CN1399642A - 制备克拉霉素的方法 - Google Patents
制备克拉霉素的方法 Download PDFInfo
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- CN1399642A CN1399642A CN00816126A CN00816126A CN1399642A CN 1399642 A CN1399642 A CN 1399642A CN 00816126 A CN00816126 A CN 00816126A CN 00816126 A CN00816126 A CN 00816126A CN 1399642 A CN1399642 A CN 1399642A
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- Prior art keywords
- erythromycin
- oxide compound
- methyl
- mixture
- clarithromycin
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- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 title claims abstract description 34
- 229960002626 clarithromycin Drugs 0.000 title claims abstract description 34
- 238000000034 method Methods 0.000 title claims description 33
- 239000000203 mixture Substances 0.000 claims description 44
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 30
- 230000002829 reductive effect Effects 0.000 claims description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- -1 Erythromycin A N-oxide compound Chemical class 0.000 claims description 21
- 239000003795 chemical substances by application Substances 0.000 claims description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 239000011734 sodium Substances 0.000 claims description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 10
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 9
- 235000011150 stannous chloride Nutrition 0.000 claims description 9
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 claims description 9
- UKLDJPRMSDWDSL-UHFFFAOYSA-L [dibutyl(dodecanoyloxy)stannyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)O[Sn](CCCC)(CCCC)OC(=O)CCCCCCCCCCC UKLDJPRMSDWDSL-UHFFFAOYSA-L 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 230000001035 methylating effect Effects 0.000 claims description 7
- 229910000545 Nickel–aluminium alloy Inorganic materials 0.000 claims description 6
- 239000007868 Raney catalyst Substances 0.000 claims description 6
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 6
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 235000019253 formic acid Nutrition 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- 229910003310 Ni-Al Inorganic materials 0.000 claims description 4
