NO127048B - - Google Patents
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- Publication number
- NO127048B NO127048B NO198070A NO198070A NO127048B NO 127048 B NO127048 B NO 127048B NO 198070 A NO198070 A NO 198070A NO 198070 A NO198070 A NO 198070A NO 127048 B NO127048 B NO 127048B
- Authority
- NO
- Norway
- Prior art keywords
- demethyl
- deoxytetracycline
- epimer
- solution
- stated
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims description 27
- 239000001257 hydrogen Substances 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 13
- RMVMLZHPWMTQGK-SOUFLCLCSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1([C@H]2O)=CC=CC(O)=C1C(O)=C1[C@@H]2C[C@H]2[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]2(O)C1=O RMVMLZHPWMTQGK-SOUFLCLCSA-N 0.000 claims description 11
- JCSGAUKCDAVARS-UHFFFAOYSA-N demethyltetracycline Natural products CN(C1C(=C(C(C2(C(=C3C(C4=C(C=CC=C4C(C3CC12)O)O)=O)O)O)=O)C(=O)N)O)C JCSGAUKCDAVARS-UHFFFAOYSA-N 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 9
- 239000004327 boric acid Substances 0.000 claims description 9
- 230000009467 reduction Effects 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 5
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 4
- 229910052796 boron Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 150000007513 acids Chemical class 0.000 claims description 3
- 150000001447 alkali salts Chemical class 0.000 claims description 3
- 229910052782 aluminium Inorganic materials 0.000 claims description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical class [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 3
- 239000013522 chelant Substances 0.000 claims description 3
- 239000011777 magnesium Chemical class 0.000 claims description 3
- 239000002798 polar solvent Substances 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical class [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical class [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- 150000008043 acidic salts Chemical class 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 239000004411 aluminium Substances 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052791 calcium Chemical class 0.000 claims description 2
- 239000011575 calcium Chemical class 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- XDVCLKFLRAWGIT-ADOAZJKMSA-N sancycline Chemical compound C([C@H]1C2)C3=CC=CC(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2[C@H](N(C)C)C(O)=C(C(N)=O)C1=O XDVCLKFLRAWGIT-ADOAZJKMSA-N 0.000 claims 6
- 230000004048 modification Effects 0.000 claims 1
- 238000012986 modification Methods 0.000 claims 1
- MTCQOMXDZUULRV-ADOAZJKMSA-N (4s,4as,5ar,12ar)-4-(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=CC=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O MTCQOMXDZUULRV-ADOAZJKMSA-N 0.000 description 32
- 239000004098 Tetracycline Substances 0.000 description 28
- 235000019364 tetracycline Nutrition 0.000 description 26
- 150000003522 tetracyclines Chemical class 0.000 description 25
- 229960002180 tetracycline Drugs 0.000 description 23
- 229930101283 tetracycline Natural products 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 239000000243 solution Substances 0.000 description 19
- 239000000203 mixture Substances 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 10
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 9
- 230000000844 anti-bacterial effect Effects 0.000 description 8
- 238000006722 reduction reaction Methods 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000003115 biocidal effect Effects 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- 229910015900 BF3 Inorganic materials 0.000 description 5
- -1 alkali metal salts Chemical class 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 230000007935 neutral effect Effects 0.000 description 5
- 229940040944 tetracyclines Drugs 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 4
- 239000004099 Chlortetracycline Substances 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- CYDMQBQPVICBEU-UHFFFAOYSA-N chlorotetracycline Natural products C1=CC(Cl)=C2C(O)(C)C3CC4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-UHFFFAOYSA-N 0.000 description 4
- 229960004475 chlortetracycline Drugs 0.000 description 4
- CYDMQBQPVICBEU-XRNKAMNCSA-N chlortetracycline Chemical compound C1=CC(Cl)=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-XRNKAMNCSA-N 0.000 description 4
- 235000019365 chlortetracycline Nutrition 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- IYWCBYFJFZCCGV-UHFFFAOYSA-N formamide;hydrate Chemical compound O.NC=O IYWCBYFJFZCCGV-UHFFFAOYSA-N 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000011946 reduction process Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 2
- 229940093475 2-ethoxyethanol Drugs 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- ICPMTQOYWXXMIG-OPDGVEILSA-K aluminum;(2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Al+3].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O ICPMTQOYWXXMIG-OPDGVEILSA-K 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000012928 buffer substance Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000010531 catalytic reduction reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000006345 epimerization reaction Methods 0.000 description 2
- 230000002949 hemolytic effect Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 238000006317 isomerization reaction Methods 0.000 description 2
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 description 2
- 239000011654 magnesium acetate Substances 0.000 description 2
- 229940069446 magnesium acetate Drugs 0.000 description 2
- 235000011285 magnesium acetate Nutrition 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal 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
- 238000002156 mixing Methods 0.000 description 2
- 238000004816 paper chromatography Methods 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 238000002798 spectrophotometry method Methods 0.000 description 2
- 125000001935 tetracenyl group Chemical group C1(=CC=CC2=CC3=CC4=CC=CC=C4C=C3C=C12)* 0.000 description 2
- NWXMGUDVXFXRIG-PMXORCKASA-N (4r,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O NWXMGUDVXFXRIG-PMXORCKASA-N 0.000 description 1
- CIJFGLCHAOVWRZ-QKYUADJBSA-N (4s,4as,5ar,12ar)-4-(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydrochloride Chemical compound Cl.C1C2=CC=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O CIJFGLCHAOVWRZ-QKYUADJBSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- YTTFFPATQICAQN-UHFFFAOYSA-N 2-methoxypropan-1-ol Chemical compound COC(C)CO YTTFFPATQICAQN-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 241000186984 Kitasatospora aureofaciens Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000009920 chelation Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000003245 coal Substances 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000004508 fractional distillation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical group [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- OFVLGDICTFRJMM-WESIUVDSSA-N tetracycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O OFVLGDICTFRJMM-WESIUVDSSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical class OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Framgangsmåte for framstilling av 6-demetyl-6-deoksytetracyclin. Process for the production of 6-demethyl-6-deoxytetracycline.
Foreliggende oppfinnelse vedrører fram-stillingen av nye forbindelser av tetracyc-linserien. The present invention relates to the production of new compounds of the tetracycline series.
