CN1861598A - 噻托溴铵无水物制备方法 - Google Patents
噻托溴铵无水物制备方法 Download PDFInfo
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- CN1861598A CN1861598A CN 200610054866 CN200610054866A CN1861598A CN 1861598 A CN1861598 A CN 1861598A CN 200610054866 CN200610054866 CN 200610054866 CN 200610054866 A CN200610054866 A CN 200610054866A CN 1861598 A CN1861598 A CN 1861598A
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- China
- Prior art keywords
- anhydrous
- solution
- preparation process
- anhydrous compound
- thiatro bromoaminium
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- 150000001875 compounds Chemical class 0.000 title claims description 24
- FNXLCIKXHOPCKH-UHFFFAOYSA-N bromamine Chemical compound BrN FNXLCIKXHOPCKH-UHFFFAOYSA-N 0.000 title claims description 20
- 238000002360 preparation method Methods 0.000 title claims description 18
- 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 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 15
- 229960000257 tiotropium bromide Drugs 0.000 claims abstract description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 26
- 239000000243 solution Substances 0.000 claims description 26
- 239000000047 product Substances 0.000 claims description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 238000001953 recrystallisation Methods 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- -1 filter Substances 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 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 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- 229960004499 scopolamine hydrobromide Drugs 0.000 claims description 6
- WTGQALLALWYDJH-MOUKNHLCSA-N scopolamine hydrobromide (anhydrous) Chemical compound Br.C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 WTGQALLALWYDJH-MOUKNHLCSA-N 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 4
- TUCRZHGAIRVWTI-UHFFFAOYSA-N 2-bromothiophene Chemical compound BrC1=CC=CS1 TUCRZHGAIRVWTI-UHFFFAOYSA-N 0.000 claims description 3
- FIMXSEMBHGTNKT-UHFFFAOYSA-N Scopine Natural products CN1C2CC(O)CC1C1C2O1 FIMXSEMBHGTNKT-UHFFFAOYSA-N 0.000 claims description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 3
- 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 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- LOMVENUNSWAXEN-UHFFFAOYSA-N Methyl oxalate Chemical compound COC(=O)C(=O)OC LOMVENUNSWAXEN-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- AUALQMFGWLZREY-UHFFFAOYSA-N acetonitrile;methanol Chemical compound OC.CC#N AUALQMFGWLZREY-UHFFFAOYSA-N 0.000 claims description 2
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 230000006837 decompression Effects 0.000 claims description 2
- 238000010790 dilution Methods 0.000 claims description 2
- 239000012895 dilution Substances 0.000 claims description 2
- 239000012065 filter cake Substances 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000010410 layer Substances 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000012044 organic layer Substances 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- 238000005086 pumping Methods 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
- 238000001291 vacuum drying Methods 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 1
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 abstract 1
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 abstract 1
- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 abstract 1
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 abstract 1
- 229960002646 scopolamine Drugs 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 19
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 16
- 229910052799 carbon Inorganic materials 0.000 description 16
- 238000001228 spectrum Methods 0.000 description 16
- 239000000126 substance Substances 0.000 description 16
