EP1592697A1 - Nucleoside analogues with apoptosis-inducing characteristics for treating diseases caused by rapidly proliferating cells - Google Patents
Nucleoside analogues with apoptosis-inducing characteristics for treating diseases caused by rapidly proliferating cellsInfo
- Publication number
- EP1592697A1 EP1592697A1 EP04709602A EP04709602A EP1592697A1 EP 1592697 A1 EP1592697 A1 EP 1592697A1 EP 04709602 A EP04709602 A EP 04709602A EP 04709602 A EP04709602 A EP 04709602A EP 1592697 A1 EP1592697 A1 EP 1592697A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- aryl
- alkyl
- acyl
- geranyl
- derivatives
- 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.)
- Withdrawn
Links
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
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- 125000003118 aryl group Chemical group 0.000 claims 26
- 125000000217 alkyl group Chemical group 0.000 claims 25
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims 18
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims 16
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- 229960002436 cladribine Drugs 0.000 description 1
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- 125000001995 cyclobutyl group Chemical class [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
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- 229960001904 epirubicin Drugs 0.000 description 1
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- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
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- 230000003834 intracellular effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
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- 239000002547 new drug Substances 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002718 pyrimidine nucleoside Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
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- 208000013077 thyroid gland carcinoma Diseases 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
-
- 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
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
Definitions
- the present invention relates to compounds and medicaments for the treatment of diseases caused by highly proliferating cells, and to processes for the preparation of such compounds and medicaments.
- ALL acute lymphoblastic leukemia
- Tumor diseases such as thyroid carcinoma, very common breast cancer, difficult to access medulloblastoma or towards gliomas.
- a benign skin condition that is also treated with such therapies is psoriasis (psoriasis). It is one of the most common skin diseases that affect two to four percent of people. The therapy for this disease is also in great need of improvement.
- WO 2080923 AI describes nucleoside analogues that trigger apoptosis and have a cytostatic effect. These compounds have in common a ring structure which contains a diene system to which an iron tricarbonyl is preferably coordinatively bound. Because of the diene structure, the known substances are difficult to synthesize. The substances tend to undesirable side reactions due to the reactivity of the diene and are therefore relatively unstable. This is disadvantageous both for storage and preparation in connection with other pharmaceutical components, and for the specificity after administration.
- Velcicky et al., 2002 discloses a general synthetic strategy for nucleoside analogs using targeted protecting groups. According to the authors, the synthesis should make it possible to produce a large variety of nucleoside analogues that could potentially have biological activity.
- Nucleoside analogues have an antiviral potential.
- EP-A-0 358 154 discloses cyclobutane derivatives and a process for their preparation.
- FR-A-2 662 165 discloses branched nucleoside derivatives, a process for their preparation and their use in a medicament.
- the invention is therefore based on the object of providing corresponding substances. Another task is to provide substances with alternative and new mechanisms of action in order to expand and supplement the treatment options. The invention is also based on the object of providing corresponding substances which are simple to manufacture and are relatively stable.
- the invention does not relate to the compounds described in Velcicky et al. (2002).
- the subject of the invention are, as far as claimed, corresponding medicaments.
- the authors did not recognize that some of the products and intermediate products disclosed are themselves particularly suitable for the treatment of tumors.
- the invention relates to the various stereoisomers of the compounds according to the invention, the individual enantiomers and the corresponding racemates.
- the cis configuration in the compounds according to the invention denotes that the radicals Y and Z are on the same side of the central five-membered ring.
- the compounds according to the invention can be used to prepare a medicament for the treatment of malignant diseases of the bone marrow or other hematopoietic organs, solid tumors, epithelial tumors, benign or semimalignant rapidly proliferating tumors or skin diseases, in particular psoriasis vulgaris, keloids and basaliomas, lymphomas, in particular Hodgkin's and non-Hodgkin's lymphomas, inflammatory, chronically inflammatory, bacterial and autoimmune diseases, as well as for antibacterial, antifungal, anti-protozoa, anti-plasmodia, anti-helminthic, antiviral or immunosuppressive therapy.
- the pharmaceuticals and compounds according to the invention are unexpectedly suitable for the therapy of pathologically rapidly proliferating tissue, in particular bone marrow, but also of solid tumors, such as epithelial tumors or in particular brain tumors. Furthermore, the applicability of the substances described also extends to the treatment of benign, hyperproliferative diseases of the skin, such as, for. B. the psoriasis or the keloid.
- the drugs and substances of the invention are characterized in that they are particularly suitable, selectively that Inhibit growth of highly proliferating cells. As a result, they initiate apoptosis of highly proliferating cells and thus destroy them, with healthy cells being affected very little.
- the experiments carried out show that substances according to the invention trigger apoptosis unusually quickly. The experiments carried out suggest that apoptosis could be initiated using a new mechanism.
- the substances are particularly preferably membrane-permeable, which leads to a high intracellular active substance concentration. The high effectiveness is therefore likely to be achieved through the pronounced lipophilicity of the substances.
- the substances differ fundamentally from known nucleoside analogues used for therapy, such as cytarabine, cladribine and fludarabine 5'-dihydrogen phosphate. They are able to break existing cytostatic resistances.
- the pharmaceuticals and compounds of the invention are particularly suitable for the treatment of tumor diseases and leukemia. They induce apoptotic cell death not only in permanent cell lines (BJAB cells) formed from tumor cells, but also in primary cells from patients with acute lymphoblastic leukemia (ALL). This allows the substances according to the invention against tumor diseases of the bone marrow, but also against tumors of another provenance, such as. B. epithelial tumors, sarcomas or malignant diseases of the skin, etc. are used.
- the developed substances are able to cross the blood-brain barrier unhindered due to their lipophilicity. Therefore, they can be used to treat malignant brain tumors, such as, for. B. the medulloblastoma or gliomas can be used.
- the substances according to the invention can be used to treat malignant diseases of the bone marrow or other hematopoietic organs, solid tumors, epithelial tumors, benign or semi-malignant rapidly proliferating skin diseases, in particular psoriasis vulgaris, keloids and basaliomas, as well as inflammatory and chronic inflammatory diseases. They are also suitable for antiviral, antibacterial, antifungal, anti-protozoa, anti-helminthic or immunosuppressive therapy.
- the compounds and medicaments of the invention have the advantage over the known substances from WO02 / 080923 that they are easier to synthesize, handle and store, and have little tendency to undesirable side reactions in the preparation of the medicament and also in the body.
- apoptosis shows that the cell death triggered by the novel nucleoside analogs is not undifferentiated necrosis but apoptosis.
- the measurement of apoptosis is based on a method that demonstrates the fragmentation of DNA typical of apoptosis at the individual cell level, which distinguishes this cell death form from necrosis.
- BJAB cells were treated for 72 h with a concentration of 20 ⁇ mol / l of different nucleoside analogs. Controls contained appropriate amounts of the solubilizer ethanol. After the treatment, the fragmentation of the DNA was stained with propidium iodide and then quantified by flow cytometry as described by Eßmann et al. (2000). The values are given as% apoptotic cells of the total population. Duplicate values were measured the mean value given was confirmed after two independent repetitions of the experiment (deviations ⁇ 3%).
- FIG. 3 shows apoptosis induction via the resulting DNA fragmentation on primary lymphoblasts - of children with acute lymphoblastic leukemia (ALL). After isolation of the primary lymphoblasts and dilution with cell culture medium, they were treated with 20 ⁇ M each of the nucleoside analog for 36 h.
- ALL acute lymphoblastic leukemia
- Controls contained appropriate amounts of the solubilizer ethanol. After the treatment, the fragmentation of the DNA was stained with propidium iodide and then quantified by flow cytometry as described by Eßmann et al. (2000). The values are given as% apoptotic cells of the total population. Duplicate values were measured, the mean value being confirmed after two independent repetitions of the experiment (deviations ⁇ 3%).
- Procaspase-3, Pro-C-8 and Pro-C-9 became more specific Immunodetection in a Western blot as described by Eßmann et al. (2000).
- the positions of the procaspases and the processed subunits in the SDS-polyacrylamide gel are indicated by dashes on the left edge of FIG. 4.
- the addition of 20 ⁇ mol / l of the substances to the medium of BJAB cells triggers a processing of the Procaspasen-3, -8 and -9 in these cells.
- the specific, immunochemical detection of the active subunits of caspases-3, -8 and -9 in treated cells can be seen in contrast to the corresponding control cells.
- the nucleoside analogue (-) - 159b induces the caspase processing (FIG. 4) so quickly that even at the time of measurement after 36 h hardly any of the procaspases-3, -8 and -9 are present.
- 5 already contains a first indication of the apoptosis signal cascade activated by the novel nucleoside analogs. 5 shows that the BJAB cells incubated with the novel nucleoside analogs over 48 h are driven into the mitchondrial apoptosis pathway. This was visualized by staining the cells with the mitochondrial specific 'ifischen dye JC-1, such as by re et al. (2001). Incubation of the cells with the new nucleoside analogues led to a significant increase in the proportion of cells with a reduced mitochondrial, membrane potential ( ⁇ m ) from 5% in the control to 80%, which indicates a strong activation of the mitochondria during the apoptotic process indicates (Fig. 5).
- the compound racx4 (FIG. 6) shows an apoptosis of approximately 42% at a concentration of 100 ⁇ g / ml.
- the usability of the substances according to the invention for the therapy of various malignant diseases of the hematopoietic system has been successfully tested in vitro on cells from patients with different diseases.
- the substances of general structural formula 2 are thus effective as agents against certain tumor cells, particularly those of childish ALL, but also against other malignant diseases of different origins.
- the medicaments according to the invention can be administered topically or intravenously.
- the substances are administered in the concentration range between 0.1 to 100 ⁇ g / ml, based on the patient's blood volume.
- the substances are rubbed into the diseased skin in a concentration of 0.1 to .5% by weight, based on the finished preparation.
- racemic precursors of the rac-100 type are prepared by known methods (see WO 02/080923 and Velcicky et al., 2002).
- To produce the optically active compounds as explained in WO 02/080923, either the chirogenic step of the synthesis (Pauson-Khand reaction) is carried out enantioselectively, or a racemate resolution is carried out at a subsequent stage.
- the following reactions can be carried out by individual enantiomers or by the racemate.
- a solution of lOOa-e (lmmol) and PPTS (76 mg, 300 ⁇ mol, 30 mol%) in absolute acetone (10 ml) was stirred under reflux for 3 h.
- IR (ATR, cm “1 ): 3177 (w, NH), 3050 (w, NH), 2954 (m, CH), 2864 (m, C-
- the compound (-) - 113b was obtained as a colorless oil (48 mg, 99% yield) according to the general experimental procedure.
- the compound (-) - 113d-l was obtained according to the general experimental procedure as a mixture of the protected and free alcohol, which was used directly in the following reaction to remove the protective group.
- IR (ATR, cm “1 ): 3330 (bm, OH), 3199 (m, NH), 2954 (m, CH), 2863 (m,
- the compound (-) - 159c-1 was obtained as a light yellow liquid according to the general experimental procedure (23 mg, 79% yield).
- Rho-GDI 2 The GDP dissociation inhibitor, D4-GDI (Rho-GDI 2), but not the homologous Rho-GDI 1, is cleaved by caspase-3 during drug-induced apoptosis, Biochem. J. 346, 777-783.
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract
Description
Nuk.eosidanaloqa mit Apoptose-induzierenden Eigenschaften zur Therapie durch hoch-proliferierende Zellen verursachter Erkrankungen Nuk.eosidanaloqa with apoptosis-inducing properties for the therapy of diseases caused by highly proliferating cells
Die vorliegende Erfindung betrifft Verbindungen und Arzneimittel zur Behandlung von Erkrankungen, die durch hoch-proliferierende Zellen verursacht werden, sowie Verfahren zur Herstellung solcher Verbindungen und Arzneimittel.The present invention relates to compounds and medicaments for the treatment of diseases caused by highly proliferating cells, and to processes for the preparation of such compounds and medicaments.
Die Entstehung maligner, semimaligner Tumore und anderer gutartiger hyperproliferativer Erkrankungen, wie z. B. der Schuppenflechte oder des Keloids, ist auf eine gestörte Balance zwischen der Gewebeneubildung und dem regulierten Absterben von Zellen aus dem Gewebeverbund zurückzuführen. In der klinischen Praxis wird durch den Einsatz zytotoxischer Behandlungsmethoden, wie der Chemotherapie, der Strahlentherapie und der Hyperthermie, versucht, diese gestörte Balance wieder ins Gleichgewicht zu bringen und die überschüssigen Tumorzellen gleichzeitig abzutöten. Es ist allgemein anerkannt, dass die meisten derzeit in der klinischen Praxis eingesetzten Chemotherapeutika ihre Wirkung durch Einleitung der Apoptose (programmierter Zelltod) entfalten (Hannun, 1997). Allerdings entwickelt ein Teil der an malignen Tumoren erkrankten Patienten frühzeitig eine Chemotherapie- und Strahlenresistenz oder ist primär therapierefraktär (Hickman, 1996). Weiterhin ist bekannt, dass Primärtumor und Metastasen auf zytotoxische Therapien oft ganz different ansprechen. Aufgrund neuerer Untersuchungen ist wahrscheinlich, dass die Ursache für Resistenzen in unterschiedlichen Störungen der Apoptosesignalkaskade liegt (Raisova et al., 2000).The emergence of malignant, semimalignant tumors and other benign hyperproliferative diseases, such as. B. psoriasis or the keloid, is due to a disturbed balance between the formation of new tissue and the regulated death of cells from the tissue composite. In clinical practice, the use of cytotoxic treatment methods such as chemotherapy, radiation therapy and hyperthermia tries to bring this disturbed balance back into balance and to kill the excess tumor cells at the same time. It is generally accepted that most chemotherapeutic agents currently used in clinical practice develop their effects by induction of apoptosis (programmed cell death) (Hannun, 1997). However, some of the patients suffering from malignant tumors develop chemotherapy and radiation resistance at an early stage or are primarily refractory to therapy (Hickman, 1996). It is also known that primary tumors and metastases often respond very differently to cytotoxic therapies. Based on recent studies, it is likely that the cause of resistance lies in different disorders of the apoptosis signal cascade (Raisova et al., 2000).
Besonders die Therapie eines Rezidivs der kindlichen akuten lymphoblastischen Leukämie (ALL), der häufigsten malignen Erkrankung im Kindesalter, ist noch immer nicht befriedigend gelöst. So versterben z. B. trotz aggressiver Therapie ca. 70% der erkrankten Kinder im Rezidiv der ALL. Ähnliches trifft auch auf andere teilweise schwer therapierbareIn particular, the therapy of a relapse of childhood acute lymphoblastic leukemia (ALL), the most common malignancy in childhood, has still not been satisfactorily resolved. So die B. Despite aggressive therapy, about 70% of the children with illness in the relapse of ALL. The same applies to others, some of which are difficult to treat
BESTÄT1GÜWOSI 0PIE Tumorerkrankungen, wie das Schilddrüsenkarzinom, das sehr häufige Mammakarzinom, das schwer zugängliche Medulloblastom oder auf Gliome zu. Eine gutartige Hauterkrankung, die auch mit solchen Therapien behandelt wird, ist die Psoriasis (Schuppenflechte). Sie stellt eine der häufigsten Erkrankungen der Haut dar, an der zwei bis vier Prozent der Menschen leiden. Auch die Therapie dieser Erkrankung ist noch stark verbesserungsbedürftig.BESTÄT1GÜWOSI 0PIE Tumor diseases such as thyroid carcinoma, very common breast cancer, difficult to access medulloblastoma or towards gliomas. A benign skin condition that is also treated with such therapies is psoriasis (psoriasis). It is one of the most common skin diseases that affect two to four percent of people. The therapy for this disease is also in great need of improvement.
In der WO 2080923 AI werden Nukleosidanaloga beschrieben, die die Apoptose auslösen und zytostatisch wirken. Diesen Verbindungen ist eine Ringstruktur gemeinsam, die ein Dien-System enthält, an das vorzugsweise ein Eisentricarbonyl koordinativ gebunden ist. Wegen der Dienstruktur sind die bekannten Substanzen aufwändig zu synthetisieren. Die Substanzen neigen aufgrund der Reaktivität des Diens zu unerwünschten Nebenreaktionen und sind daher relativ instabil. Dies ist nachteilig sowohl für die Lagerung und Zubereitung in Verbindung mit anderen Arzneimittelkomponenten, als auch für die Spezifität nach Verabreichung.WO 2080923 AI describes nucleoside analogues that trigger apoptosis and have a cytostatic effect. These compounds have in common a ring structure which contains a diene system to which an iron tricarbonyl is preferably coordinatively bound. Because of the diene structure, the known substances are difficult to synthesize. The substances tend to undesirable side reactions due to the reactivity of the diene and are therefore relatively unstable. This is disadvantageous both for storage and preparation in connection with other pharmaceutical components, and for the specificity after administration.
Zahlreiche weitere Nukleosidanaloga mit biologischer Aktivität werden in der WO 02/100354 und der EP0468352 A2 offenbart.Numerous other nucleoside analogs with biological activity are disclosed in WO 02/100354 and EP0468352 A2.
In Velcicky et al., 2002, wird eine allgemeine Synthesestrategie für Nucleosidanaloga unter Verwendung gezielter Schutzgruppen offenbart. Nach Angabe der Autoren soll es die Synthese ermöglichen, eine große Vielzahl von Nucleosidanaloga herzustellen, die potentiell biologische Aktivität aufweisen könnten. In diesem Zusammenhang wird auf die biologische Aktivität der bekannten carbozyklischen Nucleosidanaloga Carbovir und Abacavir verwiesen. Durch die beschriebenen Synthesen sind nur Racemate, nicht jedoch die Enantiomeren, erhältlich.Velcicky et al., 2002, discloses a general synthetic strategy for nucleoside analogs using targeted protecting groups. According to the authors, the synthesis should make it possible to produce a large variety of nucleoside analogues that could potentially have biological activity. In this context, reference is made to the biological activity of the known carbocyclic nucleoside analogues carbovir and abacavir. Only the racemates, but not the enantiomers, are obtainable from the syntheses described.
In Tetrahedron Letters, Vol. 34, No. 18, pp. 2993-2994, 1993, wird über Modifikationen in der Kohlenhydratkette von Pyrimidinnukleosiden berichtet. Die dort offenbarten Verbindungen sollen Anti-HIV-Aktivitätan in vitro aufweisen. In Tetrahedron Vol. 51, No. 7, pp. 2029-2038, 1995, wird berichtet, dass 2', 3'-Dideoxy-cyclo-2'-pentenyl-3'-C-hydroximethylcarbozyklischeIn Tetrahedron Letters, Vol. 34, No. 18, pp. 2993-2994, 1993, modifications in the carbohydrate chain of pyrimidine nucleosides are reported. The compounds disclosed therein are said to have anti-HIV activity in vitro. In Tetrahedron Vol. 51, No. 7, pp. 2029-2038, 1995, it is reported that 2 ', 3'-dideoxy-cyclo-2'-pentenyl-3'-C-hydroximethylcarbocyclic
Nukleosidanaloga ein antivirales Potential besitzen.Nucleoside analogues have an antiviral potential.
In Tetrahedron Vol. 49, No. 44, pp. 10061-10068, 1993, wird eine neue Synthese von 2', 3'-Dideoxy-2', 3',-didehydro-3'-C-substituierten Thymidinen offenbart. Solche Verbindungen haben inhibitive Wirkung auf HlV-reverse Transkriptase.In Tetrahedron Vol. 49, No. 44, pp. 10061-10068, 1993, a new synthesis of 2 ', 3'-dideoxy-2', 3 ', - didehydro-3'-C-substituted thymidines is disclosed. Such compounds have inhibitory effects on HIV reverse transcriptase.
EP-A-0 358 154 offenbart Cyclobutanderivate und ein Verfahren zu deren Herstellung.EP-A-0 358 154 discloses cyclobutane derivatives and a process for their preparation.
FR-A-2 662 165 offenbart verzweigte Nukleosidderivate, ein Verfahren zu ihrer Hersteilung und ihre Verwendung in einem Arzneimittel.FR-A-2 662 165 discloses branched nucleoside derivatives, a process for their preparation and their use in a medicament.
Es besteht ein starkes Bedürfnis, Substanzen und Arzneimittel zu entwickeln, mit denen die Heilungserfolge und die Überlebenschancen von Patienten verbessert werden, die an den oben aufgeführten Erkrankungen leiden. Insbesondere bei Tumorerkrankungen und Leukämien ist es von Bedeutung, neue Arzneimittel bereitzustellen, die hochselektiv gegen unnatürlich proliferierende Zellen wirken und dabei gesunde Zellen möglichst wenig angreifen. Darüber hinaus ist es von besonderer Wichtigkeit, Therapiestoffe gegen solche Tumoren bereitzustellen, die sich gegenüber bereits bekannten Substanzen als resistent erweisen. Der Erfindung liegt somit die Aufgabe zugrunde, entsprechende Substanzen bereitzustellen. Eine weitere Aufgabe ist es, Substanzen mit alternativen und neuen Wirkungsmechanismen bereitzustellen, um die Behandlungsmöglichkeiten auszuweiten und zu ergänzen. Der Erfindung liegt außerdem die Aufgabe zugrunde, entsprechende Substanzen bereitzustellen, die möglichst einfach herstellbar sind und relativ stabil sind.There is a strong need to develop substances and drugs that improve the healing success and survival of patients suffering from the diseases listed above. In the case of tumor diseases and leukaemias in particular, it is important to provide new drugs that are highly selective against unnaturally proliferating cells and thereby attack healthy cells as little as possible. In addition, it is of particular importance to provide therapeutic substances against those tumors which have proven to be resistant to known substances. The invention is therefore based on the object of providing corresponding substances. Another task is to provide substances with alternative and new mechanisms of action in order to expand and supplement the treatment options. The invention is also based on the object of providing corresponding substances which are simple to manufacture and are relatively stable.
Überraschenderweise wird die der Erfindung zugrundeliegende Aufgabe gelöst durch Verbindungen gemäß den Patentansprüchen 1 bis 5 und Arzneimittel gemäß den Patentansprüchen 6 bis 9, einem Verfahren zur Herstellung von Arzneimitteln nach Anspruch 10 und Syntheseverfahren nach Anspruch 11 und 12.Surprisingly, the object on which the invention is based is achieved by compounds according to claims 1 to 5 and medicaments according to claims 6 to 9, a process for the preparation of Medicaments according to claim 10 and synthesis methods according to claims 11 and 12.
Nicht Gegenstand der Erfindung sind die Verbindungen, die in Velcicky et al. (2002) offenbart werden. Gegenstand der Erfindung sind jedoch, soweit beansprucht, entsprechende Arzneimittel. Die Autoren haben bei ihren rein synthetischen Arbeiten nicht erkannt, dass einige der offenbarten Produkte und Zwischenprodukte selbst in besonderem Maße zur Behandlung von Tumoren geeignet sind.The invention does not relate to the compounds described in Velcicky et al. (2002). The subject of the invention, however, are, as far as claimed, corresponding medicaments. In their purely synthetic work, the authors did not recognize that some of the products and intermediate products disclosed are themselves particularly suitable for the treatment of tumors.
Gegenstand der Erfindung sind die verschiedenen Stereoisomere der erfindungsgemäßen Verbindungen, die einzelnen Enantiomere und die entsprechenden Racemate. Mit cis-Konfiguration ist bei den erfindungsgemäßen Verbindungen bezeichnet, dass die Reste Y und Z auf der gleichen Seite des zentralen Fünfrings stehen.The invention relates to the various stereoisomers of the compounds according to the invention, the individual enantiomers and the corresponding racemates. The cis configuration in the compounds according to the invention denotes that the radicals Y and Z are on the same side of the central five-membered ring.
Die erfindungsgemäßen Verbindungen können werden verwendet werden zur Herstellung eines Arzneimittels zur Behandlung maligner Erkrankungen des Knochenmarks oder anderer blutbildender Organe, solider Tumoren, epithelialer Tumoren, gutartiger oder semimaligner schnell proliferierender Tumore oder Hauterkrankungen, insbesondere Psoriasis vulgaris, Keloide und Basaliome, Lymphome, insbesonder Hodgkin- und Non-Hodgkin-Lymphome, entzündlicher, chronisch entzündlicher, bakterieller und autoimmuner Erkrankungen, sowie zur antibakteriellen, antimykotischen, anti-Protozoen, anti-Plasmodien, anti-helminthischen, antiviralen oder immunsuppressiven Therapie.The compounds according to the invention can be used to prepare a medicament for the treatment of malignant diseases of the bone marrow or other hematopoietic organs, solid tumors, epithelial tumors, benign or semimalignant rapidly proliferating tumors or skin diseases, in particular psoriasis vulgaris, keloids and basaliomas, lymphomas, in particular Hodgkin's and non-Hodgkin's lymphomas, inflammatory, chronically inflammatory, bacterial and autoimmune diseases, as well as for antibacterial, antifungal, anti-protozoa, anti-plasmodia, anti-helminthic, antiviral or immunosuppressive therapy.
