DE3044740C2 - - Google Patents
Info
- Publication number
- DE3044740C2 DE3044740C2 DE3044740A DE3044740A DE3044740C2 DE 3044740 C2 DE3044740 C2 DE 3044740C2 DE 3044740 A DE3044740 A DE 3044740A DE 3044740 A DE3044740 A DE 3044740A DE 3044740 C2 DE3044740 C2 DE 3044740C2
- Authority
- DE
- Germany
- Prior art keywords
- fluorouridine
- chloroform
- group
- mmol
- residue
- 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
Links
- 239000002904 solvent Substances 0.000 claims description 78
- -1 azido fatty acid Chemical class 0.000 claims description 68
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 41
- 150000002148 esters Chemical class 0.000 claims description 39
- 238000002360 preparation method Methods 0.000 claims description 36
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 35
- 229930195729 fatty acid Natural products 0.000 claims description 35
- 239000000194 fatty acid Substances 0.000 claims description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 34
- 238000006243 chemical reaction Methods 0.000 claims description 33
- 150000004665 fatty acids Chemical class 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 33
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 25
- 239000002777 nucleoside Substances 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 24
- 150000001875 compounds Chemical class 0.000 claims description 21
- 238000005886 esterification reaction Methods 0.000 claims description 20
- 150000001413 amino acids Chemical class 0.000 claims description 16
- 230000032050 esterification Effects 0.000 claims description 16
- FHIDNBAQOFJWCA-UAKXSSHOSA-N 5-fluorouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 FHIDNBAQOFJWCA-UAKXSSHOSA-N 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 125000006239 protecting group Chemical group 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 238000006482 condensation reaction Methods 0.000 claims description 9
- 229920006395 saturated elastomer Polymers 0.000 claims description 9
- 239000000010 aprotic solvent Substances 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 230000007062 hydrolysis Effects 0.000 claims description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- 238000009833 condensation Methods 0.000 claims description 6
- 230000005494 condensation Effects 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 150000004671 saturated fatty acids Chemical class 0.000 claims description 5
- 108090000623 proteins and genes Proteins 0.000 claims description 4
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 102000004169 proteins and genes Human genes 0.000 claims description 3
- 150000003512 tertiary amines Chemical class 0.000 claims description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 229910001502 inorganic halide Inorganic materials 0.000 claims description 2
- 244000005700 microbiome Species 0.000 claims description 2
- 150000005622 tetraalkylammonium hydroxides Chemical class 0.000 claims description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 206
- 239000000243 solution Substances 0.000 description 84
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 66
- 239000000203 mixture Substances 0.000 description 61
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 59
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 58
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 53
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 48
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 47
- 239000000741 silica gel Substances 0.000 description 47
- 229910002027 silica gel Inorganic materials 0.000 description 47
