NO171316B - PROCEDURE FOR THE PREPARATION OF 2 ', 3'-DIDEOXY-2', 3'-DIDEHYDRONUCLEOSIDES R - Google Patents
PROCEDURE FOR THE PREPARATION OF 2 ', 3'-DIDEOXY-2', 3'-DIDEHYDRONUCLEOSIDES R Download PDFInfo
- Publication number
- NO171316B NO171316B NO913459A NO913459A NO171316B NO 171316 B NO171316 B NO 171316B NO 913459 A NO913459 A NO 913459A NO 913459 A NO913459 A NO 913459A NO 171316 B NO171316 B NO 171316B
- Authority
- NO
- Norway
- Prior art keywords
- dideoxy
- pyrimidine
- purine
- formula
- base
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 21
- 238000002360 preparation method Methods 0.000 title claims description 4
- 239000000543 intermediate Substances 0.000 claims description 13
- -1 deaza-purine Chemical compound 0.000 claims description 12
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 11
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 8
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 claims description 6
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 claims description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 239000002798 polar solvent Substances 0.000 claims description 4
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 claims description 3
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 claims description 3
- 229940045145 uridine Drugs 0.000 claims description 3
- XZLIYCQRASOFQM-UHFFFAOYSA-N 5h-imidazo[4,5-d]triazine Chemical compound N1=NC=C2NC=NC2=N1 XZLIYCQRASOFQM-UHFFFAOYSA-N 0.000 claims description 2
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
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- 239000012048 reactive intermediate Substances 0.000 claims description 2
- 239000002342 ribonucleoside Substances 0.000 claims description 2
- DWRXFEITVBNRMK-JXOAFFINSA-N ribothymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 DWRXFEITVBNRMK-JXOAFFINSA-N 0.000 claims 1
- 125000001425 triazolyl group Chemical group 0.000 claims 1
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- 239000000047 product Substances 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000007787 solid Substances 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 11
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical group O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
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- 241000725303 Human immunodeficiency virus Species 0.000 description 7
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
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- 229910052757 nitrogen Inorganic materials 0.000 description 4
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- 238000003756 stirring Methods 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 150000003833 nucleoside derivatives Chemical class 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 229940113082 thymine Drugs 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
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- JPBRYDQRCOMYRY-IVZWLZJFSA-N [(2r,3s,5r)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)-3-methylsulfonyloxyoxolan-2-yl]methyl methanesulfonate Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COS(C)(=O)=O)[C@@H](OS(C)(=O)=O)C1 JPBRYDQRCOMYRY-IVZWLZJFSA-N 0.000 description 2
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- 125000006592 (C2-C3) alkenyl group Chemical group 0.000 description 1
- 125000006593 (C2-C3) alkynyl group Chemical group 0.000 description 1
- YQHCGMPQZCIQPS-VNSJUHMKSA-N 1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(trityloxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound C([C@@H]1[C@H]([C@H]([C@@H](O1)N1C(NC(=O)C=C1)=O)O)O)OC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 YQHCGMPQZCIQPS-VNSJUHMKSA-N 0.000 description 1
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- 229940035893 uracil Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
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Description
Foreliggende oppfinnelse vedrører en forbedret fremgangsmåte for fremstilling av 2 ',3'-dideoksy-2'3'-didehydronukleo-sider . The present invention relates to an improved method for the production of 2',3'-dideoxy-2'3'-didehydronucleosides.
Erhvervet immunsviktsyndrom (AIDS) er resultatet av en infeksjon med humant immunsviktvirus (HIV)<1>. Dette retro-viruset utviser spesifikk tropisme for hjelpe/induktor T-celler<2>, hvilket fører til at cellene oppbrukes. Den resulterende immunundertrykkelsen predisponerer HIV-pasienter for livstruende opportunistiske infeksjoner. Acquired immunodeficiency syndrome (AIDS) is the result of an infection with the human immunodeficiency virus (HIV)<1>. This retrovirus exhibits specific tropism for helper/inducer T cells<2>, leading to the exhaustion of the cells. The resulting immunosuppression predisposes HIV patients to life-threatening opportunistic infections.
Selv om det for øyeblikket ikke finnes noen helbredelse overfor AIDS, har et nukleosiddervat, 3'-azido-3'-deoksy-tymidin (AZT, Retrovir) allerede vist seg å være et virksomt middel ved behandling av AIDS i kliniske forsøk, og er blitt frigitt av myndighetene for anvendelse på pasienter med AIDS<3>. Et antall andre kjemiske og biologiske midler har vist seg å være biologisk aktive overfor HIV. 2',3'-dideoksy-cytidin (ddC), 2 ' , 3'-dideoksyadenosin (ddA)<4>, 2',3'-dideoksy-2'-3'-didehydrocytidin (d4C)<5>, suramin og analoger derav<**>, ribavarin<7>, foscarnet<8>, HPA-23^, d-penicillamin<10>, kas-tanospermin11, fusidinsyre<12>, 3'-azidoguanosin (AZG)<13> og 3'-f luor-3'-deoksytymidin (FDDT)<14> har alle vist seg å være effektive overfor HIV. Although there is currently no cure for AIDS, a nucleoside derivative, 3'-azido-3'-deoxy-thymidine (AZT, Retrovir) has already been shown to be an effective agent in the treatment of AIDS in clinical trials, and is has been released by the authorities for use on patients with AIDS<3>. A number of other chemical and biological agents have been shown to be biologically active against HIV. 2',3'-dideoxy-cytidine (ddC), 2',3'-dideoxyadenosine (ddA)<4>, 2',3'-dideoxy-2'-3'-didehydrocytidine (d4C)<5>, suramin and analogs thereof<**>, ribavarin<7>, foscarnet<8>, HPA-23^, d-penicillamine<10>, castanospermine11, fusidic acid<12>, 3'-azidoguanosine (AZG)<13> and 3'-fluoro-3'-deoxythymidine (FDDT)<14> have all been shown to be effective against HIV.
Et antall beskrivelser som er fremkommet i litteraturen har vist at 2' ,3 '-dideoksy-2*,3'-didehydrotymidin (d4T) er i besittelse av aktivitet in vitro overfor HIV i flere cellelinjer155. A number of descriptions that have appeared in the literature have shown that 2',3'-dideoxy-2*,3'-didehydrothymidine (d4T) possesses activity in vitro against HIV in several cell lines155.
2',3'-dideoksy-2',3'-didehydrotymidin (d4T) er blitt fremstilt av Horwitz et al. ifølge to forskjellige veier1*''17. Ved den første av disse fremgangsmåtene underkastes 3',5'-anhydroderivatet av tymidineliminerende reaksjonsbetingelser. Ved den andre av disse fremgangsmåtene 2',3'-dideoxy-2',3'-didehydrothymidine (d4T) has been prepared by Horwitz et al. according to two different ways1*''17. In the first of these methods, the 3',5'-anhydro derivative is subjected to thymidine-eliminating reaction conditions. By the second of these methods
underkastes det 5'-O-beskyttende 2,3 *-anhydronukleosid- subjected to the 5'-O-protecting 2,3*-anhydronucleoside-
derivatet av tymidin ringåpnings-eliminerende reaksjonsbetingelser. the derivative of thymidine ring-opening-eliminating reaction conditions.
Anvendelsen av anhydronukleosider som mellomprodukter ved nukleosidfremstilling er beskrevet innenfor teknikken, som foreliggende oppfinnelse hører inn under<18>. The use of anhydronucleosides as intermediates in nucleoside production is described within the technique, to which the present invention belongs<18>.
Med den nylige oppdagelsen av styrken av 2',3'-dideoksy-2'3'-didehydrotymidin (d4T) som et anti-HIV-middel, blir en fremgangsmåte som muliggjør billig fremstilling av 2',3'-dideoksy-2'3'-didehydronukleosider, herunder d4T, i stor målestokk viktig. With the recent discovery of the potency of 2',3'-dideoxy-2'3'-didehydrothymidine (d4T) as an anti-HIV agent, a method that enables the inexpensive preparation of 2',3'-dideoxy-2' 3'-didehydronucleosides, including d4T, are important on a large scale.
