DK172165B1 - Mellemprodukter til fremstilling af terapeutisk aktive 2-beta-D-ribofuranosylselenazol-4-carboxamidforbindelser - Google Patents
Mellemprodukter til fremstilling af terapeutisk aktive 2-beta-D-ribofuranosylselenazol-4-carboxamidforbindelser Download PDFInfo
- Publication number
- DK172165B1 DK172165B1 DK025093A DK25093A DK172165B1 DK 172165 B1 DK172165 B1 DK 172165B1 DK 025093 A DK025093 A DK 025093A DK 25093 A DK25093 A DK 25093A DK 172165 B1 DK172165 B1 DK 172165B1
- Authority
- DK
- Denmark
- Prior art keywords
- benzoyl
- intermediates
- solvent
- ribofuranosylselenazole
- preparation
- Prior art date
Links
- 239000000543 intermediate Substances 0.000 title claims description 9
- 238000002360 preparation method Methods 0.000 title claims description 7
- CKMBACZHCFMPLQ-DBRKOABJSA-N 2-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,3-selenazole-4-carboxamide Chemical class NC(=O)C1=C[se]C([C@H]2[C@@H]([C@H](O)[C@@H](CO)O2)O)=N1 CKMBACZHCFMPLQ-DBRKOABJSA-N 0.000 title description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 7
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 7
- 125000001589 carboacyl group Chemical group 0.000 claims description 7
- 239000000741 silica gel Substances 0.000 claims description 5
- 229910002027 silica gel Inorganic materials 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 4
- 238000004458 analytical method Methods 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims 2
- 239000000377 silicon dioxide Substances 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- SPVXKVOXSXTJOY-UHFFFAOYSA-N selane Chemical compound [SeH2] SPVXKVOXSXTJOY-UHFFFAOYSA-N 0.000 description 4
- 229910000058 selane Inorganic materials 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VQZAECCYOCVHGC-PILSHRGASA-N 3-[(3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-2H-1,3-selenazole-4-carboxamide Chemical compound NC(=O)C1=C[Se]CN1C1O[C@H](CO)[C@@H](O)[C@H]1O VQZAECCYOCVHGC-PILSHRGASA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 238000005915 ammonolysis reaction Methods 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- -1 isobutyryl Chemical group 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 230000000865 phosphorylative effect Effects 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- ODIRBFFBCSTPTO-UHFFFAOYSA-N 1,3-selenazole Chemical compound C1=C[se]C=N1 ODIRBFFBCSTPTO-UHFFFAOYSA-N 0.000 description 1
- LNETULKMXZVUST-UHFFFAOYSA-N 1-naphthoic acid Chemical compound C1=CC=C2C(C(=O)O)=CC=CC2=C1 LNETULKMXZVUST-UHFFFAOYSA-N 0.000 description 1
- SVPKNMBRVBMTLB-UHFFFAOYSA-N 2,3-dichloronaphthalene-1,4-dione Chemical compound C1=CC=C2C(=O)C(Cl)=C(Cl)C(=O)C2=C1 SVPKNMBRVBMTLB-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 239000005643 Pelargonic acid Substances 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- OFMYTVNDIRTGMR-UARRHKHWSA-N [(2r,3r,4s,5s)-3,4-dibenzoyloxy-5-cyanooxolan-2-yl]methyl benzoate Chemical compound O([C@H]1[C@H](C#N)O[C@@H]([C@H]1OC(=O)C=1C=CC=CC=1)COC(=O)C=1C=CC=CC=1)C(=O)C1=CC=CC=C1 OFMYTVNDIRTGMR-UARRHKHWSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 159000000032 aromatic acids Chemical class 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- HMFHBZSHGGEWLO-TXICZTDVSA-N beta-D-ribose Chemical group OC[C@H]1O[C@@H](O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-TXICZTDVSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- VICYTAYPKBLQFB-UHFFFAOYSA-N ethyl 3-bromo-2-oxopropanoate Chemical compound CCOC(=O)C(=O)CBr VICYTAYPKBLQFB-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-N propynoic acid Chemical compound OC(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- DQWPFSLDHJDLRL-UHFFFAOYSA-N triethyl phosphate Chemical compound CCOP(=O)(OCC)OCC DQWPFSLDHJDLRL-UHFFFAOYSA-N 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D421/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms
- C07D421/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings
- C07D421/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no 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
- C07D307/20—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Description
DK 172165 B1
Den foreliggende opfindelse angår hidtil ukendte mellemprodukter, der er nyttige til fremstilling af terapeutisk aktive 2-|3-D-ribofuranosylselenazol-4-carboxamidforbindelser af den art, der er omhandlet i stamansøgningen DK 1299/83 (DK patent 5 nr. 167.765).