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 239000012295 chemical reaction liquid Substances 0.000 description 38
- 239000007864 aqueous solution Substances 0.000 description 36
- 239000000047 product Substances 0.000 description 35
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 33
- 239000002253 acid Substances 0.000 description 32
- 238000004440 column chromatography Methods 0.000 description 28
- 238000000921 elemental analysis Methods 0.000 description 28
- 230000000259 anti-tumor effect Effects 0.000 description 26
- 239000012071 phase Substances 0.000 description 23
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 22
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 21
- 239000011541 reaction mixture Substances 0.000 description 21
- 229910052938 sodium sulfate Inorganic materials 0.000 description 21
- 235000011152 sodium sulphate Nutrition 0.000 description 21
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 17
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 16
- LHTMLCXJMYPWGR-NPDIDSPYSA-N 5-fluoro-1-[(4r,6r)-6-(hydroxymethyl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrimidine-2,4-dione Chemical compound N1([C@@H]2O[C@H](CO)C3OC(OC32)(C)C)C=C(F)C(=O)NC1=O LHTMLCXJMYPWGR-NPDIDSPYSA-N 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 150000007513 acids Chemical class 0.000 description 15
- 125000003835 nucleoside group Chemical group 0.000 description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 125000003277 amino group Chemical group 0.000 description 11
- 239000008346 aqueous phase Substances 0.000 description 11
- 239000007832 Na2SO4 Substances 0.000 description 10
- 125000002252 acyl group Chemical group 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- 238000002329 infrared spectrum Methods 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 229940024606 amino acid Drugs 0.000 description 8
- 235000001014 amino acid Nutrition 0.000 description 8
- MVGLBXWFOSHCCP-UHFFFAOYSA-N chloroform;tetrachloromethane Chemical compound ClC(Cl)Cl.ClC(Cl)(Cl)Cl MVGLBXWFOSHCCP-UHFFFAOYSA-N 0.000 description 8
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical group C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 8
- 238000001819 mass spectrum Methods 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 231100000419 toxicity Toxicity 0.000 description 6
- 230000001988 toxicity Effects 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 239000007795 chemical reaction product Substances 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 231100000053 low toxicity Toxicity 0.000 description 5
- 230000000144 pharmacologic effect Effects 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- FKEFWONOONUTEI-FSNPWBFUSA-N [(2r,3s,4r,5r)-5-(5-fluoro-2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl (2s)-3-methyl-2-(phenylmethoxycarbonylamino)butanoate Chemical compound N([C@@H](C(C)C)C(=O)OC[C@@H]1[C@H]([C@@H](O)[C@@H](O1)N1C(NC(=O)C(F)=C1)=O)O)C(=O)OCC1=CC=CC=C1 FKEFWONOONUTEI-FSNPWBFUSA-N 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- AYJRCSIUFZENHW-UHFFFAOYSA-L barium carbonate Chemical compound [Ba+2].[O-]C([O-])=O AYJRCSIUFZENHW-UHFFFAOYSA-L 0.000 description 4
- 150000007514 bases Chemical class 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
- OEAFZNRGZZNREY-SEFVSHJNSA-N 1-o-benzyl 2-o-[[(2r,3s,4r,5r)-5-(5-fluoro-2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl] (2s)-pyrrolidine-1,2-dicarboxylate Chemical compound C([C@H]1C(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)N2C(NC(=O)C(F)=C2)=O)CCN1C(=O)OCC1=CC=CC=C1 OEAFZNRGZZNREY-SEFVSHJNSA-N 0.000 description 3