Fremgangsmåten ifølge Horwitz for fremstilling av d4T ut fra 3 ' , 5 '-anhydroforbindelsen1**, er ikke gjennomført i større målestokk på grunn av at fullstendig fjerning av det store volumet DMSO, som anvendes ved utøvelse av fremgangsmåten ifølge Horwitz i større målestokk, er meget vanskelig å oppnå, og krever høyvakuum (0,01 mmHg og oppvarming i et temperaturområde på ca. 40-50°C) i et omfattende tidsrom. Disse betingelsene fører til spaltning av glykosidbindingen som danner tymidin som et uønsket biprodukt. Forlenget utsettelse av basiske betingelser, som er nødvendige ved anvendelse av andre oppløsningsmidler enn DMSO (f.eks. THF, DMF), fører også til dekomponering av d4T, som igjen gir tymidin som et uønsket biprodukt. The method according to Horwitz for the preparation of d4T from the 3', 5'-anhydro compound 1** has not been carried out on a large scale due to the fact that complete removal of the large volume of DMSO, which is used when carrying out the method according to Horwitz on a large scale, is very difficult to achieve, and requires high vacuum (0.01 mmHg and heating in a temperature range of about 40-50°C) for an extensive period of time. These conditions lead to cleavage of the glycosidic bond forming thymidine as an unwanted by-product. Prolonged exposure to basic conditions, which is necessary when using solvents other than DMSO (eg THF, DMF), also leads to decomposition of d4T, which in turn gives thymidine as an unwanted byproduct.
Den alternative fremgangsmåten ifølge Horwitz krever beskyttelse av 5'-OH-stillingen forut for dannelse av 2,5'-anhydronukleosidet. Dette 2,5'-anhydronukleosidet kan åpnes for oppnåelse av det 5'-O-beskyttende nukleosidet. The alternative method according to Horwitz requires protection of the 5'-OH position prior to formation of the 2,5'-anhydronucleoside. This 2,5'-anhydronucleoside can be opened to obtain the 5'-O-protecting nucleoside.
Det ønskede 2,3'-anhydronukleosidet kan fremstilles direkte ved omsetning av tymidin med dietyl -(2-klor-l,1-2-tri-fluoretyl)amin<1>^. The desired 2,3'-anhydronucleoside can be prepared directly by reacting thymidine with diethyl-(2-chloro-1,1-2-trifluoroethyl)amine<1>^.
Foreliggende oppfinnelse vedrører en fremgangsmåte for fremstilling av 2',3'-dideoksy-2'3'-didehydronukleosider med formelen The present invention relates to a method for the production of 2',3'-dideoxy-2'3'-didehydronucleosides with the formula
hvor where
B er valgt fra gruppen av baser bestående av purin-, aza-purin-, deaza-purin-, pyrimidin-, aza-pyrimidin-, deazapyrimidin- og triazolringbaser, kjennetegnet ved at man B is selected from the group of bases consisting of purine, aza-purine, deaza-purine, pyrimidine, aza-pyrimidine, deazapyrimidine and triazole ring bases, characterized in that
a) omsetter et utgangs-ribonukleosid med formelen a) reacts a starting ribonucleoside of the formula
med et acyloksyisobutyrylbromid, i et polart oppløsningsmid-del under vannfrie betingelser ved en forhøyet temperatur på 75-100°c i 1-3 timer for oppnåelse av et reaktivt mellomprodukt med formelen with an acyloxyisobutyryl bromide, in a polar solvent under anhydrous conditions at an elevated temperature of 75-100°C for 1-3 hours to obtain a reactive intermediate of the formula
hvor where
R er acyloksyisobutyrylgruppen, og R' er acylgruppen i acyloksyisobutyrylbromidet, R is the acyloxyisobutyryl group, and R' is the acyl group in the acyloxyisobutyryl bromide,
b) underkaster mellomproduktet fra trinn (a) en eliminerende reaksjon ved behandling av mellomproduktet i et aprotisk polart oppløsningsmiddel med et Zn/Cu-reagens for oppnåelse av et mellomprodukt med formelen b) subjecting the intermediate from step (a) to an elimination reaction by treating the intermediate in an aprotic polar solvent with a Zn/Cu reagent to obtain an intermediate of the formula
c) avspalter den 5'-O-beskyttende gruppen i mellomproduktet fra trinn (b) ved behandling av mellomproduktet med en c) cleaves off the 5'-O-protecting group in the intermediate from step (b) by treating the intermediate with a
mild base for oppnåelse av avledet 23'-dideoksy-2',3'-didehydronukleosid. mild base to obtain the derivative 23'-dideoxy-2',3'-didehydronucleoside.
Utgangsmaterialet for fremstilling av 2',3'-dideoksy-2',3'-didehydronukleosidet er et 2'-deoksynukleosid og basekompo-nenten B er avledet fra en gruppe av baser bestående av usubstituert eller substituert pyrimidin, azapyrimidin eller deazapyrimidin, fortrinnsvis usubstituert eller substituert pyrimidin. Som basedel anvendes fortrinnsvis usubstituert eller substituert pyrimidin, svarende til den nedenfor angitte formelen for passende usubstituerte eller substituerte pyrimidinbaser. Mere foretrukket anvendes som basedel ved disse to utførelsesformene tymin (5-metyl-2,6-dihydroksypyrimidin ), cytosin (2-hydroksy-6-aminopyrimidin), uracil (2,6-dihydroksypyrimidin) eller 5-etyl-, 5-vinyl-, 5-halogenvinyl-, 5-halogenmetyl- eller 5-halogenetyl-2,6-dihydroksypyrimidin-3-yl. Mest foretrukket anvendes tymin som basedel ved disse to utførelsesformene. The starting material for the production of the 2',3'-dideoxy-2',3'-didehydronucleoside is a 2'-deoxynucleoside and the base component B is derived from a group of bases consisting of unsubstituted or substituted pyrimidine, azapyrimidine or deazapyrimidine, preferably unsubstituted or substituted pyrimidine. Unsubstituted or substituted pyrimidine is preferably used as the base part, corresponding to the formula given below for suitable unsubstituted or substituted pyrimidine bases. More preferably, thymine (5-methyl-2,6-dihydroxypyrimidine), cytosine (2-hydroxy-6-aminopyrimidine), uracil (2,6-dihydroxypyrimidine) or 5-ethyl-, 5-vinyl -, 5-halovinyl-, 5-halomethyl- or 5-haloethyl-2,6-dihydroxypyrimidin-3-yl. Most preferably, thymine is used as the base part in these two embodiments.
Egnede usubstituerte og substituerte purinbaser omfatter purinbasene med formelen Suitable unsubstituted and substituted purine bases include the purine bases of the formula
hvor where
R<1> og R<2> kan være like eller forskjellige, og er valgt blant hydrogen, hydroksy, halogen (F, Cl, Br), amino, monoalkyl-amino, dialkylamino, alkoksy og cyano, hvor alkyldelen er valgt blant C^_3-alkyl. R<1> and R<2> can be the same or different, and are selected from hydrogen, hydroxy, halogen (F, Cl, Br), amino, monoalkyl-amino, dialkylamino, alkoxy and cyano, where the alkyl part is selected from C 3-alkyl.
Egnede usubstituerte eller substituerte pyrimidinbaser omfatter pyrimidinbasene med formelen Suitable unsubstituted or substituted pyrimidine bases include the pyrimidine bases of the formula
hvor where
R er hydroksy, amino eller sulfhydryl, R is hydroxy, amino or sulfhydryl,
R<4> er hydrogen, hydroksy, amino eller sulfhydryl, R<4> is hydrogen, hydroxy, amino or sulfhydryl,
r<5> er hydroksy eller amino, og r<5> is hydroxy or amino, and
R*" er hydrogen, C^.^-alkyl, C2_3-alkenyl, C2_3-halogenalkenyl med 1-5 halogenatomer som definert ovenfor, C2_3~alkynyl, alkoksy, hvor alkyldelen inneholder 1-3 karbonatomer, cyano og halogen (F, Cl, Br eller I). R*" is hydrogen, C2-3-alkyl, C2-3-alkenyl, C2-3-haloalkenyl with 1-5 halogen atoms as defined above, C2-3-alkynyl, alkoxy, where the alkyl part contains 1-3 carbon atoms, cyano and halogen (F, Cl , Br or I).
Når B er avledet fra purinbaser, kan følgende representative eksempler nevnes: When B is derived from purine bases, the following representative examples can be mentioned:
6-aminopurin-9-yl 6-aminopurin-9-yl
2-aminopurin-9-yl 2-aminopurin-9-yl
2,6-diaminpurin-9-yl 2,6-diaminopurin-9-yl
2-amino-6-hydroksypurin-9-yl (guanin-9-yl) 6-hydroksypurin-9-yl. 2-amino-6-hydroxypurin-9-yl (guanin-9-yl) 6-hydroxypurin-9-yl.
