US3541079A - Process for the manufacture of nucleosides - Google Patents
Process for the manufacture of nucleosides Download PDFInfo
- Publication number
- US3541079A US3541079A US738858A US3541079DA US3541079A US 3541079 A US3541079 A US 3541079A US 738858 A US738858 A US 738858A US 3541079D A US3541079D A US 3541079DA US 3541079 A US3541079 A US 3541079A
- Authority
- US
- United States
- Prior art keywords
- fractions
- sugar
- solution
- adenosine
- acid
- 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.)
- Expired - Lifetime
Links
- 238000000034 method Methods 0.000 title description 11
- 230000008569 process Effects 0.000 title description 10
- 239000002777 nucleoside Substances 0.000 title description 9
- 238000004519 manufacturing process Methods 0.000 title description 6
- 125000003835 nucleoside group Chemical group 0.000 title description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
- 235000000346 sugar Nutrition 0.000 description 18
- 229920000137 polyphosphoric acid Polymers 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- -1 phenyl ester Chemical class 0.000 description 12
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 11
- 229960005305 adenosine Drugs 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229960000643 adenine Drugs 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 229920000388 Polyphosphate Polymers 0.000 description 4
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 4
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 4
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 150000007523 nucleic acids Chemical class 0.000 description 4
- 102000039446 nucleic acids Human genes 0.000 description 4
- 108020004707 nucleic acids Proteins 0.000 description 4
- 230000000269 nucleophilic effect Effects 0.000 description 4
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 4
- 239000001205 polyphosphate Substances 0.000 description 4
- 235000011176 polyphosphates Nutrition 0.000 description 4
- XZZNDPSIHUTMOC-UHFFFAOYSA-N triphenyl phosphate Chemical compound C=1C=CC=CC=1OP(OC=1C=CC=CC=1)(=O)OC1=CC=CC=C1 XZZNDPSIHUTMOC-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229930024421 Adenine Natural products 0.000 description 3
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 150000001973 desoxyriboses Chemical class 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 150000003833 nucleoside derivatives Chemical class 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 3
- XFBOJHLYDJZYSP-UHFFFAOYSA-N 2,8-dioxoadenine Chemical compound N1C(=O)N=C2NC(=O)NC2=C1N XFBOJHLYDJZYSP-UHFFFAOYSA-N 0.000 description 2
- OIVLITBTBDPEFK-UHFFFAOYSA-N 5,6-dihydrouracil Chemical compound O=C1CCNC(=O)N1 OIVLITBTBDPEFK-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
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- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 2
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
- BVIAOQMSVZHOJM-UHFFFAOYSA-N N(6),N(6)-dimethyladenine Chemical compound CN(C)C1=NC=NC2=C1N=CN2 BVIAOQMSVZHOJM-UHFFFAOYSA-N 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 239000000824 cytostatic agent Substances 0.000 description 2
- 230000001085 cytostatic effect Effects 0.000 description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- DRAVOWXCEBXPTN-UHFFFAOYSA-N isoguanine Chemical compound NC1=NC(=O)NC2=C1NC=N2 DRAVOWXCEBXPTN-UHFFFAOYSA-N 0.000 description 2
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 description 2
- 238000004816 paper chromatography Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
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- 238000001953 recrystallisation Methods 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
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- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- RGKLWAHLGYLIKT-UHFFFAOYSA-N 2,3-dihydrotriazolo[4,5-d]pyrimidine-7-thione Chemical compound S=C1N=CN=C2NNN=C12 RGKLWAHLGYLIKT-UHFFFAOYSA-N 0.000 description 1
- REZCUNDZKVUACL-UHFFFAOYSA-N 2,4-diethoxypyrimidine Chemical compound CCOC1=CC=NC(OCC)=N1 REZCUNDZKVUACL-UHFFFAOYSA-N 0.000 description 1
- MWBWWFOAEOYUST-UHFFFAOYSA-N 2-aminopurine Chemical compound NC1=NC=C2N=CNC2=N1 MWBWWFOAEOYUST-UHFFFAOYSA-N 0.000 description 1
- PDWIQYODPROSQH-PYHARJCCSA-N 2-deoxy-D-ribofuranose Chemical compound OC[C@H]1OC(O)C[C@@H]1O PDWIQYODPROSQH-PYHARJCCSA-N 0.000 description 1
- RQAQLPFCVVKMSH-UHFFFAOYSA-N 3-methyl-1,2,4-triazine Chemical compound CC1=NC=CN=N1 RQAQLPFCVVKMSH-UHFFFAOYSA-N 0.000 description 1
- OTLNPYWUJOZPPA-UHFFFAOYSA-N 4-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-N 0.000 description 1
- LXHOFEUVCQUXRZ-RRKCRQDMSA-N 6-azathymidine Chemical compound O=C1NC(=O)C(C)=NN1[C@@H]1O[C@H](CO)[C@@H](O)C1 LXHOFEUVCQUXRZ-RRKCRQDMSA-N 0.000 description 1