Den foreliggende opfindelse angår nærmere betegnet hidtil ukendte mellemprodukter til fremstilling af 2-jS-D-ribofurano-sylselenazol-4-carboxamidforbindelser, hvilke mellemprodukter er ejendommelige ved, at de har den almene formel R3OCH2 2 i!/
2 ^1 RO 0RX
1 0 10 hvori R og R hver er hydrogen, lavere alkanoyl eller ben-*2 zoyl, R er hydrogen, lavere alkanoyl, benzoyl eller
O
II
HO-P-;
15 I
OH
og Z er -C(NH2)Se eller selenazol-4-(lavere alkyl)-carboxy-lat-2-yl.
Foretrukne forbindelser er følgende: 20 2,5-anhydro-3,4,6-tri-O-benzoyl-D-allonseleno-carboxamid og ethyl-2- (2,3,5-tri-0-benzoyl-2-/3-D-ribofuranosyl) -selenasol-4 -carboxylat.
Særlige betydninger af R , R og R i forbindelserne ifølge opfindelsen som foretrukne lavere alkanoylgrupper er acetyl, DK 172165 Bl 2 propionyl, butyryl og isobutyryl.
Når Rx og R begge er H, er R fortrinsvis H, C-L-Cg-alkanoyl, 0 1 1 1 3 5 eller HO-P-, og når R og R begge er C^-Cø-alkanoyl, er R-3
OH
Οχ-Cø-alkanoyl.
Alkanoylgrupperne kan vælges blandt ligekædede, forgrenede, 10 substituerede, umættede, mættede eller aromatiske syrer, såsom, men ikke nødvendigvis begrænset til, eddikesyre, tri-fluoreddikesyre, propionsyre, n-smørsyre, isosmørsyre, valerianesyre, capronsyre, pelargonsyre, ønantsyre, caprylsyre, mælkesyre, acrylsyre, propargylsyre, palmitinsyre, benzoesy-15 re, phthalsyre, salicylsyre, kanelsyre og naphthalencarboxyl-syre.
Mellemprodukterne ifølge opfindelsen er nyttige ved en fremgangsmåde til fremstilling af de terapeutiske aktive ribofu-ranosylselenazol-4-carboxamidforbindelser ifølge DK patent 20 nr. 167.765. Fremgangsmåden omfatter, at man a) underkaster et alkyl-2-(2,3,5-tri-0-acyl-j8-D-ribofurano-syl)selenazol-4-carboxylat ammonolyse, b) phosphorylerer 2-/3-D-ribofuranosylselenazol-4-carboxamid, c) acylerer 2-j8-D-robofuranosylselenazol-4-carboxamid, og 25 d) isolerer produktet, eventuelt i form af et salt.
Ammonolysereaktionen til fremstilling af 2-/3-D-ribofuranosyl-selenazol-4-carboxamid (forbindelse 1) udføres i et passende opløsningsmiddel, såsom methanol. Reaktionsbetingelserne kan varieres, såsom f.eks. ved omgivelsernes temperatur og tryk, 30 fortrinsvis ved stuetemperatur, indtil reaktionen er afsluttet, f.eks. i ca. 24 timer. Produktet isoleres fra reaktions- DK 172165 B1 3 blandingen på en hvilken som helst egnet måde, såsom ved hjælp af søjlekromatografi. Udgangsmaterialets alkyl- og acylgrupper kan varieres inden for vide grænser, eftersom de fjernes under reaktionen, og valget deraf er således ikke 5 kritisk. Foretrukne alkylgrupper er C-^-Cg-alkylgrupper. Foretrukne acylgrupper er acetylgruppen, n-butyrylgruppen og benzoylgruppen.
Phosphoryleringsreakt ionen til fremstilling af 2-jS-D-ribo-furanosylselenazol-4-carboxamid-5'-phosphatforbindelser ud-10 føres med den nævnte forbindelse 1 (eller et 2'-0-acyl-, 3'-0-acyl- eller 2',3-di-O-acylderivat deraf) samt et phospho-ryleringsmiddel, såsom phosphorylchlorid, fordelagtigt i kulden, i et passende medium, såsom triethylphosphat eller pyridin og acetonitril. Produktet isoleres fra reaktionsblan-15 dingen på en hvilken som helst egnet måde, såsom ved ionbytningskromatografi. Acylering udføres ved omsætning af forbindelsen 1 med acyleringsmidlet, såsom et syreanhydrid eller syrechlorid, fortrinsvis i overskud ved omgivelsernes temperatur, indtil reaktionen er afsluttet.