- 229910045601 alloy Inorganic materials 0.000 claims description 4
- 239000000956 alloy Substances 0.000 claims description 4
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical group BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 239000012975 dibutyltin dilaurate Substances 0.000 claims description 4
- 238000005984 hydrogenation reaction Methods 0.000 claims description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 4
- ZUHZGEOKBKGPSW-UHFFFAOYSA-N tetraglyme Chemical compound COCCOCCOCCOCCOC ZUHZGEOKBKGPSW-UHFFFAOYSA-N 0.000 claims description 4
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 claims description 2
- RRQYJINTUHWNHW-UHFFFAOYSA-N 1-ethoxy-2-(2-ethoxyethoxy)ethane Chemical compound CCOCCOCCOCC RRQYJINTUHWNHW-UHFFFAOYSA-N 0.000 claims description 2
- CAQYAZNFWDDMIT-UHFFFAOYSA-N 1-ethoxy-2-methoxyethane Chemical compound CCOCCOC CAQYAZNFWDDMIT-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Natural products CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000102 alkali metal hydride Inorganic materials 0.000 claims description 2
- 150000008046 alkali metal hydrides Chemical class 0.000 claims description 2
- 150000004703 alkoxides Chemical class 0.000 claims description 2
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 claims description 2
- 239000011790 ferrous sulphate Substances 0.000 claims description 2
- 235000003891 ferrous sulphate Nutrition 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 claims description 2
- 229910000359 iron(II) sulfate Inorganic materials 0.000 claims description 2
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 claims description 2
- 229940102396 methyl bromide Drugs 0.000 claims description 2
- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 claims description 2
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 claims description 2
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 claims description 2
- 229910003446 platinum oxide Inorganic materials 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 2
- XQKBFQXWZCFNFF-UHFFFAOYSA-K triiodosamarium Chemical compound I[Sm](I)I XQKBFQXWZCFNFF-UHFFFAOYSA-K 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- 229960003276 erythromycin Drugs 0.000 abstract description 10
