNUJIB-UHFFFAOYSA-N 0.000 description 2
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 1
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- 125000005919 1,2,2-trimethylpropyl group Chemical group 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- WZHVDKJZQPMSOI-UHFFFAOYSA-N 1,6-dichloro-4-(trifluoromethyl)cyclohexa-2,4-dien-1-ol Chemical compound OC1(Cl)C=CC(C(F)(F)F)=CC1Cl WZHVDKJZQPMSOI-UHFFFAOYSA-N 0.000 description 1
- 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 1
- CFIPQRIPCRRISV-UHFFFAOYSA-N 1-methoxy-4-(trifluoromethyl)benzene Chemical compound COC1=CC=C(C(F)(F)F)C=C1 CFIPQRIPCRRISV-UHFFFAOYSA-N 0.000 description 1
- JUXXCHAGQCBNTI-UHFFFAOYSA-N 1-n,1-n,2-n,2-n-tetramethylpropane-1,2-diamine Chemical compound CN(C)C(C)CN(C)C JUXXCHAGQCBNTI-UHFFFAOYSA-N 0.000 description 1
- BNASHXXLSULNNI-UHFFFAOYSA-N 2,2-dimethylpropane Chemical compound CC(C)(C)C.CC(C)(C)C BNASHXXLSULNNI-UHFFFAOYSA-N 0.000 description 1
- QNMPMQCWNDAVBA-UHFFFAOYSA-N 2-[2-iodo-4-(trifluoromethyl)phenoxy]oxane Chemical compound IC1=CC(C(F)(F)F)=CC=C1OC1OCCCC1 QNMPMQCWNDAVBA-UHFFFAOYSA-N 0.000 description 1
- HLAFIWWTHKRMKZ-UHFFFAOYSA-N 2-[2-phenylsulfanyl-4-(trifluoromethyl)phenoxy]oxane Chemical compound C=1C=CC=CC=1SC1=CC(C(F)(F)F)=CC=C1OC1CCCCO1 HLAFIWWTHKRMKZ-UHFFFAOYSA-N 0.000 description 1
- BHTKIYIEMXRHGL-UHFFFAOYSA-N 2-amino-4-(trifluoromethyl)phenol Chemical compound NC1=CC(C(F)(F)F)=CC=C1O BHTKIYIEMXRHGL-UHFFFAOYSA-N 0.000 description 1
- DTEDKIRYMYDIGO-UHFFFAOYSA-N 2-bromo-4-(trifluoromethyl)phenol Chemical compound OC1=CC=C(C(F)(F)F)C=C1Br DTEDKIRYMYDIGO-UHFFFAOYSA-N 0.000 description 1
- ISPYQTSUDJAMAB-UHFFFAOYSA-N 2-chlorophenol Chemical compound OC1=CC=CC=C1Cl ISPYQTSUDJAMAB-UHFFFAOYSA-N 0.000 description 1
- 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 1
- AUGPEVLQKDQWBL-UHFFFAOYSA-N 2-hydroxy-5-(trifluoromethyl)benzene-1,3-dicarboxylic acid Chemical compound OC(=O)C1=CC(C(F)(F)F)=CC(C(O)=O)=C1O AUGPEVLQKDQWBL-UHFFFAOYSA-N 0.000 description 1
- WFRURKYDETYZGF-UHFFFAOYSA-N 2-methoxy-5-(trifluoromethyl)benzaldehyde Chemical compound COC1=CC=C(C(F)(F)F)C=C1C=O WFRURKYDETYZGF-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- SIIVSJJXGOXPRE-UHFFFAOYSA-N 2-methylsulfanyl-4-(trifluoromethyl)phenol Chemical compound CSC1=CC(C(F)(F)F)=CC=C1O SIIVSJJXGOXPRE-UHFFFAOYSA-N 0.000 description 1
- JZBVVNOPMZSANQ-UHFFFAOYSA-N 3,3-dimethylbutan-2-one Chemical compound CC(=O)C(C)(C)C.CC(=O)C(C)(C)C JZBVVNOPMZSANQ-UHFFFAOYSA-N 0.000 description 1
- FJWPLVKSMFSXFQ-UHFFFAOYSA-N 3,4-diethylhept-3-ene Chemical group CCCC(CC)=C(CC)CC FJWPLVKSMFSXFQ-UHFFFAOYSA-N 0.000 description 1
- YWJMFYOMJODKJY-UHFFFAOYSA-N 3-bromo-4-(trifluoromethyl)phenol Chemical compound OC1=CC=C(C(F)(F)F)C(Br)=C1 YWJMFYOMJODKJY-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- 238000005618 Fries rearrangement reaction Methods 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 238000006612 Kolbe reaction Methods 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229940027987 antiseptic and disinfectant phenol and derivative Drugs 0.000 description 1
- 150000008365 aromatic ketones Chemical class 0.000 description 1
- 150000005840 aryl radicals Chemical class 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000005620 boronic acid group Chemical class 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- VHHHONWQHHHLTI-UHFFFAOYSA-N hexachloroethane Chemical compound ClC(Cl)(Cl)C(Cl)(Cl)Cl VHHHONWQHHHLTI-UHFFFAOYSA-N 0.000 description 1
- 239000004312 hexamethylene tetramine Substances 0.000 description 1
- 235000010299 hexamethylene tetramine Nutrition 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229910052500 inorganic mineral Chemical class 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000001282 iso-butane Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- QWTDNUCVQCZILF-UHFFFAOYSA-N isopentane Chemical compound CCC(C)C QWTDNUCVQCZILF-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- FJVKSHACIRATIW-UHFFFAOYSA-N methyl 5-iodo-2-methoxybenzoate Chemical compound COC(=O)C1=CC(I)=CC=C1OC FJVKSHACIRATIW-UHFFFAOYSA-N 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Chemical class 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 231100000219 mutagenic Toxicity 0.000 description 1
- 230000003505 mutagenic effect Effects 0.000 description 1
- DIHKMUNUGQVFES-UHFFFAOYSA-N n,n,n',n'-tetraethylethane-1,2-diamine Chemical compound CCN(CC)CCN(CC)CC DIHKMUNUGQVFES-UHFFFAOYSA-N 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940094933 n-dodecane Drugs 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- YKVJZSZZQKQJMO-UHFFFAOYSA-N n-methoxy-n-methylpropanamide Chemical compound CCC(=O)N(C)OC YKVJZSZZQKQJMO-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 125000001190 organyl group Chemical group 0.000 description 1
- 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 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 238000006303 photolysis reaction Methods 0.000 description 1
- 230000015843 photosynthesis, light reaction Effects 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000011814 protection agent Substances 0.000 description 1
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 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 1
- 239000002002 slurry Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- UYCAUPASBSROMS-AWQJXPNKSA-M sodium;2,2,2-trifluoroacetate Chemical compound [Na+].[O-][13C](=O)[13C](F)(F)F UYCAUPASBSROMS-AWQJXPNKSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 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 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- 238000006692 trifluoromethylation reaction Methods 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
- LVTRCGWMZFJGNV-UHFFFAOYSA-N trimethyl-[2-(oxan-2-yloxy)-5-(2,2,2-trifluoroethyl)phenyl]silane Chemical compound C[Si](C1=C(C=CC(=C1)CC(F)(F)F)OC1OCCCC1)(C)C LVTRCGWMZFJGNV-UHFFFAOYSA-N 0.000 description 1
- BOKMNRDXJVLMIP-UHFFFAOYSA-N trimethyl-[2-(oxan-2-yloxy)-5-(trifluoromethyl)phenyl]silane Chemical compound C[Si](C)(C)C1=CC(C(F)(F)F)=CC=C1OC1OCCCC1 BOKMNRDXJVLMIP-UHFFFAOYSA-N 0.000 description 1
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
- RSJKGSCJYJTIGS-UHFFFAOYSA-N undecane Chemical compound CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
- C07F7/0827—Syntheses with formation of a Si-C bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/50—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions decreasing the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/24—Halogenated derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C47/00—Compounds having —CHO groups
- C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
- C07C47/56—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing hydroxy groups
- C07C47/565—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing hydroxy groups all hydroxy groups bound to the ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/15—Preparation of carboxylic acids or their salts, halides or anhydrides by reaction of organic compounds with carbon dioxide, e.g. Kolbe-Schmitt synthesis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
- C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
- C07C65/05—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring o-Hydroxy carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
- C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
-
- 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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
Definitions
- the invention is in the field of derivatives of 4- (trifluoromethyl) phenol and derivatives of 4- (trifluoro-10 methylphenyl) -2- (tetrahydrop ⁇ ranyl) ether and relates to new derivatives and a process for the preparation of these derivatives.
- WO 98/42664 describes the synthesis of 2-hydroxy-5-trifluoromethylbenzaldehyde by reacting 4- (trifluoromethyl) phenol with tin tetrachloride and paraformaldehyde at 110 ° C. and a reaction time of 12 hours. In addition to the low yield (12%), here too
- N-formylpiperidine is available from K.K. Laali, G.F. Koser, S. Subramanyam, D.A. Forsyth, J. Org. Chem. 58 (1993) 1385. The yield is only 41%.
- FR 2735771 describes the synthesis of 2-hydroxy-5-trifluoromethylbenzoic acid from the potassium salt of 4- (trifluoromethyl) phenol via Kolbe synthesis.
- the reaction requires a reaction temperature of 180 ° C and a carbon dioxide pressure of 10 bar. This requires special equipment. In addition, the yield is only 45%.
- An alternative preparation is from S. Yamamoto, S. Hashiguchi, S. Miki, Y. Igata, T. Watanabe.
- EP 206951 AI describes the synthesis of 2-chloro-4- (trifluoromethyl) phenol by trifluoromethylation of 2-chlorophenol
- J.-C. Blazejewski, R. Dorme, C. Wakselman, J. Chem. Soc, Perkin Trans. 1 (1987) 1861 describe the synthesis of 2-chloro-4- (trifluoromethyl) phenol by reacting 4- (trifluoromethyl) - phenol with N triumchlorite and sulfuric acid. In both cases the yield is less than 10% and the product is with a variety other components contaminated.
- the direct chlorination of 4- (trifluoromethyl) phenol is described in EP 0188031 B1, DE 2311638 Cl and CH 567359.
- Simple and quick implementation of the procedure and low demands on the safety devices were desirable. value. In particular, handling toxicologically questionable chemicals should be avoided. A lengthy purification of the product from the reaction mixture should also be avoided. Ideally, it should be possible to use the products directly for further reactions without further purification.
- a further task was the production of new, previously unknown 2- and 2,5-disubstituted derivatives of 4- (trifluoromethyl) phenol and 2- and 2,5-disubstituted derivatives of 4- (trifluoromethylphenyl) -2- ( tetrahydropyranyl) - ethers.
- the present invention therefore relates to a process for the preparation of compounds of the general formula (1)
- R is hydrogen, tetrahydropyran-2-yl
- Aryl independently of one another represents phenyl, naphthyl, R 1 -C 6 H 4 , characterized in that the compound of formula (2) 4- (trifluoromethylphenyl) -2- (tetrahydropyranyl) ether
- Essential to the invention is the use of the 4- (trifluoromethylphenyl) -2- (tetrahydropyranyl) ether, it enables targeted derivatization in 2 or in 2 and 5 positions.
- monosubstituted derivatives are produced.
- both the symmetrical derivatives (X and Y identical) and the asymmetrical derivatives (X different from Y) can be produced.
- the preparation of the symmetrical derivatives is particularly preferred.
- the compound of formula (2) ' 4- (trifluoromethylphenyl) -2- (tetrahydropyranyl) ether is known, it is available synthetically as for example from A. Ouedraogo, J. Lessard, Can. J. Chem. 69 (1991) 474.
- EX and / or EY compounds are used as electrophiles, in which E represents a good leaving group and X and / or Y inserts the desired side chain.
- EX CHO
- the compound of the general formula X-NR 1 2 (3) is suitable as the electrophile EX
- alkyl radicals for R 1 are branched or unbranched Ci-C ⁇ -alkyl chains, preferably methyl, ethyl, isopropyl, n-propyl, 1-methylethyl, n-butyl, 2-butyl, sec-butyl, tert-butyl, 1- Methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, n-pentyl, 2-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 2- Hexyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,
- alkyl radical R 1 can be localized in the o-, m- and p-positions.
- Suitable solvents are all solvents which are inert under the reaction conditions.
- Preferred solvents are tetrahydrofuran (THF), dioxane and Ci-C ⁇ -ether, simple or mixed Ci-C ß- ether, C 4 -C ⁇ 2 hydrocarbons, such as n-butane, isobutane
- Alkali organyls can be used as bases. It is particularly preferred to use lithium organyl compounds, such as n-butyllithium, sec-butyllithium, t-butyllithium and methyllithium.
