CN1103335C - 2,5-二取代吡啶的制备方法 - Google Patents
2,5-二取代吡啶的制备方法 Download PDFInfo
- Publication number
- CN1103335C CN1103335C CN98118370A CN98118370A CN1103335C CN 1103335 C CN1103335 C CN 1103335C CN 98118370 A CN98118370 A CN 98118370A CN 98118370 A CN98118370 A CN 98118370A CN 1103335 C CN1103335 C CN 1103335C
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- China
- Prior art keywords
- pyridine
- group
- compound
- propyl
- base
- 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.)
- Expired - Lifetime
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- 238000000034 method Methods 0.000 title claims abstract description 33
- -1 2,5-disubstituted pyridines Chemical class 0.000 title abstract description 15
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- 229910000039 hydrogen halide Inorganic materials 0.000 claims abstract description 6
- 239000012433 hydrogen halide Substances 0.000 claims abstract description 6
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 150000002367 halogens Chemical class 0.000 claims abstract description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 15
- 239000000460 chlorine Substances 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- 239000007789 gas Substances 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- 150000005826 halohydrocarbons Chemical class 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- 150000002825 nitriles Chemical class 0.000 claims description 3
- 150000003222 pyridines Chemical class 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 3
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 18
- 239000002585 base Substances 0.000 description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- 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
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 8
- 239000001301 oxygen Substances 0.000 description 8
