CN1444579A - 用作镇咳药的2,2－二取代的1,3－二氧环戊烷 - Google Patents
用作镇咳药的2,2－二取代的1,3－二氧环戊烷 Download PDFInfo
- Publication number
- CN1444579A CN1444579A CN01813457A CN01813457A CN1444579A CN 1444579 A CN1444579 A CN 1444579A CN 01813457 A CN01813457 A CN 01813457A CN 01813457 A CN01813457 A CN 01813457A CN 1444579 A CN1444579 A CN 1444579A
- Authority
- CN
- China
- Prior art keywords
- phenyl
- compound
- glycol
- expression
- piperazine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000003434 antitussive agent Substances 0.000 title 1
- 229940124584 antitussives Drugs 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 14
- 230000003287 optical effect Effects 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 26
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 claims description 11
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 claims description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 229910052705 radium Inorganic materials 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- -1 sulphur ester Chemical class 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- NLEYJUPWYFIWBV-UHFFFAOYSA-N 3-(1,3-dioxolan-2-yl)propane-1,2-diol Chemical class OCC(O)CC1OCCO1 NLEYJUPWYFIWBV-UHFFFAOYSA-N 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- 239000005864 Sulphur Substances 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 125000002837 carbocyclic group Chemical group 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims 1
- 150000003839 salts Chemical class 0.000 abstract description 10
- PTVWPYVOOKLBCG-UHFFFAOYSA-N 3-(4-phenyl-1-piperazinyl)propane-1,2-diol Chemical compound C1CN(CC(O)CO)CCN1C1=CC=CC=C1 PTVWPYVOOKLBCG-UHFFFAOYSA-N 0.000 abstract description 4
- 239000000543 intermediate Substances 0.000 abstract description 3
- PTVWPYVOOKLBCG-ZDUSSCGKSA-N levodropropizine Chemical compound C1CN(C[C@H](O)CO)CCN1C1=CC=CC=C1 PTVWPYVOOKLBCG-ZDUSSCGKSA-N 0.000 abstract description 3
- 229960002265 levodropropizine Drugs 0.000 abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N methyl alcohol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 13
- 239000000243 solution Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