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 abstract description 8
- 239000003638 chemical reducing agent Substances 0.000 abstract description 2
- MWBJRTBANFUBOX-SQYJNGITSA-N (3r,4s,5s,6r,7r,9r,10e,11s,12r,13s,14r)-6-[(2s,3r,4s,6r)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-14-ethyl-12,13-dihydroxy-10-hydroxyimino-4-[(2r,4r,5s,6s)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-7-methoxy-3,5,7,9,11,13-hexamethyl-oxacyclot Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=N/O)/[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MWBJRTBANFUBOX-SQYJNGITSA-N 0.000 abstract 2
- 239000012022 methylating agents Substances 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- 239000000843 powder Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 239000013078 crystal Substances 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
- 239000006227 byproduct Substances 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 229930006677 Erythromycin A Natural products 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 238000009835 boiling Methods 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 235000017550 sodium carbonate Nutrition 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 238000007069 methylation reaction Methods 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- HOSGXJWQVBHGLT-UHFFFAOYSA-N 6-hydroxy-3,4-dihydro-1h-quinolin-2-one Chemical group N1C(=O)CCC2=CC(O)=CC=C21 HOSGXJWQVBHGLT-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 230000036571 hydration Effects 0.000 description 3
- 238000006703 hydration reaction Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 3
- 241000590002 Helicobacter pylori Species 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229940037467 helicobacter pylori Drugs 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- FGRVOLIFQGXPCT-UHFFFAOYSA-L dipotassium;dioxido-oxo-sulfanylidene-$l^{6}-sulfane Chemical compound [K+].[K+].[O-]S([O-])(=O)=S FGRVOLIFQGXPCT-UHFFFAOYSA-L 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- DJEHXEMURTVAOE-UHFFFAOYSA-M potassium bisulfite Chemical compound [K+].OS([O-])=O DJEHXEMURTVAOE-UHFFFAOYSA-M 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 235000010259 potassium hydrogen sulphite Nutrition 0.000 description 1
