CN1660819A - N4－氧羰基胞嘧啶衍生物及制备方法与应用 - Google Patents
N4－氧羰基胞嘧啶衍生物及制备方法与应用 Download PDFInfo
- Publication number
- CN1660819A CN1660819A CN2004100164722A CN200410016472A CN1660819A CN 1660819 A CN1660819 A CN 1660819A CN 2004100164722 A CN2004100164722 A CN 2004100164722A CN 200410016472 A CN200410016472 A CN 200410016472A CN 1660819 A CN1660819 A CN 1660819A
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- Prior art keywords
- general formula
- alkyl
- ethynyl
- base
- meant
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Links
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Natural products NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title claims description 14
- 229940104302 cytosine Drugs 0.000 title abstract description 3
- 239000003814 drug Substances 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 9
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 claims abstract description 8
- 230000000118 anti-neoplastic effect Effects 0.000 claims abstract description 7
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000002585 base Substances 0.000 claims description 21
- -1 flucytosine carbamate series Chemical class 0.000 claims description 20
- 229910052760 oxygen Inorganic materials 0.000 claims description 20
- 239000001301 oxygen Substances 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 13
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 229960004117 capecitabine Drugs 0.000 claims description 10
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 10
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 claims description 9
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 229920002554 vinyl polymer Polymers 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 claims description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 6
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 229960004413 flucytosine Drugs 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- ADOBXTDBFNCOBN-UHFFFAOYSA-N 1-heptadecene Chemical compound CCCCCCCCCCCCCCCC=C ADOBXTDBFNCOBN-UHFFFAOYSA-N 0.000 claims description 4
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 claims description 4
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 claims description 4
- KDKYADYSIPSCCQ-UHFFFAOYSA-N but-1-yne Chemical group CCC#C KDKYADYSIPSCCQ-UHFFFAOYSA-N 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 4