- CKOMXBHMKXXTNW-UHFFFAOYSA-N 6-methyladenine Chemical compound CNC1=NC=NC2=C1N=CN2 CKOMXBHMKXXTNW-UHFFFAOYSA-N 0.000 description 1
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- 229960005508 8-azaguanine Drugs 0.000 description 1
- MSSXOMSJDRHRMC-UHFFFAOYSA-N 9H-purine-2,6-diamine Chemical compound NC1=NC(N)=C2NC=NC2=N1 MSSXOMSJDRHRMC-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
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- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
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- 235000010233 benzoic acid Nutrition 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 1
- MPQBLCRFUYGBHE-JRTVQGFMSA-N digitalose Chemical compound O=C[C@H](O)[C@@H](OC)[C@@H](O)[C@@H](C)O MPQBLCRFUYGBHE-JRTVQGFMSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- DLRVVLDZNNYCBX-CQUJWQHSSA-N gentiobiose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)C(O)O1 DLRVVLDZNNYCBX-CQUJWQHSSA-N 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 150000002337 glycosamines Chemical class 0.000 description 1
- 150000002386 heptoses Chemical class 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 150000002402 hexoses Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000002454 idoses Chemical class 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 150000002584 ketoses Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 150000002700 mannoheptoses Chemical class 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000002763 monocarboxylic acids Chemical class 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 229960005010 orotic acid Drugs 0.000 description 1
- 150000002972 pentoses Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- BNZYRKVSCLSXSJ-IOSLPCCCSA-N psicofuranin Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@]1(CO)O[C@H](CO)[C@@H](O)[C@H]1O BNZYRKVSCLSXSJ-IOSLPCCCSA-N 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 150000003216 pyrazines Chemical class 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 235000021309 simple sugar Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- GBPFVXUOVFWJRW-UHFFFAOYSA-N sulfuric acid;2h-triazolo[4,5-d]pyrimidine-5,7-diamine Chemical compound OS(O)(=O)=O.N1=C(N)N=C(N)C2=NNN=C21.N1=C(N)N=C(N)C2=NNN=C21 GBPFVXUOVFWJRW-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003538 tetroses Chemical class 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 150000003641 trioses Chemical class 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 229960003636 vidarabine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/098—Esters of polyphosphoric acids or anhydrides
Definitions
- nucleosides can be obtained by heating sugar with a nitrogen base in the presence of polyphosphoric acid ethyl ester (see German patent specification No. 1,206,907).
- this process has the disadvantage that it is ditficult to reproduce and does not always give satisfactory results.
- the nitrogen base contains free amino-groups, an undesired alkylation can take place.
- the present invention is based on the observation that nucleosides are obtained in a simple manner and in good yield by reacting a sugar or a sugar derivative containing a free carbonyl function with a heterocyclic nitrogen base containing at least one nucleophilic nitrogen atom in the ring in an inert solvent and in the presence of polyphosphoric acid phenyl ester, of which the phenyl residue may contain lower alkyl groups or halogen atoms.
- aldoses such as trioses, tetroses, pentoses, hexoses and heptoses, and also the corresponding ketoses.
- aldoses such as trioses, tetroses, pentoses, hexoses and heptoses, and also the corresponding ketoses.
- derivatives containing a free carbonyl group can be employed. These include: desoxy-sugars, for example, rhamnose, digitalose, fucose and .desoxy-ribose; acylated amino-sugars, for example, N-acetyl-glucose-amine, N-acetyl-glactosamine and N- acetyl-mannosarnine; oligosaccharides, such as lactose, gentiobiose, melibose and maltose; and monocarboxylic acids of sugars, for example glucuronic acid and galacturonic acid, in the form of esters with alcohols such as methanol, ethanol, propanol, butanol and benzyl alcohol.
- desoxy-sugars for example, rhamnose, digitalose, fucose and .desoxy-ribose
- acylated amino-sugars for example, N
- sugar derivatives in which one or more hydroxyl groups are etherified, especially by methyl groups, or are esterified', for example, with acetic acid, benzoic acid or para-nitrobenzoic acid can also be used as starting materials.
- those apurinic acid formed by splitting off the purine residues from nucleic acids in a weakly acid solution and liberating the aldehyde function of the ribose or desoxyribose without impairing the degree of polymerisation of the nucleic acids may also be used as sugar components.