- KAQHZJVQFBJKCK-UHFFFAOYSA-L potassium pyrosulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OS([O-])(=O)=O KAQHZJVQFBJKCK-UHFFFAOYSA-L 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 description 1
- 238000011935 selective methylation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- CSMWJXBSXGUPGY-UHFFFAOYSA-L sodium dithionate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)S([O-])(=O)=O CSMWJXBSXGUPGY-UHFFFAOYSA-L 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- JXAZAUKOWVKTLO-UHFFFAOYSA-L sodium pyrosulfate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)OS([O-])(=O)=O JXAZAUKOWVKTLO-UHFFFAOYSA-L 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- XTQHKBHJIVJGKJ-UHFFFAOYSA-N sulfur monoxide Chemical compound S=O XTQHKBHJIVJGKJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Veterinary Medicine (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
克拉霉素可以通过使红霉素AN-氧化物与甲基化试剂反应生成6-O-甲基红霉素AN-氧化物;再用还原剂处理以上得到的6-O-甲基红霉素AN-氧化物,以高收率容易地制备。
Description
技术领域
本发明涉及使用红霉素A N-氧化物制备克拉霉素的方法;以及在所述方法中制备的新的中间体。
背景技术
克拉霉素,6-O-甲基红霉素A,是一种半合成大环内酯抗生素,其显示宽范围的抗革兰氏阳性菌、一些革兰氏阴性菌、厌氧菌、支原体、衣原体(Chlamidia)和幽门螺杆菌(Helicobacter pylori)的抗菌活性。
克拉霉素可以通过将红霉素A的6-羟基甲基化而制备。然而,6-羟基的选择性甲基化难以实现,这是因为红霉素A具有包括6-羟基在内的四个活性羟基,以及在甲基化反应过程中能够发生季铵化的二甲基氨基。
为了解决这种问题,已经开发了多种方法用于克拉霉素的制备。
举例来说,已经公开了使用红霉素A 9-肟衍生物作为中间体,制备克拉霉素的常规方法(见欧洲专利0,158,467;0,195,960;0,269,938;和0,272,110以及国际公开WO 97/36912和WO97/36913)。虽然这种方法给出相对高的收率,但该方法由于需要包括肟化、保护肟基、脱去肟基保护基以及去肟化在内的多步反应步骤造成的低生产效率而受到限制。
另一种用于制备克拉霉素的常规方法在欧洲专利0,147,062和0,177,696中报导。在欧洲专利0,147,062中公开的方法包括下列步骤:用苄氧基羰基保护红霉素A的2-羟基和氨基;甲基化6-羟基;脱去两个苄氧羰基保护基;以及甲基化氨基以获得克拉霉素。然而,这种方法除了有在大规模生产中使用柱色谱分离产品的困难之外,还受到从13.1%至18.5%的低收率问题的困扰,并且需要使用过量的苄氧碳酰氯。
因此,存在开发用于制备克拉霉素的改进方法的需要。
发明内容
因此,本发明的一个目的是提供制备克拉霉素的方法。
本发明的另一目的是提供在所述方法中制备的新的中间体。
根据本发明的一个方面,提供了制备分子式(I)的克拉霉素的方法,所述方法包括下列步骤:
(a)使分子式(II)的红霉素A N-氧化物与甲基化试剂反应,得到分子式(III)的6-O-甲基红霉素A N-氧化物;以及
根据本发明的另一方面,提供了分子式(III)的6-O-甲基红霉素A N-氧化物:
具体实施方式
分子式(I)的化合物可以从红霉素A N-氧化物开始如下制备:步骤(a)
通过使分子式(II)的红霉素A N-氧化物与甲基化试剂在碱的存在下,在有机溶剂中反应制备分子式(III)的6-O-甲基红霉素A N-氧化物,所述分子式(II)的红霉素A N-氧化物根据熟知的方法[E.H.Flynn等,J.Am.Chem.Soc.,
76,3121(1954)和P.H.Jones和E.K.Rowley.,J.Org.Chem.,
33,665(1968)]以大于98%的收率从红霉素A制备。