- 229910052760 oxygen Inorganic materials 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- 229910052708 sodium Inorganic materials 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- XYDHSCZUHCZWHJ-UHFFFAOYSA-N 5-methylpyridine-2-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)N=C1 XYDHSCZUHCZWHJ-UHFFFAOYSA-N 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- YGHRJJRRZDOVPD-UHFFFAOYSA-N 3-methylbutanal Chemical compound CC(C)CC=O YGHRJJRRZDOVPD-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 210000003038 endothelium Anatomy 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 229940044551 receptor antagonist Drugs 0.000 description 5
- 239000002464 receptor antagonist Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 239000000908 ammonium hydroxide Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- HXAZFIXWZPERHB-UHFFFAOYSA-N 5-propan-2-ylpyridine-2-sulfonic acid Chemical compound CC(C)C1=CC=C(S(O)(=O)=O)N=C1 HXAZFIXWZPERHB-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- VXLYOURCUVQYLN-UHFFFAOYSA-N 2-chloro-5-methylpyridine Chemical compound CC1=CC=C(Cl)N=C1 VXLYOURCUVQYLN-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- KZVLNAGYSAKYMG-UHFFFAOYSA-N pyridine-2-sulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=N1 KZVLNAGYSAKYMG-UHFFFAOYSA-N 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 2
- 229940124530 sulfonamide Drugs 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 150000003568 thioethers Chemical class 0.000 description 2
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 2
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 229940118365 Endothelin receptor antagonist Drugs 0.000 description 1
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Ethyl malonate Chemical compound CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-N Thiophosphoric acid Chemical compound OP(O)(S)=O RYYWUUFWQRZTIU-UHFFFAOYSA-N 0.000 description 1
- QRSFFHRCBYCWBS-UHFFFAOYSA-N [O].[O] Chemical compound [O].[O] QRSFFHRCBYCWBS-UHFFFAOYSA-N 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 125000005233 alkylalcohol group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- HDFRDWFLWVCOGP-UHFFFAOYSA-N carbonothioic O,S-acid Chemical compound OC(S)=O HDFRDWFLWVCOGP-UHFFFAOYSA-N 0.000 description 1
