NZ700642B2 - Method for preparation of medetomidine with chloroacetone - Google Patents
Method for preparation of medetomidine with chloroacetone Download PDFInfo
- Publication number
- NZ700642B2 NZ700642B2 NZ700642A NZ70064212A NZ700642B2 NZ 700642 B2 NZ700642 B2 NZ 700642B2 NZ 700642 A NZ700642 A NZ 700642A NZ 70064212 A NZ70064212 A NZ 70064212A NZ 700642 B2 NZ700642 B2 NZ 700642B2
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- New Zealand
- Prior art keywords
- reaction
- reac
- compound
- formula
- acid
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- BULLHNJGPPOUOX-UHFFFAOYSA-N Chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 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 title abstract description 16
- 229960002140 medetomidine Drugs 0.000 title abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 189
- 150000001875 compounds Chemical class 0.000 claims abstract description 128
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 85
- 239000000203 mixture Substances 0.000 claims abstract description 85
- 239000002904 solvent Substances 0.000 claims abstract description 71
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 56
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims abstract description 54
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 51
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 33
- -1 C1-6 alkanol Chemical compound 0.000 claims abstract description 32
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 24
- JOYRKODLDBILNP-UHFFFAOYSA-N ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims abstract description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000003054 catalyst Substances 0.000 claims abstract description 23
- 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 18
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 17
- 230000002378 acidificating Effects 0.000 claims abstract description 16
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims abstract description 16
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims abstract description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 13
- 239000000126 substance Substances 0.000 claims abstract description 13
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M Lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims abstract description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 10
- 235000019253 formic acid Nutrition 0.000 claims abstract description 10
- 239000003456 ion exchange resin Substances 0.000 claims abstract description 10
- 229920003303 ion-exchange polymer Polymers 0.000 claims abstract description 10
- FVSKHRXBFJPNKK-UHFFFAOYSA-N Propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims abstract description 9
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000011777 magnesium Substances 0.000 claims abstract description 9
- 229910052749 magnesium Inorganic materials 0.000 claims abstract description 9
- 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 abstract description 9
- 229910017981 Cu(BF4)2 Inorganic materials 0.000 claims abstract description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N NMP Substances CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims abstract description 8
- CFOAUYCPAUGDFF-UHFFFAOYSA-N TosMIC Chemical compound CC1=CC=C(S(=O)(=O)C[N+]#[C-])C=C1 CFOAUYCPAUGDFF-UHFFFAOYSA-N 0.000 claims abstract description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 8
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims abstract description 8
- 229940098779 methanesulfonic acid Drugs 0.000 claims abstract description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 8
- 235000011007 phosphoric acid Nutrition 0.000 claims abstract description 8
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 8
- WMWLMWRWZQELOS-UHFFFAOYSA-N Bismuth(III) oxide Chemical compound O=[Bi]O[Bi]=O WMWLMWRWZQELOS-UHFFFAOYSA-N 0.000 claims abstract description 7
- 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 abstract description 7
- PMDCZENCAXMSOU-UHFFFAOYSA-N N-ethylacetamide Chemical compound CCNC(C)=O PMDCZENCAXMSOU-UHFFFAOYSA-N 0.000 claims abstract description 7
- IIACRCGMVDHOTQ-UHFFFAOYSA-N Sulfamic acid Chemical compound NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 claims abstract description 7
- XTHFKEDIFFGKHM-UHFFFAOYSA-N dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims abstract description 7
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910052744 lithium Inorganic materials 0.000 claims abstract description 7
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910003074 TiCl4 Inorganic materials 0.000 claims abstract description 6
- XJDNKRIXUMDJCW-UHFFFAOYSA-J Titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims abstract description 6
- DLFVBJFMPXGRIB-UHFFFAOYSA-N acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims abstract description 6
- YIYZHARUXWKUEN-UHFFFAOYSA-N benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1.NS(=O)(=O)C1=CC=CC=C1 YIYZHARUXWKUEN-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 6
- 229910052801 chlorine Inorganic materials 0.000 claims abstract 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 abstract description 6
- 229910052782 aluminium Inorganic materials 0.000 claims abstract description 5
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910003480 inorganic solid Inorganic materials 0.000 claims abstract description 5
- OHUDHPKMAJDBPI-UHFFFAOYSA-N isocyanomethylsulfonylbenzene Chemical compound [C-]#[N+]CS(=O)(=O)C1=CC=CC=C1 OHUDHPKMAJDBPI-UHFFFAOYSA-N 0.000 claims abstract description 5
- SRSXLGNVWSONIS-UHFFFAOYSA-N Benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims abstract description 4
- HXWOCVNAFNNHPI-UHFFFAOYSA-N CC(=O)Nc1ccc(cc1)S(=O)(=O)C[N+]#[C-] Chemical compound CC(=O)Nc1ccc(cc1)S(=O)(=O)C[N+]#[C-] HXWOCVNAFNNHPI-UHFFFAOYSA-N 0.000 claims abstract description 4
- MIOPJNTWMNEORI-UHFFFAOYSA-N Camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 claims abstract description 4
- CSELYUIIXLJXHS-UHFFFAOYSA-N FC(F)(F)S(=O)(=O)C[N+]#[C-] Chemical compound FC(F)(F)S(=O)(=O)C[N+]#[C-] CSELYUIIXLJXHS-UHFFFAOYSA-N 0.000 claims abstract description 4
- VKYKSIONXSXAKP-UHFFFAOYSA-N Hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 claims abstract description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N Perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims abstract description 4
- HPGGPRDJHPYFRM-UHFFFAOYSA-J Tin(IV) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims abstract description 4
- DUNKXUFBGCUVQW-UHFFFAOYSA-J Zirconium(IV) chloride Chemical compound Cl[Zr](Cl)(Cl)Cl DUNKXUFBGCUVQW-UHFFFAOYSA-J 0.000 claims abstract description 4
- 229910007932 ZrCl4 Inorganic materials 0.000 claims abstract description 4
- YQMARKZVVTYGOK-UHFFFAOYSA-M [Br-].CCC[Mg+] Chemical compound [Br-].CCC[Mg+] YQMARKZVVTYGOK-UHFFFAOYSA-M 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
- 229940092714 benzenesulfonic acid Drugs 0.000 claims abstract description 4
- 239000004202 carbamide Substances 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
- RYEXTBOQKFUPOE-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].CC[CH2-] RYEXTBOQKFUPOE-UHFFFAOYSA-M 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
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000011701 zinc Substances 0.000 claims abstract description 4
- 229910052725 zinc Inorganic materials 0.000 claims abstract description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K Aluminium chloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims abstract 10
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L MgCl2 Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims abstract 8
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract 6
- ILAHWRKJUDSMFH-UHFFFAOYSA-N Boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract 5
- 235000011149 sulphuric acid Nutrition 0.000 claims abstract 5
- 229910015844 BCl3 Inorganic materials 0.000 claims abstract 4
- JHXKRIRFYBPWGE-UHFFFAOYSA-K Bismuth chloride Chemical compound Cl[Bi](Cl)Cl JHXKRIRFYBPWGE-UHFFFAOYSA-K 0.000 claims abstract 4
- HWSZZLVAJGOAAY-UHFFFAOYSA-L Lead(II) chloride Chemical compound Cl[Pb]Cl HWSZZLVAJGOAAY-UHFFFAOYSA-L 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
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 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
- 229910015845 BBr3 Inorganic materials 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
- 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
- 239000002253 acid Substances 0.000 claims description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 14
- IMNIMPAHZVJRPE-UHFFFAOYSA-N DABCO Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 10
- MNWBNISUBARLIT-UHFFFAOYSA-N Sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 8
- 229940035295 Ting Drugs 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 6
- 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
- 229910000323 aluminium silicate Inorganic materials 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- KZHJGOXRZJKJNY-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Si]=O.O=[Al]O[Al]=O.O=[Al]O[Al]=O.O=[Al]O[Al]=O KZHJGOXRZJKJNY-UHFFFAOYSA-N 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 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
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-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
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 4
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N 1-Hexanol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 claims description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L Calcium hydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N DBU Substances C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M Potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N Tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- 239000000920 calcium hydroxide Substances 0.000 claims description 2
- 235000011116 calcium hydroxide Nutrition 0.000 claims description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 claims description 2
- LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 claims description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N n-pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 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
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 2
- 235000015320 potassium carbonate Nutrition 0.000 claims 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 2
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-Dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 claims 1
- PRKQVKDSMLBJBJ-UHFFFAOYSA-N Ammonium carbonate Chemical compound N.N.OC(O)=O PRKQVKDSMLBJBJ-UHFFFAOYSA-N 0.000 claims 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M Potassium bicarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims 1
- 235000012501 ammonium carbonate Nutrition 0.000 claims 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims 1
- 239000011736 potassium bicarbonate Substances 0.000 claims 1
- 235000015497 potassium bicarbonate Nutrition 0.000 claims 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims 1
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 1
- 235000017550 sodium carbonate Nutrition 0.000 claims 1
- 150000007522 mineralic acids Chemical class 0.000 abstract description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 abstract description 3
- 239000011575 calcium Substances 0.000 abstract description 3