- the process according to the invention includes the knowledge that for the synthesis of the onosubstituted derivatives the base is added in equimolar amounts up to a maximum of 1.8 molar excess. The synthesis of the disubstituted derivatives requires the addition of 2 to 4 equivalents of base.
- the reaction is carried out in the presence of an amine, in particular a tertiary diamine.
- amines such as, for example, tetramethylethylenediamine and especially tetraethylethylenediamine diamine and especially tetraethylethylenediamine diamine and especially tetraethylethylenediamine diamine are particularly suitable as suitable amines, such as tetramethylethylene diamine, tetraethylethylene diamine, tetra-n-propylethylene diamine, tetramethylpropylene diamine, tetraethyl-propylene diamine, tetra-n-propylpropylene diamine.
- the strong base is usually placed in a solvent which is inert under the reaction conditions.
- the 5 educt 4- (trifluoromethylphenyl) -2- (tetrahydropyranyl) ether which may be dissolved in, for example, tetrahydrofuran or used directly as a melt.
- the electrophile is then added. This can be in bulk or as a solution. Alternatively, it is possible to present the electrophile and add the lithium organyl. In the synthesis of the disubstituted derivatives, it has proven to be advantageous to submit the base and the ether and then to add the electrophile.
- the molar ratio of starting material to electrophile depends on the desired compounds and, in the case of the synthesis of the onosubstituted derivatives, is generally between 1: 1 and 1: 1.9; in the case of disubstituted derivatives, usually between 1: 2 and 1: 4.
- the reaction is carried out at -100 to + 100 ° C, preferably at temperatures between -20 ° C and + 20 ° C.
- the reaction is carried out in a pressure range from 0.0001 to 200 bar, in particular 0.001 to 20 bar, preferably from 0.001 to 6 bar.
- the preferred molar ratio of the amine to the lithium organyl is 0: 1 to 30 10: 1, in particular 0: 1 to 5: 1. 0: 1, 1: 1 and 2: 1 are very particularly preferred.
- the course of the reaction can be determined by detecting the starting material ⁇ 4- (trifluoromethylphenyl) -2- (tetrahydropyranyl) ether in the reaction
- the 2 and 2,5 -substituted derivatives of 4- (trifluoromethyl) phenol are obtained by splitting off the tetrahydropyranyl group of the corresponding 2 and 2,5-substituted derivatives of 4- (trifluoromethylphenyl) -2- (tetrahydropyranyl) ether , This cleavage is usually carried out under acid catalysis.
- Carboxylic acids and mineral acids are suitable for acid-catalyzed removal of the tetrahydropyranyl group.
- Trifluoroacetic acid and hydrochloric acid are particularly preferred.
- the process according to the invention can be carried out batchwise or continuously, for example using a reaction tube or a stirred reactor cascade.
- the 2- and 2,5-substituted derivatives of 4- (trifluoromethyl) phenol and 4- (trifluoromethylphenyl) -2- (tetrahydropyranyl) ether produced by the process according to the invention can be used as starting products for the synthesis of dyes, crop protection agents and / or Medicines are used.
- Another object of the present invention relates to
- R is hydrogen or tetrahydropyran-2-yl and when R is hydrogen
- Aryl represents phenyl, R 1 - C 5 H 4 , when R is tetrahydropyran-2-yl
- R 1 is C 1 -C 8 alkyl
- Aryl represents phenyl, R ⁇ —C ⁇ EI.
- the present invention further relates to 2,5-disubstituted derivatives of 4- (trifluoromethyl) phenol and / or 2,5-disubstituted derivatives of 4- (trifluoromethylphenyl) -2- (tetrahydropyranyl) ether of the following formula
- R is hydrogen, tetrahydropyran-2-yl
- Y is independent of X for B (OH) 2 , B (OR 1 ), B (OAryl) 2 ,
- R 1 independently of one another for Ci-Cs-alkyl
- Aryl independently of one another represents phenyl, naphthyl, R 1 -CgH 4 ,
- a cloudy solution is formed, which is added dropwise after 15 min to 750 ml of 38% hydrochloric acid in 500 ml of water within 30 min at a maximum of 45 ° C. There is a strong gas development.
- the mixture is stirred overnight, the aqueous phase is separated off, 70 ml of M 5 dioxane / HCl solution are added to the organic phase and the mixture is stirred again overnight.
- the product is crystallized by cooling to -30 ° C (2 to 3 h), suction filtered, washed with 500 ml of cold pentane and that Product air-dried. 220 g (GC: 98.3%, 1.13 mol, yield 75%) of 2-hydroxy-5- (trifluoromethyl) benzaldehyde are obtained in the form of colorless crystals (mp: 60.1 to 61.8 ° C.).
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Abstract
The invention relates to a method for producing 2- and 2,5-substituted derivatives of 4-(trifluoromethyl)-phenol and 4-(2-trifluoromethyl)-phenyl)-2-tetrahydropyranyl) ether and to novel derivatives. Said method is characterised in that a compound of formula (2) 4-(trifluoromethylphenyl)-2-(tetrahydropyranyl) ether is reacted with an electrophile E-X or a combination of electrophiles E-X and E-Y in the presence of a base, X and Y having the meanings given in the description.
Description
DERIVATE DES 4- (TRIFLUORMETHYL) -PHENOLS SOWIE DES 4- (TRIFLUORMETHYLPHENYL) -2- (TETRAHYDROPYRANYL) ETHERS UND VERFAHREN ZU IHRER HERSTELLUNGDERIVATIVES OF THE 4- (TRIFLUORMETHYL) -PHENOL AND THE 4- (TRIFLUORMETHYLPHENYL) -2- (TETRAHYDROPYRANYL) ETHER AND METHOD FOR THE PRODUCTION THEREOF
Einleitungintroduction
Die Erfindung befindet sich auf dem Gebiet der Derivate des 4-(Trifluormethyl)-phenols und der Derivate der 4- (Trifluor- 10 methylphenyl) -2-(tetrahydropγranyl) ether und betrifft neue Derivate sowie ein Verf hren zur Herstellung dieser Derivate .The invention is in the field of derivatives of 4- (trifluoromethyl) phenol and derivatives of 4- (trifluoro-10 methylphenyl) -2- (tetrahydropγranyl) ether and relates to new derivatives and a process for the preparation of these derivatives.
Stand der TechnikState of the art
15 Die Synthese von 2-Hydroxy-5-trifluormethylbenzaldehγd ist in WO 98/29411 durch Umsetzung von 4-(Trifluormethyl) -phenol mit Hexamethylentetramin beschrieben. Neben der unbefriedigenden Ausbeute (43 %) ist die lange Reaktionszeit (24 h) , der Einsatz der korrosiven und giftigen Trifluoressigsäure sowie die erfor-15 The synthesis of 2-hydroxy-5-trifluoromethylbenzaldehγd is described in WO 98/29411 by reacting 4- (trifluoromethyl) phenol with hexamethylenetetramine. In addition to the unsatisfactory yield (43%), the long reaction time (24 h), the use of corrosive and toxic trifluoroacetic acid and the required
20 derliche chromatographische Aufreinigung nachteilig. WO 98/42664 beschreibt die Synthese von 2-Hydroxy-5-trifluormethylbenzaldehyd durch Umsetzung von 4- (Trifluormethyl) -phenol mit Zinntetrachlorid und Paraformaldehyd bei 110°C und einer Reaktionszeit von 12 Stunden. Neben der geringen Ausbeute (12 %) , ist auch hier die20 such chromatographic purification disadvantageous. WO 98/42664 describes the synthesis of 2-hydroxy-5-trifluoromethylbenzaldehyde by reacting 4- (trifluoromethyl) phenol with tin tetrachloride and paraformaldehyde at 110 ° C. and a reaction time of 12 hours. In addition to the low yield (12%), here too
25 erforderliche chromatographische Aufreinigung des Produktes sowie der Einsatz von giftigem Zinnchlorid und mutagenem Paraformaldehyd nachteilig.25 necessary chromatographic purification of the product and the use of toxic tin chloride and mutagenic paraformaldehyde disadvantageous.
Die Synthese von 2-Methoxy-5-trifluormethylbenzaldehyd durch 30 Umsetzung von p-Trifluormethylanisol mit Butyllithium undThe synthesis of 2-methoxy-5-trifluoromethylbenzaldehyde by reaction of p-trifluoromethylanisole with butyllithium and
N-Formylpiperidin ist von K.K. Laali, G.F. Koser, S. Subramanyam, D.A. Forsyth, J. Org. Chem. 58 (1993) 1385 beschrieben. Die Ausbeute beträgt nur 41 % .N-formylpiperidine is available from K.K. Laali, G.F. Koser, S. Subramanyam, D.A. Forsyth, J. Org. Chem. 58 (1993) 1385. The yield is only 41%.
35 Die Synthese von 2-Hydroxy-5-trifluormethylacetophenon durch35 The synthesis of 2-hydroxy-5-trifluoromethylacetophenone by
Photolyse (Photo-Fries-Umlagerung) von 4- (Trifluormethyl) -phenol in Gegenwart von 3 , 3-Dimethyl-2-butanon (Pinacolon) oder 1,1, 1-Trichlorethan ist beschrieben in M.A. Miranda, J. Chem. Soc, Chem. Commun. (1995) 2009; F. Galindo, M.C. Jimenez,Photolysis (Photo-Fries rearrangement) of 4- (trifluoromethyl) phenol in the presence of 3, 3-dimethyl-2-butanone (pinacolone) or 1,1, 1-trichloroethane is described in M.A. Miranda, J. Chem. Soc, Chem. Commun. (1995) 2009; F. Galindo, M.C. Jimenez,
40 M.A. Miranda, R. Tor os, J. Photochem. Photobiol., A 97 (1996) 151 und H. Garcia, Synthesis (1985) 901. Der Umsatz beträgt jedoch nur 25 %, wobei ein Reaktionsprodukt erhalten wird das zu 63 % 2-Hydroxy-5-trifluormethylacetophenon enthält.40 M.A. Miranda, R. Tor os, J. Photochem. Photobiol., A 97 (1996) 151 and H. Garcia, Synthesis (1985) 901. However, the conversion is only 25%, a reaction product being obtained which contains 63% 2-hydroxy-5-trifluoromethylacetophenone.
45 DE 2653601 AI beschreibt die Herstellung von 2-Hydroxy-5-tri- fluormethylacetophenon via Friedel - Crafts - Acylierung von 4- (Trifluormethyl) -phenol mit Carbonsäurehalogeniden. Jedoch
erfordert diese Reaktion die Verwendung von wasserfreiem Fluorwasserstoff, der sehr korrosiv und extrem toxisch ist.45 DE 2653601 AI describes the preparation of 2-hydroxy-5-trifluoromethylacetophenone via Friedel - Crafts - acylation of 4- (trifluoromethyl) phenol with carboxylic acid halides. however This reaction requires the use of anhydrous hydrogen fluoride, which is very corrosive and extremely toxic.
DE 2907379 beschreibt die Synthese von aromatischen Ketonen (R = H, X = CO(Aryl)) in einer Grignard Reaktion aus demDE 2907379 describes the synthesis of aromatic ketones (R = H, X = CO (aryl)) in a Grignard reaction from the
O-methylgeschützten 2-Cyano-4- (trifluormethyl) -phenol . Dieser Syntheseweg hat folgende Nachteile: 2-Cyano-4- (trifluormethyl) - phenol ist nur über viele Reaktionsstufen zugänglich. Die Herstellung von Grignard-Reagenzien birgt die Gefahr der Edukt- ' Akkumulation. Die Methylschutzgruppe muss anschließend in einer eigenen Reaktionsstufe mit Bortrichlorid, das sehr teuer ist, wieder abgespalten werden.O-methyl protected 2-cyano-4- (trifluoromethyl) phenol. This synthetic route has the following disadvantages: 2-cyano-4- (trifluoromethyl) phenol is only accessible via many reaction stages. The production of Grignard reagents carries the risk of starting material 'accumulation. The methyl protective group must then be split off again in a separate reaction step with boron trichloride, which is very expensive.
