DD152564B1 - Process for the preparation of deoxyribonucleoside and ribonucleoside polyphosphates - Google Patents
Process for the preparation of deoxyribonucleoside and ribonucleoside polyphosphatesInfo
- Publication number
- DD152564B1 DD152564B1 DD152564B1 DD 152564 B1 DD152564 B1 DD 152564B1 DD 152564 B1 DD152564 B1 DD 152564B1
- Authority
- DD
- German Democratic Republic
- Prior art keywords
- deoxyribonucleoside
- preparation
- ribonucleoside
- polyphosphates
- general formula
- Prior art date
Links
- 229920000388 Polyphosphate Polymers 0.000 title claims description 7
- 239000001205 polyphosphate Substances 0.000 title claims description 7
- 239000005549 deoxyribonucleoside Substances 0.000 title claims description 6
- 235000011176 polyphosphates Nutrition 0.000 title claims description 6
- 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 title claims description 5
- 238000000034 method Methods 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title claims description 5
- 239000002342 ribonucleoside Substances 0.000 title claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- XPPKVPWEQAFLFU-UHFFFAOYSA-J Pyrophosphate Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 235000011180 diphosphates Nutrition 0.000 claims description 2
- 239000002777 nucleoside Substances 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 230000000875 corresponding Effects 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 238000002955 isolation Methods 0.000 claims 1
- 150000003833 nucleoside derivatives Chemical class 0.000 claims 1
- 239000003960 organic solvent Substances 0.000 claims 1
- 125000000714 pyrimidinyl group Chemical group 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 description 6
- IQFYYKKMVGJFEH-XLPZGREQSA-N DEOXYTHYMIDINE Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 230000002194 synthesizing Effects 0.000 description 3
- 229920005654 Sephadex Polymers 0.000 description 2
- 239000012507 Sephadex™ Substances 0.000 description 2
- 229940104230 Thymidine Drugs 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N Trimethylglycine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- NHVNXKFIZYSCEB-XLPZGREQSA-N dTTP Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)C1 NHVNXKFIZYSCEB-XLPZGREQSA-N 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- IWSZDQRGNFLMJS-UHFFFAOYSA-N 2-(dibutylamino)ethanol Chemical compound CCCCN(CCO)CCCC IWSZDQRGNFLMJS-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N 289-95-2 Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- RZCIEJXAILMSQK-JXOAFFINSA-N 5-Methyluridine triphosphate Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 RZCIEJXAILMSQK-JXOAFFINSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- GLUYADGKGBGXRV-UHFFFAOYSA-L chloro phosphate Chemical compound [O-]P([O-])(=O)OCl GLUYADGKGBGXRV-UHFFFAOYSA-L 0.000 description 1
- 238000010192 crystallographic characterization Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- AFQIYTIJXGTIEY-UHFFFAOYSA-N hydrogen carbonate;triethylazanium Chemical compound OC(O)=O.CCN(CC)CC AFQIYTIJXGTIEY-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- VKFFEYLSKIYTSJ-UHFFFAOYSA-N tetraazanium;phosphonato phosphate Chemical compound [NH4+].[NH4+].[NH4+].[NH4+].[O-]P([O-])(=O)OP([O-])([O-])=O VKFFEYLSKIYTSJ-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 201000007023 thrombotic thrombocytopenic purpura Diseases 0.000 description 1
Description
Dr. Б. Bauschke Dr. M0 Meisel Dr. T. BrankovDr. Б. Bauschke M 0 Meisel T. Brankov
Verfahren zur Herstellung von Desoxyribonucleosid- und Ribo-Process for the preparation of deoxyribonucleoside and ribo
nucleo.qid-polyphosphatennucleo.qid-polyphosphates ii
Die Erfindung betrifft ein Verfahren zur Herstellung von Desoxyribonucleosid- und Ribonucleosid^polyphosphaten der allgemeinen Formel I ^"The invention relates to a process for the preparation of deoxyribonucleoside and Ribonucleosid ^ polyphosphates of the general formula I ^
D "D "
Ό-ρ-Ό-ρ-
^ η^ η
ОН (O)HОН (O) H
in der n=1,2,3 B= Purin und Pyrimidinba-in the n = 1,2,3 B = purine and pyrimidine base
m = η + 1 sen und deren Derivatem = η + 1 sen and their derivatives
bedeuten.mean.
Anwendungsgebiet ist die Hucleotidchemie, Biochemie, Radiochemische Synthese·Field of application is the nucleotide chemistry, biochemistry, radiochemical synthesis ·
Charakteristik der bekannten technischen Lösungen Bekannt sind bereits Synthesen der Desoxyribonucleosid- und Ribonucleosidpolyphosphaten der allgemeinen Formel I(vgl. L. A. Slotin Synthesis (1977) 237 - 52), jedoch besteht der Kachteil der meisten Verfahren für diese Synthesen in zeit- und arbeitsaufwendigen Mehrstufenpräparationen, bzw« waren die Ausbeuten der Synthesen im kleinen Maßstab, z. B. /U mol, stark reduziert. Characteristics of the Known Technical Solutions Syntheses of the deoxyribonucleoside and ribonucleoside polyphosphates of the general formula I have already been disclosed (see LA Slotin Synthesis (1977) 237-52), but the majority of the processes for these syntheses consist of time-consuming and labor-intensive multistage preparations, or were the yields of the syntheses on a small scale, z. B. / U mol, greatly reduced.