Disse nye forbindelser fremstilt i hen- These new compounds prepared in
hold til oppfinnelsen omfatter 6-demetyl-6-deoksytetracyclin med den generelle formelen: according to the invention includes 6-demethyl-6-deoxytetracycline with the general formula:
og 4-epimeret av nevnte 6-demetyl-6-deoksytetracyclin. Oppfinnelsen omfatter and the 4-epimer of said 6-demethyl-6-deoxytetracycline. The invention includes
også framstilling av de terapeutisk aktive also production of the therapeutically active ones
sure og basiske salter og kompleksforbin-delser av nevnte 6-demetyl-6-deoksytetra-cyclin og 5-epimeret av nevnte 6-demetyl-6-deoksytetracyclin, f. eks. mineralsyre-saltene, alkalimetallsaltene og jordalkali-metallsaltene såvel som forskjelige kom-pleksforbindelser, nemlig forbindelser som acidic and basic salts and complex compounds of said 6-demethyl-6-deoxytetracycline and the 5-epimer of said 6-demethyl-6-deoxytetracycline, e.g. the mineral acid salts, the alkali metal salts and the alkaline earth metal salts as well as various complex compounds, namely compounds which
fås ved reaksjon med salter av aluminium, obtained by reaction with salts of aluminium,
magnesium og kalsium med sterke syrer. magnesium and calcium with strong acids.
De nye forbindelser fremstilt i henhold The new compounds prepared according to
til oppfinnelsen er beslektet med den vel-kjente og i stor utstrekning anvendte bred-spektrete antibiotiske tetracyclin. 6-demetyl-6-deoksytetracyclinet som her be-skrives, atskiller seg essensielt fra tetracyclin ved at hydroksygruppen og metyl- to the invention is related to the well-known and widely used broad-spectrum antibiotic tetracycline. The 6-demethyl-6-deoxytetracycline described here differs essentially from tetracycline in that the hydroxy group and methyl
gruppen i 6-stillingen i naftacenringen hver er blitt erstattet med et hydrogen-atom. Denne endring medfører en slående forskjell med hensyn til aktiviteten av det resulterende 6-demetyl-6-deoksytetracyclin som har en og en halv gange den biologiske aktivitet like overfor Staphyloccus aureus som tetracyclin oppviser. Dessuten er 6-demetyl-6-deoksytetracyclin aktiv likeoverfor visse stammer av bakterier som er motstandsdyktige likeoverfor tetracyclin. the group in the 6-position of the naphthacene ring has each been replaced by a hydrogen atom. This change results in a striking difference in the activity of the resulting 6-demethyl-6-deoxytetracycline, which has one and a half times the biological activity against Staphyloccus aureus that tetracycline exhibits. Moreover, 6-demethyl-6-deoxytetracycline is active against certain strains of bacteria which are resistant against tetracycline.
Det er et meget overraskende trekk ved foreliggende oppfinnelse at 6-demetyl-6-deoksytetracyclinet bibeholder den typiske bredspektrede antibakterielle aktivitet av tetracyclin, særlig når man tar i betrakt-ning at anhydrotetracyclin som også mangler en hydroksygruppe i 6-stillingen i naf-tasenringen, oppviser en betydelig lavere antibakteriell aktivitet enn tetracyclin. Videre er det helt uventet at en forbindelse som mangler metyl- og hydroksygruppene i tetracyclin ville være mer antibakterielt aktivt enn selve tetracyclinet. It is a very surprising feature of the present invention that the 6-demethyl-6-deoxytetracycline retains the typical broad-spectrum antibacterial activity of tetracycline, especially when one takes into account that anhydrotetracycline, which also lacks a hydroxy group in the 6-position of the naphthase ring, exhibits a significantly lower antibacterial activity than tetracycline. Furthermore, it is completely unexpected that a compound lacking the methyl and hydroxy groups in tetracycline would be more antibacterially active than the tetracycline itself.
Et passende kjemisk navn for dette tetracyclin analogt med foreliggende oppfinnelse er i henhold til den nomenklatur som brukes av Chemical Abstracts, 4-de-metylamino-1, 4, 4a, 5, 5a, 6, 11, 12a-okta-hydro-3, 10, 12, 12a-tetrahydroksy-l, 11-diokso-2-naftacenkarboksamid. Et hen-siktsmessig vanlig navn på denne forbindelse er 6-demetyl-6-deoksytetracyclin som her generelt skal anvendes. A suitable chemical name for this tetracycline analogous to the present invention is according to the nomenclature used by Chemical Abstracts, 4-de-methylamino-1, 4, 4a, 5, 5a, 6, 11, 12a-octa-hydro-3 , 10, 12, 12α-tetrahydroxy-1, 11-dioxo-2-naphthacenecarboxamide. An appropriate common name for this compound is 6-demethyl-6-deoxytetracycline, which will generally be used here.