Når B er avledet fra pyrimidinbase kan følgende representative eksempler nevnes: 2,4-dihydroksypyrimidin-l-yl When B is derived from pyrimidine base the following representative examples can be mentioned: 2,4-dihydroxypyrimidin-1-yl
5-metyl-2,4-dihydroksypyridimin-l-yl 5-methyl-2,4-dihydroxypyridimin-1-yl
5-etyl-2,4-amlnopyrImidin-1-yl 5-ethyl-2,4-aminopyrimidin-1-yl
2-hydroksy-4-aminopyridin-l-yl 2-hydroxy-4-aminopyridin-1-yl
5-vinyl-2,4-dihydroksypyrimidin-l-yl 5-vinyl-2,4-dihydroxypyrimidin-1-yl
5-halogenvinyl-2,4-dihydroksypyrimidin-l-yl 5-halogenmetyl-2,4-dihydroksypyrimidin-l-yl 5-halogenety1-2,4-dihydroksypyrimidin-l-yl 5-Halovinyl-2,4-dihydroxypyrimidin-1-yl 5-Halomethyl-2,4-dihydroxypyrimidin-1-yl 5-halogenety1-2,4-dihydroxypyrimidin-1-yl
Ovennevnte 5-metyl- og 5-etylsubstituenter er representative eksempler på 5-alkylsubstituenter og 5-vinylsubstituenten er et representativt eksempel på 5-alkenylsubstituenter. Eksempler på halogenatomer i 5-halogenvinyl- (eller 5-halogenalkenyl)-gruppen omfatter 1-4 F-, Cl- eller Br-atomer. The above-mentioned 5-methyl and 5-ethyl substituents are representative examples of 5-alkyl substituents and the 5-vinyl substituent is a representative example of 5-alkenyl substituents. Examples of halogen atoms in the 5-halovinyl (or 5-haloalkenyl) group include 1-4 F, Cl or Br atoms.
Problemene ved de i litteraturen kjente fremgangsmåtene for fremstilling av de ønskede 2',3'-dideoksy-2'3'-didehydro-nukleosider ved hjelp av det reaktive 2,3'-anhydromel-lomproduktet omfatter anvendelsen av dietyl(2-klor-l,1,2-trifluoretyl)amin, et fluoraminreagens, som er vnaskelig å fremstille og som krever spesielt utstyr. Et alternativ beskrives i litteraturen og omfatter en langvarig 4-trinns-metode som omfatter 5'-O-tritylering, 3'-O-mesylering, detritylering og anhydrodannelse. I litteraturen beskrives at forskjellige andre produkter og biprodukter enn de ønskede 2',3'-dideoksy-2'3'-didehydronukleosidprodukter dannes. The problems with the methods known in the literature for preparing the desired 2',3'-dideoxy-2'3'-didehydro-nucleosides by means of the reactive 2,3'-anhydro intermediate include the use of diethyl (2-chloro- 1,1,2-trifluoroethyl)amine, a fluoramine reagent, which is difficult to prepare and which requires special equipment. An alternative is described in the literature and comprises a lengthy 4-step method comprising 5'-O-tritylation, 3'-O-mesylation, detritylation and anhydro formation. In the literature it is described that various other products and by-products than the desired 2',3'-dideoxy-2'3'-didehydronucleoside products are formed.
De spesifikke forbedringene som blir foretatt i den foreliggende fremgangsmåten og som forløper via det reaktive 2,3'-anhydromellomproduktet omfatter den overraskende erkjennelse at anvendelsen av reagenset, tetrabutylammoniumfluorid (TBAF), under ikke-nukleofile betingelser gir det ønskede produktet i ren tilstand, og i stort utbytte. Anvendelsen av KOtBu/DMSO og NaOH/DMF, men ikke NaCN/DMF eller DBU/DMF eller NaOH/MeOH eller KOtBu/BuOH, i stedet for TBAF i THF eller DMF gir det ønskede produktet, selv om utbyttet er mindre og det oppnås noen uønskede biprodukter (3'-epi-tymidin) ved anvendelse av NaOH/DMF. The specific improvements made in the present process which proceed via the reactive 2,3'-anhydro intermediate include the surprising realization that the use of the reagent, tetrabutylammonium fluoride (TBAF), under non-nucleophilic conditions gives the desired product in the pure state, and in large dividends. The use of KOtBu/DMSO and NaOH/DMF, but not NaCN/DMF or DBU/DMF or NaOH/MeOH or KOtBu/BuOH, instead of TBAF in THF or DMF gives the desired product, although the yield is lower and some unwanted by-products (3'-epi-thymidine) using NaOH/DMF.
Fremgangsmåten ifølge foreliggende oppfinnelse er følgelig nyttig ved fremstilling av forskjellige 2',3'-dideoksy-2<*>3'-didehydronukleosider, spesielt pyrimidin- og pyrinnukleo-sider, med antiviral, antimetabolsk og antineoplastisk aktivitet samt aktivitet overfor human immunsvikt-virus. The method according to the present invention is consequently useful in the production of various 2',3'-dideoxy-2<*>3'-didehydronucleosides, especially pyrimidine and pyrin nucleosides, with antiviral, antimetabolic and antineoplastic activity as well as activity against human immunodeficiency virus .
De følgende eksempler belyser noen få representative utførel-sesformer for fremgangsmåten ifølge foreliggende oppfinnelse. Hvis ikke annet er angitt, er alle delene og prosent-angivelsene på vektbasis og alle temperaturangivelsene er i The following examples illustrate a few representative embodiments of the method according to the present invention. Unless otherwise noted, all parts and percentages are by weight and all temperature indications are in
•c. c.
Biologiske data, herunder anti-HIV-data for d4T fremstilt ved en fremgangsmåte ifølge oppfinnelsen er ført opp i tabell I. Disse data er i overensstemmelse med publiserte data. Biological data, including anti-HIV data for d4T produced by a method according to the invention are listed in Table I. These data are in accordance with published data.
FORSØK ATTEMPT
Smeltepunkter bestemmes på et "Elektrotermal"-kappilært apparat, og er ukorrigerte. TLC utføres på silisiumoksydgel-"60 F-254"-plater fra E.Merck & Co., og kolonnekromatografi utføres på flammesilisiumoksydgel (40 um partikkelstørrelse, Baker). Elementanalyse utføres av den analytiske avdelingen, Bristol-Myers, Wallingford. ^-H- og <13>C-NMR-spektre ble opptatt på et "AM360 Bruker NMR"-spektrometer med tetrametyl-silan som den interne standard. Kjemiske skift ble notert i ppm. Analytisk HPLC ble utført på en "Waters C18"-reversfase-kolonne. Melting points are determined on an "Electrothermal" capillary apparatus, and are uncorrected. TLC is performed on silica gel "60 F-254" plates from E.Merck & Co., and column chromatography is performed on flame silica gel (40 µm particle size, Baker). Elemental analysis is performed by the Analytical Department, Bristol-Myers, Wallingford. 3-H and <13>C-NMR spectra were recorded on an "AM360 Bruker NMR" spectrometer with tetramethyl-silane as the internal standard. Chemical shifts were noted in ppm. Analytical HPLC was performed on a "Waters C18" reverse phase column.
3', 5'- Di- 0-( metansulfonyl) tymidin 3', 5'-Di-O-(methanesulfonyl)thymidine
En 3 liters, 3-halset, rundbundet kolbe ble utstyrt med en ovenfra montert omrører med propell, en 500 ml skilletrakt og en Claisen-adapter inneholdende tørrerør og termometer. Tymidin (200 g, 0,82 M) og pyridin (750 ml) ble satt til kolben. Blandingen ble omrørt og oppvarmet på et vannbad (20 minutter) for oppnåelse av en klar oppløsning. Deretter ble oppløsningen avkjølt i et isbad til 0-3°C og skilletrakten ble fylt med metansulfonylklorid (206,5 g, 1,08 M). Metansul-fonylkloridet ble deretter tilsatt dråpevis i løpet av 40 minutter uten tydelig eksoterm reaksjon. Oppløsningen ble omrørt ved 0°C i 1 time, og henstod deretter ved 5°C i 18 timer. Den lysebrune blandingen ble deretter utfelt i hurtig omrørt vann (3 liter) inneholdende is (ca. 500 g). Det ønskede produktet ble omgående utkrystallisert. Etter omrøring i 1/2 time ble produktet oppsamlet ved filtrering og flere ganger vasket med vann (3 x 100 ml). Det hvite faste stoffet ble deretter tørket over vakuum natten over (vekt i rå tilstand 322 g, 98$ utbytte). Produktet ble omkrystallisert fra varm aceton for oppnåelse av 267 g av et hvitt faststoff (81# utbytte), sm.p. 169-171°C (lit. 170-171°C). A 3 L, 3-necked, round-necked flask was fitted with a top-mounted propeller stirrer, a 500 mL separatory funnel, and a Claisen adapter containing a drying tube and thermometer. Thymidine (200 g, 0.82 M) and pyridine (750 mL) were added to the flask. The mixture was stirred and heated on a water bath (20 minutes) to obtain a clear solution. Then the solution was cooled in an ice bath to 0-3°C and the separatory funnel was filled with methanesulfonyl chloride (206.5 g, 1.08 M). The methanesulfonyl chloride was then added dropwise over 40 minutes without any apparent exothermic reaction. The solution was stirred at 0°C for 1 hour, and then left at 5°C for 18 hours. The light brown mixture was then precipitated in rapidly stirred water (3 litres) containing ice (approx. 500 g). The desired product was immediately crystallized. After stirring for 1/2 hour, the product was collected by filtration and washed several times with water (3 x 100 ml). The white solid was then dried under vacuum overnight (crude weight 322 g, 98% yield). The product was recrystallized from hot acetone to give 267 g of a white solid (81% yield), m.p. 169-171°C (lit. 170-171°C).
