NZ700641B2 - Method for preparation of 2-(2,3-dimethylphenyl)-1-propanal - Google Patents
Method for preparation of 2-(2,3-dimethylphenyl)-1-propanal Download PDFInfo
- Publication number
- NZ700641B2 NZ700641B2 NZ700641A NZ70064112A NZ700641B2 NZ 700641 B2 NZ700641 B2 NZ 700641B2 NZ 700641 A NZ700641 A NZ 700641A NZ 70064112 A NZ70064112 A NZ 70064112A NZ 700641 B2 NZ700641 B2 NZ 700641B2
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- New Zealand
- Prior art keywords
- reaction
- acid
- reac
- compound
- formula
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- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- GNEYVIZQCGXVEV-UHFFFAOYSA-N 2-(2,3-dimethylphenyl)propanal Chemical compound O=CC(C)C1=CC=CC(C)=C1C GNEYVIZQCGXVEV-UHFFFAOYSA-N 0.000 title description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 158
- 150000001875 compounds Chemical class 0.000 claims abstract description 85
- 239000000203 mixture Substances 0.000 claims abstract description 67
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 55
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 36
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims abstract description 28
- -1 Ce(OTf)3 Chemical compound 0.000 claims abstract description 27
- 230000002378 acidificating Effects 0.000 claims abstract description 23
- 239000003054 catalyst Substances 0.000 claims abstract description 21
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims abstract description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims abstract description 15
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims abstract description 14
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M Lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims abstract description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 12
- 235000019253 formic acid Nutrition 0.000 claims abstract description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 11
- 235000011007 phosphoric acid Nutrition 0.000 claims abstract description 11
- VSCWAEJMTAWNJL-UHFFFAOYSA-K Aluminium chloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims abstract description 10
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims abstract description 10
- CUHVIMMYOGQXCV-NSHDSACASA-N dexmedetomidine Chemical compound C1([C@@H](C)C=2C(=C(C)C=CC=2)C)=CNC=N1 CUHVIMMYOGQXCV-NSHDSACASA-N 0.000 claims abstract description 9
- 239000003456 ion exchange resin Substances 0.000 claims abstract description 9
- 229920003303 ion-exchange polymer Polymers 0.000 claims abstract description 9
- 229960002140 medetomidine Drugs 0.000 claims abstract description 9
- 229940098779 methanesulfonic acid Drugs 0.000 claims abstract description 9
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims abstract description 9
- ILAHWRKJUDSMFH-UHFFFAOYSA-N Boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims abstract description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 8
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 8
- 229910017981 Cu(BF4)2 Inorganic materials 0.000 claims abstract description 7
- 229910003480 inorganic solid Inorganic materials 0.000 claims abstract description 7
- SRSXLGNVWSONIS-UHFFFAOYSA-N Benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims abstract description 6
- 229940092714 benzenesulfonic acid Drugs 0.000 claims abstract description 6
- VLTRZXGMWDSKGL-UHFFFAOYSA-N Perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910003074 TiCl4 Inorganic materials 0.000 claims abstract description 5
- HPGGPRDJHPYFRM-UHFFFAOYSA-J Tin(IV) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims abstract description 5
- XJDNKRIXUMDJCW-UHFFFAOYSA-J Titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims abstract description 5
- DUNKXUFBGCUVQW-UHFFFAOYSA-J Zirconium(IV) chloride Chemical compound Cl[Zr](Cl)(Cl)Cl DUNKXUFBGCUVQW-UHFFFAOYSA-J 0.000 claims abstract description 5
- 229910007932 ZrCl4 Inorganic materials 0.000 claims abstract description 5
- 229910015845 BBr3 Inorganic materials 0.000 claims abstract description 4
- LXNAVEXFUKBNMK-UHFFFAOYSA-N acetic acid;palladium Chemical compound [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 claims abstract description 4
- HWUPLUNLNUHIQZ-UHFFFAOYSA-N copper;trifluoromethanesulfonic acid Chemical compound [Cu].OS(=O)(=O)C(F)(F)F.OS(=O)(=O)C(F)(F)F HWUPLUNLNUHIQZ-UHFFFAOYSA-N 0.000 claims abstract description 4
- QEKXARSPUFVXIX-UHFFFAOYSA-L nickel(2+);triphenylphosphane;dibromide Chemical compound [Ni+2].[Br-].[Br-].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QEKXARSPUFVXIX-UHFFFAOYSA-L 0.000 claims abstract description 4
- HLRHYHUGSPVOED-UHFFFAOYSA-N trifluoromethanesulfonic acid;ytterbium Chemical compound [Yb].OS(=O)(=O)C(F)(F)F.OS(=O)(=O)C(F)(F)F.OS(=O)(=O)C(F)(F)F HLRHYHUGSPVOED-UHFFFAOYSA-N 0.000 claims abstract description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L MgCl2 Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims abstract 8
- WMWLMWRWZQELOS-UHFFFAOYSA-N Bismuth(III) oxide Chemical compound O=[Bi]O[Bi]=O WMWLMWRWZQELOS-UHFFFAOYSA-N 0.000 claims abstract 6
- QMMRZOWCJAIUJA-UHFFFAOYSA-L Nickel(II) chloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims abstract 6
- 235000011149 sulphuric acid Nutrition 0.000 claims abstract 6
- 229910015844 BCl3 Inorganic materials 0.000 claims abstract 4
- OTCKOJUMXQWKQG-UHFFFAOYSA-L Magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 claims abstract 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L Zinc chloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims abstract 4
- 229910001623 magnesium bromide Inorganic materials 0.000 claims abstract 4
- 229910001629 magnesium chloride Inorganic materials 0.000 claims abstract 4
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 claims abstract 4
- 239000011592 zinc chloride Substances 0.000 claims abstract 4
- 235000005074 zinc chloride Nutrition 0.000 claims abstract 4
- PQLAYKMGZDUDLQ-UHFFFAOYSA-K Aluminium bromide Chemical compound Br[Al](Br)Br PQLAYKMGZDUDLQ-UHFFFAOYSA-K 0.000 claims abstract 3
- JHXKRIRFYBPWGE-UHFFFAOYSA-K Bismuth chloride Chemical compound Cl[Bi](Cl)Cl JHXKRIRFYBPWGE-UHFFFAOYSA-K 0.000 claims abstract 3
- 229910005267 GaCl3 Inorganic materials 0.000 claims abstract 3
- UPWPDUACHOATKO-UHFFFAOYSA-K Gallium trichloride Chemical compound Cl[Ga](Cl)Cl UPWPDUACHOATKO-UHFFFAOYSA-K 0.000 claims abstract 3
- PSCMQHVBLHHWTO-UHFFFAOYSA-K Indium(III) chloride Chemical compound Cl[In](Cl)Cl PSCMQHVBLHHWTO-UHFFFAOYSA-K 0.000 claims abstract 3
- RBTARNINKXHZNM-UHFFFAOYSA-K Iron(III) chloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims abstract 3
- HWSZZLVAJGOAAY-UHFFFAOYSA-L Lead(II) chloride Chemical compound Cl[Pb]Cl HWSZZLVAJGOAAY-UHFFFAOYSA-L 0.000 claims abstract 3
- BLQJIBCZHWBKSL-UHFFFAOYSA-L Magnesium iodide Chemical compound [Mg+2].[I-].[I-] BLQJIBCZHWBKSL-UHFFFAOYSA-L 0.000 claims abstract 3
- 229910002666 PdCl2 Inorganic materials 0.000 claims abstract 3
- CLSUSRZJUQMOHH-UHFFFAOYSA-L Platinum(II) chloride Chemical compound Cl[Pt]Cl CLSUSRZJUQMOHH-UHFFFAOYSA-L 0.000 claims abstract 3
- 229910019032 PtCl2 Inorganic materials 0.000 claims abstract 3
- 229910018057 ScCl3 Inorganic materials 0.000 claims abstract 3
- DVMZCYSFPFUKKE-UHFFFAOYSA-K Scandium chloride Chemical compound Cl[Sc](Cl)Cl DVMZCYSFPFUKKE-UHFFFAOYSA-K 0.000 claims abstract 3
- 229910001641 magnesium iodide Inorganic materials 0.000 claims abstract 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims abstract 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- 239000003153 chemical reaction reagent Substances 0.000 claims description 33
- 239000002904 solvent Substances 0.000 claims description 32
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 26
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 14
- 239000003205 fragrance Substances 0.000 claims description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 14
- 239000007795 chemical reaction product Substances 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 13
- 235000011054 acetic acid Nutrition 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 239000008079 hexane Substances 0.000 claims description 9
- MUBZPKHOEPUJKR-UHFFFAOYSA-N oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 9
- 239000000460 chlorine Substances 0.000 claims description 8
- MHAJPDPJQMAIIY-UHFFFAOYSA-N hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N NMP Substances CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 7
- XTHFKEDIFFGKHM-UHFFFAOYSA-N dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 7
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 7
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 6
- KFSLWBXXFJQRDL-UHFFFAOYSA-N peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 6
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tBuOOH Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 5
- FVSKHRXBFJPNKK-UHFFFAOYSA-N Propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 5
- 235000019270 ammonium chloride Nutrition 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-Bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 4
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 claims description 4
- SUKJFIGYRHOWBL-UHFFFAOYSA-N Sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 4
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 4
- 239000003570 air Substances 0.000 claims description 4
- 229910000323 aluminium silicate Inorganic materials 0.000 claims description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 4
