NO140177B - LOAD TRANSPORT CONTAINER. - Google Patents
LOAD TRANSPORT CONTAINER. Download PDFInfo
- Publication number
- NO140177B NO140177B NO52/73A NO5273A NO140177B NO 140177 B NO140177 B NO 140177B NO 52/73 A NO52/73 A NO 52/73A NO 5273 A NO5273 A NO 5273A NO 140177 B NO140177 B NO 140177B
- Authority
- NO
- Norway
- Prior art keywords
- hydrogen
- deoxy
- demethyl
- product
- chloro
- Prior art date
Links
- 238000000034 method Methods 0.000 claims description 69
- 150000001875 compounds Chemical class 0.000 claims description 55
- 229910052739 hydrogen Inorganic materials 0.000 claims description 46
- 239000001257 hydrogen Substances 0.000 claims description 45
- 239000002253 acid Substances 0.000 claims description 31
- 239000004098 Tetracycline Substances 0.000 claims description 30
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 28
- 229910052736 halogen Inorganic materials 0.000 claims description 25
- 239000000460 chlorine Substances 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 22
- 239000007858 starting material Substances 0.000 claims description 21
- 229960002180 tetracycline Drugs 0.000 claims description 21
- 150000002367 halogens Chemical class 0.000 claims description 19
- 229910052801 chlorine Inorganic materials 0.000 claims description 18
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 16
- 150000002431 hydrogen Chemical group 0.000 claims description 16
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 13
- 230000002829 reductive effect Effects 0.000 claims description 12
- 125000003277 amino group Chemical group 0.000 claims description 10
- 239000011701 zinc Substances 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 229910052725 zinc Inorganic materials 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 7
- 239000011707 mineral Substances 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 6
- 230000003115 biocidal effect Effects 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- GRWZHXKQBITJKP-UHFFFAOYSA-N dithionous acid Chemical compound OS(=O)S(O)=O GRWZHXKQBITJKP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000510 noble metal Inorganic materials 0.000 claims description 2
- 229910052703 rhodium Inorganic materials 0.000 claims description 2
- 239000010948 rhodium Substances 0.000 claims description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims 2
- 239000011260 aqueous acid Substances 0.000 claims 1
- 230000003197 catalytic effect Effects 0.000 claims 1
- 238000007327 hydrogenolysis reaction Methods 0.000 claims 1
- 229910052751 metal Inorganic materials 0.000 claims 1
- 239000002184 metal Substances 0.000 claims 1
- 229910052697 platinum Inorganic materials 0.000 claims 1
- 108090000623 proteins and genes Proteins 0.000 claims 1
- 239000000047 product Substances 0.000 description 106
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 67
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 63
- 239000000203 mixture Substances 0.000 description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 40
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 35
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
- 239000000243 solution Substances 0.000 description 30
- 238000004458 analytical method Methods 0.000 description 29
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 24
- 239000002904 solvent Substances 0.000 description 24
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 23
- 235000019364 tetracycline Nutrition 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- 150000003522 tetracyclines Chemical class 0.000 description 17
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 15
- 238000001914 filtration Methods 0.000 description 15
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 15
- 239000004100 Oxytetracycline Substances 0.000 description 14
- 238000010521 absorption reaction Methods 0.000 description 14
- 230000000694 effects Effects 0.000 description 14
- 229960000625 oxytetracycline Drugs 0.000 description 14
- 229930101283 tetracycline Natural products 0.000 description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 13
- 150000007513 acids Chemical class 0.000 description 13
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 13
- 229910052794 bromium Inorganic materials 0.000 description 13
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 12
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 12
- OWFJMIVZYSDULZ-PXOLEDIWSA-N (4s,4ar,5s,5ar,6s,12ar)-4-(dimethylamino)-1,5,6,10,11,12a-hexahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C1=CC=C2[C@](O)(C)[C@H]3[C@H](O)[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 OWFJMIVZYSDULZ-PXOLEDIWSA-N 0.000 description 11
- 230000002140 halogenating effect Effects 0.000 description 11
- 238000006396 nitration reaction Methods 0.000 description 11
- 235000019366 oxytetracycline Nutrition 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 description 11
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- 229940040944 tetracyclines Drugs 0.000 description 9
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 238000006722 reduction reaction Methods 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 7
- -1 tetracycline compound Chemical class 0.000 description 7
- 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 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 235000010755 mineral Nutrition 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- WSNMPAVSZJSIMT-UHFFFAOYSA-N COc1c(C)c2COC(=O)c2c(O)c1CC(O)C1(C)CCC(=O)O1 Chemical compound COc1c(C)c2COC(=O)c2c(O)c1CC(O)C1(C)CCC(=O)O1 WSNMPAVSZJSIMT-UHFFFAOYSA-N 0.000 description 5
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical group BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 5
- 229910002651 NO3 Inorganic materials 0.000 description 5
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 5
- 239000002021 butanolic extract Substances 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 238000005658 halogenation reaction Methods 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- XIYOPDCBBDCGOE-IWVLMIASSA-N (4s,4ar,5s,5ar,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methylidene-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C=C1C2=CC=CC(O)=C2C(O)=C2[C@@H]1[C@H](O)[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O XIYOPDCBBDCGOE-IWVLMIASSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- 230000026030 halogenation Effects 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 244000005700 microbiome Species 0.000 description 4
- 229910017604 nitric acid Inorganic materials 0.000 description 4
- XHFXMNZYIKFCPN-UHFFFAOYSA-N perchloryl fluoride Chemical compound FCl(=O)(=O)=O XHFXMNZYIKFCPN-UHFFFAOYSA-N 0.000 description 4
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 3
- RPNNPZHFJPXFQS-UHFFFAOYSA-N methane;rhodium Chemical compound C.[Rh] RPNNPZHFJPXFQS-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 235000009518 sodium iodide Nutrition 0.000 description 3
- WZKHBEGQWSEAJI-UHFFFAOYSA-N 2-(2-hydroxyethoxy)ethanol;1-methoxy-2-(2-methoxyethoxy)ethane Chemical compound OCCOCCO.COCCOCCOC WZKHBEGQWSEAJI-UHFFFAOYSA-N 0.000 description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 2
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- QZRGKCOWNLSUDK-UHFFFAOYSA-N Iodochlorine Chemical compound ICl QZRGKCOWNLSUDK-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 206010034133 Pathogen resistance Diseases 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 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 2
- 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 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 150000002366 halogen compounds Chemical class 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 150000002497 iodine compounds Chemical class 0.000 description 2
- CBEQRNSPHCCXSH-UHFFFAOYSA-N iodine monobromide Chemical compound IBr CBEQRNSPHCCXSH-UHFFFAOYSA-N 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- FWLGGSWAIHNLLW-UHFFFAOYSA-N n-bromo-n-phenylacetamide Chemical compound CC(=O)N(Br)C1=CC=CC=C1 FWLGGSWAIHNLLW-UHFFFAOYSA-N 0.000 description 2
- VBTQNRFWXBXZQR-UHFFFAOYSA-N n-bromoacetamide Chemical compound CC(=O)NBr VBTQNRFWXBXZQR-UHFFFAOYSA-N 0.000 description 2
- HSPSCWZIJWKZKD-UHFFFAOYSA-N n-chloroacetamide Chemical compound CC(=O)NCl HSPSCWZIJWKZKD-UHFFFAOYSA-N 0.000 description 2
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 229910021653 sulphate ion Inorganic materials 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 229960004989 tetracycline hydrochloride Drugs 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- NWXMGUDVXFXRIG-WESIUVDSSA-N (4s,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-WESIUVDSSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
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- VFTOHJFKIJLYKN-UHFFFAOYSA-N 7-nitro-9h-fluoren-2-ol Chemical group [O-][N+](=O)C1=CC=C2C3=CC=C(O)C=C3CC2=C1 VFTOHJFKIJLYKN-UHFFFAOYSA-N 0.000 description 1
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- 239000005711 Benzoic acid Substances 0.000 description 1
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- 238000009835 boiling Methods 0.000 description 1
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- LVGQIQHJMRUCRM-UHFFFAOYSA-L calcium bisulfite Chemical compound [Ca+2].OS([O-])=O.OS([O-])=O LVGQIQHJMRUCRM-UHFFFAOYSA-L 0.000 description 1
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- 238000006555 catalytic reaction Methods 0.000 description 1
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- 239000001630 malic acid Substances 0.000 description 1
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- 239000000463 material Substances 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 125000001415 nervonoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
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- 229910017464 nitrogen compound Inorganic materials 0.000 description 1
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- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229960004368 oxytetracycline hydrochloride Drugs 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000004816 paper chromatography Methods 0.000 description 1
- YAOULQGDLCJSSG-UHFFFAOYSA-N perchloric acid hydrochloride Chemical compound Cl(=O)(=O)(=O)O.Cl YAOULQGDLCJSSG-UHFFFAOYSA-N 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000004323 potassium nitrate Substances 0.000 description 1
- 235000010333 potassium nitrate Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- VYGBQXDNOUHIBZ-UHFFFAOYSA-L sodium formaldehyde sulphoxylate Chemical compound [Na+].[Na+].O=C.[O-]S[O-] VYGBQXDNOUHIBZ-UHFFFAOYSA-L 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 229910052712 strontium Inorganic materials 0.000 description 1
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 1
- 229940072172 tetracycline antibiotic Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A47—FURNITURE; DOMESTIC ARTICLES OR APPLIANCES; COFFEE MILLS; SPICE MILLS; SUCTION CLEANERS IN GENERAL
- A47F—SPECIAL FURNITURE, FITTINGS, OR ACCESSORIES FOR SHOPS, STOREHOUSES, BARS, RESTAURANTS OR THE LIKE; PAYING COUNTERS
- A47F1/00—Racks for dispensing merchandise; Containers for dispensing merchandise
- A47F1/04—Racks or containers with arrangements for dispensing articles, e.g. by means of gravity or springs
- A47F1/08—Racks or containers with arrangements for dispensing articles, e.g. by means of gravity or springs dispensing from bottom
- A47F1/10—Racks or containers with arrangements for dispensing articles, e.g. by means of gravity or springs dispensing from bottom having mechanical dispensing means, e.g. with buttons or handles
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65G—TRANSPORT OR STORAGE DEVICES, e.g. CONVEYORS FOR LOADING OR TIPPING, SHOP CONVEYOR SYSTEMS OR PNEUMATIC TUBE CONVEYORS
- B65G1/00—Storing articles, individually or in orderly arrangement, in warehouses or magazines
- B65G1/02—Storage devices
- B65G1/04—Storage devices mechanical
- B65G1/06—Storage devices mechanical with means for presenting articles for removal at predetermined position or level
- B65G1/08—Storage devices mechanical with means for presenting articles for removal at predetermined position or level the articles being fed by gravity
-
- G—PHYSICS
- G07—CHECKING-DEVICES
- G07F—COIN-FREED OR LIKE APPARATUS
- G07F11/00—Coin-freed apparatus for dispensing, or the like, discrete articles
- G07F11/02—Coin-freed apparatus for dispensing, or the like, discrete articles from non-movable magazines
- G07F11/04—Coin-freed apparatus for dispensing, or the like, discrete articles from non-movable magazines in which magazines the articles are stored one vertically above the other
-
- G—PHYSICS
- G07—CHECKING-DEVICES
- G07F—COIN-FREED OR LIKE APPARATUS
- G07F11/00—Coin-freed apparatus for dispensing, or the like, discrete articles
- G07F11/02—Coin-freed apparatus for dispensing, or the like, discrete articles from non-movable magazines
- G07F11/04—Coin-freed apparatus for dispensing, or the like, discrete articles from non-movable magazines in which magazines the articles are stored one vertically above the other
- G07F11/16—Delivery means
- G07F11/163—Delivery means characterised by blocking access to the output bins
Landscapes
- Physics & Mathematics (AREA)
- General Physics & Mathematics (AREA)
- Engineering & Computer Science (AREA)
- Mechanical Engineering (AREA)
- Stacking Of Articles And Auxiliary Devices (AREA)
- Selective Calling Equipment (AREA)
- Vending Machines For Individual Products (AREA)
- Details Of Rigid Or Semi-Rigid Containers (AREA)
- Non-Mechanical Conveyors (AREA)
- Warehouses Or Storage Devices (AREA)
- Bidet-Like Cleaning Device And Other Flush Toilet Accessories (AREA)
- Catching Or Destruction (AREA)
Description
Fremgangsmåte ved fremstilling av nye 6-methylen-tetracyclinforbindelser. Procedure for the production of new 6-methylene-tetracycline compounds.