在本发明中可以适当使用的示例性甲基化试剂为溴代甲烷、碘代甲烷、硫酸二甲酯、对甲苯磺酸甲酯、甲磺酸甲酯以及它们的混合物。基于分子式(II)的红霉素A N-氧化物的量,所使用的甲基化试剂的量在1至3当量的范围内。
在上述甲基化反应中可以使用的示例性溶剂包括N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基-2-吡咯烷酮、二甲亚砜、环丁砜、N,N,N′,N′,N″,N″-六甲基磷酰胺、四氢呋喃、1,4-二噁烷、1,2-二甲氧基乙烷、1,2-二乙氧基乙烷、2-甲氧基乙醚、2-乙氧基乙醚、1,2-二(2-甲氧基乙氧基)乙烷、四甘醇二甲醚、丙酮、乙腈以及它们的混合物。
此外,选自碱金属氢化物、氢氧化物和烷氧化物的碱,例如氢化钠、氢化钾、氢氧化钠、氢氧化钾以及叔丁醇钾可以在该方法中适当地使用。基于分子式(II)的红霉素A N-氧化物的量,所使用的碱的量可以在0.9至2当量的范围内。甲基化反应可以在-15至40℃的温度范围内进行,优选为0℃至室温。
甲基化反应完成后,将水加入所得混合物中,并用氯仿萃取混合物。将萃取物浓缩,并向残余物中加入丙酮,然后搅拌使副产物沉淀。将所得混合物过滤以除去副产物,将滤液浓缩,获得粗品6-O-甲基红霉素A N-氧化物(收率:67至73%,纯度:50至57%)。
上面获得的粗品6-O-甲基红霉素A N-氧化物可以在如步骤(b)中使用,或者用乙酸乙酯重结晶进行纯化以获得精制的6-O-甲基红霉素A N-氧化物(纯度为83%至88%,收率为40至44%),其可以用氯仿重结晶进一步进行纯化以获得纯度大于95%的6-O-甲基红霉素A N-氧化物晶体。步骤(b)
分子式(I)的克拉霉素通过使步骤(a)中获得的6-O-甲基红霉素AN-氧化物与还原剂在有机溶剂中反应以脱去N-氧化物而制备。
在本发明中可以适当地使用的示例性还原剂为氢化催化剂如钯、Raney镍或氧化铂(PtO2)存在下的氢;与氢氧化钾组合的镍-铝合金(Ni-Al合金);甲酸或乙酸存在下的金属锌;碲化氢钠(NaTeH);碘化钐(SmI2);二氯化锡(SnCl2);六丁基二锡(Bu3SnSnBu3);环己烯和四氧化锇(OsO4);以及硫酸亚铁,且在实施本发明时,优选的还原剂为二氯化锡(SnCl2)、六丁基二锡(Bu3SnSnBu3)、与氢氧化钾组合的镍-铝合金以及Raney镍或氧化铂(PtO2)催化剂存在下的氢。
如果将二氯化锡用作还原剂,可以使用溶剂如甲醇、乙醇、异丙醇、乙酸乙酯、乙腈、丙酮、四氢呋喃、1,2-二甲氧基乙烷、二氯甲烷、氯仿以及它们的混合物。基于分子式(III)的6-O-甲基红霉素A N-氧化物的量,所使用的二氯化锡的量在1至3摩尔当量的范围内,并且反应可以在0℃至所使用的溶剂的沸点的温度范围内进行,优选温度为10至45℃。反应结束后,克拉霉素可以通过下列方法分离:(1)用碱如三乙胺中和反应混合物;向其中加入水;并用有机溶剂萃取混合物;或(2)向反应混合物中加入水;用碱如碳酸氢钠、碳酸钠、氢氧化钠溶液以及氨水中和所得混合物;并用有机溶剂萃取混合物。
如果将六丁基二锡用作还原剂,可以使用溶剂如乙酸乙酯、乙腈、丙酮、四氢呋喃、1,2-二甲氧基乙烷以及它们的混合物。基于分子式(III)的6-O-甲基红霉素A N-氧化物的量,所使用的六丁基二锡的量在1至3摩尔当量的范围内,并且反应可以在室温至所使用的溶剂的沸点的温度范围内进行。
当将Ni-Al合金与氢氧化钾一起用作还原剂时,可以采用水和低级醇,例如甲醇和乙醇,的混合物作为溶剂。基于一摩尔分子式(III)的6-O-甲基红霉素A N-氧化物,所使用的Ni-Al合金与氢氧化钾的量分别在0.5至3g和2至20摩尔的范围内。反应可以在室温至所使用的溶剂的沸点的温度范围内进行。
当实施催化氢化作为进行步骤(b)的反应的方法时,可以将低级醇,或水和低级醇的混合物用作溶剂,并且将氢化催化剂如Raney镍用作催化剂,在氢气氛中,在室温至所使用的溶剂的沸点的温度范围内进行。
步骤(b)的反应还可以使用无机还原剂进行,例如亚硫酸氢钠(NaHSO3)、亚硫酸钠(Na2SO3)、硫代硫酸钠(Na2S2O3)、连二亚硫酸钠(Na2S2O4)、焦硫酸钠(Na2S2O5)、连二硫酸钠(Na2S2O6)、亚硫酸氢钾(KHSO3)、硫代硫酸钾(K2S2O3)和焦硫酸钾(K2S2O5)。反应可以在水和低级醇如甲醇、乙醇和异丙醇,的混合物中,在0℃至所使用的溶剂的沸点的温度范围内进行。基于分子式(III)的6-O-甲基红霉素A N-氧化物的量,所用还原剂的量在1至20当量的范围内,优选为1至4当量。
在使用硫氧化物作为还原剂实施步骤(b)的反应时,除分子式(I)的克拉霉素外,分子式(IV)的3′-N-去甲基-6-O-甲基红霉素A可能作为副产物形成。在这种情况下,根据已知的方法[参见Eschweiler &Clarke,Org.React.,
5,290(1945)],该副产物可以通过使用甲酸和甲醛将副产物的仲胺基甲基化而转化为克拉霉素。
以下参考例和实施例用于进一步说明本发明,而不是限制其范围;除非特别指出,本发明中使用的实验方法可以根据本文以下给出的参考例和实施例进行。
此外,除非特别指出,下面给出的固体在固体混合物中、液体在液体中、固体在液体中的百分比分别以wt/wt、vol/vol和wt/vol表示。参考例:红霉素A N-氧化物的制备
