DK2867211T3 - Fremgangsmåde til fremstilling af medetomidin med chloracetone - Google Patents
Fremgangsmåde til fremstilling af medetomidin med chloracetone Download PDFInfo
- Publication number
- DK2867211T3 DK2867211T3 DK12787007.9T DK12787007T DK2867211T3 DK 2867211 T3 DK2867211 T3 DK 2867211T3 DK 12787007 T DK12787007 T DK 12787007T DK 2867211 T3 DK2867211 T3 DK 2867211T3
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- Denmark
- Prior art keywords
- reaction
- compound
- reagent
- formula
- acid
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- 238000000034 method Methods 0.000 title claims description 26
- HRLIOXLXPOHXTA-UHFFFAOYSA-N medetomidine Chemical compound C=1C=CC(C)=C(C)C=1C(C)C1=CN=C[N]1 HRLIOXLXPOHXTA-UHFFFAOYSA-N 0.000 title claims description 16
- 229960002140 medetomidine Drugs 0.000 title claims description 16
- BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 title claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 179
- 150000001875 compounds Chemical class 0.000 claims description 130
- 239000003153 chemical reaction reagent Substances 0.000 claims description 82
- 239000000203 mixture Substances 0.000 claims description 79
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 78
- 239000002904 solvent Substances 0.000 claims description 76
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 64
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 52
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 48
- 229910021529 ammonia Inorganic materials 0.000 claims description 32
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- -1 C 1-6 alkanol Chemical compound 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 20
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims description 20
- 239000003054 catalyst Substances 0.000 claims description 20
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 18
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 17
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 16
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 13
- 235000011149 sulphuric acid Nutrition 0.000 claims description 13
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 12
- 230000002378 acidificating effect Effects 0.000 claims description 11
- BZVJOYBTLHNRDW-UHFFFAOYSA-N triphenylmethanamine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(N)C1=CC=CC=C1 BZVJOYBTLHNRDW-UHFFFAOYSA-N 0.000 claims description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- 239000007795 chemical reaction product Substances 0.000 claims description 10
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 235000019253 formic acid Nutrition 0.000 claims description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 9
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 claims description 9
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 8
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 8
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 8
- 239000003456 ion exchange resin Substances 0.000 claims description 8
- 229920003303 ion-exchange polymer Polymers 0.000 claims description 8
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- 235000015320 potassium carbonate Nutrition 0.000 claims description 8
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 7
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 7
- 239000011777 magnesium Substances 0.000 claims description 7
- 229910052749 magnesium Inorganic materials 0.000 claims description 7
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 7
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 7
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 6
- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 claims description 6
- CFOAUYCPAUGDFF-UHFFFAOYSA-N tosmic Chemical compound CC1=CC=C(S(=O)(=O)C[N+]#[C-])C=C1 CFOAUYCPAUGDFF-UHFFFAOYSA-N 0.000 claims description 6
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims description 5
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 5
- 229910052744 lithium Inorganic materials 0.000 claims description 5
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 claims description 5
- PKOFBDHYTMYVGJ-UHFFFAOYSA-N n-(4-sulfamoylphenyl)acetamide Chemical compound CC(=O)NC1=CC=C(S(N)(=O)=O)C=C1 PKOFBDHYTMYVGJ-UHFFFAOYSA-N 0.000 claims description 5