<i>H.-NMR (360 MHz, d6-DMS0) S: 11,40 (s, 1H, NH), 7,50 (s, 1H, H-6), 6,21 (t, 1H, H-l'), 5,29 (m, 1H, H-3<*>), 4,45 (m, 2H, H-5'), 4,35 (m, 1H, H-4'), 3,31 (s, 6H, S02CH3), 2,50 (m, 2H, E-2' ), 1,78 (s, 3H, CH3). <i>H.-NMR (360 MHz, d6-DMS0) S: 11.40 (s, 1H, NH), 7.50 (s, 1H, H-6), 6.21 (t, 1H, H -1'), 5.29 (m, 1H, H-3<*>), 4.45 (m, 2H, H-5'), 4.35 (m, 1H, H-4'), 3 .31 (s, 6H, SO 2 CH 3 ), 2.50 (m, 2H, E-2' ), 1.78 (s, 3H, CH 3 ).
Analyse (C12<H>18<N>209S2) C, H, N. Analysis (C12<H>18<N>209S2) C, H, N.
l-( 3. 5- anhydro- 2- deoksy- g- D- treo- pentofuranosyl) tymin l-(3.5- anhydro- 2- deoxy- g- D- threo- pentofuranosyl) thymine
3',5'-Di-0-(metansulfonyl)tymidin (248 g, 0,62 M) ble porsjonsvis satt til en omrørt oppløsning av natriumhydroksid (74,7 g, 1,87 M) i vann (1,6 1). Ved tilsetningen ble reaksjonsblandingen en gulorange oppløsning. Den omrørte 3',5'-Di-O-(methanesulfonyl)thymidine (248 g, 0.62 M) was added portionwise to a stirred solution of sodium hydroxide (74.7 g, 1.87 M) in water (1.6 L ). Upon addition, the reaction mixture became a yellow-orange solution. It stirred
oppløsningen ble deretter oppvarmet med tilbakekjøling i 2 timer. Ved avkjøling av reaksjonsblandingen til romtemperatur, ble 6N (100 ml) saltsyre tilsatt. Reaksjonsblandingen ble konsentrert i vakuum ved fjernelse av 1,3 1 vann. Den resulterende oppslemmingen ble avkjølt i et isbad i 2 timer. Deretter ble det faste stoffet frafiltrert og vasket forsiktig med isvann, og tørket i vakuum til konstant vekt (103,7 g, 7456). Produktet 3, sm.p. 188-190'C (lit. 190-193°C) ble anvendt under ytterligere rensning. the solution was then heated under reflux for 2 hours. Upon cooling the reaction mixture to room temperature, 6N (100 mL) hydrochloric acid was added. The reaction mixture was concentrated in vacuo by removing 1.3 L of water. The resulting slurry was cooled in an ice bath for 2 hours. Then the solid was filtered off and washed carefully with ice water, and dried in vacuo to constant weight (103.7 g, 7456). The product 3, m.p. 188-190'C (lit. 190-193°C) was used during further purification.
<1>H-NME (360 MHz, d6-DMS0) S : 11,35 (s, 1H, NH), 8,01 (s, 1H, H-6), 6.49 (q, 1H, H-l' ), 5,47 (m, 1H, H-3'), 4,88 og 4,67 (m, 2H, H-5'), 4,22 (d, 1H, H-4'), 2,47 (m, 2H, H-2<*>), 1,77 (s, 3H, CH3). <1>H-NME (360 MHz, d6-DMS0) S : 11.35 (s, 1H, NH), 8.01 (s, 1H, H-6), 6.49 (q, 1H, H-l' ), 5.47 (m, 1H, H-3'), 4.88 and 4.67 (m, 2H, H-5'), 4.22 (d, 1H, H-4'), 2.47 ( m, 2H, H-2<*>), 1.77 (s, 3H, CH3).
<13>C-NMR (75 MHz, d6-DMS0): 163,64 (C2), 151,10 (C4), 136,57 (C6), 109,62 (C5), 88,29 (C4'), 86,85 (cl'), 79,83 (C3'), 75,14 (C5'), 37,17 (C2'), 12,33 (CH3). <13>C-NMR (75 MHz, d6-DMS0): 163.64 (C2), 151.10 (C4), 136.57 (C6), 109.62 (C5), 88.29 (C4') , 86.85 (cl'), 79.83 (C3'), 75.14 (C5'), 37.17 (C2'), 12.33 (CH3).
Analyse (C10<H>12<N>2046) C, H, N. Analysis (C10<H>12<N>2046) C, H, N.
l-( 2. 3- dideoksy- P- D- glysero- pent- 2- enofuranosyl) tymin l-(2.3- dideoxy-P-D-glycero-pent-2-enofuranosyl)thymine
Til en trehalset 1 liters kolbe med rund bunn, utstyrt med mekanisk omrører, termometer og nitrogentilledning, ble tørt DMSO (400 ml) og oksetan (90,0 g, 0,402 M) tilsatt. Til oppløsningen ble 97$ KOtBu (74 g, 0,643 M) tilsatt i porsjoner på 1,5 g i løpet av 25 minutter. Temperaturen ble holdt mellom 18 og 22°C ved hjelp av et eksternt isbad. Etter endt tilsetning ble reaksjonsblandingen omrørt i ytterligere 1 time og det ble ikke iaktatt noen ytterligere stigning i temperaturen og TLC indikerte at omsetningen var løpt ca. 90% til ende. Reaksjonsblandingen ble omrørt ved 21°C i 16 timer, hvorpå TLC indikerte at reaksjonen var slutt. Viskoseopp-løsningen ble helt i kaldt (4°C) toluen (3 liter), som resulterte i et beige-farvet presipitat. Blandingens temperatur steg til 20"C ved tilsetning av DMSO-oppløsningen. Blandingen ble omrystet av og til i 20 minutter, og filtrert på en 18,5 cm Buchner-trakt. Det oppsamlede, gulaktige, faste stoffet ble vasket to ganger med kald toluen og tørket under sug i 1 time. Det faste stoffet ble oppløst i 30 ml vann og 2 faser ble dannet. Blandingen ble overført til en skilletrakt og den øvre fasen (inneholdende resterende toluen) ble kastet. Den vandige fasen ble overført til et 1 liter begerglass tilsatt pH-probe, magnetpinne og termometer. Temperaturen ble senket til 10°C ved anvendelse av et eksternt isbad. Konsentrert HC1 ble dråpevis tilsatt til den omrørte oppløsningen ved en slik hastighet at temperaturen ble holdt under 15<0>C. Etter tilsetning av HC1 (50,5 ml, 0,61 M) var pH = 7 + 0,1 og det ble dannet et presipitat. Til den tykke blandingen ble kalsiumklorid (70 g) tilsatt, og omrøringen ble fortsatt ved 5°C i 1 time. Presipitatet ble oppsamlet og tørket i sug i 2 timer og lufttørket i 16 timer. Faststoffet ble knust og oppslemmet i varm aceton (500 ml) og filtrert. Resten på filterpapiret ble renset med varm aceton (2 x 200 ml), igjen oppslemmet i varm aceton (300 ml), filtrert og påny vasket med varm aceton (2 x 100 ml). Det kombinerte filtratet ble konsentrert til tørrhet for oppnåelse av 51,3 g (57$) d4T som et of f-white fast stoff, sm.p. 165-166°C To a three-necked 1 L round-bottom flask equipped with a mechanical stirrer, thermometer, and nitrogen line, dry DMSO (400 mL) and oxetane (90.0 g, 0.402 M) were added. To the solution was added 97% KOtBu (74 g, 0.643 M) in 1.5 g portions over 25 minutes. The temperature was maintained between 18 and 22°C using an external ice bath. After the addition was complete, the reaction mixture was stirred for a further 1 hour and no further increase in temperature was observed and TLC indicated that the reaction had run approx. 