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- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000004862 dioxolanes Chemical class 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 238000006386 neutralization reaction Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 206010011224 Cough Diseases 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 2
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
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- 235000011187 glycerol Nutrition 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229960002510 mandelic acid Drugs 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000007069 methylation reaction Methods 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
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- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000003252 repetitive effect Effects 0.000 description 2
- 238000005201 scrubbing Methods 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- MIOPJNTWMNEORI-XVKPBYJWSA-N (R)-camphorsulfonic acid Chemical compound C1C[C@]2(CS(O)(=O)=O)C(=O)C[C@H]1C2(C)C MIOPJNTWMNEORI-XVKPBYJWSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical class C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- 125000006091 1,3-dioxolane group Chemical class 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- IUDNGVFSUHFMCF-UHFFFAOYSA-N 4-(chloromethyl)-1,3-dioxolane Chemical class ClCC1COCO1 IUDNGVFSUHFMCF-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- QBZODDIRPJEEQW-UHFFFAOYSA-N Cl.OCC(O)CN1CCN(CC1)c1ccccc1 Chemical compound Cl.OCC(O)CN1CCN(CC1)c1ccccc1 QBZODDIRPJEEQW-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-LWMBPPNESA-L D-tartrate(2-) Chemical compound [O-]C(=O)[C@@H](O)[C@H](O)C([O-])=O FEWJPZIEWOKRBE-LWMBPPNESA-L 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 description 1
- 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 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 238000006359 acetalization reaction Methods 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229910001508 alkali metal halide Inorganic materials 0.000 description 1