- 235000011007 phosphoric acid Nutrition 0.000 claims description 5
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 claims description 5
- 239000011698 potassium fluoride Substances 0.000 claims description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 4
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 4
- 229910052782 aluminium Inorganic materials 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 claims description 4
- OHUDHPKMAJDBPI-UHFFFAOYSA-N isocyanomethylsulfonylbenzene Chemical compound [C-]#[N+]CS(=O)(=O)C1=CC=CC=C1 OHUDHPKMAJDBPI-UHFFFAOYSA-N 0.000 claims description 4
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 claims description 4
- 229910001623 magnesium bromide Inorganic materials 0.000 claims description 4
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 4
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 4
- 229910021585 Nickel(II) bromide Inorganic materials 0.000 claims description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 3
- 239000012973 diazabicyclooctane Substances 0.000 claims description 3
- 229910003480 inorganic solid Inorganic materials 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- IPLJNQFXJUCRNH-UHFFFAOYSA-L nickel(2+);dibromide Chemical compound [Ni+2].[Br-].[Br-] IPLJNQFXJUCRNH-UHFFFAOYSA-L 0.000 claims description 3
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 3
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 2
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- HXWOCVNAFNNHPI-UHFFFAOYSA-N N-[4-(isocyanomethylsulfonyl)phenyl]acetamide Chemical compound CC(=O)Nc1ccc(cc1)S(=O)(=O)C[N+]#[C-] HXWOCVNAFNNHPI-UHFFFAOYSA-N 0.000 claims description 2
- 229910002666 PdCl2 Inorganic materials 0.000 claims description 2
- 229910019032 PtCl2 Inorganic materials 0.000 claims description 2
- 101100237460 Rattus norvegicus Mgll gene Proteins 0.000 claims description 2
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- 229910007932 ZrCl4 Inorganic materials 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 239000004202 carbamide Substances 0.000 claims description 2
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- VYUZAWHIOAWCTR-UHFFFAOYSA-N isocyano(methylsulfonyl)methane Chemical compound CS(=O)(=O)C[N+]#[C-] VYUZAWHIOAWCTR-UHFFFAOYSA-N 0.000 claims description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 2
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 claims description 2
- UGVPKMAWLOMPRS-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].CC[CH2-] UGVPKMAWLOMPRS-UHFFFAOYSA-M 0.000 claims description 2
- RYEXTBOQKFUPOE-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].CC[CH2-] RYEXTBOQKFUPOE-UHFFFAOYSA-M 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- CSELYUIIXLJXHS-UHFFFAOYSA-N trifluoro(isocyanomethylsulfonyl)methane Chemical compound FC(F)(F)S(=O)(=O)C[N+]#[C-] CSELYUIIXLJXHS-UHFFFAOYSA-N 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- DUNKXUFBGCUVQW-UHFFFAOYSA-J zirconium tetrachloride Chemical compound Cl[Zr](Cl)(Cl)Cl DUNKXUFBGCUVQW-UHFFFAOYSA-J 0.000 claims description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 2
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 claims 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 2
- 229910003074 TiCl4 Inorganic materials 0.000 claims 2
- JHXKRIRFYBPWGE-UHFFFAOYSA-K bismuth chloride Chemical compound Cl[Bi](Cl)Cl JHXKRIRFYBPWGE-UHFFFAOYSA-K 0.000 claims 2
- HWSZZLVAJGOAAY-UHFFFAOYSA-L lead(II) chloride Chemical compound Cl[Pb]Cl HWSZZLVAJGOAAY-UHFFFAOYSA-L 0.000 claims 2
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims 2
- 235000017550 sodium carbonate Nutrition 0.000 claims 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims 2
- 229910016264 Bi2 O3 Inorganic materials 0.000 claims 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims 1
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims 1
- 229910005267 GaCl3 Inorganic materials 0.000 claims 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 claims 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims 1
- 229910018057 ScCl3 Inorganic materials 0.000 claims 1
