CN1053194C - 制备n4－酰基－5'－脱氧－5－氟胞苷衍生物的方法 - Google Patents
制备n4－酰基－5'－脱氧－5－氟胞苷衍生物的方法 Download PDFInfo
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- CN1053194C CN1053194C CN95109396A CN95109396A CN1053194C CN 1053194 C CN1053194 C CN 1053194C CN 95109396 A CN95109396 A CN 95109396A CN 95109396 A CN95109396 A CN 95109396A CN 1053194 C CN1053194 C CN 1053194C
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- 238000000034 method Methods 0.000 title claims description 15
- 125000003118 aryl group Chemical group 0.000 claims abstract description 18
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 14
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 10
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 24
- 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 claims description 18
- 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 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- -1 butoxy carbonyl cytidine Chemical compound 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 10
- 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 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 125000004744 butyloxycarbonyl group Chemical group 0.000 claims description 3
- 239000003125 aqueous solvent Substances 0.000 claims description 2
- 230000020176 deacylation Effects 0.000 abstract description 2
- 238000005947 deacylation reaction Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 10
- 229910052731 fluorine Inorganic materials 0.000 description 9
- 239000011737 fluorine Substances 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 8
- 150000001721 carbon Chemical group 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
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- 150000007530 organic bases Chemical class 0.000 description 5
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- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000019635 sulfation Effects 0.000 description 2
- 238000005670 sulfation reaction Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- OXHNLMTVIGZXSG-UHFFFAOYSA-N 1-Methylpyrrole Chemical compound CN1C=CC=C1 OXHNLMTVIGZXSG-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- YSNABXSEHNLERR-UHFFFAOYSA-N CC(C(C1O)O)OC1N(C=C(C(N)=N1)F)C1=O Chemical compound CC(C(C1O)O)OC1N(C=C(C(N)=N1)F)C1=O YSNABXSEHNLERR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- NRDQFWXVTPZZAZ-UHFFFAOYSA-N butyl carbonochloridate Chemical compound CCCCOC(Cl)=O NRDQFWXVTPZZAZ-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 125000004803 chlorobenzyl group Chemical group 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000004175 fluorobenzyl group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 150000005826 halohydrocarbons Chemical class 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000006178 methyl benzyl group Chemical group 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000006502 nitrobenzyl group Chemical group 0.000 description 1