Die Erfindung hat das Ziel, ein technisch einfaches und schnelles Verfahren zur Herstellung von Verbindungen der Formel I und für kleine Ansatzgrößen, z· В· м mol-Maßstab, zu entwickeln«,The invention aims a technically simple and rapid method for preparing compounds of formula I and for small batch sizes, such · В · м mole scale to develop "
Erfindungsgemäß werden Verbindungen der Formel I hergestellt, indem man in einem Eintopfverfahren IJ- oder/und O-geschützte oder ungeschützte Nucleoside der allgemeinen Formel ROH, wobei R = Desoxy- oder Ribonucleosid bedeutet, wie Thymidin oder 2',31-Isopropyliden-Üridin im Pyridin mit Chlorphosphatbetain umsetzt und nach einigen Minuten Phosphat, Pyrophosphat oder höhere lineare Polyphosphate als organische Ammoniumsalze hinzugibt·According to the invention compounds of formula I are prepared by reacting in a one-pot IJ- and / or O-protected or unprotected nucleosides of the general formula ROH, wherein R = deoxy- or ribonucleoside means, such as thymidine or 2 ', 3 1 -isopropyliden-uridine in the pyridine with chlorophosphatbetain and after a few minutes added phosphate, pyrophosphate or higher linear polyphosphates as organic ammonium salts ·
Hach weiteren Minuten wird durch Zugabe von H2O oder Puffer der Ansats hydrolysiert, im Vakuum eingeengt und auf eine Anionenaustauscher-Säuie z. B· DEAE-Sephadex-A 25» gegeben und durch Elution das gewünschte Produkt isoliert· Durch die Einfachheit und gute Produktausbeute dieses Syntheseweges, eignet sich dieses Verfahren auch gut für die Umsetzung spezieller, derivatisierter Uukleoside in kleiner Ansatzgröße·Hach another minutes is hydrolyzed by the addition of H 2 O or buffer of Ansats, concentrated in vacuo and z on a Anionenaustauscher. B · DEAE-Sephadex A 25 »and the desired product isolated by elution · The simplicity and good product yield of this synthetic route, this method is also well suited for the implementation of specific, derivatized Uukleoside in small batch size ·
Das folgende Ausführungsbeispiel erläutert die Erfindung näher:The following embodiment explains the invention in more detail:
Eint prüfverfahren - Synthese Thymidintriphosphat 3 mg (12 /Umol) Thymidin wurden zu einer Lösung von 11 rag (62 /Umol) Chlorphosphatbetain in 0,5 ml absolutem Pyridin gegeben und 15 min leicht geschüttelt* Anschließend wurden 400 /Umol Tri-(u-butyl)-ammoniumpyrophosphat in 1 ml absolutem Pyridin hinzugegeben und weitere 15 min geschüttelt. Nach Zugabe von 1 ml 1 M Triäthylammoniumbicarbonat-Lösung wurde im Vakuum (p = 1 Torr) eingeengt, mit 0»5 ml Aqua-de3t. wurde der feste Rückstand aufgenommen und auf eine DBAE-Sephadex- Conclusion - Synthesis Thymidine triphosphate 3 mg (12 / umol) of thymidine was added to a solution of 11 rag (62 / umol) chlorophosphate betaine in 0.5 ml of absolute pyridine and shaken gently for 15 min * Then 400 / umol of tri- (u- butyl) ammonium pyrophosphate in 1 ml of absolute pyridine and shaking for an additional 15 minutes. After addition of 1 ml of 1 M Triäthylammoniumbicarbonat solution was concentrated in vacuo (p = 1 Torr), with 0 »5 ml Aqua de3t. the solid residue was taken up and assayed for a DBAE Sephadex
A 25-Säule in KCO^-Form aufgetragen. Die Dimension der Säule war 0.5 x 15 cm» flach dem Spülen des Gelbettes mit H2O erfolgte die Eiution mit kontinuierlichem Gradienten 50 ml H2O zu 50 ml 0.8 M Triäthylammoniumbicarbonatpuffer. Nach 37 ml-Vorlauf wurde еіпеЮ ml Fraktion aufgefangen, die 2.4 /Umol Thymidin 5'-triphosphat enthielt. Die Gesamtausbeute über alle Reaktions- und Reinigungsschritte betrug 20 %. Produktcharakterisierung erfolgte dünnschichtchromatographischen Vergleich (TTP der Pirma Boehringer) Rf =' 0.23 im Laufmittelgemisch Dioxan: 25 % HIU : H2OA 25 column in KCO ^ form applied. The dimension of the column was 0.5 x 15 cm. Flattening of the gel bed with H 2 O was followed by continuous gradient elution with 50 ml of H 2 O to 50 ml of 0.8 M triethylammonium bicarbonate buffer. After 37 ml flow, ε_pеЮ ml fraction containing 2.4 / umol thymidine 5'-triphosphate was collected. The total yield over all reaction and purification steps was 20 %. Product characterization was carried out by thin-layer chromatography (TTP from Pirma Boehringer) Rf = '0.23 in the solvent mixture dioxane: 25% HIU: H 2 O.
wie 6 : 1 : 4like 6: 1: 4
Rf β 0.08 im Laufmittelgemisch n-Propanol:25% ИТЦ : H2ORf β 0.08 in eluent mixture n-propanol: 25% ИТЦ: H 2 O.
wie 6 : 3 : 1like 6: 3: 1
(UV _ = 260 nm pH = 7)(UV = 260 nm pH = 7)
Claims (1)
o-p-Il
op-
bedeuten,m = (n + 1)
mean,
Family
ID=
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