- 229910001615 alkaline earth metal halide Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- 239000012455 biphasic mixture Substances 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- GKIPXFAANLTWBM-UHFFFAOYSA-N epibromohydrin Chemical compound BrCC1CO1 GKIPXFAANLTWBM-UHFFFAOYSA-N 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 229940116298 l- malic acid Drugs 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical group O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- 230000021962 pH elevation Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000009283 thermal hydrolysis Methods 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/28—Radicals substituted by nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61P11/14—Antitussive agents
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
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Abstract
本发明叙述了(±)3－(4－苯基－1－哌嗪基)－1，2－丙二醇环缩醛类、它们光学拆分法、以及其用作制备(－)3－(4－苯基－1－哌嗪基)－1，2－丙二醇(左羟丙哌嗪)及其盐类的中间体。
Description
技术领域
本发明涉及(±)3-(4-苯基-1-哌嗪基)-1，2-丙二醇环缩醛类、它们的光学拆分法以及其用作为制备(-)3-(4-苯基-1-哌嗪基)-1，2-丙二醇(左羟丙哌嗪)及其盐类的中间体。
发明内容
更准确地说，本发明涉及以一般式(1)表示的(±)2，2-取代的1，3-二氧环戊烷：
式中：
每个Ra和Rb可以相同或不同，表示氢、C1-C6烷基、苯基，或
Ra和Rb与它们连接的碳原子一起形成可选择性取代的4至7个原子数的碳环。
在以一般式(1)表示的本发明的化合物中，Ra和Rb优选为含有少于6个碳原子的烷基。Ra和Rb优选相同；Ra和Rb更优选为甲基或乙基或者，与它们连接的碳原子一起形成含有5至6个碳原子的环。
本发明还涉及以一般式(1)表示的2，2-取代的1，3-二氧环戊烷的纯对映体一价盐，其含有药学上可接受的手性酸，如L-苹果酸、D-酒石酸和L-酒石酸、D-扁桃酸和L-扁桃酸、L-樟脑磺酸和D-樟脑磺酸。
本发明特别优选的化合物是：
(±)1，2-亚环戊基-3-(4-苯基-哌嗪-1-基)-丙-1，2-二醇；
(±)1，2-亚环己基-3-(4-苯基哌嗪-1-基)-丙-1，2-二醇；
(±)1，2-(2-亚丙基)-3-(4-苯基-哌嗪-1-基)-丙-1，2-二醇；
(±)1，2-(3-亚戊基)-3-(4-苯基-哌嗪-1-基)-丙-1，2-二醇；
S(-)-1，2-亚环己基-3-(4-苯基哌嗪-1-基)-丙-1，2-二醇L-酒石酸盐；
S(-)-1，2-亚环戊基-3-(4-苯基哌嗪-1-基)-丙-1，2-二醇L-酒石酸盐。
以一般式(1)表示的本发明的化合物是以苯基哌嗪与以一般式(2)表示的(±)1，2-甘油基-二氧环戊烷反应而制成：
式中：X选自由氯、溴、碘及适当磺酯(R-SO3-)组成的组，其中R选自由C1-C3烷基(优选为甲基)、三氟甲基、苯基、对甲苯基及对甲氧苯基组成的组。
以一般式(2)表示的二氧环戊烷为已知化合物和/或可按已知方法制备。
以一般式(2)(X＝R-SO3-)表示的磺酯是用酸酐或用一般式(3)表示的烷基和/或芳基磺酰氯与以一般式(4)表示的(±)2，2-取代的1，3-二氧环戊烷-4-甲醇经酯化作用而制备：
R-SO3H (3)式中：Ra和Rb的定义同上所述。
以一般式(4)表示的化合物为已知化合物。事实上，以一般式(4)表示的外消旋物已经用作发酵拆分法的底物[美国专利US5,190,867(02.03.1993)]。在Org.Synth.Coll.Vol III的一文中叙述了以甘油为原料制备消旋-异亚丙基甘油。
以一般式(2)表示的4-卤甲基-二氧环戊烷，式中X是氯、溴或碘，可以用一般式(2)表示的相应磺酸盐(X＝RSO3-，其中的R同上所述)为原料，通过在惰性溶剂中与碱或碱土金属卤化物反应而制成，而惰性溶剂选自由丙酮、甲乙酮、四氢呋喃、二恶烷、二甲基亚砜、乙腈、C1-C4醇及它们的混合物组成的组。所述化合物的优选合成方法包括如欧洲专利EP0930311(21.07.1999)所述那样，使相应的3-卤-1，2-丙二醇进行二氧环戊烷化反应。特别优选为3-氯-丙-1，2二醇；优选缩醛剂是甲醛、乙醛和苯甲醛、丙酮、二乙酮、二苯甲酮、环己酮、缩醛和/或其烯醇酯，如2，2-二甲氧丙烷、2，2-二甲氧乙烷、2-甲氧基-丙烯。