- N-containing heterocycles having at least one nucleophilic nitrogen atom (an N-atom capable of being substituted by nucleophilic reagents) in the ring.
- derivatives of ice pyrimidine such as uracil, dihydro-uracil and 2,4-di ethoxypyrimidine, cytosine, thymine, orotic acid, and also barbituric acid and other cyclic ureides and those derived from imidazole, such as purine, 2-aminopurine, 6-methylaminopurine, 6-dimethylaminopurine, Z-methyl-adenine, 2,6-diaminopurine, hypoxanthine, isoguanine, 2,8-dihydroxy-adenine, mercaptopurine, 6-mercapto 2 amino purine, theophylline, Z-aZa-adenine, 8-aza-adenine, 8-aza- 6-mercaptopur
- polyphosphoric acid phenyl esters are especially suitable. Those esters that are derived from PPP by replacing one or more of the hydrogen atoms in the phenyl residues by lower alkyl groups or halogen atoms may also be used. There may be mentioned, for example, tri-para-chlorophenyl polyphosphate and tri-para-tolyl polyphosphate.
- the polyphosphoric acid phenyl esters used as condensing agents are obtained by heating phosphorus pentoxide with triphenyl phosphate or a tri-alkylphenyl or tri-halogenphenyl phosphate at a temperature above about 200 C.
- the duration of the reaction depends on the temperature. Thus, at 200 C. the reaction terminates after about 15 to 40 hours and at 300 C. it terminates after 2 to 5 hours. It is not essential to use the components in molar ratio.
- triphenyl phosphate is used in an excess of up to 2.5 to 1.
- the reaction products are at room temperature, depending on the relative proportions, clear, vitreous to highly viscous masses, which can, however, be easily handled at 50 C. They dissolve very well in chloroform, dimethyl-formamide, dimethyl sulphoxide and dioxane, but are sparingly soluble in ether, petroleum ether, benzene and water.
- the syntheses of the nucleosides can be carried out in two ways. Either the sugar is first phosphorylated and reacts subsequently with the base, or the base is first phosphorylated and then reacts with the sugar. The latter method is preferred.
- the process of the invention is advantageously carried out by reacting the nitrogen base in an inert solvent with the polyphosphoric acid ester and a few drops of acid, then adding the solution of the sugar, evaporating the solvent, and heating the homo geneous reaction mixture that remains behind. As the yields are higher the larger the quantity of base used. About 1.5 to 20 parts of the base will generally be used for each 1 part of the sugar. It is indeed possible to carry out the reactions with molar proportions of sugar and base, but then some of the sugar used is lost due to side reactions. The excess of the base can be increased beyond the proportion mentioned above, for example, up
- solvents for use in the process those in which the sugar and the base dissolve well, and which do not themselves react with the reactants, are suitable.
- the products of the process are advantageously isolated by dissolving the reaction mixture in water and neutralising the solution. Unconsumed polyphosphoric acid ester remains behind undissolved and can be removed by filtration.
- the nucleoside can be recovered from the aqueous solution by column chromatography on Dowex formate and elution with ammonium formate solution or by simple concentration.
- PPP or the aforesaid substituted PPP, instead of polyphosphoric acid ethyl ester has the advantage that no alkylation of the reaction product is to be feared. Furthermore, the PPPs can be much more easily prepared and are considerably more stable, so that the manufacture of the nucleoside is simplified, the yields are improved and the formation of decomposition products is suppressed.
- adenosine serves as a circulatory agent
- psicofuranine and also arabinosyladenine and arabinosylcytosine S.S. Cohen, Progr. Nucleic Acid Research 5, 1 (1966)
- cytostatics S.S. Cohen, Progr. Nucleic Acid Research 5, 1 (1966)
- 2-(2'-desoxy-D- ribofuranosyl) 6 methyl-asym-triazine 3,5 (2,4) dione (Azathymidine, I. Am. Chem. Soc. vol. 80 (1958), p. 1138) acts as an inhibitor of the DNA-synthesis.
- nucleic acids obtainable by the use of apurinic acids in the process of the invention exhibit a considerable influence on the cell metabolism and can be used as cytostatics, for example, as inhibitors of bacteria, or for the transformation of organisms, for exam le, for the production of virus mutants.
- EXAMPLE 1 Preparation of polyphosphoric acid phenyl ester 44.93 grams of phosphorus pentoxide (0.158 mol) were introduced into 131.5 grams (0.404 mol) of molten triphenyl phosphate (melting point 49 C.), and stirred well at room temperature until the initial suspension had become a stiff mass and the evolution of heat had subsided. The flask was then heated in a domed heating chamber at 300 C. After about 2.5 hours all the phosphorus pentoxide had dissolved and a homogeneous product was obtained. The latter was then stirred for a further minutes at 300 C.
