HRP920907A2 - Postupak za dobivanje derivata 9-supstituiranih gvanina i intermedijeri koji se upotrebljavaju u ovom postupku - Google Patents
Postupak za dobivanje derivata 9-supstituiranih gvanina i intermedijeri koji se upotrebljavaju u ovom postupku Download PDFInfo
- Publication number
- HRP920907A2 HRP920907A2 HRP920907AA HRP920907A HRP920907A2 HR P920907 A2 HRP920907 A2 HR P920907A2 HR P920907A A HRP920907A A HR P920907AA HR P920907 A HRP920907 A HR P920907A HR P920907 A2 HRP920907 A2 HR P920907A2
- Authority
- HR
- Croatia
- Prior art keywords
- imidazole
- amino
- image
- carboxamide
- thiocarbamoyl
- Prior art date
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- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical class O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 title claims description 18
- 238000000034 method Methods 0.000 title claims description 17
- 239000000543 intermediate Chemical class 0.000 title claims description 4
- 238000002360 preparation method Methods 0.000 title description 2
- -1 peroxy compound Chemical class 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 13
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 10
- 229910001385 heavy metal Inorganic materials 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 4
- 125000000824 D-ribofuranosyl group Chemical group [H]OC([H])([H])[C@@]1([H])OC([H])(*)[C@]([H])(O[H])[C@]1([H])O[H] 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- QMYVMPRLRSVZBL-UHFFFAOYSA-N 4-(carbamothioylamino)-1h-imidazole-5-carboxamide Chemical class NC(=S)NC=1N=CNC=1C(N)=O QMYVMPRLRSVZBL-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical group [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 32
- 229910001868 water Inorganic materials 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- 229910052739 hydrogen Inorganic materials 0.000 description 22
- 239000000047 product Substances 0.000 description 22
- 150000001875 compounds Chemical class 0.000 description 21
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000000843 powder Substances 0.000 description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 12
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 7
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 6
- 229960004150 aciclovir Drugs 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- WDOYBEPLTCFIRQ-UHFFFAOYSA-N 2-amino-9-ethyl-3h-purin-6-one Chemical compound N1C(N)=NC(=O)C2=C1N(CC)C=N2 WDOYBEPLTCFIRQ-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 4
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 229940029575 guanosine Drugs 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- KZYOKOLLHMHOLR-UHFFFAOYSA-N 1-benzyl-5-(carbamothioylamino)imidazole-4-carboxamide Chemical compound NC(=S)NC1=C(C(N)=O)N=CN1CC1=CC=CC=C1 KZYOKOLLHMHOLR-UHFFFAOYSA-N 0.000 description 3
- ZBNZAJFNDPPMDT-UHFFFAOYSA-N 1h-imidazole-5-carboxamide Chemical compound NC(=O)C1=CNC=N1 ZBNZAJFNDPPMDT-UHFFFAOYSA-N 0.000 description 3
- SMHBTBYHDWNJEG-UHFFFAOYSA-N 2-amino-9-benzyl-3h-purin-6-one Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1CC1=CC=CC=C1 SMHBTBYHDWNJEG-UHFFFAOYSA-N 0.000 description 3
- OSFDSLRVYKUBOP-UHFFFAOYSA-N 2-amino-9-propyl-3h-purin-6-one Chemical compound N1C(N)=NC(=O)C2=C1N(CCC)C=N2 OSFDSLRVYKUBOP-UHFFFAOYSA-N 0.000 description 3
- NSXZKVSKOIMUKN-UHFFFAOYSA-N 5-(carbamothioylamino)-1-ethylimidazole-4-carboxamide Chemical compound CCN1C=NC(C(N)=O)=C1NC(N)=S NSXZKVSKOIMUKN-UHFFFAOYSA-N 0.000 description 3
- QTKYYXIZORIEEI-UHFFFAOYSA-N 5-(carbamothioylamino)-1-methylimidazole-4-carboxamide Chemical compound CN1C=NC(C(N)=O)=C1NC(N)=S QTKYYXIZORIEEI-UHFFFAOYSA-N 0.000 description 3
- DVNYTAVYBRSTGK-UHFFFAOYSA-N 5-aminoimidazole-4-carboxamide Chemical class NC(=O)C=1N=CNC=1N DVNYTAVYBRSTGK-UHFFFAOYSA-N 0.000 description 3
- UUWJNBOCAPUTBK-UHFFFAOYSA-N 9-methylguanine Chemical compound N1=C(N)N=C2N(C)C=NC2=C1O UUWJNBOCAPUTBK-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 229910000365 copper sulfate Inorganic materials 0.000 description 3
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 3
- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- BIPYIUKMNFPYHS-UHFFFAOYSA-N 5-(benzoylcarbamothioylamino)-1-methylimidazole-4-carboxamide Chemical compound CN1C=NC(C(N)=O)=C1NC(=S)NC(=O)C1=CC=CC=C1 BIPYIUKMNFPYHS-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- SOIFLUNRINLCBN-UHFFFAOYSA-N ammonium thiocyanate Chemical compound [NH4+].[S-]C#N SOIFLUNRINLCBN-UHFFFAOYSA-N 0.000 description 2