Foreliggende oppfinnelse angår en The present invention relates to a
fremgangsmåte til fremstilling av nye 6-methylen-tetracyclin-forbindelser ved de-halogenering av lla-halo-6-methylente-tracyclinforbindelser. process for the production of new 6-methylene-tetracycline compounds by de-halogenation of 11a-halo-6-methylene-tracycline compounds.
Tetracyclin-antibiotica omfatter en gruppe biologisk aktive perhydronaftha-cen-derivater med følgende strukturelle hovedtrekk. Det anvendte nummererings-system er det som brukes i «Chemical Ab-stracts». Tetracycline antibiotics comprise a group of biologically active perhydronaphthacene derivatives with the following main structural features. The numbering system used is that used in "Chemical Abstracts".
Blant de biologisk aktive stoffer i denne gruppe er de som inneholder følgende sub-stituerende grupper: Among the biologically active substances in this group are those containing the following substitutive groups:
Ved foreliggende fremgangsmåte fremstilles nye 6-methylentetracyclinforbindel-ser av den generelle formel I By the present method, new 6-methylenetetracycline compounds of the general formula I are produced
hvor enten a) E er hydroxyl, A er hydrogen eller halogen, ;X0 er hydrogen, ;X7 er hydrogen eller en aminogruppe, eller b) iE er hydrogen, A er hydrogen eller klor, og X(. og X7 er hydrogen, halogen eller en av dem kan være en aminogruppe, ved at en forbindelse med den generelle formel where either a) E is hydroxyl, A is hydrogen or halogen, ;X0 is hydrogen, ;X7 is hydrogen or an amino group, or b) iE is hydrogen, A is hydrogen or chlorine, and X(. and X7 are hydrogen, halogen or one of them may be an amino group, whereby a compound of the general formula
hvor enten a) E er hydroxyl, where either a) E is hydroxyl,
A er hydrogen eller halogen, A is hydrogen or halogen,
Xg1, er hydrogen, og Xg1, is hydrogen, and
X7i er hydrogen eller en nitrogruppe, X7i is hydrogen or a nitro group,
eller b) E er hydrogen, or b) E is hydrogen,
A er hydrogen eller klor, og X(. pg X7 er hydrogen, halogen eller enten Xfi eller X7 kan være en nitrogruppe A is hydrogen or chlorine, and X(. pg X7 is hydrogen, halogen or either Xfi or X7 can be a nitro group
og Hal betyr halogen, dehalogeneres i lia-, stillingen under reduktive betingelser og slik at en eventuelt tilstedeværende nitrogruppe samtidig reduseres til en aminogruppe, og i de tilfelle hvor X(i eller X7 betyr hydrogen, nitreres derpå, om ønskes, med påfølgende reduksjon til den tilsvarende aminogruppe. and Hal means halogen, is dehalogenated in the lia-, position under reductive conditions and so that a possibly present nitro group is simultaneously reduced to an amino group, and in those cases where X(i or X7 means hydrogen, is then nitrated, if desired, with subsequent reduction to the corresponding amino group.
Reaksjonene ved fremstilling av de nye forbindelser ved foreliggende fremgangsmåte fremgår av følgende reaksjonsskje-maer, The reactions in the production of the new compounds by the present method appear from the following reaction schemes,
hvor forbindelsen Ila viser forbindelsen II når E er hydroxyl og Z er hydrogen, og hvor forbindelsen Ilb viser forbindelsen II når E er hydrogen og Z er hydrogen eller klor, og hvor where compound IIa shows compound II when E is hydroxyl and Z is hydrogen, and where compound IIb shows compound II when E is hydrogen and Z is hydrogen or chlorine, and where
X er halogen, X is halogen,
X, er klor eller fluor, X, is chlorine or fluorine,
X4 er hydrogen, klor, brom eller jod, X- er hydrogen eller amino, X4 is hydrogen, chlorine, bromine or iodine, X- is hydrogen or amino,
X,, og X7 er hydrogen, klor, brom eller jod, eller en av dem kan være en aminogruppe, og X,, and X7 are hydrogen, chlorine, bromine or iodine, or one of them may be an amino group, and
X8 er klor, brom eller jod. X8 is chlorine, bromine or iodine.
Fremstilling av de nye utgangsmaterialer for foreliggende fremgangsmåte. De nye utgangsmaterialer som anvendes ved foreliggende fremgangsmåte, 11a-halogen-6-methylentetracyclin-forbindelsene med den generelle formel II, hvor X(. og X7 i den generelle formel I er hydrogen og A er Z, kan fremstilles ved å halogenere et passende tetracyclin(IX) og derpå de-hydratisere den erholdte forbindelse X som fremgår av følgende reaksjonsskjema: Production of the new starting materials for the present method. The new starting materials used in the present process, the 11α-halo-6-methylenetetracycline compounds of the general formula II, where X(. and X7 in the general formula I are hydrogen and A is Z, can be prepared by halogenating an appropriate tetracycline (IX) and then de-hydrate the obtained compound X as shown in the following reaction scheme:
hvor X er halogen, Z er hydrogen eller klor, og E er hydrogen eller hydroxyl, idet når E er hydroxyl er Z hydrogen. where X is halogen, Z is hydrogen or chlorine, and E is hydrogen or hydroxyl, since when E is hydroxyl, Z is hydrogen.
lla-halogen-6-methylentetracyclin-forbindelsene (II), kan fremstilles ved å The lla-halo-6-methylenetetracycline compounds (II) can be prepared by
omsette et passende tetracyclin (IX), f. eks. tetracyclin, oxytetracyclin eller klortetracyclin, med et mildtvirkende halogeneringsmiddel, såsom brom, klor, jodklorid, jodbromid, N-klor-, N-jod- eller N-brom- convert a suitable tetracycline (IX), e.g. tetracycline, oxytetracycline or chlortetracycline, with a mild halogenating agent, such as bromine, chlorine, iodochloride, iodobromide, N-chloro-, N-iodo or N-bromo-
lavere-alkansyre-amid, f. eks. N-klor- og N-bromacetamid; hydrocarbon-dicarboxylsyreimider, f. eks. N-klor-, N-brom- og N-jodsuccinimid, ! -fthalimid o.L; N-lavere-alkanoylanilider, f. eks. N-bromacetanilid, lower alkanoic acid amide, e.g. N-chloro- and N-bromoacetamide; hydrocarbon-dicarboxylic acid imides, e.g. N-chloro-, N-bromo and N-iodosuccinimide, ! -phthalimide etc.; N-lower alkanoylanilides, e.g. N-bromoacetanilide,
-propionanilid 6.1.; 3-klor-, 3-brom, 3,5-diklor- eller 3,5-dibrom-5,5-dimethylhydant-ion; pyridin-perbromid-hydrobromid eller pyridin-perklorid-hydroklorid, eller lavere-alkyl-hypokloriter, f. eks. tertiært butyl-hypoklorit. I alminnelighet anvendes 1—1,2 mol halogeneriirgsmiddel pr. mol tetracyc-linforbindelse. i -propionanilide 6.1.; 3-chloro-, 3-bromo, 3,5-dichloro- or 3,5-dibromo-5,5-dimethylhydant ion; pyridine-perbromide-hydrobromide or pyridine-perchloride-hydrochloride, or lower-alkyl hypochlorites, e.g. tertiary butyl hypochlorite. In general, 1-1.2 mol of halogenating agent are used per moles of tetracycline compound. in
Reaksjonen' utføres i et oppløsnings-middel som er inert overfor reaktantene, f. eks. dioxan- j tetrahydrofuran, methylether av diethylenglycol (diglyme) og ethylenglycolmethylether (monoglyme). The reaction' is carried out in a solvent which is inert to the reactants, e.g. dioxane- j tetrahydrofuran, methyl ether of diethylene glycol (diglyme) and ethylene glycol methyl ether (monoglyme).
Oppløsningsmiddelsystemet velges fortrinsvis slik at det dannede lla-halogen-produkt krystalliserer ut eftersom det dannes, spesielt ved brom- og jodforbindelsene. Eksempelvis er en 1:1 blanding av benzen-dimethylether av ethylenglycol et foretrukket system for lla-bromering av oxytetracyclin, idet produktet skilles ut eftersom det dannes. Hvis dette produkt for-blir i oppløsning i; lengre tid, vil en betrak-telig spaltning finne sted. The solvent system is preferably chosen so that the formed lla-halogen product crystallizes out as it is formed, especially at the bromine and iodine compounds. For example, a 1:1 mixture of benzene-dimethyl ether of ethylene glycol is a preferred system for lla-bromination of oxytetracycline, the product being separated as it is formed. If this product remains in solution in; longer time, a considerable cleavage will take place.
Reaksjonen utføres vanligvis ved en temperatur på 0—50°C. The reaction is usually carried out at a temperature of 0-50°C.