- 239000011777 magnesium Substances 0.000 claims description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- ZNOVTXRBGFNYRX-UHFFFAOYSA-N 2-[[4-[(2-amino-5-methyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl)methylamino]benzoyl]amino]pentanedioic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 ZNOVTXRBGFNYRX-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- 235000015165 citric acid Nutrition 0.000 claims description 3
- 150000002500 ions Chemical class 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
- 229910052744 lithium Inorganic materials 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 235000006408 oxalic acid Nutrition 0.000 claims description 3
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 claims description 3
- XYPISWUKQGWYGX-UHFFFAOYSA-N 2,2,2-trifluoroethaneperoxoic acid Chemical compound OOC(=O)C(F)(F)F XYPISWUKQGWYGX-UHFFFAOYSA-N 0.000 claims description 2
- GLVYLTSKTCWWJR-UHFFFAOYSA-N 2-carbonoperoxoylbenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1C(O)=O GLVYLTSKTCWWJR-UHFFFAOYSA-N 0.000 claims description 2
- 229910014265 BrCl Inorganic materials 0.000 claims description 2
- CODNYICXDISAEA-UHFFFAOYSA-N Bromine monochloride Chemical compound BrCl CODNYICXDISAEA-UHFFFAOYSA-N 0.000 claims description 2
- YQHLDYVWEZKEOX-UHFFFAOYSA-N Cumene hydroperoxide Chemical compound OOC(C)(C)C1=CC=CC=C1 YQHLDYVWEZKEOX-UHFFFAOYSA-N 0.000 claims description 2
- FFHWGQQFANVOHV-UHFFFAOYSA-N Dimethyldioxirane Chemical compound CC1(C)OO1 FFHWGQQFANVOHV-UHFFFAOYSA-N 0.000 claims description 2
- OMPJBNCRMGITSC-UHFFFAOYSA-N Incidol Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N Meta-Chloroperoxybenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 2
- XCRBXWCUXJNEFX-UHFFFAOYSA-N Peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 claims description 2
- 229940035295 Ting Drugs 0.000 claims description 2
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 235000019441 ethanol Nutrition 0.000 claims description 2
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- 239000011347 resin Substances 0.000 claims description 2
- 229920005989 resin Polymers 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-Chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- PFUVRDFDKPNGAV-UHFFFAOYSA-N Sodium peroxide Chemical compound [Na+].[Na+].[O-][O-] PFUVRDFDKPNGAV-UHFFFAOYSA-N 0.000 claims 1
- 229910052782 aluminium Inorganic materials 0.000 claims 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims 1
- LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 11
- 239000002304 perfume Substances 0.000 abstract description 8
- 239000000126 substance Substances 0.000 abstract description 7
- MIOPJNTWMNEORI-UHFFFAOYSA-N Camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 abstract description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- YIEVSJJAWVBFTE-UHFFFAOYSA-N 2-methoxy-5-morpholin-4-ylsulfonylaniline Chemical compound C1=C(N)C(OC)=CC=C1S(=O)(=O)N1CCOCC1 YIEVSJJAWVBFTE-UHFFFAOYSA-N 0.000 description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- 150000001299 aldehydes Chemical class 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 238000004821 distillation Methods 0.000 description 8
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 8
- PPBRXRYQALVLMV-UHFFFAOYSA-N styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 150000001335 aliphatic alkanes Chemical class 0.000 description 6
- 238000009835 boiling Methods 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000005712 crystallization Effects 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 150000002373 hemiacetals Chemical class 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
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- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 description 1
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
- C07C1/20—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from organic compounds containing only oxygen atoms as heteroatoms
- C07C1/22—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from organic compounds containing only oxygen atoms as heteroatoms by reduction
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- C07C1/20—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from organic compounds containing only oxygen atoms as heteroatoms
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C15/40—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts substituted by unsaturated carbon radicals
- C07C15/42—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts substituted by unsaturated carbon radicals monocyclic
- C07C15/44—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts substituted by unsaturated carbon radicals monocyclic the hydrocarbon substituent containing a carbon-to-carbon double bond
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- C07C2531/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- C07C2531/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- C07C2531/025—Sulfonic acids
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
- C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
- C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
- C07C29/40—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones with compounds containing carbon-to-metal bonds
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C33/18—Monohydroxylic alcohols containing only six-membered aromatic rings as cyclic part
- C07C33/20—Monohydroxylic alcohols containing only six-membered aromatic rings as cyclic part monocyclic
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- 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
- C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
- C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
- C07C45/58—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom in three-membered rings
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
- C07C45/86—Use of additives, e.g. for stabilisation
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C47/00—Compounds having —CHO groups
- C07C47/20—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms
- C07C47/228—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing six-membered aromatic rings, e.g. phenylacetaldehyde
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/58—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
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- C07D301/02—Synthesis of the oxirane ring
- C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
- C07D301/12—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with hydrogen peroxide or inorganic peroxides or peracids
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- C07D301/02—Synthesis of the oxirane ring
- C07D301/24—Synthesis of the oxirane ring by splitting off HAL—Y from compounds containing the radical HAL—C—C—OY
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- C07D303/02—Compounds containing oxirane rings
- C07D303/04—Compounds containing oxirane rings containing only hydrogen and carbon atoms in addition to the ring oxygen atoms
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- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11B—PRODUCING, e.g. BY PRESSING RAW MATERIALS OR BY EXTRACTION FROM WASTE MATERIALS, REFINING OR PRESERVING FATS, FATTY SUBSTANCES, e.g. LANOLIN, FATTY OILS OR WAXES; ESSENTIAL OILS; PERFUMES
- C11B9/00—Essential oils; Perfumes
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- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11B—PRODUCING, e.g. BY PRESSING RAW MATERIALS OR BY EXTRACTION FROM WASTE MATERIALS, REFINING OR PRESERVING FATS, FATTY SUBSTANCES, e.g. LANOLIN, FATTY OILS OR WAXES; ESSENTIAL OILS; PERFUMES
- C11B9/00—Essential oils; Perfumes
- C11B9/0061—Essential oils; Perfumes compounds containing a six-membered aromatic ring not condensed with another ring
Abstract
The invention discloses a method for preparation of a compound of formula (XXI); the method comprises a step (N); step (N) comprises a reaction (N-reac); reaction (N-reac) is a reaction of compound of formula (XXII) with a catalyst (N-cat); catalyst (N-cat) is selected from the group consisting of acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, HCl, HBr, H2SO4, HNO3, H3PO4, HClO4, BCl3, BBr3, BF3OEt2, BF3SMe2, BF3THF, MgCl2, MgBr2, MgI2, AlCl3, Al(O C1 4 alkyl)3, SnCl4, TiCl4, Ti(O C1 4 alkyl)4, ZrCl4, Bi2O3, BiCl3, ZnCl2, PbCl2, FeCl3, ScCl3, NiCl2, Yb(OTf)3, Yb(Cl)3, GaCl3, AlBr3, Ce(OTf)3, LiCl, Cu(BF4)2, Cu(OTf)2, NiBr2(PPh3)2, NiBr2, NiCl2, Pd(OAc)2, PdCl2, PtCl2, InCl3, acidic inorganic solid substance, acidic ion exchange resin, carbon treated with inorganic acid and mixtures thereof. The invention is also directed towards the use of the compound of formula (XXI), its use in perfumes and its use for the preparation of medetomidine. cetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, HCl, HBr, H2SO4, HNO3, H3PO4, HClO4, BCl3, BBr3, BF3OEt2, BF3SMe2, BF3THF, MgCl2, MgBr2, MgI2, AlCl3, Al(O C1 4 alkyl)3, SnCl4, TiCl4, Ti(O C1 4 alkyl)4, ZrCl4, Bi2O3, BiCl3, ZnCl2, PbCl2, FeCl3, ScCl3, NiCl2, Yb(OTf)3, Yb(Cl)3, GaCl3, AlBr3, Ce(OTf)3, LiCl, Cu(BF4)2, Cu(OTf)2, NiBr2(PPh3)2, NiBr2, NiCl2, Pd(OAc)2, PdCl2, PtCl2, InCl3, acidic inorganic solid substance, acidic ion exchange resin, carbon treated with inorganic acid and mixtures thereof. The invention is also directed towards the use of the compound of formula (XXI), its use in perfumes and its use for the preparation of medetomidine.