En annen av de mer viktige fordeler som den nye forbindelse fremstilt i henhold til den foreliggende oppfinnelse er i besittelse av, likeoverfor de tidligere beskrevne tetracycliner, er deres økte stabilitet i syrer og alkali. Syreustabiliteten av tetracyclin og alkali-ustabiliteten av klortetracyclin er alminnelig kjent. Klortetracyclin i en vandig oppløsning med en natri-umkarbonatpuffersubstans ved pH 9,85 taper 50 pst. av aktiviteten i løpet av 29,2 min. ved 23° C. I motsetning hertil taper 6-demetyl-6-deoksytetracyclin ikke mer enn 1 pst. av aktiviteten i løpet av 24 timer under de samme forhold. Tetracyclin har en halv levetid av mindre enn 1 minutt i mindre enn 3 normal klorhydrogensyre ved 100° C. 6-demetyl-6-deoksytetracyclin har på den annen side en halv levetid av 1644 min. under de samme forhold. Tetracyclin har en halv levetid av ca. 6 min. i 0,1 normal natriumhydroksydoppløsning ved 100° C. I motsetning hertil har 6-demetyl-6-deoksytetracyclin en halv levetid av 198 min. under de samme forhold. Disse uven-tede egenskaper er meget verdifulle forså-vidt som syreustabiliteten av tetracyclin og alkali-ustabiliteten av klortetracyclin har begrenset eller fullstendig hindret bru-ken av disse antibiotika for mange øyemed. Som følge av den meget bedre stabilitet av det nye 6-demetyl-6-deoksytetracyclin er det mulig å fremstille mange farmasøytiske Another of the more important advantages that the new compound prepared according to the present invention possesses, directly opposite the previously described tetracyclines, is their increased stability in acids and alkali. The acid instability of tetracycline and the alkali instability of chlortetracycline are well known. Chlortetracycline in an aqueous solution with a sodium carbonate buffer substance at pH 9.85 loses 50 per cent of its activity in 29.2 min. at 23° C. In contrast, 6-demethyl-6-deoxytetracycline does not lose more than 1 percent of its activity during 24 hours under the same conditions. Tetracycline has a half-life of less than 1 minute in less than 3 normal hydrochloric acid at 100° C. 6-Demethyl-6-deoxytetracycline, on the other hand, has a half-life of 1644 minutes. under the same conditions. Tetracycline has a half-life of approx. 6 min. in 0.1 normal sodium hydroxide solution at 100° C. In contrast, 6-demethyl-6-deoxytetracycline has a half-life of 198 min. under the same conditions. These unexpected properties are very valuable insofar as the acid instability of tetracycline and the alkali instability of chlortetracycline have limited or completely prevented the use of these antibiotics for many purposes. As a result of the much better stability of the new 6-demethyl-6-deoxytetracycline, it is possible to prepare many pharmaceutical
produkter som ikke på en tilfredsstillende products that are not on a satisfactory
måte kunne fremstilles med de tidligere kjente tetracycliner. Den økte stabilitet gjør det også mulig å forbedre utvinnings-og rensningsprosessene da der kan anvendes mer drastiske pH og temperaturforhold uten at den nye forbindelse ødelegges. way could be prepared with the previously known tetracyclines. The increased stability also makes it possible to improve the extraction and purification processes as more drastic pH and temperature conditions can be used without the new compound being destroyed.
Som nevnt ovenfor er den antibakterielle aktivitet av 6-demetyl-6-deoksytetra-cyclin i mange henseender meget lik aktiviteten av de tidligere kjente tetracycliner og i enkelte tilfeller, særlig overfor Staphyl loccus aureus, er den meget større, og den nye forbindelse kan således administreres av legen på den samme måte og i omtrent-lig de samme doseringer som med tetra-cyclinene som for tiden er i bruk. Det nye tetracyclin kan videre, da det oppviser den typiske bred-spektrede antibiotiske aktivitet av de tidligere kjente tetracycliner, anvendes ved behandlingen av forskjellige infeksjoner som frembringes av både Gram-positive og Gram-negative bakterier hvor behandlingen av slike infeksjoner med tetracyclin eller klortetracyclin er ønskelig. As mentioned above, the antibacterial activity of 6-demethyl-6-deoxytetracycline is in many respects very similar to the activity of the previously known tetracyclines and in some cases, particularly against Staphyl loccus aureus, it is much greater, and the new compound can thus administered by the doctor in the same way and in approximately the same dosages as with the tetracyclines currently in use. The new tetracycline can furthermore, as it exhibits the typical broad-spectrum antibiotic activity of the previously known tetracyclines, be used in the treatment of various infections caused by both Gram-positive and Gram-negative bacteria, where the treatment of such infections with tetracycline or chlortetracycline is desirable.
Det antibakterielle spektrum av den nye forbindelse, som representerer den mengde som kreves for å hemme veksten av forskjellige typiske bakterier, ble bestemt på vanlig måte ved næringsmiddelfortyn-ningsrørteknikken som i alminnelighet brukes for å prøve nye antibiotika. Mini-mumskonsentrasj onene som bevirker hem-ning og uttrykt i gamma pr. milliliter av 6-demetyl-6-deoksytetracyclin like overfor forskjellige prøveorganismer er anført i den følgende tabell. For sammenlignings skyld er også oppført den antibakterielle aktivitet av tetracyclin likeoverfor de samme organismer. The antibacterial spectrum of the new compound, which represents the amount required to inhibit the growth of various typical bacteria, was determined in the usual manner by the nutrient dilution tube technique commonly used to test new antibiotics. The minimum concentrations that cause inhibition and expressed in gamma per milliliters of 6-demethyl-6-deoxytetracycline equally against various test organisms is listed in the following table. For the sake of comparison, the antibacterial activity of tetracycline against the same organisms is also listed.
Av det foran anførte vil det sees at i mange henseender er det antibakterielle spektrum av den nye forbindelse meget nært parallelt med det antibakterielle spektrum for tetracyclin, men i tilslutning hertil er den nye forbindelse effektiv likeoverfor visse tetracyclin-resistente stammer av bakterier, som f. eks. Streptococcus plogenes gamma hemolytic, Micococcus pyogenes var albus, Streptococcus pyogenes beta hemolytic, osv., likesom også den nye forbindelse er 1 besiddelse av den meget viktige fordel å oppvise en biologisk verdi av oa. en og en halv gang den for tetracyclin likeoverfor Staphylococcus aureus målt ved den vanlige turbidimetriske prøve (Annals of the New York Academy of Sciences, 5, 218 (1940)). 6-demetyl-6-deoksytetracyclin fremstilles i overensstemmelse med oppfinnelsen ved en temmelig enestående katalytisk reduksjon av et demetyltetracyclin eller den 4-epimere av et demetyl-tetracyclin. De-metyltetracyclinene som er antibiotika, har følgende formel: From the foregoing, it will be seen that in many respects the antibacterial spectrum of the new compound is very closely parallel to the antibacterial spectrum for tetracycline, but in addition, the new compound is equally effective against certain tetracycline-resistant strains of bacteria, such as e.g. Streptococcus plogenes gamma hemolytic, Micococcus pyogenes var albus, Streptococcus pyogenes beta hemolytic, etc., as also the new compound is 1 possession of the very important advantage of exhibiting a biological value of oa. one and a half times that of tetracycline compared to Staphylococcus aureus measured by the usual turbidimetric test (Annals of the New York Academy of Sciences, 5, 218 (1940)). 6-Demethyl-6-deoxytetracycline is prepared in accordance with the invention by a rather unique catalytic reduction of a demethyltetracycline or the 4-epimer of a demethyltetracycline. The de-methyltetracyclines, which are antibiotics, have the following formula:
hvor Z er hydrogen, klor eller brom og er beskrevet i J. A. C. S. 79, 4561 (1957) og fremstilles av visse mutante stammer av S. aureofaciens av hvilke noen er gitt num-rene S605, S1071, V62 og B740. where Z is hydrogen, chlorine or bromine and is described in J. A. C. S. 79, 4561 (1957) and is produced by certain mutant strains of S. aureofaciens some of which are given the numbers S605, S1071, V62 and B740.