Die erfindungsgemäßen Arzneimittel und Verbindungen eignen sich unerwarteterweise zur Therapie von pathologisch schnell proliferierendem Gewebe, besonders von Knochenmark, aber auch von soliden Tumoren, wie epithelialen Tumoren oder insbesondere Hirntumoren. Weiterhin erstreckt sich die Anwendbarkeit der beschriebenen Substanzen auch auf die Behandlung gutartiger, hyperproliferativer Erkrankungen der Haut, wie z. B. die Psoriasis oder das Keloid. Die Arzneimittel und Substanzen der Erfindung zeichnen sich dadurch aus, dass sie in besonderem Maße geeignet sind, selektiv das Wachstum von hochproliferierenden Zellen zu inhibieren. Dadurch leiten sie die Apoptose von hochproliferierenden Zellen ein und bewirken so deren Zerstörung, wobei gesunde Zellen sehr wenig beeinträchtigt werden. Die durchgeführten Experiment zeigen, dass erfindungsgemäße Substanzen die Apoptose ungewöhnlich schnell auslösen. Die durchgeführten Experimente deuten darauf hin, dass die Apoptose über einen neuartigen Mechanismus eingleitet werden könnte.The pharmaceuticals and compounds according to the invention are unexpectedly suitable for the therapy of pathologically rapidly proliferating tissue, in particular bone marrow, but also of solid tumors, such as epithelial tumors or in particular brain tumors. Furthermore, the applicability of the substances described also extends to the treatment of benign, hyperproliferative diseases of the skin, such as, for. B. the psoriasis or the keloid. The drugs and substances of the invention are characterized in that they are particularly suitable, selectively that Inhibit growth of highly proliferating cells. As a result, they initiate apoptosis of highly proliferating cells and thus destroy them, with healthy cells being affected very little. The experiments carried out show that substances according to the invention trigger apoptosis unusually quickly. The experiments carried out suggest that apoptosis could be initiated using a new mechanism.
Die Substanzen sind vozugsweise im besonderen Maße membrangängig, was zu einer hohen intrazellulären Wirkstoffkonzentration führt. Die hohe Wirksamkeit wird daher wahrscheinlich durch die ausgeprägte Lipophilie der Substanzen erzielt. Die Substanzen unterscheiden sich grundlegend von bereits bekannten zur Therapie verwendeten Nukleosidanaloga, wie Cytarabin, Cladribine und Fludarabin-5'-dihydrogenphosphat. Sie sind in der Lage, vorhandene Zytostatikaresistenzen zu brechen.The substances are particularly preferably membrane-permeable, which leads to a high intracellular active substance concentration. The high effectiveness is therefore likely to be achieved through the pronounced lipophilicity of the substances. The substances differ fundamentally from known nucleoside analogues used for therapy, such as cytarabine, cladribine and fludarabine 5'-dihydrogen phosphate. They are able to break existing cytostatic resistances.
Die Arzneimittel und Verbindungen der Erfindung sind insbesondere geeignet zur Behandlung von Tumorerkrankungen und Leukämie. Sie leiten den apoptotischen Zelltod nicht nur in aus Tumorzellen entstandenen permanenten Zellinien (BJAB-Zellen), sondern auch in primären Zellen von Patienten mit einer akuten lymphoblastischen Leukämie (ALL) ein. Dadurch können die erfindungsgemäßen Substanzen gegen Tumorerkrankungen des Knochenmarks, aber auch gegen Tumore einer anderen Provenienz, wie z. B. epitheliale Tumore, Sarkome oder maligne Erkrankungen der Haut usw. eingesetzt werden.The pharmaceuticals and compounds of the invention are particularly suitable for the treatment of tumor diseases and leukemia. They induce apoptotic cell death not only in permanent cell lines (BJAB cells) formed from tumor cells, but also in primary cells from patients with acute lymphoblastic leukemia (ALL). This allows the substances according to the invention against tumor diseases of the bone marrow, but also against tumors of another provenance, such as. B. epithelial tumors, sarcomas or malignant diseases of the skin, etc. are used.
In besonderen Ausführungsformen ist mit den entwickelten Substanzen aufgrund ihrer Lipophilie eine ungehinderte Überschreitung der Blut- Hirnschranke möglich, daher können diese zur Behandlung von malignen Hirntumore, wie z. B. das Medulloblastom oder Gliome, eingesetzt werden. Insgesamt können die erfindungsgemäßen Substanzen zur Behandlung maligner Erkrankungen des Knochenmarks oder anderer blutbildender Organe, solider Tumoren, epithelialer Tumoren, gutartiger oder semimaligner schnell proliferierender Hauterkrankungen, insbesondere Psoriasis vulgaris, Keloide und Basaliome, sowie entzündlicher und chronisch entzündlicher Erkrankungen verwendet werden. Sie sind auch geeignet zur antiviralen, antibakteriellen, antimykotischen, anti-Protozoen, anti-helminthischen oder immun- suppressiven Therapie.In special embodiments, the developed substances are able to cross the blood-brain barrier unhindered due to their lipophilicity. Therefore, they can be used to treat malignant brain tumors, such as, for. B. the medulloblastoma or gliomas can be used. Overall, the substances according to the invention can be used to treat malignant diseases of the bone marrow or other hematopoietic organs, solid tumors, epithelial tumors, benign or semi-malignant rapidly proliferating skin diseases, in particular psoriasis vulgaris, keloids and basaliomas, as well as inflammatory and chronic inflammatory diseases. They are also suitable for antiviral, antibacterial, antifungal, anti-protozoa, anti-helminthic or immunosuppressive therapy.
Die Verbindungen und Arzneimittel der Erfindung haben gegenüber den bekannten Substanzen aus der WO02/080923 den Vorteil, dass sie einfacher zu synthetisieren, zu handhaben und zu lagern sind, und bei der Zubereitung zum Arzneimittel und auch im Körper nur wenig zu unerwünschten Nebenreaktionen neigen.The compounds and medicaments of the invention have the advantage over the known substances from WO02 / 080923 that they are easier to synthesize, handle and store, and have little tendency to undesirable side reactions in the preparation of the medicament and also in the body.
In der Fig. 1 ist gezeigt, dass die neuartigen Nukleoside bei einer Konzentration im Zellkulturmedium von 30 μmol/l in BJAB-Zellen eine Zytotoxizität bis zu 85 % zeigen. Hierbei wird der Zelltod über die Freisetzung der Lactatdehydrogenase (LDH) nach 48 h gemessen, welche nur nach Schädigung der Zellmembran das Zytoplasma der Zelle verlassen kann. Dabei wurden Doppelwerte gemessen, wobei der angegebene Mittelwert sich nach zweimaliger unabhängiger Wiederholung des Experiments bestätigte (Abweichungen < 3%). Gezeigt sind die Ergebnisse für die Substanzen (-)- 159a bis d und (-)-113b.1 shows that the novel nucleosides show a cytotoxicity of up to 85% in BJAB cells at a concentration in the cell culture medium of 30 μmol / l. Here, cell death is measured by the release of lactate dehydrogenase (LDH) after 48 hours, which can only leave the cell's cytoplasm after damage to the cell membrane. Duplicate values were measured, the mean value being confirmed after two independent repetitions of the experiment (deviations <3%). The results are shown for the substances (-) - 159a to d and (-) - 113b.
In der Fig. 2 wird ersichtlich, dass es sich bei dem durch die neuartigen Nukleosidanaloga ausgelösten Zelltod nicht um undifferenzierte Nekrose sondern um Apoptose handelt. .Die Messung der Apoptose basiert auf einer Methode, die die für die Apoptose typische Fragmentierung der DNA auf Einzelzellniveau nachweist, die diese Zelltodform von der Nekrose unterscheidet. Dazu wurden BJAB-Zellen 72 h mit einer Konzentration von 20 μmol/l unterschiedlicher Nukleosidanaloga behandelt. Kontrollen enthielten entsprechende Mengen des Lösungsvermittlers Ethanol. Nach der Behandlung wurde die Fragmentierung der DNA durch Färbung mit Propidiumiodid und anschließender Quantifizierung mittels Durchfluss-Zytometrie, wie von Eßmann et al. (2000) beschrieben, gemessen. Die Werte sind gegeben als % apoptotische Zellen der Gesamtpopulation. Es wurden Doppelwerte gemessen, wobei der angegebene Mittelwert sich nach zweimaliger unabhängiger Wiederholung des Experiments bestätigte (Abweichungen < 3%).2 shows that the cell death triggered by the novel nucleoside analogs is not undifferentiated necrosis but apoptosis. The measurement of apoptosis is based on a method that demonstrates the fragmentation of DNA typical of apoptosis at the individual cell level, which distinguishes this cell death form from necrosis. For this purpose, BJAB cells were treated for 72 h with a concentration of 20 μmol / l of different nucleoside analogs. Controls contained appropriate amounts of the solubilizer ethanol. After the treatment, the fragmentation of the DNA was stained with propidium iodide and then quantified by flow cytometry as described by Eßmann et al. (2000). The values are given as% apoptotic cells of the total population. Duplicate values were measured the mean value given was confirmed after two independent repetitions of the experiment (deviations <3%).
Die Substanzen wirken jedoch nicht nur auf permanente Zellinien, sondern auch auf Lymphoblasten, die direkt von Kindern mit einer ALL gewonnen wurden, proapoptotisch (Fig. 3). Im Unterschied zum bereits bekannten und sehr verbreitet eingesetzten Chemotherapeutika, wie Epirubicin oder Cytosinarabinosid, leiten die getesteten neuartigen Nukleosidanaloga auch in therapieresistenten Patientenzellen in vitro die Apoptose ein (Daten nicht gezeigt). In der Fig. 3 wird die Apoptose-Induktion über die resultierende DNA-Fragmentierung an primären Lymphoblasten - von Kindern mit einer akuten lymphoblastischen Leukämie (ALL) gezeigt. Nach Isolation der primären Lymphoblasten und Verdünnung mit Zellkulturmedium wurden sie für 36 h mit jeweils 20 μM des Nukleosidanalogons behandelt. Kontrollen enthielten entsprechende Mengen des Lösungsvermittlers Ethanol. Nach der Behandlung wurde die Fragmentierung der DNA durch Färbung mit Propidiumiodid und anschließender Quantifizierung mittels Durchfluss- Zytometrie, wie von Eßmann et al. (2000) beschrieben, gemessen. Die Werte sind angegeben als % apoptotische Zellen der Gesamtpopulation. Es wurden Doppelwerte gemessen, wobei der angegebene Mittelwert sich nach zweimaliger unabhängiger Wiederholung des Experiments bestätigte (Abweichungen < 3%).However, the substances have a proapoptotic effect not only on permanent cell lines, but also on lymphoblasts obtained directly from children with an ALL (FIG. 3). In contrast to the already known and widely used chemotherapeutic agents, such as epirubicin or cytosine arabinoside, the novel nucleoside analogs tested also initiate apoptosis in therapy-resistant patient cells in vitro (data not shown). FIG. 3 shows apoptosis induction via the resulting DNA fragmentation on primary lymphoblasts - of children with acute lymphoblastic leukemia (ALL). After isolation of the primary lymphoblasts and dilution with cell culture medium, they were treated with 20 μM each of the nucleoside analog for 36 h. Controls contained appropriate amounts of the solubilizer ethanol. After the treatment, the fragmentation of the DNA was stained with propidium iodide and then quantified by flow cytometry as described by Eßmann et al. (2000). The values are given as% apoptotic cells of the total population. Duplicate values were measured, the mean value being confirmed after two independent repetitions of the experiment (deviations <3%).
In der Abfolge der Apoptose kommt es zur Aktivierung einer Familie von Cysteinproteasen, den sogenannten Caspasen, die die Zelle während des ablaufenden Todesprogramms von innen heraus auflösen (Cohen, 1997). Um die Spezifität der erfindungsgemäßen Substanzen näher zu untersuchen, wurde mittels Western Blot-Technik die Prozessierung und Aktivierung der Caspase-3, Caspase-8 und Caspase-9 nachgewiesen (Fig. 4). Dazu wurden BJAB-Zellen 36 h mit einer Konzentration von 20 μmol/l der Nukleosidanaloga behandelt. Kontrollen enthielten entsprechende Mengen des Lösungsvermittlers Ethanol (EtOH). Nach der Behandlung wurde die Prozessierung der Procaspase-3, Pro-C-8 und Pro-C-9 mittels spezifischer Immundetektion im Western Blot, wie von Eßmann et al. (2000) beschrieben, bestimmt. Die Positionen der Procaspasen und der prozessierten Untereinheiten im SDS-Polyacrylamidgel sind durch Querstriche am linken Rand von Fig. 4 gekennzeichnet. Die Zugabe von 20 μmol/l der Substanzen zum Medium von BJAB-Zellen löst in diesen Zellen eine Prozessierung der Procaspasen-3, -8 und -9 aus. Zu sehen ist der spezifische, immunchemische Nachweis der aktiven Untereinheiten der Caspasen-3, -8 und -9 in behandelten Zellen im Unterschied zu den entsprechenden Kontrollzellen. Das Ergebnis macht deutlich, dass die erfindungsgemäßen Substanzen spezifisch eine apoptotische Kaskade induzieren. Das Nukleosidanalogon (-)-159b induziert die Caspasen-Prozessierung (Fig. 4) so schnell, dass bereits zum Messzeitpunkt nach 36 h kaum mehr die Procaspasen-3, -8 und -9 vorhanden sind.The sequence of apoptosis leads to the activation of a family of cysteine proteases, the so-called caspases, which dissolve the cell from the inside during the ongoing death program (Cohen, 1997). In order to investigate the specificity of the substances according to the invention in more detail, the processing and activation of caspase-3, caspase-8 and caspase-9 was detected using the Western blot technique (FIG. 4). For this purpose, BJAB cells were treated for 36 h with a concentration of 20 μmol / l of the nucleoside analogs. Controls contained appropriate amounts of the solubilizer ethanol (EtOH). After treatment, the processing of Procaspase-3, Pro-C-8 and Pro-C-9 became more specific Immunodetection in a Western blot as described by Eßmann et al. (2000). The positions of the procaspases and the processed subunits in the SDS-polyacrylamide gel are indicated by dashes on the left edge of FIG. 4. The addition of 20 μmol / l of the substances to the medium of BJAB cells triggers a processing of the Procaspasen-3, -8 and -9 in these cells. The specific, immunochemical detection of the active subunits of caspases-3, -8 and -9 in treated cells can be seen in contrast to the corresponding control cells. The result makes it clear that the substances according to the invention specifically induce an apoptotic cascade. The nucleoside analogue (-) - 159b induces the caspase processing (FIG. 4) so quickly that even at the time of measurement after 36 h hardly any of the procaspases-3, -8 and -9 are present.
In Fig. 5 enthält man bereits einen ersten Hinweis auf die von den neuartigen Nukleosidanaloga aktivierte Apoptosesignal-Kaskade. In der Fig. 5 wird gezeigt, dass die mit den neuartigen Nukleosidanaloga über 48 h inkubierten BJAB-Zellen in den mitchondrialen Apoptoseweg getrieben werden. Dies wurde mittels Färbung der Zellen mit dem Mitochondrien-spez'ifischen Farbstoff JC-1, wie von Wieder et al. (2001) beschrieben, nachgewiesen. Die Inkubation der Zellen mit den neuen Nukleosidanaloga führte hierbei zu einer signifikanten Erhöhung des Anteils von Zellen mit einem erniedrigten mitochondrialen, Membranpotential (ΔΨm) von 5 % in der Kontrolle bis auf 80 %, was auf eine starke Aktivierung der Mitochondrien während des apoptotischen Prozesses hinweist (Fig. 5).5 already contains a first indication of the apoptosis signal cascade activated by the novel nucleoside analogs. 5 shows that the BJAB cells incubated with the novel nucleoside analogs over 48 h are driven into the mitchondrial apoptosis pathway. This was visualized by staining the cells with the mitochondrial specific 'ifischen dye JC-1, such as by re et al. (2001). Incubation of the cells with the new nucleoside analogues led to a significant increase in the proportion of cells with a reduced mitochondrial, membrane potential (ΔΨ m ) from 5% in the control to 80%, which indicates a strong activation of the mitochondria during the apoptotic process indicates (Fig. 5).
Die Verbindung racx4 (Fig. 6) zeigt eine Apoptose von etwa 42% bei einer Konzentration von 100 μg/ml.The compound racx4 (FIG. 6) shows an apoptosis of approximately 42% at a concentration of 100 μg / ml.
Die Verwendbarkeit der erfindungsgemäßen Substanzen für die Therapie verschiedener bösartiger Erkrankungen des blutbildenden Systems wurde an Zellen von Patienten mit unterschiedlichen Erkrankungen erfolgreich in vitro getestet. Damit werden mit den Substanzen der allgemeinen Strukturformel 2 als wirksame Mittel gegen bestimmte Tumorzellen, besonders die der kindlichen ALL, aber auch gegen andere maligne Erkrankungen unterschiedlicher Herkunft, bereitgestellt.The usability of the substances according to the invention for the therapy of various malignant diseases of the hematopoietic system has been successfully tested in vitro on cells from patients with different diseases. The substances of general structural formula 2 are thus effective as agents against certain tumor cells, particularly those of childish ALL, but also against other malignant diseases of different origins.
Die erfindungsgemäßen Arzneimittel können topisch oder intravenös appliziert werden. Bei intravenöser Applikation werden die Substanzen im Konzentrationsbereich zwischen 0,1 bis 100 μg/ml, bezogen auf das Blutvolumen des Patienten, verabreicht. Die Substanzen werden in einer Konzentration von 0,1 bis .5 Gew.-%, bezogen auf das fertige Präparat, in die erkrankte Haut eingerieben. The medicaments according to the invention can be administered topically or intravenously. In the case of intravenous administration, the substances are administered in the concentration range between 0.1 to 100 μg / ml, based on the patient's blood volume. The substances are rubbed into the diseased skin in a concentration of 0.1 to .5% by weight, based on the finished preparation.
Svnthesevorsch riftenRule Svnthese
NB = Nukleobase 1.) H30+ NB = nucleobase 1.) H 3 0 +
R = ThxMe2Si, f-BuPh2SiR = ThxMe 2 Si, f-BuPh 2 Si
2.) R-Cl2.) R-Cl
Allgemeine one-pot-Reaktϊon für Hydrolyse und SilylierungGeneral one-pot reaction for hydrolysis and silylation
(-)-lOO (+)-95 und (+)-155 (-) - 100 (+) - 95 and (+) - 155
(+)-95 R = ThxMe2Si (+)-155 R = f-BuPh2Si (+)-95 R = ThxMe2Si a (R ' = H, X=OH) a (R ' =Br, X=OH) e (X=OCONPh2, Y=NHAc) b (R ' = F, X=OH) b (R ' =F, X=OH) c (R ' =Me, X=OH) c (R ' =H, X=NHBz) (+)-155 R = fr-BuPh2Si d (R ' =H, X=NHBz) d (X=OCONPh2, Y=NHAc)(+) - 95 R = ThxMe 2 Si (+) - 155 R = f-BuPh 2 Si (+) - 95 R = ThxMe 2 Si a (R '= H, X = OH) a (R' = Br, X = OH) e (X = OCONPh 2 , Y = NHAc) b (R '= F, X = OH) b (R' = F, X = OH) c (R '= Me, X = OH) c ( R '= H, X = NHBz) (+) - 155 R = fr-BuPh 2 Si d (R' = H, X = NHBz) d (X = OCONPh 2 , Y = NHAc)
Die Herstellung der racemischen Vorstufen vom Typ rac-100 erfolgt nach bekannten Methoden (siehe WO 02/080923 und Velcicky et al., 2002). Zur Herstellung der optisch aktiven Verbindungen wird, wie dies in der WO 02/080923 erläutert, entweder der chirogene Schritt der Synthese (Pauson- Khand-Reaktion) enantioselektiv durchgeführt, oder auf einer Folgestufe eine Racematspaltung vorgenommen. Allgemein können die folgenden Reaktionen können von einzelnen Enantiomeren oder vom Racemat durchgeführt werden. Eine Lösung von lOOa-e (lmmol) und PPTS (76 mg, 300 μmol, 30 mol%) in absolutem Aceton (10 ml) wurde unter Rückfluss über 3 h gerührt. Das Lösungsmittel wurde abgezogen und das Gefäß dreimal mit Argon gespült. Anschließend wurden 3 ml absolutes Pyridin hinzugefügt und nach Rühren über 5 min. bei RT ThxMe2SiCI (310 μl, 1.5 mmol, 1.5 equiv.) oder t-BuPh2SiCl (79 μl, 300 μmol, 1.5 äquiv. für 200 μmol of 100) hinzugegeben. Nach Rühren bei RT über 16 h wurde das Reaktionsgemisch mit gesättigter wässriger NaHCO3-Lsg.(20 ml) gequencht. Nach Rühren über 30 min. bei RT wurde die wässrige Phase mit EtOAc (4 x 20 ml) extrahiert und die gesammelten organischen Phasen mit 10 %iger wässriger HCL-Lsg. (3 x 20 ml), gesättigter wässriger NaHCO3-Lsg. (20 ml) und NaCI-Lsg. (40 ml) gewaschen, über MgSO4 getrocknet und durch Destillation von dem Lösungsmittel befreit. Der Rückstand wurde durch Flash-Chromatographie gereinigt.The racemic precursors of the rac-100 type are prepared by known methods (see WO 02/080923 and Velcicky et al., 2002). To produce the optically active compounds, as explained in WO 02/080923, either the chirogenic step of the synthesis (Pauson-Khand reaction) is carried out enantioselectively, or a racemate resolution is carried out at a subsequent stage. In general, the following reactions can be carried out by individual enantiomers or by the racemate. A solution of lOOa-e (lmmol) and PPTS (76 mg, 300 μmol, 30 mol%) in absolute acetone (10 ml) was stirred under reflux for 3 h. The solvent was removed and the vessel was flushed three times with argon. Then 3 ml of absolute pyridine were added and after stirring for 5 min. at RT ThxMe 2 SiCI (310 μl, 1.5 mmol, 1.5 equiv.) or t-BuPh 2 SiCl (79 μl, 300 μmol, 1.5 equiv. for 200 μmol of 100) added. After stirring at RT for 16 h, the reaction mixture was quenched with saturated aqueous NaHCO 3 solution (20 ml). After stirring for 30 min. at RT the aqueous phase was extracted with EtOAc (4 x 20 ml) and the collected organic phases with 10% aqueous HCL solution. (3 x 20 ml), more saturated aqueous NaHCO 3 solution. (20 ml) and NaCl solution. (40 ml), dried over MgSO 4 and freed from the solvent by distillation. The residue was purified by flash chromatography.
Darstellung von (+)-(3/?, 5S)-5-[Dimethyi-(l,l,2Hrrimethyl-propyl)- silanyloxy]-3-(2 ' ,4 ' -dioxo-3 ' ,4 ' -dϊhydro-2 f-pyrimidin-l ' -yl)- cyclopent-1-encarbaldehyd (95a)Preparation of (+) - (3 /?, 5S) -5- [Dimethyi- (l, l, 2Hrrimethyl-propyl) - silanyloxy] -3- (2 ', 4' -dioxo-3 ', 4' -dϊhydro -2 f-pyrimidine-1'-yl) - cyclopent-1-encarbaldehyde (95a)
Die Verbindung (+)-95a erhielt man gemäß der allgemeinen Versuchsvorschrift als klare Flüssigkeit (309 mg, 82% Ausbeute).The compound (+) - 95a was obtained according to the general test instructions as a clear liquid (309 mg, 82% yield).
rn.p. = 115-116°C (EtOAc/CyHex).rn.p. = 115-116 ° C (EtOAc / CyHex).
TLC: Rf = 0.24 in EtOAc/CyHex = 4+1.TLC: R f = 0.24 in EtOAc / CyHex = 4 + 1.
[ä]D 20 = +59.3 (c 0.62, CHCI3), [ä]54620 = +72.2, [ä]4o5 20 = +169.6, [ä]365 20 [ä] D 20 = +59.3 (c 0.62, CHCI 3 ), [ä] 54 6 20 = +72.2, [ä] 4 o 5 20 = +169.6, [ä] 3 6 5 20
= +223.6. H NMR (250 MHz, CDCI3): δ = 9.85 (s, IH, HC=O); 8.78 (bs, IH, NH); 7.47 (d, = 8.0, IH, H-6 '); 5.56 (dd, = J2= 2.2, IH, H-2); 5.90 (dddd, = 9.5, j2 = 7.1, J3 = J4 = 2.2, IH, H-3); 5.71 (dd, = 8.0, J2 = 2.4, IH, H-5 '); 4.27 (dd, = 10.0, J2 = 3.0, IH, SiOCHa); 3.58 (dd, = 10.0, J2 = 2.5, IH, SiOCHb); 3.18 (m, IH, H-5); 2.79 (ddd, = 14.2, J2= J3 = 9.5, IH, H-4a); 1.82 (ddd, =, 14.2, J2 = J3 = 7.5, IH, H-4b); 1.56 (septet, J = 6.8, IH, Me2CH); 0.81 (d, J = 6.8 Hz, 6H, (CH3)2CH); 0.788 + 0.786 (2s, 6H, C(CH3)2); 0.042 + 0.036 (2s, 6H, SiCH3).= +223.6. H NMR (250 MHz, CDCI 3 ): δ = 9.85 (s, IH, HC = O); 8.78 (bs, IH, NH); 7.47 (d, = 8.0, IH, H-6 '); 5.56 (dd, = J 2 = 2.2, IH, H-2); 5.90 (dddd, = 9.5, j 2 = 7.1, J 3 = J 4 = 2.2, IH, H-3); 5.71 (dd, = 8.0, J 2 = 2.4, IH, H-5 '); 4.27 (dd, = 10.0, J 2 = 3.0, IH, SiOCHa); 3.58 (dd, = 10.0, J 2 = 2.5, IH, SiOCHb); 3.18 (m, IH, H-5); 2.79 (ddd, = 14.2, J 2 = J 3 = 9.5, IH, H-4a); 1.82 (ddd, =, 14.2, J 2 = J3 = 7.5, IH, H-4b); 1.56 (septet, J = 6.8, IH, Me 2 CH); 0.81 (d, J = 6.8 Hz, 6H, (CH 3 ) 2 CH); 0.788 + 0.786 (2s, 6H, C (CH 3) 2); 0.042 + 0.036 (2s, 6H, SiCH 3 ).