- 238000006482 condensation reaction Methods 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- VQOXUMQBYILCKR-UHFFFAOYSA-N 1-Tridecene Chemical group CCCCCCCCCCCC=C VQOXUMQBYILCKR-UHFFFAOYSA-N 0.000 claims description 2
- 125000006021 1-methyl-2-propenyl group Chemical group 0.000 claims description 2
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 239000012298 atmosphere Substances 0.000 claims description 2
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000002704 decyl group Chemical group [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])* 0.000 claims description 2
- 125000003438 dodecyl group Chemical group [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])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000006038 hexenyl group Chemical group 0.000 claims description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 claims description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002960 margaryl 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])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000006178 methyl benzyl group Chemical group 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 125000001421 myristyl 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])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- AFFLGGQVNFXPEV-UHFFFAOYSA-N n-decene Natural products CCCCCCCCC=C AFFLGGQVNFXPEV-UHFFFAOYSA-N 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000001196 nonadecyl 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])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 claims description 2
- 125000001400 nonyl 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])[H] 0.000 claims description 2
- 125000002347 octyl 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])[H] 0.000 claims description 2
- 125000000913 palmityl 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])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000002958 pentadecyl 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])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 150000003016 phosphoric acids Chemical class 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 125000002889 tridecyl 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])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 2
- 125000005065 undecenyl group Chemical group C(=CCCCCCCCCC)* 0.000 claims description 2
- 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 claims description 2
- 125000005023 xylyl group Chemical group 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims 1