Description
METHOD FOR ATION OF 2-(2,3-DIMETHYLPHENYL)PROPANAL
The invention discloses a method for ation of 2-(2,3-dimethylphenyl)propanal from
1-bromo 2,3-dimethylbenzene and acetone, its use in es and its use for the preparation
of medetomidine.
Aromatic aldehydes are widely used as flavours and fragrances in cosmetics, perfumes, and
numerous household products. Alpha, nsaturated ic aldehydes, such as
substituted cinnamic aldehydes, are disclosed to have distinct fragrance and are therefore used
in the perfume industry.
WO 98/45237 A discloses certain aromatic aldehydes, a method for producing them starting
from acetophenone acetals, their use as perfumes and their use as intermediates for the
ation of 3-arylpropanals. They have a musky fragrance.
Mukherjee-Müller et al., Helvetica Chimica Acta, 1977, 60, 1758-1780, discloses a process for
the preparation of 2-(dimethylphenyl) propanaldehydes as a mixture of 3 unidentified isomers.
The position of the methyl on the aromatic groups is unknown. These compounds are prepared
by a ngement reaction in the presence of an acidic catalyst (sulfuric acid) from certain
tricyclic alcohols.
The perfume and household product industry has a nt need for new perfumes with
interesting, new and not yet available fragrances in order to increase the available choice of
fragrances and to adapt the nces to the ever changing demand of fashion. Furthermore
the respective substances need to be synthesized economically and with consistent quality.
High purity and strong fragrances are desired. The present invention es a new alpha,
beta-unsaturated aromatic aldehyde analogue, which has strong and interesting, aldehydic
fragrance, ely spicy and sweet, and an improved process for the production f.
In the following text,
halogen means F, Cl, Br or I, preferably Cl, Br or I;
"alkyl" means linear, branched, cyclic or cyclo alkyl, preferably it means the commonly
accepted meaning linear or branched alkyl; if not otherwise stated. Examples of "alkyl"
include , ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl,
heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl,
adamantyl, and the like;
"cyclic alkyl" or "cyclo alkyl" are ed to include cyclo aliphatic, bicyclo aliphatic and
tricycle aliphatic residues;
"alkane" means a linear, branched or cyclic , preferably linear or branched alkane;
"alkanol" means a hydroxyalkane, with alkane having the meaning as defined above also with
its preferred embodiments;
Ac acetyl;
tBu tertiary butyl;
DBU 1,8-diazabicyclo[5 .4.0]undecene;
DABCO l,4-diazabicyclo[2.2.2]octane;
DIPEA N-ethyl-N,N—diisopropylamine;
DMA N,N—dimethylacetamide;
DMF N,N—dimethylformamide;
EDTA—Nag ethylene diamine tetraacetic acid disodium;
hexanes mixture of isomeric hexanes;
NMP N—methyl-Z—pyrrolidone;
OTf trifluoromethanesulfonate, also known as triflate;
MPS KHSOs, also known as potassium peroxymonosulfate or potassium
monopersulfate, and marketed as a triple salt with the formula 2 KH805 KHSO4
K2804 under the trade names ® and , therefore KH805 is often
used in form of this triple salt;
salen ligand obtained from a condensation of salicylaldehyde or of a substituted
salicylaldehyde derivative with ethylene diamine or with a substituted ethylene
e;
sulfamic acid HO-SOg-NHzg
TEMPO 6—tetramethylpiperidine l-oxyl;
THF tetrahydrofuran;
xylene methylbenzene, 1,3-dimethylbenzene, 1,4-dimethylbenzene or a mixture
thereof;
if not otherwise stated.
Subject of the invention is a method for preparation of compound of formula (XXI);
CH3 CH3
0 CH3
(XXI)
WO 11156 2012/072797
the method comprises a step (N);
step (N) comprises a reaction (N—reac);
reaction (N-reac) is a on of compound of formula (XXII) with a catalyst (N-cat);
CH3 CH3
(xx11)
catalyst (N-cat) is selected from the group consisting of acetic acid, formic acid,
trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,
rsulfonic acid, HCl, HBr, H2804, HNO3, H3PO4, HClO4, BC13, BBr3, BFgoEtz,
BngMez, BFgTHF, MgClz, MgBrz, Mglz, AlClg, Al(O-C1_4 alkyl)3, SnCl4, TiCl4,
Ti(O-C1_4 alkyl)4, ZrCl4, B1203, B1Cl3, ZnClz, PbClz, FCCl3, SCCl3,N1C12, Yb(OTf)3,
Yb(Cl)3, GaClg, AlBrg, Ce(OTf)3, LiCl, Cu(BF4)2, Cu(OTf)2,NiBr2(PPh3)2,NiBr2,NiC12,
Pd(OAc)2, PdClz, PtClz, InC13, acidic inorganic solid substance, acidic ion exchange
resin, carbon treated with inorganic acid and mixtures thereof.
Preferably, the acidic nic solid substance is aluminosilicates.
Preferably, the acidic ion exchange resin is selected from the group consisting of copolymers
of styrene and divinylbenzene and of perfluorinated branched or linear hylenes,
these polymers being functionalized with SO3H groups;
more preferably, the acidic ion exchange resin is ed from the group consisting of
copolymers of styrene and divinylbenzene containing more than 5% of divinylbenzene,
preferably being macroreticular, and ofperfluorinated polyethylenes, these polymers
being functionalized with SOgH groups.
ably, the inorganic acid, with which the carbon was treated, is selected from the group
consisting of HCl, H2804 and HNO3.
Preferably, the catalyst (N-cat) is selected from the group consisting of acetic acid, formic
acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, HCl, HBr, H2804,
W0 20131011156
H3PO4, BC13, BF30Et2, MgClg, MgBrg, AlCl3, ZnClg, Cu(BF4)2, osilicates, acidic
ion exchange , carbon treated with HCl, H2804 or HNO3,and mixtures thereof;
more preferably, the catalyst (N-cat) is selected from the group consisting of acetic acid,
formic acid, methanesulfonic acid, p-toluenesulfonic acid, HCl, H2804, BF30Et2,
Cu(BF4)2, aluminosilicates, acidic ion ge resins, and mixtures thereof.