此外，以一般式(2)(X为氯或溴)表示的二氧环戊烷也可以按照法国专利FR1522153或Blicke FF等人在J.A.C.S(74：1735页，1972年及76：1226页，1954年)所述制备(+)2-氯甲基-1，4-二螺[4，5]-癸烷的方法，以表氯醇或表溴醇与环烷酮进行缩醛作用而制成。
在用于把仲胺转化成叔胺的常规反应条件下，每摩尔以一般式(2)表示的烷基化剂配至少1摩尔或稍稍过量的苯基哌嗪，在至少1摩尔中和碱的存在下使苯基哌嗪与以一般式(2)表示的1，2-甘油基-二氧环戊烷进行烷基化反应。使用的中和碱与以一般式(2)表示的烷基化剂至少等摩尔量，并选自由磨细的无机碱，如碱或碱土金属(钠、钾、镁、钙)的碳酸盐或碳酸氢盐或钙或镁的氧化物，或叔胺，如三乙胺、二甲苯胺或二乙苯胺，芳香胺，如吡啶、甲基吡啶和可力丁，以及若有需要，苯基哌嗪本身组成的组，而苯基哌嗪可在以后再循环进入后续生产循环。
甲基化反应可在加热，选择性地可在诸如甲苯或二甲苯等惰性溶剂中进行，当反应在溶剂回流的条件下进行时，有利于缩短反应时间。
甲基化反应完成后，过滤或通过离心去掉任何不溶性物质，然后用水反复洗涤有机相直至容易除去杂质和副产物，蒸发掉溶剂，得到高产率残余物，其由以一般式(1)表示的基本纯1，3-二氧环戊烷组成，通过直接结晶或与1摩尔等量的羧酸进行成盐作用都可以回收该化合物。
化合物(1)及其盐均很容易从常规溶剂结晶析出：因此，本发明的方法使由于微量缩水甘油和/或表卤代醇以潜在杂质存在的污染危险减至最小。
以一般式(1)表示的化合物的一价盐可通过常规方法制备，如以等分子量所需要的酸在一适当溶剂中进行成盐作用，然后通过结晶析出所生成的盐。
业已发现，化合物(1)与手性酸，特别是与酒石酸的成盐作用是一种高产率回收化合物(1)的S-对映体的有效光学拆分法。
所述(S)(-)对映体及其盐用作镇咳药或者作为以一般式(1)表示的(-)1，3-二氧环戊烷的水溶液进行热水解反应合成(-)3-(4-苯基-1-哌嗪基)-丙-1，2-二醇(左羟丙哌嗪)的中间体，过量1摩尔无机酸，如盐酸，或羧酸，如乙酸、丙二酸或柠檬酸的稀释水溶液可加快水解反应的进行。
具体实施方式
以下，结合实施例对本发明作进一步说明。实施例1
边强烈搅拌边向11.98g(±)2，3-氧-(3-亚戊基)-甘油甲苯磺酸盐的正丁醇溶液(70ml)中加入4.5g磨细的碳酸钠，再加入6ml苯基哌嗪。混合物在搅拌条件下回流，并在回流温度下反应20小时。然后，在减压下蒸发掉正丁醇，用水使残余物溶解，用乙酸乙酯反复萃取。干燥和过滤混合有机相，再在真空条件下蒸发溶剂，将所得的残余物在含水甲醇中结晶析出，得到8.95g(±)1，2-(3-亚戊基)-3-(4-苯基-哌嗪-1-基)-丙-1，2-二醇，也称为4-苯基哌嗪、1-(2，2-二乙基-1，3-二氧环戊烷-4-基-甲基)。实施例2
按实施例1所述步骤，用(±)2，3-氧-(2-亚丙基)-甘油甲苯磺酸盐制成(±)1，2-(2-亚丙基)-3-(4-苯基-哌嗪-1-基)-丙-1，2-二醇，也称为4-苯基哌嗪、1-(2，2-二甲基-1，3-二氧环戊烷-4-基-甲基)。实施例3
在惰性气氛中，向3.28g(±)1，4-二螺-[4，5]癸烷-2-氯甲烷的甲苯溶液(16mL)加入5.45ml苯基哌嗪。然后，使反应混合物回流直至反应完成(约8小时)。将反应混合物冷却至大约50℃，加入10ml水，强烈搅拌至少10分钟。分离有机相和水相，并用水反复洗涤有机相。蒸发掉溶剂，得到溶解在加热异丙醇的粘稠油品(15mL)。所得溶液缓慢地冷却，分离出结晶固体，即(±)1，2-亚环己基-3-(4-苯基哌嗪-1-基)-丙-1，2-二醇。
1H-NMRδ7.26(t，2H，J＝7.4Hz)；δ6.95(d，2H，J＝8.9Hz)；δ6.85(t，1H，J＝7.28Hz)；δ4.3(m，1H，J＝6.1Hz)；δ4.1(dd，1H，J1＝8.0Hz，J2＝6.1Hz)；δ3.65(dd，1H，J1＝8.0，J2＝7.1Hz)；δ3.2(t，4H，J＝5.05Hz)；δ2.9÷2.55(m，6H)；δ1.7÷1.3(m，10H)。实施例4
按实施例1和3所述步骤，以1，3-二氧环戊烷，其选自下列组成的组：
(±)1，4-二螺-[4，4]壬烷-2-甲醇，甲磺酸盐；
(±)1，4-二螺-[4，4]壬烷-2-氯甲基；
(±)1，4-二螺-[4，5]癸烷-2-甲醇，三氟甲磺酸盐；
(±)1，4-二螺-[4，5]癸烷-2-甲醇，甲磺酸盐；
(±)1，3-二氧环戊烷-4-氯甲基-2，2-二甲基；
(±)1，3-二氧环戊烷-4-溴-甲基-2，2-二甲基；
与苯基哌嗪反应，生成下列化合物：
(±)1，2-亚环戊基-3-(4-苯基-哌嗪-1-基)-丙-1，2-二醇；
(±)1，2-亚环己基-3-(4-苯基-哌嗪-1-基)-丙-1，2-二醇；
(±)1，2-(2-亚丙基)-3-(4-苯基-哌嗪-1-基)-丙-1，2-二醇。实施例5