- 229910052791 calcium Inorganic materials 0.000 abstract description 3
- WLPXNBYWDDYJTN-UHFFFAOYSA-N 1-bromo-2,3-dimethylbenzene Chemical compound CC1=CC=CC(Br)=C1C WLPXNBYWDDYJTN-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000384 adrenergic alpha-2 receptor agonist Substances 0.000 abstract description 2
- 230000001624 sedative Effects 0.000 abstract description 2
- 239000000932 sedative agent Substances 0.000 abstract description 2
- 230000003444 anaesthetic Effects 0.000 abstract 2
- VYUZAWHIOAWCTR-UHFFFAOYSA-N isocyano(methylsulfonyl)methane Chemical compound CS(=O)(=O)C[N+]#[C-] VYUZAWHIOAWCTR-UHFFFAOYSA-N 0.000 abstract 2
- 230000000202 analgesic Effects 0.000 abstract 1
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- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- 239000000284 extract Substances 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 235000011054 acetic acid Nutrition 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 239000002585 base Substances 0.000 description 12
- 238000000605 extraction Methods 0.000 description 12
- 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
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 10
- 238000001704 evaporation Methods 0.000 description 10
- 230000005712 crystallization Effects 0.000 description 9
- 238000004821 distillation Methods 0.000 description 9
- 239000008079 hexane Substances 0.000 description 9
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- 239000000047 product Substances 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
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- 238000004587 chromatography analysis Methods 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- GGZZISOUXJHYOY-UHFFFAOYSA-N 8-amino-4-hydroxynaphthalene-2-sulfonic acid Chemical compound C1=C(S(O)(=O)=O)C=C2C(N)=CC=CC2=C1O GGZZISOUXJHYOY-UHFFFAOYSA-N 0.000 description 5
- 150000001335 aliphatic alkanes Chemical class 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- XDTMQSROBMDMFD-UHFFFAOYSA-N cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N Chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 150000002373 hemiacetals Chemical class 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- 229940011051 isopropyl acetate Drugs 0.000 description 4
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 239000008096 xylene Substances 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 239000011261 inert gas Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 235000006408 oxalic acid Nutrition 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N (+)-tartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N 1,1-Diethoxyethane Chemical group CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 2
- HBBGAESXDKCELE-UHFFFAOYSA-N 2-[(2,3-dimethylphenyl)methyl]oxirane Chemical compound CC1=CC=CC(CC2OC2)=C1C HBBGAESXDKCELE-UHFFFAOYSA-N 0.000 description 2
- 238000004566 IR spectroscopy Methods 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N Methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- KERBAAIBDHEFDD-UHFFFAOYSA-N N-ethylformamide Chemical compound CCNC=O KERBAAIBDHEFDD-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 239000004698 Polyethylene (PE) Substances 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 229960004132 diethyl ether Drugs 0.000 description 2
- 150000002118 epoxides Chemical class 0.000 description 2
- 238000010574 gas phase reaction Methods 0.000 description 2
- 150000003840 hydrochlorides Chemical class 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Substances Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
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- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000006263 metalation reaction Methods 0.000 description 2
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 2
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- 238000005580 one pot reaction Methods 0.000 description 2
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- 125000006239 protecting group Chemical group 0.000 description 2
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Inorganic materials [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
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- PPBRXRYQALVLMV-UHFFFAOYSA-N styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- SSUJUUNLZQVZMO-UHFFFAOYSA-N 1,2,3,4,8,9,10,10a-octahydropyrimido[1,2-a]azepine Chemical compound C1CCC=CN2CCCNC21 SSUJUUNLZQVZMO-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZXOFAHRGRROAQR-UHFFFAOYSA-N 1-(isocyanomethylsulfonyl)-2-methylbenzene Chemical compound CC1=CC=CC=C1S(=O)(=O)C[N+]#[C-] ZXOFAHRGRROAQR-UHFFFAOYSA-N 0.000 description 1
- LCFVNOPFCICOIS-UHFFFAOYSA-N 1-methyl-2-(3-phenylprop-1-ynyl)benzene Chemical compound CC1=CC=CC=C1C#CCC1=CC=CC=C1 LCFVNOPFCICOIS-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- ZQEXIXXJFSQPNA-UHFFFAOYSA-N 1H-imidazole-5-carbaldehyde Chemical compound O=CC1=CNC=N1 ZQEXIXXJFSQPNA-UHFFFAOYSA-N 0.000 description 1
- UIFVCPMLQXKEEU-UHFFFAOYSA-N 2,3-dimethylbenzaldehyde Chemical compound CC1=CC=CC(C=O)=C1C UIFVCPMLQXKEEU-UHFFFAOYSA-N 0.000 description 1
- GNEYVIZQCGXVEV-UHFFFAOYSA-N 2-(2,3-dimethylphenyl)propanal Chemical compound O=CC(C)C1=CC=CC(C)=C1C GNEYVIZQCGXVEV-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butanoic acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- PSXLCTPHDAEPLK-UHFFFAOYSA-N CC(C)[Mg] Chemical compound CC(C)[Mg] PSXLCTPHDAEPLK-UHFFFAOYSA-N 0.000 description 1
- 101700067048 CDC13 Proteins 0.000 description 1
- MJEMIOXXNCZZFK-UHFFFAOYSA-N Ethylone Chemical compound CCNC(C)C(=O)C1=CC=C2OCOC2=C1 MJEMIOXXNCZZFK-UHFFFAOYSA-N 0.000 description 1
- 241000229754 Iva xanthiifolia Species 0.000 description 1
- VWBWQOUWDOULQN-UHFFFAOYSA-N NMP N-methylpyrrolidone Chemical compound CN1CCCC1=O.CN1CCCC1=O VWBWQOUWDOULQN-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- UGAPHEBNTGUMBB-UHFFFAOYSA-N acetic acid;ethyl acetate Chemical compound CC(O)=O.CCOC(C)=O UGAPHEBNTGUMBB-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 230000001476 alcoholic Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000001808 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000001419 dependent Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide DMF Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethylcyclohexane Chemical compound CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- PJYPCKZZTIAODG-UHFFFAOYSA-M magnesium;1,2-dimethylbenzene-6-ide;bromide Chemical compound [Mg+2].[Br-].CC1=CC=C[C-]=C1C PJYPCKZZTIAODG-UHFFFAOYSA-M 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- XOBKSJJDNFUZPF-UHFFFAOYSA-N methoxyethyl Chemical compound CCOC XOBKSJJDNFUZPF-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N oxane Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran THF Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 1
Classifications
-
- 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
- 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
-
- 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
Abstract
The technical problem of the invention relates to a method for the preparation of medetomidine starting from 1-bromo-2,3-dimethylbenzene and chloroacetone. Medetomidine is the compound of formula (XX) and is an alpha2 adrenergic agonist, which is currently being used as a veterinary sedative and analgesic and is evaluated as anesthetic. The solution to the problem involves a method for the preparation of a compound of formula (XX); the method comprises four steps, the four steps are a step (Q1), a step (Q2), a step (N) and a step (M1); compound of formula (XX) is prepared in step (M1); step (M1) comprises a reaction (M1-reac); reaction (M1-reac) is a reaction between a compound of formula (XXI); a reagent (M-reag) and a reagent (M-A) in a solvent (M-solv); reagent (M-reag) is selected from the group consisting of p-toluenesulfonylmethyl isocyanide, trifluoromethanesulfonylmethyl isocyanide, methanesulfonylmethyl isocyanide, benzenesulfonylmethyl isocyanide, and 4-acetamidobenzenesulfonylmethyl isocyanide, or mixtures thereof; reagent (M-A) is selected from the group consisting of ammonia, sulfamic acid, p-toluenesulfonamide, benzenesulfonamide, 4-acetamidobenzenesulfonamide, tritylamine, formamide, urea, urotropine, ethyl carbamate, and acetamide, or mixtures thereof; solvent (M-solv) is selected from the group consisting of N,N-dimethylformamide, C1-6 alkanol, formamide, 1,2-dimethoxyethane, NMP, toluene, acetonitrile, propionitrile, ethyl carbamate, N,N-dimethylacetamide, water, and acetamide, or mixtures thereof; compound of formula (XXI) is prepared in step (N); step (N) comprises a reaction (N-reac); reaction (N-reac) is a reaction of a 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, and carbon treated with inorganic acid, or mixtures thereof; step (Q1) comprises a reaction (Q1-reac); reaction (Q1-reac) is a reaction of a compound of formula (XXV) with a reagent (Q1-reag) to provide a reaction product of reaction (Q1-reac); R1 is Br, Cl, or I; reagent (Q1-reag) is selected from the group consisting of lithium, magnesium, aluminum, zinc, calcium, propylmagnesium chloride, propylmagnesium bromide, and butyllithium, or mixtures thereof; step (Q2) comprises a reaction (Q2-reac); reaction (Q2-reac) is a reaction of the reaction product of reaction (Q1-reac) with chloroacetone; compound of formula (XXII) is prepared by the reaction (Q2-reac). lgesic and is evaluated as anesthetic. The solution to the problem involves a method for the preparation of a compound of formula (XX); the method comprises four steps, the four steps are a step (Q1), a step (Q2), a step (N) and a step (M1); compound of formula (XX) is prepared in step (M1); step (M1) comprises a reaction (M1-reac); reaction (M1-reac) is a reaction between a compound of formula (XXI); a reagent (M-reag) and a reagent (M-A) in a solvent (M-solv); reagent (M-reag) is selected from the group consisting of p-toluenesulfonylmethyl isocyanide, trifluoromethanesulfonylmethyl isocyanide, methanesulfonylmethyl isocyanide, benzenesulfonylmethyl isocyanide, and 4-acetamidobenzenesulfonylmethyl isocyanide, or mixtures thereof; reagent (M-A) is selected from the group consisting of ammonia, sulfamic acid, p-toluenesulfonamide, benzenesulfonamide, 4-acetamidobenzenesulfonamide, tritylamine, formamide, urea, urotropine, ethyl carbamate, and acetamide, or mixtures thereof; solvent (M-solv) is selected from the group consisting of N,N-dimethylformamide, C1-6 alkanol, formamide, 1,2-dimethoxyethane, NMP, toluene, acetonitrile, propionitrile, ethyl carbamate, N,N-dimethylacetamide, water, and acetamide, or mixtures thereof; compound of formula (XXI) is prepared in step (N); step (N) comprises a reaction (N-reac); reaction (N-reac) is a reaction of a 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, and carbon treated with inorganic acid, or mixtures thereof; step (Q1) comprises a reaction (Q1-reac); reaction (Q1-reac) is a reaction of a compound of formula (XXV) with a reagent (Q1-reag) to provide a reaction product of reaction (Q1-reac); R1 is Br, Cl, or I; reagent (Q1-reag) is selected from the group consisting of lithium, magnesium, aluminum, zinc, calcium, propylmagnesium chloride, propylmagnesium bromide, and butyllithium, or mixtures thereof; step (Q2) comprises a reaction (Q2-reac); reaction (Q2-reac) is a reaction of the reaction product of reaction (Q1-reac) with chloroacetone; compound of formula (XXII) is prepared by the reaction (Q2-reac).