将220.2g(0.3mol)红霉素A溶解在1500ml甲醇和1000ml水的混合物中。以在E.H.Flynn等,J.Am.Chem.Soc.,
76,3121(1954)和P.H.Jones等,J.Org.Chem.,
33,665(1968)中描述的类似的方法,在15至20℃的温度范围内向溶液中滴加79ml(0.9mol)35%的过氧化氢,并在室温下搅拌20小时。在减压下将所得混合物浓缩至一半体积,并用1000ml和500ml部分氯仿连续萃取。将合并的氯仿萃取物用盐水洗涤,用无水硫酸镁干燥,然后在减压下浓缩获得泡沫状残余物。将1000ml丙酮加入残余物中,并在室温下搅拌3小时。将形成的晶体物质过滤,并在45℃干燥过夜,以98%的收率获得220g红霉素A N-氧化物。mp:218~221℃(文献中的mp:222~224℃)1H-NMR(CDCl3,ppm):δ5.00(dd,1H,13-H),4.86(d,1H,1″-H),4.50(d,1H,1′-H),3.34(s,3H,克拉定糖-OCH3),3.17(d,6H,德糖胺-N(CH3)2),1.43(s,3H,18-H),0.82(t,3H,15-H)MS(m/z):ESI 750[M+1]+ 实施例1:6-O-甲基红霉素A N-氧化物的制备
将75.0g(0.1mol)在参考例中获得的红霉素A N-氧化物悬浮在450ml二甲亚砜和450ml四氢呋喃的混合物中,并冷却至5℃。向其中加入8.1ml碘代甲烷和7.26g 85%的氢氧化钾粉末,并将混合物搅拌1小时。向所得混合物中加入1000ml冷水,并用1000ml和500ml部分氯仿连续萃取。将合并的萃取物用500ml水洗涤两次,用无水硫酸镁干燥,然后在减压下浓缩。将500ml丙酮加入泡沫状残余物中,并在室温下搅拌5小时。过滤所得混合物以除去沉淀的副产物。在减压下浓缩滤液后,获得52.7g纯度为57%的粗品6-O-甲基红霉素A N-氧化物。
将300ml乙酸乙酯加入粗产物中,并搅拌以获得晶体。过滤晶体,并在45℃干燥过夜,获得30.3g纯度为88%的6-O-甲基红霉素A N-氧化物晶体粉末。
将该晶体粉末用氯仿重结晶后,以27%的收率获得20.1g纯度大于95%的标题化合物。mp:204~207℃IR(KBr,cm-1):3446,2972,2938,1733,1693,1462,1379,1169,1111,10791H-NMR(CDCl3,ppm):δ5.06(dd,1H,13-H),4.93(d,1H,1″-H),4.55(d,1H,1′-H),4.02(dq,1H,5″-H),3.76(d,1H,11-H),3.73(dd,1H,3-H),3.70(d,1H,5-H),3.65(ddq,1H,5′-H),3.38(s,3H,3″-OCH3),3.19(d,6H,3′-N(CH3)2),3.05(s,3H,6-OCH3),2.91(dq,1H,2-H),2.59(ddq,1H,8-H),1.41(s,3H,18-H),1.12(s,3H,6-CH3),0.83(t,3H,14-H)13C-NMR(CDCl3,ppm):δ221.4(C1=O),176.2(C9=O),102.9(C1′),96.5(C1″),81.6(C5),79.0(C6),78.7(C3),78.2(C4″),77.6(C3′),77.0(C13),76.7(C2′),74.7(C12),73.1(C3″),69.5(C11),67.4(C5′),66.3(C5″),59.1(C8′),52.8(C7′),51.0(C22),50.1(C8″),45.7(C8),45.4(C2),39.7(C7),39.6(C4),37.7(C10),35.3(C2″),32.0(C4′),22.0(C6′),21.7(C7″),21.4(C14),20.2(C18),19.1(C6″),18.4(C19),16.4(C21),16.3(C16),12.7(C20),11.0(C15),9.4(C17)MS(m/z):ESI 764[M+1]+ 实施例2:6-O-甲基红霉素A N-氧化物的制备
将75.0g(0.1mol)参考例中获得的红霉素A N-氧化物悬浮在450ml二甲亚砜和450ml四氢呋喃的混合物中,并冷却至5℃。向其中加入8.1ml碘代甲烷和7.26g 85%的氢氧化钾粉末,并将混合物搅拌1.5小时。向所得混合物中加入1000ml的冷水,并用1000ml和500ml部分氯仿连续萃取。将合并的萃取物用500ml水洗涤两次,用无水硫酸镁干燥,然后在减压下浓缩,获得泡沫状残余物。将500ml丙酮加入残余物中,并在室温下搅拌5小时。过滤所得混合物以除去沉淀的副产物。在减压下浓缩滤液,获得50.4g纯度为55%的粗品6-O-甲基红霉素A N-氧化物。实施例3:使用二水合二氯化锡作为还原剂制备克拉霉素