边搅拌边向(±)1，2-亚环己基-3-(4-苯基-哌嗪-1-基)-丙-1，2-二醇(6.32g)的无水乙醇溶液(70ml)加入3g酒石酸。混合物搅拌至完全溶解，然后，冷却至5-8℃。得到4.05g结晶固体，将所得结晶固体在无水乙醇中再结晶，得到3.82g S(-)-1，2-亚环己基-3-(4-苯基-哌嗪-1-基)丙-1，2-二醇L-酒石酸盐，熔点为131-132℃，[α]D＝-9.6°(c＝3％；甲醇)；
1H-NMRδ7.5(dd，2H，J1＝8.7，J2＝7.3)；δ7.2(m，3H)；δ4.8(m，1H)；δ4.4(s，2H)；δ4.35(dd，1H，J1＝8.9Hz，J2＝6.7Hz)；δ3.86(dd，1H，J1＝8.9Hz，J2＝5.8Hz)；δ3.6-3.4(m，10H)；δ1.8-1.48(m，10H)。实施例6
向2.4g S(-)-1，2-亚环己基-3-(4-苯基-哌嗪-1-基)丙-1，2-二醇L-酒石酸盐的水溶液加入2N氢氧化钠，进行碱化作用(pH＝8.5)，然后用乙酸乙酯完全萃取。用10％磷酸氢钠溶液洗涤混合有机相，以硫酸钠干燥，并使其蒸干，再在异丙醇中结晶析出，得到1.52g S(-)-1，2-亚环己基-3-(4-苯基-哌嗪-1-基)丙-1，2-二醇，熔点为63-64℃，[α]D＝-7.8°(1％甲醇)。
1H-NMRδ7.26(t，2H，J＝7.4Hz)；δ6.95(d，2H，J＝8.9Hz)；δ6.85(t，1H，J＝7.28Hz)；δ4.3(m，1H，J＝6.1Hz)；δ4.1(dd，1H，J1＝8.0Hz，J2＝7.1Hz)；δ3.65(dd，1H，J1＝8.0，J2＝7.1Hz)；δ3.2(t，4H，J＝5.05Hz)；δ2.9÷2.55(m，6H)；δ1.7÷1.3(m，10H)。实施例7
按实施例1至4的方法，使1，3-二氧环戊烷与L-酒石酸进行成盐反应，并把所得的盐分级再结晶，生成下列化合物：
S(-)-1，2-亚环戊基-3-(4-苯基-哌嗪-1-基)-丙-1，2-二醇，L-酒石酸盐；
S(-)-1，2-(2-亚丙基)-3-(4-苯基-哌嗪-1-基)-丙-1，2-二醇，L-酒石酸盐；
S(-)-1，2-(3-亚戊基)-3-(4-苯基-哌嗪-1-基)-丙-1，2-二醇，L-酒石酸盐；
随后按照实施例6的方法中和这些化合物，得到相应的游离碱。实施例8
使70ml含水乙酸(10％重量/体积)与2.8g S(-)-1，2-亚环戊基-3-(4-苯基-哌嗪-1-基)-丙-1，2-二醇的悬浮液回流2小时，使悬浮液中的蒸气冒泡，馏出环戊酮，从而达到分离的目的。加入10％氢氧化钠溶液使水相中和至pH值等于7.5，然后冷却至5-10℃，得到1.97g(-)3-(4-苯基-哌嗪-1-基)-丙二醇，熔点为102-103℃，[α]D＝-23.5°(2.8％二氯甲烷)。实施例9
另外，边搅拌边把0.35摩尔当量的实施例6和7所述其中一种1，3-二氧环戊烷衍生物：S(-)1，2-(2-亚丙基)-3-(4-苯基-哌嗪-1-基)-丙-1，2-二醇、S(-)1，2-亚环戊基-3-(4-苯基-哌嗪-1-基)-丙-1，2-二醇、S(-)-1，2-亚环己基-3-(4-苯基-哌嗪-1-基)丙-1，2-二醇，分批加到45ml水中含有36％盐酸(36ml)的溶液中；悬浮液加热至80℃，得到澄清溶液，在该温度再保持30分钟，然后冷却至20-25℃，用二氯甲烷(3×15ml)反复萃取水相，再加入正丁醇(0.5l)。使二相混合物回流，蒸馏出水和正丁醇共沸物，回收大约300ml馏出液，然后冷却以加快(-)3-(4-苯基-哌嗪-1-基)-丙二醇氢氯化物的结晶析出(85g)。
使125ml氢氯化物的水溶液在50℃加热15分钟，并用活性炭(2.2g)脱色，过滤后，再加入氢氧化铵水溶液(30％重量/重量)中和。迅速加热至50℃之后，加入(-)3-(4-苯基-哌嗪-1-基)-丙二醇晶体，溶液就开始结晶。同时，让悬浮液自身冷却，在+2-+4℃保持2小时，最后过滤得到70-72g(-)3-(4-苯基-哌嗪-1-基)-1，2-丙二醇。
Claims (8)
1.以一般式(1)表示的化合物，其特征在于：一般式(1)表示如下
式中，每个Ra和Rb可以相同或不同，表示氢、C1-C6烷基、苯基，或Ra和
Rb与它们连接的碳原子一起形成可选择性取代的4至7个原子的碳环。
2.如权利要求1所述的化合物，其特征在于：Ra和Rb相同。
3.如权利要求1或2所述的化合物，其特征在于：Ra和Rb是甲基或乙基。
4.如权利要求1所述的化合物，其特征在于：所述化合物选自以下化合物：
(±)1，2-亚环戊基-3-(4-苯基-哌嗪-1-基)-丙-1，2-二醇；
(±)1，2-亚环己基-3-(4-苯基-哌嗪-1-基)-丙-1，2-二醇；
(±)1，2-(2-亚丙基)-3-(4-苯基-哌嗪-1-基)-丙-1，2-二醇；
(±)1，2-(3-亚戊基)-3-(4-苯基-哌嗪-1-基)-丙-1，2-二醇；
S(-)-1，2-亚环己基-3-(4-苯基-哌嗪-1-基)-丙-1，2-二醇L-酒石酸盐；
S(-)-1，2-亚环戊基-3-(4-苯基-哌嗪-1-基)-丙-1，2-二醇L-酒石酸盐。