- OGNSCSPNOLGXSM-UHFFFAOYSA-N 2,4-diaminobutyric acid Chemical compound NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000006181 N-acylation Effects 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- 239000007868 Raney catalyst Substances 0.000 description 3
- IJEXALGVUIGOKF-DLVXIWMQSA-N [(2R,3S,4R,5R)-5-(5-fluoro-2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl 12-azidododecanoate Chemical compound N(=[N+]=[N-])CCCCCCCCCCCC(=O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N1C(=O)NC(=O)C(=C1)F)O)O IJEXALGVUIGOKF-DLVXIWMQSA-N 0.000 description 3
- FCOTUHRKUGCRDH-VPCXQMTMSA-N [(2R,3S,4R,5R)-5-(5-fluoro-2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl 2-azidoacetate Chemical compound N(=[N+]=[N-])CC(=O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N1C(=O)NC(=O)C(=C1)F)O)O FCOTUHRKUGCRDH-VPCXQMTMSA-N 0.000 description 3
- KYCJQEYMORQHGI-NFSOJESZSA-N [(2R,3S,4R,5R)-5-(5-fluoro-2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl 2-azidobutanoate Chemical compound N(=[N+]=[N-])C(C(=O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N1C(=O)NC(=O)C(=C1)F)O)O)CC KYCJQEYMORQHGI-NFSOJESZSA-N 0.000 description 3
- CGCIUEIMFGFGID-GKXSTHLISA-N [(2R,3S,4R,5R)-5-(5-fluoro-2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl 2-azidodecanoate Chemical compound N(=[N+]=[N-])C(C(=O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N1C(=O)NC(=O)C(=C1)F)O)O)CCCCCCCC CGCIUEIMFGFGID-GKXSTHLISA-N 0.000 description 3
- PYRDPMAEQWXKCO-BOMQDIOLSA-N [(2R,3S,4R,5R)-5-(5-fluoro-2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl 2-azidopentanoate Chemical compound N(=[N+]=[N-])C(C(=O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N1C(=O)NC(=O)C(=C1)F)O)O)CCC PYRDPMAEQWXKCO-BOMQDIOLSA-N 0.000 description 3
- MJNRDCNHIRDETA-UGKPPGOTSA-N [(2R,3S,4R,5R)-5-(5-fluoro-2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl 4-azidobutanoate Chemical compound N(=[N+]=[N-])CCCC(=O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N1C(=O)NC(=O)C(=C1)F)O)O MJNRDCNHIRDETA-UGKPPGOTSA-N 0.000 description 3
- GACCSTZFRJFITN-UORFTKCHSA-N [(2R,3S,4R,5R)-5-(5-fluoro-2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl 5-azidopentanoate Chemical compound N(=[N+]=[N-])CCCCC(=O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N1C(=O)NC(=O)C(=C1)F)O)O GACCSTZFRJFITN-UORFTKCHSA-N 0.000 description 3
- ZCXMFBUYRUWFAQ-PBEGBBSFSA-N [(2r,3s,4r,5r)-5-(5-fluoro-2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl (2s)-2-(butanoylamino)-3-methylbutanoate Chemical compound O[C@@H]1[C@H](O)[C@@H](COC(=O)[C@H](C(C)C)NC(=O)CCC)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZCXMFBUYRUWFAQ-PBEGBBSFSA-N 0.000 description 3
- GLPMXIIHERHMQE-QBRBXANFSA-N [(2r,3s,4r,5r)-5-(5-fluoro-2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl (2s)-3-phenyl-2-(phenylmethoxycarbonylamino)propanoate Chemical compound C([C@@H](C(=O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N1C(NC(=O)C(F)=C1)=O)O)O)NC(=O)OCC=1C=CC=CC=1)C1=CC=CC=C1 GLPMXIIHERHMQE-QBRBXANFSA-N 0.000 description 3
- DYADTGFGLFIFLN-LMWHNAIISA-N [(2r,3s,4r,5r)-5-(5-fluoro-2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl (2s)-4-methylsulfanyl-2-(pentanoylamino)butanoate Chemical compound O[C@@H]1[C@H](O)[C@@H](COC(=O)[C@H](CCSC)NC(=O)CCCC)O[C@H]1N1C(=O)NC(=O)C(F)=C1 DYADTGFGLFIFLN-LMWHNAIISA-N 0.000 description 3
- MLQWYFQUCCRUKI-DNNBLBMLSA-N [(2r,3s,4r,5r)-5-(5-fluoro-2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl 5-morpholin-4-ylpentanoate Chemical compound C([C@@H]1[C@H]([C@H]([C@@H](O1)N1C(NC(=O)C(F)=C1)=O)O)O)OC(=O)CCCCN1CCOCC1 MLQWYFQUCCRUKI-DNNBLBMLSA-N 0.000 description 3