- 150000001721 carbon Chemical group 0.000 claims 1
- 238000009833 condensation Methods 0.000 claims 1
- 230000005494 condensation Effects 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- LBTQRHGOZGICFV-UHFFFAOYSA-N pentyl n-(5-fluoro-2-oxo-1h-pyrimidin-6-yl)carbamate Chemical compound CCCCCOC(=O)NC1=NC(=O)NC=C1F LBTQRHGOZGICFV-UHFFFAOYSA-N 0.000 abstract 1
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 6
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012809 cooling fluid Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000001291 vacuum drying Methods 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
- 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
- C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
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Abstract
本发明属于药物化学技术领域。本发明公开了通式I的N4－氧羰基胞嘧啶衍生物及制备，并提供了以N4－戊氧羰基－5氟胞嘧啶为起始原料制备氟胞嘧啶氨基甲酸酯类抗肿瘤药物卡培他滨的方法，该方法成本低，质量好，收率高。
Description
技术领域
本发明属于药物化学技术领域。具体涉及N4-氧羰基胞嘧啶衍生物及制备方法与应用。
背景技术
N4-氧羰基胞嘧啶衍生物是制备胞嘧啶氨基甲酸酯类抗癌药物的重要原料。
卡培他滨是第一个氟代胞嘧啶氨基甲酸酯类抗肿瘤药物，其化学名为：5’-脱氧-5-氟-N4-戊氧羰基胞苷，即：5’-deoxy-5-fluoro-N4-(pentyloxycarbony)cytidine。其结构式如下：
目前文献及专利报道的卡培他滨的合成路线主要有三种，现列举如下：
Scheme 1：
参考文献：Drugs of the Future 1996，21(4)：358～360
Scheme 2：
参考文献：US005476932
Scheme 3：
参考文献：Bioorganic & Medicinal Chemistry 8(2000)：1697～1706
发明内容
本发明所要解决的技术问题在于研究设计以N4-戊氧羰基-5-氟胞嘧啶为原料制备卡培他滨的方法。
本发明提供了通式I的胞嘧啶衍生物：
式中R1为烷基、环烷基、链烯基、芳烷基或芳基；R2为卤素原子氟或碘，乙烯基，乙炔基或被卤素、烷基、环烷基、芳环烷基或芳杂环基所取代的乙烯基、乙炔基。
本发明的另一目的是提供了通式I的胞嘧啶衍生物的制备方法，该方法以通式II与通式III进行缩合反应制备而得。
(III)
通式II中R3为卤素原子(如氟，碘等)，乙烯基，乙炔基或被卤素、烷基、环烷基、芳环烷基或芳杂环基所取代的乙烯基、乙炔基；
通式III中X代表离去基团，R4代表烷基、环烷基、链烯基、芳烷基或芳基。
通式II与通式III的缩合反应，可以在一种溶剂如吡啶、二氯甲烷、1，2-二氯乙烷或水中进行，也可以在二个或二个以上混合溶剂中进行，但需存在酸性接受体如三乙胺、吡啶、甲基吡啶、碱金属氢氧化物、碱金属碳酸盐或磷酸盐。反应温度可以在较宽范围内变化，一般为-20℃～20℃，最好在0℃左右进行。通式II与通式III的摩尔比为1∶1.05～1∶1.20。
按上述方法制备的化合物可以用一般的技术(例如蒸发、过滤、提取、沉淀、重结晶以及合并使用这些方法)分离和纯化。
本发明的又一目的是提供了通式I中N4-氧羰基-5-氟胞嘧啶衍生物，以通式IV表示。
通式IV中R5为烷基、环烷基、链烯基、芳烷基或芳基。
N4-氧羰基-5-氟胞嘧啶衍生物(通式IV)与5-脱氧-D-呋喃核糖类化合物(通式V)反应，可制备氟胞嘧啶氨基甲酸酯类抗肿瘤药物。该合成方法是降低该类药物合成成本、提高质量的有效途径。
通式V中R6为氢原子、乙酰基或苯甲酰基。
本发明的另一目的是提供了以N4-戊氧羰基-5氟胞嘧啶为起始原料制备氟胞嘧啶氨基甲酸酯类抗肿瘤药物卡培他滨的方法，该方法包括下列步骤：
以N4-戊氧羰基-5-氟胞嘧啶与5-脱氧-1，2，3-三-O-乙酰基-D-呋喃核糖反应生成N4-戊氧羰基-5-氟胞苷，经过氨气—甲醇液的水解得卡培他滨产品。
用作上述反应原料的N4-戊氧羰基-5-氟胞嘧啶是由5-氟胞嘧啶与氯甲酸正戊酯缩合反应而得，是由本发明人制备的一种新化合物，对该化合物的2位羰基保护可用三甲基硅氧烷(OSi(CH3)3)或六甲基二硅氮烷(N[Si(CH3)3]2)或碘化钠与三甲基氯硅烷在无水乙腈、二氯甲烷、1，2-二氯乙烷或甲苯中进行加热回流。
经实验证明，本发明路线可大大降低生产成本，所获得的产品质量可靠、性能稳定。
本发明所应用的术语“烷基”是指有1～19个碳原子的直链或带支链的烷基：甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、己基、异己基、庚基、辛基、壬基、癸基、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、十六烷基、十七烷基或十九烷基；