- 150000001718 carbodiimides Chemical class 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- TUWDPWSZHGLVHH-UHFFFAOYSA-N (4,6-dimethoxy-1,3,5-triazin-2-yl)-(methoxymethyl)cyanamide Chemical compound COCN(C#N)C1=NC(OC)=NC(OC)=N1 TUWDPWSZHGLVHH-UHFFFAOYSA-N 0.000 description 1
- SCOKPTHVGOEBIW-UHFFFAOYSA-N 2-[(5-amino-4-carbamoylimidazol-1-yl)methoxy]ethyl acetate Chemical compound CC(=O)OCCOCN1C=NC(C(N)=O)=C1N SCOKPTHVGOEBIW-UHFFFAOYSA-N 0.000 description 1
- WJSVJNDMOQTICG-UHFFFAOYSA-N 2-amino-1-[(2-methyl-4-methylidene-5-oxooxolan-2-yl)methyl]-7h-purin-6-one Chemical class NC1=NC=2N=CNC=2C(=O)N1CC1(C)CC(=C)C(=O)O1 WJSVJNDMOQTICG-UHFFFAOYSA-N 0.000 description 1
- QURCXIIQSAIIAR-UHFFFAOYSA-N 5-(benzoylcarbamothioylamino)-1-benzylimidazole-4-carboxamide Chemical compound C=1C=CC=CC=1C(=O)NC(=S)NC1=C(C(=O)N)N=CN1CC1=CC=CC=C1 QURCXIIQSAIIAR-UHFFFAOYSA-N 0.000 description 1
- AIVZNYNMAVQYDV-UHFFFAOYSA-N 5-(benzoylcarbamothioylamino)-1-ethylimidazole-4-carboxamide Chemical compound CCN1C=NC(C(N)=O)=C1NC(=S)NC(=O)C1=CC=CC=C1 AIVZNYNMAVQYDV-UHFFFAOYSA-N 0.000 description 1
- ALUGLKCVKRCHSR-UHFFFAOYSA-N 5-(benzoylcarbamothioylamino)-1-propylimidazole-4-carboxamide Chemical compound CCCN1C=NC(C(N)=O)=C1NC(=S)NC(=O)C1=CC=CC=C1 ALUGLKCVKRCHSR-UHFFFAOYSA-N 0.000 description 1
- DRPRDPXASLIYCT-UUOKFMHZSA-N 5-(carbamothioylamino)-1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]imidazole-4-carboxamide Chemical compound NC(=S)NC1=C(C(N)=O)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 DRPRDPXASLIYCT-UUOKFMHZSA-N 0.000 description 1
- SECGBANTEUNXGO-UHFFFAOYSA-N 5-(carbamothioylamino)-1-[hydroxy(1-hydroxypropan-2-yloxy)methyl]imidazole-4-carboxamide Chemical compound OCC(C)OC(O)N1C=NC(C(N)=O)=C1NC(N)=S SECGBANTEUNXGO-UHFFFAOYSA-N 0.000 description 1
- APLNCUAOMQJOIZ-UHFFFAOYSA-N 5-(carbamothioylamino)-1-propylimidazole-4-carboxamide Chemical compound CCCN1C=NC(C(N)=O)=C1NC(N)=S APLNCUAOMQJOIZ-UHFFFAOYSA-N 0.000 description 1
- QFCCFUBHVTZGJS-UHFFFAOYSA-N 5-amino-1-[hydroxy(1-hydroxypropan-2-yloxy)methyl]imidazole-4-carboxamide Chemical compound OCC(C)OC(O)N1C=NC(C(N)=O)=C1N QFCCFUBHVTZGJS-UHFFFAOYSA-N 0.000 description 1
- JAODJMVGFQELNO-UHFFFAOYSA-N 5-amino-1-benzylimidazole-4-carboxamide Chemical compound NC1=C(C(=O)N)N=CN1CC1=CC=CC=C1 JAODJMVGFQELNO-UHFFFAOYSA-N 0.000 description 1
- WMRBKFPTMPNISL-UHFFFAOYSA-N 5-amino-1-ethylimidazole-4-carboxamide Chemical compound CCN1C=NC(C(N)=O)=C1N WMRBKFPTMPNISL-UHFFFAOYSA-N 0.000 description 1
- UZHKJZZQGXMAKP-UHFFFAOYSA-N 5-amino-1-methylimidazole-4-carboxamide Chemical compound CN1C=NC(C(N)=O)=C1N UZHKJZZQGXMAKP-UHFFFAOYSA-N 0.000 description 1
- LVONFJCKVYNYTJ-UHFFFAOYSA-N 5-amino-1-propylimidazole-4-carboxamide Chemical compound CCCN1C=NC(C(N)=O)=C1N LVONFJCKVYNYTJ-UHFFFAOYSA-N 0.000 description 1
- RTRQQBHATOEIAF-UHFFFAOYSA-N AICA riboside Natural products NC1=C(C(=O)N)N=CN1C1C(O)C(O)C(CO)O1 RTRQQBHATOEIAF-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
- HEMHJVSKTPXQMS-DYCDLGHISA-M Sodium hydroxide-d Chemical compound [Na+].[2H][O-] HEMHJVSKTPXQMS-DYCDLGHISA-M 0.000 description 1
- 206010042674 Swelling Diseases 0.000 description 1
- RTRQQBHATOEIAF-UUOKFMHZSA-N acadesine Chemical compound NC1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 RTRQQBHATOEIAF-UUOKFMHZSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003245 coal Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- OMZSGWSJDCOLKM-UHFFFAOYSA-N copper(II) sulfide Chemical compound [S-2].[Cu+2] OMZSGWSJDCOLKM-UHFFFAOYSA-N 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000000864 peroxy group Chemical group O(O*)* 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with 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
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/052—Imidazole radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Biotechnology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
Područje tehnike
Ovaj izum je iz područja organske i farmaceutske kemije. Prema Međunarodnoj patentnoj klasifikaciji spada u skupinu C07 i A61K.
Tehnički problem
Ovaj izum se odnosi na postupak za dobivanje derivata 9-supstituiranog gvanina opće formule Ι
[image]
u kojoj je R C1-C4 alkil opcijski supstituiran s jednom ili više hidroksilnih skupina,
ili je R
[image]
benzil, ribozil, 2'-dezoksiribozil ili (CH2)n-OR1 gdje je n 1 ili 2, i R1 je CH2CH2OH ili
[image]
ili njihove soli.
Spojevi ovog tipa su terapeutski aktivni spojevi koji imaju antivirusno djelovanje ili su intermedijeri za dobivanje spojeva koji su od interesa u tehnologiji gena.