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 125000004915 dibutylamino group Chemical group C(CCC)N(CCCC)* 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002308 endothelin receptor antagonist Substances 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- USKZHEQYENVSMH-UHFFFAOYSA-N hepta-1,3,5-triene Chemical compound CC=CC=CC=C USKZHEQYENVSMH-UHFFFAOYSA-N 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000002780 morpholines Chemical class 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- DWJMBQYORXLGAE-UHFFFAOYSA-N pyridine-2-sulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=N1 DWJMBQYORXLGAE-UHFFFAOYSA-N 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/08—Preparation by ring-closure
- C07D213/09—Preparation by ring-closure involving the use of ammonia, amines, amine salts, or nitriles
- C07D213/10—Preparation by ring-closure involving the use of ammonia, amines, amine salts, or nitriles from acetaldehyde or cyclic polymers thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及到制备结构式(I)的2,5-二取代吡啶的方法它包括下面的步骤:a)结构式(II)的化合物R1-CH=CH-R2 (II)与结构式(III)的丙烯类化合物反应形成结构式(IV)的化合物和b)在无水的条件下用卤化氢反应结构式(IV)的化合物,在这些结构式中,R1表示低级烷基,R2表示二-(低级烷基)氨基或5-或6-元-N-杂环基团,它在氮原子上有自由价键,并且X表示卤素。
Description
结构式(I)的化合物是已知的化合物并且可被用于制备内皮受体拮抗剂(endothelin receptor antagonist),如在欧洲专利0713875A1和WO96/19459中公开的,化合物例如吡啶-2-基-氨基甲酸2-[6-(5-异丙基-吡啶-2-磺酰基氨基)-5-(2-甲氧基-苯氧基)-2-吗啉-4-基-嘧啶-4-基氧]-乙基酯和5-异丙基-吡啶-2-磺酸{6-(2-羟基-乙氧基)-5-(2-甲氧基-苯氧基)-2-[2-(1H-四唑-5-基)-吡啶-4-基]-嘧啶-4-基}-酰胺被包括在其中。
制备2-卤代-5-烷基吡啶的方法已在例如欧洲专利-A-0 584 491和欧洲专利-A-0 162 464中公开了。通过本发明的方法,可以较高的收率和较少的反应步骤获得2-卤代-5-低级烷基吡啶。
根据本发明,通过一种方法可以制备上述结构式(I)的化合物,该方法包括下面的步骤:a)结构式(II)的化合物
R1-CH=CH-R2
(II)与结构式(III)的丙烯酸类化合物反应
(III)形成结构式(IV)的化合物并且b)在无水的条件下用卤化氢反应结构式(IV)的化合物在这些结构式中,R2为二-(低级烷基)氨基或5-或6-元-N-杂环基团,它在氮原子上有自由价键并且R1和X的定义如上。
低级烷基表示直链或支链的C1-C8-烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基的异构体、己基的异构体和辛基的异构体。
卤素包括氟代、氯代、溴代和碘代,以溴代,并且特别地,氯代是优选的。
在一个优选的方面,本方面涉及到制备结构式(I)的化合物,其中R1为支化的低级烷基,特别是异丙基,并且X为氯。
二-(低级烷基)氨基基团R2的实例为二甲基氨基、二乙基氨基、二丙基氨基、二异丙基氨基、二丁基氨基、乙基甲基氨基、乙基丙基氨基、乙基异丙基氨基、丁基乙基氨基、甲基丙基氨基、异丙基甲基氨基、丁基甲基氨基、丁基丙基氨基、丁基异丙基氨基。优选的二-(低级烷基)氨基基团R2为二乙基氨基。