Forbindelsene X som er hemiketal-forbindelser, behandles så med en sterk syre med dehydratiserende virkning. Flere slike syrer kan brukes ifor formålet, dog foretrekkes mineralsyrér, såsom svovelsyre, fosforsyre, polyfosforsyre, perklorsyre, og også andre syrer såsoni iseddik (inneholdende bortrifluorid), hydrogenfluorid (fortrinsvis i væskeform) og; trihalogeneddiksyre såsom trifluoreddiksyre. Likeledes foretrekkes det å bruke mineralsyrene i konsentrert form, eksempelvis minst 60 pst. i vann. Når mineralsyrér anvendes, erholdes særlig fordelaktige resultater med syrene i følgende konsentrasjoner: The compounds X, which are hemiketal compounds, are then treated with a strong acid with a dehydrating effect. Several such acids can be used for the purpose, however mineral acids are preferred, such as sulfuric acid, phosphoric acid, polyphosphoric acid, perchloric acid, and also other acids such as glacial acetic acid (containing boron trifluoride), hydrogen fluoride (preferably in liquid form) and; trihaloacetic acid such as trifluoroacetic acid. Likewise, it is preferred to use the mineral acids in concentrated form, for example at least 60 per cent in water. When mineral acids are used, particularly advantageous results are obtained with the acids in the following concentrations:
Reaksjonstiden og temperaturen synes ikke å være kritisk. Ved utførelsen av denne prosess settes utgangsforbindelsen til den valgte syre som deretter får stå i forholds-vis kort tidsrom. Eksempelvis settes utgangsforbindelsen tii; hydrogenfluorid, fortrinsvis flytende hydrogenfluorid, ved 0-50° C og gies henstand 1 5—7 minutter eller lengre, f. eks. noen timer, hvoretter hydrogenfluoridet avdampes. Residuet behandles derpå på kjent måte for oppnåelse av et krystallinsk produkt i form av hydrofluoridsaltet, eksempelvis innrøres det i et ikke-oppløsningsmiddel og omkrystalliseres fra oppløsningsmidler som f. eks. lavere alka-noler. Når svovelsyre anvendes, foretrekker man temperaturer under 20°C. Når perklorsyre anvendes, utføres reaksjonen fortrinsvis ved temperaturer fra ca. 50°C og oppover og fortrinsvis fra 60 til 70°C. Enda mere konsentrert perklorsyre kan anvendes ved denne prosess, men foretrekkes ikke på grunn av eksplosjonsfaren. Reaksjonstiden synes ikke å være kritisk da reaksjonen synes å foregå nesten momentant. Eksempelvis har man funnet at en reaksjonstid på 5— 15 minutter vanligvis gir utmerkede resultater når reaksjonstemperaturen er mellom 60 og 70° C. Når trifluoreddiksyre eller eddiksyre brukes, utføres reaksjonen fortrinsvis ved romtemperatur i løpet av ca. 24 timer. Når reaksjonen er fullstendig, erholdes det ønskede produkt ved i og for seg vanlige metoder. Det er f. eks. meget bekvemt bare å fortynne reaksjonsblandingen med et ikke-oppløsningsmiddel, eksempelvis vann som resulterer i utfelling av produktet i form av syresaltet. Produktet fra The reaction time and temperature do not seem to be critical. When carrying out this process, the starting compound is added to the selected acid, which is then allowed to stand for a relatively short period of time. For example, the output connection tii is set; hydrogen fluoride, preferably liquid hydrogen fluoride, at 0-50° C and allowed to stand for 15-7 minutes or longer, e.g. a few hours, after which the hydrogen fluoride evaporates. The residue is then treated in a known manner to obtain a crystalline product in the form of the hydrofluoride salt, for example it is stirred into a non-solvent and recrystallized from solvents such as e.g. lower alkanols. When sulfuric acid is used, temperatures below 20°C are preferred. When perchloric acid is used, the reaction is preferably carried out at temperatures from approx. 50°C and above and preferably from 60 to 70°C. Even more concentrated perchloric acid can be used in this process, but is not preferred because of the danger of explosion. The reaction time does not seem to be critical as the reaction seems to take place almost instantaneously. For example, it has been found that a reaction time of 5-15 minutes usually gives excellent results when the reaction temperature is between 60 and 70° C. When trifluoroacetic acid or acetic acid is used, the reaction is preferably carried out at room temperature during approx. 24 hours. When the reaction is complete, the desired product is obtained by usual methods. It is e.g. very conveniently just diluting the reaction mixture with a non-solvent, for example water which results in precipitation of the product in the form of the acid salt. The product from
syre-dehydratiseringen kan overføres fra the acid dehydration can be transferred from
det resulterende syresalt til den frie base eller et annet ønsket salt på vanlig måte. the resulting acid salt to the free base or other desired salt in the usual manner.
Når utgangsforbindelsen i denne prosess er en lla-fluorforbindelse, oppnåes de beste resultater ved bruk av perklorsyre. When the starting compound in this process is a 11a-fluorine compound, the best results are obtained by using perchloric acid.
Produktene fra dehydratiseringsproses-sen er lla-halogentetracycliner med strukturen II som betegnes 6-deoxy-6-demethyl-6- methylen-lla-halogen-tetracycliner. Den forbindelse hvor Z er H, som mineralsyre-saltet, viser ved infrarød analyse KBr-ta-blett carbonylabsorpsjon ved eller nær 5,70 mikroner. Denne absorpsjon foreligger, som nevnt ovenfor, ikke for lla-halogen-hemi-ketalutgangsforbindelsen. Videre er der en sterk forskyvning av det ultrafiolette absorpsjonsmaksimum (målt i 0,01 N methanolisk saltsyre) fra omkring 345 mp. The products from the dehydration process are 11a-halogen tetracyclines with structure II, which are called 6-deoxy-6-demethyl-6-methylene-11a-halogen tetracyclines. The compound where Z is H, as the mineral acid salt, shows by infrared analysis KBr-ta stained carbonyl absorption at or near 5.70 microns. This absorption does not exist, as mentioned above, for the 11a-halogen-hemi-ketal starting compound. Furthermore, there is a strong shift of the ultraviolet absorption maximum (measured in 0.01 N methanolic hydrochloric acid) from about 345 mp.
(som er karakteristisk for hemi-ketal-utgangsforbindelsene) til omkring 375 m^ (which is characteristic of the starting hemiketal compounds) to about 375 m^
(som er karakteristisk for de dehydratiserte produkter). De dehydratiserte produkter viser også to ytterligere ultrafiolette absorp-sjonsmaksima som henholdsvis er ca. 4,2 og 5 ganger mere intense enn nevnte maksimum ved 375 imi. De to ytterligere topper finnes ved eller nær 240 og 277 m^ henholdsvis. Den ovenfor nevnte karakteristiske topp ved ca. 375 m^ i for forbindelser hvor Z er H, ligger ved ca. 380—390 mu for forbindelser i hvilke Z er klor eller brom. (which is characteristic of the dehydrated products). The dehydrated products also show two further ultraviolet absorption maxima which are respectively approx. 4.2 and 5 times more intense than the mentioned maximum at 375 imi. The two further peaks are found at or near 240 and 277 m^ respectively. The above-mentioned characteristic peak at approx. 375 m^ i for compounds where Z is H, lies at approx. 380—390 mu for compounds in which Z is chlorine or bromine.
Andre 1 la-halogen-methylentetracycliner fremstilles fra D-ring-substituerte lla-halogen-tetracyclin-6,12-hemi-ketaler på samme måte. Slike D-ring-substituerte hemi-ketaler fremstilles ved ovenfor beskrevne metoder. Således kan man frem-stille 7- og/eller 9-substituerte 6-methylen-lla-halogentetracycliner i hvilke sub-stituenten er halogen, nitro eller amino. Other 11a-halo-methylenetetracyclines are prepared from D-ring-substituted 11a-halo-tetracycline-6,12-hemi-ketals in the same manner. Such D-ring-substituted hemiketals are prepared by the methods described above. Thus, 7- and/or 9-substituted 6-methylene-lla-halotetracyclines can be produced in which the substituent is halogen, nitro or amino.
Halogenering av forbindelser med strukturen II. Halogenation of compounds with the structure II.
Ved f. eks. halogenering av forbindelser med strukturen II ved å omsette dem med et mildtvirkende halogeneringsmiddel i et oppløsningsmiddel som er inert overfor reaktantene i reaksjonen, erholdes forbindelser med strukturene III og VI. Ved fremstilling av de nye lla-halogentetracycliner hvor halogenet er klor, brom eller jod, kan forskjellige halogeneringsmidler anvendes i et reaksjonsinert oppløsnings-middel. Egnede halogeningsmidler innbefatter brom, klor, jodklorid, jodbromid, N-klor, N-jod og N-brom-lavere-alkansyre-amid, f. eks. N-klor- og N-bromacetamid; hydrocarbon-dicarboxylsyreimider, f. eks. N-klor- og N-brom- og N-jodsuccinimid, -fthalimid o. 1., og N-lavere-alkanoyl-ani-lid, som f. eks. N-bromacetanilid, -propionanilid o. 1.; 3-klor-, 3-brom-, 3,5-diklor-og 3,5-dibrom-5,5-dimethyl-hydantoin; pyridin-perbromid og perklorid-hydrohalo-genider, såsom pyridin-perbromid-hydrobromid, pyridin-perklorid-hydroklorid ; By e.g. halogenation of compounds with the structure II by reacting them with a mild halogenating agent in a solvent which is inert to the reactants in the reaction, compounds with the structures III and VI are obtained. In the production of the new 11a-halogen tetracyclines where the halogen is chlorine, bromine or iodine, various halogenating agents can be used in a reaction-inert solvent. Suitable halogenating agents include bromine, chlorine, iodochloride, iodobromide, N-chloro, N-iodine and N-bromo-lower-alkanoic acid amide, e.g. N-chloro- and N-bromoacetamide; hydrocarbon-dicarboxylic acid imides, e.g. N-chloro- and N-bromo- and N-iodosuccinimide, -phthalimide etc., and N-lower-alkanoyl-anilide, such as e.g. N-bromoacetanilide, -propionanilide etc. 1.; 3-chloro-, 3-bromo-, 3,5-dichloro- and 3,5-dibromo-5,5-dimethyl-hydantoin; pyridine perbromide and perchloride hydrohalides, such as pyridine perbromide hydrobromide, pyridine perchloride hydrochloride;
og lavere-alkyl-hypokloriter, såsom tert-butyl-hypoklorit. Åpenbart kan i alminnelighet hvilket som helst halogeneringsmiddel som vanligvis er anvende-lig på området, brukes, men ovennevnte forbindelser foretrekkes. Vanligvis foretrekker man å bruke 1—1,2 mol halogeneringsmiddel pr. mol tetracyclin-utgangsforbindelse. and lower alkyl hypochlorites, such as tert-butyl hypochlorite. Obviously, in general, any halogenating agent commonly applicable in the field can be used, but the above compounds are preferred. Usually it is preferred to use 1-1.2 mol of halogenating agent per mol tetracycline starting compound.
Med uttrykket «reaksjons-inert opp-løsningsmiddel» menes i det foreliggende et oppløsningsmiddel som under reaksjo-nens betingelser ikke reagerer på uønsket måte med utgangsforbindelsene eller sluttproduktene. Ved hjelp av litt eksperimentering i laboratoriet kan man finne frem til passende oppløsnings-midler for utførelse av fremgangsmåten. Eksempelvis kan man bruke slike oppløsningsmidler som dioxan, tetrahydrofuran, methylether av diethylenglykol (diglyme) og ethylenglykol-methylether (monoglyme). Selv om det ikke er nødvendig foretrekker man vanligvis å utelukke vann fra reaksjonsblandingen når utgangsforbindelsen er en lla-brom- eller jod-forbindelse, som synes å være noe ømtålelig overfor vann. Hvis vann foreligger i reaksjonsblandingen, bør dette ikke holdes i kontakt med lla-brom- eller jod-forbindelser i lengre tid da dette kan resultere i betydelig ned-settelse av utbyttet av det ønskede produkt. Temperaturen synes ikke å være kritisk ved foreliggende fremgangsmåte; temperaturer mellom 0 og 50° C er blitt funnet passende. Temperaturer over 50°C bør fortrinsvis unngåes på grunn av mulig dannelse av 5a,6-anhydro-forbindelser som nedsetter prosessens effektivitet. Valget av de beste reaksjonsbetingelser, såsom temperatur, oppløsningsmiddel, halogeneringsmiddel etc, er et spørsmål om helt ordinær forsøksvirksomhet. Man foretrekker å vel-ge et oppløsningsmiddelsystem fra hvilket lla-halogen-produktet krystalliserer etter dannelsen, spesielt tilfelle av brom- og jodforbindelsene. Eksempelvis er 1:1 ben-zenmonoglym (dimethylether av ethylenglykol) funnet å være et foretrukket opp-løsningsmiddelsystem for lla-brominering av oxytetracyclin. Produktet utskiller seg lett fra reaksjonsblandingen etter dannelsen. Når man går ut fra forbindelser med strukturen Ha hvor E er OH, vil halogeneringen hovedsakelig finne sted i 7-stillingen, med noen substitusjon også i 9-stillingen og i mindre utstrekning både i 7- og 9-stillingene. Når man går ut fra forbindelser med strukturen Hb hvor E er hydrogen, vil halogeneringen hovedsakelig finne sted ved 6-methylen-gruppen og i mindre utstrekning ved 9-stillingen og/eller begge stillinger. The term "reaction-inert solvent" is used herein to mean a solvent which, under the conditions of the reaction, does not react in an undesirable manner with the starting compounds or end products. With the help of a little experimentation in the laboratory, suitable solvents can be found for carrying out the method. For example, you can use such solvents as dioxane, tetrahydrofuran, methyl ether of diethylene glycol (diglyme) and ethylene glycol methyl ether (monoglyme). Although not necessary, it is usually preferred to exclude water from the reaction mixture when the starting compound is an lla-bromo or iodo compound, which appears to be somewhat sensitive to water. If water is present in the reaction mixture, this should not be kept in contact with lla-bromine or iodine compounds for a long time as this can result in a significant reduction in the yield of the desired product. The temperature does not seem to be critical in the present method; temperatures between 0 and 50°C have been found suitable. Temperatures above 50°C should preferably be avoided due to the possible formation of 5a,6-anhydro compounds which reduce the efficiency of the process. The choice of the best reaction conditions, such as temperature, solvent, halogenating agent, etc., is a matter of completely ordinary experimental activity. One prefers to choose a solvent system from which the 11a-halogen product crystallizes after its formation, especially in the case of the bromine and iodo compounds. For example, 1:1 benzene monoglyme (dimethyl ether of ethylene glycol) has been found to be a preferred solvent system for lla-bromination of oxytetracycline. The product separates easily from the reaction mixture after formation. When starting from compounds with the structure Ha where E is OH, the halogenation will mainly take place in the 7-position, with some substitution also in the 9-position and to a lesser extent in both the 7- and 9-positions. When starting from compounds with the structure Hb where E is hydrogen, the halogenation will mainly take place at the 6-methylene group and to a lesser extent at the 9-position and/or both positions.
