WO2006021559A2 - Verfahren zur herstellung von tiotropiumsalzen und silicium-derivate als zwischenprodukte - Google Patents
Verfahren zur herstellung von tiotropiumsalzen und silicium-derivate als zwischenprodukte Download PDFInfo
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- WO2006021559A2 WO2006021559A2 PCT/EP2005/054131 EP2005054131W WO2006021559A2 WO 2006021559 A2 WO2006021559 A2 WO 2006021559A2 EP 2005054131 W EP2005054131 W EP 2005054131W WO 2006021559 A2 WO2006021559 A2 WO 2006021559A2
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- Prior art keywords
- formula
- methyl
- compound
- ethyl
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- LERNTVKEWCAPOY-DZZGSBJMSA-N tiotropium Chemical class O([C@H]1C[C@@H]2[N+]([C@H](C1)[C@@H]1[C@H]2O1)(C)C)C(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 LERNTVKEWCAPOY-DZZGSBJMSA-N 0.000 title claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 title abstract description 3
- 239000000543 intermediate Substances 0.000 title description 3
- -1 silyl compound Chemical class 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims description 62
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 48
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 23
- 239000002904 solvent Substances 0.000 claims description 21
- 238000002360 preparation method Methods 0.000 claims description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 238000011065 in-situ storage Methods 0.000 claims description 15
- FVEJUHUCFCAYRP-UHFFFAOYSA-N 2-hydroxy-2,2-dithiophen-2-ylacetic acid Chemical compound C=1C=CSC=1C(O)(C(=O)O)C1=CC=CS1 FVEJUHUCFCAYRP-UHFFFAOYSA-N 0.000 claims description 14
- 239000002585 base Substances 0.000 claims description 13
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 13
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 11
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 10
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 9
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
- 230000008878 coupling Effects 0.000 claims description 8
- 238000010168 coupling process Methods 0.000 claims description 8
- 238000005859 coupling reaction Methods 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 150000001450 anions Chemical class 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 3
- 229910004013 NO 2 Inorganic materials 0.000 claims description 3
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims description 3
- SOFDTMPXXZJJMJ-UHFFFAOYSA-N (2-nitrobenzoyl) 2-nitrobenzoate Chemical compound [O-][N+](=O)C1=CC=CC=C1C(=O)OC(=O)C1=CC=CC=C1[N+]([O-])=O SOFDTMPXXZJJMJ-UHFFFAOYSA-N 0.000 claims description 2
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims description 2
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 claims description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 2
- 238000003776 cleavage reaction Methods 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical class ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 2
- 230000007017 scission Effects 0.000 claims description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 claims description 2
- VRAVWQUXPCWGSU-UHFFFAOYSA-N bis(1h-1,2,4-triazol-5-yl)methanone Chemical compound N1=CNN=C1C(=O)C=1N=CNN=1 VRAVWQUXPCWGSU-UHFFFAOYSA-N 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 30
- 238000001816 cooling Methods 0.000 description 21
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 18
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 15
- IKDFZBCJDLZSNH-UHFFFAOYSA-M 1508-46-9 Chemical compound [Br-].C[N+]1(C)C2CC(O)CC1C1C2O1 IKDFZBCJDLZSNH-UHFFFAOYSA-M 0.000 description 13
- LERNTVKEWCAPOY-VOGVJGKGSA-N C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 Chemical compound C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 LERNTVKEWCAPOY-VOGVJGKGSA-N 0.000 description 13
- 229960000257 tiotropium bromide Drugs 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 239000012043 crude product Substances 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 9
- 229960000583 acetic acid Drugs 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- 239000012362 glacial acetic acid Substances 0.000 description 9