Description
/072798
METHOD FOR PREPARATION OF MEDETOMIDINE WITH CHLOROACETONE
The invention discloses a method for the preparation of medetomidine starting from l-bromo
2,3-dimethylbenzene and chloroacetone.
Medetomidine is the compound of formula (XX) and is an alpha2 adrenergic agonist, which is
currently being used as veterinary sedative and sic and is evaluated as etic.
Medetomidine is a 4-alkylimidazole. 4-Alkylimidazoles without onal substituents at the
nitrogen moiety are usually mixtures of two tautomers. For instance, in the case of
midine, two tautomeric forms, represented by compound of formula (XX) and
compound of formula (XX-T),
<\ I
(XX-T)
will usually interconvert if medetomidine is ved or in a ystalline state. If one of
the tautomeric forms prevails or if they are present in equal amounts is dependent on various
factors, such as pH, solvent or temperature.
In the text, formula (XX) is used for medetomidine, and is meant to comprise both tautomeric
forms as well as their mixture.
US 2010/0048915 A discloses a method for the preparation of medetomidine by on of
halogenated imidazoles with 2,3-dimethylbenzaldehyde using Grignard reagents.
Cordi et al., Synth. Commun. 1996, 26, 1585-1593, discloses the preparation of
medetomidine by reaction of 4-imidazolcarboxaldehyde with 2,3-dimethylphenylmagnesium
bromide.
WO 00/42851 A discloses the use of medetomidine for inhibition of marine bio fouling on
surfaces.
Previously disclosed methods of preparation of compound of formula (XX) often use
protecting groups, for example triphenylmethyl (trityl) residues, which entails high al
consumption and the need for protection/deprotection steps. Consequently, these syntheses
are long and expensive. Furthermore rather expensive and non-readily available starting
materials are used.
There was a need for a synthetic route, which does not need protecting groups, starts with less
ive substrates, avoids large amounts of waste and has satisfying yields.
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, , cyclopropyl, cyclobutyl, cyclopentyl, exyl, eptyl,
norbornyl, adamantyl, and the like;
"cyclic alkyl" or "cyclo alkyl" are intended to include cyclo aliphatic, bicyclo aliphatic and
tricycle aliphatic residues;
"alkane" means a linear, branched or cyclic alkane, preferably linear or branched ;
"alkanol" means a hydroxyalkane, with alkane having the meaning as defined above also with
its preferred embodiments;
Ac acetyl;
tBu ry butyl;
DBU 1,8-diazabicyclo[5.4.0]undecene;
DABCO 1,4-diazabicyclo[2.2.2]octane;
DMF N,N-dimethylformamide;
hexanes mixture of isomeric hexanes;
NMP N-methylpyrrolidone;
OTf trifluoromethanesulfonate, also known as triflate;
sulfamic acid HO-SO2-NH2;
THF tetrahydrofuran;
xylene l,2-dimethylbenzene, l,3-dimethylbenzene, l,4-dimethylbenzene or a
mixture thereof;
if not otherwise stated.
Subject of the invention is a method for preparation of compound of formula (XX);
H3 CH3
N CH3
</ l (XX)
the method comprises four steps, the four steps are a step (Q1), a step (Q2), a step (N) and a
step (Ml);
compound of formula (XX) is prepared in step (Ml);
step (Ml) comprises a reaction (Ml-reac);
reaction (Ml-reac) is a reaction n a compound of formula (XXI),
CH3 CH3
0 CH3
H (XXI)
a reagent (M-reag) and a reagent (M-A) in a solvent V);
reagent (M-reag) is selected from the group consisting of p-toluenesulfonylmethyl isocyanide,
trifluoromethanesulfonylmethyl isocyanide, esulfonylmethyl isocyanide,
benzenesulfonylmethyl isocyanide, 4-acetamidobenzenesulfonylmethyl isocyanide
and es thereof;
reagent (M-A) is selected from the group consisting of ammonia, sulfamic acid, p-
esulfonamide, benzenesulfonamide, 4-acetamidobenzenesulfonamide,
tritylamine, formamide, urea, urotropine, ethyl carbamate, acetamide and mixtures
thereof;
solvent V) is selected from the group consisting ofN,N—dimethylformamide, C1_6
l, formamide, methoxyethane, NMP, toluene, acetonitrile, propionitrile,
ethyl carbamate, N,N-dimethylacetamide, water, acetamide and mixtures thereof;
nd of formula (XXI) is prepared in step (N);
step (N) comprises a reaction (N-reac);
reaction (N-reac) is a reaction of a compound of a (XXII) with a catalyst );
CH3 CH3
(XXII)
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, H2804, HNOg, H3PO4, HClO4, BClg, BBI‘g, BFgoEtz,
BngMez, BFgTHF, MgClz, MgBrz, MgIz, AlClg, Al(O-C1_4 alkyl)3, SnCl4, TiCl4,
Ti(O-C1_4 alkyl)4, ZrCl4, Bi203, BlClg, ZnClz, PbClz, FeClg, SCClg, NiClz, Yb(OTf)3,
Yb(Cl)3, GaClg, AlBrg, Ce(OTf)3, LiCl, Cu(BF4)2, Cu(OTf)2, NiBr2(PPh3)2, NiBrz, NiClz,
Pd(OAc)2, PdClz, PtClz, InClg, acidic inorganic solid substance, acidic ion exchange
resin, carbon treated with inorganic acid and mixtures thereof;
step (Ql) ses a reaction (Ql-reac);
reaction (Ql-reac) is a reaction of compound of formula (XXV) with a reagent (Ql-reag);
Rl CH3
(XXV)
R1 is Br, Cl, or I;
2012/072798
reagent (Ql-reag) is selected from the group consisting of lithium, magnesium, um,
zinc, calcium, propylmagnesium chloride, propylmagnesium bromide, butyllithium and
mixtures thereof;
step (Q2) comprises a on (Q2-reac);
reaction (Q2-reac) is a reaction of the reaction product of reaction (Ql-reac) with
chloroacetone;
compound of formula (XXII) is prepared by the reaction (Q2-reac).
ably, reagent (M-reag) is selected from the group consisting of p-toluenesulfonylmethyl
isocyanide, esulfonylmethyl nide and mixtures f;
more ably, reagent (M-reag) is p-toluenesulfonylmethyl isocyanide.