Nitrering av forbindelser med strukturen II. Nitration of compounds with the structure II.
Nitrering av forbindelser med strukturen II gir forbindelser med strukturene V og VIII. Nitreringen utføres ved hjelp av hvilken som helst standardmetode for dette formål. Eksempelvis kan utgangsforbindelsen omsettes med salpetersyre som sådan eller dannet in situ, f. eks. av kaliumnitrat og svovelsyre. For oppnåelse av de beste resultater utføres nitreringsreaksjonen i et Nitration of compounds with structure II gives compounds with structures V and VIII. The nitration is carried out by any standard method for this purpose. For example, the starting compound can be reacted with nitric acid as such or formed in situ, e.g. of potassium nitrate and sulfuric acid. To achieve the best results, the nitration reaction is carried out in a
oppløsningsmiddel, såsom en lavere alkan-syre, eksempelvis ediksyre, men mange andre oppløsningsmidler kan også anvendes. Det foretrukne oppløsningsmiddel er solvent, such as a lower alkanoic acid, for example acetic acid, but many other solvents can also be used. The preferred solvent is
flytende hydrogenfluorid. Andre egnede liquid hydrogen fluoride. Others suitable
oppløsningsmidler kan velges ved hjelp av enkle laboratorieforsøk. Reaksjonsbetingel-sene kan variere i betydelig grad, dog bør solvents can be selected using simple laboratory tests. The reaction conditions can vary considerably, but should
man unngå høye temperaturer. Tilfredsstillende resultater erholdes innenfor tem-peraturområdet mellom ca. —25° C og ca. 50° C, idet romtemperatur foretrekkes som den mest bekvemme. Reaksjonstiden er high temperatures are avoided. Satisfactory results are obtained within the temperature range between approx. -25° C and approx. 50° C, room temperature being preferred as the most convenient. The reaction time is
ikke i særlig grad kritisk, spesielt i betrakt-ning av utgangsforbindelsenes stabilitet overfor de sure| reaksjonsbetingelser. For å sikre tilfredsstillende utbytte foretrekker man å bruke reaksjonstider mellom 15 minutter og ca. 12 timer. Nitrering av forbindelser med strukturen Ila hvor E er OH, gir hovedsakelig 9-nitro-forbindelser og i mindre utstrekning 7-nitro- og 6-nitro-methylen-forbindelser. Ved nitrering av forbindelser med strukturen Ilb hvor E er hydrogen, vil nitreringen hovedsakelig finne sted ved 6-methylen-gruppen, samt i 9 stillingen og i mindre utstrekning i 7-stillingen. not particularly critical, especially in consideration of the stability of the starting compounds vis-à-vis the acidic ones reaction conditions. To ensure a satisfactory yield, one prefers to use reaction times between 15 minutes and approx. 12 hours. Nitration of compounds with the structure IIa where E is OH gives mainly 9-nitro compounds and to a lesser extent 7-nitro and 6-nitro-methylene compounds. In nitration of compounds with the structure Ilb where E is hydrogen, the nitration will mainly take place at the 6-methylene group, as well as in the 9-position and to a lesser extent in the 7-position.
Nitrering av forbindelser med strukturene III og\ VI. Nitration of compounds with the structures III and\ VI.
Nitrering av forbindelser med strukturene III og VI gir forbindelser med strukturene IV og Vllj henholdsvis. Nitreringen utføres ved hjelp<1> av de ovenfor beskrevne fremgangsmåter. , Nitration of compounds with structures III and VI gives compounds with structures IV and Vllj respectively. The nitration is carried out using<1> the methods described above. ,
lla- dehalo<g>enering. lla- dehalo<g>enation.
Forbindelsene' med strukturene II, III, IV, V, VI, VII. og VIII, som i det følgende benevnes 6-methyl-1 la-halogentetracycliner, er utgangsstoffer for fremstilling av tilsvarende lla-deshalogen- dvs. 6-methylentetracycliner (forbindelser med strukturene Ia og Ib). The compounds' with structures II, III, IV, V, VI, VII. and VIII, which in the following are referred to as 6-methyl-1 la-halotetracyclines, are starting materials for the production of corresponding lla-dehalogens, i.e. 6-methylenetetracyclines (compounds with the structures Ia and Ib).
Skjønt slike strukturer hos noen av disse forbindelser synes å være isomere med kjente 5a,6-anhydrotetracycliner, er de ve-sentlig forskjellig i fra disse, spesielt ved deres bredere spektrum når det gjelder aktivitet overfor månge forskjellige mikroorganismer, høyere aktivitet overfor indi-viduelle organismer og spesielt overfor antibiotisk resistente', organismer. Videre gir de foreliggende forbindelser beskyttelse mot organismer som forårsaker sykdommer hos dyr, hvilken egenskap de kjente 5a,6-anhydro-forbindelsér ikke oppviser, hvilket er vel kjent. Although such structures in some of these compounds appear to be isomeric with known 5α,6-anhydrotetracyclines, they are essentially different from these, especially in their broader spectrum in terms of activity against many different microorganisms, higher activity against individuals organisms and especially against antibiotic-resistant', organisms. Furthermore, the present compounds provide protection against organisms that cause diseases in animals, which property the known 5α,6-anhydro compounds do not exhibit, which is well known.
Dehalogeneringsreaksjonen kan utføres ved forskjellige kjente metoder til å fjerne halogen, både ved kjemiske og katalytiske reduksjonsmetoder.; En sådan katalytisk reaksjon utføres ved behandling med hy-drogengass over en edelmetallkatalysator, eksempelvis palladium eller rhodium-kata-lysatorer, ved trykkj fra atmosfæretrykk til 1000 atmosfærer fra 0 til 100° C. Forskjellige kjemiske metoder kan brukes. En sådan metode omfatter reduksjon med alkalime-tall-hydrosulfiter. Utgangsforbindelsen settes til en vandig oppløsning av det valgte hydrosulfit og får henstå ved romtemperatur, som bekvemt kan anvendes for denne reaksjon. Ytterligere metoder til å fjerne lla-halogen vil være nærliggende for fagfolk på området innbefatter: (a) behandling med en fortynnet vandig The dehalogenation reaction can be carried out by various known methods to remove halogen, both by chemical and catalytic reduction methods.; Such a catalytic reaction is carried out by treatment with hydrogen gas over a noble metal catalyst, for example palladium or rhodium catalysts, at pressures from atmospheric pressure to 1000 atmospheres from 0 to 100° C. Different chemical methods can be used. One such method involves reduction with alkali metal hydrosulphites. The starting compound is added to an aqueous solution of the chosen hydrosulphite and allowed to stand at room temperature, which can conveniently be used for this reaction. Additional methods of removing the lla halogen will be apparent to those skilled in the art include: (a) treatment with a dilute aqueous
j odhydrogensyre, j odohydrogen acid,
(b) behandling med metallisk sink i nær-vær av en proton donor, som f. eks. eddiksyre, (c) behandling med sinkstøv i et inert (b) treatment with metallic zinc in the presence of a proton donor, such as e.g. acetic acid, (c) treatment with zinc dust in an inert
oppløsningsmiddel, solvent,
(d) behandling med natriumjodid i et or-ganisk oppløsningsmiddel, fulgt av behandling av den resulterende jodfor-bindelse med metallisk sink. Fremgangsmåte under (d) finnes ofte å være lite effektiv idet den første reaksjon synes å være i beste fall ufullstendig. Det har overraskende vist seg at lla-halogentetracycliner lett lar seg dehalogenere ved samtidig behandling av lla-halogenforbindelser med sink og natriumjodid i et reaksjons-inert oppløsningsmiddel (fortrinsvis lavere alkanoner, eksempelvis aceton) ved temperaturer fra romtemperatur til koketemperatur under anvendelse av fra ekvivalente mengder opp til overskudd av reagensene på 100 mol pst. eller mere. Ved tilbakeløpstemperatur fåes fullstendig reaksjon i løpet av 30 minutter. Etter at reaksjonen er fullført, erholdes produktet ved filtrering og inndampning av reak-sionsblandingen. Under betingelser for re-duktiv fjernelse av lla-halogen som beskrevet ovenfor, reduseres nitrogruppene til aminogrupper under dannelse av de tilsvarende aminoderivater som angitt ved strukturene Ia og Ib. (d) treatment with sodium iodide in an organic solvent, followed by treatment of the resulting iodide compound with metallic zinc. Method under (d) is often found to be not very effective as the first reaction seems to be incomplete at best. It has surprisingly been shown that lla-halogen tetracyclines can easily be dehalogenated by simultaneous treatment of lla-halogen compounds with zinc and sodium iodide in a reaction-inert solvent (preferably lower alkanones, for example acetone) at temperatures from room temperature to boiling temperature using from equivalent amounts up to an excess of the reagents of 100 mol percent or more. At reflux temperature, a complete reaction is obtained within 30 minutes. After the reaction is complete, the product is obtained by filtering and evaporating the reaction mixture. Under conditions of reductive removal of the 11a halogen as described above, the nitro groups are reduced to amino groups with the formation of the corresponding amino derivatives as indicated by the structures Ia and Ib.
Ved overføring av lla-halogen-tetracyclin-hemi-ketalet, forbindelse X, til 11a-halogen-6-methylentetracycliner og derpå til 6-methylentetracycliner foretrekkes 11a-klortetracyclin-hemi-ketalene da disse forbindelser vanligvis synes å være ganske stabile og lett lar seg dehalogenere. Ila-fluorforbindelsene lar seg ikke så lett dehalogenere. In the transfer of the 11a-halo-tetracycline hemi-ketal, compound X, to 11a-halo-6-methylenetetracyclines and then to 6-methylenetetracyclines, the 11a-chlorotetracycline hemi-ketals are preferred as these compounds usually appear to be quite stable and readily allow dehalogenate themselves. The 11a-fluorine compounds are not easily dehalogenated.
lla-deshalogen-forbindelsene dvs. 6-methylentetracycliner, har en overraskende høy aktivitet ved forsøk in vitro overfor en lang rekke forskjellige sykdomsfrembringende organismer og har vist seg åvære spesielt effektive mot antibiotisk resistente stammer av mikroorganismer. The 11a-dehalogen compounds, i.e. 6-methylenetetracyclines, have a surprisingly high activity when tested in vitro against a wide range of different disease-causing organisms and have been shown to be particularly effective against antibiotic-resistant strains of microorganisms.