13C NMR (63 MHz, CDCI3): δ = 188.9 (CH=O), 163.2 (C4'), 150.8 (C2'), 150.3 (Cl), 147.8 (C2), 141.4 (C6'), 103.2 (C5'), 62.2 (CH2OSi), 58.9 (C3), 44.3 (C5), 34.0 Me2CH), 33.3 (C4), 25.4 (Me2CSi), 20.3 und 20.2 ((CH3)2CH), 18.5 und 18.4 ((CH3)2CSi), -3.5 und -3.6 ((CH3)2Si). 13 C NMR (63 MHz, CDCI 3 ): δ = 188.9 (CH = O), 163.2 (C4 '), 150.8 (C2'), 150.3 (Cl), 147.8 (C2), 141.4 (C6 '), 103.2 ( C5 '), 62.2 (CH 2 OSi), 58.9 (C3), 44.3 (C5), 34.0 Me 2 CH), 33.3 (C4), 25.4 (Me 2 CSi), 20.3 and 20.2 ((CH 3 ) 2 CH) , 18.5 and 18.4 ((CH 3 ) 2 CSi), -3.5 and -3.6 ((CH 3 ) 2 Si).
IR (ATR, cm"1): = 3038 (w, N-H), 2955 (m, C-H), 2865 (w, C-H), 1697 (s, C=O), 1680 (s, C=O), 1649 (s, C=C), 1473 (w), 1445 (w), 1425 (w), 1383 (m), 1276 (m), 1248 (m, C-O), 1186 (m), 1111 (m), 1063 (w), 1019 (w), 998 (w), 979 (w), 849 (m), 828 (m), 804 (m), 779 (m), 761 (m). MS (EI, 70 eV) : m/z (%): 295 (7), 294 (17), 293 (100) [M-85]+, 275 (27), 250 (18), 201 (55), 181 (62), 169 (26), 151 (8), 137 (5), 99 (7), 91 (5), 89 (7), 85 (6), 77 (6), 75 (23), 73 (18), 69. (6), 59 (8), 57 (5). HRMS (EI) C13H17N2O4Si [M-85]+: calcd. 293.096, found : 293.096.IR (ATR, cm "1 ): = 3038 (w, NH), 2955 (m, CH), 2865 (w, CH), 1697 (s, C = O), 1680 (s, C = O), 1649 (s, C = C), 1473 (w), 1445 (w), 1425 (w), 1383 (m), 1276 (m), 1248 (m, CO), 1186 (m), 1111 (m), 1063 (w), 1019 (w), 998 (w), 979 (w), 849 (m), 828 (m), 804 (m), 779 (m), 761 (m). MS (EI, 70 eV): m / z (%): 295 (7), 294 (17), 293 (100) [M-85] + , 275 (27), 250 (18), 201 (55) , 181 (62), 169 (26), 151 (8), 137 (5), 99 (7), 91 (5), 89 (7), 85 (6), 77 (6), 75 (23) , 73 (18), 69. (6), 59 (8), 57 (5). HRMS (EI) C 13 H 17 N 2 O 4 Si [M-85] + : calcd. 293,096, found: 293,096.
Darstellung von (-)-(3S, 5Ä)-5-[Dimethyl-(l,l,2-trimethyl-propyl)- silanyloxy]-3-(2 ' ,4 '-dioxo-3 ' ,4 '-dihydro-2f/-pyrimidin-l '-yl)~ cyclopent-l-encarbaldehyd (95a)Preparation of (-) - (3S, 5Ä) -5- [dimethyl- (l, l, 2-trimethyl-propyl) -silanyloxy] -3- (2 ', 4' -dioxo-3 ', 4' -dihydro -2f / -pyrimidine-l'-yl) ~ cyclopent-l-encarbaldehyde (95a)
Die Verbindung (-)-95a wurde gemäß der allgemeinen Versuchsvorschrift als klare Flüssigkeit erhalten (264 mg, 70% Ausbeute).Compound (-) - 95a was obtained as a clear liquid (264 mg, 70% yield) according to the general experimental procedure.
[ä]D 20 = -55.5 (c 0.45, CHCI3), [ä3546 20 = -67.7, [ä]405 20 = -159.0, [ä]365 20 = -209.3.[ä] D 20 = -55.5 (c 0.45, CHCI 3 ), [ä3 546 20 = -67.7, [ä] 405 20 = -159.0, [ä] 3 6 5 20 = -209.3.
Darstellung von (+)-(3/?, 5S)-3-(5 '-Fluor-2 ',4 '-dioxo-3 ,4 '-dϊhydro- 2 -pyrimidin-l '-yl)-5-[dimethyl-(lΛl,2-trimethyl-propyI)-silanyloxy]- cyclopent-1-encarbaldehyd (95b)Preparation of (+) - (3 /?, 5S) -3- (5 '-Fluor-2', 4 '-dioxo-3, 4' -dϊhydro- 2 -pyrimidin-l '-yl) -5- [ dimethyl- (l Λ l, 2-trimethyl-propyl) -silanyloxy] - cyclopent-1-encarbaldehyde (95b)
Die Verbindung (+)-95b wurde gemäß der allgemeinen Versuchsvorschrift als klare Flüssigkeit erhalten (173 mg, 74% Ausbeute).Compound (+) - 95b was obtained as a clear liquid according to the general experimental procedure (173 mg, 74% yield).
m.p. = 148-149°C (EtOAc/Hex).m.p. = 148-149 ° C (EtOAc / Hex).
TLC: Rf = 0.50 in EtOAc/CyHex = 4+1.TLC: R f = 0.50 in EtOAc / CyHex = 4 + 1.
[ä]D 20 = +53.6 (c 0.50, CHCI3), [ä]546 20 = +65.2, [ä]4o5 20 = +148.5, [ä]365 20 [ä] D 20 = +53.6 (c 0.50, CHCI 3 ), [ä] 546 20 = +65.2, [ä] 4 o 5 20 = +148.5, [ä] 365 20
= +186.9.= +186.9.
XW MMR (250 MHz, CDCI3) : δ = 9.86 (s, IH, HC=0); 9.06 (bs, IH, NH); 7.55 X W MMR (250 MHz, CDCI 3 ): δ = 9.86 (s, IH, HC = 0); 9.06 (bs, IH, NH); 7:55
(d, 3 = 5.6, IH, H-6 ' ); 6.56 (dd, = J2= 2.1, IH, H-2); 5.90 (m, IH, H-3);(d, 3 = 5.6, IH, H-6 '); 6.56 (dd, = J 2 = 2.1, IH, H-2); 5.90 (m, IH, H-3);
4.29 (dd, = 10.1, J2 = 2.9, IH, SiOCHa); 3.58 dd, = 10.1, J2 = 2.2, IH,4.29 (dd, = 10.1, J 2 = 2.9, IH, SiOCHa); 3.58 dd, = 10.1, J 2 = 2.2, IH,
SiOC/Vb); 3.18 (m, IH, H-5); 2.79 (ddd, = 14.2, J2 = J3 = 9.4, IH, H-4a);SiOC / Vb); 3.18 (m, IH, H-5); 2.79 (ddd, = 14.2, J 2 = J 3 = 9.4, IH, H-4a);
1.82 (ddd, = 14.3, J2 = J3 = 6.7, IH, H-4b); 1.57 (septet, J = 6.8, IH, Me2CH); 0.82 (d, J = 7.4, 6H, (CH3)2CH); 0.798 + 0.794 (2s, 6H, C(CH3)2); 0.06 (s, 6H, SiCH3).1.82 (ddd, = 14.3, J 2 = J 3 = 6.7, IH, H-4b); 1.57 (septet, J = 6.8, IH, Me 2 CH); 0.82 (d, J = 7.4, 6H, (CH 3 ) 2 CH); 0.798 + 0.794 (2s, 6H, C (CH 3) 2); 0.06 (s, 6H, SiCH 3 ).
13C NMR (63 MHz, CDCI3): δ = 188.7 (CH=O), 156.6 (d, JC,F = 27, C4 ' ), 150.6 (C2 ' ), 149.3 (Cl), 147.0 (C2), 145.0 (d, JC,F = 269, C5 ' ), 125.2 (d, JC,F = 32, C6 '), 62.3 (CH2OSi), 59.4 (C3), 44.3 (C5), 34.0 (Me2CH), 32.9 (C4), 25.5 (Me2CSi), 20.4 und 20.2 ((CH3)2CH), 18.44 und 18.37 ((CH3)2CSi), -3.4 und -3.6 (CH3Si). 13 C NMR (63 MHz, CDCI 3 ): δ = 188.7 (CH = O), 156.6 (d, J C , F = 27, C4 ' ), 150.6 (C2'), 149.3 (Cl), 147.0 (C2) , 145.0 (d, J C , F = 269, C5 '), 125.2 (d, J C , F = 32, C6'), 62.3 (CH 2 OSi), 59.4 (C3), 44.3 (C5), 34.0 ( Me 2 CH), 32.9 (C4), 25.5 (Me 2 CSi), 20.4 and 20.2 ((CH 3 ) 2 CH), 18.44 and 18.37 ((CH 3 ) 2 CSi), -3.4 and -3.6 (CH 3 Si ).
IR (ATR, cm"1) : = 3160 (w, N-H), 3049 (m, N-H), 2955 (m, C-H), 2866 (m, C- H), 2830 (w), 1720 (s, C=O), 1711 (s, C=O), 1685 (s, C=O), 1657 (s, C=C), 1468 (m), 1390 (m), 1384 (m), 1379 (m), 1348 (w), 1273 (m), 1267 (m), 1248 (s, C-O), 1203 (w), 1183 (m), 1155 (m), 1110 (s), 1058 (m), 1015 (m), 995 (w), 983 (m), 889 (m), 872 (m), 830 (s), 780 (s), 743 (m), 725 (w), 704 (m), 668 (w).IR (ATR, cm "1 ): = 3160 (w, NH), 3049 (m, NH), 2955 (m, CH), 2866 (m, C-H), 2830 (w), 1720 (s, C = O), 1711 (s, C = O), 1685 (s, C = O), 1657 (s, C = C), 1468 (m), 1390 (m), 1384 (m), 1379 (m) , 1348 (f), 1273 (m), 1267 (m), 1248 (s, CO), 1203 (f), 1183 (m), 1155 (m), 1110 (s), 1058 (m), 1015 ( m), 995 (w), 983 (m), 889 (m), 872 (m), 830 (s), 780 (s), 743 (m), 725 (w), 704 (m), 668 ( w).
MS (EI, 70 eV) : m/z (%): 863 (2), 825 (6), 755 (2), 555 (5), 529 (8), 445 (13), 413 (100), 409 (56), 397 [M+H]+ (49), 387 (4), 267 (6), 251 (25), 237 (14), 181 (2), 121 (5), 107 (8).MS (EI, 70 eV): m / z (%): 863 (2), 825 (6), 755 (2), 555 (5), 529 (8), 445 (13), 413 (100), 409 (56), 397 [M + H] + (49), 387 (4), 267 (6), 251 (25), 237 (14), 181 (2), 121 (5), 107 (8) ,
Darstellung von (-)-(3S, 5/?)~3-(5 '-Fluor- 2 ' ,4 '-dioxo-3 ' ,4 '-dihydro- 2r/-pyrimidin-l ' -yl)-5-[dimethyl-(l lΛ2-trimethyl-propyl)-siIanyIoxy]- cyclopent-1-encarbaldehyd (95b)Preparation of (-) - (3S, 5 /?) ~ 3- (5 '-fluoro-2', 4 '-dioxo-3', 4 ' -dihydro-2r / -pyrimidin-l' -yl) -5 - [dimethyl- (ll Λ 2-trimethyl-propyl) -siIanyIoxy] - cyclopent-1-encarbaldehyde (95b)
Die Verbindung (-)-95b wurde gemäß der allgemeinen Versuchsvorschrift als klare Flüssigkeit erhalten (171 mg, 73% Ausbeute)Compound (-) - 95b was obtained as a clear liquid according to the general experimental procedure (171 mg, 73% yield)
[ä]D 20 = -53.3 (c 0.52, CHCI3), [ä35 620 = -65.2, [a]405 20 = -148.4, [ä]365 20 = -187.4.[ä] D 20 = -53.3 (c 0.52, CHCI 3 ), [ä3 5 6 20 = -65.2, [a] 405 20 = -148.4, [ä] 365 20 = -187.4.
Darstellung von (+)-(3Λ, 5S)-5-[Dimethyl-(l l,2-trimethyI-propyI)- silanyloxy]-3-(5 '-methyl-2 '/4 '-dϊoxo-3 ' 4 -dihydro-2H-pyrimidin-Representation of (+) - (3Λ, 5S) -5- [dimethyl- (ll, 2-trimethyI-propyI) - silanyloxy] -3- (5'-methyl-2 ' / 4' -dϊoxo-3 '4 - dihydro-2H-pyrimidine
1 ' -yI)-cyclopent-l-encarbaldehyd (95c) Die Verbindung (+)-95c wurde gemäß der allgemeinen Versuchsvorschrift als klare Flüssigkeit erhalten (252 mg, 64% Ausbeute).1'-yI) -cyclopent-l-encarbaldehyde (95c) Compound (+) - 95c was obtained as a clear liquid according to the general experimental procedure (252 mg, 64% yield).
m.p. = 58-61°C (EtOAc/CyHex).m.p. = 58-61 ° C (EtOAc / CyHex).
TLC: Rf = 0.26 in EtOAc/CyHex = 4+1.TLC: R f = 0.26 in EtOAc / CyHex = 4 + 1.
[ä]D 20 = +28.8 (c 0.53, CHCI3), [ä]546 20 = +35.4, [ä]40520 = +104.1, [ä]365 20 [ä] D 20 = +28.8 (c 0.53, CHCI 3 ), [ä] 546 20 = +35.4, [ä] 40 5 20 = +104.1, [ä] 365 20
= +173.7. NMR (250 MHz, CDCI3) : δ = 10.06 (bs, IH, NW); 9.81 (s, IH, HC=O); 6.99= +173.7. NMR (250 MHz, CDCI 3 ): δ = 10.06 (bs, IH, NW); 9.81 (s, IH, HC = O); 6.99
(q, J = 1.2, IH, H-6 ' ) ; 6.58 (m, IH, H-2); 5.83 (dddd, = J2 = 8.6, J3 = J4 =(q, J = 1.2, IH, H-6 ' ); 6.58 (m, IH, H-2); 5.83 (dddd, = J 2 = 8.6, J 3 = J 4 =
2.4, IH, H-3); 4.18 (dd, = 10.0, J2 = 3.4, IH, SiOCb/a); 3.53 (dd, =2.4, IH, H-3); 4.18 (dd, = 10.0, J 2 = 3.4, IH, SiOCb / a); 3.53 (dd, =
10.0, J2 = 2.4, IH, SiOCHb); 3.10 (m, IH, H-5); 2.65 (ddd, = 13.4, J2 = J3 10.0, J 2 = 2.4, IH, SiOCHb); 3.10 (m, IH, H-5); 2.65 (ddd, = 13.4, J 2 = J 3
= 8.8, IH, H-4a); 1.85 (d, J = 1.2, 3H, CH3); 1.80 (ddd, = 13.4, J2 = J3 == 8.8, IH, H-4a); 1.85 (d, J = 1.2, 3H, CH 3); 1.80 (ddd, = 13.4, J 2 = J 3 =
8.4, IH, H-4b); 1.51 (septet, J = 7.1, IH, Me2CH); 0.83 (d, J = 7.1, 6H,8.4, IH, H-4b); 1.51 (septet, J = 7.1, IH, Me 2 CH); 0.83 (d, J = 7.1, 6H,
(CH3)2CH); 0.793 + 0.790 (2s, 6H, C(CH3)2); 0.058 + 0.057 (2s, 6H, S\CH3).(CH 3 ) 2 CH); 0.793 + 0.790 (2s, 6H, C (CH 3) 2); 0.058 + 0.057 (2s, 6H, S \ CH 3 ).
13C NMR (63 MHz, CDCI3): δ = 188.9 (CH=O), 164.1 (C4 ' ), 151.1 (C2 ' ), 13 C NMR (63 MHz, CDCI 3 ): δ = 188.9 (CH = O), 164.1 (C4 '), 151.1 (C2'),
149.8 (Cl), 148.4 (C2), 136.2 (C6 '), 111.8 (C5 ' ), 61.4 (CH2OSi), 59.0 (C3),149.8 (Cl), 148.4 (C2), 136.2 (C6 '), 111.8 (C5'), 61.4 (CH 2 OSi), 59.0 (C3),
44.2 (C5), 34.0 (Me2CH), 33.4 (C4), 25.1 (Me2CSi), 20.2 und 20.2 ((CH3)2CH),44.2 (C5), 34.0 (Me 2 CH), 33.4 (C4), 25.1 (Me 2 CSi), 20.2 and 20.2 ((CH 3 ) 2 CH),
18.4 und 18.4 ((CH3)2CSi), 12.3 (CH3), -3.5 und -3.7 (SiCH3).18.4 and 18.4 ((CH 3 ) 2 CSi), 12.3 (CH 3 ), -3.5 and -3.7 (SiCH 3 ).
IR (ATR, cm"1): = 3177 (w, N-H), 3050 (w, N-H), 2954 (m, C-H), 2864 (m, C-IR (ATR, cm "1 ): = 3177 (w, NH), 3050 (w, NH), 2954 (m, CH), 2864 (m, C-
H), 1683 (s, C=O), 1464 (m), 1376 (m), 1279 (m), 1249 (m, C-O), 1153 (w),H), 1683 (s, C = O), 1464 (m), 1376 (m), 1279 (m), 1249 (m, C-O), 1153 (w),
1113 (m), 1057 (w), 1017 (w), 982 (w), 874 (m), 830 (m), 778(m), 722 (w).1113 (m), 1057 (w), 1017 (w), 982 (w), 874 (m), 830 (m), 778 (m), 722 (w).
MS (EI, 70 eV): m/z (%): 393 (4) [M+l]+, 365 (13), 341 (5), 307 (100), 289MS (EI, 70 eV): m / z (%): 393 (4) [M + l] + , 365 (13), 341 (5), 307 (100), 289
(27), 264 (10), 215 (52), 183 (31), 181 (73), 167 (12), 151 (7), 137 (5), 113(27), 264 (10), 215 (52), 183 (31), 181 (73), 167 (12), 151 (7), 137 (5), 113
(4), 89 (7), 75 (15), 59 (4).(4), 89 (7), 75 (15), 59 (4).
HRM (ESI) C20H33N2O4Si [M + l]+: calcd 393.2209, found 393.2209.HRM (ESI) C 20 H 33 N 2 O 4 Si [M + 1] + : calcd 393.2209, found 393.2209.
Darstellung von (-)-(3S, 5R)-5-[Dimethyl-(l,l,2-trϊmethyl-propyl)- silanyloxy]-3-(5 '-methyl-2 4 '-dioxo-3 ' ,4 '-dihydro-2J -pyrimidin-Preparation of (-) - (3S, 5R) -5- [dimethyl- (l, l, 2-trϊmethyl-propyl) -silanyloxy] -3- (5'-methyl-2 4 '-dioxo-3', 4 '-dihydro-2J -pyrimidine-
1 '-yl)-cyclopent-l~encarbaldehyd (95c) Die Verbindung (-)-95c wurde gemäß der allgemeinen Versuchsvorschrift als klare Flüssigkeit erhalten (235 mg, 60% Ausbeute).1 '-yl) -cyclopent-1 ~ encarbaldehyde (95c) Compound (-) - 95c was obtained as a clear liquid (235 mg, 60% yield) according to the general experimental procedure.
[ä]D 20 = -23.6 (c 0.54, CHCI3), [ä]54620 = -29.4, [ä]405 20 = -88.2, [ä]365 20 = -146.9.[ä] D 20 = -23.6 (c 0.54, CHCI 3 ), [ä] 54 6 20 = -29.4, [ä] 405 20 = -88.2, [ä] 365 20 = -146.9.
Darstellung von (+)-(3K, 5S)-/V-(l-{4-[Dimethyl-(l,l,2-trimethyl- propyl)-silanyIoxy]-3-formyl-cyclopent-2-enyl>-2 '-oxo-1 ' ,1 ' - dϊhydro-pyrimidin-4 '-yl)-benzamid (95d)Preparation of (+) - (3K, 5S) - / V- (l- {4- [dimethyl- (l, l, 2-trimethyl-propyl) -silanyloxy] -3-formyl-cyclopent-2-enyl> - 2 '-oxo-1', 1 '- dϊhydro-pyrimidin-4' -yl) -benzamide (95d)
Die Verbindung (+)-95d wurde gemäß der allgemeinen Versuchsvorschrift als hellgelbe Flüssigkeit erhalten (324 mg, 67% Ausbeute).Compound (+) - 95d was obtained as a light yellow liquid (324 mg, 67% yield) according to the general experimental procedure.
m.p. = 78-81°C (EtOAc/CyHex).m.p. = 78-81 ° C (EtOAc / CyHex).
TLC: Rf = 0.28 in EtOAc/CyHex = 4+1.TLC: R f = 0.28 in EtOAc / CyHex = 4 + 1.
[ä]D 20 = +59.5 (c 0.59, CHCI3), [ä]546 20 = +70.5, [ä]405 20 = +97.5.[ä] D 20 = +59.5 (c 0.59, CHCI 3 ), [ä] 546 20 = +70.5, [ä] 405 20 = +97.5.
XH NMR (250 MHz, CDCI3): δ = 9.88 (s, IH, HC=O); 8.23 (bs, IH, NH); 7.89 X H NMR (250 MHz, CDCI 3 ): δ = 9.88 (s, IH, HC = O); 8.23 (bs, IH, NH); 7.89
(d, J = 6.3, 3H, H-6 ' + 2H-Ph); 7.63-7.46 (m, 4H, H-5 ' + 3H-Ph); 6.63 (t, J =(d, J = 6.3, 3H, H-6 ' + 2H-Ph); 7.63-7.46 (m, 4H, H-5 '+ 3H-Ph); 6.63 (t, J =
2.1, IH, H-2); 6.10 (m, IH, H-3); 4.26 (dd, = 10.0, Jz = 3.2, IH, SiOCHa);2.1, IH, H-2); 6.10 (m, IH, H-3); 4.26 (dd, = 10.0, J z = 3.2, IH, SiOCHa);
3.59 (dd, = 10.0, J2 = 2.3, IH, SiOCHb); 3.22 (m, IH, H-5); 2.90 (ddd, =3.59 (dd, = 10.0, J 2 = 2.3, IH, SiOCHb); 3.22 (m, IH, H-5); 2.90 (ddd, =
14.0, J2 = J3 = 9.3, IH, H-4a); 1.84 (ddd, Jα = 14.0, J2 = J3 = 6.7, IH, H-4b);14.0, J 2 = J 3 = 9.3, IH, H-4a); 1.84 (ddd, J α = 14.0, J 2 = J 3 = 6.7, IH, H-4b);
1.57 (septet, J = 6.8, IH, Me2CH); 0.82 (d, J - 6.9, 6H, (CH3)2CH); 0.80 (s,1.57 (septet, J = 6.8, IH, Me 2 CH); 0.82 (d, J - 6.9, 6H, (CH 3 ) 2 CH); 0.80 (s,
6H, C(CH3)2); 0.05 (s, 6H, SiCH3).6H, C (CH 3 ) 2 ); 0.05 (s, 6H, SiCH 3 ).
13C NMR (63 MHz, CDCI3) : δ = 188.9 (CH=O), 161.9 (C=O (Bz)), 150.4 13 C NMR (63 MHz, CDCI 3 ): δ = 188.9 (CH = O), 161.9 (C = O (Bz)), 150.4
(C2 ' ); 147.9 (C6 ') 146.1 (C2), 133.3 und 129.0 und 127.6 (alle von Ph),(C2 ' ); 147.9 (C6 ') 146.1 (C2), 133.3 and 129.0 and 127.6 (all from Ph),
62.3 (CH2OSi), 60.6 (C3), 44.5 (C5), 34.3 (C4), 33.0 (Me2CH), 25.4 (Me2CSi),62.3 (CH 2 OSi), 60.6 (C3), 44.5 (C5), 34.3 (C4), 33.0 (Me 2 CH), 25.4 (Me 2 CSi),
20.4 und 20.2 ((CH3)2CH), 18.5 und 18.4 ((CH3)2CSi), -3.47 und -3.49 (Si(CH3)2).20.4 and 20.2 ((CH 3 ) 2 CH), 18.5 and 18.4 ((CH 3 ) 2 CSi), -3.47 and -3.49 (Si (CH 3 ) 2 ).
IR (ATR, cm"1): = 3230 (w, N-H), 3142 (w, N-H), 3061 (w, N-H), 2954 (m, C-H), 2864 (m, C-H), 1684 (s, C=O), 1661 (s, C=N), 1622 (s, C=C), 1554 (m), 1484 (s), 1376 (m), 1309 (m), 1249 (s, C-O), 1181 (m), 1107 (m), 1070 (w), 1001 (w), 978 (w), 844 (m), 830 (m), 802 (m), 780 (m), 705 (m); MS (ESI, 70 eV): m/z (%) : 1241 (21), 1209 (34), 1177 [2M + Na]+ (11), 632 (49), 610 [M+Na]+ (100), 600 (27), 578 [M+H]+ (27), 484 (2), 417 (2), 238 (6), 216 (57), 121 (2), 105 (4).IR (ATR, cm "1 ): = 3230 (w, NH), 3142 (w, NH), 3061 (w, NH), 2954 (m, CH), 2864 (m, CH), 1684 (s, C = O), 1661 (s, C = N), 1622 (s, C = C), 1554 (m), 1484 (s), 1376 (m), 1309 (m), 1249 (s, CO), 1181 (m), 1107 (m), 1070 (w), 1001 (w), 978 (w) , 844 (m), 830 (m), 802 (m), 780 (m), 705 (m); MS (ESI, 70 eV): m / z (%): 1241 (21), 1209 (34), 1177 [2M + Na] + (11), 632 (49), 610 [M + Na] + (100 ), 600 (27), 578 [M + H] + (27), 484 (2), 417 (2), 238 (6), 216 (57), 121 (2), 105 (4).