Preferably, reagent (M-A) is selected from the group consisting of ammonia, sulfamic acid, p-
toluenesulfonamide, benzenesulfonamide, 4-acetamidobenzenesulfonamide,
amine, formamide and mixtures thereof;
more preferably, reagent (M-A) is selected from the group consisting of a, p-
toluenesulfonamide, benzenesulfonamide, formamide, 4-
acetamidobenzenesulfonamide, tritylamine and mixtures thereof;
even more preferably, reagent (M-A) is selected from the group consisting of ammonia, p-
toluenesulfonamide, formamide, and mixtures thereof;
especially, reagent (M-A) is ammonia or formamide.
Preferably, on (Ml-reac) is done in the presence of a compound (M-comp), compound
(M-comp) is selected from the group consisting of ammonia, amine, NaCN,
KCN, piperidine, DBU, DABCO, triethylamine, tributylamine, 4-
dimethylaminopyridine, pyridine, tBuOK, tBuONa, NaHCOg, N32C03, (NH4)HC03,
(NH4)2C03, KHCOg, K2C03, NaOAc, KOAc, NaOH, KOH, Ca(OH)2, KF and
mixtures thereof;
preferably, compound (M-comp) is selected from the group consisting of ammonia,
tritylamine, NaCN, KCN, piperidine, tBuOK, tBuONa, KOH, K2C03, N32C03, KF
and mixtures thereof;
more preferably, compound (M-comp) is selected from the group consisting of ammonia,
NaCN, KCN, piperidine, tBuOK, tBuONa, K2C03, N32C03, KF and mixtures thereof;
even more preferably, nd (M-comp) is selected from the group consisting of
ammonia, NaCN, K2C03, tBuOK, tBuONa, N32C03 and mixtures thereof;
especially, nd (M-comp) is selected from the group consisting of ammonia, NaCN,
tBuOK, tBuONa, K2C03, N32C03 and mixtures thereof;
more especially, compound (M-comp) is K2C03, Na2C03,NaCN or ammonia;
even more especially, compound (M-comp) is N32C03’ NaCN or ammonia.
Preferably, solvent (M-solv) is selected from the group consisting ofN,N—
dimethylformamide, methanol, ethanol, n-propanol, isopropanol, butanol, pentanol,
hexanol, water, formamide, l,2-dimethoxyethane, NMP, toluene, acetonitrile,
propionitrile, ethyl carbamate, N,N-dimethylacetamide, acetamide and mixtures
thereof;
more preferably, solvent (M-solv) is selected from the group ting ofN,N—
ylformamide, methanol, l, ethyl carbamate, formamide, acetamide and
mixture thereof.
The reagent (M-A) can be used as such or in form of a solution in a solvent (M-A). Solvent
(M-A) is identical or different from solvent (M-solv), preferably cal, and comprises the
same group of solvents as solvent (M-solv), also with respect to all of the preferred
embodiments of solvent (M-solv).
When reagent (M-A) is ammonia, then reagent (M-A) is preferably used in form of a solution,
preferably in form of a solution in methanol or ethanol.
In case of ethyl carbamate, formamide and acetamide, reagent (M-A) can be identical with
t (M-solv) and can be used as solvent (M-solv).
Preferably, the reaction temperature of reaction ac) is from -lO to 250 CC, more
preferably from 0 to 200 OC, even more preferably from 10 to 180 oC.
The reaction (Ml-reac) can be done in a system, that is closed or open to the atmosphere;
preferably the reaction (Ml-reac) is done in a closed system.
In a closed system, the re depends mainly on the boiling point of the solvent v),
on the amount of ammonia used, and on the reaction temperature of reaction (Ml-
reac);
ably, the reaction (Ml-reac) is done at a pressure of from atmospheric pressure to 20
bar, more preferably of from atmospheric pressure to 10 bar, even more preferably of from
atmospheric re to 5 bar.
Preferably, the reaction time of on (Ml-reac) is from 30 min to 72 h, more preferably
from 30 min to 48 h, even more preferably from 30 min to 24 h.
on (Ml-reac) may be conducted at a constant temperature, or the temperature may be
d during the progress ofthe reaction. For instance, the reaction may be run for a
certain time at first temperature, and then for a given time at second ature different
from the first temperature;
atively, the temperature may be modified continuously during the reaction.
Preferably, from 0.5 to 10 mol equivalents, more preferably from 0.5 to 5 mol equivalents,
even more preferably from 0.5 to 3 mol lents of reagent (M-reag) are used, the mol
equivalents being based on the mol of compound of formula (XXI).
When one or more reagents (M-A) different from ammonia, formamide and ethyl carbamate
are used, the total amount of substances ent from ammonia, formamide and ethyl
carbamate used as reagent (M-A) is 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,
the mol equivalents being based on the mol of compound of formula (XXI).
When ammonia, formamide, ethyl carbamate or mixtures thereof are used as reagent (M-A),
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 ammonia, formamide, ethyl
carbamate or mixtures f are used, the mol equivalents being based on the mol of
compound of formula (XXI).
When one or more substances selected from the group ammonia, formamide and ethyl
carbamate, and one or more nces different from ammonia, formamide and ethyl
carbamate are used as reagent (M-A), the given amounts for ammonia, formamide and ethyl
carbamate, and the given amounts for the one or more substances different from ammonia,
formamide and ethyl carbamate, add up to the total amount of reagent (M-A); the total
amount of reagent (M-A) is preferably from 1.0 to 100 mol equivalents, more ably from
1.1 to 50 mol equivalents, even more preferably from 1.1 to 30 mol equivalents, the mol
equivalents being based on the mol of compound of formula (XXI).
Preferably from 0.01 to 15 mol equivalents, more preferably from 0.02 to 10 mol equivalents,
even more preferably from 0.02 to 5 mol equivalents of compound (M-comp) are used, the
mol equivalents being based on the mol of compound of formula (XXI).
When t (M-A) is not one or more substances selected from the group ammonia,
formamide and ethyl carbamate, then preferably from 1 to 15 mol equivalents, more
preferably from 1 to 10 mol equivalents, even more preferably from 1 to 5 mol equivalents of
compound (M-comp) are used, the mol equivalents being based on the mol of compound of
formula (XXI).
Preferably, the amount of solvent v) is from 0.5 to 20 fold, more preferably from 1 to
fold, even more preferably of from 2 to 20 fold, of the weight of compound of formula
(XXI).
Preferably, the reaction (Ml-reac) is done under inert atmosphere.
When amine is used as reagent (M-A), the product of reaction (Ml-reac) may be N-trityl
medetomidine and the trityl residue would have to be removed.
Preferably in this case, the method for preparation of compound of formula (XX) comprises a
further step (M2); step (M2) is done after step (Ml); step (M2) comprises a reaction (M2-
reac);
reaction (M2-reac) is the treatment of the t of reaction (Ml-reac) with an acid (M-acid
detrit). Acid (M-acid detrit) is preferably selected from the group consisting of acetic acid,
propionic acid, formic acid, HCl or mixtures thereof.
Acid d ) can be used as an aqueous solution.
Any sequence of the on of reagent (M-reag) and of reagent (M-A) with the nd of
formula (XXI) in reaction (Ml-reac) can be used:
nd of formula (XXI) can first be reacted with reagent (M-reag) and then reagent (M-
A) added;
2012/072798
compound of formula (XXI) can first be reacted with reagent (M-A) and then reagent (M-
reag) added;
compound of formula (XXI) can simultaneously be reacted with reagent (M-reag) and with
reagent (M-A), this embodiment is preferably suited for the case that reagent (M-A) and
solvent (M-solv) are identical and are formamide, ethyl carbamate or acetamide; preferably
formamide.
Preferably, compound of formula (XXI) is first reacted with reagent (M-reag) and then
reagent (M-A) added;
nd of formula (XXI) is simultaneously reacted with reagent (M-reag) and with reagent
(M-A).
Step (Ml) can therefore be done in three alternatives, the three alternatives are alternative
(M l -A l ), alternative (M 1 -A2) and ative (M 1 -A3).
Alternative (Ml-Al) comprises two consecutive steps, a first step (Ml-Al-l) and a second
step (M 1 -Al -2);
step (Ml-Al-l) comprises a on (Ml-Al-l);
reaction (Ml-Al-l) is a reaction of compound of formula (XXI) with reagent (M-reag) in the
presence of compound (M-comp) in solvent (M-solv);
step (Ml-Al-2) comprises a reaction (Ml-Al-2);
reaction (Ml-Al-2) is a on of the reaction product of reaction (Ml-Al-l) with reagent
(M-A) in solvent (M-solv).
ably, the on temperature of reaction (Ml-Al-l) is from -10 to 250 CC, more
ably from 0 to 200 OC, even more preferably from 10 to 180 oC.
Preferably, the reaction temperature of reaction (Ml-Al-2) is from 20 to 250 CC, more
ably from 50 to 200 oC, even more preferably from 80 to 180 oC.