Stanje tehnike
Poznato je (J. Org. Chem. 51 1271-1282 (1986)) da se gvanozin može dobiti iz 4-karboksamid-5-amino-1-ribofuranozil imidazola postupkom u tri stupnja koji obuhvaća kondenzaciju s derivatima karbodiimida, ciklizaciju sa PdO i tretiranje s NH4OH. Ovaj postupak nije atraktivan jer zahtijeva upotrebu toksičnog spoja fozgena da bi se dobili derivati karbodiimida i zato jer je za ciklizaciju i naknadno tretiranje s NH4OH potrebno veoma dugo vrijeme.
Također je poznato da se spojevi formule Ι u kojoj je R H mogu dobiti postupkom u kojem se spoj formule ΙΙ
[image]
prvo metilira, pri čemu se stvara odgovarajući tiometil spoj, koji se zatim ciklizira u alkalnom mediju (A. Yamazaki, Nucl. Acids. Res., 3, 1976, 251-259). Ovaj postupak ima taj nedostatak, što se kao nusproizvod oblikuje metilmerkaptan, koji je toksičan i izaziva zloćudno bujanje, a osim toga prinos je mali. U članku je objavljeno da nije moguća ciklizacija spojeva II upotrebom soli teškog metala HgO.
Rješenje izuma
Međutim, mi smo iznenađujuće pronašli da je moguće izvesti ciklizaciju N1-supstituiranih derivata spojeva formule II bez prethodnog metiliranja, a upotrebom soli teškog metala u alkalnom mediju ili upotrebom peroksi spojeva.
Postupak prema izumu se karakterizira time što se 1-supstituirani 5-(tiokarbamoil)amino-1H-imidazol-4-karboksamid opće formule ΙΙΙ
[image]
u kojoj R ima isto značenje kao u formuli Ι, ciklizira
a) tretiranjem sa soli teškog metala iz skupine od Cu-, Ag-, Pb- i Hg-soli u vodenom alkalnom mediju koji sadrži najmanje četiri ekvivalenta OH- iona na temperaturi od oko 0°C do temperature refluksa, ili
b) tretiranjem sa peroksi spojem u vodenom alkalnom mediju na temperaturi od oko 0-30°C, poslije čega se izolira Ι tretiranjem s kiselinom, i ako se želi, prevodi se u sol.
Polazni spojevi formule ΙΙΙ
[image]
u kojoj je R C1-C4-alkil opcijski supstituiran s jednom ili više hidroksilnih skupina, ili je R
[image]
benzil, ribozil, 2'-dezoksiribozil ili (CH2)n-OR1 gdje je n 1 ili 2, i R1 je CH2CH2OH ili
[image]
ili njihove soli, su novi spojevi, i izum dalje obuhvaća ove spojeve kao intermedijere za dobivanje 9-supstituiranih derivata gvanina formule Ι.
Polazni materijali formule ΙΙΙ mogu se dobiti reakcijom 1-supstituiranih 5-amino-1H-imidazol-4-karboksamida formule ΙV
[image]
u kojoj R ima isto značenje kao u formuli Ι i u kojoj hidroksilne skupine, ako ih ima, u R mogu biti acilirane, s acilizotiocijanatom i zatim podvrgnute hidrolizi da bi se uklonila N-acil skupina.
Spojevi formule ΙV mogu se dobiti alkiliranjem poznatog spoja 5-amino-1H-imidazol-4-karboksamida na poznat način.
Najbolji način za izvođenje izuma
Postupak prema izumu u varijanti a) prvenstveno se izvodi upotrebljavajući bakarnu sol kao sol teškog metala. Pritom se dobiva visok prinos s jeftinim reagensom.
Osim toga, izum se u varijanti a) pogodno izvodi na taj način, što se vodeni alkalni medij osigurava s hidroksidom alkalnog metala, prvenstveno s natrij ili kalij hidroksidom.
Postupak prema izumu u varijanti b) se prvenstveno izvodi upotrebljavajući vodik peroksid kao peroksidni spoj, a u prisustvu volframatnih iona kao katalizatora.
Dobivanje polaznihmaterijala
Dobivanje 5-(N'-benzoiltiokarbamoil)amino-1-metil-1H-imidazol-4-karboksamida
5-amino-1-metil-1H-imidazol-4-karboksamid (6,5 g, 45 nM) i benzoilizoticijanat (7,7 g, 47 nM) se refluksiraju u acetonu (90 ml) u tijeku četiri sata pod N2. Poslije hlađenja u ledenoj kupki, oblikovani proizvod se profiltrira, opere se acetonom i osuši. Na taj način se izolira 13,0 g (95%) naslovnog spoja u obliku bijelog praha, t.t. 194-196°C.
5-(N'-benzoiltiokarbamoil)amino-1-etil-1H-imidazol-4-karboksamid
se dobiva na sličan način iz 5-amino 1-etil-1H-imidazol-4-karboksamida, t.t. 178-180°C.
5-(N'-benzoiltiokarbamoil)amino-1-(1-propil)-1H-imidazol-4-karboksamid
se dobiva na sličan način iz 5-amino-1-(1-propil)-1H-imidazol-4-karboksamida, t.t. 163-164°C.
5-(N'-benzoiltiokarbamoil)amino-1-benzil-1H-imidazol-4-karboksamid
se dobiva na sličan način iz 5-amino-(1-benzil)-1H-imidazol-4-karboksamida, t.t. 181-182°C.
1-/(2-Hidroksietoksi)metil/5-(tiokarbamoil)amino-1H-imidazol-4-karboksamid.
5-Amino-1-//2-(acetiloksi)etoksi/metil/-1H-imidazol-4-karboksamid (44,0 g, 182 nM) i benzoilizoticijanat (29,7 g, 182 nM) se refleksira u acetonu (430 ml) tijekom jednog sata. U dobivenu otopinu se dodaje metanol (438 ml) i kalij karbonat (14,9 g, 108 mM) otopljen u vodi (45 ml) poslije čega se smjesa refluksira tijekom četiri sata. Poslije hlađenja na sobnoj temperaturi dodaje se octena kiselina do pH vrijednosti od 8. Oblikovani proizvod se profiltrira na 0°C opere se i osuši. Na taj način se izolira 39,2 g (83%) naslovnog spoja kao bijelog praha, t.t. 181-182°C (rasp.). Uzorak kristaliziran iz vode imao je t.t. 182-183°C (rasp.). 13C-NMR(DMSO-d6) ppm: 183.9; 163.7; 134.9; 129.3; 127.9; 74.0; 70.4; 59.7.