Kulturer av disse stammer er deponert i American Type Culture Collection i Was-hington D. C. og er blitt gitt ATCC-rekke-numrene 12551, 12552, 12553 og 125554. Cultures of these strains are deposited in the American Type Culture Collection in Washington, D.C. and have been assigned ATCC accession numbers 12551, 12552, 12553, and 125554.
I overensstemmelse med oppfinnelsen fremstilles de nye forbindelser i henhold til oppfinnelsen ved katalytisk reduksjon av et demetyltetracyclin med formelen II eller et 4-epimer herav i oppløsning i et inert polart oppløsningsmiddel i nærvær av en substans som er i stand til å danne en chelatring med et peri-dioksygenert hydronaftalin. Reduksjonen kan utføres med hydrogen i nærvær av en passende katalysator, som f. eks. findelt metallisk palladium eller et annet metall av platinafamilien eller palladiumhydroksyd på benkull. Passende forbindelser som er i besittelse av denne egenskap å danne en chelatring og som kan anvendes med godt resultat ved denne reduksjonsprosess, er borsyre, bor-trihalogenider, som f. eks. bor-trifluorid, aluminium- og magnesiumsalter, som aluminiumklorid, magnesiumacetat osv. Borsyre eller bor-trihalogenider synes å være de mest nyttige forbindelser med hensyn til utbyttene av det ønskede produkt. Vanligvis er borsyre eller bor-trihalogenid til-stede i i det minste mol for mol mengder. Reduksjonen kan utføres ved temperaturer varierende fra 0° C til 100° C og fortrinnsvis fra ca. romtemperatur til ca. 50° C og ved hydrogentrykk av fra ca. y2 til ca. 100 atmosfærer. In accordance with the invention, the new compounds according to the invention are prepared by catalytic reduction of a demethyltetracycline of the formula II or a 4-epimer thereof in solution in an inert polar solvent in the presence of a substance capable of forming a chelate ring with a peri-dioxygenated hydronaphthalene. The reduction can be carried out with hydrogen in the presence of a suitable catalyst, such as e.g. finely divided metallic palladium or another metal of the platinum family or palladium hydroxide on bone charcoal. Suitable compounds which possess this property of forming a chelate ring and which can be used with good results in this reduction process are boric acid, boron trihalides, such as e.g. boron trifluoride, aluminum and magnesium salts, such as aluminum chloride, magnesium acetate, etc. Boric acid or boron trihalides appear to be the most useful compounds in terms of yields of the desired product. Generally, boric acid or boron trihalide is present in at least mole for mole amounts. The reduction can be carried out at temperatures varying from 0° C to 100° C and preferably from approx. room temperature to approx. 50° C and at hydrogen pressure from approx. y2 to approx. 100 atmospheres.
Passende inerte oppløsningsmidler som kan anvendes ved reduksjonen, er forskjellige polare oppløsningsmidler, som vann, dioksan, iseddek, 2-etoksyetanol og etylacetat. Et en-til-en forhold av vann og dimetylformamid har vist seg å være en særlig god oppløsningsmiddelblanding for denne reaksjon. En liten mengde perklorsyre tilsettes vanligvis til oppløsningen. Suitable inert solvents which can be used in the reduction are various polar solvents, such as water, dioxane, glacial acetic acid, 2-ethoxyethanol and ethyl acetate. A one-to-one ratio of water and dimethylformamide has been found to be a particularly good solvent mixture for this reaction. A small amount of perchloric acid is usually added to the solution.
En kontentrasjon av en katalysator av i det minste 5 vektsprosent av 6-de-metyltetracyclinet er nødvendig og opp til 100 vektsprosent kan anvendes. Hydrogeneringen utføres vanligvis inntil et mol hydrogen er blitt absorbert når 6-demetyl-6-deoksy-tetracyclin er utgangsmaterialet, og på dette tidspunkt har absorpsjonen en tendens til å avta. Når 7-glor-6-demetyl-tetracyclin anvendes, kreves det naturlig-vis 2 mol hydrogen. Det må utøves noen forsiktighet for at ikke hydrogeneringen skal fortsette i alt for lang tid da det i så fall kan finne sted ytterligere og uønskete reduksjoner under dannelse av mindre ønskete produkter. A concentration of a catalyst of at least 5% by weight of the 6-demethyltetracycline is necessary and up to 100% by weight can be used. The hydrogenation is usually carried out until one mole of hydrogen has been absorbed when 6-demethyl-6-deoxy-tetracycline is the starting material, at which point the absorption tends to decrease. When 7-chloro-6-dimethyl-tetracycline is used, naturally 2 moles of hydrogen are required. Care must be taken not to allow the hydrogenation to continue for too long, as in that case further and undesirable reductions may take place with the formation of less desirable products.
Substansene som er i stand til å danne en chelatring som beskrevet ovenfor, som anvendes ved den beskrevne reduksjonsprosess, er meget viktige reagenser da de tydeligvis virker som kompleksdannende midler og tjener til å hindre reduksjon av oksygenfunksjonene ved 11- og 12-stillin-gene i naftacenringen. Disse reagenser er meget viktige ved reduksjonen da ved et fravær av slike midler reduseres fortrins-vis 12-stillingen og ikke 6-stillingen, og den resulterende forbindelse oppviser,ikke noen biologisk aktivitet. Ved den beskrevne reduksjonsprosess tjener imidlertid chelati-seringen til å binde disse oksygenfunksjo-ner og hindrer deres reduksjon, slik at den antibakterielle aktivitet av forbindelsen bibeholdes. The substances capable of forming a chelating ring as described above, which are used in the described reduction process, are very important reagents as they clearly act as complexing agents and serve to prevent reduction of the oxygen functions at the 11- and 12-positions in the naphthacene ring. These reagents are very important in the reduction, since in the absence of such agents, the 12-position is preferentially reduced and not the 6-position, and the resulting compound exhibits no biological activity. In the described reduction process, however, the chelation serves to bind these oxygen functions and prevents their reduction, so that the antibacterial activity of the compound is maintained.