- EXAMPLE 2 aand ⁇ 3-9-D-ribofuranosyl-adenine 5 grams of adenine (37 mmol) were dissolved in 500 ml. freshly distilled dimethyl-formamide to which 3 ml. of concentrated hydrochloric acid had been added. The pH-value of the solution as measured with a glass electrode was less than 1. After the addition of 16 grams of polyphosphoric acid phenyl ester the mixture was heated at 50 C. for 5 minutes. Then 1 gram of ribose (7.4 mmol) in 250 ml. of dimethyl-formamide were added and the solvent was distilled off in a rotary evaporator under reduced pressure at 100 C. A yellow rubber-like residue remained behind.
- the residue was heated for 2 to 3 minutes at 98 C. and, after being cooled, was dissolved in 25 ml. of water. the pH-value being adjusted to 7 by means of a 2 N-solution of sodium hydroxide.
- the solution was inserted in a cooling cabinet, and after a short time a precipitate consisting of adenine and phenyl polyphosphate separated out and was filtered otf.
- the filtrate was concentrated, and adjusted to a pH-value of 11 by means of an ammonia solution of 25 percent strength.
- a column x 3.6 cm.) filled with Dowex-lXlO-formate which had been equilibrated with a 0.01 molar solution of ammonium formate was used.
- the filtrate was fed to the column and elution was carried out at a pH-value of 10.2 with a 0.01 molar solution of ammonium formate.
- the eluate was collected in fractions of 20 ml. and in each fraction the ultra-violet absorption was determined.
- the fractions 41 to 65 contained principally oc-EldCIlOSlI'lC and fractions 66 to 103 contained principally fl-adenosine.
- EXAMPLE 3 aand 3-9-D-desoxyribofuranosyl-adenine 500 m. (3.7 mmols) of adenine were dissolved in ml. of dimethyl-formamide to which 0.3 ml. of concentrated hydrochloric acid had been added. After the addition of 1.3 grams of polyphosphoric acid phenyl ester the mixture was heated for five minutes at 50 C. Then 0.1 gram of 2-desoxyribose (0.67 mmol) in 50 ml. of dimethyl-formamide was added, and the pH-value was adjusted to 2 to 2.5 by the addition of about 0.33 ml. of triethylamine.
- the solvent was distilled off under reduced pressure in a rotary evaporator at a bath temperature of 50 C., and the slightly yellowish residue was heated for a further 10 minutes at 50 C. It was then dissolved in 5 ml. of water, and the solution was neutralised with a 2 N-solution of sodium hydroxide. During cooling in a cooling cabinet, unconsumed phenyl polyphosphate precipitated out in a short time, and the precipitate was removed by filtration. The filtrate was adjusted to a pH- value of 10.5 by means of a solution of ammonia of 25 percent strength.
- Fractions 11 to 60 contained a mixture of aand B-desoxyadenosine as determined by paper chromatography in a mixture of butanol and water.
- the mixture of the anomers was concentrated to a volume of 3 to 5 ml. and chromatographed over a column of Dowex-lXZ-OH with the use of methanol of 30 percent strength as elution medium.
- the eluate was collected in 20 ml. fractions. Pure 0cdesoxyadenosine appeared in fractions 46 to 60.
- the residue was dissolved in a small quantity of methanol, precipitated with ethyl ether, and then recrystallised from methanol.
- the product melted at 209 to 211 C., and had a specific rotation [11] of 71 (in water).
- the total yield of uand fi-desoxy-adenosine amounted to 35 to 40 percent, calculated on desoxyribose.
- the quantity of u-desoxy-adenosine was somewhat greater than that of fi-desoxyadenosine.
- nucleosides by reaction of a sugar or sugar derivative having a free carbonyl group with an N-heterocyclic base having at least one nucleophilic nitrogen atom as the heterocyclic atom in the ring, in the presence of a polyphosphoric acid ester, the improvement wherein said polyphosphoric acid ester is a polyphosphoric acid phenyl ester or a polyphosphoric acid phenyl ester in which the phenyl groups are substituted with lower alkyl groups or halogen atoms, said esters being prepared by heating triphenyl phosphate, a tri-lower alkyl phenyl phosphate, or a tri-halophenyl phosphate, respectively, with phosphorus pentoxide at a temperature above about 200 C.