“环烷基”是指环丙基、环丁基、环戊基或环己基；
“链烯基”是指有3～19个碳原子的未取代或取代的链烯基，烯丙基、丁烯基、3-甲基-2-丁烯基、1-甲基-2-丙烯基、己烯基、癸烯基、十一碳烯基、十三碳烯基、十五碳烯基、十七碳烯基、十九碳烯基或2-苯基乙烯基；
“芳烷基”是指未取代或取代的芳烷基，例如苄基、1-苯基乙基、甲基苄基或苯乙基；
“芳基”是指未取代或取代的芳基，例如苯基、苯甲基、二甲苯基或乙基苯基；
“被卤素、烷基、环烷基、芳环烷基或芳杂环基所取代的乙烯基、乙炔基”是指1-氯乙烯基、2-溴乙烯基、1-氯-2-溴乙烯基、2-苯乙烯基、1-丙炔基、1-丁炔基、1-戊炔基、1-己炔基、3，3-二甲基-1-丁炔基、环戊乙炔基、环己乙炔基、苯乙炔基、3-苯基-1-丙炔基、吡啶-2-乙炔基或咪唑-2-乙炔基。
具体实施方式
实施例1 N4-戊氧羰基-5-氟胞嘧啶的制备
在冰盐浴冷却和惰性气氛下，向250mL四口烧瓶中加入180mL1，2-二氯乙烷、10mL无水吡啶和13g(0.1mol)5-氟胞嘧啶，当反应液温度降到0℃时，在搅拌下滴加氯甲酸正戊酯18mL(0.12mol)，滴加速度要保证反应液温度不超过5℃。滴加完毕，在该温度范围内继续反应2小时。减压浓缩到总体积约10mL，向浓缩液中加入50mL正己烷，室温下搅拌30分钟。过滤，将所得滤饼用蒸馏水洗涤2～4次，每次50mL。将所得白色固体产品于65℃进行快速真空干燥。收率：78％；mp：108～109℃。IR(KBr)：2959，1743，1653cm-1；1Hnmr(300MHZ，d-DMSO)：δ0.8(t，3H)，1.33(m，4H)，1.65(m，2H)，3.3(s，1H)，4.3(t，2H)，8.0(d，1H)，8.4(s，1H)；ESI-MS m/z(2M+Na+)509；元素分析：计算值C 49.38％，H 5.83％，N 17.28％，F 7.82％；实测值C 49.13％，H 5.87％，N 17.34％，F 7.71％。
实施例2 2’，3’-二-O-乙酰基-5’-脱氧-5-氟-N4-戊氧羰基胞苷的制备
将N4-戊氧羰基-5-氟胞嘧啶24.3g(0.1mol)悬浮在50mL甲苯和六甲基二硅氮烷8g(0.05mol)中，在氮气氛下加热回流，用薄层色谱法跟踪反应，展开剂为甲醇∶氯仿＝1∶6，在254nm紫外下显色。
当硅烷保护反应完全后，降温到室温，加入150mL二氯甲烷。在冰浴下加入5-脱氧-1，2，3-三-O-乙酰基-D-呋喃核糖31.2g(0.12mol)和无水SnCl4 31.2g(0.12mol)，加料完毕，在室温下反应过夜。加入50g碳酸氢钠并滴加50mL水，继续室温下搅拌1小时，过滤。滤液用4％碳酸氢钠溶液洗涤3次，每次25mL。有机层用无水硫酸钠干燥后进行减压浓缩，得淡黄色油状物。收率：76％。
实施例3 5’-脱氧-5-氟-N4-戊氧羰基胞苷(卡培他滨)的制备
将44.3g(0.1mol)2’，3’-二-O-乙酰基-5’-脱氧-5-氟-N4-戊氧羰基胞苷溶于50mL甲醇中，在室温下通入氨气，搅拌反应过夜。反应结束，浓缩至干。将残余物溶于50mL乙酸乙酯中，将浆液冷却到0℃，陈化1小时，将晶体回收，用2×20mL正己烷∶乙酸乙酯＝1∶1冷却液洗涤，在真空下将超白产物—卡培他滨于40℃干燥过夜。收率：90％。
Claims (7)
1.一种胞嘧啶衍生物，其特征在于该衍生物具有下列结构通式I：
式中R1为烷基、环烷基、链烯基、芳烷基或芳基；R2为卤素原子氟或碘，乙烯基，乙炔基或被卤素、烷基、环烷基、芳环烷基或芳杂环基所取代的乙烯基、乙炔基。
2.一种通式I的胞嘧啶衍生物的制备方法，其特征在于该方法为将通式II与通式III的化合物进行缩合反应，反应需在酸性接受体三乙胺、吡啶、甲基吡啶、碱金属氢氧化物、碱金属碳酸盐或磷酸盐存在下，在溶剂吡啶、二氯甲烷、1，2-二氯乙烷或水，或在二个及二个以上的混合溶剂中，于-20℃～20℃进行，通式II与通式III的摩尔比为1∶1.05～1∶1.20。
3.一种N4-氧羰基-5氟胞嘧啶衍生物，其特征在于该衍生物具有下列结构式IV：
通式IV中R5为烷基、环烷基、链烯基、芳烷基或芳基。
4.一种N4-氧羰基-5氟胞嘧啶衍生物在制备氟胞嘧啶氨基甲酸酯类抗肿瘤药物中的应用。
5.一种氟胞嘧啶氨基甲酸酯类抗肿瘤药物卡培他滨的制备方法，其特征在于该方法以N4-戊氧羰基-5氟胞嘧啶为原料，先与三甲基硅氧烷或六甲基二硅氮烷或碘化钠与三甲基氯硅烷在无水乙腈、二氯甲烷或甲苯中进行加热回流，再与5-脱氧-1，2，3-三-O-乙酰基-D-呋喃核糖反应，最后在惰性气氛下经氨气-甲醇液水解制得卡培他滨。
6.根据权利要求5所述的一种氟胞嘧啶氨基甲酸酯类抗肿瘤药物卡培他滨的制备方法，其特征在于其中所述的N4-戊氧羰基-5-氟胞嘧啶是由5-氟胞嘧啶与氯甲酸正戊酯缩合制得。
7.根据权利要求1、2或3所述的通式I、II、III和IV化合物，其特征在于其中所述的“烷基”是指有1～19个碳原子的直链或带支链的烷基：甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、己基、异己基、庚基、辛基、壬基、癸基、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、十六烷基、十七烷基或十九烷基；
“环烷基”是指环丙基、环丁基、环戊基或环己基；
“链烯基”是指有3～19个碳原子的未取代或取代的链烯基，烯丙基、丁烯基、3-甲基-2-丁烯基、1-甲基-2-丙烯基、己烯基、癸烯基、十一碳烯基、十三碳烯基、十五碳烯基、十七碳烯基、十九碳烯基或2-苯基乙烯基；
“芳烷基”是指未取代或取代的芳烷基，例如苄基、1-苯基乙基、甲基苄基或苯乙基；