5-或6-元-N-杂环基团可以是取代的或未取代的并且可以合有其它的杂原子,例如N、O和硫,因此其它的氮原子可以被低级烷基基团取代。这些杂环基团的实例为哌嗪、吡咯、吡唑、咪唑、1H-氮杂环庚三烯、氮杂环丁烷、氮丙啶,优选的为吡咯烷和哌啶,并且最优选的为吗啉。
根据本发明的方法中的反应步骤a)和b)可以在无水的纯净条件下或优选地在一种溶剂的存在下进行。
该方法的步骤a)可以在一种溶剂中进行,例如卤代烃、酮、腈、酯、醚或醇或这些溶剂的混合物。这些溶剂的实例为二氯甲烷、氯仿、二氯乙烷、丙酮、甲乙酮、环己酮、乙腈、较低烷基的甲酸酯、较低烷基的乙酸酯、较低烷基的丙酸酯、四氢呋喃、二氧六环和较低的烷基醇。更优选的是在有机或无机的无水酸例如烷基酸或氢卤酸存在下的上述的溶剂或它们的混合物。特别优选的是乙酸乙酯/乙酸的组合,并且特别地对每摩尔化合物(III),乙酸乙酯含有0.01-1摩尔的乙酸,并且最优速地0.03-0.1摩尔乙酸。
该方法的步骤b)可以在一种不与气体卤化氢反应的溶剂中进行,例如卤代烃或酯或它们的一种混合物。这些溶剂的实例为二氯甲烷、氯仿、二氯乙烷和较低烷基的甲酸酯、较低烷基的乙酸酯和较低烷基的丙酸酯。
通过采用在步骤a)中介绍的酯和酸的混合物,根据本发明,在整个过程中不需要改变溶剂。
反应步骤a)和b)可以在室温或不超过所用反应物和溶剂的沸点下进行。通过采用高压釜,更高的温度是可以的。
在步骤a)中,采用聚合反应阻聚剂例如对苯二酚是优选的,以防止丙烯酸类化合物的聚合反应。
在步骤b)中,环丁烷(IV)在无水的条件下用气体HX处理,优选地采用气体HBr并且特别优选地采用气体HCl处理,因此出现直接向(I)的顺利转化。该反应可以在上述的溶剂中进行,这样(IV)的形成及它向(I)的转化可以在一釜中进行,因而避免了(IV)的分离及提纯以及在操作过程中同时出现的物料的损失。优选地采用蒸馏提纯产物(I)。
在一个优选的方面,本方面涉及到上述的方法,其中步骤a)是在无水酸的存在下在无水的溶剂中进行,该溶剂是从卤代烃、酮、腈、酯、醚、醇或它们的混合物中选出的。特别优选的是乙酸乙酯和乙酸的混合物。
上述的方法也是优选的,其中在步骤b)中结构式(IV)的化合物就地与气体HBr或HCl反应。
本发明的另一个优选的方面是上述的方法,其中R1为支化的低级烷基,并且特别地为异丙基。
同样特别优选的是上述的方法,其中的X为氯。
而且,本方面的优选的方面是上述的方法,其中R2为吗啉基。
本方面的另一个优选的方面是在内皮受体拮抗剂中的结构式(I)的化合物的转化,特别是在欧洲专利0713875A1和WO 96/19459中介绍的内皮受体拮抗剂,例如吡啶-2-基-氨基甲酸2-[6-(5-异丙基-吡啶-2-磺酰基氨基)-5-(2-甲氧基-苯氧基)-2-吗啉-4-基-嘧啶-4-基氧]-乙基酯和/或5-异丙基-吡啶-2-磺酸{6-(2-羟基-乙氧基)-5-(2-甲氧基-苯氧基)-2-[2-(1H-四唑-5-基)-吡啶-4-基]-嘧啶-4-基}-酰胺和/或5-甲基-吡啶-2-磺酸{6-(2-羟基-乙氧基)-5-(2-甲氧基-苯氧基)-2-[2-(1H-四唑-5-基)-吡啶-4-基]-嘧啶-4-基}-酰胺。一般,该转化可以通过下面的反应进行:采用一种从硫醚、氢化硫醚、硫代碳酸、硫代磺酸或硫代磷酸衍生来的适当的硫亲核试剂或采用硫脲,将2-卤代吡啶转化为2-吡啶硫醇。该2-吡啶硫醇易被氧化为相应的磺酸,通过采用氨以标准的途径,它可以被活化并转化为磺酰胺。在含卤胺氧化剂的场合,当用氨处理时,中间体卤硫化物直接提供磺酰胺。采用碱脱质子化吡啶磺酰胺并用不同的取代4,6-二卤代嘧啶处理它的盐,提供了吡啶-2-磺酸6-卤代-嘧啶-4-基-酰胺。在碱的存在下,采用乙二醇,它被转化为吡啶-2-磺酸6-(2-羟基乙氧基)-嘧啶-4-基-酰胺。接着与吡啶-2-羰基叠氮化合物反应,产生最终产物种类,吡啶-2-基-氨基甲酸2-[6-吡啶-2-磺酰基氨基)-嘧啶-4-基氧]乙基酯(参阅欧洲专利0713875A1)。
该方法完全不被被限制于欧洲专利0713875A1中介绍的活泼物质,并且可以用于制备其它的内皮受体拮抗剂,如在WO 96/19459中介绍的那些。
特别优选的是如上面介绍的方法,其中通过下面的步骤,1-(N-吗啉基)-3-(甲基)-丁烯-1被转化为2-氯-5-异丙基-吡啶:
a)与氯代酰基腈反应,
b)在无水的条件下加成卤化氢。
同样特别优选的是上述的方法,通过下面的步骤,其中的2-氯-5-异丙基-吡啶被转化为吡啶-2-基-氨基甲酸2-[6-(5-异丙基-吡啶-2-磺酰基氨基)-5-(2-甲氧基-苯氧基)-2-吗啉-4-基-嘧啶-4-基氧]-乙基酯:
a)与硫脲反应形成5-异丙基-吡啶-2-硫醇,
b)与氯反应形成5-异丙基-吡啶-2-磺酰氯,
c)与氢氧化铵反应形成5-异丙基-吡啶-2-磺酰胺,