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 9
- 229910000104 sodium hydride Inorganic materials 0.000 description 9
- 239000012312 sodium hydride Substances 0.000 description 9
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- 229910052708 sodium Inorganic materials 0.000 description 7
- 239000000047 product Substances 0.000 description 6
- WQDRNDLXGQHRKY-UHFFFAOYSA-M sodium;2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound [Na+].C=1C=CSC=1C(C([O-])=O)(O)C1=CC=CS1 WQDRNDLXGQHRKY-UHFFFAOYSA-M 0.000 description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- OHZAHWOAMVVGEL-UHFFFAOYSA-N 2,2'-bithiophene Chemical group C1=CSC(C=2SC=CC=2)=C1 OHZAHWOAMVVGEL-UHFFFAOYSA-N 0.000 description 4
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 150000004682 monohydrates Chemical class 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- FIMXSEMBHGTNKT-UHFFFAOYSA-N Scopine Natural products CN1C2CC(O)CC1C1C2O1 FIMXSEMBHGTNKT-UHFFFAOYSA-N 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 description 2
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 229940065524 anticholinergics inhalants for obstructive airway diseases Drugs 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 239000000812 cholinergic antagonist Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 150000007928 imidazolide derivatives Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- FIMXSEMBHGTNKT-UPGAHCIJSA-N scopine Chemical compound C([C@@H]1N2C)C(O)C[C@@H]2[C@@H]2[C@H]1O2 FIMXSEMBHGTNKT-UPGAHCIJSA-N 0.000 description 2
- FIMXSEMBHGTNKT-RZVDLVGDSA-N scopine Chemical compound C([C@@H]1N2C)[C@H](O)C[C@@H]2[C@@H]2[C@H]1O2 FIMXSEMBHGTNKT-RZVDLVGDSA-N 0.000 description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- ZFPGARUNNKGOBB-UHFFFAOYSA-N 1-Ethyl-2-pyrrolidinone Chemical compound CCN1CCCC1=O ZFPGARUNNKGOBB-UHFFFAOYSA-N 0.000 description 1
- DDFHBQSCUXNBSA-UHFFFAOYSA-N 5-(5-carboxythiophen-2-yl)thiophene-2-carboxylic acid Chemical compound S1C(C(=O)O)=CC=C1C1=CC=C(C(O)=O)S1 DDFHBQSCUXNBSA-UHFFFAOYSA-N 0.000 description 1
- KLZUFWVZNOTSEM-UHFFFAOYSA-K Aluminium flouride Chemical compound F[Al](F)F KLZUFWVZNOTSEM-UHFFFAOYSA-K 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 125000005210 alkyl ammonium group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- KFSZGBHNIHLIAA-UHFFFAOYSA-M benzyl(trimethyl)azanium;fluoride Chemical compound [F-].C[N+](C)(C)CC1=CC=CC=C1 KFSZGBHNIHLIAA-UHFFFAOYSA-M 0.000 description 1
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 125000000753 cycloalkyl 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
- 150000002148 esters Chemical class 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- VNIGOEWLNPGGQW-UHFFFAOYSA-N lithium;imidazol-3-ide Chemical compound [Li+].C1=C[N-]C=N1 VNIGOEWLNPGGQW-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Inorganic materials [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000005207 tetraalkylammonium group Chemical group 0.000 description 1
- QSUJAUYJBJRLKV-UHFFFAOYSA-M tetraethylazanium;fluoride Chemical compound [F-].CC[N+](CC)(CC)CC QSUJAUYJBJRLKV-UHFFFAOYSA-M 0.000 description 1
- AAIWQSJMMIXYGQ-UHFFFAOYSA-M tetrahexylazanium;fluoride Chemical compound [F-].CCCCCC[N+](CCCCCC)(CCCCCC)CCCCCC AAIWQSJMMIXYGQ-UHFFFAOYSA-M 0.000 description 1
- QGAKFUJUPKPDCN-UHFFFAOYSA-M tetraoctylazanium;fluoride Chemical compound [F-].CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC QGAKFUJUPKPDCN-UHFFFAOYSA-M 0.000 description 1
- MQLXPRBEAHBZTK-SEINRUQRSA-M tiotropium bromide hydrate Chemical compound O.[Br-].C[N+]1(C)[C@H]2C[C@@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 MQLXPRBEAHBZTK-SEINRUQRSA-M 0.000 description 1
- CYHOMWAPJJPNMW-JIGDXULJSA-N tropine Chemical group C1[C@@H](O)C[C@H]2CC[C@@H]1N2C CYHOMWAPJJPNMW-JIGDXULJSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
- C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
Definitions
- the invention relates to a novel process for the preparation of tiotropium salts of general formula 1
- Anticholinergics can be therapeutically useful in a variety of diseases. Special mention should be made, for example, of the treatment of asthma or COPD (chronic obstructive pulmonary disease).