Darstellung von (-)-(3S, 5Λ)-/V-(l-{4-[Dimethyl-(l,l,2-trimethyl- propyl)-sϊlanyloxy]-3-formyl-cyclopent-2-enyl}-2 '-oxo-1 ' ,1 '- dihydro-pyrimidin-4 '-yl)-benzamid (95d)Preparation of (-) - (3S, 5Λ) - / V- (l- {4- [dimethyl- (l, l, 2-trimethylpropyl) -sϊlanyloxy] -3-formyl-cyclopent-2-enyl} - 2'-oxo-1 ', 1' - dihydro-pyrimidin-4 '-yl) -benzamide (95d)
Die Verbindung (-)-95d wurde gemäß der allgemeinen Versuchsvorschrift als gelbe Flüssigkeit erhalten (316 mg, 66% Ausbeute).Compound (-) - 95d was obtained as a yellow liquid according to the general experimental procedure (316 mg, 66% yield).
[ä]D 20 = -47.1 (c θ.32, CHCI3), [ä]54620 = -56.3, [ä]405 20 = -64.4.[ä] D 20 = -47.1 (c θ.32, CHCI 3 ), [ä] 54 6 20 = -56.3, [ä] 405 20 = -64.4.
Darstellung von (+)-(3/?, 5S)-DiphenyI-carbaminsäure 2 '-acetyl- amino-9 '-(4-[dimethyl-(l,l,2-trimethyl-propyl)-silanyloxy]-3-formyl- cycIopent-2-enyI}-9Af-purin~6 '-yl ester (95e)Preparation of (+) - (3 /?, 5S) -diphenyI-carbamic acid 2'-acetylamino-9 '- (4- [dimethyl- (l, l, 2-trimethyl-propyl) -silanyloxy] -3- formyl-cycIopent-2-enyI} -9Af-purin ~ 6 '-yl ester (95e)
Die Verbindung (+)-95e wurde gemäß der allgemeinen Versuchsvorschrift als hellgelbe Flüssigkeit erhalten (895 mg, 68% Ausbeute).Compound (+) - 95e was obtained as a light yellow liquid according to the general experimental procedure (895 mg, 68% yield).
m.p. = 79-84°C (EtOAc/CyHex).m.p. = 79-84 ° C (EtOAc / CyHex).
TLC: Rf = 0.33 in EtOAc/CyHex = 4+1.TLC: R f = 0.33 in EtOAc / CyHex = 4 + 1.
[ä]D 20 = +5.7 (c 0.37, CHCI3), [ä]54620 = +5.7, [ä]405 20 = -28.5, [ä]36S 20 = -[ä] D 20 = +5.7 (c 0.37, CHCI 3 ), [ä] 5 46 20 = +5.7, [ä] 405 20 = -28.5, [ä] 36S 20 = -
110.1.110.1.
XH NMR (250 MHz, CDCI3): δ = 9.88 (s, IH, HC=O); 8.06 (s, IH, H-8 '); 7.99 (s, IH, N/V); 7.40-6.72 (m, 10H, 2 x Ph); 6.72 (s, IH, H-2); 5.82 (m, IH, H- 3); 4.17 (dd, = 8.5, J2 = 3.5, IH, SiOCHa); 3.69 (dd, = 8.3, J2 = 2.3, IH, SiOCHb); 3.27 (m, IH, H-5); 2.89 (ddd, = 11.5, J2 = J3 = 7.5, IH, H-4a); 2.52 (s, 3H, CH3CO); 2.12 (ddd, = 11.5, J2 = J3 = 6.0, IH, H-4b); 1.56 (septet, J = 6.8, IH, Me2CH); 0.81 (d, J = 6.9, 6H, (CH3)2CH); 0.79 (s, 6H, C(CH3)2); 0.05 (s, 6H, SiCH3). X H NMR (250 MHz, CDCI 3 ): δ = 9.88 (s, IH, HC = O); 8.06 (s, IH, H-8 ' ); 7.99 (s, IH, N / A); 7.40-6.72 (m, 10H, 2 x Ph); 6.72 (s, IH, H-2); 5.82 (m, IH, H-3); 4.17 (dd, = 8.5, J 2 = 3.5, IH, SiOCHa); 3.69 (dd, = 8.3, J 2 = 2.3, IH, SiOCHb); 3.27 (m, IH, H-5); 2.89 (ddd, = 11.5, J 2 = J3 = 7.5, IH, H-4a); 2:52 (s, 3H, CH 3 CO); 2.12 (ddd, = 11.5, J 2 = J 3 = 6.0, IH, H-4b); 1:56 (septet, J = 6.8, IH, Me 2 CH); 0.81 (d, J = 6.9, 6H, (CH 3 ) 2 CH); 0.79 (s, 6H, C (CH 3) 2); 0.05 (s, 6H, SiCH 3 ).
13C NMR (63 MHz, CDCI3) : δ = 189.1 (CH=O), 170.6 (CH3C=O), 154.7 (C4 ' ), 156.3 und 152.1 und 150.4 (C4 ' + C6 ' + Ph2NC=O), 149.7 (Cl), 146.8 (C2), 142.1 (C8 ' ), 141.7 und 129.1 und 127.0 (br) (alle von Ph), 120.6 (C5 ' ), 62.2 (CH2OSi), 57.9 (C3), 44.7 (C5), 35.0 (C4), 34.0 (MezCH), 25.3 (Me2CSi), 25.0 (CH3C=O), 20.35 und 20.29 ((CH3)2CH), 18.45 und 18.43 ((CH3)2CSi), -3.55 (Si(CH3)2). 13 C NMR (63 MHz, CDCI 3 ): δ = 189.1 (CH = O), 170.6 (CH 3 C = O), 154.7 (C4 '), 156.3 and 152.1 and 150.4 (C4' + C6 '+ Ph 2 NC = O), 149.7 (Cl), 146.8 (C2), 142.1 (C8 '), 141.7 and 129.1 and 127.0 (br) (all of Ph), 120.6 (C5'), 62.2 (CH 2 OSi), 57.9 (C3 ), 44.7 (C5), 35.0 (C4), 34.0 (MezCH), 25.3 (Me 2 CSi), 25.0 (CH 3 C = O), 20.35 and 20.29 ((CH 3 ) 2 CH), 18.45 and 18.43 (( CH 3 ) 2 CSi), -3.55 (Si (CH 3 ) 2 ).
IR (ATR, cm"1) : = 3272 (w, N-H), 3060 (w, N-H), 2954 (m, C-H), 2864 (w, C- H), 1740 (s, C=O); 1685 (s, C=O), 1617 (s, C=C), 1586 (s), 1490 (s), 1444 (m), 1374 (s), 1334 (s), 1280 (s, C-O), 1214 (s), 1186 (s), 1167 (s), 1109 (m), 1059 (s), 1032 (m), 1002 (s), 931 (w), 907 (m), 873 (m), 830 (s), 779 (m), 757 (m), 739 (m), 699 (s), 643 (m).IR (ATR, cm "1 ): = 3272 (w, NH), 3060 (w, NH), 2954 (m, CH), 2864 (w, C-H), 1740 (s, C = O); 1685 (s, C = O), 1617 (s, C = C), 1586 (s), 1490 (s), 1444 (m), 1374 (s), 1334 (s), 1280 (s, CO), 1214 (s), 1186 (s), 1167 (s), 1109 (m), 1059 (s), 1032 (m), 1002 (s), 931 (w), 907 (m), 873 (m), 830 (s), 779 (m), 757 (m), 739 (m), 699 (s), 643 (m).
Darstellung von (-)-(3S, 5R)-DϊphenyI-carbaminsäure 2 '-acetyl- amino-9 '-{4-[dϊmethyl-(l,l 2-trimethyl-propyl)-silanyloxy]-3-formyl- cyclopent-2-enyl}-9A -purin- 6 '-yl ester (95e)Preparation of (-) - (3S, 5R) -DϊphenyI-carbamic acid 2 '-acetylamino-9' - {4- [dϊmethyl- (l, l 2-trimethyl-propyl) -silanyloxy] -3-formyl-cyclopent -2-enyl} -9A -purin- 6 '-yl ester (95e)
Die Verbindung (-)-95e wurde gemäß der allgemeinen Versuchsvorschrift als hellgelbe Flüssigkeit erhalten (877 mg, 67% Ausbeute).Compound (-) - 95e was obtained as a light yellow liquid according to the general experimental procedure (877 mg, 67% yield).
[ä]D 20 = -7.0 (c 0.60, CHCI3). [ä]546 20 = -7.4, [a]405 20 = +27.5, [ä]365 20 = + 112.6.[ä] D 20 = -7.0 (c 0.60, CHCI3). [ä] 546 20 = -7.4, [a] 405 20 = +27.5, [ä] 365 20 = + 112.6.
Darstellung von (+)-(3R, 5S)-3-(5 ' -Fluor-2 ' 4 ' -dιoxo-3 ',4 ' -dihydro-Representation of (+) - (3R, 5S) -3- (5 ' -Fluor-2' 4 '-dιoxo-3', 4 '-dihydro-
2- -pyrimidϊn-l '-vl)-5-(£_ert--3utyl-diphenyI-siIanyI-oxvmethyl)- cvclopent-l-encarbaldeh d (155a)2- -pyrimidϊn-l '-vl) -5- (£ _ ert - 3utyl-diphenyI-siIanyI-oxvmethyl) - cvclopent-l-encarbaldeh d (155a)
Die Verbindung (+)-155a wurde gemäß der allgemeinen Versuchsvorschrift als klare Flüssigkeit erhalten (29 mg, 59% Ausbeute).The compound (+) - 155a was obtained as a clear liquid according to the general experimental procedure (29 mg, 59% yield).
TLC: Rf = 0.49 in EtOAc/CyHex = 4+1.TLC: R f = 0.49 in EtOAc / CyHex = 4 + 1.
[ä]D 20 = +63.0 (c 0.56, CHCI3); [ä]546 20 = +76.5, [ä]405 20 = +178.6, [ä]365 20 [ä] D 20 = +63.0 (c 0.56, CHCI3); [ä] 546 20 = +76.5, [ä] 405 20 = +178.6, [ä] 365 20
= +250.4. X NMR (250 MHz, CDCI3) : δ - 9.88 (s, IH, HC=O); 9.67 (bs, IH, NH); 7.56 (d, J = 5.9, 4H, Ph); 7.45-7.31 (m, 6H, Ph) ; 7.29 (d, J = 5.5, IH, H-6 ' ); 6.61 (dd, = J2 = 2.1, IH, H-2); 5.86 (dd, = J2 = 7.7, IH, H-3); 4.23 (dd, = 10.3, J2 = 4.1, IH, SiOCHa); 3.74 (dd, = 10.3, J2 = 2.7, IH, SiOCHb); 3.19 (m, IH, H-5); 2.76 (ddd, = 13.9, J2 = J3 = 9.0, IH, H-4a); 1.85 (ddd, = 13.9, J2 = J3 = 7.7, l'H, H-4b); 1.02 (s, 9H, SiCH3).= +250.4. X NMR (250 MHz, CDCI 3 ): δ - 9.88 (s, IH, HC = O); 9.67 (bs, IH, NH); 7.56 (d, J = 5.9, 4H, Ph); 7.45-7.31 (m, 6H, Ph); 7.29 (d, J = 5.5, IH, H-6 '); 6.61 (dd, = J 2 = 2.1, IH, H-2); 5.86 (dd, = J 2 = 7.7, IH, H-3); 4.23 (dd, = 10.3, J 2 = 4.1, IH, SiOCHa); 3.74 (dd, = 10.3, J 2 = 2.7, IH, SiOCHb); 3.19 (m, IH, H-5); 2.76 (ddd, = 13.9, J 2 = J 3 = 9.0, IH, H-4a); 1.85 (ddd, = 13.9, J 2 = J 3 = 7.7, 1 ' H, H-4b); 1.02 (s, 9H, SiCH 3 ).
13C NMR (63 MHz, CDCI3) : δ = 188.6 (CH=O), 156.8. (d, JC,F = 27, C4 '), 150.6 (C2 ' ), 149.5 (Cl), 146.8 (C2), 140.9 (d, JC/F = 241, C5 ' ), 135.6 und 135.4 und 133.1 und 132.8 und 129.9 und 127.78 und 127,76 (all of Ph), 124.8 (d, JC,F = 33, C6 ' ), 62.9 (CH2OSi), 59.8 (C3), 44.3 (C5), 33.3 (C4), 26.9 ((CH3)3CSi), 19.3 (Me2CSi). 13 C NMR (63 MHz, CDCI 3 ): δ = 188.6 (CH = O), 156.8. (d, J C , F = 27, C4 '), 150.6 (C2'), 149.5 (Cl), 146.8 (C2), 140.9 (d, J C / F = 241, C5 '), 135.6 and 135.4 and 133.1 and 132.8 and 129.9 and 127.78 and 127.76 (all of Ph), 124.8 (d, J C , F = 33, C6 '), 62.9 (CH 2 OSi), 59.8 (C3), 44.3 (C5), 33.3 ( C4), 26.9 ((CH 3 ) 3 CSi), 19.3 (Me 2 CSi).
IR (ATR, cm"1) : = 3181 + 3166 (w, N-H), 3065 (m, N-H), 2952 + 2927 (m, C-H), 2883 (w, CH), 2853 (m, CH), 1714 (s, C=O), 1683 (s, C=O), 1587 (w), 1468 (m), 1425 (m), 1382 (m), 1341 (m), 1273 (m), 1243 (s, C-O), 1186 (m), 1153 (m), 1107 (s), 1057 (m), 1015 (w), 995 (w), 984 (w), 935 (w), 888 (m), 851 (w), 821 (m), 786 (m), 742 (m), 702 (s).IR (ATR, cm "1 ): = 3181 + 3166 (w, NH), 3065 (m, NH), 2952 + 2927 (m, CH), 2883 (w, CH), 2853 (m, CH), 1714 (s, C = O), 1683 (s, C = O), 1587 (w), 1468 (m), 1425 (m), 1382 (m), 1341 (m), 1273 (m), 1243 (s , CO), 1186 (m), 1153 (m), 1107 (s), 1057 (m), 1015 (w), 995 (w), 984 (w), 935 (w), 888 (m), 851 (w), 821 (m), 786 (m), 742 (m), 702 (s).
MS (EI, 70 eV) : m/z (%) : 1055 (2), 1039 (3), 1023 [2M + K]+ (2), 1007 [2M + Na]+ (1), 547 (100), 515 [M+Na]+ (14), 493 [M + H]+ (2), 429 (21), 415 (11), 285 (5), 251 (6), 219 (2), 167 (4), 121 (5).MS (EI, 70 eV): m / z (%): 1055 (2), 1039 (3), 1023 [2M + K] + (2), 1007 [2M + Na] + (1), 547 (100 ), 515 [M + Na] + (14), 493 [M + H] + (2), 429 (21), 415 (11), 285 (5), 251 (6), 219 (2), 167 (4), 121 (5).
Darstellung von (+)-(3K, 5S)-3-(5 '-Brom-2 ',4 '-dioxo-3 ',4'-dihydro-Representation of (+) - (3K, 5S) -3- (5 '-Brom-2', 4 '-dioxo-3', 4'-dihydro-
2H-pyrimϊdin-l '-yl)-5-(tert-butyl-diphenyl-silanyloxymethyl)- cyclopent-1-encarbaldehyd (155b)2H-pyrimϊdin-l '-yl) -5- (tert-butyl-diphenyl-silanyloxymethyl) - cyclopent-1-encarbaldehyde (155b)
Die Verbindung (+)-155b wurde gemäß der allgemeinen Versuchsvorschrift als klare Flüssigkeit erhalten (55 mg, 50% Ausbeute), (76% Ausbeute als racemisches Gemisch).Compound (+) - 155b was obtained according to the general experimental procedure as a clear liquid (55 mg, 50% yield), (76% yield as a racemic mixture).
m.p. = 121-123°C (EtOAc/CyHex).m.p. = 121-123 ° C (EtOAc / CyHex).
TLC: Rf = 0.53 in EtOAc/CyHex = 4+1.TLC: R f = 0.53 in EtOAc / CyHex = 4 + 1.
[ä]D 20 = +101.4 (c 0.31, CHCI3), [ä]546 20 = +122.4, [ä] 05 20 = +311.5,[ä] D 20 = +101.4 (c 0.31, CHCI 3 ), [ä] 546 20 = +122.4, [ä] 05 20 = +311.5,
[ä]365 20 = +472.4, [ä]334 20 = +518.2. XH NMR (250 MHz, CDCI3): δ = 9.90 (s, IH, HC=O); 8.50 (bs, IH, NH); 7.59 - 7.32 (m, 10H, Ph), 7.46 (s, IH, H-6 ' ); 6.62 (dd, J1 = J2 = 2.1, IH, H-2); 5.81 (dddd, = J2 = 2.5, J3 = = 8.4, IH, H-3); 4.20 (dd, = 10.3, J2 = 4.4, IH, SiOCHa); 3.74 (dd, J1 = 10.3, J2 = 2.6, IH, SiOCHb); 3.18 (m, IH, H-5); 2.74 (ddd, = 13.4, J2 = J3 = 8.7, IH, H-4a); 1.85 (ddd, J1 = 13.6, J2 = J3 =8.2, IH, H-4b); 1.03 (s, 9H, S CH3).[ä] 365 20 = +472.4, [ä] 334 20 = +518.2. X H NMR (250 MHz, CDCI 3 ): δ = 9.90 (s, IH, HC = O); 8.50 (bs, IH, NH); 7.59 - 7.32 (m, 10H, Ph), 7.46 (s, IH, H-6 ' ); 6.62 (dd, J 1 = J 2 = 2.1, IH, H-2); 5.81 (dddd, = J 2 = 2.5, J 3 = = 8.4, IH, H-3); 4.20 (dd, = 10.3, J 2 = 4.4, IH, SiOCHa); 3.74 (dd, J 1 = 10.3, J 2 = 2.6, IH, SiOCHb); 3.18 (m, IH, H-5); 2.74 (ddd, = 13.4, J 2 = J 3 = 8.7, IH, H-4a); 1.85 (ddd, J 1 = 13.6, J 2 = J 3 = 8.2, IH, H-4b); 1:03 (s, 9H, S CH3).
13C NMR (63 MHz, CDCI3) : δ = 188.8 (CH=O), 159.3 (C4 ' ), 150.40 und 150.35 (Cl und C2 ' ), 147.1 (C2), 139.9 (C6 ' ), 135.5 und 135.3 und 133.0 und 132.8 und 129.8 und 129.4 und 127.7 und 127.6 (alle von Ph), 97.8 (C5 ' ), 62.5 (CH2OSi), 60.1 (C3), 44.3 (C5), 34.0 (C4), 26.9 ((CH3)3CSi), 19.3 (Me2CSi). 13 C NMR (63 MHz, CDCI 3 ): δ = 188.8 (CH = O), 159.3 (C4 ' ), 150.40 and 150.35 (Cl and C2'), 147.1 (C2), 139.9 (C6 ' ), 135.5 and 135.3 and 133.0 and 132.8 and 129.8 and 129.4 and 127.7 and 127.6 (all of Ph), 97.8 (C5 '), 62.5 (CH 2 OSi), 60.1 (C3), 44.3 (C5), 34.0 (C4), 26.9 ((CH 3 ) 3 CSi), 19.3 (Me 2 CSi).
IR (ATR, cm"1) : = 3177 und 3067 und 3048 (w, N-H), 2953 und 2928 (m, C- H), 2888 (m, CH), 2854 (w, CH), 1704 (s, C=O), 1683 (s, C=O), 1619 (m, C=C), 1588 (w), 1470 (m), 1443 (m), 1426 (m), 1389 (w), 1362 (m), 1337 (w), 1276 (m), 1261 (m), 1242 (m, C-O), 1209 (w), 1189 (w), 1151 (w), 1110 (s),' 1060 (m), 1037 (m), 1018 (w), 997 (m), 983 (m), 940 (w), 909 (w), 841 (m), 821 (m), 741 (m), 701 (m).IR (ATR, cm "1 ): = 3177 and 3067 and 3048 (w, NH), 2953 and 2928 (m, C-H), 2888 (m, CH), 2854 (w, CH), 1704 (s, C = O), 1683 (s, C = O), 1619 (m, C = C), 1588 (w), 1470 (m), 1443 (m), 1426 (m), 1389 (w), 1362 ( m), 1337 (w), 1276 (m), 1261 (m), 1242 (m, CO), 1209 (w), 1189 (w), 1151 (w), 1110 (s), ' 1060 (m) , 1037 (m), 1018 (w), 997 (m), 983 (m), 940 (w), 909 (w), 841 (m), 821 (m), 741 (m), 701 (m) ,
Darstellung von (+)-(3 ?, 5S)-.V~[l-[4-( -rer£-butyl-diphenyl- silanyloxymethyl)-3-formyl-cyclopent-2-enyl]-2 ' -oxo-l ',2 '-dihydro- pyrimidin-4 ' -yl>-benzamid (155c)Preparation of (+) - (3?, 5S) -. V ~ [l- [4- (-rer £ -butyl-diphenyl-silanyloxymethyl) -3-formyl-cyclopent-2-enyl] -2 ' -oxo- l ' , 2 ' -dihydro-pyrimidin-4 '-yl> -benzamide (155c)
Die Verbindung (+)-155c wurde gemäß der allgemeinen Versuchsvorschrift als blassgelbe Flüssigkeit erhalten (52 mg, 57% Ausbeute).Compound (+) - 155c was obtained as a pale yellow liquid (52 mg, 57% yield) according to the general experimental procedure.
m.p. = 104-108°C (EtOAc/CyHex).m.p. = 104-108 ° C (EtOAc / CyHex).
TLC: Rf = 0.25 in EtOAc/CyHex = 4+1.TLC: R f = 0.25 in EtOAc / CyHex = 4 + 1.
[ä]D 20 = +45.1 (c θ.32, CHCI3), [ä]546 20 = +52.6, [ä3405 20 = +42.2.[ä] D 20 = +45.1 (c θ.32, CHCI 3 ), [ä] 546 20 = +52.6, [ä3 405 20 = +42.2.
X NMR (250 MHz, CDCI3) : δ = 9.89 (s, IH, HC=O); 7.88 (d, J = 7.2, 2H, H- X NMR (250 MHz, CDCI 3 ): δ = 9.89 (s, IH, HC = O); 7.88 (d, J = 7.2, 2H, H-
6 ' + lH-Ph); 7.63 (d, J = 7.4, IH, H-5 ' ); 7.60-7.33 (m, 14H, Ph); 6.66 (s,6 ' + 1H-Ph); 7.63 (d, J = 7.4, IH, H-5 ' ); 7.60-7.33 (m, 14H, Ph); 6.66 (s,
IH, H-2); 6.07 (m, IH, H-3); 4.28 (dd, = 10.3, J2 = 3.9, IH, SiOCHa);IH, H-2); 6.07 (m, IH, H-3); 4.28 (dd, = 10.3, J 2 = 3.9, IH, SiOCHa);
3.74 (dd, = 10.1, J2 = 2.7, 1Η, SiOCHb); 3.24 (m, 1Η, Η-5) ; 2.92 (ddd, = 14.2, J2 = J3 = 9.3, IH, H-4a); 1.90 (ddd, = 14.2, J2 = J3 = 7.1, IH, H-4b);3.74 (dd, = 10.1, J 2 = 2.7, 1Η, SiOCHb); 3.24 (m, 1Η, Η-5); 2.92 (ddd, = 14.2, J 2 = J 3 = 9.3, IH, H-4a); 1.90 (ddd, = 14.2, J 2 = J 3 = 7.1, IH, H-4b);
1.04 (s, 9H, SiCH3).1.04 (s, 9H, SiCH 3 ).
13C NMR (63 MHz, CDCI3) : δ = 188.8 (CH=O), 161.9 (NHC=O), 150.4 (C2 '); 13 C NMR (63 MHz, CDCI 3 ): δ = 188.8 (CH = O), 161.9 (NHC = O), 150.4 (C2 ');
147.7 (C6 ' ) 145.7 (C2), 135.6 und 135.4 und 135.2 und 133.3 und 133.2 und147.7 (C6 ') 145.7 (C2), 135.6 and 135.4 and 135.2 and 133.3 and 133.2 and
132.8 und 130.3 und 130.0 und 129.1 und 128.0 und 127.8 und 127.6 (alle von Ph), 97.8 (C5 ' ), 63.2 (CH2OSi), 60.8 (C3), 44.5 (C5), 34.4 (C4), 27.0 (SiC(CH3)3), 19.4 (SiC(CH3) ).132.8 and 130.3 and 130.0 and 129.1 and 128.0 and 127.8 and 127.6 (all of Ph), 97.8 (C5 '), 63.2 (CH 2 OSi), 60.8 (C3), 44.5 (C5), 34.4 (C4), 27.0 (SiC (CH 3 ) 3 ), 19.4 (SiC (CH 3 )).
Darstellung von (+)-(3/?, 5S)-Diphenyl-carbamϊnsäure 2 '- acetylamino-9 '-[4-(terf-butyl-diphenyl-silanyloxymethyl)-3-forrηyl- cyclopent-2-enyl]-9H-purin-6 '-yI ester (155d)Preparation of (+) - (3 /?, 5S) -diphenyl-carbamic acid 2 '- acetylamino-9' - [4- (terf-butyl-diphenyl-silanyloxymethyl) -3-formyl-cyclopent-2-enyl] -9H -purin-6 '-yI ester (155d)
Die Verbindung (+)-155d wurde gemäß der allgemeinen Versuchsvorschrift als klare Flüssigkeit erhalten (112 mg, 37% Ausbeute).Compound (+) - 155d was obtained as a clear liquid according to the general experimental procedure (112 mg, 37% yield).