d)与4,6-二氯代-5-(2-甲氧基-苯氧基)-2-吗啉-4-基-嘧啶反应形成5-异丙基-吡啶-2-磺酸6-氯代-5-(2-甲氧基-苯氧基)-2-吗啉-4-基-嘧啶-4-基-酰胺,
e)在乙二醇中与钠反应形成5-异丙基-吡啶-2-磺酸6-(2-羟基-乙氧基)-5-(2-甲氧基-苯氧基)-2-吗啉-4-基-嘧啶-4-基-酰胺,
f)与吡啶-2-羰基叠氮化合物反应形成吡啶-2-基-氨基甲酸2-[6-(5-异丙基-吡啶-2-磺酰基氨基)-5-(2-甲氧基-苯氧基)-2-吗啉-4-基-嘧啶-4-基氧]-乙基酯。
同样特别优选的是上述的方法,通过下面的步骤,其中的2-氯代-5-异丙基-吡啶被转化成5-异丙基-吡啶-2-磺酸{6-(2-羟基-乙氧基)-5-(2-甲氧基-苯氧基)-2-[2-(1H-四唑-5-基)-吡啶-4-基]-嘧啶-4-基}-酰胺:
a)与硫脲反应形成5-异丙基-吡啶-2-硫醇,
b)与氯反应形成5-异丙基-吡啶-2-磺酰氯,
c)与氢氧化铵反应形成5-异丙基-吡啶-2-磺酰胺,
d)与4-[4,6-二氯代-5-(2-甲氧基-苯氧基)-嘧啶-2-基]-吡啶-1-氧化物反应形成5-异丙基-吡啶-2-磺酸6-氯代-5-(2-甲氧基-苯氧基)-2-(1-氧-吡啶-4-基)-嘧啶-4-基-酰胺,
e)在乙二醇中与钠反应形成5-异丙基-吡啶-2-磺酸6-(2-羟基-乙氧基)-5-(2-甲氧基-苯氧基)-2-(1-氧-吡啶-4-基)-嘧啶-4-基-酰胺,
f)与三甲基甲硅烷基氰化物和三乙胺反应,形成5-异丙基-吡啶-2-磺酸2-(2-氰基-吡啶-4-基)-6-(2-羟基-乙氧基)-5-(2-甲氧基-苯氧基)-嘧啶-4-基-酰胺,
g)与氯化铵和叠氮化钠反应,形成5-异丙基-吡啶-2-磺酸{6-(2-羟基-乙氧基)-5-(2-甲氧基-苯氧基)-2-[2-(1H-四唑-5-基)-吡啶-4-基]-嘧啶-4-基}-酰胺。
上面的方法同样是本发明的一部分,通过下面的步骤,其中1-(N-吗啉基)-丙烯-1被转化为2-氯代-5-甲基-吡啶:
a)与氯代酰基腈反应,
b)在无水的条件下与卤化氢反应。
本发明的另一部分是上面的方法,通过下面的步骤,其中的2-氯代-5-甲基-吡啶被转化成5-甲基-吡啶-2-磺酸{6-(2-羟基-乙氧基)-5-(2-甲氧基-苯氧基)-2-[2-(1H-四唑-5-基)-吡啶-4-基]-嘧啶-4-基}-酰胺:
a)与硫脲反应形成5-甲基-吡啶-2-硫醇,
b)与氯反应形成5-甲基-吡啶-2-磺酰氯,
c)与氢氧化铵反应形成5-甲基-吡啶-2-磺酰胺,
d)与4-[4,6-二氯-5-(2-甲氧基-苯氧基)-嘧啶-2-基]-吡啶-1-氧化物反应形成5-甲基-吡啶-2-磺酸6-氯代-5-(2-甲氧基-苯氧氧基)-2-(1-氧-吡啶-4-基)-嘧啶-4-基-酰胺,
e)在乙二醇中与钠反应形成5-甲基-吡啶-2-磺酸6-(2-羟基-乙氧基)-5-(2-甲氧基-苯氧基)-2-(1-氧-吡啶-4-基)-嘧啶-4-基-酰胺,
f)与三甲基甲硅烷基氰化物和三乙胺反应,形成5-甲基-吡啶-2-磺酸2-(2-氰基-吡啶-4-基)-6-(2-羟基-乙氧基)-5-(2-甲氧基-苯氧基)-嘧啶-4-基-酰胺,
g)与氯化铵和叠氮化合物钠反应,形成5-甲基-吡啶-2-磺酸{6-(2-羟基-乙氧基)-5-(2-甲氧基-苯氧基)-2-[2-(1H-四唑-5-基)-吡啶-4-基]-嘧啶-4-基}-酰胺。
同样优选的是采用上面的方法制备内皮受体拮抗剂,例如5-甲基-吡啶-2-磺酸{6-(2-羟基-乙氧基)-5-(2-甲氧基-苯氧基)-2-[2-(1H-四唑-5-基)-吡啶-4-基]-嘧啶-4-基}-酰胺并且特别优选的例如吡啶-2-基-氨基甲酸2-[6-(5-异丙基-吡啶-2-磺酰基氨基)-5-(2-甲氧基-苯氧基)-2-吗啉-4-基-嘧啶-4-基氧]-乙基酯和/或5-异丙基-吡啶-2-磺酸{6-(2-羟基-乙氧基)-5-(2-甲氧基-苯氧基)-2-[2-(1H-四唑-5-基)-吡啶-4-基]-嘧啶-4-基}-酰胺。
本发明的另一个优选的方面是通过上述方法得到的化合物。
实施例
在氩气气氛下60分钟内将3.54升(32.7摩尔)3-甲基丁醛加入到28℃的2.61升(30摩尔)吗啉在25升环己烷中的溶液中。用另外的5升环己烷将剩余的3-甲基丁醛冲洗到反应混合物中。在80℃下将混合物加热22小时,并共沸除去水,然后在45℃/180毫巴下蒸发。加入1.5升乙酸乙酯并再次在减压下除去。残留的剩余物为1-(N-吗啉基)-3-(甲基)-丁烯-1。