Preferably from 0.01 to 1 mol equivalents, more preferably from 0.02 to 1 mol equivalents,
even more preferably from 0.02 to 1 mol equivalents of compound (M-comp) are used in
reaction (Ml-Al-l), the mol equivalents being based on the mol of nd of formula
(XXI).
on (Ml-Al-2) can be done in the presence of compound (M-comp).
When reagent (M-A) is not one or more substances selected from the group ammonia,
formamide and ethyl carbamate, then reaction -2) is preferably done in the
ce of compound (M-comp); preferably from 1 to 15 mol equivalents, more
preferably from 1 to 10 mol equivalents, even more preferably from 1 to 5 mol
equivalents of compound (M-comp) are used, the mol equivalents being based on the mol
of compound of formula (XXI).
After reaction (M 1 -Al -l), the reaction product of reaction (Ml-Al -l) can be isolated by
standard methods such as hydrolysis, filtration, evaporation of the volatile components,
extraction, washing, drying, concentration, crystallization, distillation, chromatography
and any combination thereof, which are known per se to the person skilled in the art.
The on t of reaction -l) is the compound of formula (XXIII);
CH3 CH3
0 CH3
( XXIII
I? < >
N S\
wherein
R2 is 4-tolyl, phenyl, 4-acetamidophenyl, methyl or trifluoromethyl;
preferably, R2 is 4-tolyl, which is compound of formula (23).
CH3 CH3
<3 CH3
/? (23)
N S§O
Compound of formula (XXIII) can be isolated after reaction (Ml-Al-l) by addition of water
to the reaction mixture as obtained from reaction (Ml-Al-l). The addition of water
precipitates compound of formula (XXIII). Compound of formula (XXIII) can then be
isolated by filtration, followed preferably by washing and drying. nd of formula
(XXIII) can be fiarther purified by crystallization.
The volume of water used for this itation is preferably from 0.01 to 5 fold, more
preferably from 0.05 to 2 fold, of the volume of solvent (M-solv).
Alternative (Ml-A2) comprises two utive steps, a first step (Ml-AZ-l) and second a
step (Ml-A2-2);
step (Ml-AZ-l) comprises a on (Ml-AZ-l);
reaction (Ml-AZ-l) is a reaction of compound of formula (XXI) with reagent (M-A) in
solvent (M-solv);
step -2) ses a reaction (Ml-A2-2).
reaction (Ml-A2-2) is a reaction of the reaction product of reaction (Ml-AZ-l) with reagent
(M-reag) in the presence of compound (M-comp) in solvent (M-solv).
Preferably, the reaction temperature of on (Ml-AZ-l) is from 0 to 250 CC, more
preferably from 10 to 200 OC, even more preferably from 20 to 180 oC.
Preferably, the reaction temperature of reaction (Ml-A2-2) is from -10 to 250 CC, more
preferably from 0 to 200 OC, even more preferably from 20 to 180 0C.
In case of reagent (M-A) not being ammonia and tritylamine, reaction (Ml-AZ-l) can be done
in the presence of an acid (Ml-AZ-l); acid (Ml-AZ-l) is selected from the group
consisting of p-toluenesulfonic acid, methanesulfonic acid and esulfonic acid;
preferably from 0.01 to 1 mol equivalents, more preferably from 0.05 to 0.5 mol equivalents,
even more preferably from 0.1 to 0.3 mol equivalents of acid (Ml-AZ-l) are used in
reaction (Ml-AZ-l), the mol lents being based on the mol of nd of formula
(XXI).
Reaction -l) can be done in the presence of compound (M-comp).
When reagent (M-A) is not one or more substances selected from the group ammonia,
formamide and ethyl carbamate, then reaction (Ml-AZ-l) is ably done in the
presence of compound (M-comp); preferably from 1 to 15 mol equivalents, more
preferably from 1 to 10 mol equivalents, even more preferably from 1 to 5 mol
equivalents of compound (M-comp) are used, the mol equivalents being based on the mol
of compound of formula (XXI).
Preferably from 0.01 to 1 mol equivalents, more preferably from 0.02 to 1 mol equivalents,
even more preferably from 0.02 to 1 mol equivalents of compound (M-comp) are used in
reaction (Ml-A2-2), the mol equivalents being based on the mol of nd of formula
(XXI).
Alternative ) comprises a step (Ml-A3-l)
step (Ml-A3-l) comprises a reaction (Ml-A3-l);
reaction -l) is a on of compound of formula (XXI) with reagent (M-reag) and
with reagent (M-A) in t (M-solV).
Preferably, the reaction temperature of reaction (Ml-A3-l) is from 0 to 250 CC, more
preferably from 20 to 200 OC, even more preferably from 50 to 180 oC.
on (Ml-A3-l) can be done in the presence of compound (M-comp); preferably from 1
to 15 mol equivalents, more preferably from 1 to 10 mol equivalents, even more
preferably from 1 to 5 mol equivalents of compound (M-comp) are used in reaction (Ml-
A3-l), the mol equivalents being based on the mol of nd of formula (XXI).
In case of all these three alternatives, reagent (M-reag), reagent (M-A), compound (M-comp)
and solvent (M-solV) are as defined , also with all their preferred embodiments.
When the reaction (Ml-reac) is completed, the compound of formula (XX) can be isolated by
standard methods such as evaporation of volatile components, extraction, washing, drying,
tration, filtration, crystallization, distillation, chromatography and any combination
thereof, which are known per se to the person skilled in the art.
ably, the le components of the reaction mixture are removed by evaporation under
reduced pressure.
Preferably, the reaction mixture resulting from reaction (Ml-reac) or the reaction e
resulting from reaction (M2-reac) can be extracted with a solvent (M-extract),
solvent (M-extract) is preferably selected from the group consisting of water, toluene,
benzene, xylene, chlorobenzene, dichloromethane, chloroform, acetic acid C1_g alkyl ester and
combinations f;
the acetic acid C1_g 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 (M-extract) is selected from the group consisting of toluene,
dichloromethane, ethyl acetate, isopropyl acetate and mixtures thereof.
The extraction can be followed by filtration and concentration of the extract.
Preferably, after an extraction with a solvent (M-extract), the extract resulting from the
extraction with solvent (M-extract) can be extracted with an aqueous solution of an acid (M-
acid). Acid d) is preferably selected from the group consisting of oxalic acid, citric
acid, maleic acid, fumaric acid, tartaric acid, NH4Cl, HCl, HBr, H2804, H3PO4 and es
thereof.
The extract resulting from the tion with an aqueous solution of acid d) can be
washed with a solvent (M-wash).
ably, solvent (M-wash) is selected from the group consisting of toluene, benzene,
xylene, chlorobenzene, dichloromethane, chloroform, acetic acid C1_g alkyl ester and
es f; the acetic acid C1_g 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.
The product can be isolated by concentration of the extract that was washed with solvent (M-
wash).
In another preferred embodiment, the reaction e resulting from reaction (Ml-reac) or
the reaction mixture resulting from reaction (M2-reac) can be, without above mentioned
extraction with solvent (M-extract), acidified by mixing with an aqueous solution of acid (M-
acid). The mixture, that is thereby obtained, can be washed with solvent (M-wash), and the
product can be isolated by concentration.
If the deprotonated medetomidine is to be isolated, a suspension or solution of the salt of
medetomidine, preferably an s suspension or solution of the salt of
medetomidine, can be basified by addition of a base (M-basify) or of an aqueous
solution of base (M-basify);
preferably base ify) is selected from the group ting ofNaHCOg, N32C03, NaOH
and mixtures thereof.
Preferably, base (M-basify) is added in such an amount, that the pH of the ing mixture is
from 7 to 12, more preferably from 8 to 10, even more preferably from 8 to 9.
After the addition of base (M-basify), an aqueous phase can be extracted with solvent (M-
extract), ed by isolation of the product by concentration of the extract.
Preferably, any washing of any organic phase after reaction (Ml-reac) or after reaction (M2-
reac) can be done with water, with base (M-basify), with an aqueous solution of base (M-
basify) or with brine.
Preferably, any extraction of any aqueous phase after reaction (Ml-reac) or after reaction
(M2-reac) is done with solvent (M-extract).
Preferably, the reaction mixture after reaction (Ml-reac) or after on (M2-reac) is first
concentrated under reduced pressure, then diluted with water and acidified with acid (M-acid)
as described above, washed with solvent (M-wash), preferably solvent (M-wash) is toluene,
basified with base (M-basify), preferably base (M-basify) is an aqueous on ofNaHCOg,
and then ted with solvent (M-extract), ably solvent (M-extract) is selected from
the group consisting of toluene, dichloromethane, pyl e and ethyl acetate;
followed by isolation of the product by concentration of the extract.
In another preferred embodiment, compound of a (XX) is ed after reaction (Ml-
reac) or after reaction (M2-reac) by chromatography.
Any organic phase can be dried, preferably over MgSO4 or NaZSO4.