“芳基”是指未取代或取代的芳基，例如苯基、苯甲基、二甲苯基或乙基苯基；
“被卤素、烷基、环烷基、芳环烷基或芳杂环基所取代的乙烯基、乙炔基”是指1-氯乙烯基、2-溴乙烯基、1-氯-2-溴乙烯基、2-苯乙烯基、1-丙炔基、1-丁炔基、1-戊炔基、1-己炔基、3，3-二甲基-1-丁炔基、环戊乙炔基、环己乙炔基、苯乙炔基、3-苯基-1-丙炔基、吡啶-2-乙炔基或咪唑-2-乙炔基。
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| PCT/CN2004/000744 WO2005080351A1 (fr) | 2004-02-23 | 2004-07-05 | Preparation et application de derives n4-oxycarbonylcytosine |
| ARP040102558A AR046077A1 (es) | 2004-02-23 | 2004-07-20 | Derivados de n4- oxicarbonilcitimidina, procedimientos de eleaboracion y usos de los mismos |
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2004
- 2004-02-23 CN CNB2004100164722A patent/CN100383128C/zh not_active Expired - Lifetime
- 2004-07-05 WO PCT/CN2004/000744 patent/WO2005080351A1/zh active Application Filing
- 2004-07-20 AR ARP040102558A patent/AR046077A1/es unknown
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| WO2009082844A1 (fr) * | 2007-12-28 | 2009-07-09 | Topharman Shanghai Co., Ltd | Dérivé hydroxyle de la capécitabine, ses procédés de préparation et ses utilisations pour préparer la capécitabine |
| WO2009094847A1 (fr) * | 2007-12-28 | 2009-08-06 | Topharman Shanghai Co., Ltd. | Dérivé hydroxyle de capécitabine, procédés de préparation et d' utilisation de la capécitabine |
| WO2009082846A1 (fr) * | 2007-12-28 | 2009-07-09 | Topharman Shanghai Co., Ltd. | Dérivé hydroxyle de la capécitabine, ses procédés de préparation et ses utilisations pour préparer la capécitabine |
| CN101469008B (zh) * | 2007-12-29 | 2013-08-07 | 上海特化医药科技有限公司 | 卡培他滨羟基衍生物、其制备方法和用于制备卡培他滨 |
| CN102245621A (zh) * | 2009-01-27 | 2011-11-16 | 霍夫曼-拉罗奇有限公司 | 用于回收β-乙酰基呋喃糖苷的方法 |
| CN101987857A (zh) * | 2009-08-07 | 2011-03-23 | 合肥华方医药科技有限公司 | 一种抗肿瘤药物卡培他滨及其中间体的合成方法 |
| CN101830953A (zh) * | 2010-05-26 | 2010-09-15 | 南京亚东启天药业有限公司 | 一种卡培他滨及其中间体的制备方法 |
| CN101928314A (zh) * | 2010-08-27 | 2010-12-29 | 广东肇庆星湖生物科技股份有限公司 | 一种卡培他滨的制备方法 |
| CN102924548A (zh) * | 2012-11-30 | 2013-02-13 | 安润医药科技（苏州）有限公司 | 卡培他滨的合成方法 |
| CN102924548B (zh) * | 2012-11-30 | 2015-05-20 | 安润医药科技（苏州）有限公司 | 卡培他滨的合成方法 |
| CN103897005B (zh) * | 2012-12-27 | 2017-07-28 | 鲁南制药集团股份有限公司 | 一种连续操作合成卡培他滨的方法 |
| CN103333119A (zh) * | 2013-05-28 | 2013-10-02 | 中国药科大学 | 1,2-二氢-6-甲基-4-取代氨基-5-嘧啶羧酸类化合物及其制备方法和用途 |
| CN104478975A (zh) * | 2014-11-24 | 2015-04-01 | 苏州乔纳森新材料科技有限公司 | 一种卡培他滨的合成方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100383128C (zh) | 2008-04-23 |
| WO2005080351A1 (fr) | 2005-09-01 |
| AR046077A1 (es) | 2005-11-23 |
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