- 230000008878 coupling Effects 0.000 description 12
- 238000010168 coupling process Methods 0.000 description 12
- 238000005859 coupling reaction Methods 0.000 description 12
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 8
- WHLUQAYNVOGZST-UHFFFAOYSA-N tifenamil Chemical group C=1C=CC=CC=1C(C(=O)SCCN(CC)CC)C1=CC=CC=C1 WHLUQAYNVOGZST-UHFFFAOYSA-N 0.000 description 8
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 6
- 238000003929 heteronuclear multiple quantum coherence Methods 0.000 description 6
- XILIYVSXLSWUAI-UHFFFAOYSA-N 2-(diethylamino)ethyl n'-phenylcarbamimidothioate;dihydrobromide Chemical compound Br.Br.CCN(CC)CCSC(N)=NC1=CC=CC=C1 XILIYVSXLSWUAI-UHFFFAOYSA-N 0.000 description 5
- ZPOLNCDBPYJDSE-UHFFFAOYSA-N 3-[4-[bis(2-chloroethyl)amino]phenyl]-2-formamidopropanoic acid Chemical compound O=CNC(C(=O)O)CC1=CC=C(N(CCCl)CCCl)C=C1 ZPOLNCDBPYJDSE-UHFFFAOYSA-N 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 238000006073 displacement reaction Methods 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 238000005100 correlation spectroscopy Methods 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 239000005864 Sulphur Substances 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 238000003919 heteronuclear multiple bond coherence Methods 0.000 description 3
- 238000001052 heteronuclear multiple bond coherence spectrum Methods 0.000 description 3
- CSJDCSCTVDEHRN-UHFFFAOYSA-N methane;molecular oxygen Chemical compound C.O=O CSJDCSCTVDEHRN-UHFFFAOYSA-N 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 3
- 238000002211 ultraviolet spectrum Methods 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- WYZSHSYANZLLRM-UHFFFAOYSA-N 2-thiophen-2-yloxyacetic acid Chemical compound OC(=O)COC1=CC=CS1 WYZSHSYANZLLRM-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 239000004593 Epoxy Substances 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 241000242847 Scopolia japonica Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000002072 distortionless enhancement with polarization transfer spectrum Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 229910001385 heavy metal Inorganic materials 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 229960001361 ipratropium bromide Drugs 0.000 description 2
- KEWHKYJURDBRMN-ZEODDXGYSA-M ipratropium bromide hydrate Chemical compound O.[Br-].O([C@H]1C[C@H]2CC[C@@H](C1)[N@@+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 KEWHKYJURDBRMN-ZEODDXGYSA-M 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 230000009965 odorless effect Effects 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- STECJAGHUSJQJN-USLFZFAMSA-N LSM-4015 Chemical class C1([C@@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-USLFZFAMSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- GIIZNNXWQWCKIB-UHFFFAOYSA-N Serevent Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1 GIIZNNXWQWCKIB-UHFFFAOYSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 238000002447 crystallographic data Methods 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000119 electrospray ionisation mass spectrum Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
- 229910052939 potassium sulfate Inorganic materials 0.000 description 1
- 235000011151 potassium sulphates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229960004017 salmeterol Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000011003 system suitability test Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229930192474 thiophene Natural products 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
- 230000009466 transformation Effects 0.000 description 1
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- 238000000207 volumetry Methods 0.000 description 1
Images