- COPD chronic obstructive pulmonary disease
- WO 02/03289 proposes anticholinergics which have a scopin, tropenol or tropine skeleton.
- the tiotropium bromide is disclosed in particular in the prior art as a highly potent anticholinergic. Tiotropium bromide is known, for example, from EP 418 716 A1.
- the present invention relates to a process for the preparation of tiotropium salts of formula 1 wherein
- X may mean a singly negatively charged anion, preferably an anion selected from the group consisting of chloride, bromide, iodide, methanesulfonate or trifluoromethanesulfonate,
- R is a radical selected from the group consisting of N-imidazolyl, N-triazolyl,
- R " is C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkylene-N (C 1 -C 4 -alkyl) 2 ;
- the present invention relates to a process for the preparation of tiotropium salts of formula 1, wherein X "is a single negatively charged anion selected from the group consisting of chloride, bromide, iodide, methanesulfonate or trifluoromethanesulfonate, preferably chloride, bromide or methanesulfonate, more preferably bromide , can mean.
- R is methyl, ethyl or cyclohexyl; R "is methyl, ethyl, cyclohexyl, C 2 -C 3 -alkylene-N (methyl) 2 or
- a method particularly preferred according to the invention is characterized in that that the reaction takes place with an in situ generated compound of formula 3, in which
- R is a radical selected from the group consisting of N-imidazolyl, N-triazolyl,
- R 1 and R 2 identical or different, denote methyl, ethyl, propyl or butyl, preferably methyl or ethyl, more preferably methyl;
- R 2 is methyl or ethyl, preferably methyl.
- Alkyl groups and alkyl groups which are part of other groups are branched and unbranched alkyl groups having 1 to 4 carbon atoms. Examples include: methyl, ethyl, propyl, butyl. Unless otherwise stated, of the above designations, propyl, butyl includes all of the possible isomeric forms. For example, the term propyl includes the two isomeric radicals n-propyl and iso-propyl, the term butyl n-butyl, iso-butyl, sec. Butyl and tert. Butyl.
- alkylene bridge or alkylene group unless otherwise stated, branched and unbranched alkyl groups having 1 to 4 carbon atoms, for example methylene, Etyhlen, propylene, butylene bridges referred to. Particularly preferred
- phenyl-methyl and phenyl-NÜ2 stand for phenyl rings by
- Methyl or NO 2 are substituted. All possible isomers (ortho, meta or para) are included here, the para- or meta-substitution being of particular importance.
- cycloalkyl radicals having 3 to 6 carbon atoms are for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
- the procedure may be as described below.
- the compound of formula 3 is generated in situ.
- the term "in situ” stands for the representation of the compound of the formula 3 without this being subsequently isolated.
- the representation of the formula 3 takes place by reacting dithienylglycolic acid, preferably of alkali metal salts of dithienylglycolic acid, more preferably of sodium dithienyl glycolate with a coupling reagent selected from the group consisting of carbonyldiimidazole, carbonyldi-l, 2,4-triazole, dicyclohexylcarbodiimide, ethyldimethylaminopropylcarbodiimide, toluenesulfonyl chloride, pivaloyl chloride, nitrobenzoic anhydride, oxalyl chloride, Phosgene, sulfonyl chloride and phosphorus chlorides preferably carbonyldiimidazole
- radicals R 1 and R 2 may have the abovementioned meanings and L is a leaving group, which is preferably selected from the group consisting of halide, methanesulfonate, trifluoromethanesulfonate and para-toluenesulfonate, more preferably methanesulfonate, trifluoromethanesulfonate, Bromine or chlorine, furthermore preferably bromine or chlorine, chlorine having particular importance according to the invention.