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 claims 1
- UPWPDUACHOATKO-UHFFFAOYSA-K gallium trichloride Chemical compound Cl[Ga](Cl)Cl UPWPDUACHOATKO-UHFFFAOYSA-K 0.000 claims 1
- 235000010299 hexamethylene tetramine Nutrition 0.000 claims 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 claims 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 28
- 239000000284 extract Substances 0.000 description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 235000011054 acetic acid Nutrition 0.000 description 14
- 238000000605 extraction Methods 0.000 description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 11
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- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- AHZJKOKFZJYCLG-UHFFFAOYSA-K trifluoromethanesulfonate;ytterbium(3+) Chemical compound [Yb+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F AHZJKOKFZJYCLG-UHFFFAOYSA-K 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Saccharide Compounds (AREA)
Claims (13)
1. Fremgangsmåde til fremstilling af forbindelse med formlen (XX);
(XX) hvor fremgangsmåden omfatter fire trin, hvor de fire trin er et trin (Q1), et trin (Q2), et trin (N) og et trin (M1); forbindelsen med formlen (XX) fremstilles i trin (M1); trin (M1) omfatter en reaktion (M1-reac); reaktionen (M1-reac) er en reaktion mellem en forbindelse med formlen (XXI),
(XXI) et reagens (M-reag) og et reagens (M-A) i et opløsningsmiddel (M-solv); reagenset (M-reag) er udvalgt fra gruppen bestående af p-toluensulfonylmethylisocyanid, trifluormethansulfonylmethylisocyanid, methansulfonylmethylisocyanid, benzensulfonylmethylisocyanid, 4- acetamidobenzensulfonylmethylisocyanid og blandinger deraf; reagenset (M-A) er udvalgt fra gruppen bestående af ammoniak, sulfaminsyre, p-toluensulfonamid, benzensulfonamid, 4-acetamidobenzensulfonamid, tritylamin, formamid, urea, urotropin, ethylcarbamat, acetamid og blandinger deraf; opløsningsmiddel (M-solv) er udvalgt fra gruppen bestående af N,N-dimethylformamid, Ci-6-alkanol, formamid, 1,2-dimethoxyethan, NMP, toluen, acetonitril, propionitril, ethylcarbamat, Ν,Ν-dimethylacetamid, vand, acetamid og blandinger deraf; forbindelsen med formlen (XXI) fremstilles i trin (N); trin (N) omfatter en reaktion (N-reac); reaktion (N-reac) er en reaktion af en forbindelse med formlen (XXII) med en katalysator (N-cat);
(XXTT) katalysatoren (N-cat) er udvalgt fra gruppen bestående af eddikesyre, myresyre, trifluoreddikesyre, methansulfonsyre, benzensulfonsyre, p-toluensulfonsyre, camphersulfonsyre, HCI, HBr, H2S04, HN03, H3P04, HCI04, BCI3, BBr3, BF3OEt2, BF3SMe2, BF3THF, MgCI2, MgBr2, Mgl2, AICI3, Al(0-Ci_4 alkyl)3, SnCI4, TiCI4, Ti(0-Ci_ 4 alkyl)4, ZrCI4, Bi203, BiCI3, ZnCI2, PbCI2, FeCI3, ScCI3, NiCI2, Yb(OTf)3, Yb(CI)3, GaCI3, AIBr3, Ce(OTf)3, LiCI, Cu(BF4)2, Cu(OTf)2, NiBr2(PPh3)2, NiBr2, NiCI2, Pd(OAc)2, PdCI2, PtCI2, lnCI3, surt, uorganisk faststof, sur ionbytterharpiks, carbon behandlet med uorganisk syre og blandinger deraf; trin (Q1) omfatter en reaktion (Q1-reac); reaktionen (Q1-reac) er en reaktion af forbindelsen med formlen (XXV) med et reagens (Q1-reag);
(XXV) R1 er Br, Cl eller I; reagenset (Q1-reag) er udvalgt fra gruppen bestående af lithium, magnesium, aluminium, zink, calcium, propylmagnesiumchlorid, propylmagnesiumbromid, butyllithium og blandinger deraf; trin (Q2) omfatter en reaktion (Q2-reac); reaktionen (Q2-reac) er en reaktion af reaktionsproduktet fra reaktionen (Q1-reac) med chloracetone; forbindelsen med formlen (XXII) fremstilles ved hjælp af reaktionen (Q2-reac).
2. Fremgangsmåde ifølge krav 1, hvor trin (M1) omfatter to konsekutive trin, et første trin (M1-A1-1) og et andet trin (M1-A1-2); trin (M1-A1-1) omfatter en reaktion (M1-A1-1); reaktion (M1-A1-1) er en reaktion af forbindelsen med formlen (XXI) med et reagens (M-reag) i nærvær af forbindelsen (M-comp) i opløsningsmiddel (M-solv); trin (M1-A1-2) omfatter en reaktion (M1-A1-2); reaktionen (M1-A1-2) er en reaktion af reaktionsproduktet fra reaktionen (M1-A1-1) med et reagens (M-A) i opløsningsmiddel (M-solv).
3. Fremgangsmåde ifølge krav 1 eller 2, hvor reagenset (M-reag) er udvalgt fra gruppen bestående af p-toluensulfonylmethylisocyanid, benzensulfonylmethylisocyanid og blandinger deraf.