20 Mellemproduktet 2,5-anhydro-3,4,6-tri-O-acyl-D-allonseleno-carboxamid ifølge opfindelsen, hvori Z er -C(NH2)Se, kan fremstilles ved omsætning af 2,3,5-tri-0-acyl-/3-D-ribofurano-sylcyanid med flydende hydrogenselenid i nærværelse af amin-katalysator. Katalysatoren kan være en alkylaminopyridin, 25 fortrinsvis 4-dimethylaminopyridin. Acylgrupperne i nævnte 2,5-anhydro-3,4,6-tri-O-acyl-D-allonselenocarboxamid kan være lavere alkanoyl eller benzoyl, fortrinsvis acetyl eller benzoyl. Reaktionen får lov at forløbe i en trykbeholder, såsom en lukket bombe, ved omgivelsernes temperatur og tryk i 3 0 1 til 24 timer. Selenocarboxamiderne opnås i ren form ved at fjerne overskuddet af hydrogenselenid og underkaste resten ekstraktion og kromatografi.
Mellemprodukterne ifølge opfindelsen, hvor Z er en selenazol- 4-(lavere alkyl)carboxylat-2-yl-gruppe, kan fremstilles ved 4 DK 172165 B1 cyklisering af 2,5-anhydro-3,4,6-tri-O-acyl-D-allonseleno-carboxamid med et lavere (C-^-Cg) alkylbrompyruvat (ROCOCOCH2-Br) til opnåelse af et alkyl-2-(2,3,5-tri-0-acyl-/3-D-ribo-furanosyl)selenazol-4-carboxylat. Cykliseringsreaktionen ud-5 føres i kulden i et egnet opløsningsmiddel, såsom acetonitril eller en lavtkogende alkohol.
Fremstillingen af mellemprodukterne ifølge opfindelsen og deres anvendelse ved fremstillingen af slutprodukterne ifølge DK patent nr. 167.765 er belyst i eksemplerne nedenfor.
10 Eksempel 1 2,5-anhydro-3,4,6-tri-O-benzoyl-D-allonselenocarboxamid.
En blanding af 2,3,5-tri-0-benzoyl-/?-D-ribofuranosylcyanid (10,0 g, 21,2 mmol), 4-dimethylaminopyridin (200 mg) og flydende hydrogenselenid (kondenseret under en N2-atmosfære, 15 20 ml) blev omrørt i en lukket bombe ved stuetemperatur i 20 timer. Hydrogenselenid fik lov til at afdampe. Den mørkt farvede rest blev opløst i chloroform (200 ml) og vasket i rækkefølge med vand (3 x 50 ml) , mættet NaHC03 (3 x 50 ml) efterfulgt af vand (2 x 50 ml) . Chloroformportionen blev 20 tørret (MgS04) og under vakuum inddampet til opnåelse af produktet som et skum i næsten kvantitativt udbytte. Produktet med analyserenhed blev opnået ved hjælp af søjlekromatografi (silicagel, 5% ethylacetat i chloroform).
Produktet udviklede en violet farve, når silicagelkromato-25 grammet af produktet blev sprøjtet med en fortyndet ethanol-opløsning af 2,3-dichlornaphthoquinon, og blev udsat for ammoniak. Analyse beregnet for ^27^23^7^0: C 58,91; H 4,21;
Se 13,98. Fundet: C 58,81; H 4,29; N 2,51; Se 13,74.
DK 172165 Bl 5
Eksempel 2
Ethyl-2-(2,3,5-tri-O-benzoyl-D-ribofuranosyl)selenazol-4-carboxylater.