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- Organic Chemistry (AREA)
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- Life Sciences & Earth Sciences (AREA)
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Description
United States Patent US. Cl. 260-2115 1 Claim ABSTRACT OF THE DISCLOSURE A process of manufacture of nucleosides by reacting a sugar or a sugar derivative having a free carbonyl func tion with a heterocyclic base containing at least one nucleophilic nitrogen atom in the ring in the presence of polyphosphoric acid phenyl ester.
It is known that nucleosides can be obtained by heating sugar with a nitrogen base in the presence of polyphosphoric acid ethyl ester (see German patent specification No. 1,206,907). However this process has the disadvantage that it is ditficult to reproduce and does not always give satisfactory results. Moreover, when the nitrogen base contains free amino-groups, an undesired alkylation can take place.
The present invention is based on the observation that nucleosides are obtained in a simple manner and in good yield by reacting a sugar or a sugar derivative containing a free carbonyl function with a heterocyclic nitrogen base containing at least one nucleophilic nitrogen atom in the ring in an inert solvent and in the presence of polyphosphoric acid phenyl ester, of which the phenyl residue may contain lower alkyl groups or halogen atoms.
As sugars for use in the process of the invention, aldoses, such as trioses, tetroses, pentoses, hexoses and heptoses, and also the corresponding ketoses, are suitable. There may be mentioned, for example, arbinose, ribose, xylose, lyxose, fructose, glucose, allose, altrose, gulose, talose, mannose, idose, psicose, sorbose, galactose, mannoheptose, galaheptulose, erythrose and threose.
Apart from these simple sugars, derivatives containing a free carbonyl group can be employed. These include: desoxy-sugars, for example, rhamnose, digitalose, fucose and .desoxy-ribose; acylated amino-sugars, for example, N-acetyl-glucose-amine, N-acetyl-glactosamine and N- acetyl-mannosarnine; oligosaccharides, such as lactose, gentiobiose, melibose and maltose; and monocarboxylic acids of sugars, for example glucuronic acid and galacturonic acid, in the form of esters with alcohols such as methanol, ethanol, propanol, butanol and benzyl alcohol. Those sugar derivatives in which one or more hydroxyl groups are etherified, especially by methyl groups, or are esterified', for example, with acetic acid, benzoic acid or para-nitrobenzoic acid, can also be used as starting materials. In particular it must be mentioned that those apurinic acid formed by splitting off the purine residues from nucleic acids in a weakly acid solution and liberating the aldehyde function of the ribose or desoxyribose without impairing the degree of polymerisation of the nucleic acids [cf. J. Biol. Chem. 195, 49 1952)] may also be used as sugar components.
As the second reaction component there comes into consideration N-containing heterocycles having at least one nucleophilic nitrogen atom (an N-atom capable of being substituted by nucleophilic reagents) in the ring. As examples there may be mentioned derivatives of ice pyrimidine, such as uracil, dihydro-uracil and 2,4-di ethoxypyrimidine, cytosine, thymine, orotic acid, and also barbituric acid and other cyclic ureides and those derived from imidazole, such as purine, 2-aminopurine, 6-methylaminopurine, 6-dimethylaminopurine, Z-methyl-adenine, 2,6-diaminopurine, hypoxanthine, isoguanine, 2,8-dihydroxy-adenine, mercaptopurine, 6-mercapto 2 amino purine, theophylline, Z-aZa-adenine, 8-aza-adenine, 8-aza- 6-mercaptopurine, 8-aza-guanine, 'S-aZa-isoguanine, S-azahypoxanthine, 8-aZa-2,6-diaminopurine, desaza-adenine, and guanine. Derivatives of pyrazole or of triazole, and also derivatives of pyrazine, for example, the piperidines, may also be mentioned.
As condensing agents, polyphosphoric acid phenyl esters (PPP) are especially suitable. Those esters that are derived from PPP by replacing one or more of the hydrogen atoms in the phenyl residues by lower alkyl groups or halogen atoms may also be used. There may be mentioned, for example, tri-para-chlorophenyl polyphosphate and tri-para-tolyl polyphosphate.
The polyphosphoric acid phenyl esters used as condensing agents are obtained by heating phosphorus pentoxide with triphenyl phosphate or a tri-alkylphenyl or tri-halogenphenyl phosphate at a temperature above about 200 C. The duration of the reaction depends on the temperature. Thus, at 200 C. the reaction terminates after about 15 to 40 hours and at 300 C. it terminates after 2 to 5 hours. It is not essential to use the components in molar ratio. Advantageously, triphenyl phosphate is used in an excess of up to 2.5 to 1. The reaction products are at room temperature, depending on the relative proportions, clear, vitreous to highly viscous masses, which can, however, be easily handled at 50 C. They dissolve very well in chloroform, dimethyl-formamide, dimethyl sulphoxide and dioxane, but are sparingly soluble in ether, petroleum ether, benzene and water.