4. Fremgangsmåde ifølge et hvilket som helst af kravene 1 til 3, hvor reagenset (M-A) er udvalgt fra gruppen bestående af ammoniak, sulfaminsyre, p-toluensulfonamid, benzensulfonamid, 4-acetamidobenzensulfonamid, tritylamin, formamid og blandinger deraf.
5. Fremgangsmåde ifølge et hvilket som helst af kravene 1 til 4, hvor opløsningsmidlet (M-solv) er udvalgt fra gruppen bestående af Ν,Ν-dimethylformamid, methanol, ethanol, n-propanol, isopropanol, butanol, pentanol, hexanol, vand, formamid, 1,2-dimethoxyethan, NMP, toluen, acetonitril, propionitril, ethylcarbamat, N,N-dimethylacetamid, acetamid og blandinger deraf.
6. Fremgangsmåde ifølge et hvilket som helst af kravene 1 til 5, hvor reaktionen (M1-reac) sker i nærvær af en forbindelse (M-comp), forbindelsen (M-comp) er udvalgt fra gruppen bestående af ammoniak, tritylamin, NaCN, KCN, piperidin, DBU, DABCO, triethylamin, tributylamin, 4-dimethylaminopyridin, pyridin, tBuOK, tBuONa, NaHC03, Na2C03, (NH4)HC03, (NH4)2C03, KHC03, K2C03, NaOAc, KOAc, NaOH, KOH, Ca(OH)2, KF og blandinger deraf.
7. Fremgangsmåde ifølge krav 6, hvor forbindelsen (M-comp) er udvalgt fra gruppen bestående af ammoniak, tritylamin, NaCN, KCN, piperidin, tBuOK, tBuONa, KOH, K2C03, Na2C03, KF og blandinger deraf.
8. Fremgangsmåde ifølge et hvilket som helst af kravene 1 til 7, hvor katalysatoren (N-cat) er udvalgt fra gruppen bestående af eddikesyre, myresyre, trifluoreddikesyre, methansulfonsyre, p-toluensulfonsyre, HCI, HBr, H2S04, H3P04, BCI3, BF3OEt2, MgCI2, MgBr2, AICI3, ZnCI2, Cu(BF4)2, aluminiumsilicat, sur ionbytterharpiks, carbon behandlet med HCI, H2S04 eller HN03, og blandinger deraf.
9. Fremgangsmåde ifølge et hvilket som helst af kravene 1 til 8, hvor R1 er Br.
10. Fremgangsmåde ifølge et eller flere af kravene 1 eller 9, hvor reagenset (Q1-reag) er udvalgt fra gruppen bestående af lithium, magnesium, aluminium, isopropylmagnesiumchlorid, isopropylmagnesiumbromid, n-butyllithium, sec-butyllithium, tert-butyllithium, og blandinger deraf.
11. Fremgangsmåde ifølge et hvilket som helst af kravene 1 til 10, hvor reaktion (Q1-reac) sker i nærvær af en katalysator (Q1 -cat); katalysatoren (Q1-cat) er udvalgt fra gruppen bestående af iod, 1,2-dibromethan, TiCI4, AICI3, PbCI2, BiCI3, LiCI og blandinger deraf.
12. Forbindelse med formlen (XXIII),
(XXIII) hvor R2 er 4-tolyl, phenyl, 4-acetamidophenyl, methyl eller trifluormethyl.