将由上面反应得到的1-(N-吗啉)-3-(甲基)-丁烯-1溶解在30升乙酸乙酯中。加入0.18升乙酸和0.012公斤对苯二酚后,使混合物在78℃下回流。当在1-2小时内加入3.72升(46.32摩尔)氯代酰基腈时,使温度保持在78℃。继续在78℃下搅拌1小时,然后当通入1.59公斤HCl气体时,在75℃下搅拌3小时。在惰性气体下将混合物冷却到22℃,并且在10℃下2小时内用37升的碳酸氢钠(3.6公斤)水溶液使pH达到8。在21℃下搅拌15分钟后,分离有机相并用15升乙酸乙酯萃取2-氯-5-异丙基-吡啶两次,合并的萃取物用15升氯化钠溶液(4.8公斤NaCl)洗涤两次。在45℃/25毫巴下蒸发有机相,并且使产物进行真空蒸馏(短柱)。在40-45℃/1毫巴下蒸馏2-氯代-5-异丙基-吡啶。以这种方法,得到了从3-甲基丁醛来的60%总收率的2-氯-5-异丙基-吡啶。
2-氯代-5-异丙基-吡啶可以转化为吡啶-2-基-氨基甲酸2-[6-(5-异丙基-吡啶-2-磺酰基氨基)-5-(2-甲氧基-苯氧基)-2-吗啉-4-基-嘧啶-4-基氧]-乙基酯或5-异丙基-吡啶-2-磺酸{6-(2-羟基-乙氧基)-5-(2-甲氧基-苯氧基)-2-[2-(1H-四唑-5-基)-吡啶-4-基]-嘧啶-4-基}-酰胺,如下所示:
在水性HCl中,通过与硫脲的反应,2-氯代-5-异丙基-吡啶被转化为5-异丙基-吡啶-2-硫醇。在乙酸中5-异丙基-吡啶-2-硫醇与氯的氯化反应得到5-异丙基-吡啶-2-磺酰氯,通过用水性氢氧化铵处理,它被转化为5-异丙基-吡啶-2-磺酰胺。
用5-异丙基-吡啶-2-磺酰胺的钾盐处理4,6-二氯代-5-(2-甲氧基-苯氧基)-2-吗啉-4-基-嘧啶形成5-异丙基-吡啶-2-磺酸6-氯代-5-(2-甲氧基-苯氧基)-2-吗啉-4-基-嘧啶-4-基-酰胺。然后将该化合物加入到钠的乙二醇溶液中。加热后得到5-异丙基-吡啶-2-磺酸6-(2-羟基-乙氧基)-5-(2-甲氧基-苯氧基)-2-吗啉-4-基-嘧啶4-基-酰胺,然后将它加入到吡啶-2-羰基叠氮化合物的二氧六环溶液中,形成吡啶-2-基-氨基甲酸2-[6-(5-异丙基-吡啶-2-磺酰基氨基)-5-(2-甲氧基-苯氧基)-2-吗啉-4-基-嘧啶-4-基氧]-乙基酯(见欧洲专利0713875A1)。
通过4-氰基-吡啶与钠的甲醇溶液的反应,然后通过加入氯化铵,4-氰基-吡啶被转化为4-脒基-吡啶氯化氢。
将二乙基-(2-甲氧基-苯氧基)丙二酸酯溶解在钠的甲醇溶液中。之后,加入4-脒基-吡啶的氯化氢,得到5-(2-甲氧基-苯氧基)-2-(吡啶-4-基)-嘧啶-4,6-二醇(或互变异构体衍生物)。该化合物与三氯氧磷一起加热,得到4,6-二氯代-5-(2-甲氧基-苯氧基)-2-吡啶-4-基)-嘧啶,它与过乙酸一起煮,得到4-[4,6-二氯代-5-(2-甲氧基-苯氧基)-嘧啶-2-基]-吡啶-1-氧化物。通过该化合物与这里的5-异-异丙基-2-吡啶-2-磺酰胺钾的反应,得到5-异丙基-吡啶-2-磺酸6-氯代-5-(2-甲氧基-苯氧基)-2-(1-氧-吡啶-4-基)-嘧啶-4-基-酰胺,它作为在二甲氧基乙烷中的溶液被加入到钠的乙二醇溶液中。得到了5-异丙基-吡啶-2-磺酸6-(2-羟基-乙氧基)-5-(2-甲氧基-苯氧基)-2-(1-氧-吡啶-4-基)-嘧啶-4-基-酰胺,它在乙腈中与三甲基硅氰化物和三乙胺一起加热,得到了5-异丙基-吡啶-2-磺酸2-(氰基-吡啶4-基)-6-(2-羟基-乙氧基)-5-(2-甲氧基-苯氧基)-嘧啶-4-基-酰胺。然后在二甲基甲酰胺中,它与氯化铵和叠氮化钠一起被加热,得到5-异丙基-吡啶-2-磺酸{6-(2-羟基-乙氧基)-5-(2-甲氧基-苯氧基)-2-[2-(1H-四唑-5-基)-吡啶-4-基]-嘧啶-4-基}-酰胺(见WO 96/19459)。
Claims (8)
2.根据权利要求1的方法,其中步骤a)是在无水酸的存在下在无水的溶剂中进行,该溶剂是从卤代烃、酮、腈、酯、醚、醇或它们的混合物选出的。
3.根据权利要求1或2的方法,其中的溶剂是乙酸乙酯和乙酸的混合物。
4.根据权利要求1的方法,其中在步骤b)中结构式(IV)的化合物就地与气体HBr或HCl反应。
5.根据权利要求1的方法,其中R1为支链的低级烷基。
6.根据权利要求1的方法,其中R1为异丙基。
7.根据权利要求1的方法,其中的X为氯。
8.根据权利要求1的方法,其中的R2为吗啉基。
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US6743783B1 (en) * | 1993-12-01 | 2004-06-01 | Marine Polymer Technologies, Inc. | Pharmaceutical compositions comprising poly-β-1→4-N-acetylglucosamine |
US6417360B1 (en) | 1999-03-03 | 2002-07-09 | Hoffmann-La Roche Inc. | Heterocyclic sulfonamides |