90% to the end. The reaction mixture was stirred at 21°C for 16 hours, whereupon TLC indicated that the reaction was complete. The viscose solution was poured into cold (4°C) toluene (3 liters), which resulted in a beige-colored precipitate. The temperature of the mixture rose to 20°C upon addition of the DMSO solution. The mixture was shaken occasionally for 20 minutes and filtered on an 18.5 cm Buchner funnel. The collected yellowish solid was washed twice with cold toluene and dried under suction for 1 hour. The solid was dissolved in 30 mL of water and 2 phases formed. The mixture was transferred to a separatory funnel and the upper phase (containing residual toluene) was discarded. The aqueous phase was transferred to a 1 liter beaker with pH probe, magnetic stick, and thermometer. The temperature was lowered to 10°C using an external ice bath. Concentrated HCl was added dropwise to the stirred solution at such a rate that the temperature was kept below 15<0>C. After addition of HCl (50.5 mL, 0.61 M) pH = 7 + 0.1 and a precipitate formed To the thick mixture calcium chloride (70 g) was added and stirring was continued at 5°C for 1 The precipitate was collected and dried under suction for 2 hours and air dried for 16 hours. The solid was crushed and slurried in hot acetone (500 mL) and filtered. The residue on the filter paper was cleaned with hot acetone (2 x 200 ml), reslurried in hot acetone (300 ml), filtered and washed again with hot acetone (2 x 100 ml). The combined filtrate was concentrated to dryness to afford 51.3 g (57%) d 4 T as an off-white solid, m.p. 165-166°C
[Q]<g0> = 46,1<»> (c = 0,7, vann) [Q]<g0> = 46.1<»> (c = 0.7, water)
<1->H-NMR (360 MHz, d6-DMS0) S: 11,29 (s, 1H, NH), 7,63 (s, 1H, H-6), 6,80 (d, 1H, J=l,2 Hz, H-l'), 6,38 (d, 1H, J=5,9 Hz, H-3'), 5,90 (dd, 1H, J=l,l, 4,7 Hz, H-3' ), 5,01 (m, 1H, OH), 4,76 (s, 1H, H-4'), 3,60 (dd, 2H, J=4,8, 3,6 Hz, H-5'), 1,71 (d, 3H, J = l ,2 Hz, CH3). <1->H-NMR (360 MHz, d6-DMS0) S: 11.29 (s, 1H, NH), 7.63 (s, 1H, H-6), 6.80 (d, 1H, J =l.2 Hz, H-l'), 6.38 (d, 1H, J=5.9 Hz, H-3'), 5.90 (dd, 1H, J=l,l, 4.7 Hz, H-3' ), 5.01 (m, 1H, OH), 4.76 (s, 1H, H-4'), 3.60 (dd, 2H, J=4.8, 3.6 Hz, H-5'), 1.71 (d, 3H, J = 1.2 Hz, CH 3 ).
<13>C-NMR (75 MHz, d6-DMS0): 164,42 (C4), 151,30(C2), 137,23 (C2'), 135,36 (C3'), 126,35 (C6), 109,33 (C5), 89,15 (Cl'), 87,56 (C4'), 62,41 (C5'), 12,15 (C5CH3). <13>C-NMR (75 MHz, d6-DMS0): 164.42 (C4), 151.30(C2), 137.23 (C2'), 135.36 (C3'), 126.35 (C6 ), 109.33 (C5), 89.15 (Cl'), 87.56 (C4'), 62.41 (C5'), 12.15 (C5CH3).
MS m/e (metan DCI) (relativ intensitet): 225 (+H, 20), 207 (15), 193 (8), 155 (13), 127 (100), 99 (20). MS m/e (methane DCI) (relative intensity): 225 (+H, 20), 207 (15), 193 (8), 155 (13), 127 (100), 99 (20).
IR (cm-<1>): 3463, 3159, 3033, 1691, 1469, 1116, 1093. Analyse (C10<H>12<N>204) C, H, N. IR (cm-<1>): 3463, 3159, 3033, 1691, 1469, 1116, 1093. Analysis (C10<H>12<N>204) C, H, N.
1-( 2. 3- dideoksy- g- D- glysero- pent- 2- enofuranosyl) tymin Tetrabutylammoniumfluorid (0,22 ml, 0,22 mM, 1,0 M) ble satt til en suspensjon av anhydronukleosidet (25 mg, 0,11 mM) i tørt THF (3 ml). Etter omrøring ved 22°C i 3 timer viste TLC bare utgangsmateriale. Blandingen ble oppvarmet med til-bakekjøling i 18 timer hvoretter reaksjonen forekom å være gått til ende. Etter avkjøling ble oppløsningsmidlene fjernet i vakuum og resten oppløst i CH2Cl2/Me0H/NH40H (90:10:1). Opprensingen ble utført på en 20 mm lynkromatografisk kolonne under eluering med CHgClg/MeOH/NB^OH (90:10:1). Konsentrering av fraksjonene inneholdende produktet ga 18 mg (72$) d4T. 1-(2.3- dideoxy-g-D-glycero-pent-2- enofuranosyl) thymine Tetrabutylammonium fluoride (0.22 mL, 0.22 mM, 1.0 M) was added to a suspension of the anhydronucleoside (25 mg, 0.11 mM) in dry THF (3 mL). After stirring at 22°C for 3 hours, TLC showed only starting material. The mixture was heated with re-cooling for 18 hours, after which the reaction appeared to have gone to completion. After cooling, the solvents were removed in vacuo and the residue dissolved in CH2Cl2/MeOH/NH4OH (90:10:1). The purification was carried out on a 20 mm flash chromatography column eluting with CHgClg/MeOH/NB^OH (90:10:1). Concentration of the fractions containing the product gave 18 mg (72$) of d4T.
l-( 5- 0- trityl- 2'. 3'- tiokarbonmylribofuranosylluracil l-(5-O-trityl-2'.3'-thiocarbonmylribofuranosyluracil
5'-O-trityluridin (10,6 g, 22 mM) ble overført til en tørr 250 ml rundbundet kolbe under argonatmosfære. Tørt tetrahydrofuran (110 ml) ble tilsatt, og reaksjonsblandingen Omrørt helt til den ble homogen. Ved tilsetning av 1,1-tiokarbonyldiimidazol (4,3 g, 27 mM) til oppløsningen ble reaksjonsblandingen gul, og den henstod deretter under omrøring ved romtemperatur i 72 timer. Oppløsningsmidlet ble fjernet i vakuum og den resulterende sirupen ble lynkromatografert på silisiumoksydgel med etylacetat/heksan (75:25) som elueringsmiddel. Produktet ble isolert og omkrystallisert fra absolutt etanol for oppnåelse av et off-white pulver (0,8 g, 77*). 5'-O-trityluridine (10.6 g, 22 mM) was transferred to a dry 250 mL round-bottomed flask under argon atmosphere. Dry tetrahydrofuran (110 mL) was added and the reaction mixture stirred until homogeneous. Upon addition of 1,1-thiocarbonyldiimidazole (4.3 g, 27 mM) to the solution, the reaction mixture turned yellow, and it was then allowed to stir at room temperature for 72 hours. The solvent was removed in vacuo and the resulting syrup was flash chromatographed on silica gel with ethyl acetate/hexane (75:25) as eluent. The product was isolated and recrystallized from absolute ethanol to give an off-white powder (0.8 g, 77*).
<1>H-NMR (360 MHz, CDC13) 5: 8,9 (br s, 1H, NH), 7,3 (m, 16H, 3xC6H5, H6), 5,7 (d, 1H, H5), 5,6 (m, 2H, H2', H3' ), 5,4 (m, 1H, Hl'),3,4 (q, 2H, H5'). <1>H-NMR (360 MHz, CDCl3) δ: 8.9 (br s, 1H, NH), 7.3 (m, 16H, 3xC6H5, H6), 5.7 (d, 1H, H5), 5.6 (m, 2H, H2', H3'), 5.4 (m, 1H, H1'), 3.4 (q, 2H, H5').