FR 2735771 beschreibt die Synthese von 2-Hydroxy-5-trifluor- methylbenzoesäure aus dem Kaliumsalz von 4- (Trifluormethyl) - phenol via Kolbe - Synthese. Die Reaktion erfordert eine Reaktionstemperatur von 180°C und ein Kohlendioxid-Überdruck von 10 bar. Dies erfordert Spezialapparaturen. Außerdem liegt die Ausbeute nur bei 45 %. Eine alternative Herstellung ist von S. Yamamoto, S. Hashiguchi, S. Miki, Y. Igata, T. Watanabe,. FR 2735771 describes the synthesis of 2-hydroxy-5-trifluoromethylbenzoic acid from the potassium salt of 4- (trifluoromethyl) phenol via Kolbe synthesis. The reaction requires a reaction temperature of 180 ° C and a carbon dioxide pressure of 10 bar. This requires special equipment. In addition, the yield is only 45%. An alternative preparation is from S. Yamamoto, S. Hashiguchi, S. Miki, Y. Igata, T. Watanabe.
M. Shiraishi, Chem. Pharm. Bull. 44 (1996) 734 beschrieben, ausgehend von 5-Iod-2-methoxybenzoesäuremethylester setzt man diesen mit Natriumtrifluoracetat in Gegenwart von Kupferiodid bei 160°C um. Die Abspaltung der Methylgruppen erfolgt mit Bortribromid. Die Ausbeute über beide Stufen liegt bei 16 %. Eine weiterer Syntheseweg wird von J. Alexander, Org. Prep. Proced. Int. 18 (1986) 213 beschrieben: dort wird 3-Brom-4- (Trifluormethyl) - phenol mit Dimethylsulfat methyliert, mit Butyllithium lithiiert, mit Kohlendioxid umgesetzt und schließlich mit Pyridiniumchlorid de ethyliert. Die Syntheseroute über die Bromverbindung und das Schützen der Hydroxygruppe mit einer Methylgruppe, die in einer separaten Reaktionsstufefwieder abgespalten werden musss ist umständlich. In US 5,712,279 wird schließlich 4- (Trifluormethyl) - phenol mit Diethylcarbamylchlorid umgesetzt, mit s-Butyllithium / Kohlendioxid bei -73°C carboxyliert und die Schutzgruppe dann mit Zitronensäure abgespalten. Der Umgang mit s-Butyllithium ist im Gegensatz zu n-Butyllithium nicht unproblematisch. Weiterhin ist der Einsatz von Diethylcarbamylchlorid aus toxikologischen Gründen unerwünscht (Krebs erzeugend, vererbbare Schäden verursachen) .M. Shiraishi, Chem. Pharm. Bull. 44 (1996) 734, starting from methyl 5-iodo-2-methoxybenzoate, this is reacted with sodium trifluoroacetate in the presence of copper iodide at 160 ° C. The methyl groups are split off with boron tribromide. The yield over both stages is 16%. Another synthetic route is described by J. Alexander, Org. Prep. Proced. Int. 18 (1986) 213: there 3-bromo-4- (trifluoromethyl) phenol is methylated with dimethyl sulfate, lithiated with butyllithium, reacted with carbon dioxide and finally de-ethylated with pyridinium chloride. The synthesis route via the bromo compound and protecting the hydroxy group with a methyl group, which are cleaved in a separate Reaktionsstufefwieder must s is cumbersome. In US Pat. No. 5,712,279, 4- (trifluoromethyl) phenol is finally reacted with diethylcarbamyl chloride, carboxylated with s-butyllithium / carbon dioxide at -73 ° C. and the protective group is then split off with citric acid. In contrast to n-butyllithium, handling s-butyllithium is not without problems. Furthermore, the use of diethylcarbamyl chloride is undesirable for toxicological reasons (carcinogenic, causing inheritable damage).
EP 206951 AI beschreibt die Synthese von 2-Chlor-4- (trifluormethyl) -phenol durch Trifluormethylierung von 2-Chlorphenol, J.-C. Blazejewski, R. Dorme, C. Wakselman, J. Chem. Soc, Perkin Trans. 1 (1987) 1861 beschreiben die Synthese von 2-Chlor-4-(tri- fluormethyl) -phenol durch Umsetzung von 4- (Trifluormethyl) -phenol mit N triumchlorit und Schwefelsäure. In beiden Fällen liegt die Ausbeute unter 10 % und das Produkt ist mit einer Vielzahl
anderer Komponenten verunreinigt . Die direkte Chlorierung von 4- (Trifluormethyl) -phenol ist in EP 0188031 Bl, DE 2311638 Cl sowie CH 567359 beschrieben. Auch die nukleophile aromatische Substitution eines Chlors von 1, 2-Dichloro-4- (trifluormethyl )- phenol führt zu dem gewünschten Produkt . Allerdings sind für die Reaktion drastische Bedingungen (Kaliumhydroxid in DMSO) und lange Reaktionszeiten (47 h) erforderlich um auf gute Ausbeuten (90 %) zu kommen (FR 2529197, EP 19388, JP 59139336, US 4548640).EP 206951 AI describes the synthesis of 2-chloro-4- (trifluoromethyl) phenol by trifluoromethylation of 2-chlorophenol, J.-C. Blazejewski, R. Dorme, C. Wakselman, J. Chem. Soc, Perkin Trans. 1 (1987) 1861 describe the synthesis of 2-chloro-4- (trifluoromethyl) phenol by reacting 4- (trifluoromethyl) - phenol with N triumchlorite and sulfuric acid. In both cases the yield is less than 10% and the product is with a variety other components contaminated. The direct chlorination of 4- (trifluoromethyl) phenol is described in EP 0188031 B1, DE 2311638 Cl and CH 567359. The nucleophilic aromatic substitution of a chlorine of 1,2-dichloro-4- (trifluoromethyl) phenol also leads to the desired product. However, drastic conditions (potassium hydroxide in DMSO) and long reaction times (47 h) are required for the reaction in order to achieve good yields (90%) (FR 2529197, EP 19388, JP 59139336, US 4548640).
Die Herstellung von 2-Brom-4-(trifluormethyl) -phenol durch direkte Bromierung von 4- (Trifluormethyl) -phenol mit elementarem Brom ist beschrieben (S. Yamamoto, S. Hashiguchi, S. Miki, Y. Igata, T. Watanabe, M. Shiraishi, Chem. Pharm. Bull. 44 (1996) 734; WO 9749710, EP 477789, EP 49383). Elementares Brom ist giftig und korrosiv. Der Umgang mit diesem Stoff erfordert erhebliche Sicherheitsmaßnahmen.The preparation of 2-bromo-4- (trifluoromethyl) phenol by direct bromination of 4- (trifluoromethyl) phenol with elemental bromine is described (S. Yamamoto, S. Hashiguchi, S. Miki, Y. Igata, T. Watanabe , M. Shiraishi, Chem. Pharm. Bull. 44 (1996) 734; WO 9749710, EP 477789, EP 49383). Elemental bromine is toxic and corrosive. The handling of this substance requires considerable safety measures.
JP 57136591 beschreibt die Verwendung von 2-Methylmercapto-4- (trifluormethyl) -phenol (R = H, X = SR1) .JP 57136591 describes the use of 2-methylmercapto-4- (trifluoromethyl) phenol (R = H, X = SR 1 ).
4- (Trifluormethyl) -1, 2-benzenediol erhält man durch Diazotierung und Verkochung von 2-Amino-4-(trifluormethyl) -phenol. Die Ausbeute liegt bei 45 % (J.P. Chupp, C.R. Jones, M.L. Dahl, J. Hetero- cycl. Chem. 30 (1993) 789).4- (Trifluoromethyl) -1, 2-benzenediol is obtained by diazotization and boiling down of 2-amino-4- (trifluoromethyl) phenol. The yield is 45% (J.P. Chupp, C.R. Jones, M.L. Dahl, J. Heterocycl. Chem. 30 (1993) 789).
Im Stand der Technik sind eine Vielzahl von Methoden zur Synthese einzelner 2-substituierter Derivates des 4- (Trifluormethyl) - phenols beschrieben. Nachteilig an allen bekannten Verfahren sind die z.T. langen Reaktionszeiten, die geringen Ausbeuten sowie der Einsatz von toxikologisch bedenklichen Chemikalien. In einer Anzahl der bekannten Verfahren ist eine aufwendige chromatographische Reinigung zum Erhalt des Reaktionsproduktes erforderlich.A large number of methods for the synthesis of individual 2-substituted derivatives of 4- (trifluoromethyl) phenol are described in the prior art. A disadvantage of all known methods are the partially long reaction times, low yields and the use of toxicologically questionable chemicals. In a number of the known processes, complex chromatographic purification is required to obtain the reaction product.
Die 2 , 5-disubstituierten Derivate des 4- (Trifluormethyl) -phenols sowie die 2-substituierten und die 2 , 5-disubstituierten Derivate des 4- (Trifluormethylphenyl) -2- (tetrahydropyranyl) ethers sowie Verfahren zu ihrer Herstellung sind im Stand der Technik nicht beschrieben.The 2, 5-disubstituted derivatives of 4- (trifluoromethyl) phenol and the 2-substituted and the 2, 5-disubstituted derivatives of 4- (trifluoromethylphenyl) -2- (tetrahydropyranyl) ether and processes for their preparation are known in the art Technology not described.
Aufgabe der vorliegenden Erfindung war es, ein Verfahren zu entwickeln, daß es ermöglicht eine Vielzahl von 2- und 2,5-substi- tuierten Derivaten des 4- (Trifluormethyl) -phenols sowie 2- und 2, 5-substituierten Derivaten des 4- (Trifluormethylphenyl) -2- (tetrahydropyranyl) ethers mit hoher Ausbeute herzustellen. Dabei waren eine einfache und schnelle Verfahrensdurchführung sowie geringe Anforderungen an die Sicherheitseinrichtungen wünschens-
wert. Insbesondere eine Handhabung von toxikologisch bedenklichen Chemikalien sollte vermieden werden. Weiterhin sollte eine langwierige Aufreinigung des Produktes aus dem Reaktionsansatz vermieden werden. Idealerweise sollte es möglich sein die Produkte direkt, ohne weitere Aufreinigung, für weitere Reaktionen einzusetzen. Eine weitere Aufgabe war die Herstellung von neuen, bisher nicht bekannten 2- und 2 , 5-disubstituierten Derivaten des 4- (Trifluormethyl) -phenols sowie von 2- und 2 , 5-disubstituierten Derivaten des 4- (Trifluormethylphenyl) -2- (tetrahydropyranyl) - ethers .It was an object of the present invention to develop a process which enables a large number of 2- and 2,5-substituted derivatives of 4- (trifluoromethyl) phenol and 2- and 2,5-substituted derivatives of 4- (Trifluoromethylphenyl) -2- (tetrahydropyranyl) ether to produce in high yield. Simple and quick implementation of the procedure and low demands on the safety devices were desirable. value. In particular, handling toxicologically questionable chemicals should be avoided. A lengthy purification of the product from the reaction mixture should also be avoided. Ideally, it should be possible to use the products directly for further reactions without further purification. A further task was the production of new, previously unknown 2- and 2,5-disubstituted derivatives of 4- (trifluoromethyl) phenol and 2- and 2,5-disubstituted derivatives of 4- (trifluoromethylphenyl) -2- ( tetrahydropyranyl) - ethers.
Beschreibungdescription
Es wurde gefunden, daß mit dem erfindungsgemäßen Verfahren diese Verbindungen in einfacher Weise und mit hoher Ausbeute hergestellt werden können. Der Einsatz toxikologisch bedenklicher Chemikalien wird vermieden und die apparativen Anforderungen sind gering.It has been found that these compounds can be prepared in a simple manner and with a high yield using the process according to the invention. The use of toxicologically questionable chemicals is avoided and the equipment requirements are low.