- L is a leaving group, which is preferably selected from the group consisting of halide, methanesulfonate, trifluoromethanesulfonate and para-toluenesulfonate, more preferably methanesulfonate, trifluoromethanesulfonate, Bromine or chlorine, furthermore preferably bromine or chlorine, chlorine having particular importance according to the invention.
- the silyl compound 5 can either be added to the mixture of dithienylglycolic acid or dithienylglycolic acid salt with coupling reagent in the abovementioned solvent, if appropriate in the presence of a base such as, for example, pyridine, imidazole or N-alkylamine, or else together with dithienylglycolic acid or the dithienylglycolic acid salt in the abovementioned solvent, optionally in the presence of a base such as pyridine, imidazole or N-alkylamine, initially charged and then added with the above-mentioned coupling reagent.
- a base such as, for example, pyridine, imidazole or N-alkylamine
- the abovementioned three components are added in stoichiometric amounts to form the compound of the formula 3; but also in the presence of one of the three components in excess (for example, 1.1 to 1.5 equivalent) are performed.
- the solution obtained is mixed at the abovementioned temperature for about 5 minutes to 2 hours, preferably 10 minutes to 1 hour, particularly preferably 20-40 minutes, for example by stirring to form the compound of general formula 3.
- the compound of formula 2 is then added to the solution thus obtained.
- This addition can be carried out either by adding a solution or suspension of the compound of formula 2 in one or more of the abovementioned solvents or by, preferably in portions, adding the compound of formula 2 in bulk. If the compound of the formula 2 is dissolved or suspended in one or more solvents, the use of the same solvents, which is used for the in situ preparation of the compound of the formula 3, is appropriate.
- the amount in which the compound of formula 2 is added is determined by the amount of compound of formula 3 generated in situ.
- the three components dithienylglycolic acid or dithienylglycolic acid salt, coupling reagent and compound of formula 5 are obtained Used stoichiometric amounts, is compound of formula 3 in the molar amount, as it was chosen for the three components Dithienylglykolklare or Dithienylglykolklasalz, coupling reagent and compound of formula 5.
- the compound of formula 3 is in the molar amount of the least portioned component of the three starting compounds dithienylglycolic acid or dithienylglycolic acid salt , Coupling reagent and compound of formula 5.
- the molar ratio of compound of formula 2 to in situ generated compound of formula 3 is preferably in a range from 2: 1 to 1: 5, preferably 1.5: 1 to 1: 3, more preferably 1: 1 to 1: 2, wherein a ratio of 1: 1 to 1: 1.5 particular importance according to the invention.
- Suitable solvents according to the invention are the abovementioned solvents.
- the solvent which has also been used to form the compound of formula 3 is used at this point.
- the base organic or inorganic bases can be used.
- Alkali imidazolides are preferably used as organic bases, which can be generated, for example, in situ from the alkali metals and imidazole or the alkali metal hydrides and imidazole.
- Akaliimidazolide are preferably imidazolides of lithium, sodium or potassium, with sodium or lithium imidazolide being preferred according to the invention.
- alkali metal alcoholates of hindered alcohols e.g., potassium tert -butylate
- Preferred further bases are inventively selected from the group consisting of lithium diisopropylamide (LDA), lithium or sodium hexamethyldisilazane (LiHMDS or NaHMDS).
- Suitable inorganic bases are preferably hydrides of lithium, sodium or potassium. Particular preference is given to using sodium hydride as the inorganic base.
- the base solution or suspension preferably between 0.2 and 1.5 L, more preferably between 0.3 and 1 L of said solvent are used per mole of base.
- the addition of the base is preferably carried out at a temperature of -20-60 ° C, preferably from 0-45 ° C, particularly preferably from 0-25 ° C. After addition of the base, the resulting mixture is stirred for about 10 minutes to 6 hours, preferably 30 minutes to 3 hours, more preferably 45 minutes to 1.5 hours at constant temperature to form the compound of formula 4.
- a suitable acid HX is preferably carried out at a temperature of below 10 ° C, more preferably at about 0 ° C.