En opløsning af 2,5-anhydro-3,4,6-tri-O-benzoyl-D-allonse-5 lenocarboxamid (5,5 g, 10 mmol) i acetonitril (60 ml) blev kølet i is. Ethylbrompyruvat (3,0 g) i acetonitril (20 ml) blev dråbevis tilsat (10 minutter) . Isbadet blev fjernet, og reaktionsblandingen blev omrørt ved stuetemperatur i 1 time. Opløsningsmidlet blev afdampet i vakuum, og resten blev tri-10 tureret med en mættet natriumhydrogencarbonatopløsning (100 ml) samt ekstraheret med ethylether (2 x 100 ml). Den kombinerede etherportion blev vasket med vand og tørret (MgS04). Etheren blev afdampet i vakuum og resten (sirup) ført gennem en silicagelsøjle (300 g), pakket i chloroform. Eluering med 15 5% ethylacetat i chloroform resulterede i titelprodukter: nemlig den hurtigt bevægende ethyl-2-(2,3,5-tri-0-benzoyl-2-jS-D-ribofuranosyl) selenazol-4-carboxylat (2,5 g) og det langsomt bevægende ethyl-2-(2,3,5-tri-0-benzoyl-2-o;-D-ribo-furanosyl)selenazol-4-carboxylat (1,0 g), der blev isoleret 20 efter inddampning under formindsket tryk i form af tyktflydende sirupper. jS-isomeren, ethyl-2-(2,3,5-tri-0-benzoyl-2-j(?-D-ribofuranosyl)selenazol-4-carboxylat, er karakteriseret ved en optisk drejning, 1,07% i methanol, [α]^ = 34,7°. Analyse 25 beregnet for C32H27N09Se (648,51): C 59,26; H 4,20; N 2,16.
Fundet: C 59,44; H 4,21; N 1,89.
Fremstilling af 2-jS-D-ribofuranosylselenazol-4-carboxamid ifølge DK patent nr. 167.765_
Ethyl-2-(2,3,5-tri-0-benzoyl-/3-D-ribofuranosyl)selenazol-4-30 carboxylat (3,2 g, 5 mmol) blev opløst i methanol (100 ml), kølet samt mættet med ammoniak (0°C). Opløsningen blev omrørt i en trykflaske ved stuetemperatur i 48 timer. Opløsningsmidlet blev afdampet i vakuum, og resten blev ekstraheret med chloroform (3 x 25 ml). Chloroformmængden blev bortkastet.
Claims (3)
- 6 DK 172165 B1 Resten blev adsorberet på silicagel (10 g) ved hjælp af methanol og overført til en silicagelsøj le (2,8 x 45 cm) pakket i ethylacetat. Søjlen blev elueret med opløsningsmiddel E (ethylacetat, n-propanol, H20; 4:1:2; vol/vol: 5 øverste lag danner opløsningsmiddel E), og de homogene fraktioner (Rf = 0,42, silicagel-tlc i opløsningsmiddel E) indeholdende hovedproduktet blev opsamlet. Opløsningsmidlet blev afdampet i vakuum, og titelforbindelsen blev som rest krystalliseret fra 2-propanol: udbytte 900 mg af titelforbin-10 delsen (60%), med smeltepunkt 135-136°C. Resten resulterede i et andet udbytte (200 mg) med smeltepunkt 131-133°C. Analyse beregnet for CgH12N205Se: C 35,19; H 3,94; N 9,12; Se 25,71. Fundet: C 35,43; H 3,97; N 9,03; Se 25,55. [a]25 , 1,07% i 15 methanol, -22,2°. Mellemprodukter til fremstilling af terapeutisk aktive 2-β-Ό-ribofuranosylselenazol-4-carboxamidforbindelser, kende -20 tegnet ved, at de har den almene formel r3och2 2 Nl-J/I
- 2. RO OR hvori R1 og R2 hver er H, lavere alkanoyl eller benzoyl, R3 er H, lavere alkanoyl, benzoyl eller O, og Z er -C(NH2)Se HO-P-
- 25 I OH eller selenazol-4-(lavere alkyl)carboxylat-2-yl.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US36096882A | 1982-03-23 | 1982-03-23 | |
| US36096882 | 1982-03-23 | ||
| US46522183 | 1983-02-15 | ||
| US06/465,221 US4531001A (en) | 1982-03-23 | 1983-02-15 | 2-β-D-ribofuranosylselenazole-4-carboxamide compounds |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK25093A DK25093A (da) | 1993-03-08 |
| DK25093D0 DK25093D0 (da) | 1993-03-08 |
| DK172165B1 true DK172165B1 (da) | 1997-12-08 |
Family
ID=27001098
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK129983A DK167765B1 (da) | 1982-03-23 | 1983-03-22 | Analogifremgangsmaade til fremstilling af 2-beta-d-ribofuranosylselenazol-4-carboxamidforbindelser |