Gegenstand der vorliegenden Erfindung ist daher ein Verfahren zur Herstellung von Verbindungen der allgemeinen Formel (1)The present invention therefore relates to a process for the preparation of compounds of the general formula (1)
wobeiin which
R für Wasserstoff, Tetrahydropyran-2-ylR is hydrogen, tetrahydropyran-2-yl
X für B(0H)2, B(ORl)2, B(0Aryl)2, B(ORl) (OAryl) , CHO, COR1, CO(Aryl), COOH, COOR1, SiR^, Si(Aryl)3, OH, SR1, S(Aryl), Cl, Br, I,X for B (0H) 2 , B (OR 1 ) 2 , B (0 aryl) 2 , B (OR 1 ) (O aryl), CHO, COR 1 , CO (aryl), COOH, COOR 1 , SiR ^, Si ( Aryl) 3 , OH, SR 1 , S (aryl), Cl, Br, I,
Y für H, B(0H)2, B(0R1)2, B(0Aryl)2, B (OR1) (OAryl) , CHO, COR1, CO(Aryl), COOH, COOR1, SiR^ , Si(Aryl)3, OH, SR1,Y for H, B (0H) 2 , B (0R 1 ) 2 , B (0Aryl) 2 , B (OR 1 ) (OAryl), CHO, COR 1 , CO (Aryl), COOH, COOR 1 , SiR ^, Si (aryl) 3 , OH, SR 1 ,
S(Aryl), Cl, Br, I,S (aryl), Cl, Br, I,
R unabhängig voneinander für Ci-Cs-AlkylR independently of one another for Ci-Cs-alkyl
Aryl unabhängig voneinander für Phenyl, Naphthyl, R1-C6H4 steht,
dadurch gekennzeichnet, daß man die Verbindung der Formel (2) 4- (Trifluormethylphenyl) -2- (tetrahydropyranyl) etherAryl independently of one another represents phenyl, naphthyl, R 1 -C 6 H 4 , characterized in that the compound of formula (2) 4- (trifluoromethylphenyl) -2- (tetrahydropyranyl) ether
in Gegenwart einer Base mit einem Elektrophil E-X oder einer Kombination von Elektrophilien E-X und E-Y umsetzt, wobei X und Y die oben angegebenen Bedeutung besitzen.in the presence of a base with an electrophile E-X or a combination of electrophiles E-X and E-Y, where X and Y have the meaning given above.
Erfindungswesentlich ist der Einsatz des 4- (Trifluormethylphenyl) -2- (tetrahydropyranyl) ethers, er ermöglicht eine gezielte Derivatisierung in 2 bzw. in 2 und 5 Position.Essential to the invention is the use of the 4- (trifluoromethylphenyl) -2- (tetrahydropyranyl) ether, it enables targeted derivatization in 2 or in 2 and 5 positions.
Mit diesen Verfahren sind sowohl die monosubstituierten (Y = H) Derivate als auch die disubstituierten Derivate (Y H) zugänglich. In einer bevorzugten Ausführungsform werden monosubsti- tuierte Derivate hergestellt. Bei den disubstiuierten Derivaten (Substitution in 2 und 5 Position) sind sowohl die symmetrischen Derivate (X und Y identisch) als auch die unsymmetrischen Derivate (X verschieden von Y) herstellbar. Besonders bevorzugt ist die Herstellung der symmetrischen Derivate.With these methods, both the monosubstituted (Y = H) derivatives and the disubstituted derivatives (Y H) are accessible. In a preferred embodiment, monosubstituted derivatives are produced. In the case of the disubstituted derivatives (substitution in 2 and 5 positions), both the symmetrical derivatives (X and Y identical) and the asymmetrical derivatives (X different from Y) can be produced. The preparation of the symmetrical derivatives is particularly preferred.
Die entsprechenden Derivate des 4- (Trifluormethyl)phenols sind durch Abspaltung der Tetrahydropyranyl-Schutzgruppe nach erfolgter Substitution zugänglich.The corresponding derivatives of 4- (trifluoromethyl) phenol can be obtained by splitting off the tetrahydropyranyl protective group after the substitution has taken place.
Die Verbindung der Formel (2) ' 4- (Trifluormethylphenyl) -2- (tetrahydropyranyl) ether ist bekannt, sie ist synthetisch zugänglich wie beispielsweise von A. Ouedraogo, J. Lessard, Can. J. Chem. 69 (1991) 474 beschrieben.The compound of formula (2) ' 4- (trifluoromethylphenyl) -2- (tetrahydropyranyl) ether is known, it is available synthetically as for example from A. Ouedraogo, J. Lessard, Can. J. Chem. 69 (1991) 474.
Je nach zu synthetisierendem Endprodukt werden als Elektrophil E-X und/oder E-Y Verbindungen eingesetzt, bei denen E eine gute Abgangsgruppe darstellt und X und/oder Y die gewünschte Seitenkette einfügt.
Zur Herstellung von Derivaten, in denen X = CHO ist, eignet sich als Elektrophil E-X die Verbindung der allgemeinen Formel X-NR1 2 (3)Depending on the end product to be synthesized, EX and / or EY compounds are used as electrophiles, in which E represents a good leaving group and X and / or Y inserts the desired side chain. For the preparation of derivatives in which X = CHO, the compound of the general formula X-NR 1 2 (3) is suitable as the electrophile EX
Zur Herstellung von Derivaten, in denen X = COR1 bzw. X = CO(Aryl) eignen sich als Elektrophil E-X Verbindungen der allgemeinen Formel X-N(CH3) (OCH3) (4) und (5) .Compounds of the general formula XN (CH 3 ) (OCH 3 ) (4) and (5) are suitable as electrophile EX for the preparation of derivatives in which X = COR 1 or X = CO (aryl).
Zur Herstellung von Derivaten, in denen X = COORχ, eignen sich als Elektrophil E-X Verbindungen der allgemeinen Formel (6) X-OR1.For the preparation of derivatives in which X = COORχ, EX electrophilic compounds of the general formula (6) X-OR 1 are suitable.
Zur Herstellung von Derivaten, in denen X = COOH, eignen sich als Elektrophil Kohlendioxid in gasförmiger oder fester Form.For the preparation of derivatives in which X = COOH, carbon dioxide in gaseous or solid form are suitable as electrophiles.
Zur Herstellung von Derivaten, in denen X = Cl, Br, I, eignen sich als Elektrophil Chlor, Brom, Iod und/oder entsprechende Verbindungen der allgemeinen Formeln (7) und/oder (8) und/oder (9)For the preparation of derivatives in which X = Cl, Br, I, chlorine, bromine, iodine and / or corresponding compounds of the general formulas (7) and / or (8) and / or (9) are suitable as electrophiles
(7) (8) (9)(7) (8) (9)
Zur Herstellung von Derivaten, in denen X = SR1, eignen sich als Elektrophil E-X Verbindungen der allgemeinen Formel (10) : X-SR (= R1S-SR1) .
Zur Herstellung von Derivaten, in denen X = S(Aryl), eignen sich als Elektrophil Verbindungen der allgemeinen Formel (11) : X-S (Aryl) (= (Aryl) S-S (Aryl) ) .Compounds of the general formula (10) are suitable as electrophile EX for the preparation of derivatives in which X = SR 1 : X-SR (= R 1 S-SR 1 ). For the preparation of derivatives in which X = S (aryl), compounds of the general formula (11) are suitable as electrophiles: XS (aryl) (= (aryl) SS (aryl)).
Zur Herstellung von Derivaten, in denen X = B(OR1) , eignen sich als Elektrophil Verbindungen der allgemeinen Formel (12) : X-B(OR1)2 (= B(OR1)3) oder ein Gemisch aus BF3 oder BC13 und Verbindungen der allgemeinen Formel (12) .For the preparation of derivatives in which X = B (OR 1 ), compounds of the general formula (12) are suitable as electrophiles: XB (OR 1 ) 2 (= B (OR 1 ) 3 ) or a mixture of BF 3 or BC1 3 and compounds of the general formula (12).
Zur Herstellung von Derivaten, in denen X = B(OH)2, eignen sich als Elektrophil Verbindungen der allgemeinen Formel (12) oder ein Gemisch aus BF und (12) und anschließender Zugabe von Wasser.For the preparation of derivatives in which X = B (OH) 2 , compounds of the general formula (12) or a mixture of BF and (12) and subsequent addition of water are suitable as electrophiles.
Zur Herstellung von Derivaten, in denen X = OH, eignen sich als Elektrophil Verbindungen der allgemeinen Formel (12) oder ein Gemisch aus BF und Verbindungen der allgemeinen Formel (12) und anschließender Zugabe von Wasserstoffperoxid.For the preparation of derivatives in which X = OH, compounds of the general formula (12) or a mixture of BF and compounds of the general formula (12) and subsequent addition of hydrogen peroxide are suitable as electrophiles.
Zur Herstellung von Derivaten, in denen X = B (OAryl) 2, eignen sich als Elektrophil E-X Verbindungen der allgemeinen FormelFor the preparation of derivatives in which X = B (OAryl) 2 , EX compounds of the general formula are suitable as electrophile
(13) : X-B(OAryl)2 (=B(0Aryl)3) oder ein Gemisch aus BF3 oder BC13 und Verbindungen der allgemeinen Formel (13) .(13): XB (OAryl) 2 (= B (0Aryl) 3 ) or a mixture of BF 3 or BC1 3 and compounds of the general formula (13).
Zur Herstellung von Derivaten, in denen X = SiR^ eignen sich als Elektrophil E-X Verbindungen der allgemeinen Formel (14) : X-Cl (= R^SiCl) .For the preparation of derivatives in which X = SiR ^ are suitable as electrophile E-X compounds of the general formula (14): X-Cl (= R ^ SiCl).
Zur Herstellung von Derivaten, in denen X = Si(Aryl)3, eignen sich als Elektrophil E-X Verbindungen der allgemeinen Formel (15): X-Cl (= (Aryl)3SiCl)Suitable compounds for the preparation of derivatives in which X = Si (aryl) 3 are suitable as electrophile EX compounds of the general formula (15): X-Cl (= (aryl) 3 SiCl)
Zur Herstellung von Derivaten, in denen X = BfOR1) (OAryl), eignen sich als Elektrophil E-X Verbindungen der allgemeinen Formel (16) BfOR1) (OAryl)2 bzw. der allgemeine Formel (17) B (OR1) 2 (OAryl) . Für die unsymmetrische disubstituierten Verbindungen werden die entsprechenden Mischungen der Elektrophile E-X und E-Y eingesetzt bzw. die Substitution sequenziell durchgeführt.For the preparation of derivatives in which X = BfOR 1 ) (OAryl), suitable electrophile EX compounds of the general formula (16) BfOR 1 ) (OAryl) 2 or the general formula (17) B (OR 1 ) 2 ( OAryl). For the asymmetrical disubstituted compounds, the corresponding mixtures of the electrophiles EX and EY are used or the substitution is carried out sequentially.
Als Alkylreste für R1 seien verzweigte oder unverzweigte Ci-Cβ- Alkylketten, bevorzugt Methyl, Ethyl, Isopropyl, n-Propyl, 1-Methylethyl , n-Butyl, 2-Butyl, sec.-Butyl, tert.-Butyl, 1-Methylpropyl , 2-Methylpropyl, 1, 1-Dimethylethyl, n-Pentyl, 2-Pentyl, 1-Methylbutyl, 2-Methylbutyl, 3-Methylbutyl, 2,2-Di- methylpropyl , 1-Ethylpropyl, n-Hexyl, 2-Hexyl, 1, 1-Dirnethyl- propyl, 1, 2-Dimethylpropyl, 1-Methylpentyl , 2-Methylpentyl,As alkyl radicals for R 1 are branched or unbranched Ci-Cβ-alkyl chains, preferably methyl, ethyl, isopropyl, n-propyl, 1-methylethyl, n-butyl, 2-butyl, sec-butyl, tert-butyl, 1- Methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, n-pentyl, 2-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 2- Hexyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,
3-Methylpentyl, 4-Methylpentyl, 1, 1-Dimethylbutyl, 1,2-Dimethyl- butyl, 1,3-Dirnethylbutyl, 2 , 2-Dirne hylbutyl , 2,3-Dirnethylbutyl ,
3, 3-Dimethylbutyl, 1-Ethylbutyl, 2-Ethylbutyl, 1, 1,2-Trimethyl- propyl, 1,2,2-Trimethylpropyl, 1-Ethyl-l-methylpropyl, 1-Ethyl- 2-methylpropyl, n-Heptyl, 2-Ethylhexyl, n-Octyl genannt.3-methylpentyl, 4-methylpentyl, 1, 1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2, 2-whore hylbutyl, 2,3-dimethylbutyl, 3, 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1, 1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-l-methylpropyl, 1-ethyl-2-methylpropyl, n- Heptyl, 2-ethylhexyl, called n-octyl.
Als Arylreste seinen genannt Phenyl, Naphthyl sowie die substituierten Phenylreste
, wobei R1 die oben angegebenen Bedeutung besitzt. Der Alkylrest R1 kann hierbei in o-, m- und p-Stellung lokalisiert sein.As aryl radicals its called phenyl, naphthyl and the substituted phenyl radicals , wherein R 1 has the meaning given above. The alkyl radical R 1 can be localized in the o-, m- and p-positions.