- the choice of the acid is determined here by the anion X "in the desired end product of general formula 1.
- the present invention in addition to the acid HX can be carried out in addition, the addition of a suitable Desilyl michsreagenzes, which is preferably selected from the group of ammonium fluoride in the frame, particularly preferably tetrabutylammonium fluoride, tetraethylammonium fluoride, benzyltrimethylammonium fluoride, tetrahexylammonium fluoride, tetraoctylammonium fluoride or hydrogen fluoride free or complexed, such as, for example, pyridinium fluoride, triethylamine-HF complex.
- a suitable Desilyl istsreagenzes which is preferably selected from the group of ammonium fluoride in the frame, particularly preferably tetrabutylammonium fluoride, tetraethylammonium fluoride, benzyltrimethylammonium fluoride, tetrahexylammonium fluor
- the release of the compound of the formula 1 can also be effected exclusively by means of the abovementioned de-silylating reagents.
- X represents bromide
- the following procedure for the preparation of the inventive preferred tiotropium bromide is described below.
- Y is a cation such as a proton or a metal cation or ammonium, alkylammonium, tetraalkylammonium or pyridinium or a complex such as aluminum trifluoride HF or another fluoride donor such as diethylaminosulfur trifluoride (DAST)
- DAST diethylaminosulfur trifluoride
- the reaction mixture is admixed with a protic solvent, preferably with an alcohol, more preferably with methanol or ethanol or isopropanol.
- a protic solvent preferably with an alcohol, more preferably with methanol or ethanol or isopropanol.
- 0.5 to 20 L, more preferably 0.7 to 13 L alcohol are added according to the invention per mole of compound of formula 2 and the mixture obtained at a temperature of 0-60 ° C, preferably from 10-45 ° C, particularly preferably from 15-25 ° C for a period of about 0.5 to 6 hours, preferably 0.5 to 5 hours, more preferably 0.5 to 4 hours.
- a non-polar organic solvent preferably with a solvent selected from the group consisting of a ketone (such as acetone or methyl ethyl ketone), an alcohol (such as methanol, ethanol, propanol, isopropanol, butanol or amyl alcohol), toluene , Ethyl acetate, n-butyl acetate, dichloromethane, diethyl ether, methyl tert-buyl ether, tetrahydrofuran and dioxane, particularly preferably isopropanol, toluene or acetone.
- the crystallized product is separated and washed with the abovementioned solvent.
- the crude product can be mixed with water or aqueous bromide solutions, e.g. Sodium or potassium bromide solution are treated.
- the present invention further relates to compounds of the formula 3 wherein R, R 1 and R 2 may have the meanings given above, as such.
- the present invention further relates to compounds of the formula 4
- the present invention relates to the use of the abovementioned compounds of the formula 3 for the preparation of compounds of the formula 1.
- the present invention relates to the use of the abovementioned compounds of the formula 4 for the preparation of compounds of the formula 1.
- reaction mixture is extracted with 500 ml of toluene and crystallized after separation of the toluene phase with 150 ml of isopropanol at 0 ° C.
- the crude product is filtered off, washed with 30 ml of cold isopropanol and dried in vacuo. Yield 14.1g (80%, with respect to Scopinmethobromid).
- the reaction mixture is extracted twice with 200 ml of toluene and crystallized after separation of the toluene phase with 150 ml of isopropanol at 5 ° C.
- the crude product is filtered off and recrystallized from 120 ml of methanol with the addition of 5 g of activated charcoal.
- the tiotropium bromide obtained is filtered off, washed with 5 ml of cold methanol and dried in vacuo.
- the crystals thus obtained are dissolved in 20 ml of water at 90 ° C and crystallized the monohydrate of tiotropium bromide by cooling to 15 ° C.
- the product is filtered off, washed with 7 ml of water and 8 ml of acetone and sucked dry. Yield 9.8 g (40% with respect to scopine methobromide).
- the reaction mixture is extracted twice with 200 ml of toluene and crystallized in 150 ml of isopropanol by cooling to 5 ° C.