Izračunato za C8H13N5O3S: C 37,06%, H 5,05%, N 27,01%, S 12,37%
nađeno: C 36,92%, H 6,07%, N 27,30%, S 12,28%.
1-/1,3-Dihidroksi-(2-propiloksi)metil/-5-(tiokarbamoil)amino-1H-imidazol-4-karboksamid
se dobiva na sličan način iz 5-amino-/1,3-dihidroksi-(2-propiloksi)metil/-1H-imidazol-4-karboksamida, t.t. 185°C (rasp) 13C-NMR(DMSO-d6) ppm: 183.8; 163.9; 134.8; 129.8; 127.9; 80.2; 73.5; 60.7.
Izračunato za C9H15N5O4S: C 37,36%, H 5,23%, N 24,21%, S 11,08%
nađeno: C 37,34%, H 5,16%, N 23,81%, S 10,76%.
1-/(2-Hidroksietoksi)metil/-5-(tiokarbamoil)amino-1H-imidazol-4-karboksamid
Benzoilklorid (5,9 g 42 nM) se, pod N, dodaje ukapavanjem u otopinu amonijtiocijanata (3,2 g 42 nM) u acetonu (80 ml) na 20°C, i oblikovani amonij klorid se profiltrira i opere se acetonom (20 ml).
U filtrat se dodaje 5-amino-1-/2-(acetiloksi)etoksi/metil/1H-imidazol-4-karboksamid (9,7 g, 40 ml). Smjesa se refluksira pod N2 tijekom 90 minuta. Zatim se dodaje metanol (80 ml) i kalij karbonat (5,8 g, 42 mM) otopljen u vodi (12 ml) i smjesa se refluksira osam sati pod N2. Dodaje se voda (70 ml) da bi se hidrolizirala smjesa, i tretira se s aktiviranim ugljenom na 25°C.
Otopina se tada uparava na oko 70 ml, i pH vrijednost se podesi s octenom kiselinom na 7.0. Poslije hlađenja na 5°C dobiveni proizvod se profiltrira, opere se vodom i osuši. Na taj način se izolira 8,0 g (77%) naslovnog spoja kao bijelog praha, t.t. 178-180°C (rasp.). HPLC pokazuje > 96% čistoće.
1-/(2-Hidroksietoksi)metil/-5-(tiokarbamoil)amino-1H-imidazol-4-karboksamid
Acetil klorid (1,6 g, 21 mM) se, pod N2, dodaje ukapavanjem u otopinu amonij tiocijanata (1,6 g, 21 mM) u acetonu (30 ml) na 25°C tijekom pet minuta. Poslije refluksa tijekom 15 minuta ohladi se na 20°C, i oblikovani amonij klorid se profiltrira i opere se acetonom (10 ml).
U filtrat se dodaje 5-amino-1-//2(acetiloksi)etoksi/metil/-1H-imidazol-4-karboksamid (4,8 g, 20 mM). Smjesa se refluksira pod N2 tijekom 20 sati. Zatim se dodaje metanol (40 ml) i kalij karbonat (5,8 g, 42 mM) otopljen u vodi (12 ml) i smjesa se refluksira sedam sati pod N2. Dodaje se voda (50 ml) da bi se hidrolizirala smjesa, i tretira se s aktiviranim ugljenom na 25°C. Otopina se tada uparava na oko 30 ml i pH se podesi s octenom kiselinom na 7,0. Poslije hlađenja na 5°C oblikovani proizvod se filtrira, opere se vodom i osuši se. Na taj način se izolira 3,2 g (62%) naslovnog spoja kao bijelog praha, t.t. 175-177°C (rasp.). HPLC pokazuje > 94% čistoće.
1-Metil-5-(tiokarbamoil)amino-1H-imidazol-4-karboksamid
5-(N'-benzoiltiokarbamoil)amino-1-metil-1H-imidazol-4-karboksamid (12,1 g, 40 mM) se dodaje u smjesu acetona i metanola (1:1) (200 ml). Dodaje se kalij karbonat (2,8 g, 20 ml) otopljenog u vodi (12 ml). Reakcijska smjesa se refluksira šest sati pod N2, poslije čega se dodaje octena kiselina (2,9 g, 48 ml). Poslije miješanja u ledenoj kupki, proizvod se filtrira, opere se i osuši. Na taj način se izolira 7,7 g (96%) naslovnog spoja kao bijelog praha, t.t. 270-274°C (rasp.) (konverzija započinje na oko 220°C).
Uzorak kristaliziran iz vode se topi na 280-283°C (rasp.) (konverzija započinje na oko 220°C).
12C-NMP(DMSO-d6) ppm: 184.0, 163.9; 134,8; 130.2; 127.3; 30.9.
Izračunato za C6H9N5OS: C 36,17%, H 4,55%, N 35,16%
Izračunato: C 36,06% H 4,53% N 35,05%
1-Etil-5-(tiokarbamoil)amino-1H-imidazol-4-karboksamid
se dobiva na sličan način iz (5-(N'-benzoiltiokarbamoil)amino-1-(1-propiloksi)-1H-imidazol-4-karboksamida, t.t. 197-198°C (rasp.) 13C-NMR(DMSO-d6) ppm: 183.8; 163.9; 134.8; 129.2; 127.7; 45.7; 22.7; 10.8.
Izračunato za C8H13N5OS: C 42,27% H 5,77% N 30,81%
nađeno: C 42,16% H 5,84% N 30,86%
1-Benzil-5-(tiokarbamoil)amino-1H-imidazol-4-karboksamid
se dobiva na sličan način iz (5-(N'-benzoiltiokarbamoil)amino-1-1-benzil-1H-imidazol-4-karboksamida, t.t. 264-266°C (rasp.)