Lösungsmittelsolvent
Als Lösungsmittel eignen sich alle unter den Reaktionsbedingungen inerten Lösungsmitteln. Bevorzugte Lösungsmittel sind Tetrahydro- furan (THF) , Dioxan und Ci-Cβ-Ether, einfache oder gemischte Ci-Cß-Ether, C4-Cι2-Kohlenwasserstoffe, wie n-Butan, IsobutanSuitable solvents are all solvents which are inert under the reaction conditions. Preferred solvents are tetrahydrofuran (THF), dioxane and Ci-Cβ-ether, simple or mixed Ci-C ß- ether, C 4 -Cι 2 hydrocarbons, such as n-butane, isobutane
(2-Methylpropan) , n-Pentan, Isopentan (2-Methylbutan) , Neopentan (2 , 2-Dimethylpropan) , Hexan, 2,2-Dimethylbutan, 2-Methylpentan, 3-Methylpentan, n-Heptan, n-Octan, n-Nonan, n-Undecan, n-Dodecan, sowie Gemische der aufgeführten Lösungsmittel .(2-methylpropane), n-pentane, isopentane (2-methylbutane), neopentane (2, 2-dimethylpropane), hexane, 2,2-dimethylbutane, 2-methylpentane, 3-methylpentane, n-heptane, n-octane, n-nonane, n-undecane, n-dodecane, and mixtures of the solvents listed.
Basenbases
Als Basen können Alkaliorganyle eingesetzt werden. Besonders bevorzugt ist der Einsatz von LithiumorganylVerbindungen, wie beispielsweise n-But yllithium, sek.-Butyllithium, t-Butyllithium und Methyllithium. Das erfindungsgemäße Verfahren schließt die Erkenntnis mit ein, daß zur Synthese der onosubstituierten Derivate die Base äquimolar bis maximal im 1,8 molaren Überschuß zugegeben wird. Zur Synthese der disubstituierten Derivate ist die Zugabe von 2 bis 4 Äquivalenten Base erforderlich.Alkali organyls can be used as bases. It is particularly preferred to use lithium organyl compounds, such as n-butyllithium, sec-butyllithium, t-butyllithium and methyllithium. The process according to the invention includes the knowledge that for the synthesis of the onosubstituted derivatives the base is added in equimolar amounts up to a maximum of 1.8 molar excess. The synthesis of the disubstituted derivatives requires the addition of 2 to 4 equivalents of base.
Amineamines
In einer bevorzugten Ausführungsform der vorliegenden Erfindung wird die Reaktion in Gegenwart eines Amins, insbesondere eines tertiären Diamins, durchgeführt. Als geeignete Amine seinen genannt Tetramethylethylendiamin, Tetraethylethylendiamin, Tetra- n-propylethylendiamin, Tetramethylpropylendiamin, Tetraethyl- propylendiamin, Tetra-n-propylpropylendiamin besonders geeignet sind chelatisierende Amine, wie beispielsweise Tetramethylethylendiamin und Tetraethylethylendiamin insbesondere Tetramethylethylendiamin.
VerfahrenIn a preferred embodiment of the present invention, the reaction is carried out in the presence of an amine, in particular a tertiary diamine. Chelating amines such as, for example, tetramethylethylenediamine and especially tetraethylethylenediamine diamine and especially tetraethylethylenediamine diamine and especially tetraethylethylenediamine diamine are particularly suitable as suitable amines, such as tetramethylethylene diamine, tetraethylethylene diamine, tetra-n-propylethylene diamine, tetramethylpropylene diamine, tetraethyl-propylene diamine, tetra-n-propylpropylene diamine. method
Üblicherweise wird die starke Base in einem unter den Reaktionsbedingungen inerten Lösungsmittel vorgelegt. Dazu gibt man das 5 Edukt 4- (Trifluormethylphenyl) -2- (tetrahydropyranyl) ether, welches gelöst in beispielsweise Tetrahydrofuran vorliegen kann oder direkt als Schmelze eingesetzt werden kann. Danach erfolgt die Zugabe des Elektrophils . Dieses kann in Substanz oder als Lösung vorliegen. Alternativ ist es möglich das Elektrophil vor- 10 zulegen und das Lithiumorganyl zuzugeben. Bei der Synthese der disubstituierten Derivate hat es sich als vorteilhaft erwiesen die Base und den Ether vorzulegen und danach das Elektrophil zuzugeben.The strong base is usually placed in a solvent which is inert under the reaction conditions. To this are added the 5 educt 4- (trifluoromethylphenyl) -2- (tetrahydropyranyl) ether, which may be dissolved in, for example, tetrahydrofuran or used directly as a melt. The electrophile is then added. This can be in bulk or as a solution. Alternatively, it is possible to present the electrophile and add the lithium organyl. In the synthesis of the disubstituted derivatives, it has proven to be advantageous to submit the base and the ether and then to add the electrophile.
15 Das molare Verhältnis von Edukt zu Elektrophil richtet sich nach den gewünschten Verbindungen und liegt im Falle der Synthese der onosubstituierten Derivate in der Regel zwischen 1 : 1 und 1 : 1,9; im Falle der disubstituierten Derivate in der Regel zwischen 1 : 2 und 1 : 4.15 The molar ratio of starting material to electrophile depends on the desired compounds and, in the case of the synthesis of the onosubstituted derivatives, is generally between 1: 1 and 1: 1.9; in the case of disubstituted derivatives, usually between 1: 2 and 1: 4.
2020
Die Reaktion wird bei -100 bis +100°C durchgeführt, bevorzugt bei Temperaturen zwischen -20°C und +20°C. In der Regel wird die Reaktion in einem Druckbereich von 0,0001 bis 200 bar, insbesondere 0,001 bis 20 bar, bevorzugt von 0,001 bis 6 bar,The reaction is carried out at -100 to + 100 ° C, preferably at temperatures between -20 ° C and + 20 ° C. As a rule, the reaction is carried out in a pressure range from 0.0001 to 200 bar, in particular 0.001 to 20 bar, preferably from 0.001 to 6 bar.
25 durchgeführt.25 performed.
Wird ein Amin eingesetzt, so wird dieses üblicherweise zusammen mit der Base im Lösungsmittel vorgelegt. Das bevorzugte molare Verhältnis des Amins zu dem Lithiumorganyl beträgt 0 : 1 bis 30 10 : 1, insbesondere 0 : 1 bis 5 : 1. Ganz besonders bevorzugt sind 0 : 1, 1 : 1 und 2 : 1.If an amine is used, it is usually placed in the solvent together with the base. The preferred molar ratio of the amine to the lithium organyl is 0: 1 to 30 10: 1, in particular 0: 1 to 5: 1. 0: 1, 1: 1 and 2: 1 are very particularly preferred.
Den Verlauf der Reaktion kann man durch Nachweis des Eduktes ■ 4- (Trifluormethylphenyl) -2- (tetrahydropyranyl) ether im Reaktions-The course of the reaction can be determined by detecting the starting material ■ 4- (trifluoromethylphenyl) -2- (tetrahydropyranyl) ether in the reaction
35. ansatz verfolgen, hierzu eigenen sich chromatographische Methoden, wie die Gaschromatographie, HPLC oder Dünnschichtchromatographie. Sobald kein Edukt mehr im Reaktionsansatz nachgewiesen werden kann, bricht man die Reaktion in üblicher Weise ab. Falls gewünscht, kann die Aufarbeitung des Reaktionsansatzes nachFollow the 35th approach; chromatographic methods such as gas chromatography, HPLC or thin-layer chromatography are suitable for this. As soon as no more educt can be detected in the reaction mixture, the reaction is stopped in the usual way. If desired, the reaction mixture can be worked up after
40 dem Fachmann bekannten Methoden erfolgen, wie Destillation, Filtration, Zentrifugation oder Extraktion. Die so erhaltenen Rohprodukte können gegebenenfalls weiter gereinigt werden mittels Kristallisation, Extraktion und/oder chromatographischen Methoden. Ebenso möglich, und im Sinne der vorliegenden Erfindung40 methods known to the person skilled in the art, such as distillation, filtration, centrifugation or extraction. The crude products thus obtained can optionally be further purified by means of crystallization, extraction and / or chromatographic methods. Likewise possible, and in the sense of the present invention
45 bevorzugt, ist der direkte Einsatz des Reaktionsgemisches für Folgereaktionen ohne weitere Reinigung.
Die 2 bzw. 2,5 -substituierten Derivate des 4- (Trifluormethyl) - phenols erhält man durch Abspaltung der Tetrahydropyranylgruppe der entsprechenden 2 bzw. 2, 5-substituierten Derivate der 4-(Tri- fluormethylphenyl) -2- (tetrahydropyranyl) ether . Diese Abspaltung wird in der Regel säurekatalysiert durchgeführt. Zur säurekatalysierten Abspaltung der Tetrahydropyranylgruppe eignen sich beispielsweise Carbonsäuren und Mineralsäuren. Besonders bevorzugt sind Trifluoressigsäure und Salzsäure.Preferred is the direct use of the reaction mixture for subsequent reactions without further purification. The 2 and 2,5 -substituted derivatives of 4- (trifluoromethyl) phenol are obtained by splitting off the tetrahydropyranyl group of the corresponding 2 and 2,5-substituted derivatives of 4- (trifluoromethylphenyl) -2- (tetrahydropyranyl) ether , This cleavage is usually carried out under acid catalysis. Carboxylic acids and mineral acids, for example, are suitable for acid-catalyzed removal of the tetrahydropyranyl group. Trifluoroacetic acid and hydrochloric acid are particularly preferred.
Zur Reinigung der Boronsäuren kann es von Vorteil sein, entsprechend der Lehre von S. Caron, J.M. Hawkins, J. Org. Chem. (1998) 63 2054 zu verfahren.To purify the boronic acids, it can be advantageous, according to the teaching of S. Caron, J.M. Hawkins, J. Org. Chem. (1998) 63 2054.
Das erfindungsgemäße Verfahren kann sowohl diskontinuierlich (also sog. Batch-Verfahren) als auch kontinuierlich durchgeführt werden, beispielsweise unter Verwendung eines Reaktionsrohres oder einer Rührreaktorkaskade.The process according to the invention can be carried out batchwise or continuously, for example using a reaction tube or a stirred reactor cascade.
Die nach dem erfindungsgemäßen Verfahren hergestellten 2- und 2, 5-substituierten Derivate des 4- (Trifluormethyl) -phenols sowie der 4- (Trifluormethylphenyl)-2- (tetrahydropyranyl) ether können als Ausgangsprodukte für die Synthese von Farbstoffen, Pflanzenschutzmittel und/oder Arzneimitteln eingesetzt werden.The 2- and 2,5-substituted derivatives of 4- (trifluoromethyl) phenol and 4- (trifluoromethylphenyl) -2- (tetrahydropyranyl) ether produced by the process according to the invention can be used as starting products for the synthesis of dyes, crop protection agents and / or Medicines are used.
Ein weiterer Gegenstand der vorliegenden Erfindung betrifftAnother object of the present invention relates
2-substituierte Derivate des 4- (Trifluormethyl) -phenols und/oder 2-substituierte Derivate des 4- (Trifluormethylphenyl) -2- (tetrahydropyranyl) ethers der folgenden Formel2-substituted derivatives of 4- (trifluoromethyl) phenol and / or 2-substituted derivatives of 4- (trifluoromethylphenyl) -2- (tetrahydropyranyl) ether of the following formula
wobei R für Wasserstoff oder Tetrahydropyran-2-yl steht und wenn R Wasserstoff ist , where R is hydrogen or tetrahydropyran-2-yl and when R is hydrogen,
X für B (OH) 2 , B (OR1) 2 , B (OAryl) / COR2 , COOR1, SiR^ ,X for B (OH) 2 , B (OR 1 ) 2 , B (OAryl) / COR 2 , COOR 1 , SiR ^,
Si (Aryl) 3 , SR2 , S (Aryl) , I,Si (aryl) 3 , SR 2 , S (aryl), I,
R1 für Cx-Cs-AlkylR 1 for Cx-Cs-alkyl
R2 für C2-C8-AlkylR 2 for C 2 -C 8 alkyl
Aryl für Phenyl , R1- C5H4 steht,
wenn R Tetrahydropyran-2-yl istAryl represents phenyl, R 1 - C 5 H 4 , when R is tetrahydropyran-2-yl
X 'für B (OH) 2, B(OR1)2, B(OAryl)2, CHO, COR1, CO(Aryl), COOH, COOR1, SiR1 3, Si(Aryl)3, OH, SR1, S(Aryl), Cl, Br, I,X 'for B (OH) 2, B (OR 1 ) 2 , B (OAryl) 2 , CHO, COR 1 , CO (aryl), COOH, COOR 1 , SiR 1 3 , Si (aryl) 3 , OH, SR 1 , S (aryl), Cl, Br, I,
R1 für C1-C8-AlkylR 1 is C 1 -C 8 alkyl
Aryl für Phenyl, R^—CÖEI steht.Aryl represents phenyl, R ^ —C Ö EI.