5.一种用苯基哌嗪与以一般式(2)表示的(±)1，2-甘油基-二氧环戊烷反应制备以一般式(1)表示的化合物的方法，其特征在于：所述方法中所用以一般式(2)表示的化合物如下式中，X选自由氯、溴、碘及适当磺酯(R-SO3-)组成的组，其中R选自由C1-C3烷基(优选为甲基)、三氟甲基、苯基、对甲苯基及对甲氧苯基组成的组。
6.如权利要求5所述的方法，其特征在于：以甲苯或二甲苯为溶剂在碱的存在下进行反应。
7.一种通过L-酒石酸的成盐作用权利要求1-4所述化合物的光学拆分方法。
8.如权利要求1-4所述化合物作为合成相应(S)对映体的中间体的应用。
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|---|---|
| US (1) | US6916926B2 (zh) |
| EP (1) | EP1307440B1 (zh) |
| JP (1) | JP5015403B2 (zh) |
| KR (1) | KR100788532B1 (zh) |
| CN (1) | CN1216053C (zh) |
| AT (1) | ATE290533T1 (zh) |
| AU (1) | AU2001281992A1 (zh) |
| BR (1) | BR0112802A (zh) |
| CZ (1) | CZ301039B6 (zh) |
| DE (1) | DE60109299T2 (zh) |
| EE (1) | EE05159B1 (zh) |
| ES (1) | ES2237589T3 (zh) |
| HK (1) | HK1058798A1 (zh) |
| HU (1) | HU229801B1 (zh) |
| IL (2) | IL153502A0 (zh) |
| IT (1) | IT1318651B1 (zh) |
| MX (1) | MXPA02012922A (zh) |
| PL (1) | PL206308B1 (zh) |
| PT (1) | PT1307440E (zh) |
| RS (1) | RS50862B (zh) |
| RU (1) | RU2269522C2 (zh) |
| SI (1) | SI21041B (zh) |
| SK (1) | SK286795B6 (zh) |
| UA (1) | UA73790C2 (zh) |
| WO (1) | WO2002010150A1 (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1318650B1 (it) * | 2000-07-28 | 2003-08-27 | Dompe Spa | 1,3-diossolani ad attivita' antitosse. |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4049660A (en) * | 1971-06-18 | 1977-09-20 | Delalande S.A. | N-substituted derivatives of 4 (N-piperazinylmethyl) spiro dibenzocycloheptadi- (or tri-) ene-5, 2-dioxolane (1,3) their method of preparation and their application in therapeutics |
| IT1210639B (it) * | 1981-02-25 | 1989-09-14 | Menarini Sas | Prodotto: 3(4-fenil1piperazinio-1-il)-1,2-propandiolo 3(teofillin-7-il)-1propansolfonato,utilizzabile in terapia,e relativo procedimento di fabbricazione |
| IT1203721B (it) * | 1983-12-29 | 1989-02-23 | Dompe Farmaceutici Spa | Composti otticamente attivi ad attivita' antitosse e sedativa centrale,procedimento per la preparazione e composizioni che li contengono |
| SE449516B (sv) * | 1984-10-16 | 1987-05-04 | Skf Nova Ab | Klemring med reglerbar halomkrets |
| IT1254452B (it) * | 1992-02-14 | 1995-09-25 | Dompe Farmaceutici Spa | N-ossidi ed n,n'-diossidi di 3-(piperazin-1-il)-propan-1,2-dioli |