TLC: Rf = 0.41 in EtOAc/CyHex = 4+1.TLC: R f = 0.41 in EtOAc / CyHex = 4 + 1.
[ä]D 20 = +12.1 (c θ.75, CHCI3), [ä]546 20 = +13.7. H NMR (250 MHz, CDCI3) : δ = 9.84 (s, IH, HC=O); 8.46 (s, IH, NH); 7.92[ä] D 20 = +12.1 (c θ.75, CHCI 3 ), [ä] 546 20 = +13.7. H NMR (250 MHz, CDCI 3 ): δ = 9.84 (s, IH, HC = O); 8.46 (s, IH, NH); 7.92
(s, 1Η, 8 ' Η); 7.99 (s, 1Η, NH); 7.56-7.18 (m, 20Η, 4 x Ph); 6.76 (s, IH, H-(s, 1Η, 8 ' Η); 7.99 (s, 1Η, NH); 7.56-7.18 (m, 20Η, 4 x Ph); 6.76 (s, IH, H-
2); 5.74 (m, IH, H-3); 4.05 (dd, = 10.3, J2 = 6.0, IH, SiOCHa); 3.85 (dd, = 10.1, = 3.2, 1Η, SiOCHb); 3.25 (m, 1Η, Η-5); 2.85 (ddd, = 13.7, J2 2); 5.74 (m, IH, H-3); 4.05 (dd, = 10.3, J 2 = 6.0, IH, SiOCHa); 3.85 (dd, = 10.1, = 3.2, 1Η, SiOCHb); 3.25 (m, 1Η, Η-5); 2.85 (ddd, = 13.7, J 2
= J3 = 8.5, IH, H-4a); 2.43 (s, 3H, CH3CO); 2.06 (ddd, = 13.2, J2 = J3 == J 3 = 8.5, IH, H-4a); 2:43 (s, 3H, CH 3 CO); 2.06 (ddd, = 13.2, J 2 = J 3 =
5.8, 1Η, Η-4b); 1.00 (s, 9H, SiCH3).5.8, 1Η, Η-4b); 1.00 (s, 9H, SiCH 3 ).
13C NMR (63 MΗz, CDCI3): δ = 188.9 (CΗ=O), 170.5 (CH3C=O), 156.2 (C4'), 13 C NMR (63 MΗz, CDCI 3 ): δ = 188.9 (CΗ = O), 170.5 (CH 3 C = O), 156.2 (C4 '),
154.6 und 152.1 und 150.3 (C2' + C6' + Ph2NC=O), 149.4 (Cl), 146.7 (C2),154.6 and 152.1 and 150.3 (C2 '+ C6' + Ph 2 NC = O), 149.4 (Cl), 146.7 (C2),
141.75 (C8'), 141.64 und 135.5 und 135.3 und 133.1 und 132.9 und 129.75 und 129.772 und 129.1 und 127.65 und 127.60 und 126.9 (br) (alle von141.75 (C8 '), 141.64 and 135.5 and 135.3 and 133.1 and 132.9 and 129.75 and 129.772 and 129.1 and 127.65 and 127.60 and 126.9 (br) (all from
4xPh), 120.6 (C5'), 63.2 (CH2OSi), 58.2 (C3), 44.7 (C5), 35.3 (C4), 26.94xPh), 120.6 (C5 '), 63.2 (CH 2 OSi), 58.2 (C3), 44.7 (C5), 35.3 (C4), 26.9
(SiC(CH3)3), 25.0 (CH3C=O), 19.2 (SiC(CH3)3).(SiC (CH 3 ) 3 ), 25.0 (CH 3 C = O), 19.2 (SiC (CH 3 ) 3 ).
IR (ATR, cm"1): v = 3217 (w, N-H), 3064 (w, N-H), 2929 (w, C-H), 2854 (w,IR (ATR, cm "1 ): v = 3217 (w, NH), 3064 (w, NH), 2929 (w, CH), 2854 (w,
C-H), 1741 (s, NC=O); 1684 (s, CH=O), 1617 (s, C=C), 1586 (m), 1490 (m),C-H), 1741 (s, NC = O); 1684 (s, CH = O), 1617 (s, C = C), 1586 (m), 1490 (m),
1450 (w), 1425 (w), 1372 (m), 1333 (m), 1281 (s), 1213 (s), 1185 (s), 1167 (s), 1108 (m), 1059 (m), 1001 (m), 931 (w), 907 (w), 822 (w), 785 (w), 7411450 (w), 1425 (w), 1372 (m), 1333 (m), 1281 (s), 1213 (s), 1185 (s), 1167 (s), 1108 (m), 1059 (m), 1001 (m), 931 (w), 907 (w), 822 (w), 785 (w), 741
(m), 700 (s), 664 (w).(m), 700 (s), 664 (w).
MS (ESI, 70 eV) : m/z (%) = 807 (11), 806 (29), 805 (51), 775 (10), 774MS (ESI, 70 eV): m / z (%) = 807 (11), 806 (29), 805 (51), 775 (10), 774
(27), 773 ([M+Na]+, 47), 679 (3), 594 (3), 562 (5), 519 (5), 443 (2), 413(27), 773 ([M + Na] + , 47), 679 (3), 594 (3), 562 (5), 519 (5), 443 (2), 413
(5), 412 (23), 411 (100), 369 (2), 196 (17), 168 (11).(5), 412 (23), 411 (100), 369 (2), 196 (17), 168 (11).
HRMS (ESI) C43H42N6NaO5Si [M+Na]+ : calcd 773.288, found 773.288.HRMS (ESI) C 43 H 42 N 6 NaO 5 Si [M + Na] + : calcd 773.288, found 773.288.
Allgemeine Vorschrift zur Reduktion der Aldehyde (95) und (155)General regulation for the reduction of aldehydes (95) and (155)
(+)-95 (R = ThxMe2Si) (-)-113 (R = ThxMe2Si)(+) - 95 (R = ThxMe 2 Si) (-) - 113 (R = ThxMe 2 Si)
(+)-155 (R = .-BuPh2Si) (-)-159 (R = .-BuPh2Si)(+) - 155 (R =.-BuPh 2 Si) (-) - 159 (R =.-BuPh 2 Si)
Zu NaBH4 (76 mg, 2 mmol, 10 äquiv.) wurde eine Mischung von MeOH (6 ml) und CH2CI2 (12 m!) gegeben und über 3 min. bei RT gerührt, bevor die Mischung auf -78 °C abgekühlt wurde (Trockeneis-Aceton-Bad). Eine Lsg. von (+)-95 oder (+)-155 (200 μmol) in CH2CI2 (2 ml) wurde tropfenweise zugeführt. Nachdem die Reaktionsmischung 1 h bei -78 °C gerührt worden war, wurden 5 ml Aceton zugegeben und die Mischung langsam auf RT erwärmt, wobei noch 30 min lang bei RT gerührt wurde. Das Reaktionsgemisch wurde auf eine mit Kieselgel beladene Säule gegeben und mit EtOAc extrahiert. Anschließend wurde das Lösungsmittel abgedampft, wobei als Rückstand in hohem Reinheitsgrad gemäß XH NMR und TLC der Allylalkohol 113 oder (-)-159 entstand. Darstellung von (-)-(l 'Λ, 4 'S)-l-{4 '-[Dimethyl-(l,l/2-trimethyl- propyl)-silanyloxymethyl]-3 ' -hydroxymethyl- cycIopent-2 '-enyl}-lH-pyrimidin-2,4-dion (113a)A mixture of MeOH (6 ml) and CH 2 Cl 2 (12 m!) Was added to NaBH 4 (76 mg, 2 mmol, 10 equiv.) And the mixture was stirred for 3 min. stirred at RT before the mixture was cooled to -78 ° C (dry ice-acetone bath). A solution of (+) - 95 or (+) - 155 (200 μmol) in CH 2 CI 2 (2 ml) was added dropwise. After the reaction mixture had been stirred at -78 ° C. for 1 h, 5 ml of acetone were added and the mixture was slowly warmed to RT, with stirring at RT for a further 30 min. The reaction mixture was applied to a column loaded with silica gel and extracted with EtOAc. The solvent was then evaporated off, the allyl alcohol 113 or (-) - 159 being formed as the residue in a high degree of purity according to X H NMR and TLC. Preparation of (-) - (l 'Λ, 4' S) -l- {4 '- [Dimethyl- (l, l / 2-trimethyl-propyl) -silanyloxymethyl] -3' -hydroxymethyl-cyclopent-2 '- enyl} -lH-pyrimidine-2,4-dione (113a)
Die Verbindung (-)-113a wurde gemäß der allgemeinen Versuchsvorschrift als klare Flüssigkeit erhalten (59 mg, 78% Ausbeute).Compound (-) - 113a was obtained as a clear liquid (59 mg, 78% yield) according to the general experimental procedure.
m.p. = 60-62°C (EtOAc/CyHex).m.p. = 60-62 ° C (EtOAc / CyHex).
TLC: Rf = 0.17 in EtOAc/CyHex = 4+1.TLC: R f = 0.17 in EtOAc / CyHex = 4 + 1.
[ä]D 20 = -84.6 (c 0.33, CHCI3), [ä]546 20 = -101.3.[ä] D 20 = -84.6 (c 0.33, CHCI 3 ), [ä] 546 20 = -101.3.
*H NM (250 MHz, CDCI3): δ = 9.00 (bs, IH, NH); 7.34 (d, J = 8.0, 1Η, Η-6);* H NM (250 MHz, CDCI 3 ): δ = 9.00 (bs, IH, NH); 7.34 (d, J = 8.0, 1Η, Η-6);
5.67 (dd, = 8.0, J2 = 2.2, H-5); 5.62 (ddd, = 8.5, J2 = J3 = 1.9, IH, H-l ' );5.67 (dd, = 8.0, J 2 = 2.2, H-5); 5.62 (ddd, = 8.5, J 2 = J 3 = 1.9, IH, Hl ');
5.52 (s, IH, H-2 '); 4.26 (s, 2H, CH2OH); 3.79 (dd, Jx = 10.5, J2 = 3.6, IH,5.52 (s, IH, H-2 ' ); 4.26 (s, 2H, CH 2 OH); 3.79 (dd, J x = 10.5, J 2 = 3.6, IH,
SiOCHa); 3.52 (dd, = 10.5, J2 = 6.1, .1Η, SiOCHb); 2.86 (m, 1Η, Η-4 ');SiOCHa); 3.52 (dd, = 10.5, J 2 = 6.1, .1Η, SiOCHb); 2.86 (m, 1Η, Η-4 ');
2.71 (ddd, = 13.5, J2 = J3 = 8.5, IH, H-5 'a); 1.59 (septet, J = 6.8, 2H, OH2.71 (ddd, = 13.5, J 2 = J 3 = 8.5, IH, H-5 ' a); 1.59 (septet, J = 6.8, 2H, OH
+ Me2CH); 1.39 (ddd, = 13.5, J2 = J3 = 6.9, 1Η, Η-5 'b); 0.85 (d, J = 6.8,+ Me 2 CH); 1.39 (ddd, = 13.5, J 2 = J 3 = 6.9, 1Η, Η-5 'b); 0.85 (d, J = 6.8,
6H, (CH3)2CH); 0.83 (s, 6H, C(CH3)2); 0.10 + 0.09 (2 x s,' 6Η, CH3Si).6H, (CH 3 ) 2 CH); 0.83 (s, 6H, C (CH 3) 2); 0.10 + 0.09 (2 xs, ' 6Η, CH 3 Si).
13C NMR (63 MΗz, CDCI3): δ = 163.3 (C4), 152.7 (C3'), 151.0 (C2), 141.2 13 C NMR (63 MΗz, CDCI 3 ): δ = 163.3 (C4), 152.7 (C3 ' ), 151.0 (C2), 141.2
(C6), 124.7 (C2'), 102.4 (C5), 64.1 (CΗ2OSi), 60.5 (CH2OH), 59.6 (Cl'),(C6), 124.7 (C2 '), 102.4 (C5), 64.1 (CΗ 2 OSi), 60.5 (CH 2 OH), 59.6 (Cl'),
46.9 (C4'), 34.1 (C5'), 34.0 (Me2CH), 25.3 (Me2CSi), 20.3 und 20.246.9 (C4 ' ), 34.1 (C5'), 34.0 (Me 2 CH), 25.3 (Me 2 CSi), 20.3 and 20.2
((CH3)2CH), 18.5 und 18.4 ((CH3)2CSi), -3.49 und -3.51 (CH3Si).((CH 3 ) 2 CH), 18.5 and 18.4 ((CH 3 ) 2 CSi), -3.49 and -3.51 (CH 3 Si).
IR (ATR, cm"1): v = 3406 (w, O-H), 3178 (w, N-H), 3043 (m, N-H), 2951 (m,IR (ATR, cm "1 ): v = 3406 (w, OH), 3178 (w, NH), 3043 (m, NH), 2951 (m,
C-H), 2862 (m, CH), 1753 (w), 1693 (s, C=O), 1697 (s, C=O), 1666 (s, C=N),C-H), 2862 (m, CH), 1753 (w), 1693 (s, C = O), 1697 (s, C = O), 1666 (s, C = N),
1651 (m, C=C), 1461 (s), 1416 (m), 1377 (m), 1275 (m), 1248 (s, C-O),1651 (m, C = C), 1461 (s), 1416 (m), 1377 (m), 1275 (m), 1248 (s, C-O),
1174 (m), 1112 (m), 1060 (m), 1039 (m), 994 (m), 934 (w), 871 (m), 8281174 (m), 1112 (m), 1060 (m), 1039 (m), 994 (m), 934 (w), 871 (m), 828
(s), 804 (m), 775 (s), 719 (m), 694 (m), 666 (m).(s), 804 (m), 775 (s), 719 (m), 694 (m), 666 (m).
MS (EI, 70 eV): m/z (%): 333 (6), 295 [M-85]+ (10), 278 (14), 277 (38), 247MS (EI, 70 eV): m / z (%): 333 (6), 295 [M-85] + (10), 278 (14), 277 (38), 247
(3), 199 (7), 183 (18), 169 (8), 129 (4), 117 (8), 105 (23), 91 (100), 77(3), 199 (7), 183 (18), 169 (8), 129 (4), 117 (8), 105 (23), 91 (100), 77
(10), 75 (14).(10), 75 (14).
HRMS (ESI) [M + Na]+ Cι9H32N2NaO4Si: calcd 403.203, found: 403.204. Darstellung von (+)-(l 'S, 4 '/?)-l-{4 ^Dimethyl-(l,l,2-trimethyl- propyl)-silanyloxymethyI]-3 '-hydroxymethyl-cyclopent-2 '-enyl}-lf/- pyrimidin-2,4-dion (113a)HRMS (ESI) [M + Na] + Cι 9 H 32 N 2 NaO 4 Si: calcd 403.203, found: 403.204. Preparation of (+) - (l 'S, 4' /?) - l- {4 ^ Dimethyl- (l, l, 2-trimethyl-propyl) -silanyloxymethyI] -3 '-hydroxymethyl-cyclopent-2' -enyl } -lf / - pyrimidine-2,4-dione (113a)
Die Verbindung (+)-113a wurde gemäß der allgemeinen Versuchs Vorschrift als klare Flüssigkeit erhalten (72 mg, 95% Ausbeute).Compound (+) - 113a was obtained as a clear liquid (72 mg, 95% yield) according to the general experimental procedure.
[ä]D 20 = +61 (c 0.26, CHCI3), [ä]546 20 = +76, [ä]405 20 = +199, [ä]365 20 = +309, [ä]334 20 = +509.[ä] D 20 = +61 (c 0.26, CHCI 3 ), [ä] 546 20 = +76, [ä] 405 20 = +199, [ä] 365 20 = +309, [ä] 334 20 = + 509th
Darstellung von (-)-(l 'Ä, 4 'S)-5-Fluor-l-{4 '-[dimethyI-(l,l,2- trimethyl-propyl)-silanyloxymethyl]-3 '-hydroxymethyl-cyclopent-2 '- enyI>-l//-pyπmidin-2,4-dion (113b)Preparation of (-) - (l 'Ä, 4' S) -5-fluoro-l- {4 '- [dimethyl- (l, l, 2-trimethyl-propyl) -silanyloxymethyl] -3' -hydroxymethyl-cyclopent -2 '- enyI> -l // - pyπmidin-2,4-dione (113b)
Die Verbindung (-)-113b wurde gemäß der allgemeinen Versuchsvorschrift als farbloses Öl erhalten (48 mg, 99% Ausbeute).The compound (-) - 113b was obtained as a colorless oil (48 mg, 99% yield) according to the general experimental procedure.
m.p. = 165-167°C (EtOAc/Hex).m.p. = 165-167 ° C (EtOAc / Hex).
TLC: Rf = 0.40 in EtOAc/CyHex = 4+1.TLC: R f = 0.40 in EtOAc / CyHex = 4 + 1.
[ä]D 20 = -77.0 (c 0.46, CHCI3), [ä]546 20 = -95.3, [ä]405 20 = -252.8, [ä]365 20 =[ä] D 20 = -77.0 (c 0.46, CHCI 3 ), [ä] 546 20 = -95.3, [ä] 405 20 = -252.8, [ä] 365 20 =
-404.4, [ä]334 20 = - 702.2.-404.4, [ä] 334 20 = - 702.2.
XH NMR (250 MHz, CDCI3): δ = 9.92 (bs, IH, NH); 7.42 (d, JΗ;F = 5.9, IH, H- 6); 5.62 (m, IH, H-l '); 5.53 (s, IH, H-2 '); 4.31 (d, J = 14.6, IH, CHaOH); 4.23 (d, J = 15.0, IH, CHbOH); 3.80 (dd, = 10.4, J2 = 3.4, IH, SiOCHa); 3.53 (dd, = 10.4, J2 = 5.2, 1Η, SiOCHb); 2.86 (m, 1Η, Η-4 '); 2.70 (ddd, = 13.6, J2 = J3 = 8.6, 1Η, Η-5 'a); 1.58 (septet, J = 6.8, IH, Me2CH); 1.43 (ddd, = 13.7, J2 = J3 = 6.6, 1Η, Η-5 'b); 0.84 (d, J = 7.0, 6Η, (CH3)2CH); 0.82 (s, 6H, C(CH3)2); 0.10 + 0.08 (2 x s, 6Η, CH3Si). X H NMR (250 MHz, CDCI 3 ): δ = 9.92 (bs, IH, NH); 7.42 (d, J Η; F = 5.9, IH, H-6); 5.62 (m, IH, Hl '); 5.53 (s, IH, H-2 '); 4.31 (d, J = 14.6, IH, CHaOH); 4.23 (d, J = 15.0, IH, CHbOH); 3.80 (dd, = 10.4, J 2 = 3.4, IH, SiOCHa); 3.53 (dd, = 10.4, J 2 = 5.2, 1Η, SiOCHb); 2.86 (m, 1Η, Η-4 '); 2.70 (ddd, = 13.6, J 2 = J 3 = 8.6, 1Η, Η-5 'a); 1.58 (septet, J = 6.8, IH, Me 2 CH); 1.43 (ddd, = 13.7, J 2 = J 3 = 6.6, 1Η, Η-5 'b); 0.84 (d, J = 7.0, 6Η, (CH 3 ) 2 CH); 0.82 (s, 6H, C (CH 3) 2); 0.10 + 0.08 (2 xs, 6Η, CH 3 Si).
13C MMR (63 MΗz, CDCI3): δ = 157.1 (d, JC;F = 26, C4), 153.2 (C3 ' ), 149.8 (C2), 140.6 (d, JC,F = 236, C6), 125.3 (d, JC,F = 32, C5), 124.2 (C2 ' ), 63.7 (CΗ2OSi), 60.4 (CH2OH), 60.1 (Cl '), 46.8 (C4 '), 34.0 (Me2CH), 33.7 (C5 '), 25.3 (Me2CSi), 20.3 und 20.1 ((CH3)2CH), 18.41 und 18.36 ((CH3)2CSi), -3.5 und -3.6 (CH3Si). IR (ATR, cm"1): v - 3416 (w, O-H), 3178 (w, N-H), 3056 (w, N-H), 2954 (m, 13 C MMR (63 MΗz, CDCI 3 ): δ = 157.1 (d, J C; F = 26, C4), 153.2 (C3 ' ), 149.8 (C2), 140.6 (d, J C , F = 236, C6 ), 125.3 (d, J C , F = 32, C5), 124.2 (C2 '), 63.7 (CΗ 2 OSi), 60.4 (CH 2 OH), 60.1 (Cl'), 46.8 (C4 ' ), 34.0 ( Me 2 CH), 33.7 (C5 ' ), 25.3 (Me 2 CSi), 20.3 and 20.1 ((CH 3 ) 2 CH), 18.41 and 18.36 ((CH 3 ) 2 CSi), -3.5 and -3.6 (CH 3 Si). IR (ATR, cm "1 ): v - 3416 (w, OH), 3178 (w, NH), 3056 (w, NH), 2954 (m,
C-H), 2864 (m, CH), 1692 (s, C=O), 1659 (s, C=C), 1465 (m), 1389 (m),C-H), 2864 (m, CH), 1692 (s, C = O), 1659 (s, C = C), 1465 (m), 1389 (m),
1344 (w), 1273 (m), 1239 (s, C-O), 1151 (w), 1109 (m), 1088 (m), 10621344 (w), 1273 (m), 1239 (s, C-O), 1151 (w), 1109 (m), 1088 (m), 1062
(m), 1036 (m), 994 (m), 938 (w), 885 (m), 830 (s), 779 (m), 707 (w).(m), 1036 (m), 994 (m), 938 (w), 885 (m), 830 (s), 779 (m), 707 (w).
MS (ESI, 70 eV) : m/z (%) : 835 [2M+K]+ (4), 819 [2M + Na]+ (4), 463 (25),MS (ESI, 70 eV): m / z (%): 835 [2M + K] + (4), 819 [2M + Na] + (4), 463 (25),
421 [M + Na]+ (100), 399 [M + H]+ (2), 286 (4), 269 (10).421 [M + Na] + (100), 399 [M + H] + (2), 286 (4), 269 (10).
HRMS (ESI) C19H3ιFN2NaO4Si [M + Na]+: calcd. 421.194, found : 421.194.HRMS (ESI) C 19 H 3 IFN 2 NaO 4 Si [M + Na] + : calcd. 421.194, found: 421.194.
Darstellung von (+)-(! 'S, 4 'R)-5-Fluor-l~(4 '-[dimethyl-(l,l,2- trimethyl-propyl)-silanyloxymethyl]-3 '-hydroxymethyl-cyclopent-Preparation of (+) - (! 'S, 4' R) -5-fluoro-l ~ (4 '- [dimethyl- (l, l, 2-trimethyl-propyl) -silanyloxymethyl] -3' -hydroxymethyl-cyclopent -
2 "-enyl>-lH-pyrimidin-2>4-dion (113b)2 "-enyl> -lH-pyrimidine-2> 4-dione (113b)
Die Verbindung (+)-113b wurde gemäß der allgemeinen Versuchsvorschrift als gelbe Flüssigkeit erhalten (85 mg, 93% Ausbeute).Compound (+) - 113b was obtained as a yellow liquid according to the general experimental procedure (85 mg, 93% yield).
[ä]D 20 = +71.1 (c 0.68, CHCI3), [ä]546 20 = +88.3, [ä]405 20 = +234.6, [ä]334 20 = +649.1.[ä] D 20 = +71.1 (c 0.68, CHCI 3 ), [ä] 546 20 = +88.3, [ä] 405 20 = +234.6, [ä] 334 20 = +649.1.
Darstellung von (-)-(l 'R, 4 'S)-l-{4 '-[Dimethyl-(l,l,2-trimethyl- propyl)-silanyloxymethyl]-3 ' -hydroxymethyl-cyclopent-2 '-enyl}—Preparation of (-) - (l 'R, 4' S) -l- {4 '- [Dimethyl- (l, l, 2-trimethyl-propyl) -silanyloxymethyl] -3' -hydroxymethyl-cyclopent-2 '- enyl} -
5-methyl-li4r-pyrimidin-2,4-dion (113c)5-methyl-li4 r -pyrimidine-2,4-dione (113c)
Die Verbindung (-)-113c wurde gemäß der allgemeinen Versuchsvorschrift als klare Flüssigkeit erhalten (69 mg, 88% Ausbeute).Compound (-) - 113c was obtained as a clear liquid (69 mg, 88% yield) according to the general experimental procedure.
m.p. = 108-109°C (EtOAc/CyHex).m.p. = 108-109 ° C (EtOAc / CyHex).
TLC: Rf = 0.21 in EtOAc/CyHex = 4+1.TLC: R f = 0.21 in EtOAc / CyHex = 4 + 1.