Preferably, reaction (N-reac) is done in a solvent (N-solv);
solvent (N-solv) is selected from the group consisting of water, tert—butanol, isopropanol,
itrile, propionitrile, THF, methyl-THF, NMP, dioxane, 1,2-dimethoxyethane,
dichloromethane, 1,2-dichloroethane, chloroform, toluene, benzene, chlorobenzene,
hexane, cyclohexane, ethyl acetate, acetic acid, formic acid, trifluoroacetic acid and
mixtures thereof;
preferably from water, acetonitrile, propionitrile, THF, 2-methy1-THF, 1,2—dimethoxyethane,
dichloromethane, 1,2-dichloroethane, chloroform, toluene, cyclohexane, ethyl acetate,
acetic acid, formic acid and mixtures thereof;
more preferably from water, itrile, propionitrile, THF, yl-THF, 1,2-
dimethoxyethane, dichloromethane, 1,2—dichloroethane, toluene, ethyl acetate and
es thereof;
even more preferably from acetonitrile, THF, 2-methyl-THF, dichloromethane, toluene, ethyl
e and mixtures thereof.
The catalyst (N-cat) can be used in a pure form or as hydrate.
The catalyst (N-cat) can be used as a solution in solvent v).
Preferably, the molar ratio between catalyst (N-cat) and compound of formula (XXII) is from
1:1000 to 10:1, more preferably from 1:100 to 5:1, even more preferably from 1:20 to 1:1,
ally from 1:10 to 1:2.
Preferably, the reaction temperature of on (N—reac) is from —20 to 200 0C, more
preferably from 0 to 150 °C, even more preferably from 10 to 100 °C.
The reaction (N-reac) can be done in a system, that is closed or open to the atmosphere.
In a closed system, the pressure depends mainly on the boiling point of a solvent (N-solv) and
on the reaction temperature of reaction (N-reac).
Preferably, the reaction (N-reac) is done at a pressure of from 0.0] bar to 20 bar, more
preferably of from 0.1 to 10 bar, even more ably of from atmospheric pressure to 5 bar.
More preferably, the reaction (N—reac) is done in an open system.
Preferably, the reaction time of reaction (N-reac) is from 30 min to 72 h, more preferably
from 1 h to 48 h, even more ably from 2 h to 24 h.
Alternatively, reaction (N-reac) can be done as a continuous gas-phase reaction by passing the
evaporated compound of a (XXII) over the catalyst (N-cat). This gas-phase reaction
can be done in the presence of an inert gas, the inert gas is preferably ed from the group
consisting of nitrogen, a noble gas and carbon e.
After reaction (N-reac), compound of formula (XXI) can be isolated by standard methods
such as evaporation of volatile components, extraction, washing, , concentration,
filtration, crystallization, distillation, chromatography and any combination thereof, which are
known per se to the person skilled in the art.
Preferably, any le components of the reaction mixture or added or generated during
work up can be removed by evaporation under reduced pressure.
Preferably, the reaction mixture resulting from reaction (N-reac) or any aqueous phase during
the work up after reaction (N—reac) can be ted with a solvent (M-extract),
solvent ract) is preferably selected from the group consisting of water, toluene,
benzene, xylene, chlorobenzene, romethane, chloroform, acetic acid C1_g alkyl ester and
combinations thereof;
the acetic acid CH; alkyl ester is preferably an acetic acid C1_4 alkyl ester, more preferably
selected from the group consisting of ethyl acetate, isopropyl acetate and butyl acetate;
preferably solvent ract) is selected from the group consisting of toluene,
romethane, ethyl acetate, isopropyl acetate and mixtures thereof.
WO 11156
Preferably, any washing of any organic phase after reaction (N-reac) can be done with water,
with a base ify), with an aqueous solution of a base (M-basify), with an aqueous
solution of an acid d) or with brine.
ably base (M-basify) is selected from the group consisting ofNaHCOg, N32C03, NaOH
and mixtures thereof.
Preferably, base (M—basify) is added in such an amount, that the pH of the resulting mixture is
from 7 to 12, more preferably from 8 to 10, even more preferably from 8 to 9.
Preferably, acid (M—acid) is selected from the group consisting of oxalic acid, citric acid,
maleic acid, fumaric acid, tartaric acid, NH4Cl, HCl, HBr, H2804, H3PO4 and mixtures
thereof.
Any extraction or washing can be followed by filtration and concentration of the extract or of
the washed mixture.
In another preferred embodiment, compound of formula (XXI) is purified after reaction (N-
reac) by chromatography.
Any organic phase can be dried, ably over MgSO4 or NaZSO4.
Any concentration is preferably done by distillation, preferably under reduced pressure.
Compound of formula (XXI) can be obtained in step (N) as the aldehyde as depicted in
formula (XXI), but also in form of its hydrate or hemiacetal. The hemiacetal of compound of
formula (XXI), which can result as product from step (N), can be the product of an addition
on between the aldehyde as depicted in formula (XXI) and an alcohol selected from the
group consisting of utanol and isopropanol, or between the aldehyde as depicted in
formula (XXI) and any alcohol which is used during the isolation after reaction (N-reac).
Therefore formula (XXI) for the purpose of this invention encompasses the aldehyde, hydrate
and the hemiacetal.
When compound of formula (XXI) is obtained from reaction (N-reac) in form of its e
or of a hemiacetal, the hydrate or the hemiacetal can be ted into the aldehyde by
standard reactions known to the person skilled in the art.
WO 11156
Preferably, compound of formula (XXII) is prepared in a step (0) or in two steps, the two
steps are step (01) and step (02);
step (0) comprises a reaction c);
reaction (O-reac) is a reaction of nd of formula (XXIII), with a reagent (O-reag);
CH3 CH3
reagent (O-reag) is selected from the group consisting of tic acid, trifluoroperacetic
acid, perbenzoic acid, 3-chloroperbenzoic acid, monoperphthalic acid, dimethyldioxirane,
utylhydroperoxide, dibenzoyl peroxide, cumenehydroperoxide, oxygen, air, sodium
hypochlorite, KHSOs, Na202, aqueous H202, H202 ved in acetic acid, H202
dissolved in trifluoroacetic acid, and mixtures thereof;
step (01) comprises a reaction (Ol-reac);
reaction (Ol—reac) is a reaction of compound of formula (XXIII) with water and with a
compound (01-comp);
compound (Ol-comp) is selected from the group consisting of bromine, N-bromosuccinimide,
chlorine, rosuccinimide, iodine, N—iodosuccinimide, IBr, BrCl, and mixtures
thereof;
step (02) comprises a reaction (OZ-reac);
reaction (02—reac) is a reaction of the reaction product from reaction (Ol-reac) with a base
(OZ-base);
base se) is selected from the group consisting of sodium hydroxide, potassium
hydroxide, calcium hydroxide and e thereof.
Preferably, reagent (0-reag) is selected from the group consisting of peracetic acid, tertbutylhydroperoxide
, oxygen, air, sodium hypochlorite, aqueous H202, H202 dissolved in
acetic acid, H202 dissolved in trifluoroacetic acid, and mixtures thereof;
more preferably, reagent (0-reag) is aqueous H202.
Preferably, on (O-reac) is done in a solvent (O-solv);
solvent v) is selected from the group consisting of water, aqueous solutions of
NaHC03, N32C03, (NH4)HC03, (NH4)2C03, KHC03 or K2C03, benzene, toluene, NMP,
dioxane, acetone, ethyl acetate, methylethylketone, tert-butanol, acetonitrile, chloroform,
dichloromethane and mixtures thereof;
ably from water, aqueous solutions ofNaHCOg, N32C03, KHC03 or K2C03, toluene,
e, acetone, ethyl acetate, methylethylketone, tert—butanol, acetonitrile,
dichloromethane and mixtures thereof.
Reaction (O-reac) can be done in the presence of a catalyst (O-cat);
catalyst (O—cat) is selected from the group consisting of trifluoroacetic acid, trifluoroacetone,
Mn(salen) complex, aldehydes, N—methylmorpholine N-oxide, 2,2,6,6-tetramethylpiperidine
l-oxyl and mixtures thereof;
aldehydes are preferably isobutyraldehyde or benzaldehyde.
Reaction (O-reac) can be done in the presence of a buffer f);
preferably, buffer (O-buff) is an aqueous buffer and is selected from the group consisting of
K2C03 / EDTA-Naz buffer, phosphate buffer and other buffers known by the skilled ;
more preferably, buffer (O-buff) is an K2C03 / EDTA-Naz buffer.