Etterat hydrogeneringen er tilende-brakt, utvinnes 6-demetyl-6-deoksytetra-cyclinet ved hjelp av hvilke som helst ønskete midler, f. eks. ved at katalysatoren fjernes og oppløsningen konsentreres. Produktet inndampes til tørrhet, renses ved fraksjonert utfeining i metanol og kan renses ytterligere ved omkrystallisering i alkohol på vanlig måte. Det nøytrale produkt som dannes på denne måte, kan omdannes til et mineralsyresalt, dvs. til hydrokloridet, ved behandling med syre som klorvannstoffsyre ved en pH av mindre enn ca. 4. Andre sure salter som svovelsyresaltet, fosforsyresaltet, triklor-eddiksyresaltet osv. kan dannes på liknende måte. Fortrinnsvis kan 6-demetyl-6-dioksy-tetracyclinet suspenderes i et passende oppløsningsmiddel under ansyringen. Alkalimetallsaltene og jordalkalimetallsalt-ene kan ganske enkelt dannes ved å be-handle den amfotære forbindelse med om-trentlig en ekvivalent av den valgte base, dvs. natriumhydroksyd, kaliumhydroksyd, kalsiumhydroksyd, bariumhydroksyd osv. Metallsaltene kan fremstilles i vandig opp-løsning eller i et passende oppløsningsmid-del. Fortrinnsvis fremstilles de basiske salter ved en pH av 6 eller høyere. Den frie base kan oppnås ved en pH innenfor området av ca. 4—6. De komplekse forbindelser, som f. eks. 6-demetyl-6-deoksytetra-cyclin aluminium-glukonat-komplekset kan f. eks. dannes ved den enkle tilblanding av hydrokloridet av den nye forbindelse og aluminiumglukonat i en vandig oppløs-ning. After the hydrogenation is completed, the 6-demethyl-6-deoxytetracycline is recovered by any desired means, e.g. by removing the catalyst and concentrating the solution. The product is evaporated to dryness, purified by fractional distillation in methanol and can be further purified by recrystallization in alcohol in the usual way. The neutral product formed in this way can be converted to a mineral acid salt, i.e. to the hydrochloride, by treatment with an acid such as hydrochloric acid at a pH of less than approx. 4. Other acid salts such as the sulfuric acid salt, the phosphoric acid salt, the trichloroacetic acid salt, etc. can be formed in a similar way. Preferably, the 6-demethyl-6-dioxy-tetracycline can be suspended in a suitable solvent during the acidification. The alkali metal salts and alkaline earth metal salts can simply be formed by treating the amphoteric compound with approximately one equivalent of the chosen base, i.e. sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, etc. The metal salts can be prepared in aqueous solution or in a suitable solvent part. Preferably, the basic salts are prepared at a pH of 6 or higher. The free base can be obtained at a pH within the range of approx. 4-6. The complex compounds, such as The 6-demethyl-6-deoxytetracycline aluminum gluconate complex can e.g. is formed by the simple addition of the hydrochloride of the new compound and aluminum gluconate in an aqueous solution.
4-epimeret av 6-demetyl-6-deoksyte-tracyclin, som har en epimerisk form ved kullstoffatomet ved stillingen fire, den samme som er blitt beskrevet i forbindelse med andre tetracyclinforbindelser, kan også dannes ved enkel regulering av hydrogenionekonsentrasjonen av en konsentrert The 4-epimer of 6-demethyl-6-deoxytetracycline, which has an epimeric form at the carbon atom at position four, the same as has been described in connection with other tetracycline compounds, can also be formed by simple regulation of the hydrogen ion concentration of a concentrated
oppløsning av antibiotikumet til innenfor området av pH 3,0 til 5,0 og man lar opp-løsningen få henstå inntil isomeriseringen er kommet til en likevekt. solution of the antibiotic to within the range of pH 3.0 to 5.0 and the solution is allowed to stand until the isomerization has reached an equilibrium.
Isomeriseringen utføres mest hensikts-messig ved romtemperatur, skjønt en høy-ere omdannelsesgrad kan finne sted ved høyere temperaturer. pH skal være innenfor området av ca. 3,0 til 5,0 fortrinnsvis mellom 3,5 og 4,5. En del epimerisering vil finne sted ved hydrogenionekonsentra-sjoner utenfor disse områder og endog i destillert vann, men hastigheten er meget langsom. Konsentrasjonen av antibiotikumet i den vandige oppløsning kan være så høy som mulig for å oppnå de hurtigere grader av epimeriseringen. Fullstendig likevekt kan kreve en tidsperiode av ca. The isomerization is most conveniently carried out at room temperature, although a higher degree of conversion can take place at higher temperatures. The pH must be within the range of approx. 3.0 to 5.0 preferably between 3.5 and 4.5. Some epimerization will take place at hydrogen ion concentrations outside these ranges and even in distilled water, but the rate is very slow. The concentration of the antibiotic in the aqueous solution can be as high as possible to achieve the faster degrees of epimerization. Complete equilibrium may require a time period of approx.
24 timer ved 25° C, men en tilfredsstillende 24 hours at 25° C, but a satisfactory one
likevekt kan kreve en betydelig kortere tid under spesielle forhold. I alminnelighet oppnås imidlertid de beste resultater ved equilibrium may require a significantly shorter time under special conditions. In general, however, the best results are obtained by
å la oppløsningene henstå i tidsperioder av en uke eller mer. En likevekt synes å bli nådd i de fleste tilfeller ved ca. 50 pst. dvs. omtrent halvdelen av antibiotikumet omdannes til epimeret ved likevekt. allowing the solutions to stand for periods of a week or more. An equilibrium seems to be reached in most cases at approx. 50 percent, i.e. approximately half of the antibiotic is converted to the epimer at equilibrium.