Ein weiterer Gegenstand der vorliegenden Erfindung betrifft 2,5-disubstituierte Derivate des 4- (Trifluormethyl) -phenols und/oder 2,5-disubstituierte Derivate des 4- (Trifluormethylphenyl) -2- (tetrahydropyranyl) ethers der folgenden FormelThe present invention further relates to 2,5-disubstituted derivatives of 4- (trifluoromethyl) phenol and / or 2,5-disubstituted derivatives of 4- (trifluoromethylphenyl) -2- (tetrahydropyranyl) ether of the following formula
wobei in which
R für Wasserstoff, Tetrahydropyran-2-ylR is hydrogen, tetrahydropyran-2-yl
X für B(OH)2, B(OR1)2, B(OAryl)2, B(OR1) (OAryl) , CHO, COR1,X for B (OH) 2 , B (OR 1 ) 2 , B (OAryl) 2 , B (OR 1 ) (OAryl), CHO, COR 1 ,
CO(Aryl), COOH, COOR1, SiR^, Si(Aryl)3, OH, SR1, S(Aryl),CO (aryl), COOH, COOR 1 , SiR ^, Si (aryl) 3 , OH, SR 1 , S (aryl),
Cl, Br, I,Cl, Br, I,
Y unabhängig von X für B(OH)2, B(OR1) , B (OAryl) 2,Y is independent of X for B (OH) 2 , B (OR 1 ), B (OAryl) 2 ,
B(OR1) (OAryl) , CHO, COR1, CO(Aryl), COOH, COOR1, SiR^,B (OR 1 ) (OAryl), CHO, COR 1 , CO (aryl), COOH, COOR 1 , SiR ^,
Si(Aryl)3, OH, SR1, S(Aryl), Cl, Br, I,Si (aryl) 3 , OH, SR 1 , S (aryl), Cl, Br, I,
R1 unabhängig voneinander für Ci-Cs-AlkylR 1 independently of one another for Ci-Cs-alkyl
Aryl unabhängig voneinander für Phenyl, Naphthyl, R1-CgH4 steht,Aryl independently of one another represents phenyl, naphthyl, R 1 -CgH 4 ,
BeispieleExamples
Herstellung des Ausgangsmaterials: 4- (Trifluormethylphenyl) -2- (tetrahydropyranyl) etherPreparation of the starting material: 4- (trifluoromethylphenyl) -2- (tetrahydropyranyl) ether
400 g (2.47 mol) 4-Trifluormethylphenol werden in 1 1 Dichlor- ethan vorgelegt und 525 g (6.25 mol) Dihydropyran zusammen mit 1 ml 4molarem Chlorwasserstoff in Dioxan bei Raumtemperatur
zugetropft. Die Reaktion ist deutlich exotherm. Nach Rühren über Nacht wird die Reaktionsmischung mit 200 ml Natriumhydrogen- carbonat-Lösung gewaschen, die organische Phase über Natriumsulfat getrocknet und eingeengt. Der Rückstand (618 g, GC:400 g (2.47 mol) of 4-trifluoromethylphenol are placed in 1 1 of dichloroethane and 525 g (6.25 mol) of dihydropyran together with 1 ml of 4 molar hydrogen chloride in dioxane at room temperature dropwise. The reaction is clearly exothermic. After stirring overnight, the reaction mixture is washed with 200 ml of sodium hydrogen carbonate solution, the organic phase is dried over sodium sulfate and concentrated. The residue (618 g, GC:
5 90 Fl.%, 2,28 mol, Ausbeute: 92,3 %) wird ohne weitere Reinigung in die nachfolgende Stufe eingesetzt. Er kristallisiert beim Stehen bei Raumtemperatur allmählich durch (Schmelzpunkt = 38 bis5 90 area%, 2.28 mol, yield: 92.3%) is used in the subsequent step without further purification. It crystallizes gradually when standing at room temperature (melting point = 38 to
' 38,7°C). '38 .7 ° C).
10 Beispiel 110 Example 1
Herstellung von l-[2-(Tetrahydro-2fl-pyran-2-yloxy)-5-(trifluoro- methyl)phenyl]-l-propanon (R= 2-Tetrahydropyranyl, X = CHsCO, Y = H)Preparation of l- [2- (tetrahydro-2fl-pyran-2-yloxy) -5- (trifluoromethyl) phenyl] -l-propanone (R = 2-tetrahydropyranyl, X = CHsCO, Y = H)
15 24 g (0,207 mol) Tetramethylethylendiamin werden bei -10°C vorgelegt und in ca. 30 min 130 ml Butyllithium in Hexan (1,63 molar, 0,212 mol) zugetropft. Nach 15 min tropft man die Schmelze von 40 g (GC 90 %, 0,146 mol) 4- (Trifluormethylphenyl) -2- (tetrahydropyranyl) ether bei -10°C innerhalb von 30 min zu. Hierbei fällt15 24 g (0.207 mol) of tetramethylethylenediamine are introduced at -10 ° C. and 130 ml of butyllithium in hexane (1.63 molar, 0.212 mol) are added dropwise in about 30 min. After 15 minutes, the melt of 40 g (GC 90%, 0.146 mol) of 4- (trifluoromethylphenyl) -2- (tetrahydropyranyl) ether is added dropwise at -10 ° C. in the course of 30 minutes. Here falls
20 der Lithiumkomplex aus. Nach 1 Stunde werden 24 g (0,205 mol) Propionsäure-N-methoxy-N-methylamid zugegeben. Es entsteht eine trübe Lösung, die man nach 1 Stunde zu 60 ml 32 %ige Salzsäure in 40 ml Wasser zutropft. Die wässrige Phase wird abgetrennt, mit Hexan extrahiert und die organische Phasen eingeengt. Der Rück-20 the lithium complex. After 1 hour, 24 g (0.205 mol) of propionic acid-N-methoxy-N-methylamide are added. A cloudy solution is formed, which is added dropwise after 1 hour to 60 ml of 32% hydrochloric acid in 40 ml of water. The aqueous phase is separated off, extracted with hexane and the organic phases are concentrated. The back
25 stand wird aus Hexan bei -50°C umkristallisiert. Es werden 27,3 g (HPLC 96 %, 91 mmol, Ausbeute 62,3 %) l-[2-(tetrahydro-2H-pyran- 2-yloxy) -5- (trifluoromethyl)phenyl] -1-propanon in Form farbloser Kristalle erhalten (Schmp. : 54 bis 56,5°C).25 stand is recrystallized from hexane at -50 ° C. There are 27.3 g (HPLC 96%, 91 mmol, yield 62.3%) of l- [2- (tetrahydro-2H-pyran-2-yloxy) -5- (trifluoromethyl) phenyl] -1-propanone in the form Colorless crystals obtained (mp: 54 to 56.5 ° C).
30 Beispiel 230 Example 2
Herstellung von 2-Hydroxy-5-(trifluoromethyl)benzaldehyd (R = H, X = CHO, Y=H)Preparation of 2-hydroxy-5- (trifluoromethyl) benzaldehyde (R = H, X = CHO, Y = H)
241 g (2.08 mol) Tetramethylethylendiamin werden bei -10°C vor- 35 gelegt und in ca. 30 min werden 1,3 1 Butyllithium in Hexan (1,63 molar, 2,12 mol) zugetropft. Nach 45 min tropft man die Schmelze von 400 g (GC 92 %, 1,5 mol) 4- (Trifluormethylphenyl) - 2- (tetrahydropyranyl) ether bei -10°C innerhalb von 30 min zu. Hierbei fällt der Lithiumkomplex aus. Nach 2 Stunden werden 152 g 0 (2,08 mol) Dimethylformamid (DMF) zugetropft. Es entsteht eine trübe Lösung, die man nach 15 min zu 750 ml 38 %ige Salzsäure in 500 ml Wasser innerhalb von 30 min bei maximal 45°C zutropft. Es entsteht eine starke Gasentwicklung. Über Nacht wird nachgerührt, die wässrige Phase abgetrennt, die organische Phase mit 70 ml M 5 Dioxan/HCl-Lösung versetzt und erneut über Nacht gerührt . Das Produkt wird durch Abkühlen auf -30°C (2 bis 3 h) auskristallisiert, abgesaugt, mit 500 ml kaltem Pentan gewaschen und das
Produkt an der Luft getrocknet. Es werden 220 g (GC: 98.3 %, 1,13 mol, Ausbeute 75 %) 2-Hydroxy-5-(trifluoromethyl)benzaldehyd in Form farbloser Kristalle erhalten (Schmp. : 60,1 bis 61,8°C).241 g (2.08 mol) of tetramethylethylenediamine are placed at -10 ° C. and 1.3 l of butyllithium in hexane (1.63 molar, 2.12 mol) are added dropwise in about 30 min. After 45 minutes, the melt of 400 g (GC 92%, 1.5 mol) of 4- (trifluoromethylphenyl) -2- (tetrahydropyranyl) ether is added dropwise at -10 ° C. in the course of 30 minutes. The lithium complex fails here. After 2 hours, 152 g of 0 (2.08 mol) of dimethylformamide (DMF) are added dropwise. A cloudy solution is formed, which is added dropwise after 15 min to 750 ml of 38% hydrochloric acid in 500 ml of water within 30 min at a maximum of 45 ° C. There is a strong gas development. The mixture is stirred overnight, the aqueous phase is separated off, 70 ml of M 5 dioxane / HCl solution are added to the organic phase and the mixture is stirred again overnight. The product is crystallized by cooling to -30 ° C (2 to 3 h), suction filtered, washed with 500 ml of cold pentane and that Product air-dried. 220 g (GC: 98.3%, 1.13 mol, yield 75%) of 2-hydroxy-5- (trifluoromethyl) benzaldehyde are obtained in the form of colorless crystals (mp: 60.1 to 61.8 ° C.).
Beispiel 3Example 3
Herstellung von Trimethyl [2- (tetrahydro-2H-pyran-2-yloxy) -5- (tri- fluoromethyl)phenyl]silan (R = 2-Tetrahydropyranyl, Y = H; X = SiMe3)Preparation of trimethyl [2- (tetrahydro-2H-pyran-2-yloxy) -5- (trifluoromethyl) phenyl] silane (R = 2-tetrahydropyranyl, Y = H; X = SiMe 3 )
2,9 g (25 mmol) Tetramethylethylendiamin und 15,9 ml (15 %ig,2.9 g (25 mmol) tetramethylethylenediamine and 15.9 ml (15%,
26 mmol) Butyllithium in Hexan werden bei -20 °C vorgelegt und 5 g (HPLC: 98 %, 19,9 mmol) 4- (Trifluormethylphenyl) -2- (tetrahydropyranyl) ether gelöst in 10 ml Tetrahydrofuran (THF) zugetropft. Nach 30 Minuten gibt man 2,63 g (24 mmol) Chlortrimethylsilan und nach 2 Stunden 5 ml Wasser zu. Man lässt die Reaktionsmischung auf 20°C erwärmen, trennt die Phasen, wäscht die organische Phase einmal mit gesättigter Kochsalzlösung und die vereinigten wässri- gen Phasen dreimal mit je 5 ml Methyl-t-butylether. Die organischen Phasen werden vereinigt, über Natriumsulfat getrocknet und im Vakuum eingeengt. Der Rückstand wird durch Säulenσhromato- graphie (Kieselgel, Petrolether / Methyl-t-butylether = 5 : 1) gereinigt. Es werden 5,8 g (HPLC: 98 %ig, 17,9 mmol, Ausbeute 90 %) Trimethyl [2- (tetrahydro-2H-pyran-2-yloxy) -5- (trifluoro- ethyl) phenyl] silan in Form eines farblosen Feststoffs erhalten. (Schmp.: 43 bis 46°C) .26 mmol) of butyllithium in hexane are introduced at -20 ° C. and 5 g (HPLC: 98%, 19.9 mmol) of 4- (trifluoromethylphenyl) -2- (tetrahydropyranyl) ether dissolved in 10 ml of tetrahydrofuran (THF) are added dropwise. After 30 minutes, 2.63 g (24 mmol) of chlorotrimethylsilane are added, and after 2 hours 5 ml of water. The reaction mixture is allowed to warm to 20 ° C., the phases are separated, the organic phase is washed once with saturated sodium chloride solution and the combined aqueous phases three times with 5 ml each of methyl t-butyl ether. The organic phases are combined, dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography (silica gel, petroleum ether / methyl t-butyl ether = 5: 1). 5.8 g (HPLC: 98%, 17.9 mmol, yield 90%) trimethyl [2- (tetrahydro-2H-pyran-2-yloxy) -5- (trifluoroethyl) phenyl] silane in the form obtained a colorless solid. (Mp: 43 to 46 ° C).