Preferably, the reaction temperature of reaction (O—reac) is from -20 to 100 CC, more
ably from -10 to 80 °C, even more preferably from 0 to 50 OC.
The reaction (O-reac) can be done in a system, that is closed or open to the atmosphere.
In a closed system, the pressure depends on the boiling point of a t (O-solv) and on the
reaction temperature of reaction (O-reac).
Preferably, the reaction (N—reac) is done at a pressure of from 0.0] bar to 20 bar, more
preferably of from 0.1 to 10 bar, even more preferably of from atmospheric re to 5 bar.
More ably the reaction (O-reac) is done in an open .
Preferably, the reaction time of reaction (O-reac) is from 30 min to 72 h, more preferably
from 1 h to 48 h, even more preferably from 2 h to 24 h.
After the reaction (O—reac), the compound of formula (XXII) can be isolated by standard
methods such as evaporation of volatile ents, tion, washing, drying,
concentration, crystallization, lation, tography and any combination thereof.
Preferably, reaction ac) and reaction (OZ-reac) are conducted in t (O—solv), with
solvent (O-solv) as defined above, also with all its preferred embodiments.
Preferably, the reaction temperatures of reaction (Ol-reac) and of reaction (O2-reac) are
identical or different and ndently from each other from -20 to 100 °C, more preferably
from —10 to 80 °C, even more preferably from 0 to 50 oC.
Reaction (Ol-reac) and reaction (O2-reac) can independently from each other be done in
systems, that are closed or open to the here.
In a closed system, the pressure depends on the boiling point of a solvent (O-solv) and on the
reaction temperature of reaction (Ol-reac) and reaction (O-reac) respectively.
Preferably, reaction (Ol-reac) and reaction (O2-reac) are independently from each other done
at pressures of from 0.01 bar to 20 bar, more preferably of from 0.1 to 10 bar, even more
preferably of from atmospheric pressure to 5 bar.
More preferably, reaction (Ol-reac) and reaction (O2-reac) are done in a open system.
Preferably, the reaction times of reaction (Ol-reac) and of reaction (O2-reac) are
independently from each other from 30 min to 72 h, more preferably from 1 h to 48 h, even
more preferably from 2 h to 24 h.
The reaction product of reaction (Ol-reac) and the compound of formula (XXII) from
reaction (O2-reac) can be isolated by standard methods such as evaporation of volatile
components, extraction, washing, drying, concentration, filtration, crystallization, distillation,
chromatography and any combination thereof.
Reaction (Ol-reac) and reaction (O2-reac) can be done consecutively t isolation of the
on product of reaction (Ol-reac), they can be done in one pot.
Preferably, compound of formula (XXII) is not isolated, step (N) is done directly after step
(0) or step (02) respectively in one pot. For this, catalyst (N—cat) is simply added to the
reaction mixture resulting from reaction (O-reac) or from reaction (OZ-reac) respectively.
Preferably, compound of formula (XXIII) is prepared in a step (P);
step (P) ses a reaction (P-reac);
in reaction (P-reac) the compound of formula (XXIV) is exposed to a temperature (P-temp);
CH3 CH3
(XXIV)
temperature (P-temp) is from 0 to 300 °C.
Preferably, temperature (P-temp) is from 5 to 200 CC, more preferably from 100 to 150 °C.
Reaction (P-reac) can be done in a solvent (P-solv);
solvent v) is selected from the group consisting of benzene, toluene, xylene, hexane,
heptane, 1,2-dichloroethane, NMP, dichloromethane, chloroform and es thereof;
preferably from benzene, toluene, xylene, dichloromethane and mixtures thereof.
Preferably, reaction (P-reac) is done in the presence of a st (P-cat);
catalyst (P-cat) is selected from the group consisting of acetic acid, formic acid, trifluoroacetic
acid, methanesulfonic acid, benzenesulfonic acid, enesulfonic acid,
camphorsulfonic acid, HCl, HBr, H2804, KOH, NaOH, KHSO4, HNO3, H3PO4, HClO4,
BClg, BBI'3, BF30Et2, BngMez, BFgTHF, MgClz, MgBrz, MgIz, AlClg, Al(O-C1_4 alkyl)3,
12, A1203, SnCl4, TiC14, 1_4 alkyl)4, ZrCl4, B1203, B1Cl3, ZIIClz, PbClz, FGCl3,
)3, Yb(Cl)3, GaClg, AlBI'g, Ce(OTf)3, LiCl, acidic insoluble inorganic solid, acidic
ion ge , carbon treated with an inorganic acid, and es f;
preferably from methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, H2804,
KHSO4, H3PO4, acidic insoluble inorganic solid, acidic ion exchange resins, carbon
treated with an inorganic acid, and mixtures thereof.
Preferably, the acidic insoluble inorganic solid is acidic aluminosilicates or silica gel.
Preferably, the inorganic acid, with which the carbon was treated, is selected from the group
consisting of HCl, H2804 and HNOg.
ably, the acidic ion exchange resin is selected from the group consisting of copolymers
of styrene and divinylbenzene and of perfluorinated ed or linear polyethylenes,
these polymers being functionalized with SO3H groups;
more preferably, the acidic ion exchange resin is selected from the group consisting of
copolymers of styrene and divinylbenzene containing more than 5% of divinylbenzene,
preferably being macroreticular, and of perfluorinated polyethylenes, these polymers
being nalized with SO3H .
When reaction (P-reac) is done in the presence of a catalyst ), ature (P-temp) is
preferably from 0 to 200 CC, more preferably from 10 to 150 CC, even more preferably from
to 100 °C.
on (P-reac) can be done in gas phase by passing evaporated compound of formula
(XXIV) through a heated tube, the heated tube can be charged with a catalyst (P-cat).
After reaction c), the compound of formula (XXIII) can be isolated by standard
methods such as evaporation of volatile components, extraction, washing, drying,
concentration, crystallization, distillation, chromatography and any combination thereof.
Preferably, compound of formula (XXIV) is prepared in three steps, the three steps are a step
(Q1), a step (Q2) and a step (Q3);
step (Q1) comprises a reaction (Ql—reac) by a on of compound of formula (XXV) with a
reagent (Q 1—reag);
(XXV)
Q is Br, C1, or I;
reagent (Ql-reag) is selected from the group consisting of lithium, magnesium, um,
zinc, calcium, isopropylmagnesium chloride, pylmagnesium bromide, butyllithium,
sec-butyllithium and mixtures thereof;
step (Q2) ses a reaction (Q2-reac);
reaction (Q2—reac) is a reaction of the reaction product of on (Ql-reac) With e;
in step (Q3) comprises a reaction (Q3-reac);
reaction (Q3-reac) is a reaction of the reaction product of reaction ac) with a reagent
(Q3-reag);
reagent (Q3-reag) is selected from the group consisting of water, methanol, ethanol, oxalic
acid, citric acid, NH4Cl, HCl, HBr, HN03, H2804, H3PO4, acetic acid, propionic acid, formic
acid and mixtures thereof.
Preferably, Q is Br.
Preferably, reagent (Ql-reag) is selected from the group consisting of lithium, magnesium,
um, isopropylmagnesium chloride, isopropylmagnesium e and mixtures thereof.
Reaction (Ql-reac) can be catalyzed with a catalyst (Ql-cat).
st (Ql—cat) is selected from the group consisting of iodine, 1,2—dibromoethane, TiCl4,
A1C13, PbClZ, B1C13, LiCl and mixtures thereof.
Preferably, reagent (Q3-reag) is water or aqueous NH4Cl.
Preferably, reaction (Ql-reac) is performed in a solvent (Ql-solV).
Preferably, reaction (Q2-reac) is performed in a solvent (Q2-solV).
WO 11156
Preferably, reaction ac) is performed in a solvent (Q3 —solv).
Preferably, solvent (Ql-solv), solvent (Q2-solv) and solvent (Q3-solv) are identical or
different and independently from each other ed from THF, methyl-THF, NMP,
diethylether, methyl-tert-butylether, methoxycyclopentane, diisopropylether, 1,2-
dimethoxyethane, tri C1_4 alkyl amine and mixtures thereof;
more preferably from THF, 2-methyl-THF, l,2-dimethoxyethane, methyl—tert-butylether,
methoxycyclopentane, tri C1_4 alkyl amine and mixtures thereof;
even more preferably from the group consisting of THF, 2-methyl-THF, 1,2-
dimethoxyethane, triethylamine, and mixtures thereof.