- IAIWVQXQOWNYOU-FPYGCLRLSA-N nitrofural Chemical compound NC(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 IAIWVQXQOWNYOU-FPYGCLRLSA-N 0.000 description 1
- 229960001907 nitrofurazone Drugs 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- XHRRYUDVWPPWIP-UHFFFAOYSA-N pentyl carbonochloridate Chemical compound CCCCCOC(Cl)=O XHRRYUDVWPPWIP-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 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
- C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
-
- 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
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
从新的式II中间体可制得式I化合物N4-酰基-5′-脱氧-5-氟胞苷衍生物。后者是已知的抗肿瘤剂。式I和II如下，其中R是烷基、环烷基、链烯基、芳烷基、芳基。
Description
本发明提供生产式I N4-酰基-5′-脱氧-5-氟胞苷衍生物的方法，式I如下：式中R是烷基、环烷基、链烯基、芳烷基或芳基。
式I化合物是已知的化合物，它具有抗肿瘤活性，可由5′-脱氧-5-氟胞苷制得，如欧洲专利申请NO.0316704A所述。
该方法相当费时，难以工业规模地操作，它依次包括下述步骤：在该化合物的糖部分的羟基中引入保护性酰基，在该化合物的氨基中引入酰基，然后从糖部分消除酰基。
将这些酰基胞苷衍生物的糖部分脱酰化的方法已有描述[J. H.van Bloom等人，Nucleic Acids Research，第4卷(4)，第1047-63页(1977)]。人们通常知道当酰基胞苷衍生物与碱反应时，可消除糖部分上的酰基。然而，从氨基上除去酰基的情况也会发生，从而需要复杂的分离和纯化操作，以得到仅含有接在氨基上的酰基的N4-酰基-5′-脱氧-5-氟胞苷衍生物。
根据本发明，式I化合物是通过用有机或无机碱在水性溶剂或惰性有机溶剂中处理式II化合物得到的。式II如下：式中R定义同上。
在进行上述反应时，反应温度并不重要，可在-30℃到20℃的范围内，温度优选在大约-10℃至大约+10℃的范围内。在0℃得到最好的结果。惰性溶剂可以是任何与水相溶的水性或惰性有机溶剂。优选的溶剂是水；选自甲醇、乙醇、丙醇、丁醇、异丙醇的醇；醚如四氢呋喃；二氧六环；丙酮；酰胺如二甲基甲酰胺；碳卤化物如二氯甲烷；氯仿等；芳香烃如甲苯、二甲苯等；及其混合物或组合。
当使用溶剂混合物时，可通过加入相转移催化剂来进行反应。
可以使用有机或无机碱来将式II化合物转变为式III化合物。有机碱的例子包括碱金属醇盐、三乙胺、1，8-二氮杂二环(5.4.0十一碳-7-烯(被称为DBU)、N-甲基吗啉或吡啶。优选的有机碱是碱金属醇盐如甲醇钠。无机碱的例子包括氢氧化铵和氢氧化钠。优选的无机碱是氢氧化钠。将式II转变为式I所用的碱的量并不重要。将式II化合物的糖部分上的羰基选择性地水解所用的碱的量为式II化合物量的大约2-6摩尔当量。碱的优选用量是4摩尔当量。
R可以是烷基、环烷基、链烯基、芳烷基或芳基。当R是烷基时，R可以是任何具有1-22个碳原子的直链或支链烷基。优选的烷基是含有1-6个碳原子的低级烷基如甲基、乙基、丙基、异丙基、丁基、异丁基、戊基等。
当R是环烷基时，它包括任何含有3-12个碳原子的环烷基如环丙基、环丁基、环戊基、环己基、金刚烷基等。
当R是链烯基时，它可以是任何含有2-22个碳原子的取代和未取代的链烯基。当R是链烯基时，优选含有1-6个碳原子的低级链烯基。优选的低级链烯基是烯丙基、1-丙基、丁烯基、戊烯基和己烯基。当R是取代的链烯基时，优选的取代基是低级烷基或芳基。
当R是芳基时，其是可以是取代或未取代的。“芳基”一词是指单核芳烃基团如苯基，和多核芳基基团如萘基、蒽基、菲基等。单核和多核芳基可以是在一个或多个位置上取代的。当R是未取代的单核芳基时，例如可以是苯基。当R是取代的单核芳基时，优选的取代基是含有1-6个碳原子的低级烷基、卤素、低级烷氧基、硝基、氰基、乙酰基、氨基甲酰基和低级烷氧羰基。
所述芳基可以含有杂原子，其中杂原子选自氮、氧或硫。这些杂芳基可以是未取代的或者是被上述取代基取代的。
当R是单核杂芳基时，R可以是噻吩基、甲基噻吩基、呋喃基、硝基呋喃基等。
优选的多核芳基包括萘基、联苯基、吡咯基、甲基吡咯基、咪唑基、吡唑基、吡啶基、甲基吡啶基、吡嗪基等。
当R是芳烷基时，芳烷基代表芳基低级烷基，其中芳基定义如上，并且低级烷基含有1-6个碳原子。所述芳基可以是未取代的或者是被就上文关于芳基所述的取代基取代的。优选的未取代的芳烷基包括苄基和1-苯基乙基。取代的芳烷基包括甲基苄基、氟代苄基、氯代苄基、甲氧基苄基、二甲氧基苄基、硝基苄基、苯乙基、吡啶甲基、3-吲哚基甲基等。
反应完成后，结合使用常规的分离和纯化方法得到分离的纯态式I化合物。