ZA200002318B (en) * | 1999-05-22 | 2000-11-16 | Actelion Pharmaceuticals Ltd | Aqueous pharmaceutical composition. |
EP3000487B8 (en) | 2007-02-19 | 2022-06-15 | Marine Polymer Technologies, Inc. | Hemostatic compositions and therapeutic regimens |
NZ602909A (en) | 2010-04-15 | 2015-01-30 | Marinepolymer Tech Inc | Anti-bacterial applications of poly -n-acetylglucosamine nanofibers |
JP6144254B2 (ja) | 2011-04-15 | 2017-06-07 | マリン ポリマー テクノロジーズ,インコーポレーテッド | ポリ−n−アセチルグルコサミンナノファイバを用いた疾患の治療 |
CN116456984A (zh) | 2020-11-05 | 2023-07-18 | 爱杜西亚药品有限公司 | 克拉生坦二钠盐的稳定结晶水合物 |
WO2023111299A1 (en) | 2021-12-17 | 2023-06-22 | Idorsia Pharmaceuticals Ltd | Clazosentan disodium salt, its preparation and pharmaceutical compositions comprising the same |
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EP0162464A1 (en) * | 1984-05-23 | 1985-11-27 | Ici Americas Inc. | Synthesis of 2-substituted-5-methylpyridines from methylcyclo-butanecarbonitrile, valeronitrile and pentenonitrile intermediates |
EP0584491A1 (de) * | 1992-07-13 | 1994-03-02 | Bayer Ag | Verfahren zur Herstellung von 2,5-disubstituierten Pyridinen |
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US5837708A (en) * | 1994-11-25 | 1998-11-17 | Hoffmann-La Roche Inc. | Sulphonamides |
TW313568B (zh) * | 1994-12-20 | 1997-08-21 | Hoffmann La Roche |
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EP0162464A1 (en) * | 1984-05-23 | 1985-11-27 | Ici Americas Inc. | Synthesis of 2-substituted-5-methylpyridines from methylcyclo-butanecarbonitrile, valeronitrile and pentenonitrile intermediates |
EP0584491A1 (de) * | 1992-07-13 | 1994-03-02 | Bayer Ag | Verfahren zur Herstellung von 2,5-disubstituierten Pyridinen |
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EP0897914A1 (en) | 1999-02-24 |
KR100275663B1 (ko) | 2000-12-15 |
CN1210105A (zh) | 1999-03-10 |
ES2221696T3 (es) | 2005-01-01 |
CA2245169A1 (en) | 1999-02-19 |
JPH11116554A (ja) | 1999-04-27 |
CA2245169C (en) | 2004-08-10 |
KR19990023680A (ko) | 1999-03-25 |
ATE267808T1 (de) | 2004-06-15 |
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