5 '- O- trityl- 2'. 3'- dideoksy- 2', 3'- didehydrouridin l-(5'-0-trityl-23'-tiokarbonylribofuranosyl)uracil (6,0 g, 11,5 mM) ble satt til trietylfosfitt (30 ml). Trietylfosfitt ble foroppvarmet til 160°C. Reaksjonsblandingen ble oppvarmet ved 160°C i 1 time. Oppløsningsmidlet ble deretter fjernet i vakuum, og det resulterende glassaktige faste stoffet ble lynkromatografert på silisiumoksydgel under eluering med etylacetat/heksan (75:25). Det ønskede produktet ble isolert fra kolonnen og ble omkrystallisert fra etylacetat/heksan og samlet som et hvitt fast stoff (2,0 g, 4056), sm.p. 188-191°C. 5'-O-trityl-2'. 3'-dideoxy-2',3'-didehydrouridine 1-(5'-O-trityl-23'-thiocarbonylribofuranosyl)uracil (6.0 g, 11.5 mM) was added to triethyl phosphite (30 mL). Triethyl phosphite was preheated to 160°C. The reaction mixture was heated at 160°C for 1 hour. The solvent was then removed in vacuo and the resulting glassy solid was flash chromatographed on silica gel eluting with ethyl acetate/hexane (75:25). The desired product was isolated from the column and was recrystallized from ethyl acetate/hexane and collected as a white solid (2.0 g, 4056), m.p. 188-191°C.
<i>H-NMR (360 MHz, CDC13) S: 8,95 (br2, 1H, NH), 8,00 (d, 1H, H6), 7,5 (m, 15H, 3xC6H5), 7,2 (m, 1H, Hl'), 6,7 (m, 1H, H2'), 6,05 (m, 1H, H3' ), 5,2 (dd, 1H, H5), 5,10 (br s, 1H, H4'), 3,6 (m, 2H, H5'). <i>H-NMR (360 MHz, CDCl3) S: 8.95 (br2, 1H, NH), 8.00 (d, 1H, H6), 7.5 (m, 15H, 3xC6H5), 7.2 (m, 1H, Hl'), 6.7 (m, 1H, H2'), 6.05 (m, 1H, H3' ), 5.2 (dd, 1H, H5), 5.10 (br s , 1H, H4'), 3.6 (m, 2H, H5').
2' 3'- dideoksy- 2'. 3'- didehydrouridin ( d4U) 2' 3'- dideoxy- 2'. 3'-didehydrouridine (d4U)
5'-O-trityl-2',3'-dideoksy-2'3'-didehydrouridin (0,5 g, 1,1 mM) ble oppløst i en blanding av kloroform (10 ml) og metanol (2ml) inneholdende 2% p-toluensulfonsyre. Reaksjonsblandingen ble omrørt ved romtemperatur i 0,75 t. og nøytralisert med 2N NaOH (0,5 ml). Oppløsningsmidlet ble fjernet i vakuum og resten kromatografert på silisiumoksydgel under eluering med kloroform/aceton (2:1). Det ønskede produktet ble isolert som et hvitt krystallinsk fast stoff med samme fysiske og spektroskopiske karakteristika som d4U fremstilt ved en alternativ metode, sm.p. 155°C. 5'-O-trityl-2',3'-dideoxy-2'3'-didehydrouridine (0.5 g, 1.1 mM) was dissolved in a mixture of chloroform (10 mL) and methanol (2 mL) containing 2 % p-toluenesulfonic acid. The reaction mixture was stirred at room temperature for 0.75 h and neutralized with 2N NaOH (0.5 ml). The solvent was removed in vacuo and the residue chromatographed on silica gel eluting with chloroform/acetone (2:1). The desired product was isolated as a white crystalline solid with the same physical and spectroscopic characteristics as d4U prepared by an alternative method, m.p. 155°C.
1-H-NMR (360 MHz, D20/DMS0) S: 7,8 (d, 1H, H6), 6,7 (m, 1H, Hl'), 6,37 (m, 1H, H2'), 5,8 (m, 1H, H3'), 5,56 (d, 1H, H5), 4,7 (m, 1H, H4'), 3,6 (m, 2H, H5'). 1-H-NMR (360 MHz, D2O/DMSO) S: 7.8 (d, 1H, H6), 6.7 (m, 1H, H1'), 6.37 (m, 1H, H2'), 5.8 (m, 1H, H3'), 5.56 (d, 1H, H5), 4.7 (m, 1H, H4'), 3.6 (m, 2H, H5').
<13>C-NMR (70 MHz, D20/DMS0): 163 (C4), 151 (C2), 141 (C2<«>), 135 (C3'), 126 (C6), 101 (C5), 89 (cl'), 87 (C4<*>), 62 (C5* ). <13>C-NMR (70 MHz, D20/DMS0): 163 (C4), 151 (C2), 141 (C2<«>), 135 (C3'), 126 (C6), 101 (C5), 89 (cl'), 87 (C4<*>), 62 (C5* ).
2' . 3'- metoksyoretylidenuridin 2'. 3'-Methoxyorethylideneuridine
Uridin (50 g, 0,025 M) ble overført til en 1 liters rundbundet kolbe under nitrogenatmosfære. Tørt, friskt destillert tetrahydrofuran (500 ml) og pyridinium-p-toluensulfonat (5 g, 20 mM) ble satt til reaksjonsblandingen. Timetyl-ortoformiat (109 g, 1,03 M) ble deretter tilsatt langsomt via en tilsetningstrakt. Reaksjonsblandingen ble omrørt i 18 timer ved romtemepratur, hvorved reaksjonsblandingen ble homogen. Vann (18 g, IM) ble tilsatt og reaksjonsblandingen ble omrørt i ytterligere 1/2 time hvoretter pyridin (20 ml) ble tilsatt. Reaksjonsblandingen ble omrørt ved romtemperatur i ytterligere 18 timer, og oppløsningsmidlet ble fjernet i vakuum. Det resulterende hvite faste stoffet ble lynkromatografert på silisiumoksydgel for oppnåelse av det ønskede produktet som et hvitt fast stoff (40 g, 6856), sm.p. ISS-i<g>CC (lit. 189-190° ). Uridine (50 g, 0.025 M) was transferred to a 1 L round bottom flask under nitrogen atmosphere. Dry, freshly distilled tetrahydrofuran (500 mL) and pyridinium p-toluenesulfonate (5 g, 20 mM) were added to the reaction mixture. Dimethyl orthoformate (109 g, 1.03 M) was then added slowly via an addition funnel. The reaction mixture was stirred for 18 hours at room temperature, whereby the reaction mixture became homogeneous. Water (18 g, 1 M) was added and the reaction mixture was stirred for an additional 1/2 hour after which pyridine (20 mL) was added. The reaction mixture was stirred at room temperature for an additional 18 hours, and the solvent was removed in vacuo. The resulting white solid was flash chromatographed on silica gel to afford the desired product as a white solid (40 g, 6856), m.p. ISS-i<g>CC (lit. 189-190° ).
5- 0- acetvl- 2'. 3'- dideoksy- 2', 3'- didehydrouridin 5-0-acetvl-2'. 3'- dideoxy-2', 3'- didehydrouridine
Metoksymetylidenforbindelsen (11,8 g, 41 mM) ble oppløst 1 eddiksyreanhydrid (110 ml) og p-toluensulfonat (20 mg) ble tilsatt, og reaksjonsblandingen oppvarmet til 140°C i 6 timer. Reaksjonsblandingen ble avkjølt, og trietylamin (1 ml) ble tilsatt. Oppløsningsmidlene ble fjernet i vakuum og produktet kromatografert på silisiumoksydgel under eluering med kloroform/aceton (4:1) for oppnåelse av det ønskede produktet som en klar olje. The methoxymethylidene compound (11.8 g, 41 mM) was dissolved in acetic anhydride (110 mL) and p-toluenesulfonate (20 mg) was added, and the reaction mixture was heated to 140°C for 6 hours. The reaction mixture was cooled and triethylamine (1 mL) was added. The solvents were removed in vacuo and the product chromatographed on silica gel eluting with chloroform/acetone (4:1) to give the desired product as a clear oil.
<3->H-NMR (360 MHz, DMSO) S: 11,3 (br s, 1H, NH), 7,4 (d, 1H, H6), 6,8 (m, 1H, Hl'), 6,4 (m, 1H, H2'), 5,9 (m, 1H, H3'), 5,6 (d, 1H, H5), 5,0 (m, 1H, H4'), 4,2 (m, 2H, H5'), 2,0 (s, 3H, CH3). <3->H-NMR (360 MHz, DMSO) S: 11.3 (br s, 1H, NH), 7.4 (d, 1H, H6), 6.8 (m, 1H, Hl'), 6.4 (m, 1H, H2'), 5.9 (m, 1H, H3'), 5.6 (d, 1H, H5), 5.0 (m, 1H, H4'), 4.2 (m, 2H, H5'), 2.0 (s, 3H, CH3).