将3.82g(5mmol)实施例1中获得的6-O-甲基红霉素A N-氧化物悬浮在30ml异丙醇中。向其中加入2.26g(2.0mmol)二水合二氯化锡,并将混合物在30至40℃的温度范围内搅拌2小时。向所得混合物中加入饱和碳酸氢钠溶液,并用乙酸乙酯萃取两次。将合并的有机层用水洗涤,用无水硫酸镁干燥,然后在减压下浓缩,以96%的收率获得3.60g克拉霉素白色粉末。mp:220~223℃(文献中的mp:222~225℃)1H-NMR(CDCl3,ppm):δ5.06(dd,1H,13-H),4.92(d,1H,1″-H),4.44(d,1H,1′-H),4.02(dq,1H,5″-H),3.78(dd,1H,3-H),3.77(d,1H,11-H),3.67(d,1H,5-H),3.57(ddq,1H,5′-H),3.33(s,3H,3″-OCH3),3.20(dd,1H,2′-H),3.07~2.95(m,2H,10-H和4″-H),3.03(s,3H,6-OCH3),2.87(dq,1H,2-H),2.58(ddq,1H,8-H),2.40(ddd,1H,3′-H),2.37(d,1H,2″-Heq),2.28(s,6H,3′-N(CH3)2),2.00~1.80(m,3H,4-H和7-H2),1.41(s,3H,18-H),1.13(s,3H,6-CH3),0.85(t,3H,14-CH3)。实施例4:使用六丁基二锡作为还原剂制备克拉霉素
将3.82g(5mmol)实施例1中获得的6-O-甲基红霉素A N-氧化物悬浮在50ml四氢呋喃中。向其中加入5.6ml(2.2mmol)六丁基二锡,并将混合物回流24小时。在减压下将溶剂浓缩,向残余物中加入异丙醚和己烷。将形成的晶体过滤,并用己烷洗涤,以95%的收率获得3.55g克拉霉素白色粉末。实施例5:使用镍-铝合金作为还原剂制备克拉霉素
将3.82g(5mmol)实施例1中获得的6-O-甲基红霉素A N-氧化物悬浮在100ml甲醇和50ml 1N氢氧化钾的混合物中。将温度维持在35至40℃的范围内,在30分钟时间内向其中加入5g镍-铝合金,并搅拌3小时。将所得混合物用甲醇稀释,并通过次乙酰塑料板过滤以除去固体。在减压下将滤液浓缩以除去甲醇,用水稀释残余物。将形成的晶体过滤,用水洗涤并干燥后,以92%的收率得到3.44g克拉霉素白色粉末。实施例6:使用Raney镍催化剂通过氢化制备克拉霉素
将3.82g(5mmol)实施例1中获得的6-O-甲基红霉素A N-氧化物悬浮在100ml乙醇中。向其中加入0.25g W4 Raney镍,并在氢气气氛中在40至45℃的温度范围内搅拌3小时。将所得混合物在50℃或更高温度下通过次乙酰塑料板过滤以除去废催化剂。在减压下将滤液浓缩至30ml,并冷却至室温。将形成的晶体过滤并干燥,以92%的收率得到3.44g克拉霉素白色粉末。实施例7:使用亚硫酸氢钠作为还原剂制备克拉霉素
将3.82g(5mmol)实施例1中获得的6-O-甲基红霉素A N-氧化物悬浮在15ml乙醇和15ml水的混合物中。向其中加入1.05g(10mmol)亚硫酸氢钠,并在室温下搅拌1小时。将所得混合物浓缩,向其中加入水,然后用10%的碳酸钠调节pH至10。将所得混合物用乙酸乙酯萃取三次,合并有机层,用水和盐水洗涤,然后用无水硫酸镁干燥。在减压下除去溶剂,并将获得的残余物溶解在20ml乙醇中。向其中加入0.55ml甲酸和0.8ml 35%的甲醛后,将混合物回流2小时。将混合物浓缩至一半体积,并向其中加入20ml水,然后用10%的碳酸钠将所得混合物的pH调节至11,以92%的收率获得3.44g克拉霉素白色粉末。实施例8:克拉霉素的制备
通过使用75.0g(0.1mol)参考例中获得的红霉素A N-氧化物重复实施例1的步骤,获得54.0g纯度约为54%的粗品6-O-甲基红霉素A N-氧化物。
将如此获得的54.0g粗品6-O-甲基红霉素A N-氧化物溶解在400ml二氯甲烷中,并向其中加入32.6g(144mmol)二水合二氯化锡,然后在室温下搅拌1.5小时。将300ml 10%的碳酸钠加入到所得混合物中,并在减压下除去二氯甲烷。将残余物用400ml和200ml部分乙酸乙酯连续萃取,合并有机层,并用300ml水洗涤两次,然后用无水硫酸镁干燥。在减压下除去溶剂,向残余物中加入100ml乙醇,回流30分钟,并在室温下搅拌3小时。收集形成的固体并干燥,以32%的收率得到24.0g克拉霉素白色晶体。实施例9:克拉霉素的制备
通过使用75.0g(0.1mol)参考例中获得的红霉素A N-氧化物重复实施例1的步骤,获得33.2g纯度约为85%的6-O-甲基红霉素A N-氧化物晶体粉末。
将33.2g纯度为85%的6-O-甲基红霉素A N-氧化物溶解在70ml乙醇和70ml水的混合物中,向其中加入6.52g(62.6mmol)亚硫酸氢钠,然后在室温下搅拌1小时。将所得混合物浓缩至小体积,向浓缩液中加入水,然后用10%的碳酸钠调节pH至10。将所得混合物用乙酸乙酯萃取三次,合并有机层,用水和盐水洗涤,然后用无水硫酸镁干燥。在减压下除去溶剂,并将残余物溶解在80ml乙醇中。向乙醇溶液中加入5.0ml甲酸和7.1ml 35%的甲醛,然后回流2小时。向所得混合物中加入200ml水,用浓氨水调节pH至11,然后冷却至室温。过滤所形成的固体并干燥,以30%的收率获得22.5g克拉霉素白色粉末。
当本发明的实施方案被描述和说明后,很明显在不背离本发明的实质的前提下,可以作出各种改变和修饰,本发明的实质仅受所附权利要求的范围的限制。
Claims (10)