The probable course of the reaction is illustrated below by way of example in the preparation of adenosine.
IITH HO O CHzOH The syntheses of the nucleosides can be carried out in two ways. Either the sugar is first phosphorylated and reacts subsequently with the base, or the base is first phosphorylated and then reacts with the sugar. The latter method is preferred. The process of the invention is advantageously carried out by reacting the nitrogen base in an inert solvent with the polyphosphoric acid ester and a few drops of acid, then adding the solution of the sugar, evaporating the solvent, and heating the homo geneous reaction mixture that remains behind. As the yields are higher the larger the quantity of base used. About 1.5 to 20 parts of the base will generally be used for each 1 part of the sugar. It is indeed possible to carry out the reactions with molar proportions of sugar and base, but then some of the sugar used is lost due to side reactions. The excess of the base can be increased beyond the proportion mentioned above, for example, up
CHzOH to 100 times, without resulting in any substantial improvement in the yield. The temperatures and hydrogen ion concentrations to be chosen naturally depend on the properties and reactivities of the reactants. It is preferable to work at temperatures within the range of about 50 C. to 100 C. and at a pH-value (measured in dimethyl-formamide) ranging from 0.5 to 3.
As solvents for use in the process, those in which the sugar and the base dissolve well, and which do not themselves react with the reactants, are suitable. As solvents there may be mentioned, more especially, esters and alkylamides of various acids, for example, diethyl phosphite, phosphoric acid tris-dimethylamide, dimethyl sulphoxide, formamide or, more particularly dimethyl-forrnamide. The presence of small amounts of water is not harmful.
The products of the process are advantageously isolated by dissolving the reaction mixture in water and neutralising the solution. Unconsumed polyphosphoric acid ester remains behind undissolved and can be removed by filtration. The nucleoside can be recovered from the aqueous solution by column chromatography on Dowex formate and elution with ammonium formate solution or by simple concentration.
The use of PPP or the aforesaid substituted PPP, instead of polyphosphoric acid ethyl ester has the advantage that no alkylation of the reaction product is to be feared. Furthermore, the PPPs can be much more easily prepared and are considerably more stable, so that the manufacture of the nucleoside is simplified, the yields are improved and the formation of decomposition products is suppressed.
Owing to their pharmaco-dynamic action, the products of the process can be used as medicaments or as intermediate products for the manufacture of pharmaceutical products. Thus, for example, adenosine serves as a circulatory agent, psicofuranine and also arabinosyladenine and arabinosylcytosine (S.S. Cohen, Progr. Nucleic Acid Research 5, 1 (1966)) as cytostatics, and 2-(2'-desoxy-D- ribofuranosyl) 6 methyl-asym-triazine 3,5 (2,4) dione (Azathymidine, I. Am. Chem. Soc. vol. 80 (1958), p. 1138) acts as an inhibitor of the DNA-synthesis. The nucleic acids obtainable by the use of apurinic acids in the process of the invention exhibit a considerable influence on the cell metabolism and can be used as cytostatics, for example, as inhibitors of bacteria, or for the transformation of organisms, for exam le, for the production of virus mutants.
The following examples illustrate the invention, but they are not intended to limit it thereto:
EXAMPLE 1 Preparation of polyphosphoric acid phenyl ester 44.93 grams of phosphorus pentoxide (0.158 mol) were introduced into 131.5 grams (0.404 mol) of molten triphenyl phosphate (melting point 49 C.), and stirred well at room temperature until the initial suspension had become a stiff mass and the evolution of heat had subsided. The flask was then heated in a domed heating chamber at 300 C. After about 2.5 hours all the phosphorus pentoxide had dissolved and a homogeneous product was obtained. The latter was then stirred for a further minutes at 300 C.