- the crystallized crude product is filtered off and recrystallized from 120 ml of methanol with the addition of 5 g of activated carbon.
- the tiotropium bromide obtained is filtered off, washed with cold methanol and dried in vacuo.
- the product is dissolved in 24 ml of water at 90 ° C. and the monohydrate of the tiotropium bromide is crystallized by cooling to 15 ° C.
- the product is filtered off and washed with 6.5 ml of water and 10.5 ml of acetone and dried. Yield 8.1 g (42% with respect to scopine methobromide).
- the reaction mixture is treated with 800 ml of dichloromethane and stirred for 15 min at room temperature.
- the crystallized crude product is filtered off and recrystallized from 120 ml of methanol with the addition of 2 g of activated carbon.
- the tiotropium bromide obtained is filtered off, washed with cold methanol and dried in vacuo.
- the product is dissolved in 18 ml of water at 90 ° C. and the monohydrate of the tiotropium bromide is crystallized by cooling to 15 ° C.
- the product is filtered off and washed with 5 ml of water and 8 ml of acetone and dried. Yield 6.5 g (34% with respect to Scopinmethobromid).
- Synthscbcispicl 9 17.9 g (165 mmol) of chlorotrimethylsilane are added dropwise at 0 ° C. to a solution of 39.3 g (150 mmol) of sodium dithienylglycolate in 117 ml of tetrahydrofuran.
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- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Inorganic Compounds Of Heavy Metals (AREA)
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Abstract
Description
Claims
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2007528841A JP5173421B2 (ja) | 2004-08-26 | 2005-08-23 | チオトロピウム塩の新規な製造方法 |
KR1020077006836A KR101274455B1 (ko) | 2004-08-26 | 2005-08-23 | 티오트로퓸 염의 신규한 제조방법 |
CA2573373A CA2573373C (en) | 2004-08-26 | 2005-08-23 | Method for producing tiotropium salts and silicon derivatives as intermediates |
NZ553840A NZ553840A (en) | 2004-08-26 | 2005-08-23 | Novel method for producing tiotropium salts |
AU2005276432A AU2005276432B2 (en) | 2004-08-26 | 2005-08-23 | Method for producing tiotropium salts and silicon derivatives as intermediates |
BRPI0514643-7A BRPI0514643A (pt) | 2004-08-26 | 2005-08-23 | processo para a produção de sais de tiotrópio |
EP05801688A EP1794158A2 (de) | 2004-08-26 | 2005-08-23 | Verfahren zur herstellung von tiotropiumsalzen und silicium-derivate als zwischenprodukte |
IL181522A IL181522A (en) | 2004-08-26 | 2007-02-22 | Method for producing tiotropium salts |
IL213717A IL213717A0 (en) | 2004-08-26 | 2011-06-22 | Novel method for producing tiotropium salts |
IL213720A IL213720A (en) | 2004-08-26 | 2011-06-22 | Tiotropium salts |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE102004041253.7 | 2004-08-26 | ||
DE102004041253A DE102004041253A1 (de) | 2004-08-26 | 2004-08-26 | Neues Verfahren zur Herstellung von Tiotropiumsalzen |
Publications (3)
Publication Number | Publication Date |
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WO2006021559A2 true WO2006021559A2 (de) | 2006-03-02 |
WO2006021559A3 WO2006021559A3 (de) | 2006-08-17 |
WO2006021559A8 WO2006021559A8 (de) | 2006-11-16 |
Family
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Application Number | Title | Priority Date | Filing Date |
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PCT/EP2005/054131 WO2006021559A2 (de) | 2004-08-26 | 2005-08-23 | Verfahren zur herstellung von tiotropiumsalzen und silicium-derivate als zwischenprodukte |