Beispiel 4Example 4
Herstellung von 2- [2- (phenylsulfanyl) -4- (trifluoromethyl)phen- oxy] tetrahydro-2iϊ-pyran (R = 2-Tetrahydropyranyl, X = S-Phenyl, Y = H)Preparation of 2- [2- (phenylsulfanyl) -4- (trifluoromethyl) phenoxy] tetrahydro-2iϊ-pyran (R = 2-tetrahydropyranyl, X = S-phenyl, Y = H)
2,9 g (25 mmol) Tetramethylethylendiamin und 15,9 ml (15 %ig,2.9 g (25 mmol) tetramethylethylenediamine and 15.9 ml (15%,
26 mmol) Butyllithium in Hexan werden bei -20°C vorgelegt und 5 g26 mmol) butyllithium in hexane are placed at -20 ° C and 5 g
(HPLC: 98 %, 19,9 mmol) 4- (Trifluormethylphenyl) -2- (tetrahydro- pyranyl ) ether gelöst in 10 ml THF zugetropft. Nach 30 Minuten gibt man 4,8 g (22 mmol) Diphenyldisulfid und nach 2 Stunden 5 ml Wasser. Man lässt die Reaktionsmischung auf 20°C erwärmen, trennt die Phasen, wäscht die organische Phase einmal mit gesättigter Kochsalzlösung und die vereinigten wässrigen Phasen dreimal mit je 5 ml Methyl-t-butylether. Die organischen Phasen werden vereinigt, über Natriumsulfat getrocknet und im Vakuum eingeengt. Der Rückstand wird durch Säulenchromatographie (Kieselgel, Petrolether / Methyl-t-butylether = 24 : 1) gereinigt. Es werden 6,35 g (HPLC: 92,3 %ig, 16,6 mmol, Ausbeute 82,7 %) 2- [2- (phenyl- sulfanyl) -4- (trifluoromethyl)phenoxy] tetrahydro-2-H-pyran in Form eines farblosen Feststoffs erhalten. (Schmp. : 72 bis 73°C) .
Beispiel 5(HPLC: 98%, 19.9 mmol) 4- (trifluoromethylphenyl) -2- (tetrahydropyranyl) ether dissolved in 10 ml THF added dropwise. After 30 minutes, 4.8 g (22 mmol) of diphenyl disulfide are added and after 2 hours 5 ml of water. The reaction mixture is allowed to warm to 20 ° C., the phases are separated, the organic phase is washed once with saturated sodium chloride solution and the combined aqueous phases three times with 5 ml each of methyl t-butyl ether. The organic phases are combined, dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography (silica gel, petroleum ether / methyl t-butyl ether = 24: 1). 6.35 g (HPLC: 92.3%, 16.6 mmol, yield 82.7%) 2- [2- (phenylsulfanyl) -4- (trifluoromethyl) phenoxy] tetrahydro-2-H- pyran obtained in the form of a colorless solid. (Mp: 72 to 73 ° C). Example 5
Herstellung von 2-Hydroxy-5-(trifluormethyl)benzoesäure (R = H,Preparation of 2-hydroxy-5- (trifluoromethyl) benzoic acid (R = H,
X = COOH, Y = H)X = COOH, Y = H)
2,9 g (25 mmol) Tetramethylethylendiamin und 15,9 ml (15 %ig, 26 mmol) Butyllithium in Hexan werden bei -20°C vorgelegt und 5 g (HPLC: 98 %, 19,9 mmol) 4- (Trifluormethylphenyl) -2- (tetrahydropyranyl) ether gelöst in 10 ml THF zugetropft. Nach 30 Minuten •leitet man 30 min über eine Phosphorpentoxid - Kartusche getrock- netes Kohlendioxid ein. Man lässt die Reaktionsmischung über Nacht auf 20°C erwärmen, gibt 5 ml Wasser, 8 ml konz . Salzsäure und 10 ml Methyl-t-butylether zu und saugt einen farblosen Feststoff (0,4 g, 4-Hydroxybenzotrifluorid-3,5-dicarbonsäure) ab, trennt die Phasen, wäscht die organische Phase einmal mit ge- sättigter Kochsalzlösung und die vereinigten wässrigen Phasen dreimal mit je 5 ml Methyl-t-butylether. Die organischen Phasen werden vereinigt, über Natriumsulfat getrocknet und im Vakuum eingeengt. Der Rückstand wird durch Säulenchromatographie (Kieselgel, Petrolether / Methyl-t-butylether = 95 : 5, + 0,1 ml AcOH / 100 ml Laufmittel) und Extraktion im Basischen mit Methyl- t-butylether und im Sauren mit Dichlormethan gereinigt. Es werden 2,2 g (HPLC: 97,8 %ig, 14,5 mmol, Ausbeute 52,5 %) 2-Hydroxy-5- (trifluormethyl)benzoesäure in Form eines farblosen Feststoffs erhalten. (Schmp.: 149 bis 151°C) .2.9 g (25 mmol) of tetramethylethylenediamine and 15.9 ml (15%, 26 mmol) of butyllithium in hexane are initially introduced at -20 ° C. and 5 g (HPLC: 98%, 19.9 mmol) of 4- (trifluoromethylphenyl) ) -2- (tetrahydropyranyl) ether dissolved in 10 ml of THF added dropwise. After 30 minutes, carbon dioxide dried over a phosphorus pentoxide cartridge is introduced for 30 minutes. The reaction mixture is allowed to warm to 20 ° C. overnight, 5 ml of water, 8 ml of conc. Hydrochloric acid and 10 ml of methyl t-butyl ether and sucks off a colorless solid (0.4 g, 4-hydroxybenzotrifluoride-3,5-dicarboxylic acid), separates the phases, washes the organic phase once with saturated sodium chloride solution and the combined aqueous phases three times with 5 ml each of methyl t-butyl ether. The organic phases are combined, dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography (silica gel, petroleum ether / methyl t-butyl ether = 95: 5, + 0.1 ml AcOH / 100 ml eluent) and extraction in basic with methyl t-butyl ether and in acid with dichloromethane. 2.2 g (HPLC: 97.8%, 14.5 mmol, yield 52.5%) of 2-hydroxy-5- (trifluoromethyl) benzoic acid are obtained in the form of a colorless solid. (Mp: 149 to 151 ° C).
Beispiel 6Example 6
Herstellung von 4- (Trifluoromethyl) -1, 2-benzenediol (R = H,Preparation of 4- (trifluoromethyl) -1, 2-benzenediol (R = H,
X = OH, Y = H)X = OH, Y = H)
15,9 ml (15 %ig, 26 mmol) Butyllithium in Hexan werden bei -20°C vorgelegt und 5 g (HPLC: 98 %, 19,9 mmol) 4- (Trifluormethylphenyl) -2- (tetrahydropyranyl) ether gelöst in 40 ml THF zugetropft . Nach 30 Minuten gibt man eine Mischung aus 2,7 g (25 mmol) Borsäuretrimethylester und 1,62 g (50 %ig, 12 mmol) Bortrifluorid in Diethylether bei -70°C und nach 1,5 Stunden 2,3 g (30 %ig, 20 mmol) Wasserstoffperoxid zu. Man lässt die- Reaktionsmischung auf 20°C erwärmen, gibt 10 ml verdünnte Natriumdithionit- Lösung zu, trennt die Phasen, wäscht die organische Phase einmal mit gesättigter Kochsalzlösung und die vereinigten wässrigen Pha- sen zweimal mit je 5 ml THF. Die organischen Phasen werden vereinigt, über Natriumsulfat getrocknet und im Vakuum eingeengt. Der Rückstand wird durch Säulenchromatographie (Kieselgel, Petrolether / Methyl-t-butylether = 5 : 1) gereinigt. Es werden 2,2 g (HPLC: 86,1 %ig, 10,6 mmol, Ausbeute 53 %) 4-(Trifluoro- methyl)-l,2-benzenediol in Form eines rotbraunen Öls erhalten.
Beispiel 715.9 ml (15%, 26 mmol) of butyllithium in hexane are initially introduced at -20 ° C. and 5 g (HPLC: 98%, 19.9 mmol) of 4- (trifluoromethylphenyl) -2- (tetrahydropyranyl) ether are dissolved in 40 ml of THF added dropwise. After 30 minutes, a mixture of 2.7 g (25 mmol) of trimethyl borate and 1.62 g (50%, 12 mmol) of boron trifluoride in diethyl ether at -70 ° C. and after 1.5 hours 2.3 g (30 %, 20 mmol) of hydrogen peroxide. The reaction mixture is allowed to warm to 20 ° C., 10 ml of dilute sodium dithionite solution are added, the phases are separated, the organic phase is washed once with saturated sodium chloride solution and the combined aqueous phases are washed twice with 5 ml of THF. The organic phases are combined, dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography (silica gel, petroleum ether / methyl t-butyl ether = 5: 1). 2.2 g (HPLC: 86.1%, 10.6 mmol, yield 53%) of 4- (trifluoromethyl) -1, 2-benzenediol are obtained in the form of a red-brown oil. Example 7
Herstellung von 2-[2-chloro-4-(trifluoromethyl)phenoxy] tetra- hydro-2H-pyranPreparation of 2- [2-chloro-4- (trifluoromethyl) phenoxy] tetra-hydro-2H-pyran
(R = 2-Tetrahydropyranyl, X = Cl, Y = H)(R = 2-tetrahydropyranyl, X = Cl, Y = H)
14,7 ml (15 %ig, 24 mmol) Butyllithium in Hexan werden bei -70°C vorgelegt und 5 g (HPLC: 98 %, 19,9 mmol) 4- (Trifluormethylphenyl) -2- (tetrahydropyranyl) ether gelöst in 40 ml THF zuge- tropft. Nach 30 Minuten gibt man eine Lösung von 9,5 g Hexachlor- ethan in 20 ml THF bei -70°C zu. Nach 4 Stunden lässt man die Reaktionsmischung auf 20 °C erwärmen und engt die Reaktionsmischung am nächsten Tag ein. Der Rückstand wird in Petrolether aufgenommen, die unlöslichen Salze abgetrennt und die Mutterlauge nach dem Einengen durch Säulenchromatographie (Kieselgel, Petrolether / Methyl-t-butylether = 9 : 1) gereinigt. Es werden 5,2 g (HPLC: 95 %ig, 17,6 mmol, 88,7 %) 2-[2-chloro-4- (trifluoromethyl)phenoxy] tetrahydro-2H-pyran in Form eines farblosen Öls erhalten.14.7 ml (15%, 24 mmol) of butyllithium in hexane are initially introduced at -70 ° C. and 5 g (HPLC: 98%, 19.9 mmol) of 4- (trifluoromethylphenyl) -2- (tetrahydropyranyl) ether are dissolved in 40 ml of THF added dropwise. After 30 minutes, a solution of 9.5 g of hexachloroethane in 20 ml of THF is added at -70 ° C. After 4 hours, the reaction mixture is allowed to warm to 20 ° C. and the reaction mixture is concentrated the next day. The residue is taken up in petroleum ether, the insoluble salts are separated off and, after concentration, the mother liquor is purified by column chromatography (silica gel, petroleum ether / methyl t-butyl ether = 9: 1). 5.2 g (HPLC: 95%, 17.6 mmol, 88.7%) of 2- [2-chloro-4- (trifluoromethyl) phenoxy] tetrahydro-2H-pyran are obtained in the form of a colorless oil.