EXAMPLE 2 aand {3-9-D-ribofuranosyl-adenine 5 grams of adenine (37 mmol) were dissolved in 500 ml. freshly distilled dimethyl-formamide to which 3 ml. of concentrated hydrochloric acid had been added. The pH-value of the solution as measured with a glass electrode was less than 1. After the addition of 16 grams of polyphosphoric acid phenyl ester the mixture was heated at 50 C. for 5 minutes. Then 1 gram of ribose (7.4 mmol) in 250 ml. of dimethyl-formamide were added and the solvent was distilled off in a rotary evaporator under reduced pressure at 100 C. A yellow rubber-like residue remained behind. The residue was heated for 2 to 3 minutes at 98 C. and, after being cooled, was dissolved in 25 ml. of water. the pH-value being adjusted to 7 by means of a 2 N-solution of sodium hydroxide. The solution was inserted in a cooling cabinet, and after a short time a precipitate consisting of adenine and phenyl polyphosphate separated out and was filtered otf. The filtrate was concentrated, and adjusted to a pH-value of 11 by means of an ammonia solution of 25 percent strength. In order to isolate the nucleoside fraction, a column x 3.6 cm.) filled with Dowex-lXlO-formate which had been equilibrated with a 0.01 molar solution of ammonium formate was used. The filtrate was fed to the column and elution was carried out at a pH-value of 10.2 with a 0.01 molar solution of ammonium formate. The eluate was collected in fractions of 20 ml. and in each fraction the ultra-violet absorption was determined. The fractions 41 to 65 contained principally oc-EldCIlOSlI'lC and fractions 66 to 103 contained principally fl-adenosine.
For further purification the two main fractions were again chromatographed on a column of Dowex-lXZ-OH (50 x 3.6 cm.) with the use of methanol of strength as elution agent. The fractions 66 to 153 from the Dowex formate column, which contained mainly fi-adenosine, were concentrated by evaporation and chromatographed in the manner described above. Fractions 78 to 100 contained the residual a-adenosine, and the fi-adenosine appeared in fractions 165 to 220. The latter fractions were concentrated by evaporation, and the dry residue was dissolved in methanol. The fl-adenosine crystallised out from the concentrated solution. After repeated recrystallisation from methanol the compound melted at 234 to 235 C. It had the specific rotation [m] 61.6. These data agree with the values given in the literature. In order to purify the wadenosine, fractions 41 to from the Dowex formate column were chromatographed on Dowex-1X2-OH, and the eluate was collected in 20 ml. fractions. The course of the chromatography was followed by paper chromatography and ultra-violet spectroscopy. Pure 1xadenosine appeared in the vicinity of fraction 80, and pure fl-adenosine followed later. The fractions containing a-adenosine were collected and concentrated by evaporation. The residue was dissolved in methanol and the solution was concentrated to a volume of 1 to 2 ml. By the addition of about 10 ml. of ethyl ether the a-adenosine was precipitated in a crystalline form. After recrystallisation from a mixture of methanol and ethyl ether, it melted at 201 to 202 C. and had the specific rotation [a] 29.5 (in water).
aand B-adenosine were obtained in approximately equal quantities. The total yield of the two anomers amounted to 18 to 20% calculated on ribose.
EXAMPLE 3 aand 3-9-D-desoxyribofuranosyl-adenine 500 m. (3.7 mmols) of adenine were dissolved in ml. of dimethyl-formamide to which 0.3 ml. of concentrated hydrochloric acid had been added. After the addition of 1.3 grams of polyphosphoric acid phenyl ester the mixture was heated for five minutes at 50 C. Then 0.1 gram of 2-desoxyribose (0.67 mmol) in 50 ml. of dimethyl-formamide was added, and the pH-value was adjusted to 2 to 2.5 by the addition of about 0.33 ml. of triethylamine. The solvent was distilled off under reduced pressure in a rotary evaporator at a bath temperature of 50 C., and the slightly yellowish residue was heated for a further 10 minutes at 50 C. It was then dissolved in 5 ml. of water, and the solution was neutralised with a 2 N-solution of sodium hydroxide. During cooling in a cooling cabinet, unconsumed phenyl polyphosphate precipitated out in a short time, and the precipitate was removed by filtration. The filtrate was adjusted to a pH- value of 10.5 by means of a solution of ammonia of 25 percent strength. The solution was chromatographed at a pH-value of 9.6 on a column of Dowex-1X10 formate (28 x 2.6 cm.), and the eluate was collected in 15 ml. fractions. Fractions 11 to 60 contained a mixture of aand B-desoxyadenosine as determined by paper chromatography in a mixture of butanol and water.
For further purification, the mixture of the anomers was concentrated to a volume of 3 to 5 ml. and chromatographed over a column of Dowex-lXZ-OH with the use of methanol of 30 percent strength as elution medium. The eluate was collected in 20 ml. fractions. Pure 0cdesoxyadenosine appeared in fractions 46 to 60. After removing the solvent, the residue was dissolved in a small quantity of methanol, precipitated with ethyl ether, and then recrystallised from methanol. The product melted at 209 to 211 C., and had a specific rotation [11] of 71 (in water).
B-desoxyadenosine appeared in fractions 77 to 90. After evaporating the solvent, the residue was recrystallised from 1.5 ml. of water with the addition of a few drops of ammonia. The ,B-desoxy-adenosine so purified melted at 188 to 189 C. and had a specific rotation [oc] of 26.