Country Status (16)
Country | Link |
---|---|
US (2) | US7491824B2 (de) |
EP (1) | EP1794158A2 (de) |
JP (1) | JP5173421B2 (de) |
KR (1) | KR101274455B1 (de) |
CN (1) | CN100532382C (de) |
AR (1) | AR050714A1 (de) |
AU (1) | AU2005276432B2 (de) |
BR (1) | BRPI0514643A (de) |
CA (1) | CA2573373C (de) |
DE (1) | DE102004041253A1 (de) |
IL (3) | IL181522A (de) |
NZ (1) | NZ553840A (de) |
RU (1) | RU2384575C2 (de) |
TW (2) | TWI387595B (de) |
WO (1) | WO2006021559A2 (de) |
ZA (1) | ZA200610503B (de) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007012626A2 (de) * | 2005-07-27 | 2007-02-01 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neues verfahren zur herstellung von tiotropiumsalzen |
WO2012026906A1 (en) * | 2010-08-25 | 2012-03-01 | Mahmut Bilgic | New tiotropium bromide crystal and its production method |
US9707375B2 (en) | 2011-03-14 | 2017-07-18 | Rochester Medical Corporation, a subsidiary of C. R. Bard, Inc. | Catheter grip and method |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2544357A1 (en) * | 2003-11-03 | 2005-05-12 | Boehringer Ingelheim International Gmbh | Tiotropium salts, methods for the production thereof, and pharmaceutical formulations containing the same |
KR20060117334A (ko) * | 2003-11-03 | 2006-11-16 | 베링거 인겔하임 인터내셔날 게엠베하 | 티오트로피움 염의 제조방법, 티오트로피움 염 및 이를함유하는 약제학적 조성물 |
WO2006117299A2 (en) * | 2005-05-02 | 2006-11-09 | Boehringer Ingelheim International Gmbh | Novel crystalline forms of tiotropium bromide |
KR20080024532A (ko) * | 2005-06-15 | 2008-03-18 | 베링거 인겔하임 인터내셔날 게엠베하 | 신규한 티오트로퓸 염의 제조방법, 신규한 티오트로퓸 염및 이의 약제학적 조성물 |
US20080051582A1 (en) * | 2006-07-10 | 2008-02-28 | Sicor Inc. | Process for the preparation of tiotropium bromide |
ITRM20110508A1 (it) | 2011-09-27 | 2013-03-28 | Lusochimica Spa | Processo per la preparazione degli esteri della scopina. |
US8680297B2 (en) | 2011-10-06 | 2014-03-25 | Drug Process Licensing Assoc., LLC | Manufacturing process for tiotropium bromide |
CZ304808B6 (cs) | 2012-03-16 | 2014-11-05 | Zentiva, K.S. | Způsob přípravy skopinesteru kyseliny di(2-thienyl)glykolové, intermediátu v syntéze tiotropium bromidu a jeho nová forma |
CZ305012B6 (cs) | 2012-03-30 | 2015-03-25 | Zentiva, K.S. | Způsob přípravy skopinesteru kyseliny di(2-thienyl)glykolové, intermediátu v syntéze tiotropium bromidu |
JP6473738B2 (ja) | 2013-04-01 | 2019-02-20 | パルマトリックス,インコーポレイテッド | チオトロピウム乾燥粉末 |
WO2019129801A1 (en) | 2017-12-28 | 2019-07-04 | Linnea S.A. | Process for the purification of methyl-2,2-dithienylglycolate |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2003057694A1 (de) * | 2002-01-12 | 2003-07-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verfahren zur herstellung von scopinestern |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU591299B2 (en) * | 1986-06-27 | 1989-11-30 | Marion Laboratories, Inc. | 1,7-substituted heptyne-2-ones |
DE4108393A1 (de) * | 1991-03-15 | 1992-09-17 | Boehringer Ingelheim Kg | Neue ester bi- und tricyclischer aminoalkohole, ihre herstellung und ihre verwendung in arzneimitteln |
US5554120A (en) * | 1994-07-25 | 1996-09-10 | Advanced Cardiovascular Systems, Inc. | Polymer blends for use in making medical devices including catheters and balloons for dilatation catheters |
-
2004
- 2004-08-26 DE DE102004041253A patent/DE102004041253A1/de not_active Withdrawn