Any concentration is preferably done by distillation, preferably under reduced pressure.
The compound of a (XX) can be purified, preferably by crystallization or distillation
under reduced pressure, more preferably by crystallization from a mixture of cyclohexane and
toluene, even more preferably from cyclohexane : toluene 99 : 1 v/v .
The compound of formula (XX) may also be converted into a salt by mixing with an acid (M-
acid salt), acid (M-acid salt) is preferably used as s solution, acid (M-acid salt) is
preferably selected from the group consisting of acetic acid, oxalic acid, HCl and H2804;
then it can be isolated by filtration and purified by tallization in a solvent (M-cryst),
solvent (M-cryst) is preferably selected from the group consisting of water, ethanol, methanol,
isopropanol, acetonitrile, hexane, cyclohexane, heptane, toluene, ethyl acetate and mixtures
thereof; recrystallization can be repeated using a different t (M-cryst).
ably, the acidic inorganic solid substance in the list of possible compounds for catalyst
(N-cat) is aluminosilicate.
Preferably, the acidic ion exchange resin in the list of possible compounds for catalyst (N-cat)
is selected from the group consisting of copolymers of styrene and divinylbenzene and of
perfluorinated branched or linear polyethylenes, these polymers being functionalized with
SOgH groups;
more ably, the acidic ion exchange resin is selected from the group consisting of
copolymers of e and divinylbenzene containing more than 5% of divinylbenzene,
preferably being macroreticular, and of perfluorinated polyethylenes, these polymers
being fianctionalized with SOgH groups.
Preferably, the inorganic acid in the list of possible compounds for catalyst (N-cat), with
which the carbon was treated, is selected from the group consisting of HCl, H2804 and
HNOg.
ably, catalyst (N-cat) is selected from the group consisting of acetic acid, formic acid,
trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, HCl, HBr, H2804,
H3PO4, BClg, BFgoEtz, MgClz, MgBrz, AlClg, ZnClz, Cu(BF4)2, aluminosilicate, acidic
ion exchange resin, carbon treated with HCl, H2804 or HN03,and mixtures thereof;
more preferably, catalyst (N-cat) is selected from the group consisting of acetic acid, formic
acid, esulfonic acid, p-toluenesulfonic acid, HCl, H2804, BFgoEtz, Cu(BF4)2,
aluminosilicate, acidic ion exchange resin, and mixtures thereof;
even more ably st ) is selected from the group ting of
methanesulfonic acid, p-toluenesulfonic acid, H2804, BFgoEtz, Cu(BF4)2,
osilicate, acidic ion exchange resin, and mixtures thereof;
especially catalyst (N-cat) is selected from the group ting of methanesulfonic acid, p-
toluenesulfonic acid, H2804, BF30Et2 and mixtures thereof.
Preferably, reaction c) is done in a solvent (N-solv).
Solvent (N—solv) is preferably selected from the group consisting of water, tert-butanol,
isopropanol, acetonitrile, propionitrile, THF, methyl-THF, NMP, dioxane, 1,2-
dimethoxyethane, dichloromethane, 1,2-dichloroethane, chloroform, toluene, benzene,
benzene, hexane, cyclohexane, ethyl acetate, acetic acid, formic acid,
trifluoroacetic acid and mixtures thereof;
more preferably from water, acetonitrile, propionitrile, THF, 2-methyl-THF, 1,2-
dimethoxyethane, dichloromethane, 1,2-dichloroethane, chloroform, toluene,
cyclohexane, ethyl acetate, acetic acid, formic acid and mixtures thereof;
even more preferably from water, acetonitrile, propionitrile, THF, 2-methyl-THF, 1,2-
dimethoxyethane, dichloromethane, 1,2-dichloroethane, toluene, ethyl acetate and
mixtures thereof;
especially from acetonitrile, THF, 2-methyl-THF, romethane, toluene, ethyl acetate 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 (N—solv).
ably, the molar ratio n catalyst (N-cat) and compound of formula (XXII) is from
1:1000 to 10:1, more ably from 1:100 to 5:1, even more preferably from 1:50 to 1:1,
especially from 1:25 to 1:2.
ably, the reaction temperature of reaction (N-reac) is from -20 to 200 CC, more
preferably from 0 to 150 OC, even more ably from 10 to 100 oC.
The reaction (N-reac) can be done in a system that is closed or open to the here.
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 0.01 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, 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 preferably from 1.5 h to 24 h.
Alternatively, reaction c) can be done as a continuous gas-phase reaction by passing the
evaporated nd of formula (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 dioxide.
After reaction (N-reac), nd of formula (XXI) can be isolated by standard methods
such as evaporation of volatile components, extraction, washing, drying, concentration,
filtration, crystallization, distillation, chromatography and any ation thereof, which are
known per se to the person skilled in the art.
Preferably, any volatile components of the reaction mixture or added or generated during
work up can be removed by evaporation under reduced pressure.
Preferably, the reaction e resulting from reaction (N-reac) or any aqueous phase during
the work up after reaction c) can be extracted with solvent (M-extract), with solvent
(M-extract) as defined above, also with all its preferred embodiments.
Preferably, any g of any organic phase after reaction c) can be done with water,
with a base (M-basify), with an aqueous solution of a base (M-basify), with an aqueous
solution of an acid (M-acid) or with brine; with base (M-basify) and acid (M-acid) as defined
above, also with all their preferred embodiments.
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 ed after reaction (N-
reac) by chromatography.
Any organic phase can be dried, preferably over MgSO4 or Na2SO4.
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 etal of compound of
formula (XXI), which can result as product from step (N), can be the product of an on
reaction between the aldehyde as depicted in formula (XXI) and an alcohol selected from the
group consisting of tert-butanol and panol, or between the aldehyde as depicted in
formula (XXI) and any alcohol which is used during the isolation after reaction (N-reac).
Also this e and this hemiacetal can be directly used in step (M1).
When compound of formula (XXI) is ed from reaction (N-reac) in form of its hydrate
or of a hemiacetal, the hydrate or the hemiacetal can be converted into the aldehyde by
standard reactions previously disclosed in the art.
In another red embodiment, compound (XXI) is not isolated after reaction (N-reac).
Preferably, reaction (N-reac) and reaction ac) are done in the same pot. More
preferably, after reaction (N-reac) solvent (N-solv) is d by evaporation, and reaction
(M1-reac) is done after evaporation of solvent (N-solv) and in the same pot as reaction (N-
reac).
Preferably, R1 is Br.
Preferably, t (Q1-reag) is selected from the group consisting of lithium, magnesium,
aluminum, isopropylmagnesium chloride, isopropylmagnesium e, n-butyllithium,
sec-butyllithium, utyllithium, and mixtures thereof;
more preferably, reagent (Q1-reag) is selected from the group consisting of lithium,
magnesium, pylmagnesium chloride, isopropylmagnesium bromide, n-butyllithium
and mixtures thereof.
Reaction (Q1-reac) can be done in the presence of a catalyst (Q1-cat);
catalyst (Ql-cat) is selected from the group ting of iodine, l,2-dibromoethane, TiCl4,
AlClg, PbClz, BlClg, LiCl and mixtures thereof.
Preferably, reaction (Ql-reac) is performed in a solvent (Ql-solv).
Preferably, reaction (Q2-reac) is performed in a solvent (Q2-solv).
Preferably, solvent (Ql-solv) and solvent lv) are identical or different and
independently from each other selected from the group consisting of THF, toluene,
heptane, methylcyclohexane, ethylcyclohexane, hexane, 2-methyl-THF, NMP,
diethylether, -tert-butylether, methoxycyclopentane, diisopropylether, 5-
tetramethyl-THF, l,2-dimethoxyethane, N,N,N',N'-tetramethyl-l,2-ethylenediamine, 1,4-
diazabicyclo[2.2.2]octane, tri C1_4 alkyl amine and mixtures thereof;
more preferably from the group consisting of THF, toluene, heptane, hexane, 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, toluene, heptane, hexane, 2-methyl-
THF, l,2-dimethoxyethane, ylamine and mixtures f.
When e is used as solvent, it is often used as a mixture of isomeric heptanes.
In one particular embodiment, t (Ql-solv) is THF, hexane or a mixture thereof, and
solvent (Q2-solv) is THF, , toluene or a mixture f.
In another particular embodiment, solvent (Ql-solv) and solvent (Q2-solv) are identical.
The reaction temperatures of reaction (Ql-reac) and of reaction (Q2-reac) are identical or
different and independently from each other preferably from -lOO to 150 CC, more preferably
from -90 to 100 oC, and even more preferably from -80 to 80 oC.
Reaction (Ql-reac) and reaction (Q2-reac) can be done at a constant temperature, or the
temperature may be modified during the progress of the reactions. For instance, the reactions
can run for a certain time at first ature, 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) and of reaction (Q2-reac) are identical or different
and independently 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) and of solvent (Q2-solv) are identical or different and
independently from each other preferably from 2 to 40 fold, more preferably from 3 to 20
fold, even more preferably from 5 to 10 fold, of the weight of compound of formula (XXV) in
case of solvent (Ql-solv), and of the weight of the reaction product of reaction (Ql-reac) in
case of solvent (Q2-solv).