| IL111730A (en) * | 1993-11-29 | 1998-12-06 | Fujisawa Pharmaceutical Co | Piperazine derivatives, processes for their preparation and pharmaceutical preparations containing them |
| IT1318650B1 (it) * | 2000-07-28 | 2003-08-27 | Dompe Spa | 1,3-diossolani ad attivita' antitosse. |
-
2000
- 2000-07-28 IT IT2000MI001735A patent/IT1318651B1/it active
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2001
- 2001-07-18 UA UA2003021768A patent/UA73790C2/uk unknown
- 2001-07-18 MX MXPA02012922A patent/MXPA02012922A/es active IP Right Grant
- 2001-07-18 US US10/312,290 patent/US6916926B2/en not_active Expired - Fee Related
- 2001-07-18 BR BR0112802-7A patent/BR0112802A/pt not_active Application Discontinuation
- 2001-07-18 AU AU2001281992A patent/AU2001281992A1/en not_active Abandoned
- 2001-07-18 SI SI200120037A patent/SI21041B/sl not_active IP Right Cessation
- 2001-07-18 HU HU0301473A patent/HU229801B1/hu not_active IP Right Cessation
- 2001-07-18 PL PL361173A patent/PL206308B1/pl unknown
- 2001-07-18 CZ CZ20030269A patent/CZ301039B6/cs not_active IP Right Cessation
- 2001-07-18 RU RU2003105692/04A patent/RU2269522C2/ru not_active IP Right Cessation
- 2001-07-18 KR KR1020037000943A patent/KR100788532B1/ko not_active IP Right Cessation
- 2001-07-18 CN CN018134572A patent/CN1216053C/zh not_active Expired - Fee Related
- 2001-07-18 EP EP01960513A patent/EP1307440B1/en not_active Expired - Lifetime
- 2001-07-18 SK SK90-2003A patent/SK286795B6/sk not_active IP Right Cessation
- 2001-07-18 AT AT01960513T patent/ATE290533T1/de active
- 2001-07-18 RS YUP-31/03A patent/RS50862B/sr unknown
- 2001-07-18 IL IL15350201A patent/IL153502A0/xx active IP Right Grant
- 2001-07-18 EE EEP200300035A patent/EE05159B1/xx not_active IP Right Cessation
- 2001-07-18 JP JP2002515881A patent/JP5015403B2/ja not_active Expired - Fee Related
- 2001-07-18 PT PT01960513T patent/PT1307440E/pt unknown
- 2001-07-18 ES ES01960513T patent/ES2237589T3/es not_active Expired - Lifetime
- 2001-07-18 DE DE60109299T patent/DE60109299T2/de not_active Expired - Lifetime
- 2001-07-18 WO PCT/EP2001/008305 patent/WO2002010150A1/en active IP Right Grant
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2002
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