13. Forbindelse ifølge krav 12, hvor R2 er 4-tolyl.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201261665510P | 2012-06-28 | 2012-06-28 | |
| EP12174102 | 2012-06-28 | ||
| EP12188104 | 2012-10-11 | ||
| PCT/EP2012/070875 WO2012172121A1 (en) | 2012-06-28 | 2012-10-22 | Method for the preparation of medetomidine with chloroacetone |
| EP12192625 | 2012-11-14 | ||
| PCT/EP2012/072798 WO2013011157A1 (en) | 2012-06-28 | 2012-11-15 | Method for preparation of medetomidine with chloroacetone |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DK2867211T3 true DK2867211T3 (da) | 2016-02-29 |
Family
ID=47557694
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK12787007.9T DK2867211T3 (da) | 2012-06-28 | 2012-11-15 | Fremgangsmåde til fremstilling af medetomidin med chloracetone |
Country Status (20)
| Country | Link |
|---|---|
| US (2) | US9156793B2 (da) |
| EP (1) | EP2867211B1 (da) |
| JP (1) | JP5777841B2 (da) |
| KR (1) | KR101560116B1 (da) |
| CN (2) | CN104245678B (da) |
| AU (1) | AU2012285677B2 (da) |
| CA (1) | CA2866437C (da) |
| CL (2) | CL2014002907A1 (da) |
| CY (1) | CY1117492T1 (da) |
| DK (1) | DK2867211T3 (da) |
| EA (1) | EA027921B1 (da) |
| ES (1) | ES2565066T3 (da) |
| HR (1) | HRP20160216T1 (da) |
| HU (1) | HUE027382T2 (da) |
| IN (1) | IN2014DN07984A (da) |
| MY (1) | MY165218A (da) |
| PL (1) | PL2867211T3 (da) |
| SG (1) | SG11201405609WA (da) |
| TW (2) | TWI560182B (da) |
| WO (1) | WO2013011157A1 (da) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2557638T3 (es) | 2012-05-08 | 2016-01-27 | Lonza Ltd | Método para la preparación de 2-(2,3-dimetilfenil)-1-propanal |
| IN2014DN07983A (da) * | 2012-05-08 | 2015-05-01 | Lonza Ag | |
| JP5777841B2 (ja) * | 2012-06-28 | 2015-09-09 | ロンザ・リミテッド | クロロアセトンを用いてメデトミジンを調製するための方法 |
| IN2014DN08121A (da) * | 2012-06-28 | 2015-05-01 | Lonza Ag | |
| RU2718960C2 (ru) * | 2016-02-12 | 2020-04-15 | Сони Корпорейшн | Устройство и способ |
| CN106518812A (zh) * | 2016-10-25 | 2017-03-22 | 湖南大学 | 一种美托咪定及其中间体的制备方法 |
| CN113044857B (zh) * | 2020-12-30 | 2023-05-23 | 重庆柒兴克米科技有限公司 | 高收率制取高纯氰化钠或氰化钾的生产工艺 |
| CN114671811A (zh) * | 2022-04-14 | 2022-06-28 | 南京正科医药股份有限公司 | 一种右美托咪定拆分副产物的外消旋化回收方法 |
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| USRE23400E (en) | 1951-08-14 | Electkic low and high-voltage fuses | ||
| BE790604A (fr) | 1971-10-28 | 1973-04-26 | Sandoz Sa | Nouveaux aminoalcanols, leur preparation et leur application comme medicaments |
| JPS51100042A (en) | 1975-02-26 | 1976-09-03 | Kanebo Ltd | 22 * 44 isobuchirufueniru * puropionsanno seizoho |
| JPS51100041A (en) | 1975-02-26 | 1976-09-03 | Kanebo Ltd | 22 * 44 isobuchirufueniru * puropionsanno seizoho |
| GB2092569B (en) | 1981-02-05 | 1984-09-19 | Farmos Oy | Substituted imidazole derivatives and their preparation and use |
| GB2101114B (en) | 1981-07-10 | 1985-05-22 | Farmos Group Ltd | Substituted imidazole derivatives and their preparation and use |
| DE3586403T2 (de) | 1984-02-24 | 1993-02-04 | Sagami Chem Res | Methode zum isomerisieren eines glycidats. |
| JPS62103037A (ja) * | 1985-10-29 | 1987-05-13 | Hamari Yakuhin Kogyo Kk | ２−（４−イソブチルフエニル）−プロピオンアルデヒドの製造法 |
| DE19714042A1 (de) | 1997-04-05 | 1998-10-08 | Henkel Kgaa | Verfahren zur Herstellung aromatischer Aldehyde |