[ä]D 20 = -67.9 (c 0.50, CHCI3), [ä]546 20 = -83.6, [ä34o5 20 = -223.8, [ä3365 20 =[ä] D 20 = -67.9 (c 0.50, CHCI3), [ä] 546 20 = -83.6, [ä3 4 o 5 20 = -223.8, [ä3 365 20 =
-357.8, [aJ33 = -622.7. lH NMR (250 MHz, CDCI3) : δ = 8.62 (bs, IH, NH); 7.05 (d, J = 1.2, 1Η, Η-6);-357.8, [aJ33 = -622.7. 1 H NMR (250 MHz, CDCI 3 ): δ = 8.62 (bs, IH, NH); 7.05 (d, J = 1.2, 1Η, Η-6);
5.59 (dddd, = 7.8, J2 = 7.6, J3 = J4 = 2.1, IH, H-l ' ); 5.53 (s, IH, H-2 ' );5.59 (dddd, = 7.8, J 2 = 7.6, J 3 = J 4 = 2.1, IH, Hl '); 5.53 (s, IH, H-2 ');
4.27 (d, J = 5.8, 2H, CH2OH); 3.77 (dd, 31 = 10.3, J2 = 3.7, IH, SiOCHa); 3.524.27 (d, J = 5.8, 2H, CH 2 OH); 3.77 (dd, 3 1 = 10.3, J 2 = 3.7, IH, SiOCHa); 3:52
(dd, = 10.3, J2 = 6.3, 1Η, SiOCHb); 2.87 (m, 1Η, Η-4 ' ); 2.65 (ddd, = 13.3, J2 = J3 = 8.4, IH, H-5 'a); 1.88 (d, J = 1.2, 3H, CH3); 1.67 (bs, 1Η, OΗ);(dd, = 10.3, J 2 = 6.3, 1Η, SiOCHb); 2.87 (m, 1Η, Η-4 '); 2.65 (ddd, = 13.3, J 2 = J 3 = 8.4, IH, H-5 'a); 1.88 (d, J = 1.2, 3H, CH 3); 1.67 (bs, 1Η, OΗ);
1.60 (septet, J = 6.9, 1Η, Me2CH); 1.35 (ddd, = 13.6, J2 = J3 = 7.7, 1Η, Η-1.60 (septet, J = 6.9, 1Η, Me 2 CH); 1.35 (ddd, = 13.6, J 2 = J 3 = 7.7, 1Η, Η-
5 'b); 0.86 (d, J = 6,9, 6Η, (CH3)2CH); 0.83 (s, 6H, C(CH3)2); 0.11 +5 'b); 0.86 (d, J = 6.9, 6Η, (CH 3 ) 2 CH); 0.83 (s, 6H, C (CH 3) 2); 0.11 +
0.10 (2 x s, 6Η, CH3Si).0.10 (2 xs, 6Η, CH 3 Si).
13C NMR (63 MHz, CDCI3): δ = 163.8 (C4), 152.3 (C3 '), 150.1 (C2), 136.6 13 C NMR (63 MHz, CDCI 3 ): δ = 163.8 (C4), 152.3 (C3 '), 150.1 (C2), 136.6
(C6), 125.2 (C2 '), 110.1 (C5), 64.1 (CH2OSi), 60.6 (CH2OH), 59.4 (Cl '),(C6), 125.2 (C2 '), 110.1 (C5), 64.1 (CH 2 OSi), 60.6 (CH 2 OH), 59.4 (Cl'),
46.7 (C4 ' ), 34.2 (C5 '), 34.1 (Me2CH), 25.2 (MezCSi), 20.2 ((CH3)2CH), 18.546.7 (C4 '), 34.2 (C5'), 34.1 (Me 2 CH), 25.2 (MezCSi), 20.2 ((CH 3 ) 2 CH), 18.5
((CH3)2CSi), 12.4 (CH3), -3.5 und -3.6 (CH3Si).((CH 3 ) 2 CSi), 12.4 (CH 3 ), -3.5 and -3.6 (CH 3 Si).
IR (ATR, cm"1): v = 3404 (w, O-H), 3173 (w, N- H), 3042 (w, N-H), 2953 (m,IR (ATR, cm "1 ): v = 3404 (w, OH), 3173 (w, N-H), 3042 (w, NH), 2953 (m,
C-H), 2863 (m, CH), 1681 (s, C=O), 1465 (m), 1387 (m), 1378 (m), 1359C-H), 2863 (m, CH), 1681 (s, C = O), 1465 (m), 1387 (m), 1378 (m), 1359
(w), 1276 (m), 1249 (s), 1222 (m, C-O), 1149 (w), 1111 (m), 1088 (m),(w), 1276 (m), 1249 (s), 1222 (m, C-O), 1149 (w), 1111 (m), 1088 (m),
1060 (m), 1044 (m), 1009 (m), 993 (m), 937 (w), 908 (w), 874 (m), 829 (s),1060 (m), 1044 (m), 1009 (m), 993 (m), 937 (w), 908 (w), 874 (m), 829 (s),
777 (m), 763 (m).777 (m), 763 (m).
MS (EI, 70 eV): m/z (%): 380 (6), 310 (4), 293 (7), 290 (12), 276 (10), 217MS (EI, 70 eV): m / z (%): 380 (6), 310 (4), 293 (7), 290 (12), 276 (10), 217
(11), 216 (87), 186 (9), 183 (34), 178 (18), 168 (21), 112 (25), 105 (100),(11), 216 (87), 186 (9), 183 (34), 178 (18), 168 (21), 112 (25), 105 (100),
91 (28), 89 (15), 77 (29), 75 (50), 73 (30).91 (28), 89 (15), 77 (29), 75 (50), 73 (30).
HRMS (ESI) [M+Na]+ C20H34N2NaO4Si: calcd. 417.2186, found: 417.219.HRMS (ESI) [M + Na] + C 20 H 34 N 2 NaO 4 Si: calcd. 417.2186, found: 417.219.
Darstellung von (+)-(l 'S, 4 'R)-l-{4 '-[Dimethyl-(l,l,2-trimethyl- propyl)-silanyloxymethyl3-3 ' -hydroxymethyl-cyclopent-2 ' -enyI}-5- methyl-lH-pyrimidin-2,4-dion (113c)Preparation of (+) - (l 'S, 4' R) -l- {4 '- [Dimethyl- (l, l, 2-trimethyl-propyl) -silanyloxymethyl3-3' -hydroxymethyl-cyclopent-2 '-enyI } -5- methyl-lH-pyrimidine-2,4-dione (113c)
Die Verbindung (+)-113c wurde gemäß der allgemeinen Versuchsvorschrift als klare Flüssigkeit erhalten (79 mg, 99% Ausbeute).Compound (+) - 113c was obtained as a clear liquid (79 mg, 99% yield) according to the general experimental procedure.
[ä3D 20 = +70 (c 0.16, CHCI3), [ä 54620 = +87, [ä3405 20 = +223, [a 365 0 = Darstellung von (+)-(l 'S, 4 'Λ)-/V-(l-{4 '-[Dϊmethyl-(l,l,2-trimethyI- propyI)-silanyloxymethyl3-3-hydroxymethyI-cyclopent-[ä3 D 20 = +70 (c 0.16, CHCI 3 ), [ä 54 6 20 = +87, [ä3 405 20 = +223, [a 36 5 0 = Representation of (+) - (l 'S, 4' Λ) - / V- (l- {4 '- [Dϊmethyl- (l, l, 2-trimethyI-propyI) -silanyloxymethyl3-3-hydroxymethyI-cyclopent-
2 '-enyI}-2-oxo-l,2-dihydro-pyrimidin-4-yl)-benzamid (113d-l)2 '-enyI} -2-oxo-l, 2-dihydro-pyrimidin-4-yl) -benzamide (113d-l)
Die Verbindung (+)-113d-l wurde gemäß der allgemeinen Versuchsvorschrift als gelbes Öl erhalten (97 mg, 99% Ausbeute).Compound (+) - 113d-1 was obtained as a yellow oil according to the general experimental procedure (97 mg, 99% yield).
TLC: Rf = 0.55 in EtOAc/MeOH = 4+1.TLC: R f = 0.55 in EtOAc / MeOH = 4 + 1.
[ä3D 20 = +65 (c θ.12, CHCI3).[ä3 D 20 = +65 (c θ.12, CHCI 3 ).
X NMR (250 MHz, CDCI3): δ = 7.89 (d, J = 6.3, IH, H-6); 7.79 (d, J = 6.0, X NMR (250 MHz, CDCI 3 ): δ = 7.89 (d, J = 6.3, IH, H-6); 7.79 (d, J = 6.0,
IH, H-5); 7.62-7.34 (m, 5H, Ph); 5.77 (m, IH, H-l '); 5.60 (s, IH, H-2 ');IH, H-5); 7.62-7.34 (m, 5H, Ph); 5.77 (m, IH, H-1 '); 5.60 (s, IH, H-2 ');
4.30 (s, 2H, CH2OH); 3.78 (dd, = 8.8, J2 = 2.8, IH, SiOCHa); 3.51 (dd, =4.30 (s, 2H, CH 2 OH); 3.78 (dd, = 8.8, J 2 = 2.8, IH, SiOCHa); 3.51 (dd, =
8.8, J2 = 5.0, 1Η, SiOCHb); 2.90 (m, 1Η, Η-4 '); 2.86 (ddd, = 10.5, J2 = J3 =8.8, J 2 = 5.0, 1Η, SiOCHb); 2.90 (m, 1Η, Η-4 ' ); 2.86 (ddd, = 10.5, J 2 = J 3 =
7.0, 1Η, Η-5 'a); 1.60 (septet, J = 6.8, IH, Me2CH); 1.40 (ddd, = 9.3, J2 = J3 7.0, 1Η, Η-5 'a); 1.60 (septet, J = 6.8, IH, Me 2 CH); 1.40 (ddd, = 9.3, J 2 = J 3
= 5.3, 1Η, Η-5 'b); 0.86 (d, J = 5.8, 6H, (CH3)2CH); 0.84 (s, 6H, C(CH3)2);= 5.3, 1Η, Η-5 'b); 0.86 (d, J = 5.8, 6H, (CH 3 ) 2 CH); 0.84 (s, 6H, C (CH 3) 2);
0.11 + 0.09 (2 x s, 6Η, CH3Si);0.11 + 0.09 (2 xs, 6Η, CH 3 Si);
13C NMR (63 MΗz, CDCI3): δ = 161.9 (C4), 153.4 (C3 '), 145.7 (C6), 133.1 und 129.0 und 128.5 und 127.6 (all of Ph), 124.7 (C2 '), 85.1 (C5), 64.4 13 C NMR (63 MΗz, CDCI 3 ): δ = 161.9 (C4), 153.4 (C3 '), 145.7 (C6), 133.1 and 129.0 and 128.5 and 127.6 (all of Ph), 124.7 (C2'), 85.1 ( C5), 64.4
(CΗ2OSi), 61.4 (CH2OH), 60.6 (Cl '), 47.2 (C4 ' ), 35.1 (C5 '), 34.0 (Me2CH),(CΗ 2 OSi), 61.4 (CH 2 OH), 60.6 (Cl '), 47.2 (C4'), 35.1 (C5 '), 34.0 (Me 2 CH),
25.3 (Me2CSi), 20.29 und 20.19 ((CH3)2CH), 18.48 und 18.44 ((CH3)2CSi), -25.3 (Me 2 CSi), 20.29 and 20.19 ((CH 3 ) 2 CH), 18.48 and 18.44 ((CH 3 ) 2 CSi), -
3.5 (CH3Si);3.5 (CH 3 Si);
IR (ATR, cm"1): = 3295 (bw, O-H), 3062 (w, N-H), 2954 (m, C-H), 2863 (m,IR (ATR, cm "1 ): = 3295 (bw, OH), 3062 (w, NH), 2954 (m, CH), 2863 (m,
C-H), 1693 (m, C=O), 1649 (s, C=N), 1643 (s, C=C), 1620 (s, C=C), 1556C-H), 1693 (m, C = O), 1649 (s, C = N), 1643 (s, C = C), 1620 (s, C = C), 1556
(m), 1485 (s), 1380 (s), 1300 (m), 1249 (s, C-O), 1190 (m), 1176 (m), 1109(m), 1485 (s), 1380 (s), 1300 (m), 1249 (s, C-O), 1190 (m), 1176 (m), 1109
(m), 1092 (m), 1028 (m), 1002 (m), 930 (w), 873 (w), 830 (m), 802 (m),(m), 1092 (m), 1028 (m), 1002 (m), 930 (w), 873 (w), 830 (m), 802 (m),
778 (m), 704 (m), 665 (m);778 (m), 704 (m), 665 (m);
M (EI, 70 eV) : m/z (%) : 407 (6), 333 (3), 310 (10), 309 (57), 307 (18), 289M (EI, 70 eV): m / z (%): 407 (6), 333 (3), 310 (10), 309 (57), 307 (18), 289
(5), 261 (13), 217 (7), 215 (9), 201 (10), 184 (13), 183 (100), 181 (16), 174(5), 261 (13), 217 (7), 215 (9), 201 (10), 184 (13), 183 (100), 181 (16), 174
(10), 153 (4), 127 (28), 105 (36), 91 (91), 89 (25), 75 (61), 73 (33);(10), 153 (4), 127 (28), 105 (36), 91 (91), 89 (25), 75 (61), 73 (33);
HRMS (EI) [M+Na]+ C26H37N3NaO4Si : calcd 506.245, found : 506.245.HRMS (EI) [M + Na] + C 26 H 37 N 3 NaO 4 Si: calcd 506.245, found: 506.245.
Darstellung von (-)-(l 'Λ, 4 'S)-/V-(l-{4 '-[Dimethyl-(l,l,2-trimethyl- propyl)-silanyloxymethyl3-3-hydroxymethyl-cyclopent-2 '-enyl>-2- oxo-l,2-dihydro-pyrimϊdϊn-4-yl)-benzamid (113d-l)Representation of (-) - (l 'Λ, 4' S) - / V- (l- {4 '- [dimethyl- (l, l, 2-trimethyl- propyl) -silanyloxymethyl3-3-hydroxymethyl-cyclopent-2 '-enyl> -2-oxo-l, 2-dihydro-pyrimϊdϊn-4-yl) -benzamide (113d-l)
Die Verbindung (-)-113d-l wurde gemäß der allgemeinen Versuchsvorschrift als Gemisch des geschützten und freien Alkohols erhalten, welches direkt in die folgende Reaktion zur Abspaltung der Schutzgruppe eingesetzt wurde.The compound (-) - 113d-l was obtained according to the general experimental procedure as a mixture of the protected and free alcohol, which was used directly in the following reaction to remove the protective group.
Darstellung von (+)-(l 'R, 4 'S)-4-Amino-l-{4 '-[dimethyl-(l,l,2- tπmethyl-propyl)-silanyIoxymethyl3-3 ' -hydroxymethyl-cyclopent-2 ' - enyl>-lH-pyrimidin-2-on (113d)Preparation of (+) - (l 'R, 4' S) -4-amino-l- {4 '- [dimethyl- (l, l, 2-tπmethyl-propyl) -silanyloxymethyl3-3' -hydroxymethyl-cyclopent- 2 '- enyl> -lH-pyrimidin-2-one (113d)
Eine 2 M Lsg. von Ammoniak in MeOH (2 ml, 4 mmol, 40 equiv.) wurde zu einer Lsg. von (+)-113d-l (48 mg, 100 μmol) bei RT unter Argon-Atmosphäre gegeben und das Reaktionsgemisch über 16 h gerührt. Das Lösungsmittel und der Ammoniak wurde abgedampft und der Rückstand über Flash- Chromatographie (EtOAc/CyHex = 4+1? EtOAc/MeOH = 4+1) gereinigt. Die Verbindung (+)-113d wurde als gelbes Öl erhalten (36 mg, 95% Ausbeute).A 2 M solution of ammonia in MeOH (2 ml, 4 mmol, 40 equiv.) Was added to a solution of (+) - 113d-l (48 mg, 100 μmol) at RT under an argon atmosphere and the reaction mixture stirred for 16 h. The solvent and ammonia were evaporated and the residue was purified by flash chromatography (EtOAc / CyHex = 4 + 1? EtOAc / MeOH = 4 + 1). Compound (+) - 113d was obtained as a yellow oil (36 mg, 95% yield).
TLC: Rf = 0.27 in EtOAc/MeOH = 4+1.TLC: R f = 0.27 in EtOAc / MeOH = 4 + 1.
[ä3D 20 = +91.6 (c θ.31, MeOH), [ä3546 20 = +112.1, [ä3405 20 = +298.6,[ä3 D 20 = +91.6 (c θ.31, MeOH), [ä3 546 20 = +112.1, [ä3 405 20 = +298.6,
[ä3365 20 = +479.8.[ä3 365 20 = +479.8.
XH NMR (250 MHz, 4-MeOH): δ = 7.49 (d, J = 6.0, IH, H-6); 5.79 (d, J = X H NMR (250 MHz, 4 -MeOH): δ = 7.49 (d, J = 6.0, IH, H-6); 5.79 (d, J =
6.0, IH, H-5); 5.50 (bs, 2H, NH2); 4.25 (d, 3 = 13.0, -lΗ,' CHaOH); 4.10 (d, 36.0, IH, H-5); 5:50 (bs, 2H, NH 2); 4.25 (d, 3 = 13.0, -lΗ, ' CHaOH); 4.10 (d, 3
= 13.0, IH, CHbOH); 3.71 (dd, = 8.8, 32 = 3.5, IH, SiOCHa); 3.51 (m, 1Η,= 13.0, IH, CHbOH); 3.71 (dd, = 8.8, 3 2 = 3.5, IH, SiOCHa); 3.51 (m, 1Η,
SiOCHb); 3.29 (s, 1Η, Η-2 '); 3.23 (m, IH, H-l ' ); 2.81 (m, IH, H-4 '); 2.64SiOCHb); 3.29 (s, 1Η, Η-2 '); 3.23 (m, IH, H-1 '); 2.81 (m, IH, H-4 '); 2.64
(ddd, = 11.5, 32 = 33 = 7.3, IH, H-5 'a); 1.54 (septet, J = 5.5, IH, Me2CH);(ddd, = 11.5, 3 2 = 3 3 = 7.3, IH, H-5 'a); 1.54 (septet, J = 5.5, IH, Me 2 CH);
1.46 (ddd, = 11.5, J2 = J3 = 5.5, 1Η, Η-5 ' b); 0.80 (d, J = 5.5, 6H,1.46 (ddd, = 11.5, J 2 = J 3 = 5.5, 1Η, Η-5 ' b); 0.80 (d, J = 5.5, 6H,
(CH3)2CH); 0.78 (s, 6H, C(CH3)2); 0.03 + 0.01 (2 x s, 6Η, CH3Si).(CH 3 ) 2 CH); 0.78 (s, 6H, C (CH 3) 2); 0.03 + 0.01 (2 xs, 6Η, CH 3 Si).
13C MMR (63 MΗz, d4-MeOΗ): δ = 167.3 (C4), 158.9 (C2), 154.1 (C3'), 143.8 13 C MMR (63 MΗz, d 4 -MeOΗ): δ = 167.3 (C4), 158.9 (C2), 154.1 (C3 '), 143.8
(C6), 124.9 (C2'), 96.0 (C5), 64.4 (CH2OSi), 62.2 (Cl'), 60.9 (CH2OH), 48.0(C6), 124.9 (C2 '), 96.0 (C5), 64.4 (CH 2 OSi), 62.2 (Cl'), 60.9 (CH 2 OH), 48.0
(C4'), 35.9 (C5'), 35.4 (Me2CH), 26.3 (Me2CSi), 21.0 und 20.8 ((CH3)2CH),(C4 '), 35.9 (C5'), 35.4 (Me 2 CH), 26.3 (Me 2 CSi), 21.0 and 20.8 ((CH 3 ) 2 CH),
19.05 und 18.98 ((CH3)2CSi), -3.3 (CH3Si).19.05 and 18.98 ((CH 3 ) 2 CSi), -3.3 (CH 3 Si).
IR (ATR, cm"1): = 3330 (bm, O-H), 3199 (m, N-H), 2954 (m, C-H), 2863 (m,IR (ATR, cm "1 ): = 3330 (bm, OH), 3199 (m, NH), 2954 (m, CH), 2863 (m,
C-H), 1714 (w, C=O), 1640 (s, C=N), 1613 (s, C=C), 1578 (m, C=C), 1524 (m), 1487 (m), 1397 (m), 1357 (w), 1281 (m), 1250 (m, C-O), 1217 (w),CH), 1714 (w, C = O), 1640 (s, C = N), 1613 (s, C = C), 1578 (m, C = C), 1524 (m), 1487 (m), 1397 (m), 1357 (w), 1281 (m), 1250 (m, CO), 1217 (w),
1185 (m), 1112 (m), 1085 (m), 1060 (m), 996 (m), 965 (w), 931 (w), 8731185 (m), 1112 (m), 1085 (m), 1060 (m), 996 (m), 965 (w), 931 (w), 873
(w), 830 (m), 778 (m), 709 (m).(w), 830 (m), 778 (m), 709 (m).
MS (ESI, 70 eV) : m/z (%) : 797 (3), 784 (4), 783 (14), 782 (18), 781 (36),MS (ESI, 70 eV): m / z (%): 797 (3), 784 (4), 783 (14), 782 (18), 781 (36),
761 (3), 760 (7), 759 (10), 667 (2), 529 (3), 450 (3), 434 (6), 424 (5), 418761 (3), 760 (7), 759 (10), 667 (2), 529 (3), 450 (3), 434 (6), 424 (5), 418
(4), 404 (7), 403 (27), 402 [M + Na]+ (100), 374 (2), 342 (2), 325 (2), 291(4), 404 (7), 403 (27), 402 [M + Na] + (100), 374 (2), 342 (2), 325 (2), 291
(2), 277 (2), 166 (4), 134 (39), 127 (7), 112 (43).(2), 277 (2), 166 (4), 134 (39), 127 (7), 112 (43).
HRMS (ESI) C19H33N3O3NaSi [M+Na]+: calcd 402.219, found 402.218.HRMS (ESI) C 19 H 33 N 3 O 3 NaSi [M + Na] + : calcd 402.219, found 402.218.
Darstellung von (-)-(l 'S, 4 'R)~4-Amino-l-{4 '-[dimethyl-(l,l,2- trimethyl-propyl)-silanyloxymethyl3-3 ' -hydroxymethyl-cyclopent-2 ' - enyl>-lJ¥-pyrimϊdin-2~one (113d)Preparation of (-) - (l 'S, 4' R) ~ 4-amino-l- {4 '- [dimethyl- (l, l, 2-trimethyl-propyl) -silanyloxymethyl3-3' -hydroxymethyl-cyclopent- 2 '- enyl> -lJ ¥ -pyrimϊdin-2 ~ one (113d)
Die Verbindung (-)-113d wurde gemäß der Versuchsvorschrift als , klare Flüssigkeit erhalten (59 mg, 85% Ausbeute), wobei sofort, wie oben beschrieben, das Rohprodukt der Reduktionsreaktion eingesetzt wurde. m.p. = 189-193°C (dec, EtOAc/Hex).The compound (-) - 113d was obtained as a clear liquid (59 mg, 85% yield) according to the experimental procedure, the crude product of the reduction reaction being used immediately, as described above. m.p. = 189-193 ° C (dec, EtOAc / Hex).
[ä3D 20 = -97.9 (c 0.33, MeOH), [ä3546 0 = -120.6, [ä34o5 20 = -325.6, [ä3365 20 [ä3 D 20 = -97.9 (c 0.33, MeOH), [ä3 5 46 0 = -120.6, [ä3 4 o 5 20 = -325.6, [ä3 365 20
= -524.1, [ä3334 20 = -912.5.= -524.1, [ä3 334 20 = -912.5.
Darstellung von (-)-(i ' R, 4 'S)-2-Amino-9-{4 ' -[dimethyl-(l,l,2- trimethyl-propyl)-silanyloxymethyl3-3 ' -hydröxymethyl-cyclopent-2 ' - enyl>-l,9-dihydro-purin-6-on (113e)Preparation of (-) - (i 'R, 4' S) -2-amino-9- {4 '- [dimethyl- (l, l, 2-trimethyl-propyl) -silanyloxymethyl3-3' -hydroexymethyl-cyclopent- 2 '- enyl> -l, 9-dihydro-purin-6-one (113e)
(+)-95e (-)-113e Die Reduktionsreaktion erfolgte gemäß der allgemeinen Versuchsvorschrift, nur dass das Lösungsmittel nicht abgedampft . wurde sondern das Reaktionsgemisch sofort mit 2 M Ammoniak in MeOH (5 ml) über 16 h bei RT gerührt wurde. Dann wurde das Lösungsmittel abgedampft und der Rückstand mittels Flash-Chromatographie (EtOAc/MeOH = 4+1) gereinigt, wobei 30 mg der Verbindung (-)-113e als klare Flüssigkeit verblieben (71% Ausbeute).(+) - 95e (-) - 113e The reduction reaction was carried out according to the general experimental procedure, except that the solvent did not evaporate. the reaction mixture was immediately stirred with 2 M ammonia in MeOH (5 ml) at RT for 16 h. The solvent was then evaporated and the residue was purified by flash chromatography (EtOAc / MeOH = 4 + 1), leaving 30 mg of the compound (-) - 113e as a clear liquid (71% yield).
m.p. = 230°C (dec, EtOAc/CyHex).m.p. = 230 ° C (dec, EtOAc / CyHex).
TLC: Rf = 0.58 in EtOAc/MeOH = 4+1.TLC: R f = 0.58 in EtOAc / MeOH = 4 + 1.