Preferably, from 1.0 to 10 mol equivalents, more preferably from 1.1 to 5 mol equivalents,
even more ably from 1.1 to 3 mol equivalents of reagent (Ql-reag) are used, the mol
equivalents being based on the mol of nd of formula (XXV).
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 chloroacetone are used, the mol
lents being based on the mol of compound of formula (XXV).
Preferably, reaction (Ql-reac) and reaction (Q2-reac) are done at atmospheric pressure.
ably, reaction ac) and reaction (Q2-reac) are done under inert atmosphere.
Preferably, the inert atmosphere is achieved by the use if an inert gas preferably selected from
the group consisting of argon, another noble gas, lower boiling alkane, nitrogen and mixtures
thereof.
The lower boiling alkane is preferably a C1_3 alkane, i.e. e, ethane or e.
After reaction (Q2-reac), nd of formula (XXII) can be isolated by standard methods
such as evaporation of volatile ents, tion, washing, drying, concentration,
crystallization, distillation, chromatography and any combination thereof, which are known
per se to the person skilled in the art.
Preferably, the reaction product of reaction ac) is not isolated.
Preferably, reaction (Ql-reac) and reaction (Q2-reac) are done consecutively.
Preferably, reaction (Ql-reac) and reaction (Q2-reac) are done in one pot.
In another preferred embodiment, on (Ql-reac) and reaction (Q2-reac) can be done in
one pot by adding reagent (Ql-reag) to a mixture of compound of formula (XXV) and
chloroacetone in a solvent (Ql-solv).
Preferably, for the isolation of compound of formula (XXII) after reaction (Q2-reac), a
reagent (Q3) is combined with the reaction mixture derived from reaction (Q2-reac);
reagent (Q3) is selected from the group consisting of water, methanol, ethanol, oxalic acid,
citric acid, NH4Cl, HCl, HBr, HNOg, H2804, H3PO4, acetic acid, propionic acid, formic
acid and mixtures thereof.
Preferably, reagent (Q3) is water or aqueous NH4Cl;
more preferably, reagent (Q3) is water.
Preferably, from 0.01 to 1000 mol equivalents, more ably from 0.02 to 1000 mol
equivalents, of reagent (Q3) are used, the mol equivalents being based on the mol of
nd of formula (XXV). Reagent (Q3) is used to neutralize any excess of reagent (Q1-
reag), therefore the amount of reagent (Q3) is adjusted with respect to the excess of reagent
(Q l -reag) used in reaction (Q l -reac).
Compound of formula (XXII) is preferably isolated using conventional methods, such as
evaporation of volatile components, hydrolysis and optional acidification of the higherboiling
e, extraction, and distillation.
The compound of a (XXII) can be ed, preferably by crystallization or distillation
under reduced pressure.
Any extraction of an aqueous phase is done preferably with a solvent ract), solvent (Q-
t) is benzene, toluene, ethyl acetate or isopropyl acetate.
Any c phase can be dried, ably with magnesium sulphate.
Any concentration is preferably done by lation, preferably under reduced pressure.
Compounds of formula (XX), (XX-T), (XXI), , (XXIII) and (23) are chiral
compounds, and the formulae comprise any omer as well as any mixture of enantiomers
of the compounds of formula (XX), of a (XX-T), of formula (XXI), of formula (XXII),
of formula (XXIII) or of formula (23) respectively.
Enantiomers can be separated by a conventional procedure usly disclosed in organic
chemistry, such as repeated crystallizations of the (+) tartaric acid salt in alcoholic media, as
disclosed for compound of formula (XX) in Cordi et al., Synth. . 1996, 26, 1585-
1593.
Compounds of formula (XXV) are known nds and can be prepared according to
known methods.
The progress of any of the reactions on (M1-reac), reaction (N-reac), reaction (Q1-reac)
and reaction (Q2-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 (LCMS), or Thin
Layer Chromatography (TLC), and p of the reaction mixture can start, when the
conversion of the starting material exceeds 95%, or when no more starting al can be
ed. 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 , if not stated
otherwise.
Further subject of the invention is a compound of formula ).
Further subject of the invention is a compound of formula (23).
Further subject of the invention is the use of compound of formula (XXIII) for the preparation
of compound of formula (XX).
Further subject of the invention is the use of compound of formula (XXI) for the preparation
of compound of formula (XXIII) or for the preparation of compound of formula (XX).
Further subject of the invention is the use of compound of formula (XXII) for the preparation
of compound of formula (XXI).
Further subject of the invention is the use of compound of formula (XXV) for the preparation
of compound of a (XXII).
Compared to prior art, the method of the present invention offers several advantages:
Importantly, the whole carbon framework of compound of formula (XX) is built in few
chemical steps, using cheap reagents only. The few al steps obviously provide for a
cost effective procedure. No ting groups are needed and the overall amount of material
used is ore reduced, the batch size based on molar amounts is sed.
In particular no trityl or acetale 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
example a trityl or acetale protecting group is used. The method has good yields.
2012/072798
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 CDClg. Chemical shifts are expressed in parts per million
referred to TMS and coupling constants (J) in Hertz.
EI means Electron ionization mass spectra (70 eV), they were ed on an 4
spectrometer.
ESI means Electron spray ionization mass spectra
In example 1 the THF was not dried with sodium. In e 2 NaH was used for this
purpose.
Example 1: -Dimethylphenyl)methyloxirane, compound of formula (XXII),
metallation with butyllithium in THF
To a solution of 1-brom0-2,3-dimethylbenzene (0.27 ml, 2.0 mmol) in THF (4.0 ml) at -78 CC
was added n-butyllithium (2.0 ml of a 1.6 M solution in hexane, 3.2 mmol). The mixture was
stirred at -78 CC for 30 min, and then a solution of chloroacetone (0.24 ml, 3.0 mmol) in
toluene (0.42 ml) was added drop wise within 20 min. The mixture was stirred at -78 0C for 1
h, and then allowed to warm to room temperature. Analysis of a sample after 3 h at room
temperature indicated that the title epoxide was the main reaction product. After stirring at
room temperature for 3 days the mixture was poured into water (20 ml), and the product was
extracted with ethyl acetate (1 x 10 ml, 2 x 5 ml). The combined extracts were dried with
MgSO4, and concentrated under d pressure to yield the title epoxide as an oil in
quantitative yield.
1H NMR: 1.59 (s, 3H), 2.28 (s, 3H), 2.31 (s, 3H), 2.83 (br d, 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 2: 2-(2,3-Dimethylphenyl)methyloxirane, compound of formula (XXII),
metallation with magnesium in THF
2012/072798
To a sion of magnesium (89 mg, 3.66 mmol) in THF (4.0 ml) were added NaH (81 mg,
60% in oil, 2.0 mmol), and after stirring at room temperature for 10 min, 1-bromo-2,3-
dimethylbenzene (0.40 ml, 2.96 mmol). An exothermic reaction ensues, and the ing
mixture is stirred at room temperature for 1 h. The mixture is then cooled to -20 CC, and a
solution of chloroacetone (0.26 ml, 3.3 mmol) in toluene (0.63 ml) is drop wise added within
min. The mixture is then stirred at room temperature for 2 h. A sample was worked up by
mixing with water, extraction with ethyl acetate, and evaporation of the ethyl acetate with a
stream of nitrogen. Analysis of the residue by 1H NMR indicated it to be a e of xylene
and the title oxirane.
Example 3: 2-(2,3-Dimethylphenyl)pr0panal, compound of formula (XXI)
2-(2,3-Dimethylphenyl)methyloxirane, nd of formula (XXII), prepared according to
example 1 (158 mg, 0.97 mmol), was dissolved in toluene (1.57 mL) and BF30Et2 (0.006 ml,
0.05 mmol) was added at room temperature. After 2 h at room temperature, a sample was
mixed with solid NaHC03, filtered, concentrated under reduced pressure, and the residue was
analyzed by 1H NMR. The crude product consisted essentially of pure 2-(2,3-
dimethylphenyl)propanal.
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).
Example 4: 5-(1-(2,3-dimethylphenyl)ethyl)tosyl-4,5-dihydrooxazole, compound of
a (23)
To a solution of compound of formula XXII (2.07 g, 12.8 mmol) in dichloromethane (10 ml)
was added BF30Et2 (0.1 molar in EtzO, 4 ml, 0.4 mmol) within 4 h at room temperature. The
e was stirred at room temperature for 1 h, and the solvent (dichloromethane) was then
evaporated under reduced pressure. The residue was dissolved in methanol (10 ml), and
TosMIC (toluenesulfonylmethylisocyanide; 2.24 g, 11.5 mmol) and then N32C03 (102 mg,
0.96 mmol) were added. The e was d at room temperature for 1 h, and then diluted
with water (5 ml). The mixture was stirred at room temperature for further 30 min, and then
kept at 4 OC overnight. Filtration and drying yielded 3.1 g (75%) of compound of formula
(23).