Beispiel 8Example 8
Herstellung von (2-Iodo-4-(trifluoromethyl)phenyl) -(tetra- hydro-2H-pyran-2-yl) -etherPreparation of (2-iodo-4- (trifluoromethyl) phenyl) - (tetra-hydro-2H-pyran-2-yl) ether
(R = 2-Tetrahydropyranyl, X = 1, Y = H)(R = 2-tetrahydropyranyl, X = 1, Y = H)
12,2 ml (15 %ig, 20 mmol) Butyllithium in Hexan werden bei -70°C vorgelegt und 5 g (HPLC: 98 %, 19,9 mmol) 4-(Trifluor- methylphenyl) -2- (tetrahydropyranyl)ether gelöst in 40 ml THF zugetropft. Nach 30 Minuten gibt man eine Lösung von 6,3 g12.2 ml (15%, 20 mmol) of butyllithium in hexane are initially introduced at -70 ° C. and 5 g (HPLC: 98%, 19.9 mmol) of 4- (trifluoromethylphenyl) -2- (tetrahydropyranyl) ether dissolved in 40 ml of THF added dropwise. After 30 minutes, a solution of 6.3 g is added
(52,5 mmol) Iod, 7,5 ml Butyllithium in Hexan und 19 ml THF bei -70°C zu. Nach 4 Stunden lässt man die Reaktionsmischung auf 20°C erwärmen und engt die Reaktionsmischung ein. Der Rückstand wird durch Säulenchromatographie (Kieselgel, Petrolether / Methyl-t- butylether = 9 : 1) gereinigt. Es werden 5,22 g (HPLC: 94,4 %ig, 13,2 mmol, 66,6 %) (2-Iodo-4-(trifluoromethyl)phenyl)- (tetra- hydro-2iϊ-pyran-2-yl) -ether in Form eines farblosen Öls erhalten.(52.5 mmol) iodine, 7.5 ml butyllithium in hexane and 19 ml THF at -70 ° C. After 4 hours, the reaction mixture is allowed to warm to 20 ° C. and the reaction mixture is concentrated. The residue is purified by column chromatography (silica gel, petroleum ether / methyl t-butyl ether = 9: 1). 5.22 g (HPLC: 94.4%, 13.2 mmol, 66.6%) (2-iodo-4- (trifluoromethyl) phenyl) - (tetra-hydro-2iϊ-pyran-2-yl ) ether obtained in the form of a colorless oil.
Beispiel 9 Herstellung von (2- (1, 3 , 6 , 2-Dioxazaborocan-2-yl) -4- (trifluoromethyl)phenyl) - (tetrahydro-2iϊ-pyran-2-yl) -ether (R = 2-Tetrahydropyranyl, X = B(0R)2, Y = H)Example 9 Preparation of (2- (1, 3, 6, 2-dioxazaborocan-2-yl) -4- (trifluoromethyl) phenyl) - (tetrahydro-2iϊ-pyran-2-yl) ether (R = 2-tetrahydropyranyl , X = B (0R) 2 , Y = H)
5 g (HPLC: 98 %, 19,9 mmol) 4- (Tri luormethylphenyl) -2- (tetra- hydropyranyl) -ether werden gelöst in 100 ml THF vorgelegt und 27 ml (15 %ig, 44 mmol) Butyllithium in Hexan werden bei -70°C zugetropft. Nach 45 Minuten tropft man diese Lösung in eine
Mischung aus 15,04 g (80 mmol) Triisopropylborat und 40 ml THF bei -70°C langsam zu. Nach 1,5 Stunden lässt man die Reaktionsmischung auf 20°C erwärmen und engt am Rotationsverdampfer ein. Der Rückstand wird in 100 ml Toluol aufgenommen, die unlöslichen Bestandteile abgetrennt, die Mutterlauge auf 50 ml eingeengt und mit 2,1 g (20 mmol) Diethanolamin versetzt. Nach kurzer Zeit kristallisiert das Produkt aus. Der Kristallbrei wird in 50 ml MTBE aufgenommen, abgesaugt, mit MTBE gewaschen und getrocknet. Es werden 4,9 g (HPLC: 98,4 %, 13,4 mmol, 67,5 %) (2- (1 , 3 , 6, 2-Dioxazaborocan-2-yl ) -4- ( rifluoromethyl)phenyl) - (tetrahydro-2iϊ-pyran-2-yl) -ether in Form eines farblosen Feststoffs erhalten. (Schmp.: 192 °C) .
5 g (HPLC: 98%, 19.9 mmol) of 4- (trifluoromethylphenyl) -2- (tetrahydropyranyl) ether are initially dissolved in 100 ml of THF and 27 ml (15%, 44 mmol) of butyllithium in hexane are added dropwise at -70 ° C. After 45 minutes, this solution is dropped into a Mixture of 15.04 g (80 mmol) triisopropyl borate and 40 ml THF at -70 ° C slowly. After 1.5 hours, the reaction mixture is allowed to warm to 20 ° C. and concentrated on a rotary evaporator. The residue is taken up in 100 ml of toluene, the insoluble constituents are separated off, the mother liquor is concentrated to 50 ml and 2.1 g (20 mmol) of diethanolamine are added. The product crystallizes out after a short time. The crystal slurry is taken up in 50 ml of MTBE, suction filtered, washed with MTBE and dried. 4.9 g (HPLC: 98.4%, 13.4 mmol, 67.5%) (2- (1, 3, 6, 2-dioxazaborocan-2-yl) -4- (rifluoromethyl) phenyl) - (tetrahydro-2iϊ-pyran-2-yl) ether obtained in the form of a colorless solid. (Mp: 192 ° C).
Claims
1. Verfahren zur Herstellung von Verbindungen der allgemeinen Formel 11. Process for the preparation of compounds of general formula 1
wobeiin which
R für Wasserstoff, Tetrahydropyran-2-ylR is hydrogen, tetrahydropyran-2-yl
X für B(0H) , B(0R1)2, B(0Aryl)2, B(0R1) (OAryl) , CHO, COR1, CO(Aryl), COOH, COOR1, SiR^, Si(Aryl)3, OH, SR1 ,S(Aryl), Cl, Br, I,X for B (0H), B (0R 1 ) 2 , B (0Aryl) 2 , B (0R 1 ) (OAryl), CHO, COR 1 , CO (Aryl), COOH, COOR 1 , SiR ^, Si (aryl ) 3 , OH, SR 1 , S (aryl), Cl, Br, I,
Y für H, B(0H)2, B(OR1)2, B(OAryl)2, BfOR1) (OAryl) , CHO, COR1, CO(Aryl), COOH, COOR1, SiR^, Si(Aryl)3, OH, SR1, S(Aryl) , Cl, Br, I,Y for H, B (0H) 2 , B (OR 1 ) 2 , B (OAryl) 2 , BfOR 1 ) (OAryl), CHO, COR 1 , CO (Aryl), COOH, COOR 1 , SiR ^, Si ( Aryl) 3 , OH, SR 1 , S (aryl), Cl, Br, I,
R1 unabhängig voneinander für Ci-Cs-AlkylR 1 independently of one another for Ci-Cs-alkyl
Arylunabhängig voneinander für Phenyl, Naphthyl, R1-C6H4, R10-C6H steht,Aryl independently of one another represents phenyl, naphthyl, R 1 -C 6 H 4 , R 1 0-C 6 H,
dadurch gekennzeichnet, daß man die Verbindung der Formel 2 4- (Trifluormethylphenyl) -2- (tetrahydropyranyl) ethercharacterized in that the compound of formula 2 4- (trifluoromethylphenyl) -2- (tetrahydropyranyl) ether
in Gegenwart einer Base mit einem Elektrophil E-X oder einer Kombination von Elektrophilien E-X und E-Y umsetzt, wobei X und Y die oben angegebenen Bedeutung besitzen. in the presence of a base with an electrophile EX or a combination of electrophiles EX and EY, where X and Y have the meaning given above.
2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß man als Base ein Lithiumorganyl einsetzt.2. The method according to claim 1, characterized in that a lithium organyl is used as the base.
3. Verfahren nach mindestens einem der vorgenannten Ansprüche , dadurch gekennzeichnet, daß man die Reaktion in Gegenwart eines Amins durchführt.3. The method according to at least one of the preceding claims, characterized in that one carries out the reaction in the presence of an amine.
4. Verfahren nach Anspruch 3, dadurch gekennzeichnet, daß man ein chelatisierendes Amin einsetzt.4. The method according to claim 3, characterized in that one uses a chelating amine.
5. Verfahren nach mindestens einem der vorgenannten Ansprüche, dadurch gekennzeichnet, daß man die Reaktion bei einer Temperatur von -100 bis + 100°C durchführt.5. The method according to at least one of the preceding claims, characterized in that one carries out the reaction at a temperature of -100 to + 100 ° C.
6. Verfahren nach mindestens einem der vorgenannten Ansprüche, dadurch gekennzeichnet, daß man die Reaktion bei einem Druck von 1 bis 200 bar durchführt.6. The method according to at least one of the preceding claims, characterized in that one carries out the reaction at a pressure of 1 to 200 bar.
7. 2-substituierte Derivate des 4- (Trifluormethyl) -phenols sowie des 4- (2-Trifluormethyl) -phenyl) -2-tetrahydropyranyl) ethers der folgenden Formel7. 2-substituted derivatives of 4- (trifluoromethyl) phenol and 4- (2-trifluoromethyl) phenyl) -2-tetrahydropyranyl) ether of the following formula
wobei R für Wasserstoff oder Tetrahydropyran-2-yl steht und where R is hydrogen or tetrahydropyran-2-yl and
wenn R Wasserstoff ist,when R is hydrogen
X für B(OH)2, B(0R1)2, B (OAryl) 2, COOR1, SiR^, Si(Aryl)3, SR2, S(Aryl), I,X for B (OH) 2 , B (0R 1 ) 2 , B (OAryl) 2 , COOR 1 , SiR ^, Si (aryl) 3 , SR 2 , S (aryl), I,
R1 unabhängig voneinander für Cx - Cs-AlkylR 1 independently of one another for C x - Cs-alkyl
R2 unabhängig voneinander für C2 - Cβ-AlkylR 2 independently of one another for C 2 - Cβ-alkyl
Aryl für Phenyl, Naphthyl, R1_C6H4, Riθ-C6H4 steht, wenn R Tetrahydropyran-2-yl istAryl stands for phenyl, naphthyl, R1_C 6 H 4 , Riθ-C 6 H 4 , when R is tetrahydropyran-2-yl
X für B (OH) 2, B(OR1)2, B(OAryl)2, CHO, COR1, CO(Aryl), COOH, COOR1, SiR1^ Si(Aryl)3, OH, SR1, S(Aryl), Cl, Br, I,X for B (OH) 2 , B (OR 1 ) 2 , B (OAryl) 2 , CHO, COR 1 , CO (aryl), COOH, COOR 1 , SiR 1 ^ Si (aryl) 3 , OH, SR 1 , S (aryl), Cl, Br, I,
R1 unabhängig voneinander für Ci-Cs-AlkylR 1 independently of one another for Ci-Cs-alkyl
Aryl unabhängig voneinander für Phenyl, Naphthyl, R1-C6H4,R10-C6H4 steht.Aryl independently of one another represents phenyl, naphthyl, R 1 -C 6 H 4 , R 1 0-C 6 H 4 .
8. 2,5-disubstituierte Derivate des 4- (Trifluormethyl) -phenols sowie des 4- (2-Trifluormethyl) -phenyl) -2-tetrahydropyranyl ) - ethers der folgenden Formel8. 2,5-disubstituted derivatives of 4- (trifluoromethyl) phenol and 4- (2-trifluoromethyl) phenyl) -2-tetrahydropyranyl) ether of the following formula
wobei" where "
R für Wasserstoff, Tetrahydropyran-2-ylR is hydrogen, tetrahydropyran-2-yl
X für B (OH) 2, B(OR1)2, B(OAryl)2, B (OR1)(OAryl ) CHO, COR1,X for B (OH) 2 , B (OR 1 ) 2 , B (OAryl) 2 , B (OR 1 ) (OAryl) CHO, COR 1 ,
CO(Aryl), COOH, COOR1, SiR^, Si(Aryl)3, OH, SR1, S(Aryl),CO (aryl), COOH, COOR 1 , SiR ^, Si (aryl) 3 , OH, SR 1 , S (aryl),
Cl, Br, I,Cl, Br, I,
Y unabhängig von X für B(OH)2, B(OR1)2/ B(OAryl)2,Y is independent of X for B (OH) 2 , B (OR 1 ) 2 / B (OAryl) 2 ,
B(OR1) (OAryl) , CHO, COR1, CO(Aryl), COOH, COOR1, SiR^,B (OR 1 ) (OAryl), CHO, COR 1 , CO (aryl), COOH, COOR 1 , SiR ^,
Si(Aryl)3, OH, SR1, S(Aryl), Cl, Br, ISi (aryl) 3 , OH, SR 1 , S (aryl), Cl, Br, I
R1 unabhängig voneinander für Cι-C8-AlkylR 1 independently of one another for C 1 -C 8 -alkyl
Aryl unabhängig voneinander für Phenyl, Naphthyl, R1-C6H4,Aryl independently of one another for phenyl, naphthyl, R 1 -C 6 H 4 ,
RRl1n0--rCv6πH,, sσtt-fe-hhrt-.. RRl 1 n0 - rCv 6 πH ,, sσtt-fe-hhrt- ..
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PCT/EP2001/009222 WO2002014250A1 (en) | 2000-08-11 | 2001-08-09 | Derivatives of 4-(trifluoromethyl)-phenol and 4-(trifluoromethylphenyl)-2-(tetrahydropyranyl) ether and method for producing the same |
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