-
2005
- 2005-08-23 WO PCT/EP2005/054131 patent/WO2006021559A2/de active Application Filing
- 2005-08-23 EP EP05801688A patent/EP1794158A2/de not_active Ceased
- 2005-08-23 KR KR1020077006836A patent/KR101274455B1/ko not_active IP Right Cessation
- 2005-08-23 BR BRPI0514643-7A patent/BRPI0514643A/pt not_active Application Discontinuation
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- 2005-08-25 TW TW094129119A patent/TWI387595B/zh not_active IP Right Cessation
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- 2005-08-26 AR ARP050103567A patent/AR050714A1/es unknown
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WO2003057694A1 (de) * | 2002-01-12 | 2003-07-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verfahren zur herstellung von scopinestern |
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MONTSERRAT CARBALLIDO, LUIS CASTEDO, CONCEPCIÓN GONZÁLEZ-BELLO: "Synthesis of Amino Carba Sugars and Conformationally Restricted Polyhydroxy -Amino Acids from (-)-Quinic Acid" EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Nr. 17, 17. August 2004 (2004-08-17), Seiten 3663-3668, XP002374123 * |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007012626A2 (de) * | 2005-07-27 | 2007-02-01 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neues verfahren zur herstellung von tiotropiumsalzen |
JP2009507769A (ja) * | 2005-07-27 | 2009-02-26 | ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト | チオトロピウム塩の新規な製造方法 |
WO2007012626A3 (de) * | 2005-07-27 | 2010-05-06 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neues verfahren zur herstellung von tiotropiumsalzen |
EA014271B1 (ru) * | 2005-07-27 | 2010-10-29 | Бёрингер Ингельхайм Фарма Гмбх Унд Ко. Кг | Новый способ получения солей тиотропия |
EP3153512A1 (de) * | 2005-07-27 | 2017-04-12 | Boehringer Ingelheim Pharma GmbH & Co. KG | Neues verfahren zur herstellung von tiotropiumsalzen |
WO2012026906A1 (en) * | 2010-08-25 | 2012-03-01 | Mahmut Bilgic | New tiotropium bromide crystal and its production method |
US9707375B2 (en) | 2011-03-14 | 2017-07-18 | Rochester Medical Corporation, a subsidiary of C. R. Bard, Inc. | Catheter grip and method |
Also Published As
Publication number | Publication date |
---|---|
JP5173421B2 (ja) | 2013-04-03 |
CN101001855A (zh) | 2007-07-18 |
IL213720A0 (en) | 2011-07-31 |
IL181522A0 (en) | 2007-07-04 |
CA2573373C (en) | 2014-05-06 |
TWI429646B (zh) | 2014-03-11 |
US7491824B2 (en) | 2009-02-17 |
DE102004041253A1 (de) | 2006-03-02 |
AU2005276432A1 (en) | 2006-03-02 |
RU2007110951A (ru) | 2008-10-10 |
US8008495B2 (en) | 2011-08-30 |
US20090118511A1 (en) | 2009-05-07 |
KR101274455B1 (ko) | 2013-06-18 |
RU2384575C2 (ru) | 2010-03-20 |
IL213720A (en) | 2012-03-29 |
IL181522A (en) | 2011-08-31 |
TW201231466A (en) | 2012-08-01 |
IL213717A0 (en) | 2011-07-31 |
WO2006021559A8 (de) | 2006-11-16 |
ZA200610503B (en) | 2008-09-25 |
US20060047120A1 (en) | 2006-03-02 |
AU2005276432B2 (en) | 2011-11-10 |
CN100532382C (zh) | 2009-08-26 |
CA2573373A1 (en) | 2006-03-02 |
TW200617006A (en) | 2006-06-01 |
KR20070046196A (ko) | 2007-05-02 |
JP2008510774A (ja) | 2008-04-10 |
EP1794158A2 (de) | 2007-06-13 |
BRPI0514643A (pt) | 2008-06-17 |
WO2006021559A3 (de) | 2006-08-17 |
AR050714A1 (es) | 2006-11-15 |
NZ553840A (en) | 2010-06-25 |
TWI387595B (zh) | 2013-03-01 |
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