(konverzija započinje na oko 205°C. 13C-NMR(DMSO-d6) δ ppm: 183.8; 163.9; 136.5; 134.5; 129.6; 129.6; 128.6; 127.4; 47.6.
Izračunato za C12H13N5OS: C 52,34% H 4,76% N 25,44%
nađeno: C 52,31% H 4,73% N 25,52%
Sljedeći primjeri ilustriraju postupak prema izumu. Primjeri 1-7 ilustriraju postupak varijante a), a primjeri 8-12 ilustriraju postupak varijante b).
Primjer 1
9-Metilgvanin
1-Metil-5-(tiokarbamoil)amino1H-imidazol-4-karboksamid (3,98 g, 20 mM) se otopi u 1 N natrij hidroksidu (160 ml). Dodaje se bakar acetat, H20 (4,6 g, 23 mM) i reakcijska smjesa se tada refluksira tijekom jednog sata. Poslije hlađenja na 50°C oblikovani bakar sulfid se profiltrira. Filtrat se zakiseli s octenom kiselinom do pH 5.0. Dobiveni proizvod se profiltrira na 25°C, opere se vodom i osuši. Na taj način se izolira 3,16 g (96%) naslovnog spoja kao bijelog praha, t.t. > 300°C.
13C-NMR(1N NaOD) δ ppm: 170.7; 163.6; 154.0; 141.4; 120.0; 32.2
Izračunato za C6H7N5O: C 43,63% H 4,27% N 42,41%
nađeno: C 43,05% H 4,20% N 41,95%
Primjer 2
9-Etilgvanin
9-Etilgvanin se dobiva na sličan način iz 1-etil-5-(tiokarbamoil)amino-1H-imidazol-4-karboksamida, t.t. > 300°C.
Izračunato za C7H9N5O, 1/4 H2O: C 45,77% H 5,21% N 38,13%
nađeno: C 45,52% H 5,00% N 38,04%
Primjer 3
9-(1-Propil)gvanin
9-(1-Propil)gvanin se dobiva na sličan način iz 1-(1propil)- 5-(tiokarbamoil)amino1H-imidazol-4-karboksamida, t.t. > 300°C. 13C-NMR(DMSO-d6) δ ppm: 156.8; 153.3; 151.0; 137.4; 116.5; 44.2; 22.7; 10.8.
Izračunato za C8H11N5O: C 49,73% H 5,74% N 36,25%
nađeno: C 49,50% H 5,76% N 36,30%
Primjer 4
9-Benzilgvanin
9-Benzilgvanin se dobiva na sličan način iz 1-benzil-5-(tio-karbamoil)amino-1H-imidazol-4-karboksamida, t.t. 305-308°C.
13C-NMR(DMSO-d6) δ ppm: 157.0; 153.8; 151.2; 137.6; 137.3; 128.7; 127.2; 116.6; 45.9.
Izračunato za C12H11N5O: C 59,74% H 4,59% N 29,03%
Nađeno: C 59,50% H 4,51% N 28,91%
Primjer 5A
9-/(2-Hidroksietoksi)metil/gvanin (Aciklovir)
9-/(2-Hidroksietoksi)metil/-5-(tiokarbamoil)amino-1H-imidazol-4-karboksamid (10,0 g,38,6 mM) se dodaje u suspenziju bakar sulfata (7,0 g, 44 mM) u 6 N natrij hidroksidu (80 ml) i miješa se na sobnoj temperaturi tijekom četiri sata. HPLC pokazuje 100% prinos. Poslije filtracije u filtrat se dodaje 50% vodena otopina octene kiseline (80 ml). Poslije kratkog perioda refluksa materijal se ohladi na 5°C. Proizvod se profiltrira i kristalizira iz vode, tretira se s aktiviranim ugljenom. Na ovaj način se izolira 7,8 g (85%) 9-/(2-Hidroksietoksi)metil/gvanina, 3/4 H20 (Aciklovira) kao bijelog praha, HPLC pokazuje > 99% čistoću, t.t. oko 250°C (rasp.). 13C-NMR(DMSO-d6) βppm: 156.8; 153.8; 151.4; 137.8; 116.5; 72.1; 70.4 i 59.9.
Izračunato za C8H11N5O3, 3/4 H20 C 40,25% H 5,28% N 29,34%
Nađeno: C 40,39% H 5,2% N 29,37%
Primjer 5B
9-/(2-Hidroksietoksi)metil/gvanin (Aciklovir)
9-/(2-Hidroksietoksi)metil/-5-(tiokarbamoil)amino-1H-imidazol-4-karboksamid (1,30 g 5,0 mM) se dodaje u suspenziju bakar acetata, H20 (1,15 g, 5,75 mM) u 1 N natrij hidroksidu (60 ml) i refluksira se tijekom 30 minuta. HPLC pokazuje 100% prinos.
Poslije filtracije, u filtrat se dodaje octena kiselina (5 ml) i zatim se zagrijava aktiviranim ugljenom. Ugljen se profiltrira, poslije čega se materijal ohladi na 5°C. Staloženi proizvod se profiltrira, opere se vodom i osuši. Na taj način se izolira 0,93 g (77%) 9-/(2-Hidroksietoksi)metil/gvanin, 3/4 H20, kao bijeli prah. HPLC pokazuje > 99% čistoće.
Upotreba drugih soli teških metala i različitih količina natrij hidroksida u postupku iz primjera 5 ilustrirana je u sljedećoj tabeli.
Dobivanje Aciklovira
1-/(2-Hidroksietoksi)metil/ Me + (+)
5-(tiokarbamoil)amino-1H- ⎯⎯⎯⎯ Aciklovir
imidazol-4-karboksamid NaOH
[image]
Primjer 6
9-/1,3-dihidroksi-(2-propiloksi)metil/gvanin
1-/1,3-dihidroksi-(2-propiloksi)metil/-5-(tiokarbamoil)amino-1H-imidazol-4-karboksamid (0,58 g, 2,0 mM) se dodaje u suspenziju bakar sulfata (0,32 g, 2,3 mM) u 3 N natrij hidroksidu (8 ml) i refluksira se tijekom jednog sata. HPLC pokazuje 100% prinos.