Preferably the solvent (Ql—solv), solvent (Q2-solv) and solvent (Q3-solv) are identical.
The reaction atures of reaction (Ql—reac), of reaction (Q2-reac) and of on (Q3-
reac) are cal or different and idependently from each other preferably from -100 to 150
0C, more preferably from -60 to 100 oC, and even more preferably from -20 to 80 oC.
Reaction (Ql-reac), on (Q2-reac) and reaction (Q3-reac) can be done at a constant
temperature, or the temperature may be modified during the ss of the reactions. For
instance, the reactions can run for a certain time at first temperature, and then for a subsequent
time at a second temperature different from the first temperature. Alternatively, the
temperature may be modified continuously during the reaction.
The reaction times of reaction (Ql-reac), of reaction (Q2-reac) and of reaction (Q3—reac) are
identical or different and idependently from each other preferably from 30 min to 48 h, more
preferably from 1 to 24 h, even more preferably from 2 to 12 h.
The amounts of solvent (Ql-solv), of t (Q2—solv) and of solvent (Q3-solv) are are
identical or different and idependently from each other preferably from 2 to 40 fold, more
preferably from 3 to 10 fold, even more preferably from 5 to 7 fold, of the weight of
compound of formula (XXV), of the weight of the on product of reaction (Ql—reac) and
of the weight of the reaction product of reaction (Q2-reac) respectively.
2012/072797
Preferably, from 1.0 to 10 mol equivalents, more preferably from 1.1 to 5 mol equivalents,
even more preferably from 1.1 to 3 mol equivalents of reagent (Ql-reag) are used, the mol
equivalents being based on the mol of compound of formula (XXV).
ably, from 1.0 to 10 mol equivalents, more ably from 1.1 to 5 mol equivalents,
even more preferably from 1.1 to 3 mol equivalents of e are used, the mol equivalents
being based on the mol of compound of formula (XXV).
Preferably, from 1.0 to 100 mol equivalents, more preferably from 1.1 to 50 mol equivalents,
even more preferably from 1.1 to 30 mol equivalents of reagent (Q3 —reag) are used, the mol
equivalents being based on the mol of compound of formula (XXV) or of the mol of the
reaction product of reaction (Q2—reac).
Preferably, reaction ac), reaction (Q2-reac) and reaction (Q3-reac) are done at
atmospheric pressure.
Preferably, reaction (Ql-reac), reaction (Q2—reac) and reaction ac) are done under inert
atmosphere. Preferably, the inert atmosphere is achieved by the use if an inert gas selected
from the group consisting of argon, another noble gas, lower boiling alkane, nitrogen and
mixtures thereof.
The lower boiling alkane is ably a C1_3 alkane, i.e. methane, ethane or propane.
After reaction (Ql-reac), reaction (Q2-reac) and reaction (Q3-reac), the reaction product of
reaction (Ql—reac), the reaction product of reaction (Q2-reac) and compound of formula
(XXIV) respectively can be isolated by standard methods such as evaporation of volatile
components, tion, washing, drying, tration, crystallization, distillation,
chromatography and any combination thereof.
Preferably, the reaction product of reaction ac) and the reaction product of reaction
(Q2-reac) are not isolated.
Preferably, reaction ac), reaction ac) and reaction (Q3-reac) are done
consecutively; preferably, reaction (Ql-reac), reaction (Q2—reac) and reaction (Q3—reac) are
done in one pot.
In another preferred embodiment, reaction (Ql-reac) and reaction (Q2-reac) can be done in
one pot by adding t (Ql-reag) to a mixture of compound of formula (XXV) and
acetone in a solvent (Ql-solv); reaction (Q3-reac) is done thereafter, preferably in the same
pot.
Compound of formula (XXIV) is preferably isolated using conventional methods, such as
evaporation of volatile ents, hydrolysis and optional acidification of the higher-
boiling residue, extraction, and distillation.
Any aqueous phase can be extracted, preferably the extraction is done with a solvent (Q-
extract). Solvent (Q—extract) is benzene, e, ethyl acetate, or pyl acetate.
Any organic phase can be dried, preferably with magnesium sulphate.
Any concentration is preferably done by distillation, preferably under reduced pressure.
The compound of formula (XXIV) can be purified, preferably by crystallization or distillation
under d pressure.
Compounds of formula (XXI) and (XXII) are chiral nds, and the ae comprise
any enantiomer as well as any mixture of enantiomers of the compounds of formula (XXI), or
of formula (XXII) respectively.
Compounds of formula (XXV) are known compounds and can be prepared according to
known methods.
The progress of any of the ons reaction (N-reac), reaction (O-reac), reaction (Ol-reac),
on (O2—reac), reaction (P-reac), reaction (Ql-reac), reaction (Q2-reac) and reaction (Q3-
reac) can be monitored by standard techniques, such as nuclear magnetic resonance
spectroscopy (NMR), infrared spectroscopy (IR), High performance Liquid Chromatography
(HPLC), Liquid Chromatography Mass Spectrometry , or Thin Layer
Chromatography (TLC), and p of the on mixture can start, when the conversion
of the starting material exceeds 95%, or when no more ng material can be detected. The
time required for this to occur will depend on the precise reaction temperature and the precise
concentrations of all reagents, and may vary from batch to batch.
In general, any organic phase can be dried, preferably over MgSO4 or NaZSO4, if not stated
otherwise.
Further subject of the invention is the use of compound of formula (XXI) as a fragrance,
preferably in perfumes or house hold products.
r t of the invention is the use of compound of a (XXI) for the preparation
of midine.
Medetomidine is compound of formula (XX)
and is an alpha2 adrenergic agonist, which is currently being used as veterinary sedative and
analgesic and is evaluated as anesthetic.
WOZOl l/O70069A discloses a process for the preparation of medetomidine, in which the
imidazole ring is built up during a multi-step process ng from commercially affordable
methy1 benzoic acid.
Compound of formula (XX) is preferably prepared from compound of formula (XXI) by a
method, that comprises a reaction (Ml);
reaction (M1) is a reaction between a compound of formula (XXI), an isocyanide and a
compound acting as nitrogen source;
the isocyanide is preferably a reagent (M), reagent (M) is ed from the group consisting
of p-toluenesulfonylmethyl isocyanide, trifluoromethanesulfonylmethyl nide,
methanesulfonylmethyl isocyanide, benzenesulfonylmethyl isocyanide, 4-
acetamidobenzenesulfonylmethyl isocyanide and mixtures thereof;
the compound acting as a en source is preferably a reagent (M-A), reagent (M-A) is
selected from the group consisting of ammonia, sulfamic acid, p-toluenesulfonamide,
benzenesulfonamide, 4—acetamidobenzenesulfonamide, amine, formamide, urea,
urotropine, ethyl carbamate, acetamide and mixtures thereof;
preferably the reaction (M1) is done in a solvent (M), preferably solvent (M) is selected from
the group ting ofN,N—dimethylformamide, C1_6 alkanol, formamide, 1,2-
dimethoxyethane, NMP, toluene, acetonitrile, propionitrile, ethyl carbamate, N,N-
dimethylacetamide, water, acetamide and mixtures thereof.
Any sequence of the reaction of reagent (M) and ofreagent (M-A) with the compound of
formula (XXI) in reaction (Ml) can be used:
compound of formula (XXI) can first be reacted with reagent (M) and then t (M-A)
added;
compound of formula (XXI) can first be first d with reagent (M-A) and then reagent
(M) added;
or
compound of a (XXI) can simultaneously be reacted with reagent (M) and with reagent
(M-A), this embodiment is ably suited for the case that reagent (M-A) and solvent (M)
are identical and are formamide, ethyl ate or acetamide; preferably formamide.
Further subject of the invention is the use of compound of formula (XXII) for the preparation
of nd of formula (XXI).
r subject of the invention is the use of compound of formula (XXIII) for the preparation
of compound of formula (XXII).
Further subject of the invention is the use of compound of formula (XXIV) for the preparation
of compound of formula (XXIII).