The total yield of uand fi-desoxy-adenosine amounted to 35 to 40 percent, calculated on desoxyribose. The quantity of u-desoxy-adenosine was somewhat greater than that of fi-desoxyadenosine.
We claim:
1. In a process for the manufacture of nucleosides by reaction of a sugar or sugar derivative having a free carbonyl group with an N-heterocyclic base having at least one nucleophilic nitrogen atom as the heterocyclic atom in the ring, in the presence of a polyphosphoric acid ester, the improvement wherein said polyphosphoric acid ester is a polyphosphoric acid phenyl ester or a polyphosphoric acid phenyl ester in which the phenyl groups are substituted with lower alkyl groups or halogen atoms, said esters being prepared by heating triphenyl phosphate, a tri-lower alkyl phenyl phosphate, or a tri-halophenyl phosphate, respectively, with phosphorus pentoxide at a temperature above about 200 C.
References Cited UNITED STATES PATENTS 3,278,518 10/1966 Schramm et a1 260-211.5
LEWIS GOTTS, Primary Examiner J. R. BROWN, Assistant Examiner
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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DEF0052795 | 1967-06-24 |
Publications (1)
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US3541079A true US3541079A (en) | 1970-11-17 |
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ID=7105744
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Application Number | Title | Priority Date | Filing Date |
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US738858A Expired - Lifetime US3541079A (en) | 1967-06-24 | 1968-06-21 | Process for the manufacture of nucleosides |
Country Status (7)
Country | Link |
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US (1) | US3541079A (en) |
AT (1) | AT285829B (en) |
BE (1) | BE717054A (en) |
CH (1) | CH491118A (en) |
DE (1) | DE1670884A1 (en) |
FR (1) | FR1569465A (en) |
GB (1) | GB1239449A (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3755295A (en) * | 1969-10-24 | 1973-08-28 | Syntex Corp | 1-(2-amino-2-deoxy-{62 -d-ribofuranosyl) pyrimidines and derivatives thereof |
US4093796A (en) * | 1971-08-13 | 1978-06-06 | Politechnika Gdanska | Antibiotic derivatives of polyene macrolide group and method of obtaining the same |
USRE29835E (en) * | 1971-06-01 | 1978-11-14 | Icn Pharmaceuticals | 1,2,4-Triazole nucleosides |
US5602246A (en) * | 1992-11-25 | 1997-02-11 | Schering Aktiengesellschaft | Process for the preparation of fludarabine or fludarabine phosphate from guanosine |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3278518A (en) * | 1961-05-24 | 1966-10-11 | Hoechst Ag | Process for preparing nucleosides |
-
1967
- 1967-06-24 DE DE19671670884 patent/DE1670884A1/en active Pending
-
1968
- 1968-06-21 AT AT597868A patent/AT285829B/en not_active IP Right Cessation
- 1968-06-21 US US738858A patent/US3541079A/en not_active Expired - Lifetime
- 1968-06-21 CH CH931868A patent/CH491118A/en not_active IP Right Cessation
- 1968-06-24 FR FR1569465D patent/FR1569465A/fr not_active Expired
- 1968-06-24 BE BE717054D patent/BE717054A/xx unknown
- 1968-06-24 GB GB1239449D patent/GB1239449A/en not_active Expired
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3278518A (en) * | 1961-05-24 | 1966-10-11 | Hoechst Ag | Process for preparing nucleosides |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3755295A (en) * | 1969-10-24 | 1973-08-28 | Syntex Corp | 1-(2-amino-2-deoxy-{62 -d-ribofuranosyl) pyrimidines and derivatives thereof |
USRE29835E (en) * | 1971-06-01 | 1978-11-14 | Icn Pharmaceuticals | 1,2,4-Triazole nucleosides |
US4093796A (en) * | 1971-08-13 | 1978-06-06 | Politechnika Gdanska | Antibiotic derivatives of polyene macrolide group and method of obtaining the same |
US5602246A (en) * | 1992-11-25 | 1997-02-11 | Schering Aktiengesellschaft | Process for the preparation of fludarabine or fludarabine phosphate from guanosine |
US5668270A (en) * | 1992-11-25 | 1997-09-16 | Schering Aktiengesellschaft | Process for the preparation of fludarabine or fludarabine phosphate from guanosine |
Also Published As
Publication number | Publication date |
---|---|
AT285829B (en) | 1970-11-10 |
GB1239449A (en) | 1971-07-14 |
CH491118A (en) | 1970-05-31 |
BE717054A (en) | 1968-12-24 |
FR1569465A (en) | 1969-05-30 |
DE1670884A1 (en) | 1971-02-18 |
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