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
Description
分析项目 | 测定值(%) | 理论值(%) |
C | 48.50 48.37 | 48.30 |
H | 4.74 4.73 | 4.69 |
N | 3.09 3.10 | 2.96 |
S | 13.53 13.48 | 13.55 |
Br | 17.15 16.95 | 16.91 |
溶剂 | λ(nm) | ε(×104) | E | λ(nm) | ε(×104) | E | 归属 |
C2H5OH | 202 | 0.76 | 161.35 | 240 | 1.35 | 285.46 | 双键 |
0.1mol/L HCl | 202 | 1.21 | 257.03 | 238 | 1.33 | 281.03 | 双键 |
0.1mol/L NaOH | 218 | 1.25 | 263.87 | 238 | 1.43 | 303.41 | 双键 |
序号 | δH | 质子数 | 多重性(J/Hz) | COSY(位) |
4 4’ | 1.90 2.67 2.71 | 4 | d t 17.2 5.6 | 4’ 4 |
N(CH3)2 | 3.11 3.28 | 6 | s | |
2 2’ | 3.52 | 2 | s | 3 3’ |
3 3’ | 4.20 4.21 | 2 | 4 4’ | |
5 | 5.16 | 1 | t 5.6 | 4 4’ |
10 10’ | 7.00 | 2 | dd 3.6 4.8 | 9 9’ 11 11’ |
9 9’ | 7.13 | 2 | dd 1.2 3.6 | 10 10’ |
OH | 7.37 | 1 | s | |
11 11’ | 7.50 | 2 | dd 1.2 4.8 | 10 10’ |
序号 | δC | 碳原子数 | DEPT | HMQC(δH) (δC) | HMBC(位) |
4 4’ | 28.42 | 2 | ↓ | 1.90 2.67 2.72-28.42 | |
N(CH3)2 | 47.43 55.69 | 2 | ↑ | 3.11-47.43 3.28-55.69 | |
2 2’ | 53.72 | 2 | ↑ | 3.52-53.71 | |
5 | 63.84 | 1 | ↑ | 5.16-63.83 | |
3 3’ | 64.59 | 2 | ↑ | 4.20 4.21-64.59 | |
7 | 76.44 | 1 | OH | ||
9 9’ | 125.92 | 2 | ↑ | 7.13-125.92 | |
11 11’ | 126.25 | 2 | ↑ | 7.50-126.25 | |
10 10’ | 126.87 | 2 | ↑ | 7.00-126.87 | |
8 8’ | 146.74 | 2 | OH 9 9’ | ||
6 | 169.83 | 1 | OH 5 |
d-value | 2Theta | I/Io |
5.81 | 15.22 | 77 |
5.60 | 15.78 | 50 |
4.86 | 18.21 | 100 |
4.76 | 18.58 | 49 |
4.02 | 22.05 | 72 |
4.13 | 21.45 | 86.0 |
Claims (7)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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CNB2006100548666A CN100410254C (zh) | 2006-03-07 | 2006-03-07 | 噻托溴铵无水物制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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CNB2006100548666A CN100410254C (zh) | 2006-03-07 | 2006-03-07 | 噻托溴铵无水物制备方法 |
Publications (2)
Publication Number | Publication Date |
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CN1861598A true CN1861598A (zh) | 2006-11-15 |
CN100410254C CN100410254C (zh) | 2008-08-13 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CNB2006100548666A Active CN100410254C (zh) | 2006-03-07 | 2006-03-07 | 噻托溴铵无水物制备方法 |
Country Status (1)
Country | Link |
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CN (1) | CN100410254C (zh) |
Cited By (5)
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CN101230063B (zh) * | 2008-02-20 | 2010-06-02 | 南昌弘益科技有限公司 | 噻托溴铵制备方法 |
CN101768158A (zh) * | 2010-01-04 | 2010-07-07 | 南昌弘益科技有限公司 | 噻托溴铵无水物及其制备方法 |
CN101863885A (zh) * | 2010-06-03 | 2010-10-20 | 南京金丹呈医药技术有限公司 | 一种噻托溴铵的制备方法 |
CN102639531A (zh) * | 2009-08-07 | 2012-08-15 | 基因里克斯(英国)有限公司 | 噻托溴铵的无水合物 |
CN114213408A (zh) * | 2021-12-15 | 2022-03-22 | 台州仙琚药业有限公司 | 一种噻托溴铵的制备方法 |
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US5610163A (en) * | 1989-09-16 | 1997-03-11 | Boehringer Ingelheim Gmbh | Esters of thienyl carboxylic acids and amino alcohols and their quaternization products |
DE10064816A1 (de) * | 2000-12-22 | 2002-06-27 | Boehringer Ingelheim Pharma | Verfahren zur Herstellung eines Anticholinergikums |
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CN101230063B (zh) * | 2008-02-20 | 2010-06-02 | 南昌弘益科技有限公司 | 噻托溴铵制备方法 |
CN102639531A (zh) * | 2009-08-07 | 2012-08-15 | 基因里克斯(英国)有限公司 | 噻托溴铵的无水合物 |
AU2010280497B2 (en) * | 2009-08-07 | 2015-10-22 | Generics [Uk] Limited | Anhydrate of tiotropium bromide |
CN102639531B (zh) * | 2009-08-07 | 2016-01-20 | 基因里克斯(英国)有限公司 | 噻托溴铵的无水合物 |
CN101768158A (zh) * | 2010-01-04 | 2010-07-07 | 南昌弘益科技有限公司 | 噻托溴铵无水物及其制备方法 |
CN101863885A (zh) * | 2010-06-03 | 2010-10-20 | 南京金丹呈医药技术有限公司 | 一种噻托溴铵的制备方法 |
CN101863885B (zh) * | 2010-06-03 | 2012-05-30 | 南京金丹呈医药技术有限公司 | 一种噻托溴铵的制备方法 |
CN114213408A (zh) * | 2021-12-15 | 2022-03-22 | 台州仙琚药业有限公司 | 一种噻托溴铵的制备方法 |
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