Further subject of the invention is the use of compound of formula (XXV) for the preparation
of compound of formula .
Compared to prior art, the method of the present invention offers several ages:
Importantly, the whole carbon framework of compound of formula (XXI) is built in few
chemical steps, using cheap reagents only. No protecting groups are needed and the overall
amount of material used is therefore reduced, the batch size based on molar amounts is
increased.
In particular no trityl or acetal protection groups are used and no protection of the imidazoles
is necessary. Thereby the number and amount of reagents needed is reduced, and no
protecting or deprotecting steps being needed the waste is reduced, contrary to when for
e a trityl or acetal protecting group is used. The method has good yields.
nd of formula (XXI) can be easily purified and obtained in a form of high odorous of
fragrance purity or high fragrance purity. This is particularly important for products ed
for use as fragrance.
The product is distinguished by a very special fragrance sought after in the fragrance industry.
Examples
Methods
1H and 13C NMR spectra were recorded on a Varian VNMRS 500 (500 MHz for 1H and 125
MHz for 13C) instruments in CDC13. Chemical shifts are expressed in parts per million
referred to TMS and coupling constants (J) in hertz.
EI means Electron ionization mass a (70 eV), they were obtained on an AMD-604
spectrometer.
ESI means Electron spray ionization mass spectra
THF was led from sodium/benzophenone ketyl prior to use; the obtained ous THF
is called "dry THF" in the following text.
e 1: 2-(2,3-Dimethylphenyl)propanol, compound of formula (XXIV), prepared
via an organomagnesium intermediate
1-Bromo-2,3—dimethy1benzene (compound of formula (XXV), wherein Q is Br; 8.43 g, 45.6
mmol) was dissolved in dry THF (15 mL) and placed in dropping funnel. Separately, Mg wire
(1.10 g, 45.3 mmol) in dry THF (5 mL) was placed in a flask equipped with the above
mentioned dropping funnel, a r, and a reflux condenser. The l-bromo-2,3-
dimethylbenzene solution (1.0 mL) was added Via a ng flannel and the reaction was
initiated by the addition of 1,2-dibromoethane (3 drops), and then the rest of the 1—bromo—2,3-
dimethylbenzene solution was added. The content of the dropping fiinnel was added at such a
rate to maintain slight reflux. After completion of the addition, the mixture was refluxed for 1
h and then cooled to 0 0C. A solution of dry acetone (4.2 mL, 58 mmol) in dry THF (15 mL)
was added dropwise and the e was stirred at a temperature between 0 and 20 °C for 3 h.
The mixture was poured into saturated NH4C1 aqueous solution (100 mL) ted with
hexane (5 times with 50 mL each), dried with Na2SO4 and ated under reduced pressure.
The main product was isolated via silica gel column chromatography with hexanezethyl
acetate as eluent (V/V 15:1 to 10:1 gradient), to yield 3.50 g (47%) of the title compound.
1H NMR: 1.68 (s, 6H), 1.70 (s, 1H), 2.29 (s, 3H), 2.50 (s, 3H), 7.03 to 7.10 (m, 2H), 7.29 to
7.32 (m, 1H).
13C NMR: 17.72, 21.08, 31.24 145.47.
, 73.71, 123.11, 125.02, 129.02, 135.09, 138.69,
MS (E1): 164 (12), 149 (35), 146 (100), 131, 116, 105, 91.
W0 2013l011156
Example 2: 2-(2,3-Dimethylphenyl)propanol, nd of formula (XXIV), prepared
via an organolithium intermediate
1-Brom0-2,3-dimethy1benzene (compound of formula (XXV), wherein Q is Br; 4.25 g, 23.0
mmol) was ved in dry THF (20 mL) in a flask equipped with a thermometer and a
stirring bar. The mixture was cooled to —78 CC. llithium (1.6 M in hexane, 17.5 mL,
28.0 mmol) was added se via a syringe, keeping the ature below —70 0C. When
the addition was complete, the mixture was ined at —78 CC and stirred at this
temperature for 1 h. A solution of dry acetone (1.85 mL, 25.2 mmol) in dry THF (5 mL) was
then added at —78 °C. The mixture was stirred at —78 °C for 30 min, the cooling bath was
removed, and the mixture was allowed to reach room temperature. The mixture was poured
into saturated aqueous NH4Cl solution (100 mL), extracted with hexane (4 times with 50 mL
each), dried over Na2SO4, and purified by via silica gel column chromatography using
:ethyl acetate as eluent (v/v 32:1) to give 3.45 g (91%) of the title compound.
The measured NMR spectra were identical to those recorded in example 1.
Example 3: 1,2-Dimethyl(2-propenyl)benzene, compound of formula (XXIII)
2-(2,3-Dimethy1pheny1)propanol, compound of formula (XXIV), prepared according to
either example 1 or example 2, (1.10 g, 6.70 mmol), was ved in benzene (20 mL), and
p-toluenesulfonic acid monohydrate (35 mg, 0.18 mmol) was added. The mixture was stirred
at room temperature for 3 h. Silica gel (200 mg) was added, and ng was continued for ca.
16 hours, and then the reaction mixture was refluxed for 30 min. After cooling to room
temperature, the mixture was filtered, washed with aqueous K2C03 solution, conventionally
dried, and trated under reduced pressure, to yield 0.90 g (92%) of the title compound.
1H NMR: 2.02 (m, 3H), 2.21 (s, 3H), 2.28 (s, 3H), 4.82 (m, 1H), 5.17 (m, 1H), 6.97 (m, 1H),
7.05 (m, 2H).
Example 4: 2-(2,3-Dimethylphenyl)methyloxirane, compound of formula (XXII)
A buffer was prepared by dissolving K2C03 (20.7 g) and EDTA-Naz (11.5 mg) in water (100
mL). 1,2-Dimethyl—3-(2-pr0penyl)benzene, compound of formula ), prepared
according to example 3 (0.90 g, 6.16 mmol), was dissolved in a mixture of dichloromethane
and acetonitrile (v/V 1:1, 60 mL), and the buffer prepared as described above (9.3 mL) was
added. To the resulting mixture, first 1,1,1-trifluoroacetone (60 uL) and then hydrogen
peroxide (30% in water, 6.2 mL, 60.7 mmol) were added and the mixture was stirred at room
2012/072797
temperature for 2 h. The on mixture was diluted with water (100 mL), the organic phase
was separated, and the aqueous phase was extracted with dichloromethane (2 times with 50
mL each). The combined organic phases were dried over Na2SO4, concentrated under reduced
re, and the residue was purified by via silica gel column chromatography using
hexane:ethyl acetate as eluent (v/v 32: 1) to give 851 mg (85%) of the title compound.
1H NMR: 1.59 (s, 3H), 2.28 (s, 3H), 2.31 (s, 3H), 2.83 (br (1, J = 5.4, 1H), 2.98 (d, J = 5.4 Hz,
1H), 7.08 (m, 2H), 7.21 (m, 1H).
MS (E1): 162, 147, 133, 117 (100).
Example 5: 2-(2,3-Dimethylphenyl)propanal, compound of formula (XXI)
2-(2,3-Dimethylphenyl)methyloxirane, nd of formula (XXII), prepared according to
example 4 (0.84 g, 5.18 mmol), was dissolved in dry dichloromethane (50 mL) and powdered
)2 hydrate (318 mg) was added at room temperature. After 2 h at room temperature,
the mixture was washed with water, dried over Na2SO4 and concentrated under reduced
pressure to yield 0.84 g (100%) of the title product.
1H NMR: 1.40 (d, J = 7.1 Hz, 3H), 2.25 (s, 3H), 2.32 (s, 3H), 3.89 (qd, J = 7.1, 1.0 Hz, 1H),
6.89 to 6.92 (m, 1H), 7.12 (m, 2H), 9.67 (d, J =1.0 Hz, 1H).
e 6: Medetomidine, nd of formula (XX)
2-(2,3-Dimethylphenyl)propanal, compound of formula (XXI), prepared according to
example 5 (2.43 g, 15.0 mmol) and p-toluenesulfonylmethyl nide (2.73 g, 14.0 mmol)
were mixed with EtOH (30 mL). To the stirred suspension powdered NaCN (73 mg, 1.5
mmol) was added. The mixture was stirred for 1 h at room temperature, and then evaporated
under reduced pressure to dryness. The residue was placed in an ampoule and treated with
MeOH saturated with NH3 (50 mL). The ampoule was heated to 110 CC in an oil bath for
three days.