Den følgende tabell gir en oversikt over aktiviteten av 6-methylentetracyclin overfor forskj elige sykdomsfrembringende mikroorganismer innbefattende antibiotiske resistente stammer. Den minimale konsentrasjon som gir tilstrekkelig virkning CMVK) bestemmes ved den velkjente serie-fortynningsteknikk. Tabellen innbefatter MVK for lla-klor-6-methylentetracyclin og 6-deoxytetracyclin. Det bemerkes at MVK-verdiene for 6-methylentetracyclin vanligvis er lavere enn verdiene for 6-deoxytetracyclin, hvilket betyr høyere aktivi- The following table provides an overview of the activity of 6-methylenetetracycline against various disease-causing microorganisms, including antibiotic-resistant strains. The minimal concentration that gives sufficient effect (CMVK) is determined by the well-known serial dilution technique. The table includes MVK for lla-chloro-6-methylenetetracycline and 6-deoxytetracycline. It is noted that the MVK values for 6-methylenetetracycline are usually lower than those for 6-deoxytetracycline, which means higher activity
tet, spesielt overfor Micrococcus pyogenes var. aureus 400, en tetracyclin-resistens or-ganisme. tet, especially against Micrococcus pyogenes var. aureus 400, a tetracycline-resistant organism.
Tabellen nedenfor viser aktiviteten in vitro for noen representative forbindelser. The table below shows the in vitro activity of some representative compounds.
Når disse in vitro-forsøk ble gjentatt i nær-vær av menneskeserum, erholdtes lignende resultater. Den følgende tabell viser aktiviteten av ovennevnte forbindelser i tabell II ved forsøk med 20 pst. menneskeserum: Det bemerkes at 7-klor-6-deoxy-6-demethyl-6-methylen-5-oxytetracyclin har stør-re aktivitet in vitro overfor et stort antall organismer enn 6-deoxy-6-demethyl-6-me thylen - 5 -oxy tetracyclin. When these in vitro experiments were repeated in the presence of human serum, similar results were obtained. The following table shows the activity of the above-mentioned compounds in table II when tested with 20 percent human serum: It is noted that 7-chloro-6-deoxy-6-demethyl-6-methylene-5-oxytetracycline has greater activity in vitro against a large number of organisms than 6-deoxy-6-demethyl-6-me thylene - 5 -oxy tetracycline.
Når 6-deoxy-6-demethyl-6-methylen-5-oxytetracyclin ble utprøvd in vitro på både oral og parenteral veg, viste det en større aktivitet enn tetracyclin eller 5-oxytetracyclin overfor infeksjoner fremkalt med tetracyclinfølsomme mikroorganismer. PD50 (PD = beskyttende dose for den foreliggende nye forbindelse overfor en infek-sjon fremkalt med Micrococcus pyogenes var. aureus 5, er 3,2 mg/kg oralt og 0,34 mg/kg parenteralt. Den tilsvarende PD5fl for tetracyclin er 6,4 mg/kg oralt og 0,78 mg/kg parenteralt. When 6-deoxy-6-demethyl-6-methylene-5-oxytetracycline was tested in vitro by both oral and parenteral routes, it showed greater activity than tetracycline or 5-oxytetracycline against infections caused by tetracycline-sensitive microorganisms. PD50 (PD = protective dose for the present new compound against an infection caused by Micrococcus pyogenes var. aureus 5, is 3.2 mg/kg orally and 0.34 mg/kg parenterally. The corresponding PD5fl for tetracycline is 6, 4 mg/kg orally and 0.78 mg/kg parenterally.
De foreliggende nye 6rmethylen-forbindelser med strukturen Ia og Ib kan anvendes i forskjellige preparater med moder-forbindelsene. De kan benyttes til bekjempelse av sykdommer hos mennesker, og de kan brukes terapeutisk i forstbffer eller som vekststimulerende midler, i den vete-rinære praksis såvel som i jordbruket. The present new 6-methylene compounds with the structures Ia and Ib can be used in various preparations with the mother compounds. They can be used to combat diseases in humans, and they can be used therapeutically in forest products or as growth stimulants, in veterinary practice as well as in agriculture.
Ved bekjempelse av sykdommer hos mennesker er den vanlige orale dosering av de nye forbindelser fra ca. 0,1 til ca. 2 g pr. døgn for voksne. Produktene anvendes i kapsler eller tabletter inneholdende fra 25 til 250 mg av det antibiotiske stoff avhengig av aktiviteten. Suspensjoner eller oppløsninger i forskjellige bærersubstanser fremstilles med konsentrasjoner fra 5 til 125 mg/ml. For parenteral anvendelse in-tramuskulært eler intravenøst er den dag-lige dose ca. 0,1—1,0 g. Preparater til intra-muskulær bruk omfatter oppløsninger av det antibiotiske stoff i konsentrasjoner fra 50 til 100 mg/ml. Intravenøst anvendes iso-toniske oppløsninger med antibiotisk konsentrasjon, på ca. 10 mg/ml. Begge typer av det parenterale produkt markedsføres bekvemt i fast form for fremstilling av de ønskede preparater. I alle tilfeller vil selv-salt doseringen avpasses etter pasientens behov, og for barn anvendes i alminnelighet mindre doser. When fighting diseases in humans, the usual oral dosage of the new compounds is from approx. 0.1 to approx. 2 g per day for adults. The products are used in capsules or tablets containing from 25 to 250 mg of the antibiotic substance depending on the activity. Suspensions or solutions in various carrier substances are prepared with concentrations from 5 to 125 mg/ml. For parenteral use intramuscularly or intravenously, the daily dose is approx. 0.1—1.0 g. Preparations for intramuscular use include solutions of the antibiotic substance in concentrations from 50 to 100 mg/ml. Intravenously, isotonic solutions with an antibiotic concentration of approx. 10 mg/ml. Both types of parenteral product are conveniently marketed in solid form for the production of the desired preparations. In all cases, the self-salt dosage will be adjusted according to the patient's needs, and smaller doses are generally used for children.
Det skal spesielt nevnes at syre- og ba-se-saltene av de foreliggende nye amfotere tetracycliner ansees å ligge innenfor opp-finnelsens ramme. It should be mentioned in particular that the acid and base salts of the present new amphoteric tetracyclines are considered to lie within the scope of the invention.
Når det gjelder de terapeutiske aktive tetracycliner, vil salter som dannes med farmasøytiske godtagbare syrer og baser være egnet for anvendelse i passende dose-ringsform. De salter som dannes med far-masøytisk ikke godtagbare syrer og baser, er av verdi ved isolering og rensning av de foreliggende nye tetracycliner og og-så ved fremstilling av farmasøytisk godtak-bare salter. In the case of the therapeutically active tetracyclines, salts formed with pharmaceutically acceptable acids and bases will be suitable for use in appropriate dosage form. The salts which are formed with pharmaceutically unacceptable acids and bases are of value in the isolation and purification of the present new tetracyclines and also in the production of pharmaceutically acceptable salts.
De følgende eksempler vil ytterligere belyse oppfinnelsen. The following examples will further illustrate the invention.
Eksempel 1. Example 1.
6- deoxy- 6- demethyl- 6- methylentetracyclin. 6- deoxy- 6- demethyl- 6- methylenetetracycline.
5 mg lla-klor-6-deoxy-6-demethyl-6-methylentetracyclinhydroklorid fremstilt ifølge eksempel XXX oppløses i 3 ml methanol, og en ny fremstilt oppløsning av 5 mg of lla-chloro-6-deoxy-6-demethyl-6-methylenetetracycline hydrochloride prepared according to Example XXX is dissolved in 3 ml of methanol, and a newly prepared solution of
natriumhydrosulfit (20 mg i 2 ml vann) tilsettes. Blandingen får stå i 15 minutter ved romtemperatur, hvorpå methanolen avdampes og residuet ekstraheres med butanol. Butanolekstraktet inndampes, hvorpå produktet, 6-deoxy-6-demethyl-6-methylen-tetracyclin erholdes. Produktet omkrystalliseres fra acetonitril. Alternativt kry-staliseres det som hydrokloridsaltet fra vann ved tilsetning av konsentrert saltsyre. sodium hydrosulphite (20 mg in 2 ml of water) is added. The mixture is allowed to stand for 15 minutes at room temperature, after which the methanol is evaporated and the residue is extracted with butanol. The butanol extract is evaporated, whereupon the product, 6-deoxy-6-demethyl-6-methylene-tetracycline, is obtained. The product is recrystallized from acetonitrile. Alternatively, it crystallizes as the hydrochloride salt from water by adding concentrated hydrochloric acid.
Produktet ble utøvd ved forsøk med K. pneumoniae og viste en oxytetracyclin-aktivitet på minst 1100 jig/mg. Produktet viser en Rt-verdi på 0,6 i systemet: mobil fase: 20:3-toluen/pyridin mettet med en puffer med pH 4,2. The product was tested with K. pneumoniae and showed an oxytetracycline activity of at least 1100 µg/mg. The product shows an Rt value of 0.6 in the system: mobile phase: 20:3-toluene/pyridine saturated with a buffer of pH 4.2.
Ikke- mobil fase: Puffer (vandig) pH 4,2, og følger oppløsningsmiddel-fronten i det følgende system: mobil fase: nitromethan/kloroform/pyridin i forholdet 2 : 10 : 3. Non-mobile phase: Buffer (aqueous) pH 4.2, and follows the solvent front in the following system: mobile phase: nitromethane/chloroform/pyridine in the ratio 2 : 10 : 3.
Ikke- mobil fase: puffer (vandig) pH 3,5. Non-mobile phase: buffer (aqueous) pH 3.5.
Eksempel 2. Example 2.
Fremgangsmåte ifølge eksempel 1 gjentas for å deklorere lla-klor-7-klor-6-deoxy-6-demethyl-6-methylentetracyclin, og lla-klor-5-hydroxy-6-deoxy-demethyl-6- methylentetracyclin, hvorved de følgen-de produkter erholdes, hvilke tilsvarer produktet ifølge eksempel 1 i henhold til ultrafiolett og infrarød analyse (infrarød analyse viser manglende carbonylabsorpsjon da der ikke fåes et maksimum ved eller nær 5,7 mikroner): 7- klor-6-deoxy-demethyl-6-methylentetracyclin, 5-hydroxy-6-deoxy-6-demethyl-6-methylentetracyclin. The procedure according to example 1 is repeated to dechlorinate 11a-chloro-7-chloro-6-deoxy-6-demethyl-6-methylenetetracycline, and 11a-chloro-5-hydroxy-6-deoxy-demethyl-6-methylenetetracycline, whereby the following -the products are obtained, which correspond to the product according to example 1 according to ultraviolet and infrared analysis (infrared analysis shows a lack of carbonyl absorption as no maximum is obtained at or near 5.7 microns): 7-chloro-6-deoxy-demethyl-6 -methylenetetracycline, 5-hydroxy-6-deoxy-6-demethyl-6-methylenetetracycline.
Eksempel 3. Example 3.
6- methylentetracylin ( 6- deoxy- 6- demethyl- 6- methylentetracyclin). 6- methylenetetracycline ( 6- deoxy- 6- demethyl- 6- methylenetetracycline).