Da konsentrasjonen er en viktig faktor for å oppnå høye utbytter i løpet av korte tidsperioder, bør det velges et oppløsnings-middelsystem som gir den høyeste konsen-trasjon av antibiotikumet. Disse oppløs-ningsmiddelsystemer skal behandles med puffersubstanser for å få en pH innenfor det foretrukne område. Forskjellige opp-løsningsmidler omfatter metanol, etanol, butanol, aceton, 2-etoksy-etanol, 2-metoksy -propanol, iseddek, tetrahydrofuran, dimetylformamid og blandinger av disse oppløsningsmidler. Andre oppløsnings-midler kan også anvendes. Et foretrukket puffermiddel er natriumdihydrogenfosfat, skjønt andre puffersubstanser og puffer-substanspar kan anvendes som vil holde hydrogenionekonsentrasjonen innenfor det ønskete område. As the concentration is an important factor for achieving high yields within short periods of time, a solvent system should be chosen which gives the highest concentration of the antibiotic. These solvent systems must be treated with buffer substances to obtain a pH within the preferred range. Various solvents include methanol, ethanol, butanol, acetone, 2-ethoxy-ethanol, 2-methoxy-propanol, glacial acetic acid, tetrahydrofuran, dimethylformamide and mixtures of these solvents. Other solvents can also be used. A preferred buffer agent is sodium dihydrogen phosphate, although other buffer substances and buffer-substance pairs can be used which will keep the hydrogen ion concentration within the desired range.
Oppfinnelsen skal i det følgende be-skrives mer detaljert i forbindelse med de følgende spesielle eksempler. In the following, the invention will be described in more detail in connection with the following special examples.
Eksempel 1. Example 1.
Tolv gram av 6-demetyltetracyclin nøy-tral (J.A.C.S. 79, 4561 (1957)) suspenderes i 10 volumdeler av en 1 til 1 blanding av vann og dimetylformamid. Hydroklorid-saltet herav framstilles ved behandling med konsentrert saltsyre ved en pH av 1,8. Til blandingen tilsettes 1,48 gram borsyre, 12 gram uredusert 5 pst. palladium på kullstoff og 0,03 milliliter perklorsyre. Hydrogeneringen utføres ved reaksjon med hydrogen ved ca. 1,4 kg/cm på en Parr ryster i ca. 2 timer. Hydrogeneringen er tilende-brakt etterat ca. 1 mol hydrogen er blitt absorbert. Oppløsningen filtreres, og katalysatoren vaskes med 10 ml dimetylformamid og derpå en annen vasking med 10 ml vann. Twelve grams of 6-demethyltetracycline neutral (J.A.C.S. 79, 4561 (1957)) is suspended in 10 volumes of a 1 to 1 mixture of water and dimethylformamide. The hydrochloride salt thereof is produced by treatment with concentrated hydrochloric acid at a pH of 1.8. 1.48 grams of boric acid, 12 grams of unreduced 5% palladium on carbon and 0.03 milliliters of perchloric acid are added to the mixture. The hydrogenation is carried out by reaction with hydrogen at approx. 1.4 kg/cm on a Parr shaker for approx. 2 hours. The hydrogenation is completed after approx. 1 mole of hydrogen has been absorbed. The solution is filtered, and the catalyst is washed with 10 ml of dimethylformamide and then another wash with 10 ml of water.
Ekempel 2. Example 2.
Filtratet som fåes ved fremgangsmåten som var beskrevet i eksempel 1, inndampes til tørrhet. Der tilsettes 50 ml vann, og blandingen omrøres og fryse-tørkes. Det tørkete material oppslemmes i 100 ml metanol og sentrifugeres derpå. Til 88 ml av metanoloppløsningen tilsettes 88 ml eter. Der dannes utfelling, og der sentrifugeres. Den ovenstående oppløsning bestående av en 1 til 1 metanol- og eteroppløsning, og som har et volum av 130 ml, inndampes til 1/3 av sitt volum. Der tilsettes 0,5 ml konsentrert saltsyre, og oppløsningen inndampes til 5,5 ml i en atmosfære av nitrogen. Oppløsningen smittes og eldes i 18 timer ved romtemperatur. Krystallene filtreres, vaskes med aceton og derpå med eter og tørkes i vakuum ved 40° C i 20 timer, så at man får 0,675 gram 6-demetyl-6-deoksy-tetracyclin. The filtrate obtained by the method described in example 1 is evaporated to dryness. 50 ml of water is added, and the mixture is stirred and freeze-dried. The dried material is suspended in 100 ml of methanol and then centrifuged. 88 ml of ether is added to 88 ml of the methanol solution. A precipitate is formed and centrifuged. The above solution consisting of a 1 to 1 methanol and ether solution, which has a volume of 130 ml, is evaporated to 1/3 of its volume. 0.5 ml of concentrated hydrochloric acid is added there, and the solution is evaporated to 5.5 ml in an atmosphere of nitrogen. The solution is infected and aged for 18 hours at room temperature. The crystals are filtered, washed with acetone and then with ether and dried in vacuum at 40° C. for 20 hours, so that 0.675 grams of 6-demethyl-6-deoxy-tetracycline is obtained.
Eksempel 3. Example 3.
Til 1,36 gram av det rå 6-demetyl-6-deoksytetracyclin, som fremstilles som beskrevet i eksempel 2, tilsettes 196 ml vann og pH reguleres til 1,2 med saltsyre og produktet filtreres. Filtratets pH reguleres til 2,75 med ammoniumhydroksyd og vaskes 3 ganger med 200 ml eter. Den vaskete oppløsning konsentreres under redusert trykk ved 40—50° C til et volum av 50 ml. pH reguleres til 4,5 med ammoniumhydroksyd, og der dannes krystaller av nøytralt 6-demetyl-6-deoksytetracyclin. Krystallene eldes, filtreres, vaskes med vann og tørkes i vakuum ved 40° C i 23 timer. Utbyttet 0,710 gram. To 1.36 grams of the crude 6-demethyl-6-deoxytetracycline, which is prepared as described in example 2, 196 ml of water is added and the pH is adjusted to 1.2 with hydrochloric acid and the product is filtered. The pH of the filtrate is adjusted to 2.75 with ammonium hydroxide and washed 3 times with 200 ml of ether. The washed solution is concentrated under reduced pressure at 40-50° C to a volume of 50 ml. The pH is adjusted to 4.5 with ammonium hydroxide, and crystals of neutral 6-demethyl-6-deoxytetracycline are formed there. The crystals are aged, filtered, washed with water and dried in a vacuum at 40° C for 23 hours. Yield 0.710 grams.