本发明提供选择性地仅仅将羰基COOR基团从其羟基糖部分消除的方法。由于水解步骤是选择性的，因而可以通过简单的方法用几个化学步骤从式II化合物制取N4-酰基-5′-脱氧-5-氟胞苷衍生物，收率极高，可达80％。采用该方法从5-氟胞嘧啶制备可获得62％的N4-酰基-5′-脱氧-氟胞苷总收率。
根据本发明的另一个方面，通过在惰性有机溶剂中在有机碱的存在下用化合物
R-O-CO-X(式中R定义如上，X是活性基团)处理式III 5′-脱氧-5-氟脆苷可制得式II化合物。X可以是任何活性基团如卤化物、酐、混酐、硫酸化烷基例如甲磺酰基、或硫酸化芳基例如甲苯磺酰基。当X是卤化物时，可使用任何卤化物如溴、氟或氯。优选的卤化物是氯。
上述反应的反应温度并不重要。温度范围可以是大约-30℃到大约+20℃，优选大约-10℃到大约+10℃。在大约0℃可获得最佳结果。
所述溶剂可以是任何惰性极性或非极性有机溶剂，例如二甲基甲酰胺、乙腈、甲苯、氯仿、吡啶、卢剔啶或二甲基亚砜或卤代烃如二氯甲烷。优选的有机溶剂是二氯甲烷。可以使用任何有机碱例如三乙胺、三丁胺、吡啶、N，N-二甲基氨基吡啶、卢剔啶、N-甲基吗啉等。优选的有机碱是吡啶。
用作上述反应原料的5′-脱氧-5-氟胞苷是一种已知的化合物[J.Med. Chem.，22 1330(1979)]并且可用已知的方法制备，例如从5-氟胞嘧啶到5-氟胞苷[Chem. Pharm. Bull.，第26卷，第10期，2990(1978)][USP4966891](参见日本专利公告第34479/1983号)，或者按照文献[Chem. Pharm. Bull.，33，2575(1985)]所述的方法从5′-脱氧-5-氟尿苷制备。
式II化合物是新化合物并且也是本发明的一部分。
典型的式II化合物是
5′-脱氧-2′，3′-二-O-正戊氧羰基-5-氟-N4-正戊氧羰基胞苷，和
5′-脱氧-2′，3′-二-O-正丁氧羰基-5-氟-N4-正丁氧羰基胞苷。
下述实施例可进一步说明本发明。
实施例1
向已惰性化的、冷却至-10℃的500ml圆底带有夹套的烧瓶中加入125ml二氯甲烷、50ml氯代甲酸戊酯(0.33mol)和30ml吡啶(0.38mol)，同时将反应温度保持在不超过-10℃。
用一个加粉漏斗加入24.5g 5′-脱氧-5-氟胞苷，45分钟加完，同时将温度保持在-5℃以下。可见到固体开始时溶解很快，添加越往后则溶解变得不明显。用冷却系统控制轻微的放热。将反应混合物于0℃搅拌过夜。
过滤悬浮的固体，将湿滤饼用二氯甲烷洗涤3次，每次5ml。该水溶液滤饼被认定为C5H5N·HCl。将滤液在旋转蒸发器中于40℃和20mmHg汽提至干。将残余物溶于75ml乙酸乙酯中，滤除不溶物。将滤饼用乙酸乙酯(3×25ml)洗涤，将洗涤液与滤液合并。将溶液汽提至干，得到50.55g 5′-脱氧2′，3′二-O-正戊氧羰基-5-氟-N4-正戊氧基羰基胞苷，由24.5g原料可得到92％的收率。
实施例2
将实施例1的残余物(即50.55g 5′-脱氧-2′，3′二-O-正戊氧羰基-5-氟-N4-正戊氧基羰基胞苷)溶于50ml甲醇中，冷至-10℃。在保持低于-10℃温度的同时，将16g氢氧化钠溶于22ml双蒸水中的溶液用30分钟时间加到残余溶剂中。将溶液搅拌15分钟，检查反应是否完全。反应完全后，加入32ml浓盐酸(37％)从而将反应混合物的pH值降至4.5-5.5之间。
将250ml二氯甲烷与50ml水一起加到浆液中，将混合物搅拌15分钟。分出下层有机相，用50ml水洗涤，合并水层，用70ml二氯甲烷返洗。合并产物液流，汽提至干，得到5′-脱氧-5-氟-N4-正戊氧基羰基胞苷。所得粗品重40.45g，由50.55g原料获得的收率为113％。
实施例3
为了将40.45g得自实施例2的5′-脱氧-氟-N4-正戊氧羰基胞苷纯化，将实施例2的残余物在剧烈搅拌下溶于125ml乙酸乙酯中。几乎立即出现产物沉淀。当全部粗品均被溶解后，将浆液冷却至0℃，陈化1小时。将晶体回收，用2×20ml己烷/乙酸乙酯(50/50冰冷混合物)洗涤，在5mmHg真空下将超白产物于40℃干燥过夜，产量为28.7g，相当于80％的总收率(基于24.5g 5′-去氧-5-氟胞苷计得)。
实施例4
将一个带有夹套的500ml圆底烧瓶充以惰性气体，冷却至20℃，加入120ml吡啶(148mol)和5′-脱氧-5-氟胞苷(36.1g)。在将温度保持在20℃下以下的同时，用加料漏斗加入氯甲酸正丁酯(66.4g)，1小时加完。将反应混合物在20℃搅拌2小时。
将反应混合物在40℃和20mmHg的旋转蒸发器汽提至干。将残余物溶于225ml乙酸乙酯中并用120ml水洗涤。分出有机相并用165ml 10％HCl水溶液洗涤，接着用11ml饱和碳酸氢钠洗涤。
收集乙酸乙酯层，汽提至干，得到5′-脱氧-2′，3′-二-O-正丁氧基羰基-5-氟-N4-正丁氧羰基胞苷。所得粗品量63.0g，对应的收率为85％。
实施例5
将实施例4的残余物(即，63.0g 5′-脱氧-2′，3′-二-O-正丁氧羰基-5-氟-N4-正丁氧羰基胞苷)溶于125ml甲醇中并冷至0℃。在将温度保持0℃的同时，加入50％NaOH水溶液，30分钟加完。
将溶液搅拌2小时，检查反应是否完全。反应完全后，加入12ml浓盐酸(37％)从而将反应混合物的pH值降至4.5。
将150ml二氯甲烷与150ml水一起加到浆液中，将混合物搅拌15分钟。分出下层有机相，用150ml饱和碳酸氢钠洗涤。分出有机层，浓缩至干。得到5′-脱氧-5-氟-N4-正丁氧羰基胞苷，所得粗品重30.5g；对应的收率为72％。
Claims (8)
1.制备式I N4-酰基-5′-脱氧-5-氟胞苷衍生物的方法，包括用有机或无机碱在水性溶剂或惰性有机溶剂中处理式II化合物；式I和II如下：
式中R是烷基、环烷基、链烯基、芳烷基或芳基。
2.权利要求1的方法，其中所述处理是在大约-10℃到大约10℃的温度下进行的。
3.权利要求1的方法，其中所述处理是在大约0℃进行的。
4.权利要求1的方法，其中所述溶剂是水。
5.权利要求1的方法，其中所述碱是氢氧化钠并且所述溶剂是甲醇。
6.式II化合物
式中R是低级烷基。
7.权利要求6的化合物，该化合物是5′-脱氧-2′，3′-二-O-正戊氧羰基-5-氟-N4-正戊氧羰基胞苷。