- YKZUGNXYVALQQC-CTJCFNAESA-N [(2r,3s,4s,5r)-5-(5-fluoro-2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl (2s)-2-(phenylmethoxycarbonylamino)propanoate Chemical compound N([C@@H](C)C(=O)OC[C@@H]1[C@H]([C@H](O)[C@@H](O1)N1C(NC(=O)C(F)=C1)=O)O)C(=O)OCC1=CC=CC=C1 YKZUGNXYVALQQC-CTJCFNAESA-N 0.000 description 3
- GLPMXIIHERHMQE-OZOVBHBASA-N [(2r,3s,4s,5r)-5-(5-fluoro-2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl (2s)-3-phenyl-2-(phenylmethoxycarbonylamino)propanoate Chemical compound C([C@@H](C(=O)OC[C@@H]1[C@H]([C@@H]([C@@H](O1)N1C(NC(=O)C(F)=C1)=O)O)O)NC(=O)OCC=1C=CC=CC=1)C1=CC=CC=C1 GLPMXIIHERHMQE-OZOVBHBASA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 125000001980 alanyl group Chemical group 0.000 description 3
- 125000003282 alkyl amino group Chemical group 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 229960002949 fluorouracil Drugs 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 150000004820 halides Chemical class 0.000 description 3
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 239000007928 intraperitoneal injection Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 238000010979 pH adjustment Methods 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000003586 protic polar solvent Substances 0.000 description 3
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- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 125000001439 semicarbazido group Chemical group [H]N([H])C(=O)N([H])N([H])* 0.000 description 1
- 229960001153 serine Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000003396 thiol group Chemical class [H]S* 0.000 description 1
- 229960002898 threonine Drugs 0.000 description 1
- 229940034208 thyroxine Drugs 0.000 description 1
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 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
- C07H19/06—Pyrimidine radicals
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15292279A JPS5677298A (en) | 1979-11-28 | 1979-11-28 | Movel 5-fluorouridine derivative and its preparation |
| JP16920179A JPS5692299A (en) | 1979-12-27 | 1979-12-27 | 5-fluorouridine derivative and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE3044740A1 DE3044740A1 (de) | 1981-09-24 |
| DE3044740C2 true DE3044740C2 (en, 2012) | 1989-04-27 |
Family
ID=26481702
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19803044740 Granted DE3044740A1 (de) | 1979-11-28 | 1980-11-27 | Nucleosidderivate, ihre herstellung und pharmazeutische mittel |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US4340728A (en, 2012) |
| CH (1) | CH646441A5 (en, 2012) |
| DE (1) | DE3044740A1 (en, 2012) |
| FR (1) | FR2470774A1 (en, 2012) |
| GB (1) | GB2066812B (en, 2012) |
| IT (1) | IT1141100B (en, 2012) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0080305A1 (en) * | 1981-11-19 | 1983-06-01 | Beecham Group Plc | Antiviral 2'-deoxyuridines, their preparation and use |
| EP0323441B1 (en) * | 1984-10-30 | 1996-04-24 | Otsuka Pharmaceutical Co., Ltd. | 5-Fluorouracil derivatives |
| US4864021A (en) * | 1984-10-30 | 1989-09-05 | Otsuka Pharmaceutical Co., Ltd. | 5-fluorouracil derivatives |
| DE3786834T2 (de) * | 1986-04-30 | 1994-03-03 | Otsuka Pharma Co Ltd | 5-Fluoro-Uracil-Derivate. |
| DE268678T1 (de) * | 1986-05-30 | 1988-11-24 | Fuji Kagaku Kogyo K.K., Toyama | Neue 5-fluoruridin-verbindungen und deren herstellung. |
| US4994558A (en) * | 1986-12-24 | 1991-02-19 | Eli Lilly And Company | Immunoglobulin conjugates |
| AU610913B2 (en) * | 1987-07-31 | 1991-05-30 | Taiho Pharmaceutical Co., Ltd. | 2'-deoxy-5-fluorouridine derivatives |