5'-0-(2'- acetoksyi sobutyryl1- 3- 0- acetyl- 2'- brom- 2' deoksy-urldin 5'-0-(2'- acetoxyi sobutyryl1- 3- 0- acetyl- 2'- bromo- 2' deoxy-urldin
Uridin (5,0 g, 0,021 M) ble suspendert i acetonitril (90 ml), og 2-acetoksyisobutyrylbromid (12,85 g, 0,063 M) ble tilsatt i løpet av 15 minutter, og reaksjonen ble oppvarmet ved 80"C i 3 timer. Den homogene oppløsningen ble avkjølt til tomtemperatur og oppløsningsmidlet fjernet i vakuum. Den resulterende sirupen ble oppløst i EtOAC (200 ml) og vasket med NaHCOO ml). Den organiske fasen ble tørket over MgS04 og oppløsningsmidlet fjernet i vakuum. Kromatografi på S102 (75* EtOAc/25* Heks) ga 6,7 g av et hvitt skum (67*), sm.p. 68-70°C (MS M<+> = 477). Uridine (5.0 g, 0.021 M) was suspended in acetonitrile (90 mL), and 2-acetoxyisobutyryl bromide (12.85 g, 0.063 M) was added over 15 min, and the reaction was heated at 80°C for 3 hours. The homogeneous solution was cooled to room temperature and the solvent removed in vacuo. The resulting syrup was dissolved in EtOAC (200 mL) and washed with NaHCOO mL. The organic phase was dried over MgSO 4 and the solvent removed in vacuo. Chromatography on S102 ( 75* EtOAc/25* Hex) gave 6.7 g of a white foam (67*), mp 68-70°C (MS M<+> = 477).
2'. 3>- dihydro- 2,. 3'- dideoksvuridin ( D4U) 2'. 3>- dihydro- 2,. 3'-dideoxvuridine (D4U)
Bromur idin (2 g, 4,2 mM) ble oppløst i 3 ml DMF og satt dråpevis til en oppslemming av Zn/Cu (0,70 g, 10,5 mM) i tørt DMF (25 ml). Reaksjonsblandingen ble omrørt 12,5 timer ved romtemperatur og ikke noe utgangsmateriale kunne iaktaes ved TLC. Reaksjonsblandingen ble filtrert gjennom celitt, og filtratet konsentrert i vakuum i et høyvakuumsystem ved 20°C. Det resulterende hvite faste stoffet (1,1 g, 85*) ble oppløst i MeOH og avkjølt til 0°C med et is-vannbad. Vannfritt ammoniakk ble boblet gjennom i 20 minutter, og oppløsningen oppvarmet til 60"C i 18 timer. TLC avslørte en flekk svarende til D4U. Oppløsningsmidlene ble fjernet og det resulterende hvite faste stoffet ble kromatografert på S102 (10* MeOH/CH2C2) for oppnåelse av 5 g (53*) av det ønskede produktet, sm. p. 155°C (lit. 154-155°C). 1. (a) F. Barre-S1noussi, J.C. Chermann, R. Rey, M.T. Nugeyre, S. Chamaret, C. Gruest, C. Dauguet, C. Axler-Blin, C. Rouzioux, W. Rozembaum og L. Hontagnier, Science (Washington D.C.) 1983, 220, 868-871. (b) S. Broder, R.C. Gallo, N. Engl. J. Med. 1984, 311, 1292-1297. Bromidine (2 g, 4.2 mM) was dissolved in 3 mL DMF and added dropwise to a slurry of Zn/Cu (0.70 g, 10.5 mM) in dry DMF (25 mL). The reaction mixture was stirred for 12.5 hours at room temperature and no starting material could be observed by TLC. The reaction mixture was filtered through celite, and the filtrate concentrated in vacuo in a high vacuum system at 20°C. The resulting white solid (1.1 g, 85*) was dissolved in MeOH and cooled to 0°C with an ice-water bath. Anhydrous ammonia was bubbled through for 20 min and the solution heated to 60°C for 18 h. TLC revealed a spot corresponding to D4U. The solvents were removed and the resulting white solid was chromatographed on S102 (10* MeOH/CH2C2) to give of 5 g (53*) of the desired product, m.p. 155°C (lit. 154-155°C). 1. (a) F. Barre-S1noussi, J.C. Chermann, R. Rey, M.T. Nugeyre, S. Chamaret, C. Gruest, C. Dauguet, C. Axler-Blin, C. Rouzioux, W. Rozembaum and L. Hontagnier, Science (Washington D.C.) 1983, 220, 868-871.(b) S. Broder, R. C. Gallo, N. Engl. J. Med. 1984, 311, 1292-1297.
(c) S. Broder, R.C. Gallo: Annu. Rev. Immunol. 1985, 3, 321-336. (c) S. Broder, R.C. Gallo: Yes. Fox. Immunol. 1985, 3, 321-336.
2. M. Popovic, M.G. Sarngadharan, E. Read, R.C. Gallo, Science (Washington D.C.) 1984, 224, 497-500. (b) R.C. Gallo, M.G. Sarngadharan, M. Popovic, G.M. Shaw, B. Hahn, F. Wong-Stahl, M. Robert-Guroff, Z. Salahaddian, P.D. Markham, Prog. Allergy 1986, 37, 1-45. 3. M.A. Fischl, D.D. Richman, M.H. Grleco, M.S. Gottlieb, P.A. Volberding, O.L. Laskin, J.M. Leedom, J.E. Groopman, D. Mildvan, R.T. Schooley, G.G. Jackson, D.T. Durack, D. King, New Engl. J. Med., 1987, 317, 185. 4. H. Mitsuya, S. Broder, Proe. Nati. Acad. Sei. USA, 1986, 83, 1911-1915. 5. (a) T.S. Lin, R. Shinazi, M.S. Chen, E. Kinney-Thomas. W.H. Prusoff, Biochem. Pharmacol. 1987, 36, 311. (b) J. Balzarini, R. Pauwels, P. Herdewijn, E. Oe Clercq, D.A. Cooney, G-J. Kang, M. Dalai, D.G. Johns, S. Broder, Biochem. Biophys. Res. Comm. 1986, 140, 735. 6. B.D. Cheson, A.D. Levine, D. Mildvan, L.D. Kaplan, P. Wolfe, A. Rios, J. Groopman, P. Gill., P.A. Volbéderding, B.J. Poiesz, M.S. Gottlieb, H. Holden, D.J. Volsky, S.S. Silver, M.J. Hawkins, J. Amer. Med. Assoc. 1987, 258, 1347. 7. (a) J. Balzarini, H. Mitsuya, E. De Clercq, S. Broder, Int. J. Med., 1986, 37, 451. (b) S.W. Mitchell, D.R. H1cks, J.B. McCormick, Lancet 1984, 11, 1367. 8. (a). P.S. Sarin, Y. Taguchi, D, Sun, A; Thornton, R.C. Gallo, B. Oberg, Biochem. Pharmacol. 1985, 34, 4075. (b) E.G. Sandstrom, J.C. Kaplan, R.E. Byington, M.S. Hirsch, Lancet 1985, i, 480. 2. M. Popovic, M.G. Sarngadharan, E. Read, R.C. Gallo, Science (Washington D.C.) 1984, 224, 497-500. (b) R.C. Gallo, M.G. Sarngadharan, M. Popovic, G.M. Shaw, B. Hahn, F. Wong-Stahl, M. Robert-Guroff, Z. Salahaddian, P.D. Markham, Prog. Allergy 1986, 37, 1-45. 3. M.A. Fischl, D.D. Richman, M.H. Grleco, M.S. Gottlieb, P.A. Volberding, O.L. Laskin, J.M. Leedom, J.E. Groopman, D. Mildvan, R.T. Schooley, G.G. Jackson, D.T. Durack, D. King, New Engl. J. Med., 1987, 317, 185. 4. H. Mitsuya, S. Broder, Proe. Nati. Acad. Pollock. United States, 1986, 83, 1911-1915. 5. (a) T.S. Lin, R. Shinazi, M.S. Chen, E. Kinney-Thomas. W.H. Prusoff, Biochem. Pharmacol. 1987, 36, 311. (b) J. Balzarini, R. Pauwels, P. Herdewijn, E. Oe Clercq, D.A. Cooney, G-J. Kang, M. Dalai, D.G. Johns, S. Broder, Biochem. Biophys. Res. Comm. 1986, 140, 735. 6. B.D. Cheson, A.D. Levine, D. Mildvan, L.D. Kaplan, P. Wolfe, A. Rios, J. Groopman, P. Gill., P.A. Volbéderding, B.J. Poiesz, M.S. Gottlieb, H. Holden, D.J. Volsky, S.S. Silver, M.J. Hawkins, J. Amer. With. Assoc. 1987, 258, 1347. 7. (a) J. Balzarini, H. Mitsuya, E. De Clercq, S. Broder, Int. J. Med., 1986, 37, 451. (b) S.W. Mitchell, D.R. H1cks, J.B. McCormick, Lancet 1984, 11, 1367. 8. (a). p.s. Sarin, Y. Taguchi, D, Sun, A; Thornton, R.C. Gallo, B. Oberg, Biochem. Pharmacol. 1985, 34, 4075. (b) E.G. Sandstrom, J.C. Kaplan, R.E. Byington, M.S. Hirsch, Lancet 1985, i, 480.