Eksempel 4. Example 4.
To tredjedel av et gram av 6-demetyl-6-deoksytetracyclin oppslemmes i 13,5 etyl-alkohol. Der tilsettes 0,5 ml konsentrert saltsyre for å regulere pH til 0,8 til 1,0. Oppløsningen eldes i 3y2 time. 6-demetyl-6-deoksytetracyclin-hydrokloridkrystal-lene som dannes, tørkes i vakuum ved 100° C i 20 timer. Two-thirds of a gram of 6-demethyl-6-deoxytetracycline is suspended in 13.5 ethyl alcohol. 0.5 ml of concentrated hydrochloric acid is added to adjust the pH to 0.8 to 1.0. The solution is aged for 3y2 hours. The 6-demethyl-6-deoxytetracycline hydrochloride crystals that are formed are dried in a vacuum at 100° C. for 20 hours.
Produktet ha ret smeltepunkt av 215 The product has a melting point of 215
til 220° C under spaltning. to 220° C during decomposition.
Analyse: Analysis:
Beregnet for C21<H>22N207. HC1.1/21^0, molekylarvekt 459,5: C, 54,9; H, 5,26; N, 6,10; Cl, 7,72; O, 26,1; 1/2H20, 1,96. Funnet: C, 54,81; H, 5,32; N, 6,16; Cl, 7,80; O, 25,91 Calculated for C21<H>22N207. HC1.1/21^O, molecular weight 459.5: C, 54.9; H, 5.26; N, 6.10; Cl, 7.72; O, 26.1; 1/2H 2 O, 1.96. Found: C, 54.81; H, 5.32; N, 6.16; Cl, 7.80; Oh, 25.91
(ved subtraksjon); H20, 2,06. Nøytraliser - ingsekvikalent 477. (by subtraction); H 2 O, 2.06. Neutralize - ingsequicalent 477.
Produktet har en optisk dreining av 25° The product has an optical rotation of 25°
Lal D = — 109,0 (i 0,1 normal H2S04 Lal D = — 109.0 (in 0.1 normal H2S04
oppløsning). Det ultraviolette absorbsjonsspektrum bestemmes fra en prøve av forbindelsen i 0,1N svovelsyre ved en konsen-trasjon av 30,65 gamma pr. milliliter (vekts/ volum). Det infrarøde absorbsjonsspektrum bestemmes på en prøve av forbindelsen blandet med krystallet av KBr og presses til en skive. resolution). The ultraviolet absorption spectrum is determined from a sample of the compound in 0.1N sulfuric acid at a concentration of 30.65 gamma per milliliters (weight/volume). The infrared absorption spectrum is determined on a sample of the compound mixed with the crystal of KBr and pressed into a disc.
Eksempel 5. Example 5.
Til 1 gram av 6-demetyltetracyclin nøytral tilsettes 25 ml av en 1 til 1 blanding av dimetylformamid og vann, og 3 ml (10 molarekvivalenter) av en 45 pst. bor-trifluorid-eter-oppløsning. pH reguleres til 1,5 med trietylamin. Der tilsettes 1 gram 5 pst. palladium på kullstoff, og blandingen anbringes på en Parr ryster, og man lar den reagere med hydrogen i 150 min. (hy-drogenopptagelse er et mol). Den reduserte oppløsning filtreres, og det uoppløselige vaskes med 3 ml vann. Utbyttet av 6-de-meyl-6-deoksytetracyclin er ca. 26 pst. To 1 gram of 6-demethyltetracycline neutral is added 25 ml of a 1 to 1 mixture of dimethylformamide and water, and 3 ml (10 molar equivalents) of a 45% boron trifluoride ether solution. The pH is adjusted to 1.5 with triethylamine. 1 gram of 5% palladium on carbon is added, and the mixture is placed on a Parr shaker, and allowed to react with hydrogen for 150 minutes. (hydrogen uptake is one mole). The reduced solution is filtered, and the insoluble matter is washed with 3 ml of water. The yield of 6-de-meyl-6-deoxytetracycline is approx. 26 percent
Eksempel 6. Example 6.
Fremgangsmåten i henhold til foregående eksempel gjentas med unntagelse av at der anvendes 1,1 gram magnesiumacetat Mg(C2H302)2. 4H20 i stedet for bortrifluoridet som anvendes i eksempel 5. Der dannes 6-demetyl-6-deoksytetracyclin. The procedure according to the previous example is repeated with the exception that 1.1 grams of magnesium acetate Mg(C2H302)2 is used. 4H 2 O instead of the boron trifluoride used in example 5. 6-Demethyl-6-deoxytetracycline is formed there.
Eksempel 7. Example 7.
Fremgangsmåten etter det foregående eksempel gjentas med unntagelse av at der anvendes 0,55 gram kalsiumklorid i stedet for bortrifluoridet som anvendtes i eksempel 5. Der dannes 6-demetyl-6-deoksy-tetracyclin. The procedure according to the previous example is repeated with the exception that 0.55 gram of calcium chloride is used instead of the boron trifluoride used in example 5. 6-Demethyl-6-deoxy-tetracycline is formed.
Eksempel 8. Example 8.
Fremgangsmåten etter det foregående eksempel gjentas med unntagelse av at der anvendes 0,27 gram aluminiumklorid i stedet for bortrifluoridet som anvendtes i eksempel 5. Der dannes 6-demetyl-6-deok-sy tetracyclin. The procedure according to the previous example is repeated with the exception that 0.27 grams of aluminum chloride is used instead of the boron trifluoride used in example 5. 6-Demethyl-6-deoxy tetracycline is formed there.
Eksempel 9. Example 9.