8.权利要求6的化合物，该化合物是5′-脱氧-2′，3′-二-O-正丁氧羰基-5-氟-N4-正丁氧羰基胞苷。
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| US08/296,842 US5476932A (en) | 1994-08-26 | 1994-08-26 | Process for producing N4-acyl-5'-deoxy-5-fluorocytidine derivatives |
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| WO2019143860A1 (en) * | 2018-01-19 | 2019-07-25 | Nucorion Pharmaceuticals, Inc. | 5-fluorouracil compounds |
| EP3669890A1 (en) | 2018-12-18 | 2020-06-24 | Croda International PLC | Filamentous nanoparticles having vaccine adjuvant effect |
| CN115605492A (zh) | 2020-04-21 | 2023-01-13 | 配体制药股份有限公司（Us） | 核苷酸前药化合物 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0060245A1 (en) * | 1980-09-22 | 1982-09-22 | Towmotor Corp | APRON WITH LATERALLY MOVABLE FORKS. |
| EP0602478A1 (en) * | 1992-12-18 | 1994-06-22 | F. Hoffmann-La Roche Ag | Novel process for producing N4-acyl-5'-deoxy-5-fluorocytidine derivatives |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1327358C (en) * | 1987-11-17 | 1994-03-01 | Morio Fujiu | Fluoro cytidine derivatives |
| AU671491B2 (en) * | 1992-12-18 | 1996-08-29 | F. Hoffmann-La Roche Ag | N-oxycarbonyl substituted 5'-deoxy-5-fluorcytidines |
-
1994
- 1994-08-26 US US08/296,842 patent/US5476932A/en not_active Expired - Lifetime
-
1995
- 1995-08-09 DE DE69512851T patent/DE69512851T2/de not_active Expired - Lifetime
- 1995-08-09 AT AT95112521T patent/ATE185811T1/de active
- 1995-08-09 EP EP95112521A patent/EP0698611B1/en not_active Expired - Lifetime
- 1995-08-09 ES ES95112521T patent/ES2138691T3/es not_active Expired - Lifetime
- 1995-08-09 DK DK95112521T patent/DK0698611T3/da active
- 1995-08-21 JP JP21157995A patent/JP3986574B2/ja not_active Expired - Lifetime
- 1995-08-25 KR KR1019950026517A patent/KR100335542B1/ko not_active IP Right Cessation
- 1995-08-25 CN CN95109396A patent/CN1053194C/zh not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0060245A1 (en) * | 1980-09-22 | 1982-09-22 | Towmotor Corp | APRON WITH LATERALLY MOVABLE FORKS. |
| EP0602478A1 (en) * | 1992-12-18 | 1994-06-22 | F. Hoffmann-La Roche Ag | Novel process for producing N4-acyl-5'-deoxy-5-fluorocytidine derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| US5476932A (en) | 1995-12-19 |
| CN1126726A (zh) | 1996-07-17 |
| KR960007610A (ko) | 1996-03-22 |
| JP3986574B2 (ja) | 2007-10-03 |
| ATE185811T1 (de) | 1999-11-15 |
| KR100335542B1 (ko) | 2002-11-08 |
| JPH0859687A (ja) | 1996-03-05 |
| ES2138691T3 (es) | 2000-01-16 |
| DE69512851T2 (de) | 2000-05-04 |
| DE69512851D1 (de) | 1999-11-25 |
| EP0698611A1 (en) | 1996-02-28 |
| EP0698611B1 (en) | 1999-10-20 |
| DK0698611T3 (da) | 2000-03-27 |
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