En blanding av 250 mg lla-klor-6-methylentetracyclin-hydroklorid (fremstilt ifølge eksempel XXX) og 100 mg sink i 10 ml aceton omrøres i 15 minutter ved romtemperatur, hvorefter 5 ml 5 pst.'s saltsyre tilsettes. Blandingen filtreres, og aceton avdampes. Fra den konsentrerte reaksjonsblanding utskilles 6-methylen-tetracyclin-hydroklorid som frafiltreres. A mixture of 250 mg of lla-chloro-6-methylenetetracycline hydrochloride (prepared according to example XXX) and 100 mg of zinc in 10 ml of acetone is stirred for 15 minutes at room temperature, after which 5 ml of 5% hydrochloric acid is added. The mixture is filtered and the acetone is evaporated. 6-methylene-tetracycline hydrochloride separates from the concentrated reaction mixture and is filtered off.
Denne fremgangsmåte gjentaes under anvendelse av 5 ml saltsyre og 5 ml aceton som oppløsningsmiddelsystem, hvorved lignende resultater erholdes. This procedure is repeated using 5 ml of hydrochloric acid and 5 ml of acetone as solvent system, whereby similar results are obtained.
Eksempel 4. Example 4.
6- methylentetracyclin. 6- methylenetetracycline.
250 mg lla-klor-6-methylentetracyclin-hydroklorid fremstilt ifølge eksempel XXX og 250 mg natriumjodid i 25 ml aceton opvarmes under itilbakeløp i 2 timer. Reaksjonsblandingen avkjøles, filtreres og inndampes, hvorved 6-methylentetracyclin erholdes. 250 mg of 11a-chloro-6-methylenetetracycline hydrochloride prepared according to Example XXX and 250 mg of sodium iodide in 25 ml of acetone are heated under reflux for 2 hours. The reaction mixture is cooled, filtered and evaporated, whereby 6-methylenetetracycline is obtained.
Eksempel 5. Example 5.
6- methylentetracyclin- hydroklorid. 6- methylenetetracycline hydrochloride.
250 mg lla-;klor-6-methylentetracyclin-hydroklorid fremstilt ifølge eksempel XXX opvarmes under tilbakeløp i 50 ml aceton i 24 timer.| Blandingen avkjøles, filtreres slik at et klart filtrat erholdes som inndampes underj redusert trykk, hvorved 6-methylentetracyclin fåes i form av hydrokloridsaltet. 250 mg of lla-;chloro-6-methylenetetracycline hydrochloride prepared according to Example XXX is heated under reflux in 50 ml of acetone for 24 hours. The mixture is cooled, filtered so that a clear filtrate is obtained which is evaporated under reduced pressure, whereby 6-methylenetetracycline is obtained in the form of the hydrochloride salt.
Eksempel 6. Example 6.
6- methylenteiracyclin. 6- methylene teiracycline.
Til 1 g lla-brom-6-methylentetracyclin-hydrobromid i! 20 ml vann settes under omrøring 320 mg j calsiumbisulfit oppløst i 5 ml vann. Etter omrøring i 30 minutter ved romtemperatur, erholdes produktet ved filtrering av reaksjonsblandingen. To 1 g of lla-bromo-6-methylenetetracycline hydrobromide i! Add 20 ml of water while stirring and add 320 mg of calcium bisulphite dissolved in 5 ml of water. After stirring for 30 minutes at room temperature, the product is obtained by filtering the reaction mixture.
Eksempel 7. Example 7.
Hydrokloridet,| hydrobromidet, sulfatet, hydrojodidet og fosfatet av 6-methylentetracycliner fremstilles fra de tilsvarende 6-methylentetracyclin i henhold til fremgangsmåten ifølge'eksempel 36. The hydrochloride,| the hydrobromide, sulfate, hydroiodide and phosphate of 6-methylenetetracyclines are prepared from the corresponding 6-methylenetetracyclines according to the method of Example 36.
Eksempel 8. Example 8.
Natriumsaltet av 6-methylentetracyclin fremstilles ved at man oppløser te-tracyclinforbindelsen i vann inneholdende en ekvivalent mengde natriumhydroxyd. Oppløsningen frysetørres, hvorved natriumsaltet erholdes, j The sodium salt of 6-methylenetetracycline is prepared by dissolving the tetracycline compound in water containing an equivalent amount of sodium hydroxide. The solution is freeze-dried, whereby the sodium salt is obtained, j
På lignende måte fremstilles andre al-kali- og jordalkali-jmetallsalter av de foreliggende nye 6-methylenforbindelser; således kalium-, litium-, barium-, calcium-, strontium- og maignesium-saltene, samt salter av både organiske (aminer) og an-organiske baser. Sajlter dannet med farma-søytiske godtagbare baser er terapeutisk verdifulle; salter med farmasøytisk ikke godtagbare syrer eller baser kan anvendes ved rensning av de nye produkter. In a similar manner, other alkali metal and alkaline earth metal salts are prepared from the present new 6-methylene compounds; thus the potassium, lithium, barium, calcium, strontium and magnesium salts, as well as salts of both organic (amines) and inorganic bases. Cells formed with pharmaceutically acceptable bases are therapeutically valuable; salts with pharmaceutically unacceptable acids or bases can be used when purifying the new products.
Eksempel 9. Example 9.
6- deoxy- 6- demethyl- 6- methylentetracyclin- hydroklqrid. 6- deoxy- 6- demethyl- 6- methylenetetracycline hydrochloride.
En oppløsning av 50 g lla-klor-6-deoxy-6-demethyl-6-methylentetracyclin-hydroklorid i 500 ml monomethylether av ethylenglycol avkjøles til 4° C i et isbad, og oppløsningen behandles med 50 g metallisk sinkstøv under hurtig omrøring idet sinkstøvet tilsettes over et tidsrom på ca. A solution of 50 g of lla-chloro-6-deoxy-6-demethyl-6-methylenetetracycline hydrochloride in 500 ml of monomethyl ether of ethylene glycol is cooled to 4° C in an ice bath, and the solution is treated with 50 g of metallic zinc dust with rapid stirring as the zinc dust is added over a period of approx.
10 minutter. Temperaturen heves til 12° C 10 minutes. The temperature is raised to 12° C
under tilsetning. Etter endt tilsetning begynner temperaturen å falle. Etter en to-tal reaksjonstid på 15 minutter fjernes sinken ved hurtig filtrering og vaskes med oppløsningsmiddel. En liter vann tilsettes filtratet over et tidsrom på ca. 10 minutter. En gul velling av sink-komplekset av produktet dannes. Oppløsningens pH innstilles så på 6,8 med 10 pst.'s vandig natriumhydroxyd. during addition. After the addition is complete, the temperature begins to fall. After a two-number reaction time of 15 minutes, the zinc is removed by rapid filtration and washed with solvent. One liter of water is added to the filtrate over a period of approx. 10 minutes. A yellow slurry of the zinc complex of the product is formed. The pH of the solution is then adjusted to 6.8 with 10% aqueous sodium hydroxide.
Den resulterende velling holdes i et isbad i ca. 1,5 timer og filtreres. Den våte filterkake oppslemmes i 750 ml vann, og konsentrert saltsyre tilsettes dråpe vis inntil der fåes en klar oppløsning. Et lite overskudd av konsentrert saltsyre bevirker hurtig krystallisasjon av 6-deoxy-6-demethyl-6-methylentetracyclin-hydroklorid i form av glinsende nåler. Etter henstand i en time filtreres produktet og tørres. Utbyttet er 37,8 g. Produktet smelter ved 213,8— 214,2° C under spaltning. The resulting gruel is kept in an ice bath for approx. 1.5 hours and filtered. The wet filter cake is suspended in 750 ml of water, and concentrated hydrochloric acid is added drop by drop until a clear solution is obtained. A small excess of concentrated hydrochloric acid causes rapid crystallization of 6-deoxy-6-demethyl-6-methylenetetracycline hydrochloride in the form of glistening needles. After resting for an hour, the product is filtered and dried. The yield is 37.8 g. The product melts at 213.8-214.2° C during decomposition.
Eksempel 10. Example 10.
6- deoxy- 6- demethyl- 6- methylentetracyclin. 6- deoxy- 6- demethyl- 6- methylenetetracycline.
lla-klor-6-deoxy-6-demethyl-6-methylentetracyclin lar seg også effektivt deklorere, hvorved man får 6-deoxy-6-demethyl-6-methylentetracyclin under anvendelse av de følgende reagenser: lla-chloro-6-deoxy-6-demethyl-6-methylenetetracycline can also be effectively dechlorinated, whereby 6-deoxy-6-demethyl-6-methylenetetracycline is obtained using the following reagents:
Vandig fenylhydrazin-acetat, Aqueous phenylhydrazine acetate,
Vandig ferro-sulfat, Natriumformaldehyd-sulfoxylat, Hypofosforsyrling og palladium black, Jernpulver i dimethylformamid, Raney-nikkel i 50 pst. vandig eddiksyre. Det vil være klart for fagfolk på området at 6-methylentetracyclin og lla-halogen-6-methylentetracyclinene kan over-føres partielt til deres C-4-epimere under mange betingelser, spesielt ved pH-verdier mellom 2 og 6 og i slike oppløsningsmidler som iseddik. I praksis kan 6-methylentetra.-cyclin og lla-halogen-6-methylentetracyclin slik de. fåes ved de her beskrevne fremgangsmåter, inneholde små mengder — dvs. mindre enn 20 pst. — av deres C.4-epimere. 5-hydroxy-methylentetracycliner er mere motstandsdyktige overfor C-4-epimerise-ring. De C-4-epimere av forbindelsene iføl-ge oppfinnelsen kan isoleres fra blandinger ved bruk av vanlige fremgangsmåter, f. eks. ved papirkromatografi eller ved hjelp av motstrømsfordeling. De hovedsakelig rene C-4-epi-forbindelser kan igjen overføres til de normale, mere aktive former ved i og for seg kjente fremgangsmåter, f. eks. ved behandling med iseddik. Aqueous ferrous sulphate, Sodium formaldehyde sulphoxylate, Hypophosphorous acid and palladium black, Iron powder in dimethylformamide, Raney nickel in 50 per cent aqueous acetic acid. It will be clear to those skilled in the art that 6-methylenetetracycline and the 11a-halo-6-methylenetetracyclines can be partially converted to their C-4 epimers under many conditions, particularly at pH values between 2 and 6 and in such solvents as glacial acetic acid. In practice, 6-methylenetetra.-cycline and lla-halogen-6-methylenetetracycline as they. obtained by the methods described here, contain small amounts — i.e. less than 20 per cent — of their C.4 epimers. 5-hydroxy-methylenetetracyclines are more resistant to C-4 epimerization. The C-4 epimers of the compounds according to the invention can be isolated from mixtures using usual methods, e.g. by paper chromatography or by means of countercurrent distribution. The mainly pure C-4-epi compounds can again be transferred to the normal, more active forms by methods known per se, e.g. by treatment with glacial acetic acid.
Eksempel 11. Example 11.
6- deoxy- 6- demethyl- 6- methylen-5- oxytetracyclin. 6- deoxy- 6- demethyl- 6- methylene-5- oxytetracycline.