[ä3o20 = -55.4 (c 0.31, MeOH), [a3546 20 = -66.7, [ä3405 20 = -148.2, [ä3365 20 [ä3o 20 = -55.4 (c 0.31, MeOH), [a3 546 20 = -66.7, [ä3 405 20 = -148.2, [ä3 365 20
= -205.2. l NMR (250 MHz, d4-MeOH) : δ = 7.66 (s, IH, H-8); 5.80 (s, IH, H-2 ');= -205.2. l NMR (250 MHz, d 4 -MeOH): δ = 7.66 (s, IH, H-8); 5.80 (s, IH, H-2 ');
5.42 (m, IH, H-l '); 4.37 (d, 3 = 15.0, IH, CHaOH); 4.21 (d, 3 = 15.0, IH,5.42 (m, IH, H-1 '); 4.37 (d, 3 = 15.0, IH, CHaOH); 4.21 (d, 3 = 15.0, IH,
CHbOH); 3.77 (dd, 3X = 10.3, J2 = 4.9, IH, SiOCHa); 3.66 (dd, = 10.2, 3 =CHbOH); 3.77 (dd, 3 X = 10.3, J 2 = 4.9, IH, SiOCHa); 3.66 (dd, = 10.2, 3 =
4.4, 1Η, SiOCHb); 2.95 (m, 1Η, Η-4 '); 2.76 (ddd, Jt = 13.7, 32 = 33 = 8.5, 1Η,4.4, 1Η, SiOCHb); 2.95 (m, 1Η, Η-4 '); 2.76 (ddd, J t = 13.7, 3 2 = 3 3 = 8.5, 1Η,
Η-5 'a); 1.83 (ddd, = 13.6, 32 = 32 = 5.9, IH, H-5 ' b); 1.60 (septet, J = 6.9,Η-5 'a); 1.83 (ddd, = 13.6, 3 2 = 3 2 = 5.9, IH, H-5 'b); 1.60 (septet, J = 6.9,
IH, Me2CH); 0.87 (d, J = 6.9, 6Η, (CH3)2CH); 0.84 (s, 6H, C(CH3)2); 0.08 undIH, Me 2 CH); 0.87 (d, J = 6.9, 6Η, (CH 3 ) 2 CH); 0.84 (s, 6H, C (CH 3) 2); 0.08 and
0.07 (2 x s, 6Η, CH3Si).0.07 (2 xs, 6Η, CH 3 Si).
13C NMR (63 MΗz, 4-MeOΗ): δ = 159.4 (C6), 155.2 (C2), 153.8 (C4), 152.7 13 C NMR (63 MΗz, 4 -MeOΗ): δ = 159.4 (C6), 155.2 (C2), 153.8 (C4), 152.7
(C3 ' ), 137.3 (C8), 128.8 (C5), 124.4 (C2 '), 64.8 (CH2OSi), 60.9 (CH2OH),(C3 '), 137.3 (C8), 128.8 (C5), 124.4 (C2 ' ), 64.8 (CH 2 OSi), 60.9 (CH 2 OH),
59.3 (Cl '), 48.6 (C4 '), 36.7 (C5 '), 35.5 (Me2CH), 26.3 (Me2CSi), 20.93 und59.3 (Cl ' ), 48.6 (C4 ' ), 36.7 (C5 '), 35.5 (Me 2 CH), 26.3 (Me 2 CSi), 20.93 and
20.84 ((CH3)2CH), 19.00 und 18.96 ((CH3)2CSi), -3.4 ((CH3)2Si).20.84 ((CH 3 ) 2 CH), 19.00 and 18.96 ((CH 3 ) 2 CSi), -3.4 ((CH 3 ) 2 Si).
ΪR (ATR, cm"1): v = 3364 (m, O-H), 3191 (m, N-H), 2954 (m, C-H), 2865ΪR (ATR, cm "1 ): v = 3364 (m, OH), 3191 (m, NH), 2954 (m, CH), 2865
(m, C-H), 1686 (s, C=O). 1638 (s, C=N), 1608 (m, C=C), 1566 (m), 1534(m, C-H), 1686 (s, C = O). 1638 (s, C = N), 1608 (m, C = C), 1566 (m), 1534
(w), 1469 (w), 1407 (w), 1375 (m), 1314 (m), 1251 (m, C-O), 1223 (w),(w), 1469 (w), 1407 (w), 1375 (m), 1314 (m), 1251 (m, C-O), 1223 (w),
1171 (m), 1083 (m), 830 (m), 777 (m), 696 (m).1171 (m), 1083 (m), 830 (m), 777 (m), 696 (m).
MS (ESI, 70 eV): m/z (%): 883 (4), 864 (5), 863 (14), 862 (31), 861MS (ESI, 70 eV): m / z (%): 883 (4), 864 (5), 863 (14), 862 (31), 861
[2M+Na]+ (55), 484 (3), 474 (6), 464 (4), 445 (2), 444 (9), 443 (29), 442[2M + Na] + (55), 484 (3), 474 (6), 464 (4), 445 (2), 444 (9), 443 (29), 442
[M+Na]+ (100), 174 (8). HRMS (ESI) C2oH33N5NaO3Si [M+Na]+: calcd 442.225, found 442.225.[M + Na] + (100), 174 (8). HRMS (ESI) C 2 oH 33 N 5 NaO 3 Si [M + Na] + : calcd 442.225, found 442.225.
Darstellung von (+)-(l'S, 4'Λ)-2-Amino-9-{4'-[dimethyl-(l,l,2- trimethyl-propyl)-silanyloxymethyl]-3'-hydroxymethyl-cyclopent-2'- enyl}-l,9-dihydro-purin-6-on (113e)Preparation of (+) - (l ' S, 4 ' Λ) -2-amino-9- {4 ' - [dimethyl- (l, l, 2-trimethyl-propyl) -silanyloxymethyl] -3 ' -hydroxymethyl-cyclopent -2'- enyl} -l, 9-dihydro-purin-6-one (113e)
Die Verbindung 113e wurde gemäß. der allgemeinen Versuchsvorschrift als klare Flüssigkeit erhalten (32 mg, 76 % Ausbeute).Compound 113e was made according to. the general test instructions obtained as a clear liquid (32 mg, 76% yield).
[ä3D 2° = +68.1 (c 0.42, MeOH).[ä3 D 2 ° = +68.1 (c 0.42, MeOH).
Darstellung von (-)-(l'/?, 4'S)-5-Fluor-l-[4'-(£er£-butyl-diphenyl- silanyloxymethyl)-3 '-hydroxymethyl-cyclopent-2 '-enyl3-lH- pyrimidϊn-2,4-dion (159a)Preparation of (-) - (l '/ ?, 4' S) -5-fluoro-l- [4 '- (£ he £ -butyl-diphenyl-silanyloxymethyl) -3' -hydroxymethyl-cyclopent-2 '-enyl3 -lH- pyrimidϊn-2,4-dione (159a)
Die Verbindung (-)-159a wurde gemäß der allgemeinen Versuchsvorschrift als farbloses Öl erhalten (25 mg, 99% Ausbeute).Compound (-) - 159a was obtained as a colorless oil (25 mg, 99% yield) according to the general experimental procedure.
TLC: Rf = 0.43 in EtOAc/CyHex = 4+1.TLC: R f = 0.43 in EtOAc / CyHex = 4 + 1.
[ä3D 20 = -42.1 (c 0.44, CHCI3), [a s4620 = -51.5, [ä3405 20 = -142.1, [ä3365 2° =[ä3 D 20 = -42.1 (c 0.44, CHCI 3 ), [a s46 20 = -51.5, [ä3 405 20 = -142.1, [ä3 3 6 5 2 ° =
-234.6.-234.6.
lH NMR (250 MHz, CDCI3): δ = 9.20 (bs, IH, NH); 7.64-7.58 (m, 4Η, Ph); 7.46-7.35 (m, 6H, Ph); 7.31 (d, JH,F = 5.9, IH, H-6); 5.56 (m, 2H, H-l ' + H- 2 '); 4.35 (d, J = 14.7, IH, CHaOH); 4.25 (d, J = 14.8, IH, CHbOH); 3.73 (dd, = 10.5, J2 = 4.4, IH, SiOCHa); 3.64 (dd, 3t = 10.5, J2 = 5.9, 1Η, SiOCHb); 2.88 (m, 1Η, Η-4'); 2.63 (ddd, = 14.0, 32 = 33= 8.7, 1Η, Η-5'a); 1.37 (ddd, = 14.0, = 33= 7.3, IH, H-5'b); 1.06 (s, 9H, (CH3)CSi). 13C MMR (63 MΗz, CDCI3): δ= 153.6 (C3'), 149.5 (C2), 135.54 und 135.48 und 132.6 und 130.11 und 130.08 und 128.0 (alle von Ph), 125.0 (d, JC/F = 33, C6), 123.9 (C2'), 65.1 (CΗ2OSi), 60.7 (CH2OH), 60.3 (Cl'), 46.8 (C4'), 34.0 (C5'), 26.9 (SiC(CH3)3), 19.2 (SiC(CH3)3). 1 H NMR (250 MHz, CDCI 3 ): δ = 9.20 (bs, IH, NH); 7.64-7.58 (m, 4Η, Ph); 7.46-7.35 (m, 6H, Ph); 7.31 (d, J H , F = 5.9, IH, H-6); 5.56 (m, 2H, Hl ' + H-2'); 4.35 (d, J = 14.7, IH, CHaOH); 4.25 (d, J = 14.8, IH, CHbOH); 3.73 (dd, = 10.5, J 2 = 4.4, IH, SiOCHa); 3.64 (dd, 3 t = 10.5, J 2 = 5.9, 1Η, SiOCHb); 2.88 (m, 1Η, Η-4 ' ); 2.63 (ddd, = 14.0, 3 2 = 3 3 = 8.7, 1Η, Η-5 ' a); 1.37 (ddd, = 14.0, = 3 3 = 7.3, IH, H-5 ' b); 1:06 (s, 9H, (CH 3) CSi). 13 C MMR (63 MΗz, CDCI 3 ): δ = 153.6 (C3 ' ), 149.5 (C2), 135.54 and 135.48 and 132.6 and 130.11 and 130.08 and 128.0 (all from Ph), 125.0 (d, J C / F = 33, C6), 123.9 (C2 ' ), 65.1 (CΗ 2 OSi), 60.7 (CH 2 OH), 60.3 (Cl ' ), 46.8 (C4 '), 34.0 (C5 ' ), 26.9 (SiC (CH 3 ) 3 ), 19.2 (SiC (CH 3 ) 3 ).
IR (ATR, cm"1): = 3399 (w, O-H), 3176 (w, N-H), 3065 (m, N-H), 2927 (m, C- H), 2890 (w, C-H), 2854 (m, C-H), 1696 (s, C=O), 1659 (s, C=N), 1469 (m), 1425 (m), 1388 (m), 1344 (w), 1273 (m), 1239 (s), 1187 (w), 1152 (w),IR (ATR, cm "1 ): = 3399 (w, OH), 3176 (w, NH), 3065 (m, NH), 2927 (m, C-H), 2890 (w, CH), 2854 (m , CH), 1696 (s, C = O), 1659 (s, C = N), 1469 (m), 1425 (m), 1388 (m), 1344 (w), 1273 (m), 1239 (s), 1187 (w), 1152 (w),
1109 (s), 1061 (m), 995 (w), 936 (w), 888 (w), 821 (m), 784 (m), 741 (m),1109 (s), 1061 (m), 995 (w), 936 (w), 888 (w), 821 (m), 784 (m), 741 (m),
702 (s).702 (s).
MS (EI, 70 eV): m/z (%): 439 (2), 438 (5), 437 [M-57(Bu)]+ (14), 359 (8),MS (EI, 70 eV): m / z (%): 439 (2), 438 (5), 437 [M-57 (Bu)] + (14), 359 (8),
329 (3), 311 (10), 307 (17), 277 (3), 251 (11), 230 (7), 229 (41), 201 (6),329 (3), 311 (10), 307 (17), 277 (3), 251 (11), 230 (7), 229 (41), 201 (6),
200 (18), 199 (100), 197 (9), 183 (6), 181 (9), 169 (6), 167 (6), 139 (11),200 (18), 199 (100), 197 (9), 183 (6), 181 (9), 169 (6), 167 (6), 139 (11),
135 (12), 105 (8), 91 (27), 77 (8).135 (12), 105 (8), 91 (27), 77 (8).
HRMS (EI) C23H22FN2O4Si [M-57(Bu)]+: calcd 437.133, found: 437.133.HRMS (EI) C 23 H 22 FN 2 O 4 Si [M-57 (Bu)] + : calcd 437.133, found: 437.133.
Darstellung von (+)-(! '/?, 4 'S)-5-Brom-l-[4 '-(ferf-butyl-diphenyI- sHanylo^methyI)-3 '-hydroxymethy!-cy opent-2 '-enyl]-l /- pyrϊmidϊn-2,4-dion (159b)Representation of (+) - (! '/?, 4 ' S) -5-bromo-l- [4 '- (ferf-butyl-diphenyI- sHanylo ^ methyI) -3' -hydroxymethy! -Cy opent-2 ' -enyl] -l / - pyrϊmidϊn-2,4-dione (159b)
Die Verbindung (-)-159b wurde gemäß der. allgemeinen Versuchsvorschrift als farbloses Öl erhalten (56 mg, 99% Ausbeute).Compound (-) - 159b was prepared according to the. general test instructions obtained as a colorless oil (56 mg, 99% yield).
TLC: Rf = 0.39 in EtOAc/CyHex = 4+1.TLC: R f = 0.39 in EtOAc / CyHex = 4 + 1.
[ä3D 20 = +18.5 (c 0.52, CHCI3), [ä3546 20 = +21.7, [ä]334 20 = -37.5.[ä3 D 20 = +18.5 (c 0.52, CHCI 3 ), [ä3 546 20 = +21.7, [ä] 334 20 = -37.5.
XH NMR (250 MHz, CDCI3) : δ = 9.74 (s, IH, NH); 7.64 - .7.58 (m, 4Η, Ph); 7.52 (s, IH, H-6); 7.43-7.34 (m, 6H, Ph); 5.58 (d, 3 - 1.7, IH, H-2 '); 5.55 (dd, = J2 = 8.2, IH, H-l ' ); 4.37 (d, 3 = 14.6, IH, Cr/aOH); 4.27 (d, 3 = 14.7, IH, CHbOH); 3.71 (dd, =. 10.5, 32 = 4.6, IH, SiOCHa); 3.63 (dd, J1 = 10.5, 32 = 6.0, 1Η, SiOCHb); 2.87 (m, 2Η, H-4 ' + OH); 2.61 (ddd, = 13.7, 32 = 33 = 8.2, IH, H-5 'a); 1.33 (ddd, = 13.6, J2 = J3 = 7.4, IH, H-5 ' b); 1.06 (s, 9H, (CH3)3CSi). X H NMR (250 MHz, CDCI 3 ): δ = 9.74 (s, IH, NH); 7.64 - .7.58 (m, 4Η, Ph); 7.52 (s, IH, H-6); 7.43-7.34 (m, 6H, Ph); 5.58 (d, 3-1.7, IH, H-2 ' ); 5.55 (dd, = J 2 = 8.2, IH, Hl ' ); 4.37 (d, 3 = 14.6, IH, Cr / aOH); 4.27 (d, 3 = 14.7, IH, CHbOH); 3.71 (dd, =. 10.5, 3 2 = 4.6, IH, SiOCHa); 3.63 (dd, J 1 = 10.5, 3 2 = 6.0, 1Η, SiOCHb); 2.87 (m, 2Η, H-4 '+ OH); 2.61 (ddd, = 13.7, 3 2 = 3 3 = 8.2, IH, H-5 'a); 1.33 (ddd, = 13.6, J 2 = J 3 = 7.4, IH, H-5 ' b); 1:06 (s, 9H, (CH 3) 3 CSi).
13C NMR (63 MΗz, CDCI3): δ = 159.2 (C4), 153.6 (C3'); 150.4 (C2), 140.3 (C6), 135.50 und 135.48 und 132.61 und 132.58 und 130.07 und 130.03 und 127.9 (all of Ph), 123.7 (C2'), 96.7 (C5), 65.0 (CΗ2OSi), 61.0 (CH2OH), 60.6 (Cl'), 46.8 (C4'), 34.5 (C5'), 26.9 ((CH3)3CSi), 19.2 ((CH3)3CSi). IR (ATR, cm*1): v = 3425 (w, O-H), 3173 (w, N-H), 3065 (m, N-H), 3044 (w), 2927 (m, C-H), 2854 (m, C-H), 1691 (s, C=O), 1683 (s, C=O), 1615 (m, C=C), 1587 (w), 1469 (w), 1444 (m), 1426 (m), 1388 (w), 1375 (w), 1360 (w), 1331 (w), 1274 (m), 1238 (m), 1186 (w), 1150 (w), 1110 (s), 1086 (m), 13 C NMR (63 MΗz, CDCI3): δ = 159.2 (C4), 153.6 (C3 ') ; 150.4 (C2), 140.3 (C6), 135.50 and 135.48 and 132.61 and 132.58 and 130.07 and 130.03 and 127.9 (all of Ph), 123.7 (C2 '), 96.7 (C5), 65.0 (CΗ 2 OSi), 61.0 (CH 2 OH), 60.6 (Cl '), 46.8 (C4'), 34.5 (C5 '), 26.9 ((CH 3 ) 3 CSi), 19.2 ((CH 3 ) 3 CSi). IR (ATR, cm * 1 ): v = 3425 (w, OH), 3173 (w, NH), 3065 (m, NH), 3044 (w), 2927 (m, CH), 2854 (m, CH) , 1691 (s, C = O), 1683 (s, C = O), 1615 (m, C = C), 1587 (w), 1469 (w), 1444 (m), 1426 (m), 1388 ( w), 1375 (w), 1360 (w), 1331 (w), 1274 (m), 1238 (m), 1186 (w), 1150 (w), 1110 (s), 1086 (m),
1064 (m), 1036 (m), 1005 (w), 996 (w), 937 (w), 919 (w), 839 (w), 822 (m),1064 (m), 1036 (m), 1005 (w), 996 (w), 937 (w), 919 (w), 839 (w), 822 (m),
786 (w), 741 (m), 702 (s), 650 (w), 627 (w), 616 (m).786 (w), 741 (m), 702 (s), 650 (w), 627 (w), 616 (m).
MS (ESI, 70 eV): m/z (%): 1225 (2), 1035 (5), 957 (8), 663 (2), 599 (3), 597MS (ESI, 70 eV): m / z (%): 1225 (2), 1035 (5), 957 (8), 663 (2), 599 (3), 597
(4), 586 (2), 585 (9), 584 (29), 583 (100), 582 (30), 581 (92), 580 (14), 579(4), 586 (2), 585 (9), 584 (29), 583 (100), 582 (30), 581 (92), 580 (14), 579
(46), 578 (12), 577 [M+Na]+ (42), 533 (4), 517 (4), 511 (6), 504 (3), 503(46), 578 (12), 577 [M + Na] + (42), 533 (4), 517 (4), 511 (6), 504 (3), 503
(9), 502 (23), 501 (67), 463 (2), 421 (7), 389 (2), 388 (5), 387 (15), 365(9), 502 (23), 501 (67), 463 (2), 421 (7), 389 (2), 388 (5), 387 (15), 365
(2), 287 (3), 233 (2), 169 (2), 147 (6).(2), 287 (3), 233 (2), 169 (2), 147 (6).
HRMS (ESI) C27H3ιBrN2NaO4Si [M+Na]+: calcd 577.113, found: 577.114.HRMS (ESI) C 27 H 3 ιBrN 2 NaO 4 Si [M + Na] + : calcd 577.113, found: 577.114.
Darstellung von (-)-(l 'R, 4 S)-l¥--[l-[4 '-(rert-butyl-diphenyl- siIanyloxymethyl)-3 '-hydroxymethyl-cyclopent-2 '-enyI]-2-oxo-l,2- dϊhydro-pyrimidin-4-yl}-benzamid (159c-l)Preparation of (-) - (l 'R, 4 S) -l ¥ - [l- [4' - (rert-butyl-diphenyl-siIanyloxymethyl) -3 '-hydroxymethyl-cyclopent-2' -enyI] -2 -oxo-l, 2- dϊhydro-pyrimidin-4-yl} -benzamide (159c-l)
Die Verbindung (-)-159c-l wurde gemäß der allgemeinen Versuchsvorschrift als hellgelbe Flüssigkeit erhalten (23 mg, 79% Ausbeute).The compound (-) - 159c-1 was obtained as a light yellow liquid according to the general experimental procedure (23 mg, 79% yield).
m.p. = 190-193°C (EtOAc/CyHex).m.p. = 190-193 ° C (EtOAc / CyHex).
TLC: Rf = 0.54 in EtOAc/MeOH = 4+1.TLC: R f = 0.54 in EtOAc / MeOH = 4 + 1.
[ä]D 20 = -25.4 (c 1.05, CHCI3), [ä]546 20 = -33.2, [ä]405 20 = -153.2.[ä] D 20 = -25.4 (c 1.05, CHCI 3 ), [ä] 546 20 = -33.2, [ä] 405 20 = -153.2.
*H NMR (250 MHz, CDCI3) : δ = 7.90 (d, 3 = 7.5, 2H, H-6.+ H-Ph); 7.73 (d, 3* H NMR (250 MHz, CDCI 3 ): δ = 7.90 (d, 3 = 7.5, 2H, H-6 . + H-Ph); 7.73 (d. 3
= 7.4, IH, H-5); 7.59-7.34 (m, 14H, Ph); 5.71 (m, IH, H-l ' ); 5.63 (s, IH, H-= 7.4, IH, H-5); 7.59-7.34 (m, 14H, Ph); 5.71 (m, IH, H-1 '); 5.63 (s, IH, H-
2 '); 4.39 (d, 3 = 15.5, IH, CH2OH); 4.29 (d, 3 = 15.5, IH, CH2OH); 3.73 (dd, = 10.6, J2 = 4.0, IH, SiOCH2); 3.58 (dd, = 10.6, 32 = 6.3, IH, SiOCH2);2 '); 4.39 (d, 3 = 15.5, IH, CH 2 OH); 4.29 (d, 3 = 15.5, IH, CH 2 OH); 3.73 (dd, = 10.6, J 2 = 4.0, IH, SiOCH 2 ); 3.58 (dd, = 10.6, 3 2 = 6.3, IH, SiOCH 2 );
2.92 (m, 1Η, Η-4 '); 2.78 (ddd, 31 = 13.6, 32 = 33 = 8.1, 1Η, Η-5 'a); 1.34 (m,2.92 (m, 1Η, Η-4 ' ); 2.78 (ddd, 3 1 = 13.6, 3 2 = 3 3 = 8.1, 1Η, Η-5 'a); 1.34 (m,
IH, H-5 ' b); 1.05 (s, 9H, Si(CH3)3).IH, H-5 ' b); 1:05 (s, 9H, Si (CH 3) 3).
13C NMR (63 MΗz, CDCI3) : δ = 161.8 (C4), 158.9 (PhC=O), 153.4 (C3 '), 13 C NMR (63 MΗz, CDCI 3 ): δ = 161.8 (C4), 158.9 (PhC = O), 153.4 (C3 ' ),
145.5 (C6), 135.52 und 135.46 und 133.1 und 132.7 und 132.6 und 130.09 und 130.05 und 129.0 und 127.9 und 127.6 (alle von Ph), 124.4 (C2 '), 65.4145.5 (C6), 135.52 and 135.46 and 133.1 and 132.7 and 132.6 and 130.09 and 130.05 and 129.0 and 127.9 and 127.6 (all of Ph), 124.4 (C2 '), 65.4
(CΗ2OSi), 61.5 (Cl ' ), 60.8 (CH2OH), 47.0 (C4 '), 35.0 (C5 '), 26.9(CΗ 2 OSi), 61.5 (Cl '), 60.8 (CH 2 OH), 47.0 (C4'), 35.0 (C5 ' ), 26.9
(SiC(CH3)3), 19.2 (SiC(CH3)3). IR (ATR, cm"1): v = 3309 (bw, O-H), 3067 (w, N-H), 2955 (m, C-H), 2928 (m, C-H), 2855 (m, C-H), 1696 (m, C=O), 1643 (s, C=N), 1620 (s, C=C), 1556 (m), 1485 (s), 1445 (m), 1426 (m), 1382 (s), 1306 (s), 1253 (s), 1189 (w), 1110 (s), 1027 (w), 1003 (m), 933 (w), 893 (w), 822 (m), 788 (m), 741 (m), 701 (s), 677 (m), 613 (m).(SiC (CH 3 ) 3 ), 19.2 (SiC (CH 3 ) 3 ). IR (ATR, cm "1 ): v = 3309 (bw, OH), 3067 (w, NH), 2955 (m, CH), 2928 (m, CH), 2855 (m, CH), 1696 (m, C = O), 1643 (s, C = N), 1620 (s, C = C), 1556 (m), 1485 (s), 1445 (m), 1426 (m), 1382 (s), 1306 ( s), 1253 (s), 1189 (w), 1110 (s), 1027 (w), 1003 (m), 933 (w), 893 (w), 822 (m), 788 (m), 741 ( m), 701 (s), 677 (m), 613 (m).
Darstellung von (-)-(l 'Ä, 4 'S)- 4-Amino-l-[4 '-(£ert-butyl-dϊphenyl- silanyloxymethyl)-3 '-hydroxymethyl-cyclopent-2 '-enyI]-lH- pyrimidin-2-on (159c)Preparation of (-) - (l 'Ä, 4' S) - 4-Amino-l- [4 '- (Er-butyl-dϊphenyl-silanyloxymethyl) -3' -hydroxymethyl-cyclopent-2 '-enyI] - lH-pyrimidin-2-one (159c)
Die Verbindung (-)-159c wurde gemäß der allgemeinen Versuchsvorschrift für die Schutzgruppenabspaltung als klare Flüssigkeit erhalten (16 mg, 96% Ausbeute).Compound (-) - 159c was obtained as a clear liquid (16 mg, 96% yield) according to the general test procedure for deprotection.
m.p. = 198-201°C (dec, EtOAc/CyHex).m.p. = 198-201 ° C (dec, EtOAc / CyHex).
TLC: Rf = 0.33 in EtOAc/MeOH = 4+1.TLC: R f = 0.33 in EtOAc / MeOH = 4 + 1.
[ä]D 20 = -54.5 (c 0.31, MeOH), [ä]546 20 = -67.6, [ä]405 20 = -187.3, [ä]365 20 [ä] D 20 = -54.5 (c 0.31, MeOH), [ä] 546 20 = -67.6, [ä] 405 20 = -187.3, [ä] 365 20
= -310.1.= -310.1.