Poslije filtracije, u filtrat se dodaje 33% vodena otopina octene kiseline (6 ml) i refluksira se ponovno dok se tretira aktiviranim ugljenom. Ugljen se profiltrira i otopina se ohladi na 5°C. Filtracijom, pranjem vodom i sušenjem dobiva se 0,33 g (61%) 9-/1,3-dihidroksi-(2-propiloksi)metil/gvanina, 3/4 H20 kao bijelog praha, t.t. oko 245°C (rasp) 13C-NMR(DMSO-d6) βppm: 157,0; 153,9; 151,3; 137,6; 116,3; 79,9; 7,4; 60,8.
Izračunato za C9H13N5O4, 3/4 H20: C 40,22% H 5,43% N 26,06%
Nađeno: C 40,25% H 5,31% N 25,58%.
Primjer 7
9-β-D-Ribofuranozil gvanin (gvanozin)
5-Amino-1-(β-D-ribofuranozil)-1H-imidazol-4-karboksamid (5,0 g, 19,4 mM) i benzoilizoticijanat (3,3 g, 20 mM) se miješaju na sobnoj temperaturi u DMF (40 ml) jedan sat. Oslobađa se otapala u vakuumu dobivenom vodenim mlazom. Ostatak se otapa u metanolu (160 ml) i dodaje se kalij karbonat (1,6 g, 11,6 mM) u vodi (8 ml), poslije čega se smjesa refluksira dva sata. Poslije hlađenja na sobnoj temperaturi dodaje se octena kiselina do pH 6. Reakcijska smjesa se uparava u vodeno-mlaznom vakuumu i ostatak se kristalizira iz etanola. Na taj način se izolira 5,0 g sirovog 1-(β-D-Ribofuranozil)-5-(tiokarbamoil)-amino-1H-imidazol-4-karboksamida. HPLC pokazuje čistoću od oko 65% (ostatak od 35% je u biti kalij acetat).
Sirovi proizvod 1-(β-D-ribofuranozil-5-(tiokarbamoil)amino-1H-imidazol-4-karboksamid (5,0 g) se dodaje u suspenziju bakar sulfata (2,9 g, 18 mM) u 3 N natrij hidroksidu (60 ml) i refluksira se jedan sat. Poslije filtracije u filtrat se dodaje 33% vodena otopina octene kiseline (30 ml) i ponovno se refluksira uz tretiranje aktiviranim ugljenom. Ugljen se profiltrira, i otopina se ohladi na sobnu temperaturu preko noći. Filtracija, pranje vodom i sušenje daje 2,0 g (65%) 9-β-ribofuranozil gvanina, H20 (gvanozina, H20) kao bijelog praha, t.t. 250°C (rasp.). Proizvod je imao iste fizičke podatke kao i autentičan uzorak gvanozina, H20.
Primjer 8
9-(1-propil)gvanin
1-(1-propil)-5-tiokarbamoil)amino-1H-imidazol-4-karboksamid (1,14 g, 5,0 mM) i natrij volframat (0,2 g) se otope u 1 N natrij hidroksidu (50 ml) na 0°C. Ukapavanjem na 0-10°C tijekom 30 minuta se dodaje 35% vodik peroksid (1,8 ml, 20 mM) u vodi (5 ml). Poslije miješanja u ledenoj kupki tijekom jednog sata, pH se podesi s octenom kiselinom na 5. Oblikovani proizvod se profiltrira, opere se vodom i osuši. Na taj način se izolira 0,41 g (42%) naslovnog spoja kao bijelog praha. HPLC pokazuje > 98% čistoću. Proizvod je imao iste fizičke podatke kao i proizvod iz primjera 3.
Primjer 9
9-benzilgvanin
1-benzil-5-(tiokarbamoil)amino-1H-imidazol-4-karboksamid (2,75 g, 10,0 mM) i natrij volframat (0,1 g) se suspendiraju u 6 N natrij hidroksidu (20 ml) na 5°C. Dodaje se ukapavanjem na 5-15°C tijekom 30 minuta 35% vodik peroksid (4,0 ml, 44 mM).
U dobivenu reakcijsku smjesu se dodaje voda (60 ml). Poslije miješanja tijekom jednog sata u ledenoj kupki, pH se podešava na 5 s klorovodičnom kiselinom. Oblikovani proizvod se profiltrira, opere se vodom i osuši se. Na taj način se izolira 1,30 g (54%) naslovnog spoja kao bijelog praha. HPLC pokazuje oko 98% čistoće. Proizvod je imao iste fizičke podatke kao i proizvod iz primjera 4.
Primjer 10
9-metilgvanin
9-metilgvanin se dobiva na sličan način iz 1-metil-5-(tiokarbamoil)amino-1H-imidazol-4-karboksamida. Proizvod je imao iste fizičke podatke kao i proizvod iz primjera 1.
Primjer 11
9-etilgvanin
9-etilgvanin se dobiva na sličan način iz 1-etil-5-(tiokarbamoil)amino-1H-imidazol-4-karboksamida. Proizvod je imao iste fizičke podatke kao i proizvod iz primjera 2.
Primjer 12
9-/(2-hidroksietoksi)metil/gvanin (Aciklovir)
1-/(2-hidroksietoksi)metil/5-(tiokarbamoil)amino-1H-imidazol-4-karboksamid (2,59 g, 10,0 mM) i natrij volframat (0,05 g) se otope u 6 N natrij hidroksidu (20 ml) na 5°C. U tijeku 15 minuta se dodaje ukapavanjem 35% vodik peroksid (4,0 ml, 44 mM) na 5-15°C. Poslije miješanja 15 minuta na 0-5°C HPLC pokazuje 59% naslovnog spoja. pH vrijednost reakcijske smjese se podesi na 25% vodenom otopinom octene kiseline na 5,5.