| DK025093A DK172165B1 (da) | 1982-03-23 | 1993-03-08 | Mellemprodukter til fremstilling af terapeutisk aktive 2-beta-D-ribofuranosylselenazol-4-carboxamidforbindelser |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK129983A DK167765B1 (da) | 1982-03-23 | 1983-03-22 | Analogifremgangsmaade til fremstilling af 2-beta-d-ribofuranosylselenazol-4-carboxamidforbindelser |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US4531001A (da) |
| EP (1) | EP0089678B1 (da) |
| KR (1) | KR880001869B1 (da) |
| AU (1) | AU553665B2 (da) |
| CA (1) | CA1209986A (da) |
| DE (1) | DE3366378D1 (da) |
| DK (2) | DK167765B1 (da) |
| ES (5) | ES8404373A1 (da) |
| FI (1) | FI76574C (da) |
| GR (1) | GR78301B (da) |
| IE (1) | IE54520B1 (da) |
| NO (1) | NO155842C (da) |
| NZ (1) | NZ203649A (da) |
| PT (1) | PT76426B (da) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4619996A (en) * | 1984-07-09 | 1986-10-28 | Warner-Lambert Company | Process for preparing 2-β-D-ribofuranosylselenazole-4-carboxamide |
| US4801698A (en) * | 1986-08-15 | 1989-01-31 | Warner-Lambert Company | Process for preparing diaminopyrimido(4,5-d)pyrimidine glycoside and glycotide |
| US5438131A (en) * | 1992-09-16 | 1995-08-01 | Bergstrom; Donald E. | 3-nitropyrrole nucleoside |
| GB9307043D0 (en) * | 1993-04-05 | 1993-05-26 | Norsk Hydro As | Chemical compounds |
| WO1996026212A1 (en) * | 1995-02-17 | 1996-08-29 | Icn Pharmaceuticals, Inc. | Procedures for obtaining ribo-c-nucleosides |
| RU2185385C2 (ru) * | 1997-06-30 | 2002-07-20 | Ай-Си-Эн Фармасьютикалз, Инк. | Способ получения тиазофурина и других с-нуклеозидов |
| CN1166651C (zh) * | 2001-06-08 | 2004-09-15 | 北京大学药学院 | 具有抗炎和抗肿瘤作用r-双或糖苯丙异硒唑取代化合物 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3423399A (en) * | 1966-06-09 | 1969-01-21 | Takeda Chemical Industries Ltd | Method for the production of 5'-ribonucleotide |
| US3984396A (en) * | 1971-06-01 | 1976-10-05 | Icn Pharmaceuticals, Inc. | 1-(β,-D-ribofuranosyl)-1,2,4-triazole acid esters |
| US3798209A (en) * | 1971-06-01 | 1974-03-19 | Icn Pharmaceuticals | 1,2,4-triazole nucleosides |
-
1983
- 1983-02-15 US US06/465,221 patent/US4531001A/en not_active Expired - Fee Related
- 1983-03-18 IE IE580/83A patent/IE54520B1/en not_active IP Right Cessation
- 1983-03-22 AU AU12693/83A patent/AU553665B2/en not_active Expired
- 1983-03-22 KR KR1019830001203A patent/KR880001869B1/ko not_active Expired
- 1983-03-22 DK DK129983A patent/DK167765B1/da not_active IP Right Cessation
- 1983-03-22 NO NO831012A patent/NO155842C/no unknown
- 1983-03-22 PT PT76426A patent/PT76426B/pt not_active IP Right Cessation
- 1983-03-22 ES ES520826A patent/ES8404373A1/es not_active Expired
- 1983-03-22 FI FI830941A patent/FI76574C/fi not_active IP Right Cessation
- 1983-03-22 GR GR70837A patent/GR78301B/el unknown
- 1983-03-22 DE DE8383102841T patent/DE3366378D1/de not_active Expired
- 1983-03-22 NZ NZ203694A patent/NZ203649A/xx unknown
- 1983-03-22 EP EP83102841A patent/EP0089678B1/en not_active Expired
- 1983-03-22 CA CA000424166A patent/CA1209986A/en not_active Expired
- 1983-11-15 ES ES527277A patent/ES527277A0/es active Granted
- 1983-11-15 ES ES527279A patent/ES527279A0/es active Granted
- 1983-11-15 ES ES527278A patent/ES527278A0/es active Granted
- 1983-11-15 ES ES527276A patent/ES527276A0/es active Granted
-
1993
- 1993-03-08 DK DK025093A patent/DK172165B1/da not_active IP Right Cessation
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Legal Events
| Date | Code | Title | Description |
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| A0 | Application filed | ||
| B1 | Patent granted (law 1993) | ||
| PUP | Patent expired |