9. H.C. Lane, A.S. Fauci, Ann. Intern. Med. 1985, 103, 714. 9. H.C. Lane, A.S. Fauci, Ann. Intern. With. 1985, 103, 714.
10. P. Chandra, P.S. Sarin, Arznrim-Forsch/Drug Res. 1986, 36, 184. 11. A.S. Tyms, E.M. Berrie, T.A. Ryder, R.J. Nash, M.P. Hegarty, D.L. Taylor, M.A. Mobberley, J.M. Davis, E.A. Bell. D.A. Jeffries, D. Taylor-Robinson, L.E. Fellows, Lancet 1987, ii, 1025. 12. V. Faber, A. Newell, A.G. Dalgleish, M. Malkovsky, Lancet 1987, ii, 827. 13. (a) H. Hartmann, G. Hunsmann, F. Eckstein, Lanéit 1987, i, 40. (b) M. Baba, R. Pauwels, J. Balzarini, P. Herdewijn, E. De Clercq, Biochem. Biophys. Res. Comm. 1987, 145, 1080. 14. (a) P. Herdewijn, J. Balazarini, E. De Clercq, R. Pauwels, M. Baba, S. Broder, H. Vanderhaeghe, J. Med. Chem. 1987, 30, 1270. (b) E. Mattes, C. Lehmann, D. Scholz, M. von Janta-Lipinski, K. Gaertner, H.A. Rosenthal, P. Langen, Biochem. Biophys. Res. Comm. 1987, 148, 78. (c) B. Polski, J.M.W. Gold, W.D. Hardy, P.A. Baron, E.E. Zuckermann, T-C. Chou, S.M. Levine, N. Flomenberg, L. Wang, K.A. Watanabe, J.J. Fox, D. Armstrong, 27th ICAAC 1987, Abstract 368, side 161. 15. (a) T.S. Lin, M.S. Chen, Y-S. Gao, I. Ghazzouli, W.H. Prusoff, J. Med. Chem. 1987, 30, 440. (b) T.S. Lin, R.F. Shinazi, W.H. Prusoff, Biochem. Pharmacol. 1987, 17, 2713. (c) M. Baba, R. Pauwels, E. De Clercq, J. Desmyter, M. Vandeputte, Biochem. Biophys. Res. Comm. 1987, 142, 128. (d) J. Balazarini, G-J. Kang, M. Dalai, P. Herdewijn, E. De Clercq, S. Broder, D.G. Johns, Mol. Pharmacol. 1987, 32, 162. (e) Y. Hamamoto, H. Nakashima, T. Matsui, A. Matsuda, T. Ueda, N. Yamamoto, Antimicrob. Agents Chemother. 1987, 31, 907. 16. J. Horwitz, J. Chua, i "Synthetic Procedures in Nucleic Acid Chemistry" (vol. 1), W.W. Zorbach, R.S. Tipson (eds.), Interscience, New York, side 344. 17. J. Horwitz, J. Chua, M.A. Da Rooge, M. Noel, I.L. Klundt, J. Org. Chem. 1966, 31, 205. 10. P. Chandra, P.S. Sarin, Arznrim-Forsch/Drug Res. 1986, 36, 184. 11. A.S. Tyms, E.M. Berrie, T.A. Ryder, R.J. Nash, M.P. Hegarty, D.L. Taylor, M.A. Mobberley, J.M. Davis, E.A. Bell. THEN. Jeffries, D. Taylor-Robinson, L.E. Fellows, Lancet 1987, ii, 1025. 12. V. Faber, A. Newell, A.G. Dalgleish, M. Malkovsky, Lancet 1987, ii, 827. 13. (a) H. Hartmann, G. Hunsmann, F. Eckstein, Lanéit 1987, i, 40. (b) M. Baba, R. Pauwels, J. Balzarini, P. Herdewijn, E. De Clercq, Biochem. Biophys. Res. Comm. 1987, 145, 1080. 14. (a) P. Herdewijn, J. Balazarini, E. De Clercq, R. Pauwels, M. Baba, S. Broder, H. Vanderhaeghe, J. Med. Chem. 1987, 30, 1270. (b) E. Mattes, C. Lehmann, D. Scholz, M. von Janta-Lipinski, K. Gaertner, H.A. Rosenthal, P. Langen, Biochem. Biophys. Res. Comm. 1987, 148, 78. (c) B. Polski, J.M.W. Gold, W.D. Hardy, P.A. Baron, E.E. Zuckermann, T-C. Chou, S.M. Levine, N. Flomenberg, L. Wang, K.A. Watanabe, J.J. Fox, D. Armstrong, 27th ICAAC 1987, Abstract 368, page 161. 15. (a) T.S. Lin, M.S. Chen, Y-S. Gao, I. Ghazzouli, W.H. Prusoff, J. Med. Chem. 1987, 30, 440. (b) T.S. Lin, R.F. Shinazi, W.H. Prusoff, Biochem. Pharmacol. 1987, 17, 2713. (c) M. Baba, R. Pauwels, E. De Clercq, J. Desmyter, M. Vandeputte, Biochem. Biophys. Res. Comm. 1987, 142, 128. (d) J. Balazarini, G-J. Kang, M. Dalai, P. Herdewijn, E. De Clercq, S. Broder, D.G. Johns, Mol. Pharmacol. 1987, 32, 162. (e) Y. Hamamoto, H. Nakashima, T. Matsui, A. Matsuda, T. Ueda, N. Yamamoto, Antimicrob. Agents Chemother. 1987, 31, 907. 16. J. Horwitz, J. Chua, in "Synthetic Procedures in Nucleic Acid Chemistry" (vol. 1), W.W. Zorbach, R.S. Tipson (eds.), Interscience, New York, page 344. 17. J. Horwitz, J. Chua, M.A. Da Rooge, M. Noel, I.L. Klundt, J. Org. Chem. 1966, 31, 205.
18. J.J. Fox, N.C. Miller, J. Org. Chem. 1963, 28, 936. 18. J.J. Fox, N.C. Miller, J. Org. Chem. 1963, 28, 936.
19. 6. Kowollik, K. Gaertner, P. Langen, Tetrahedron Lett., 1969, nr. 44, 3863. 20. R.P. Glinski, M.S. Khan, R.L. Kal arnas, M.B. Sporn, J. Org. Chem., 1973, 38, 4299. 21. V.J. Davisson, D.R. Davis, V.M. Dixit, CD. Poulter, J. Org. Chem., 1987, 52, 1794. 22. B.E. Griffin, J. Jarman, C.B. Reese, J. Sulston, Tetrahedron, 1967, 23, 230. 19. 6. Kowollik, K. Gaertner, P. Langen, Tetrahedron Lett., 1969, No. 44, 3863. 20. R.P. Glinski, M.S. Khan, R.L. Kal arnas, M.B. Spurn, J. Org. Chem., 1973, 38, 4299. 21. V.J. Davison, D.R. Davis, V.M. Dixit, CD. Poulter, J. Org. Chem., 1987, 52, 1794. 22. B.E. Griffin, J. Jarman, C.B. Reese, J. Sulston, Tetrahedron, 1967, 23, 230.
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Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO913459A NO171316C (en) | 1988-03-24 | 1991-09-03 | PROCEDURE FOR THE PREPARATION OF 2 ', 3'-DIDEOXY-2', 3'-DIDEHYDRONUCLEOSIDES R |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/173,473 US4904770A (en) | 1988-03-24 | 1988-03-24 | Production of 2',3'-dideoxy-2',3'-didehydronucleosides |
| NO891208A NO171367C (en) | 1988-03-24 | 1989-03-20 | PROCEDURE FOR THE PREPARATION OF 2 ', 3'-DIDEOXY-2', 3'-DIDEHYDRONUCLEOSIDES |
| NO913459A NO171316C (en) | 1988-03-24 | 1991-09-03 | PROCEDURE FOR THE PREPARATION OF 2 ', 3'-DIDEOXY-2', 3'-DIDEHYDRONUCLEOSIDES R |
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| Publication Number | Publication Date |
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| NO913459L NO913459L (en) | 1989-09-25 |
| NO913459D0 NO913459D0 (en) | 1991-09-03 |
| NO171316B true NO171316B (en) | 1992-11-16 |
| NO171316C NO171316C (en) | 1993-02-24 |
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| NO913459L (en) | 1989-09-25 |
| NO913459D0 (en) | 1991-09-03 |
| NO171316C (en) | 1993-02-24 |
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