Til 1,0 gram av 6-demetyl-tetracyclin nøytral tilsettes 0,13 gram borsyre, oppløst i 28 ml i en 1 til 1 blanding av dimetylformamid-vann. pH reguleres til 2,1 med saltsyre. Til 13 ml av denne oppløsning tilsettes 0,75 gram av 5 pst. palladium på kullstoff. Blandingen anbringes i en rustfri stålbombe, og man lar den reagere med hydrogen ved et trykk av 134 kg/cm<2> i 80 min. Blandingen filtreres, og det uopp-løselige vaskes med vann. Spektrofotomet-riske undersøkelser av reduksjonsfiltratet viser tilstedeværelsen av 6-demetyl-6-de-oksytetracyclin. To 1.0 gram of 6-demethyl-tetracycline neutral is added 0.13 gram of boric acid, dissolved in 28 ml in a 1 to 1 mixture of dimethylformamide-water. The pH is adjusted to 2.1 with hydrochloric acid. To 13 ml of this solution is added 0.75 gram of 5 per cent palladium on charcoal. The mixture is placed in a stainless steel bomb and allowed to react with hydrogen at a pressure of 134 kg/cm<2> for 80 min. The mixture is filtered, and the insoluble matter is washed with water. Spectrophotometric examinations of the reduction filtrate show the presence of 6-demethyl-6-deoxytetracycline.
Eksempel 10. Example 10.
Til 5 mg av 6-demetyl-6-deoksytetra-cyclin tilsettes 1 ml iseddik. Blandingen rystes godt og man lar den henstå til likevekt ved romtemperatur i 18 timer og derpå flitreres. Papirstrimmelkromatografi viser tilstedeværelsen av 6-demetyl-6-deoksy-4-epitetracyclin med følgende Rf-verdier. To 5 mg of 6-demethyl-6-deoxytetracycline, 1 ml of glacial acetic acid is added. The mixture is shaken well and left to equilibrate at room temperature for 18 hours and then filtered. Paper strip chromatography shows the presence of 6-demethyl-6-deoxy-4-epitetracycline with the following Rf values.
Rf-verdiene i et etylacetat-pH 4,5 sys-tem er som følger: 6-demetyl-6-deoksytet3racyclin Rf = 0,75 6-demetyl-6-deoksy-4- The Rf values in an ethyl acetate pH 4.5 system are as follows: 6-demethyl-6-deoxytet3raciclin Rf = 0.75 6-demethyl-6-deoxy-4-
epitetracyclin Rf = 0,44 epitetracycline Rf = 0.44
Eksempel 11. Example 11.
Til 12 gram av 7-klor-6-demetyltetracyclin hydroklorid (J.A.C.S. 79, 4561 (1957)) tilsettes 120 ml av en 1 til 1 blanding av dimetylformamid og vann. pH reguleres til 1,8 med konsentrert saltsyre, der tilsettes 1,48 gram borsyre og 10 dråper perklorsyre. 12 gram av 5 pst. palladium på kullstoff tilsettes til blandingen, og det reageres med hydrogen på en Parr ryster i 300 min. inntil der er opptatt 2 mol hydrogen. Blandingen filtreres, og det uoppløselige skylles eller vaskes med vann og dimetylformamid. Produktet isoleres og omkrystalliseres for å danne 6-demetyl-6-deoksytetracyclin. To 12 grams of 7-chloro-6-dimethyltetracycline hydrochloride (J.A.C.S. 79, 4561 (1957)) is added 120 ml of a 1 to 1 mixture of dimethylformamide and water. The pH is adjusted to 1.8 with concentrated hydrochloric acid, to which 1.48 grams of boric acid and 10 drops of perchloric acid are added. 12 grams of 5% palladium on carbon is added to the mixture, and it is reacted with hydrogen on a Parr shaker for 300 min. until 2 moles of hydrogen are occupied. The mixture is filtered, and the insoluble matter is rinsed or washed with water and dimethylformamide. The product is isolated and recrystallized to form 6-demethyl-6-deoxytetracycline.
Eksempel 12. Example 12.
Til 4 ml av en oppløsningsmiddelopp-løsning som fåes ved å blande 25 ml av de-metylaformamid, 25 ml vann, 32,5 gram borsyre og 1 ccm perklorsyre, tilsettes 5,51 mgram av 6-demetyl-4-epitetracyclin hydroklorid og 7 mgram 5 pst. palladium på kull. Blandingen bringes til å reagere med hydrogen ved et trykk av 2,1 kg/cm<2> i 2 timer. Blandingen filtreres, og det uopp-løselige vaskes med vann. Spektrofotometrisk analyse og papirkromatografi viser tilstedeværelsen av 6-demetyl-6-deoksy-tetracyclin. To 4 ml of a solvent solution obtained by mixing 25 ml of demethylaformamide, 25 ml of water, 32.5 grams of boric acid and 1 cc of perchloric acid, 5.51 mg of 6-demethyl-4-epitetracycline hydrochloride and 7 mg 5% palladium on coal. The mixture is reacted with hydrogen at a pressure of 2.1 kg/cm<2> for 2 hours. The mixture is filtered, and the insoluble matter is washed with water. Spectrophotometric analysis and paper chromatography show the presence of 6-demethyl-6-deoxy-tetracycline.
Eksempel 13. Example 13.
Til 4 ml av den oppløsningsmiddel-blanding som fåes ved å blande 25 ml di-metylaformamid, 25 ml vann, 32,5 gram borsyre og 1 ml perklorsyre, tilsettes 5 mgram av 7-klor-6-demetyl-4-epitetracyc-lin. 7 mgram av 5 pst. palladium på kullstoff tilsettes, og blandingen bringes til å reagere med hydrogen ved et trykk av 2,1 kg/cm<2> i fire timer. Blandingen filtreres, og det uoppløselige vaskes med vann. Papirkromatografi og spektrofotometrisk analyse viser tilstedeværelsen av 6-demetyl-6-deoksy-4-epitetracyclin. To 4 ml of the solvent mixture obtained by mixing 25 ml of dimethylaformamide, 25 ml of water, 32.5 grams of boric acid and 1 ml of perchloric acid, 5 mg of 7-chloro-6-dimethyl-4-epitetracycline is added . 7 mg of 5% palladium on carbon is added, and the mixture is reacted with hydrogen at a pressure of 2.1 kg/cm<2> for four hours. The mixture is filtered, and the insoluble matter is washed with water. Paper chromatography and spectrophotometric analysis show the presence of 6-demethyl-6-deoxy-4-epitetracycline.
Claims (8)
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