2.权利要求1的方法,其中步骤(a)在碱的存在下,在-15至40℃的温度范围内,在有机溶剂中进行。
3.权利要求1的方法,其中甲基化试剂选自溴代甲烷、碘代甲烷、硫酸二甲酯、对甲苯磺酸甲酯、甲磺酸甲酯以及它们的混合物。
4.权利要求1的方法,其中基于红霉素A N-氧化物的量,甲基化试剂的量在1至3当量的范围内。
5.权利要求2的方法,其中有机溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基-2-吡咯烷酮、二甲亚砜、环丁砜、N,N,N′,N′,N″,N″-六甲基磷酰胺、四氢呋喃、1,4-二噁烷、1,2-二甲氧基乙烷、1,2-二乙氧基乙烷、2-甲氧基乙醚、2-乙氧基乙醚、1,2-二(2-甲氧基乙氧基)乙烷、四甘醇二甲醚、丙酮、乙腈或它们的混合物。
6.权利要求2的方法,其中碱选自碱金属氢化物、氢氧化物、烷氧化物以及它们的混合物。
7.权利要求2的方法,其中基于红霉素A N-氧化物的量,碱的量在0.9至2当量的范围内。
8.权利要求1的方法,其中还原剂选自氢化催化剂存在下的氢;与氢氧化钾组合的镍-铝合金(Ni-Al合金);甲酸或乙酸存在下的金属锌;碲化氢钠(NaTeH);碘化钐(SmI2);二氯化锡(SnCl2);六丁基二锡(Bu3SnSnBu3);环己烯和四氧化锇(OsO4);以及硫酸亚铁;NaHSO3;Na2SO3;Na2S2O3;Na2S2O4;Na2S2O5;Na2S2O6;KHSO3;K2S2O3;K2S2O5;以及它们的混合物。
9.权利要求1的方法,其中还原剂为二氯化锡(SnCl2)、六丁基二锡(Bu3SnSnBu3)、与氢氧化钾组合的镍-铝合金或Raney镍或氧化铂(PtO2)催化剂存在下的氢。
10.分子式(III)的6-O-甲基红霉素A N-氧化物:
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EP1313486A1 (en) * | 2000-02-29 | 2003-05-28 | Teva Pharmaceutical Industries Ltd. | Processes for preparing clarithromycin and clarithromycin intermediate, essentially oxime-free clarithromycin, and pharmaceutical composition comprising the same |
EP2664331B1 (en) | 2003-03-10 | 2015-09-16 | Merck Sharp & Dohme Corp. | Novel Antibacterial Agents |
CA2530581A1 (en) * | 2003-06-23 | 2005-01-06 | Auspex Pharmaceuticals | Novel therapeautic agents for the treatment of cancer, metabolic diseases and skin disorders |
CA2654450A1 (en) * | 2006-06-05 | 2007-12-13 | Auspex Pharmaceuticals, Inc. | Preparation and utility of substituted erythromycin analogs |
CN101917850B (zh) | 2007-10-25 | 2016-01-13 | 森普拉制药公司 | 大环内酯类抗菌剂的制备方法 |
US9072759B2 (en) | 2008-10-24 | 2015-07-07 | Cempra Pharmaceuticals, Inc. | Biodefenses using triazole-containing macrolides |
US9937194B1 (en) | 2009-06-12 | 2018-04-10 | Cempra Pharmaceuticals, Inc. | Compounds and methods for treating inflammatory diseases |
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CN103080122A (zh) | 2010-03-22 | 2013-05-01 | 森普拉制药公司 | 大环内脂的结晶形式及其用途 |
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CA2391145A1 (en) | 2001-05-31 |
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AU755838B2 (en) | 2002-12-19 |
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ES2272342T3 (es) | 2007-05-01 |
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