Dobiveni proizvod se profiltrira, opere se vodom i osuši se, pri čemu se dobiva 1,13 g (50%) naslovnog spoja kao bijelog praha. HPLC pokazuje čistoću od oko 97%. Proizvod je imao iste fizičke podatke kao i proizvod iz primjera 5.
Claims (4)
1. Postupak za dobivanje derivata 9-supstituiranog gvanina opće formule Ι
[image]
u kojoj je R C1-C4-alkil opcijski supstituiran s jednom ili više hidroksilnih skupina, ili R je
[image]
benzil, ribozil, 2'-dezoksiribozil ili (CH2)n-OR1 gdje je n 1 ili 2, i R1 je CH2CH2OH ili
[image]
i njihovih soli, naznačen time, što se 1-supstituirani 5-(tiokarbamoil)amino-1H-imidazol-4-karboksamid opće formule III
[image]
kojoj R ima isto značenje kao u formuli Ι, ciklizira
a) tretiranjem sa soli teškog metala iz skupine od Cu-, Ag-, Pb- i Hg-soli u vodenom alkalnom mediju koji sadrži najmanje četiri ekvivalenta OH- iona, na temperaturi od oko 0°C do temperature refluksa, ili
b) tretiranjem s peroksi spojem u vodenom alkalnom mediju na temperaturi od oko 0-30°C, poslije čega se izolira I tretiranjem sa kiselinom, i ako se želi, prevodi se u sol.
2. Postupak prema 1a), naznačen time, što je sol teškog metala sol bakra.
3. Postupak prema zahtjevu 1b), naznačen time, što je peroksi spoj vodik peroksid, a reakcija se prvenstveno izvodi u prisutnosti volframatnih iona kao katalizatora.
4. Intermedijeri koji se upotrebljavaju za dobivanje gvanin spojeva opće formule (I), prema zahtjevu 1, naznačen time, što su oni 1-supstituirani 5-(tiokarbamoil)amino-1H-imidazol-4-karboksamidi opće formule III
[image]
u kojoj je R C1-C4-alkil opcijski supstituiran s jednom ili s više hidroksilnih skupina, ili R je
[image]
benzil, ribozil, 2'-dezoksiribozil ili (CH2)n-OR1 gdje je n 1 ili 2, i R1 je CH2CH2OH ili
[image]
ili njihove soli.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK135489A DK135489D0 (da) | 1989-03-20 | 1989-03-20 | Fremgangsmaade til fremstilling af 9-substituerede guaninderivater og mellemprodukter til brug ved fremgangsmaaden |
| YU54590A YU47343B (sh) | 1989-03-20 | 1990-03-20 | Postupak za dobijanje derivata 9-supstituisanog gvanina i intermedijeri koji se upotrebljavaju u ovom postupku |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HRP920907A2 true HRP920907A2 (hr) | 1994-04-30 |
| HRP920907B1 HRP920907B1 (en) | 1998-06-30 |
Family
ID=8103930
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP-545/90A HRP920907B1 (en) | 1989-03-20 | 1992-10-02 | A process for the preparation of 9-substituted guanine derivatives and intermediates for use in the process |
Country Status (28)
| Country | Link |
|---|---|
| US (1) | US5223619A (hr) |
| EP (1) | EP0464112B1 (hr) |
| KR (1) | KR0142098B1 (hr) |
| AR (1) | AR245719A1 (hr) |
| AT (1) | ATE112568T1 (hr) |
| BG (1) | BG60590B1 (hr) |
| BR (1) | BR9007230A (hr) |
| CA (1) | CA2047217A1 (hr) |
| CS (1) | CS9001365A3 (hr) |
| DD (1) | DD293116A5 (hr) |
| DE (1) | DE69013146T2 (hr) |
| DK (2) | DK135489D0 (hr) |
| ES (1) | ES2061023T3 (hr) |
| FI (1) | FI97387C (hr) |
| GE (1) | GEP19971014B (hr) |
| GR (1) | GR1001096B (hr) |
| HR (1) | HRP920907B1 (hr) |
| HU (1) | HU206715B (hr) |
| IE (1) | IE62042B1 (hr) |
| LT (1) | LT3183B (hr) |
| LV (1) | LV10455B (hr) |
| NO (1) | NO178497C (hr) |
| PL (1) | PL163313B1 (hr) |
| RO (1) | RO109737B1 (hr) |
| RU (2) | RU2090566C1 (hr) |
| SI (1) | SI9010545A (hr) |
| WO (1) | WO1990011283A1 (hr) |
| YU (1) | YU47343B (hr) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1264599B1 (it) * | 1993-06-14 | 1996-10-04 | Solar Chem Sa | Processo per la sintesi della 9-(2-idrossietossimetil)- guanina |
| GB9520364D0 (en) * | 1995-10-05 | 1995-12-06 | Chiroscience Ltd | Compouundds |
| DE69922009T2 (de) * | 1998-07-23 | 2005-04-07 | Fujisawa Pharmaceutical Co., Ltd. | Imidazolverbindungen und ihre verwendung als adenosindeaminase-inhibitoren |
| US6860928B2 (en) | 2002-09-04 | 2005-03-01 | Xerox Corporation | Alkylated urea and triaminotriazine compounds and phase change inks containing same |
| US6872243B2 (en) | 2002-09-04 | 2005-03-29 | Xerox Corporation | Phase change inks containing gelator additives |
| US6761758B2 (en) | 2002-09-04 | 2004-07-13 | Xerox Corporation | Alkylated tetrakis(triaminotriazine) compounds and phase change inks containing same |
| US6811595B2 (en) | 2002-09-04 | 2004-11-02 | Xerox Corporation | Guanidinopyrimidinone compounds and phase change inks containing same |
| US7144450B2 (en) | 2004-12-04 | 2006-12-05 | Xerox Corporation | Phase change inks containing trans-1,2-cyclohexane bis(urea-urethane) compounds |
| US7220300B2 (en) | 2004-12-04 | 2007-05-22 | Xerox Corporation | Phase change inks containing bis(urea-urethane) compounds |