This experiment was repeated once more (2-(2,3-Dimethylphenyl)propanal: 3.24 g, 20.0
mmol; p-toluenesulfonylmethyl isocyanide: 3.90 g, 20.0 mmol).
Both reaction mixtures were combined, evaporated to dryness, dissolved in dichloromethane
(150 mL) and washed with 10% (w/w) aqueous Na2C03 (200 mL) and then with water (200
mL), conventionally dried, evaporated under reduced pressure and purified by via silica gel
column chromatography using romethane : methanol as eluent (v/v 15:1 to 10:1
gradient), to yield 3.0 g (44%) of medetomidine as a sticky oil. Medetomidine was
crystallized from toluene:cyclohexane, and then recrystallized from aqueous ethanol.
1H NMR: 1.56 (d, J = 7.2 Hz, 3H), 2.18 (s, 3H), 2.25 (s, 3H), 4.35 (q, J = 7.2 Hz, 1H), 6.66 (s,
1H), 6.93 (dd, J = 6.6, 2.2 Hz, 1H), 6.99 to 7.05 (m, 2H), 7.30 (d, J = 1.1 Hz, 1H), 9.84
(broad s, 1H).
13C NMR: 14.65, 20.72, 20.88, 14.12, , 124.62, 125.53, 127.91, 134.05, 134.60,
136.76,141.11,143.23.
MS (E81): 201 [M+H]+
Claims (9)
1. A method for ation of a compound of formula (XXI): the method comprises a step (N); step (N) comprises a reaction (N-reac); reaction (N-reac) is a reaction of compound of formula (XXII) with a catalyst (N-cat): catalyst (N-cat) is selected from the group consisting of acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic 15 acid, HCl, HBr, H2SO4, HNO3, H3PO4, HClO4, BCl3, BBr3, BF3OEt2, BF3SMe2, BF3THF, MgCl2, MgBr2, MgI2, AlCl3, Al(O-C1-4 3, SnCl4, TiCl4, Ti(O-C1-4 alkyl)4, ZrCl4, Bi2O3, BiCl3, ZnCl2, PbCl2, FeCl3, ScCl3, NiCl2, Yb(OTf)3, Yb(Cl)3, GaCl3, AlBr3, Ce(OTf)3, LiCl, Cu(BF4)2, Cu(OTf)2, NiBr2(PPh3)2, NiBr2, NiCl2, Pd(OAc)2, PdCl2, PtCl2, InCl3, acidic inorganic solid nce, acidic ion ge resin, carbon treated with inorganic acid and 20 mixtures thereof.
2. Method according to claim 1, wherein the catalyst (N-cat) is selected from the group ting of acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, ptoluenesulfonic acid, HCl, HBr, H2SO4, H3PO4, BCl3, BF3OEt2, MgCl2, MgBr2, AlCl3, ZnCl2, 25 Cu(BF4)2, aluminosilicates, acidic ion exchange resins, carbon d with HCl, H2SO4 or HNO3, and mixtures thereof.
3. Method according to claim 1 or claim 2, wherein reaction (N-reac) is done in a solvent (N-solv); solvent (N-solv) is selected from the group consisting of water, tert-butanol, isopropanol, acetonitrile, propionitrile, THF, methyl-THF, NMP, dioxane, 1,2-dimethoxyethane, 5 dichloromethane, 1,2-dichloroethane, chloroform, toluene, benzene, benzene, hexane, cyclohexane, ethyl acetate, acetic acid, formic acid, trifluoroacetic acid and mixtures thereof.
4. Method according to any one of claims 1 to 3, n compound of a (XXII) is prepared in a step (O) or in two steps, the two steps are step (O1) and step (O2); 10 step (O) comprises a on (O-reac); reaction (O-reac) is a reaction of nd of formula ), with a reagent (O-reag); 15 reagent g) is selected from the group consisting of peracetic acid, trifluoroperacetic acid, perbenzoic acid, 3-chloroperbenzoic acid, monoperphthalic acid, dimethyldioxirane, tert-butylhydroperoxide, dibenzoyl peroxide, cumenehydroperoxide, oxygen, air, sodium hypochlorite, KHSO5, Na2O2, aqueous H2O2, H2O2 dissolved in acetic acid, H2O2 dissolved in trifluoroacetic acid, and mixtures thereof; step (O1) comprises a reaction (O1-reac); on (O1-reac) is a reaction of compound of formula (XXIII) with water and with a compound (O1-comp); nd (O1-comp) is selected from the group consisting of bromine, N-bromosuccinimide, 25 chlorine, N-chlorosuccinimide, , N-iodosuccinimide, IBr, BrCl, and mixtures thereof; step (O2) comprises a reaction (O2-reac); reaction (O2-reac) is a reaction of the reaction product from reaction (O1-reac) with a base 30 (O2-base); base (O2-base) is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium ide and mixture thereof.
5. Method according to claim 4, wherein reagent (O-reag) is selected from the group 5 consisting of peracetic acid, tert-butylhydroperoxide, oxygen, air, sodium hypochlorite, aqueous H2O2, H2O2 dissolved in acetic acid, H2O2 ved in trifluoroacetic acid, and mixtures thereof.
6. Method according to claim 4 or claim 5, wherein compound of formula (XXIII) is 10 prepared in a step (P); step (P) comprises a on (P-reac); in on (P-reac) the compound of formula (XXIV) is exposed to a temperature (P-temp); temperature (P-temp) is from 0 to 300 °C.
7. Method according to claim 6, wherein compound of formula (XXIV) is prepared in three steps, the three steps are a step (Q1), a step (Q2) and a step (Q3); step (Q1) comprises a reaction ac) by a reaction of compound of formula (XXV) with a reagent (Q1-reag); Q is Br, Cl, or I; reagent ag) is selected from the group consisting of lithium, magnesium, aluminum, zinc, calcium, isopropylmagnesium chloride, isopropylmagnesium bromide, butyllithium, sec-butyllithium and mixtures thereof; 5 step (Q2) comprises a reaction (Q2-reac); reaction (Q2-reac) is a reaction of the reaction product of reaction (Q1-reac) with e; in step (Q3) comprises a reaction (Q3-reac); reaction ac) is a reaction of the reaction product of on (Q2-reac) with a reagent 10 ag); reagent (Q3-reag) is selected from the group consisting of water, methanol, ethanol, oxalic acid, citric acid, NH4Cl, HCl, HBr, HNO3, H2SO4, H3PO4, acetic acid, propionic acid, formic acid and es thereof.
8. Use of compound of formula (XXI) as a fragrance, with the compound of formula (XXI) as defined in claim 1.
9. Use of compound of formula (XXI) for the preparation of medetomidine, with the 20 compound of formula (XXI) as defined in claim 1.
Applications Claiming Priority (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201261644198P | 2012-05-08 | 2012-05-08 | |
EP12167135 | 2012-05-08 | ||
EP12167135.8 | 2012-05-08 | ||
US61/644,198 | 2012-05-08 | ||
EP12187354 | 2012-10-05 | ||
EP12187354.1 | 2012-10-05 | ||
PCT/EP2012/070873 WO2012172120A2 (en) | 2012-05-08 | 2012-10-22 | 2-(2,3-dimethylphenyl)-1-propanal and its use as perfume |
EPPCT/EP2012/070873 | 2012-10-22 | ||
EP12192621.6 | 2012-11-14 | ||
EP12192621 | 2012-11-14 | ||
PCT/EP2012/072797 WO2013011156A2 (en) | 2012-05-08 | 2012-11-15 | Method for preparation of 2-(2,3-dimethylphenyl)-1-propanal |
Publications (2)
Publication Number | Publication Date |
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NZ700641A NZ700641A (en) | 2016-02-26 |
NZ700641B2 true NZ700641B2 (en) | 2016-05-27 |
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