1H NMR(CDC13, 500 MHz): 1.28 (d, J = 7 Hz, 3H), 2.23 (s, 3H), 2.30 (s, 3H), 2.44 (s, 3H),
3.28 (m, 1H), 4.79 (m, 1H), 5.20 (m, 1H), 7.04 (s, 1H), 7.10 (m, 3H), 7.33 (d, J = 8 Hz, 2H),
7.73 (d, J = 8 Hz, 2H).
Example 5: midine, compound of formula (XX)
Compound of formula (23) (3.16 g, 8.84 mmol), prepared according to e 4, was
dissolved in ammonia-saturated ethanol (40 ml, containing approximately 160 mmol
ammonia) and heated to 110 0C for 3 h. The e was then evaporated to dryness, and the
residue was mixed with an aqueous, ted solution ofNaHC03 (20 ml). The mixture was
extracted with toluene (2 x 20 ml), and the ed extracts were washed with water (2 x 20
ml). The combined extracts were then extracted with 10% aqueous HCl (3 x 20 ml), and the
combined acidic extracts were basified with gaseous ammonia, and extracted with toluene (2
x 20 ml). The combined organic extracts were dried over Na2S04, and concentrated under
reduced pressure, to yield compound of formula (XX) (1.57 g, 89%).
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, 117.61, 124.62, 125.53, 127.91, 134.05, 134.60,
136.76,141.11,143.23.
MS (ESI): 201 [M+H]+
This product was redissolved in acetonitrile (10 ml), and converted into a hydrochloride salt
with concentrated aqueous hydrochloric acid (0.8 ml). The mixture was trated to
dryness, and the residue was suspended in diethylether (30 ml), and d at room
temperature overnight. tion and drying under reduced pressure yielded 1.55 g (74%) of
compound of formula (XX) as hydrochloride salt.
Claims (15)
1. Method for preparation of compound of formula (XX); CH CH 3 3 N CH (XX) 5 H the method comprises four steps, the four steps are a step (Q1), a step (Q2), a step (N) and a step (M1); 10 compound of formula (XX) is prepared in step (M1); step (M1) comprises a reaction (M1-reac); reaction (M1-reac) is a on between a compound of formula (XXI), a reagent (M-reag) and a reagent (M-A) in a solvent (M-solv); reagent (M-reag) is selected from the group consisting of p-toluenesulfonylmethyl isocyanide, trifluoromethanesulfonylmethyl isocyanide, methanesulfonylmethyl nide, 20 benzenesulfonylmethyl isocyanide, 4-acetamidobenzenesulfonylmethyl isocyanide and mixtures f; t (M-A) is selected from the group consisting of ammonia, sulfamic acid, ptoluenesulfonamide , esulfonamide, 4-acetamidobenzenesulfonamide, 25 tritylamine, formamide, urea, urotropine, ethyl carbamate, acetamide and mixtures thereof; solvent v) is ed from the group consisting of N,N-dimethylformamide, C1-6 alkanol, ide, 1,2-dimethoxyethane, NMP, toluene, acetonitrile, propionitrile, ethyl carbamate, N,N-dimethylacetamide, water, acetamide and mixtures thereof; 5 compound of formula (XXI) is ed in step (N); step (N) comprises a reaction (N-reac); reaction c) is a reaction of a 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, esulfonic 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, 15 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 nic acid and mixtures thereof; 20 step (Q1) comprises a reaction (Q1-reac); reaction (Q1-reac) is a reaction of compound of formula (XXV) with a reagent (Q1-reag); R1 is Br, Cl, or I; reagent (Q1-reag) is selected from the group consisting of lithium, magnesium, aluminum, zinc, m, propylmagnesium chloride, propylmagnesium bromide, butyllithium and mixtures thereof; step (Q2) comprises a reaction ac); reaction (Q2-reac) is a reaction of the reaction product of reaction (Q1-reac) with chloroacetone; 5 compound of formula (XXII) is prepared by the reaction (Q2-reac).
2. Method according to claim 1, wherein step (M1) ses two consecutive steps, a first step -1) and a second step (M1-A1-2); step (M1-A1-1) ses a reaction (M1-A1-1); 10 reaction (M1-A1-1) is a reaction of compound of formula (XXI) with reagent (M-reag) in the presence of compound (M-comp) in solvent (M-solv); step (M1-A1-2) comprises a reaction (M1-A1-2); reaction (M1-A1-2) is a reaction of the reaction product of on (M1-A1-1) with reagent (M-A) in t (M-solv).
3. Method according to claim 1 or claim 2, wherein reagent (M-reag) is selected from the group consisting of p-toluenesulfonylmethyl isocyanide, benzenesulfonylmethyl isocyanide and mixtures thereof. 20
4. Method according to any one of claims 1 to 3, wherein reagent (M-A) is ed from the group ting of ammonia, sulfamic acid, p-toluenesulfonamide, benzenesulfonamide, 4- acetamidobenzenesulfonamide, amine, formamide and mixtures thereof.
5. Method according to any one of claims 1 to 4, wherein solvent (M-solv) is selected from 25 the group consisting of N,N-dimethylformamide, methanol, ethanol, n-propanol, isopropanol, butanol, pentanol, hexanol, water, formamide, 1,2-dimethoxyethane, NMP, toluene, acetonitrile, propionitrile, ethyl carbamate, N,N-dimethylacetamide, acetamide and mixtures thereof. 30
6. Method according to any one of claims 1 to 5, wherein on ac) is done in the presence of a compound (M-comp), compound (M-comp) is selected from the group consisting of ammonia, tritylamine, NaCN, KCN, piperidine, DBU, DABCO, triethylamine, tributylamine, 4-dimethylaminopyridine, pyridine, tBuOK, , NaHCO3, Na2CO3, CO3, (NH4)2CO3, KHCO3, K2CO3, NaOAc, KOAc, NaOH, KOH, Ca(OH)2, KF and mixtures thereof.
7. Method according to claim 6, wherein compound (M-comp) is selected from the group 5 consisting of ammonia, tritylamine, NaCN, KCN, dine, tBuOK, tBuONa, KOH, K2CO3, , KF and mixtures thereof.
8. Method according to any one of claims 1 to 7, n catalyst (N-cat) is selected from the group consisting of acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, p- 10 toluenesulfonic acid, HCl, HBr, H2SO4, H3PO4, BCl3, BF3OEt2, MgCl2, MgBr2, AlCl3, ZnCl2, Cu(BF4)2, aluminosilicate, acidic ion exchange resin, carbon treated with HCl, H2SO4 or HNO3,and es thereof.
9. Method according to any one of claims 1 to 8, wherein R1 is Br.
10. Method ing to claim 1 or claim 9, wherein reagent (Q1-reag) is selected from the group consisting of lithium, magnesium, aluminum, isopropylmagnesium chloride, isopropylmagnesium bromide, n-butyllithium, sec-butyllithium, tert-butyllithium, and mixtures thereof.
11. Method according to any one of claims 1 to 10, wherein reaction (Q1-reac) is done in the presence of a catalyst (Q1-cat); catalyst (Q1-cat) is selected from the group consisting of iodine, 1,2-dibromoethane, TiCl4, AlCl3, PbCl2, BiCl3, LiCl and mixtures thereof.
12. Compound of a (XXIII), 30 wherein R2 is 4-tolyl, phenyl, 4-acetamidophenyl, methyl or trifluoromethyl.
13. Compound according to claim 12, wherein R2 is 4-tolyl. 5
14. A method ing to claim 1, substantially as hereinbefore described, with reference to any one of the es.
15. A compound according to claim 12, substantially as hereinbefore described, with reference to any one of the Examples.
Applications Claiming Priority (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201261665510P | 2012-06-28 | 2012-06-28 | |
EP12174102 | 2012-06-28 | ||
EP12174102.9 | 2012-06-28 | ||
US61/665,510 | 2012-06-28 | ||
EP12188104 | 2012-10-11 | ||
EP12188104.9 | 2012-10-11 | ||
PCT/EP2012/070875 WO2012172121A1 (en) | 2012-06-28 | 2012-10-22 | Method for the preparation of medetomidine with chloroacetone |
EPPCT/EP2012/070875 | 2012-10-22 | ||
EP12192625.7 | 2012-11-14 | ||
EP12192625 | 2012-11-14 | ||
PCT/EP2012/072798 WO2013011157A1 (en) | 2012-06-28 | 2012-11-15 | Method for preparation of medetomidine with chloroacetone |
Publications (2)
Publication Number | Publication Date |
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NZ700642A NZ700642A (en) | 2016-04-29 |
NZ700642B2 true NZ700642B2 (en) | 2016-08-02 |
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