Fremgangsmåte A Procedure A
Til en oppløsning av 5 g lla-klor-6-deoxy-6-demethyl-6-methylen-5-oxytetracyclin-hydrojodid (fremstilt ifølge eksempel 32) i 125 ml fortynnet saltsyre (en del konsentrert saltsyre i 55 deler vann) settes ved 20°C i 5 g sinkstøv. Efter omrø-ring i 10 minutter frafiltreres sinken, og filtratet innstilles på pH = 0,8 og ekstraheres med butanol. Butanolekstraktet inndampes under redusert trykk til et residuum som tritureres med ether. Det ether-uoppløselige residuum krystalliseres fra en blanding av methanol, aceton, konsentrert saltsyre og ether, hvorved man får produktet i form av hydroklorid-monomethanola-tet (2,5 g), som smelter ved 205° C under spaltning. Ultrafiolett analyse i 0,01 N methanolisk saltsyre viser — 252 mu, To a solution of 5 g of lla-chloro-6-deoxy-6-demethyl-6-methylene-5-oxytetracycline hydroiodide (prepared according to example 32) in 125 ml of dilute hydrochloric acid (one part concentrated hydrochloric acid in 55 parts water) is added by 20°C in 5 g zinc dust. After stirring for 10 minutes, the zinc is filtered off, and the filtrate is adjusted to pH = 0.8 and extracted with butanol. The butanol extract is evaporated under reduced pressure to a residue which is triturated with ether. The ether-insoluble residue is crystallized from a mixture of methanol, acetone, concentrated hydrochloric acid and ether, whereby the product is obtained in the form of the hydrochloride monomethanolate (2.5 g), which melts at 205° C during decomposition. Ultraviolet analysis in 0.01 N methanolic hydrochloric acid shows — 252 mu,
= 282. Infrarød analyse viser hovedtopper ved 6,03; 6,2; 6,37; og 6,87 mikroner. Biologisk utprøvning viser en verdi på 2000— 24000 \ xg/ mg (K.pneumoniae, turbimetrisk test med oxytetracyclin som standard). Ele- = 282. Infrared analysis shows major peaks at 6.03; 6.2; 6.37; and 6.87 microns. Biological testing shows a value of 2000-24000 µg/mg (K.pneumoniae, turbimetric test with oxytetracycline as standard). Ele-
mentaranalyse av produktet gir de føl-gende verdier: C, 55,0; H, 5,2; N, 5,5; Cl, 7,0; mentary analysis of the product gives the following values: C, 55.0; H, 5.2; N, 5.5; Cl, 7.0;
OCH.,, 3,4. Produktet viser Rf-verdier på henholdsvis 0 og 0,35 i de følgende syste-mer: OCH.,, 3,4. The product shows Rf values of 0 and 0.35 respectively in the following systems:
Fremgangsmåte B Procedure B
En blanding av 1 g av lla-klor-produktet ifølge eksempel 32 i 10 ml methanol inneholdende 200 mg 5 pst. rhodium på kull hydrogeneres ved romtemperatur og et hydrogentrykk på 1 atmosfære inntil en ekvimolar mengde hydrogen er tatt opp (2 timer). Katalysatoren frafiltreres, filtratet inndampes til tørrhet, og residuet krystalliseres som angitt under fremgangsmåte A. A mixture of 1 g of the lla-chlorine product according to example 32 in 10 ml of methanol containing 200 mg of 5% rhodium on charcoal is hydrogenated at room temperature and a hydrogen pressure of 1 atmosphere until an equimolar amount of hydrogen has been taken up (2 hours). The catalyst is filtered off, the filtrate is evaporated to dryness, and the residue is crystallized as indicated under method A.
I IN
Fremgangsmåte C Procedure C
En blanding av 1 g av lla-klor-produktet ifølge eksempel 32 i 70 ml vann inneholdende 1 g natmumhydrosulfit omrøres i 1/2 time ved romtemperatur. Blandingen ekstraheres med butanol, og butanolekstraktet inndampes til tørrhet. Produktet krystalliseres som beskrevet i fremgangsmåte A. A mixture of 1 g of the lla-chlorine product according to example 32 in 70 ml of water containing 1 g of sodium hydrosulphite is stirred for 1/2 hour at room temperature. The mixture is extracted with butanol, and the butanol extract is evaporated to dryness. The product is crystallized as described in method A.
Fremgangsmåte D Procedure D
Ved den under A angitte fremgangsmåte reduseres lla-fluor-6-deoxy-6-de-methylen-5-oxytétracyclinperklorat til 6-deoxy-demethyl-6-methylen-5-oxytetracyclin. In the method indicated under A, 11a-fluoro-6-deoxy-6-de-methylene-5-oxytetracycline perchlorate is reduced to 6-deoxy-demethyl-6-methylene-5-oxytetracycline.
Det krystallinske saltsyre-methanolat-produkt ifølge dette eksempel kan omkrystalliseres fra is<p>propanol i form av 6-deoxy-6-demethyl-6-methylen-5-oxytetra-cyclinhydrokloridet. Det omkrystalliserte materiale viser de følgende topper ved in-frarød analyse: 3,1; 3,75, 6,02; 6,23; 6,36; 6,55; 6,9; 7,35; 7,6; 7,8; 8,15; 8,26; 8,5; 9,27; 9,95; 10,55; 10,8; 11,53; 11,93 og 12,5 mikroner. The crystalline hydrochloric acid methanolate product according to this example can be recrystallized from is<p>propanol in the form of the 6-deoxy-6-demethyl-6-methylene-5-oxytetracycline hydrochloride. The recrystallized material shows the following peaks by infrared analysis: 3.1; 3.75, 6.02; 6.23; 6.36; 6.55; 6.9; 7.35; 7.6; 7.8; 8.15; 8.26; 8.5; 9.27; 9.95; 10.55; 10.8; 11.53; 11.93 and 12.5 microns.
Eksempel 12. Example 12.
7- klor- 6- deoxy- 6Ldemethyl- 6- methylen-5- oxytetracyclin. 7- chloro- 6- deoxy- 6L demethyl- 6- methylene-5- oxytetracycline.
Fremgangsmåte A. Procedure A.
Til en oppløsning av 0,5 g 7,11-diklor-6- deoxy-6-demethyl-6-methylen-5-oxytetracyclin-perklorat i 7,5 ml vann settes 0,45 g natriumhydrosulfit, og den resulterende blanding omrøres i 12 minutter. Produktet utskilles og oppsamles ved filtrering. Biologisk utprøvning av produktet gir en verdi på 3400 jig/mg. (Turbimetrisk test med K. pneuoniae og oxytetracyclin (1000 l^g/mg) som standard). To a solution of 0.5 g of 7,11-dichloro-6-deoxy-6-demethyl-6-methylene-5-oxytetracycline perchlorate in 7.5 ml of water is added 0.45 g of sodium hydrosulphite, and the resulting mixture is stirred in 12 minutes. The product is excreted and collected by filtration. Biological testing of the product gives a value of 3400 jig/mg. (Turbimetric test with K. pneuoniae and oxytetracycline (1000 l^g/mg) as standard).
Fremgangsmåte B. Procedure B.
20 g 7,lla-diklor-6-deoxy-6-demethy-len-5-hydroxy-tetracyclin-p-nafthalen-sulfonat suspenderes i 500 ml methanol inneholdende 5 g 5 pst. rhodium på kull, og blandingen hydrogeneres ved romtemperatur og et hydrogentrykk på 1 atmosfære. Etter at der er opptatt 700 ml hydrogen filtreres blandingen og filtratet inndampes til tørrhet, hvorved man får et residuum på 15,4 g. 20 g of 7,11a-dichloro-6-deoxy-6-demethylene-5-hydroxy-tetracycline-p-naphthalene-sulfonate are suspended in 500 ml of methanol containing 5 g of 5% rhodium on charcoal, and the mixture is hydrogenated at room temperature and a hydrogen pressure of 1 atmosphere. After 700 ml of hydrogen has been taken up, the mixture is filtered and the filtrate is evaporated to dryness, whereby a residue of 15.4 g is obtained.
En methanolisk oppløsning av 11 g av dette residuum innstilles på pH = 6,5 med triethylamin og ledes gjennom en 8 x 100 cm kolonne inneholdende 2 kg cellulose-pulver, idet vann anvendes som stasjonær fase. Kolonnen elueres med ethylacetat mettet med vann og 45 ml fraksjoner ut-tas. Elueringen følger papikromatografisk, og fraksjoner 132 til 260 forenes, inndampes til tørrhet, oppslemmes i ether og filtreres, hvilket gir 2,74 g av det rene, amorfe, amfotere produkt. A methanolic solution of 11 g of this residue is adjusted to pH = 6.5 with triethylamine and passed through an 8 x 100 cm column containing 2 kg of cellulose powder, water being used as the stationary phase. The column is eluted with ethyl acetate saturated with water and 45 ml fractions are taken out. The elution follows papichromatographically, and fractions 132 to 260 are combined, evaporated to dryness, slurried in ether and filtered, yielding 2.74 g of the pure, amorphous, amphoteric product.
Produktet krystalliseres ved oppløsning av 1,6 g i 40 ml varm methanol under skarpning. Filtrering gir 890 mg av produktet i form av den amfotere base. Infra-rød analyse viser de følgende topper: 2,96; The product is crystallized by dissolving 1.6 g in 40 ml of hot methanol while sharpening. Filtration gives 890 mg of the product in the form of the amphoteric base. Infrared analysis shows the following peaks: 2.96;
3,29; 3,42; 6,06; 6,18; 6,30; 6,58; 6,88; 7,19; 3.29; 3.42; 6.06; 6.18; 6.30; 6.58; 6.88; 7.19;
7,43; 7,70; 8,23; 9,06; 9,88; 10,63; 10,92; 7.43; 7.70; 8.23; 9.06; 9.88; 10.63; 10.92;
11,55 og 11,76 mikroner. Ultrafiolett analyse gir følgende resultater: i 0,01 N saltsyre i methanol, maksima ved 247 mjx (log e 4,28) og 326 m^ (log E 4,02) og en infleksjon ved 370 m^ (log e 3,98), i 0,01 N NaOH i methanol, maksima ved 234 m^ i (log e 4,24), 253 m|i (log £ 4,22) og 389 m^i (log e 4,12) og en inf leksjon ved 284 imi (log e 4,07); i 0,01M MgCl, i methanol, maksima ved 241 mfi (log E 4,32); 349 m^i (log e 4,04); 11.55 and 11.76 microns. Ultraviolet analysis gives the following results: in 0.01 N hydrochloric acid in methanol, maxima at 247 mjx (log e 4.28) and 326 m^ (log E 4.02) and an inflection at 370 m^ (log e 3.98 ), in 0.01 N NaOH in methanol, maxima at 234 m^ i (log e 4.24), 253 m|i (log £ 4.22) and 389 m^ i (log e 4.12) and a inf lection at 284 imi (log e 4.07); in 0.01M MgCl, in methanol, maxima at 241 mphi (log E 4.32); 349 m^i (log e 4.04);
og 372 m\ i (avtrapning) (log e 4,02). and 372 m\ in (de-escalation) (log e 4.02).
Produktet viser de følgende Rf-verdier i de angitte oppløsningsmiddelsystemer: The product shows the following Rf values in the specified solvent systems:
Biologisk utprøvning (K.pneumoniae — oxytetracyclin som standard gir en verdi på 6000 ug/m<g.>Biological testing (K.pneumoniae — oxytetracycline as standard gives a value of 6000 ug/m<g.>
Det krystallinske perklorat av produktet i det foregående eksempel hydroge- The crystalline perchlorate of the product in the previous example hydrogenated
neres, hvorved man får dette produkt, som krystalliseres fra methanol og 70 pst. perklorsyre. Perkloratet av produktet viser samme ultrafiolette spektra som den amfotere base. neres, whereby this product is obtained, which is crystallized from methanol and 70 per cent perchloric acid. The perchlorate of the product shows the same ultraviolet spectra as the amphoteric base.
Fremgangsmåte C Procedure C
Dette produkt erholdes også ved reduksjon av utgangsforbindelsen i fremgangsmåte A med sink og syre i henhold til fremgangsmåten i eksempel 11. This product is also obtained by reducing the starting compound in method A with zinc and acid according to the method in example 11.
Eksempel 13. Example 13.
7- brom- 6- deoxy- 6- demethyl- 6- methylen- 5- oxytetracyclin. 7- bromo- 6- deoxy- 6- demethyl- 6- methylene- 5- oxytetracycline.