1H NMR (250 MHz, CDCI3) : δ - 7.60-7.56 (m, 4H, Ph-H); 7.42-7.33 (m, 7H, 1 H NMR (250 MHz, CDCI 3 ): δ - 7.60-7.56 (m, 4H, Ph-H); 7.42-7.33 (m, 7H,
H-6 + Ph-H); 5.61-5.48 (m," 3H, H-l ' + H-2 ' + H-5); 4.34 (d, J = 14.6, IH,H-6 + Ph-H); 5.61-5.48 (m, " 3H, Hl '+ H-2' + H-5); 4.34 (d, J = 14.6, IH,
CHaOH); 4.24 (d, J = 14.6, IH, CHbOH); 3.74-3.52 (m, 4H, SiOCH2 + NH2);CHaOH); 4.24 (d, J = 14.6, IH, CHbOH); 3.74-3.52 (m, 4H, SiOCH 2 + NH 2 );
2.84 (m, 1Η, Η-4 '); 2.64 (m, 1Η, Η-5 'a); 1.28 (m, IH, H-5 'b); 1.03 (s, 9H,2.84 (m, 1Η, Η-4 '); 2.64 (m, 1Η, Η-5 'a); 1.28 (m, IH, H-5 'b); 1.03 (s, 9H,
Si(CH3)3).Si (CH 3 ) 3 ).
13C HMR (63 MΗz, CDC13) : δ = 153.4 (C3 ' ), 142.8 (C6), 135.53 und 135.48 und 132.9 und 132.6 und 130.06 und 129.94 und 127.89 und 127.83 (all of 13 C HMR (63 MΗz, CDC1 3 ): δ = 153.4 (C3 '), 142.8 (C6), 135.53 and 135.48 and 132.9 and 132.6 and 130.06 and 129.94 and 127.89 and 127.83 (all of
Ph), 125.1 (C2 ' ), 94.6 (C5), 65.5 (CΗ2OSi), 61.7 (Cl '), 60.8 (CH2OH), 46.9Ph), 125.1 (C2 '), 94.6 (C5), 65.5 (CΗ 2 OSi), 61.7 (Cl'), 60.8 (CH 2 OH), 46.9
(C4 '), 34.8 (C5 '), 26.9 (SiC(CH3)3). 19.2 (SiC(CH3)3).(C4 ' ), 34.8 (C5 ' ), 26.9 (SiC (CH 3 ) 3 ). 19.2 (SiC (CH 3 ) 3 ).
ΪR (ATR, cm"1): v = 3338 (bs, O-H + N-H), 2953 (m, C-H), 2928 (m, C-H),ΪR (ATR, cm "1 ): v = 3338 (bs, OH + NH), 2953 (m, CH), 2928 (m, CH),
2854 (w/ C-H), 1714 (w, C=O), 1640 (s, C=N), 1527 (m), 1486 (s), 14252854 (w / C-H), 1714 (w, C = O), 1640 (s, C = N), 1527 (m), 1486 (s), 1425
(m), 1398 (m), 1358 (m), 1280 (m), 1218 (w), 1184 (w), 1110 (m), 1083(m), 1398 (m), 1358 (m), 1280 (m), 1218 (w), 1184 (w), 1110 (m), 1083
(m), 1061 (m), 1005 (m), 996 (m), 821 (m), 778 (s), 738 (s). MS (ESI, 70 eV) : m/z (%): 1166 (3), 973 [2M+Na]+ (14), 951 [2M + H]+ (3), 606 (6), 546 (2), 530 (4), 520 (4), 514 [M + K]+ (3), 500 (10), 499 (31), 498 [M+Na]+ (100), 485 (8), 387 (8), 134 (25), 112 (27). HRMS (ESI) [M+Na]+ C27H33N3NaO.3Si: calcd 498.219, found : 498.219.(m), 1061 (m), 1005 (m), 996 (m), 821 (m), 778 (s), 738 (s). MS (ESI, 70 eV): m / z (%): 1166 (3), 973 [2M + Na] + (14), 951 [2M + H] + (3), 606 (6), 546 (2nd ), 530 (4), 520 (4), 514 [M + K] + (3), 500 (10), 499 (31), 498 [M + Na] + (100), 485 (8), 387 (8), 134 (25), 112 (27). HRMS (ESI) [M + Na] + C 27 H 33 N 3 NaO .3 Si: calcd 498.219, found: 498.219.
Darstellung von (-)-(l ' R, 4 'S)- 2-amino-9-[4 '-(£er£-butyl-diphenyl- silanyloxymethyl)-3 '-hydroxymethyl-cyclopent-2 ' -enyl]-l,9-dihydro- purin-6-one (159d)Preparation of (-) - (1 'R, 4' S) - 2-amino-9- [4 '- (£ er-butyl-diphenylsilanyloxymethyl) -3' -hydroxymethyl-cyclopent-2 '-enyl] -l, 9-dihydro-purin-6-one (159d)
Die Verbindung (-)-159d wurde gemäß der allgemeinen Versuchsvorschrift für die one pot-Reaktion mit ThxMe2Si-Guanin als klare Flüssigkeit erhalten (26 mg, 99% Ausbeute).Compound (-) - 159d was obtained as a clear liquid (26 mg, 99% yield) according to the general test procedure for the one-pot reaction with ThxMe 2 Si-guanine.
m.p. > 260°C (dec, EtOAc/CyHex).m.p. > 260 ° C (dec, EtOAc / CyHex).
TLC: Rf = 0.50 in EtOAc/MeOH = 4+1.TLC: R f = 0.50 in EtOAc / MeOH = 4 + 1.
[ä]D 20 = -34.8 (c θ.72, MeOH), [ä]546 20 = -40.6.[ä] D 20 = -34.8 (c θ.72, MeOH), [ä] 546 20 = -40.6.
XH NMR (250 MHz, d4-MeOH) : δ = 7.60-7.32 (m, 11H, Ph+H-8); 5.84 (s, IH, X H NMR (250 MHz, d 4 -MeOH): δ = 7.60-7.32 (m, 11H, Ph + H-8); 5.84 (s, IH,
H-2 ' ); 5.39 (m, IH, H-l ' ); 4.37 (d, J = 15.6, IH, CHaOH); 4.19 (d, J = 15.7,H-2 '); 5.39 (m, IH, Hl ' ); 4.37 (d, J = 15.6, IH, CHaOH); 4.19 (d, J = 15.7,
IH, CHbOH); 3.79 (dd, = 10.3, 32 = 4.9, IH, SiOCHa); 3.69 (dd, 3X = 10.3,IH, CHbOH); 3.79 (dd, = 10.3, 3 2 = 4.9, IH, SiOCHa); 3.69 (dd, 3 X = 10.3,
J2 = 5.7, 1Η, SiOCHb); 2.99 (m, 1Η, Η-4 '); 2.72 (ddd, = 13.7, J2 = J3 = 8.5,J 2 = 5.7, 1Η, SiOCHb); 2.99 (m, 1Η, Η-4 '); 2.72 (ddd, = 13.7, J 2 = J 3 = 8.5,
1Η, Η-5 ' a); 1.81 (ddd, = 13.3, J2 = J2 = 6.2, IH, H-5 ' b); 1.02 (s, 9H,1Η, Η-5 'a); 1.81 (ddd, = 13.3, J 2 = J 2 = 6.2, IH, H-5 'b); 1.02 (s, 9H,
Si(CH3)3).Si (CH 3 ) 3 ).
13C NMR (63 MΗz, d4-MeOΗ) : = 155.2 und 153.7 und 152.7 (C2+C4+C6), 13 C NMR (63 MΗz, d 4 -MeOΗ): = 155.2 and 153.7 and 152.7 (C2 + C4 + C6),
152.0 (C3 ' ), 137.1 (C8), 136.68 und 136.64 und 134.50 und 134.42 und152.0 (C3 '), 137.1 (C8), 136.68 and 136.64 and 134.50 and 134.42 and
131.00 und 130.96 (all of Ph), 124.4 (C2 ' ), 117. 9 (C5), 66.2 (CH2OSi), 61.0131.00 and 130.96 (all of Ph), 124.4 (C2 '), 117.9 (C5), 66.2 (CH 2 OSi), 61.0
(CH2OH), 59.9 (Cl '), 48.5 (C4 '), 36.7 (C5 ' ), 27.4 (SiC(CH3)3), 20.1(CH 2 OH), 59.9 (Cl ' ), 48.5 (C4'), 36.7 (C5 ' ), 27.4 (SiC (CH 3 ) 3 ), 20.1
(SiC(CH3)3).(SiC (CH 3 ) 3 ).
IR (ATR, cm"1): v = 3350 (m, O-H), 3317 und 3191 (m, N-H), 2934 (m, C-H),IR (ATR, cm "1 ): v = 3350 (m, OH), 3317 and 3191 (m, NH), 2934 (m, CH),
2891 (w, C-H), 2855 (m, C-H), 1683 (s, C=O), 1603 (m, C=C), 1531 (m),2891 (w, C-H), 2855 (m, C-H), 1683 (s, C = O), 1603 (m, C = C), 1531 (m),
1473 (w), 1370 (m), 1223 (w), 1172 (w), 1108 (m), 1072 (m), 822 (m), 7801473 (w), 1370 (m), 1223 (w), 1172 (w), 1108 (m), 1072 (m), 822 (m), 780
(m), 739 (m), 701 (s), 631 (m).' (m), 739 (m), 701 (s), 631 (m). '
MS (ESI, 70 eV): m/z (%): 747 (12), 725 (7), 389 (10), 339 (100), 279 (4),MS (ESI, 70 eV): m / z (%): 747 (12), 725 (7), 389 (10), 339 (100), 279 (4),
247 (7). (3/?S,5SK)-3-(5'-Brom-2',4'-dioxo-3',4'-dihydro-2H-pyrimidin-l yl)-5-hydroxymethyl-cyclopent-l-encarbaldehyd (rac-x2).247 (7). (3 /? S, 5SK) -3- (5 ' -Brom-2', 4'-dioxo-3 ' , 4 ' -dihydro-2H-pyrimidin-l yl) -5-hydroxymethyl-cyclopent-l-encarbaldehyde (rac-x2).
Eine Lösung von rec-xl (650 mg, 1.83 mmol) und PPTS (138 mg, 0.55 m ol) in nassem Aceton (30 ml) wurde für 3 h zum Rückfiuss erhitzt. Danach wurde das Lösungsmittel im Vakuum entfernt, das Reaktionsgemisch in CH2CI2 aufgenommen und Silica (3 g) zugegeben. Das Lösungsmittel wurde wiederum im Vakuum entfernt und der Rückstand direkt einer FlashchromatographieA solution of rec-xl (650 mg, 1.83 mmol) and PPTS (138 mg, 0.55 mol) in wet acetone (30 ml) was heated to reflux for 3 h. The solvent was then removed in vacuo, the reaction mixture was taken up in CH 2 Cl 2 and silica (3 g) was added. The solvent was again removed in vacuo and the residue was subjected to flash chromatography
(EtOAc) unterworfen. Es wurde rac-x2 als weißer Feststoff erhalten (510 mg,(EtOAc). Rac-x2 was obtained as a white solid (510 mg,
88%).88%).
DC: Rf= 0.42 in EtOAc;TLC: R f = 0.42 in EtOAc;
XH-NMR (DMSO): δ = 9.83 (s, IH, HC=O), 8.07 (s, IH, HNb), 6,91 (m, IH, H- X H-NMR (DMSO): δ = 9.83 (s, IH, HC = O), 8.07 (s, IH, H Nb ), 6.91 (m, IH, H-
2), 5.62 (m, IH, H-3), 4.85 (dd, IH, HOCHa), 3.78 (dd, IH, HOCÜ), 3.05 (m,2), 5.62 (m, IH, H-3), 4.85 (dd, IH, HIGH a ), 3.78 (dd, IH, HOCÜ), 3.05 (m,
IH, H-5), 2.65 (m, IH, H-4a), 1.73 (m, IH, H-4b)IH, H-5), 2.65 (m, IH, H-4 a ), 1.73 (m, IH, H-4 b )
(3^S,5S^)-3-(5"-S3rom-2%4'-diθ2co-3',4 -dihydro-2H-pyrimidin-l'- ' yl)-5-( e an lo v~mε*"yl) -cyclopent-1-encarbaldehyd (rac-x3).(3 ^ S, 5S ^) - 3- (5 " -S3rom-2% 4 ' -diθ2co-3 ' , 4 -dihydro-2H-pyrimidin-l ' - ' yl) -5- (e an lo v ~ m ε * "yl) -cyclopent-1-encarbaldehyde (rac-x3).
rac-x2 (510 mg, 1.62 mmol) wurde in trockenem DMF (10 ml) unter Argon vorgelegt und bei RT mit NaH versetzt (71 mg, 1.78 mmol; 60 % Suspension in Hexan). Nachdem 1 h bei RT gerührt wurde, wurde das Reaktionsgemisch mit Geranylbromid (1.06 g, 4.86 mmol) versetzt und weitere 16 h bei RT gerührt. Es wurde H2O zugegeben (40 ml) und mit EtOAc extrahiert (5 x 50 ml). Die vereinigten organischen Phasen wurden mit NaCI (5 x 50 ml) gewaschen und über MgSO4 getrocknet. Das Lösungsmittel wurde im Vakuum entfernt und der Rückstand einer Flashchromatographie unterworfen. rac-x3 (433 mg, 59%) wurde als dunkel-gelbes Öl erhalten. DC: Rf= 0.14 in CyHex/EtOAc =2 + 1; rac-x2 (510 mg, 1.62 mmol) was placed in dry DMF (10 ml) under argon and NaH was added at RT (71 mg, 1.78 mmol; 60% suspension in hexane). After stirring at RT for 1 h, the reaction mixture was mixed with geranyl bromide (1.06 g, 4.86 mmol) and stirred at RT for a further 16 h. H 2 O was added (40 ml) and extracted with EtOAc (5 x 50 ml). The combined organic phases were washed with NaCl (5 x 50 ml) and dried over MgSO4. The solvent was removed in vacuo and the residue was subjected to flash chromatography. rac-x3 (433 mg, 59%) was obtained as a dark yellow oil. TLC: R f = 0.14 in CyHex / EtOAc = 2 + 1;
XH- MR (250 MHz, CDCI3,) : δ = 9.88 (s, IH, HC=O), 7.83 (s, IH, HNb), 6,69 (m, IH, H-2), 5.88 (m, IH, H-3), 5.20 (t, IH, HGer), 5.02 (t, IH, HGer), 4.56 (d, IH, HGer), 4.08 (dd, IH, GerOCHa), 3.64 (dd, IH, GerOCHb), 3.20 (m, IH, H-5), 2.85 (m, IH, H-4a), 2.15-1.90 (m, 5H, HGer and H-4b), 1.80-1.55 (m, 9H, HGer) X H-MR (250 MHz, CDCI 3 ,): δ = 9.88 (s, IH, HC = O), 7.83 (s, IH, H Nb ), 6.69 (m, IH, H-2), 5.88 (m, IH, H-3), 5.20 (t, IH, H Ger ), 5.02 (t, IH, H Ger ), 4.56 (d, IH, H Ger ), 4.08 (dd, IH, G erOCH a ) , 3.64 (dd, IH, Ge rOCH b ), 3.20 (m, IH, H-5), 2.85 (m, IH, H-4 a ), 2.15-1.90 (m, 5H, H Ger and H-4 b ), 1.80-1.55 (m, 9H, H Ger )
(l ' ?S,4 'S/?)-5-Brom-l-[4 '-(geranyloxy-methyl)-3 '-hydroxynnethyl- cyclopent-2 '-enyl]-lH-pyrimidin-2,4-dion (rac-x4) (AL-451)(l ' ? S, 4' S /?) - 5-bromo-l- [4 '- (geranyloxy-methyl) -3' -hydroxynethyl-cyclopent-2 '-enyl] -lH-pyrimidine-2,4- dion (rac-x4) (AL-451)
NaBH4 (226 mg, 5.97mmol) wurde in einem MeOH/CH2CI2-Gemisch (12 ml + 24 ml) gelöst und auf -78°C gekühlt. rac-x3 (270 mg, 0.60 mmol) wurde in CH2CI2 (12 ml) gelöst und zugegeben. Nachdem 1 h bei RT gerührt wurde, wurde das Reaktionsgemisch mit Aceton (10 ml) versetzt und auf RT erwärmt und es wurde erneut 1 h gerührt. Die Lösung wurde über eine Fritte mit Silica abfiltriert, mit CH2CI2 (50 ml) nachgespült und das Lösungsmittel im Vakuum entfernt. Nach Flashchromatographie (EtOAc) konnte rac-x4, als gelblicher Feststoff isoliert werden (217 mg, 80%).NaBH 4 (226 mg, 5.97 mmol) was dissolved in a MeOH / CH 2 Cl 2 mixture (12 ml + 24 ml) and cooled to -78 ° C. rac-x3 (270 mg, 0.60 mmol) was dissolved in CH 2 CI 2 (12 ml) and added. After stirring at rt for 1 h, the reaction mixture was added with acetone (10 ml) and warmed to rt and stirring was continued for 1 h. The solution was filtered through a frit with silica, rinsed with CH 2 Cl 2 (50 ml) and the solvent in vacuo away. After flash chromatography (EtOAc), rac-x4 was isolated as a yellowish solid (217 mg, 80%).
DC: Rf= 0.40 in EtOAc;TLC: R f = 0.40 in EtOAc;
^-NMR (250 MHz, CDCI3,); δ = 7.77 (s, IH, HN ), 5.65 (m, IH, H-l'), 5.60 (m, IH, H-2'), 5.20 (t, IH, HGer), 5.02 (t, IH, HGer), 4.56 (d, IH, HGer), 4.35 (d, IH, HOCH,), 4.30 (d, IH, HOCHb), 3.90 (dd, IH, GerOCHa), 3.57 (dd, IH, GerOCHb), 2.90 (m, IH, H-5), 2.77 (m, IH, H-4a), 2.10-1.91 (m, 5H, HGer and H-4b), 1.85-1.55 (m, 9H, HGer); 13C-NMR (63 MHz, CDCl3) : δ = 159.0 (C4), 152.1 (C3'), 150.8 (C2), 141.1 (CGer), 139.3 (C6), 131.6 (CGer), 126.3 (CGer), 123.9 (C2'), H7.4 (CGer), 96.1 (C5), 63.6 (GerOCH2), 61.0 (CH2OH), 60.5 (Cl'), 47.2 (C4'), 41.0 (CGer), 39.6 (CGer), 34.5 (C5'), 26.4 (CGer), 25.6 (CGer). 17.7 (CGer), 16.5 (CGer); FT-IR (ATR) : 3423 (s), 2912 (m), 1700 (s), 1645(s), 1443(s), 1382 (w), 1328 (w), 1234 (m), 1030 (m), 759 (m); MS (ESI) : 475 (100) [M + Na]+, 455 (73), 327 (17), 195 (2); HRMS (ESI) C21H29BrN2O4Na : ber. 475.1208, gef. 475.121. ^ -NMR (250 MHz, CDCI 3 ,); δ = 7.77 (s, IH, H N ), 5.65 (m, IH, H-l '), 5.60 (m, IH, H-2'), 5.20 (t, IH, H Ger ), 5.02 (t, IH, H Ger ), 4.56 (d, IH, H Ger ), 4.35 (d, IH, HIGH,), 4.30 (d, IH, HIGH b ), 3.90 (dd, IH, Ger OCH a ), 3.57 (dd , IH, G e r OCH b ), 2.90 (m, IH, H-5), 2.77 (m, IH, H-4 a ), 2.10-1.91 (m, 5H, H Ger and H-4 b ), 1.85-1.55 (m, 9H, H Ger ); 13 C-NMR (63 MHz, CDCl3): δ = 159.0 (C4), 152.1 (C3 '), 150.8 (C2), 141.1 (C Ger ), 139.3 (C6), 131.6 (C Ger ), 126.3 (C Ger ), 123.9 (C2 '), H7.4 (C Ger ), 96.1 (C5), 63.6 ( Ger OCH 2 ), 61.0 (CH 2 OH), 60.5 (Cl'), 47.2 (C4 '), 41.0 (C Ger ), 39.6 (C Ger ), 34.5 (C5 '), 26.4 (C Ger ), 25.6 (C Ger ). 17.7 (C Ger ), 16.5 (C Ger ); FT-IR (ATR): 3423 (s), 2912 (m), 1700 (s), 1645 (s), 1443 (s), 1382 (w), 1328 (w), 1234 (m), 1030 (m ), 759 (m); MS (ESI): 475 (100) [M + Na] + , 455 (73), 327 (17), 195 (2); HRMS (ESI) C 21 H 29 BrN 2 O 4 Na: calc. 475.1208, found. 475,121.
Literatur:Literature:
Y. A. Hannun (1997), Apoptosis and the dilemma of cancer therapy, Biood 89, 1845-1853. j*. A. Hickman (1996), Apoptosis and chemotherapy resistance, Eur. 3. Cancer 32A, 921-926.YA Hannun (1997), Apoptosis and the dilemma of cancer therapy, Biood 89, 1845-1853. j * . A. Hickman (1996), Apoptosis and chemotherapy resistance, Eur. 3. Cancer 32A, 921-926.
M. Raisova, M. Bektas, T. Wieder, P. T. Daniel, 3. Ebene, C. E. Orfanos, C. C. Geilen (2000), Resistance to CD95/Fas-induced and ceramide-mediated apoptosis of human melanoma cells is caused by a defective mitochondrial cytochrome c release, FEBS Lett. 473, 27-32.M. Raisova, M. Bektas, T. Wieder, PT Daniel, 3rd level, CE Orfanos, CC Geilen (2000), Resistance to CD95 / Fas-induced and ceramide-mediated apoptosis of human melanoma cells is caused by a defective mitochondrial cytochrome c release, FEBS Lett. 473, 27-32.
G. M. Cohen (1997), Caspases: the executioners of apoptosis, Biochem. J. 326, 1-16.G. M. Cohen (1997), Caspases: the executioners of apoptosis, Biochem. J. 326, 1-16.
F. Eßmann, T. Wieder, A. Otto, E.-C. Müller, B. Dörken, P. T. Daniel (2000), The GDP dissociation inhibitor, D4-GDI (Rho-GDI 2), but not the homologous Rho-GDI 1, is cleaved by caspase-3 during drug-induced apoptosis, Biochem. J. 346, 777-783.F. Eßmann, T. Wieder, A. Otto, E.-C. Müller, B. Dörken, P. T. Daniel (2000), The GDP dissociation inhibitor, D4-GDI (Rho-GDI 2), but not the homologous Rho-GDI 1, is cleaved by caspase-3 during drug-induced apoptosis, Biochem. J. 346, 777-783.
E. Heßler, H.-G. Schmalz, G. Dürner (1994), Chiral Butadiene-Fe(CO)3 Complexes for Organic Synthesis. Reactions of (η4-2-Alkoxy-4-vinyl-2,5- dihydrofuran)-Fe(CO)3 Derivatives, Tetrahedron Lett. 35, 4547-4550.E. Heßler, H.-G. Schmalz, G. Dürner (1994), Chiral Butadiene-Fe (CO) 3 Complexes for Organic Synthesis. Reactions of (η 4 -2-alkoxy-4-vinyl-2,5-dihydrofuran) -Fe (CO) 3 Derivatives, Tetrahedron Lett. 35, 4547-4550.
N. Rehnberg, G. Magnusson (1990), Chiral Aldehydes by Ring Contraction of Pento- und Hexapyranoside Epoxides, J. Org. Chem. 55, 5467 - 5476.N. Rehnberg, G. Magnusson (1990), Chiral Aldehydes by Ring Contraction of Pento- and Hexapyranoside Epoxides, J. Org. Chem. 55, 5467 - 5476.
3. Velcicky, 3. Lex, H.-G. Schmalz (2002), An efficient approach to new carbocyclic nucleoside analogues, Org. Letters 4, 565 - 568.3. Velcicky, 3. Lex, H.-G. Schmalz (2002), An efficient approach to new carbocyclic nucleoside analogues, Org. Letters 4, 565 - 568.
T. Wieder, C. Perlitz, M. Wieprecht, R. T. C. Huang, C. C. Geilen, C. E. Orfanos (1995), Two new sphingomyelin analogues inhibit phosphatidylcholine biosynthesis by decreasing membranebound CTP: phosphocholine cytidylyltransferase levels in HaCaT cells, Biochem. J. 311, 873-879. T. Wieder, F. Eßmann, A. Prokop, K. Schmelz, K. Schulze-Osthoff, R. Beyaert, B. Dörken, P. T. Daniel (2001), Activation of caspase-8 in drug-induced apoptosis of B-lymphoid cells is independent of CD95/Fas receptor-ligand interaction and occurs downstream of caspase-3, Blood 97, 1378-1387.T. Wieder, C. Perlitz, M. Wieprecht, RTC Huang, CC Geilen, CE Orfanos (1995), Two new sphingomyelin analogues inhibit phosphatidylcholine biosynthesis by decreasing membranebound CTP: phosphocholine cytidylyltransferase levels in HaCaT cells, Biochem. J. 311, 873-879. T. Wieder, F. Eßmann, A. Prokop, K. Schmelz, K. Schulze-Osthoff, R. Beyaert, B. Dörken, PT Daniel (2001), Activation of caspase-8 in drug-induced apoptosis of B-lymphoid cells is independent of CD95 / Fas receptor-ligand interaction and occurs downstream of caspase-3, Blood 97, 1378-1387.
A. Prokop, T. Wieder, P. T. Daniel, H.-G. Schmalz (2002), Substances for use in therapy of diseases that are caused by highly proliferative cells, PCT WO 02/080923 AI (17.10.2002) A. Prokop, T. Wieder, P. T. Daniel, H.-G. Schmalz (2002), Substances for use in therapy of diseases that are caused by highly proliferative cells, PCT WO 02/080923 AI (10/17/2002)
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