| US4992534A (en) * | 1987-08-12 | 1991-02-12 | Otsuka Pharmaceutical Co., Ltd. | 3'-O-,5'-O-derivatives of 2'-deoxy-5-fluorouridine |
| US4877871A (en) * | 1988-06-14 | 1989-10-31 | Nabisco Brands, Inc. | Synthesis of sucrose polyester |
| US5216142A (en) * | 1989-04-17 | 1993-06-01 | Efamol Holdings Plc | Anti-virals |
| US5049551A (en) * | 1989-05-30 | 1991-09-17 | Ube Industries, Ltd. | 5-fluorouracil, 2'-deoxy-5-fluorouridine and 1-carbomoyl-5-fluorouracil compounds |
| DE69120368T2 (de) * | 1990-10-12 | 1996-11-28 | Univ Washington | Azido-substituierte Fettsäuren als Enzymsubstratanaloge |
| GB9322795D0 (en) * | 1993-11-05 | 1993-12-22 | Wellcome Found | Novel compounds |
| US5620676A (en) * | 1994-03-08 | 1997-04-15 | The United States Of America As Represented By The Department Of Health And Human Services | Biologically active ATP analogs |
| US5783689A (en) * | 1996-11-12 | 1998-07-21 | University Of Notre Dame | Antibacterial and antifungal nucleosides |
| CN111285911B (zh) * | 2020-02-26 | 2021-04-02 | 山东大学 | Gem-1mt两亲小分子化合物及其制剂、制备方法和应用 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2552293A1 (de) * | 1974-11-22 | 1976-08-12 | Asahi Chemical Ind | Antileukaemische verbindungen, verfahren zu ihrer herstellung und sie enthaltende arzneimittel |
| DE2721466A1 (de) * | 1977-05-12 | 1978-11-16 | Robugen Gmbh | Verfahren zur herstellung von 2'-desoxyribofuranosylnucleosiden |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3155646A (en) * | 1960-08-23 | 1964-11-03 | Upjohn Co | 1-arabinofuranosyl-5-halouracil and process for the preparation thereof |
| US3407191A (en) * | 1966-08-29 | 1968-10-22 | Lilly Co Eli | Adamantoate esters of nucleosides |
| US3853845A (en) * | 1971-08-18 | 1974-12-10 | Icn Pharmaceuticals | 5-n-aminoacyl-5-aminouridines |
| JPS5512440B2 (en, 2012) * | 1973-10-17 | 1980-04-02 | ||
| DE2614946C2 (de) * | 1975-04-08 | 1987-04-23 | Asahi Kasei Kogyo K.K., Osaka | Neue Nucleosidderivate |
| US4096324A (en) * | 1975-07-07 | 1978-06-20 | The Upjohn Company | Cytidine nucleoside compound |
-
1980
- 1980-11-26 US US06/210,796 patent/US4340728A/en not_active Expired - Lifetime
- 1980-11-27 DE DE19803044740 patent/DE3044740A1/de active Granted
- 1980-11-27 IT IT26289/80A patent/IT1141100B/it active
- 1980-11-28 FR FR8025348A patent/FR2470774A1/fr active Granted
- 1980-11-28 GB GB8038211A patent/GB2066812B/en not_active Expired
- 1980-11-28 CH CH883380A patent/CH646441A5/de not_active IP Right Cessation
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2552293A1 (de) * | 1974-11-22 | 1976-08-12 | Asahi Chemical Ind | Antileukaemische verbindungen, verfahren zu ihrer herstellung und sie enthaltende arzneimittel |
| US4097665A (en) * | 1974-11-22 | 1978-06-27 | Asahi Kasei Kogyo Kabushiki Kaisha | Diacylnucleosides and process for preparing the same |
| DE2721466A1 (de) * | 1977-05-12 | 1978-11-16 | Robugen Gmbh | Verfahren zur herstellung von 2'-desoxyribofuranosylnucleosiden |
Also Published As
| Publication number | Publication date |
|---|---|
| US4340728A (en) | 1982-07-20 |
| CH646441A5 (de) | 1984-11-30 |
| FR2470774B1 (en, 2012) | 1984-11-16 |
| FR2470774A1 (fr) | 1981-06-12 |
| GB2066812B (en) | 1983-07-27 |
| IT8026289A0 (it) | 1980-11-27 |
| IT1141100B (it) | 1986-10-01 |
| DE3044740A1 (de) | 1981-09-24 |
| GB2066812A (en) | 1981-07-15 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 8110 | Request for examination paragraph 44 | ||
| D2 | Grant after examination | ||
| 8364 | No opposition during term of opposition | ||
| 8339 | Ceased/non-payment of the annual fee |