| SE513474C2 (sv) | 1999-01-25 | 2000-09-18 | Hans Elwing Instutionen Foer C | Metod för att förhindra kräftdjurs, särskilt havstulpaners, etablering på fasta ytor med hjälp av en substans som stör nervsignaler, varvid substansen är medetomidin, dvs (+)-4-/1- (2,3-dimetylfenyl)-etyl/-IH-imidazol |
| EP1918282A1 (en) * | 2006-11-06 | 2008-05-07 | "Joint Stock Company Grindeks" | Method for preparing medetomidine and its salts |
| GB2453982B (en) | 2007-10-24 | 2009-09-16 | Norbrook Lab Ltd | Chemical process for the preparation of Medetomidine |
| US7902247B2 (en) | 2008-01-09 | 2011-03-08 | Allergan, Inc. | Substituted-aryl-2-phenylethyl-1H-imidazole compounds as subtype selective modulators of alpha 2B and/or alpha 2C adrenergic receptors |
| CN101921234B (zh) * | 2009-06-12 | 2012-05-30 | 中国中化股份有限公司 | 一种制备美托咪啶的方法 |
| CN102753532B (zh) * | 2009-12-09 | 2015-05-13 | I-技术有限公司 | 美托咪定的制备方法 |
| ES2557638T3 (es) | 2012-05-08 | 2016-01-27 | Lonza Ltd | Método para la preparación de 2-(2,3-dimetilfenil)-1-propanal |
| IN2014DN07983A (da) * | 2012-05-08 | 2015-05-01 | Lonza Ag | |
| WO2012172120A2 (en) * | 2012-05-08 | 2012-12-20 | Lonza Ltd | 2-(2,3-dimethylphenyl)-1-propanal and its use as perfume |
| WO2012172119A2 (en) * | 2012-05-08 | 2012-12-20 | Lonza Ltd | Method for the preparation of medetomidine |
| WO2012172122A2 (en) * | 2012-06-28 | 2012-12-20 | Lonza Ltd | Method for the preparation of 2-(2,3-dimethylphenyl)-1-propanal |
| IN2014DN08121A (da) | 2012-06-28 | 2015-05-01 | Lonza Ag | |
| JP5777841B2 (ja) * | 2012-06-28 | 2015-09-09 | ロンザ・リミテッド | クロロアセトンを用いてメデトミジンを調製するための方法 |
| WO2012172121A1 (en) * | 2012-06-28 | 2012-12-20 | Lonza Ltd | Method for the preparation of medetomidine with chloroacetone |
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- 2012-11-15 JP JP2015510662A patent/JP5777841B2/ja not_active Expired - Fee Related
- 2012-11-15 AU AU2012285677A patent/AU2012285677B2/en not_active Ceased
- 2012-11-15 EA EA201400939A patent/EA027921B1/ru not_active IP Right Cessation
- 2012-11-15 CN CN201280072210.0A patent/CN104245678B/zh not_active Expired - Fee Related
- 2012-11-15 WO PCT/EP2012/072798 patent/WO2013011157A1/en not_active Ceased
- 2012-11-15 HU HUE12787007A patent/HUE027382T2/en unknown
- 2012-11-15 EP EP12787007.9A patent/EP2867211B1/en not_active Not-in-force
- 2012-11-15 CA CA2866437A patent/CA2866437C/en not_active Expired - Fee Related
- 2012-11-15 IN IN7984DEN2014 patent/IN2014DN07984A/en unknown
- 2012-11-15 MY MYPI2014002579A patent/MY165218A/en unknown
- 2012-11-15 DK DK12787007.9T patent/DK2867211T3/da active
- 2012-11-15 SG SG11201405609WA patent/SG11201405609WA/en unknown
- 2012-11-15 PL PL12787007T patent/PL2867211T3/pl unknown
- 2012-11-15 US US14/385,797 patent/US9156793B2/en not_active Expired - Fee Related
- 2012-11-15 ES ES12787007.9T patent/ES2565066T3/es active Active
- 2012-11-15 KR KR1020147029607A patent/KR101560116B1/ko not_active Expired - Fee Related
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- 2012-11-15 CN CN201510621358.0A patent/CN105218453B/zh not_active Expired - Fee Related
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- 2013-06-26 TW TW105114874A patent/TWI560182B/zh not_active IP Right Cessation
- 2013-06-26 TW TW102122683A patent/TWI543970B/zh not_active IP Right Cessation
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