| US7314949B2 (en) | 2004-12-04 | 2008-01-01 | Xerox Corporation | Trans-1,2-cyclohexane bis(urea-urethane) compounds |
| US7317122B2 (en) | 2004-12-04 | 2008-01-08 | Xerox Corporation | Curable trans-1,2-cyclohexane bis(urea-urethane) compounds |
| US7153349B2 (en) | 2004-12-04 | 2006-12-26 | Xerox Corporation | Phase change inks containing curable trans-1,2-cyclohexane bis(urea-urethane) compounds |
| US7560587B2 (en) | 2004-12-04 | 2009-07-14 | Xerox Corporation | Bis[urea-urethane] compounds |
| SI3062949T2 (sl) | 2013-10-29 | 2023-08-31 | Swep International Ab | Postopek trdega lotanja ploščatega izmenjevalnika toplote s pomočjo s sitotiskom nanešenega lota |
| CN115504977B (zh) * | 2022-09-23 | 2024-02-09 | 海南锦瑞制药有限公司 | 更昔洛韦的制备方法及注射用更昔洛韦的制备方法 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0126813A1 (en) * | 1983-05-24 | 1984-12-05 | Newport Pharmaceuticals International, Inc. | Process for preparing imidazole compounds |
| EP0219838A2 (en) * | 1985-10-22 | 1987-04-29 | Takeda Chemical Industries, Ltd. | Carbocyclic purine nucleosides, their production and use |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS56152437U (hr) * | 1980-04-14 | 1981-11-14 | ||
| US4451478A (en) * | 1982-03-12 | 1984-05-29 | Newport Pharmaceuticals International, Inc. | Imidazole compounds |
| US4602089A (en) * | 1982-03-12 | 1986-07-22 | Newport Pharmaceuticals, Inc. | Process for preparing purine compounds |
| JPS6055071B2 (ja) * | 1982-04-16 | 1985-12-03 | 四国化成工業株式会社 | イミダゾリル琥珀酸化合物および該化合物を用いるエポキシ樹脂硬化方法 |
| MY101126A (en) * | 1985-12-13 | 1991-07-31 | Beecham Group Plc | Novel compounds |
-
1989
- 1989-03-20 DK DK135489A patent/DK135489D0/da not_active Application Discontinuation
-
1990
- 1990-03-16 IE IE99490A patent/IE62042B1/en unknown
- 1990-03-19 RU RU9093004872A patent/RU2090566C1/ru active
- 1990-03-19 ES ES90905442T patent/ES2061023T3/es not_active Expired - Lifetime
- 1990-03-19 CA CA002047217A patent/CA2047217A1/en not_active Abandoned
- 1990-03-19 US US07/761,890 patent/US5223619A/en not_active Expired - Fee Related
- 1990-03-19 DE DE69013146T patent/DE69013146T2/de not_active Expired - Fee Related
- 1990-03-19 AT AT90905442T patent/ATE112568T1/de not_active IP Right Cessation
- 1990-03-19 KR KR1019910701187A patent/KR0142098B1/ko not_active Expired - Fee Related
- 1990-03-19 HU HU902874A patent/HU206715B/hu not_active IP Right Cessation
- 1990-03-19 EP EP90905442A patent/EP0464112B1/en not_active Expired - Lifetime
- 1990-03-19 WO PCT/DK1990/000077 patent/WO1990011283A1/en not_active Ceased
- 1990-03-19 DK DK90905442.1T patent/DK0464112T3/da active
- 1990-03-19 RO RO148411A patent/RO109737B1/ro unknown
- 1990-03-19 BR BR909007230A patent/BR9007230A/pt not_active Application Discontinuation
- 1990-03-20 SI SI9010545A patent/SI9010545A/sl unknown
- 1990-03-20 YU YU54590A patent/YU47343B/sh unknown
- 1990-03-20 GR GR900100212A patent/GR1001096B/el unknown
- 1990-03-20 PL PL90284379A patent/PL163313B1/pl unknown
- 1990-03-20 CS CS901365A patent/CS9001365A3/cs unknown
- 1990-03-20 DD DD90338906A patent/DD293116A5/de not_active IP Right Cessation
- 1990-03-20 AR AR90316421A patent/AR245719A1/es active
-
1991
- 1991-09-19 RU SU915001705A patent/RU2042668C1/ru active
- 1991-09-19 NO NO913686A patent/NO178497C/no unknown
- 1991-09-19 FI FI914418A patent/FI97387C/fi active
- 1991-09-20 BG BG95145A patent/BG60590B1/bg unknown
-
1992
- 1992-10-02 HR HRP-545/90A patent/HRP920907B1/xx not_active IP Right Cessation
- 1992-12-02 LV LVP-92-250A patent/LV10455B/en unknown
-
1993
- 1993-01-27 LT LTIP297A patent/LT3183B/lt not_active IP Right Cessation
- 1993-08-25 GE GEAP19931494A patent/GEP19971014B/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0126813A1 (en) * | 1983-05-24 | 1984-12-05 | Newport Pharmaceuticals International, Inc. | Process for preparing imidazole compounds |
| EP0219838A2 (en) * | 1985-10-22 | 1987-04-29 | Takeda Chemical Industries, Ltd. | Carbocyclic purine nucleosides, their production and use |
Non-Patent Citations (2)
| Title |
|---|
| J. Chem. Soc. Perkin Trans. 1, 1987, C.B. Reese et al.: "The conversion of the 2',3'-0-isopropylidene derivative of 5-amino-1-D-ribofuranosylimidazole-4-carboxamide (AICA riboside) into 2',3'-0-isopropylidene-isoquanosine", vidi stranicu 1527-stranice 1531 * |
| Nucleic Acids Research, Vol. 3, br. 1, 1986, A. Yamazaki et al.: "Synthesis of guanosine and its derivatives from 5-amino-1-ß-D-ribofuranolsyl-4-imidazolecarboxamide. IV. A new route to guanosine via cyanamide derivative. 1,2", vidi stranice 251-stranice 259 * |
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