Dette produkt erholdes fra 7-brom-lla-klor-6-deoxy-6-demethyl-6-methylen-5-oxytetracyclin ved den i behandling med natriumhydrosulfit som er beskrevet i eksempel 12. This product is obtained from 7-bromo-lla-chloro-6-deoxy-6-demethyl-6-methylene-5-oxytetracycline by treating it with sodium hydrosulphite as described in example 12.
De følgende forbindelser: 7-klor-lla-fluor-6-deoxy-6-demethyl-6- methylen-5-oxytetracyclin, 7-jod-lla-klor-6-deoxy-6-demethyl-6- methylen-5-oxytetracyclin, 7-brom-lla-fluor-6-deoxy-6-demethyl-6- methylen-5-oxytetracyclin, The following compounds: 7-chloro-lla-fluoro-6-deoxy-6-demethyl-6- methylene-5-oxytetracycline, 7-iodo-lla-chloro-6-deoxy-6-demethyl-6- methylene-5-oxytetracycline, 7-bromo-lla-fluoro-6-deoxy-6-demethyl-6- methylene-5-oxytetracycline,
overføres til de tilsvarende lla-deshalogen-forbindelser ved de før nevnte fremgangsmåter. are transferred to the corresponding 11a-dehalogen compounds by the previously mentioned methods.
Eksempel 14. Example 14.
9- amino- 6- deoxy- 6- demethyl- 6- methylen- 5- oxytetracyclin. 9- amino- 6- deoxy- 6- demethyl- 6- methylene- 5- oxytetracycline.
lla-klor-9-nitro-6-deoxy-6-demethyl-6-methylen-5-oxytetracyclin-nitrat dehalo- j lla-chloro-9-nitro-6-deoxy-6-demethyl-6-methylene-5-oxytetracycline nitrate dehalo- j
generes i henhold til tidligere beskrevne reduksjonsmetoder, hvorved ovennevnte forbindelse erholdes. is generated according to previously described reduction methods, whereby the above compound is obtained.
Eksempel 15. Example 15.
Ved anvendelse av følgende utgangs-forbindelser: 7-klor-lla-fluor-9-nitro-6-deoxy-deme thyl-6-methylen-5-oxytetacyclin, By using the following starting compounds: 7-chloro-lla-fluoro-9-nitro-6-deoxy-deme thyl-6-methylene-5-oxytetacycline,
7-brom-lla-klor-9-nitro-6-deoxy-6-demethyl-6-methylen-5-oxytetracyclin, 7-bromo-lla-chloro-9-nitro-6-deoxy-6-demethyl-6-methylene-5-oxytetracycline,
7 -j od-1 la-f luor-9 -nitro-deoxy -6 -derne - 7-iod-1 la-fluoro-9-nitro-deoxy-6-derene -
thyl-6-methylen-5-oxytetracyclin, fåes 7-brom-, jod- og klor-9-amino-6-deoxy-6-demethyl-6-methylen-5-oxy tetracyclin ved reduksjonsmetoder som er beskrevet ovenfor. thyl-6-methylene-5-oxytetracycline, 7-bromo-, iodo- and chloro-9-amino-6-deoxy-6-demethyl-6-methylene-5-oxy tetracycline is obtained by the reduction methods described above.
Eksempel 16. Example 16.
7- klor- 9- nitro- 6- deoxy- 6- demethyl-6- methylen- 5- oxytetracyclin. 7- chloro- 9- nitro- 6- deoxy- 6- demethyl-6- methylene- 5- oxytetracycline.
Til en oppløsning av 1,0 g 7-klor-6-deoxy-6 -demethyl-5 -methylen -5 -oxy tetra - cyclin-base i 8 ml vannfritt flytende hydrogenfluorid (HF) ved 0°C settes 220 mg KNO.,. Blandingen omrøres i 30 minutter ved 6°C, og HF avdampes under nitrogen. Residuet oppslemmes i tørr ether, filtreres og tørres. Produktet viser de følgende Rf-verdier i de angitte oppløsningsmiddelsy-; stemer: 220 mg of KNO is added to a solution of 1.0 g of 7-chloro-6-deoxy-6-demethyl-5-methylene-5-oxy tetracycline base in 8 ml of anhydrous liquid hydrogen fluoride (HF) at 0°C. ,. The mixture is stirred for 30 minutes at 6°C, and the HF is evaporated under nitrogen. The residue is suspended in dry ether, filtered and dried. The product shows the following Rf values in the indicated solvent sy-; voices:
Ultrafiolett analyse i 0.01M NaOH i methanol viser maksima ved 248,341 og 447 m|.i og en avtrapning ved 275 myi. Biologisk ut-prøvning viser en verdi på mindre enn 100 jig/mg (turbidimetrisk tets med K.pneumoniae og med oxytetracyclin stom standard). Ultraviolet analysis in 0.01M NaOH in methanol shows maxima at 248,341 and 447 mI and a tapering off at 275 mI. Biological testing shows a value of less than 100 µg/mg (turbidimetric tests with K.pneumoniae and with oxytetracycline blank standard).
Eksempel 17. Example 17.
9- nitro- 6- deoxy- 6- demethyl- 6- methylen- 5- oxytetracyclin. 9- nitro- 6- deoxy- 6- demethyl- 6- methylene- 5- oxytetracycline.
Til en blanding av 500 mg 6-deoxy-6-demethyl-6-methylen-5-oxytetracyclin i To a mixture of 500 mg of 6-deoxy-6-demethyl-6-methylene-5-oxytetracycline in
1,5 ml vannfritt flytende hydrogenfluorid settes 100 mg KNO,,. Blandingen omrøres ved 15°C i 30 minutter og inndampes til tørrhet. Residuet oppslemmes i ether, og råproduktet erholdes ved filtrering, hvorefter dette oppslemmes i 5 pst.'s vandig saltsyre; der filtreres og ekstraheres med butanol. Butanolekstraktet inndampes, hvorved produktet erholdes, og dette omkrystalliseres fra vann med saltsyre. 1.5 ml anhydrous liquid hydrogen fluoride is added to 100 mg KNO,,. The mixture is stirred at 15°C for 30 minutes and evaporated to dryness. The residue is suspended in ether, and the crude product is obtained by filtration, after which this is suspended in 5 per cent aqueous hydrochloric acid; where it is filtered and extracted with butanol. The butanol extract is evaporated, whereby the product is obtained, and this is recrystallized from water with hydrochloric acid.
Eksempel 18. Example 18.
7- klor- 9- amino- 6- deoxy- 6- demethyl-6- methylen- 5- oxy tetracyclin. 7- chloro- 9- amino- 6- deoxy- 6- demethyl-6- methylene- 5- oxy tetracycline.
Til en oppløsning av 1,42 g 7-klor-9-nitro-6-deoxy-6-demethyl-6-methylen-5-oxytetracyclin oppløst i 50 ml vann og 2 ml konsentrert saltsyre settes 1,3 g sink-støv under omrøring ved 20°C. Etter 15 minutter filtreres blandingen, pH innstil- To a solution of 1.42 g of 7-chloro-9-nitro-6-deoxy-6-demethyl-6-methylene-5-oxytetracycline dissolved in 50 ml of water and 2 ml of concentrated hydrochloric acid, add 1.3 g of zinc dust under stirring at 20°C. After 15 minutes, the mixture is filtered, the pH adjusted
les på 2,5, og blandingen ekstraheres med 5 x 30 ml butanol. Butanolekstraktet gir read at 2.5, and the mixture is extracted with 5 x 30 ml of butanol. The butanol extract gives
ved inndampning 760 mg av produktet (som dihydrokloridet). Biologisk utprøvning (K.pneumoniae) gir en verdi på 680 [xg/ mg. Ultrafiolett analyse i 0,01 N saltsyre i methanol viser maksima ved 262 og 348 m|x; i 0,01 N natriumhydroxyd i methanol, 264 og 380 mi.i. by evaporation 760 mg of the product (as the dihydrochloride). Biological testing (K.pneumoniae) gives a value of 680 [xg/ mg. Ultraviolet analysis in 0.01 N hydrochloric acid in methanol shows maxima at 262 and 348 m|x; in 0.01 N sodium hydroxide in methanol, 264 and 380 ml.
Produktet viser Rf-verdier som følger: The product shows Rf values as follows:
Produktet erholdes også ved reduksjon (med vandig natriumhydrosulfit) av 9-nitro-7,lla-diklor-6-deoxy-6-demethyl-6-methylen-5-oxytetracyclin. The product is also obtained by reduction (with aqueous sodium hydrosulphite) of 9-nitro-7,11a-dichloro-6-deoxy-6-demethyl-6-methylene-5-oxytetracycline.
Eksempel 19. Example 19.
9- amino- 6- deoxy- 6- demethyl- 6- methylen- 5- oxytetracyclin. 9- amino- 6- deoxy- 6- demethyl- 6- methylene- 5- oxytetracycline.
Dette produkt erholdes ved reduksjon av den tilsvarende 9-nitroforbindelse med natriumhydrosulfit eller SnCl, i saltsyre. This product is obtained by reduction of the corresponding 9-nitro compound with sodium hydrosulphite or SnCl, in hydrochloric acid.
, Eksempel 20. , Example 20.
6- deoxy- 6J, demethyl- 6- klormethylen- 6- deoxy- 6J, demethyl- 6- chloromethylene-
j tetracyclin. j tetracycline.
Til 1 mol lla-klor-6-deoxy-6-demethyl-6-klormethylentetracyclin (produktet iføl-ge eksempel 34) i 25 ml methanol settes 100 mg pst.'s rhodium på kull. Blandingen hydrogeneres under rysting ved romtemperatur og et hydrogentrykk på 1 atmosfære inntil der er opptatt 1 mol hydrogen. Efter frafiltrering |av katalysatoren inndampes oppløsningen! til tørrhet under redusert trykk. Residuet oppslemmes i ether, filtreres og tørres; hvorved produktet erholdes. To 1 mol of lla-chloro-6-deoxy-6-demethyl-6-chloromethylenetetracycline (the product according to example 34) in 25 ml of methanol is added 100 mg of rhodium on charcoal. The mixture is hydrogenated with shaking at room temperature and a hydrogen pressure of 1 atmosphere until 1 mole of hydrogen is occupied. After filtering off the catalyst, the solution is evaporated! to dryness under reduced pressure. The residue is suspended in ether, filtered and dried; whereby the product is obtained.
Under anvendelse av denne fremgangsmåte fremstilles de følgende forbindelser av de tilsvarende lla-halogenforbindelser. Åpenbart reduseres nitroforbindelser til aminoforbindelser ved denne reaksjon, hvilket nødvendiggjør mere enn 1 mol hydrogen.. Using this method, the following compounds are prepared from the corresponding 11a halogen compounds. Obviously, nitro compounds are reduced to amino compounds by this reaction, which requires more than 1 mol of hydrogen.
6-deoxy-6-demethyl-6-brommethylen-tetracyclin, 6-deoxy-6-demethyl-6-bromomethylene-tetracycline,
9-brom-6-deoxy-6-demethyl-6-brom-methylentetracyclin, 9-bromo-6-deoxy-6-demethyl-6-bromo-methylenetetracycline,
9-klor-5-deoxy-6-demethyl-6-brom-methylentetracyclin, 7-klor-6-deoxy-6-demethyl-6-klor-methylentetracyclin, 7-klor-6-deoxy-6-demethyl-6-brom-methylentetracyclin, 9-chloro-5-deoxy-6-demethyl-6-bromo-methylenetetracycline, 7-chloro-6-deoxy-6-demethyl-6-chloro-methylenetetracycline, 7-chloro-6-deoxy-6-demethyl-6- bromethylenetetracycline,
9-amino-6-deoxy-6-demethyl-6-methylentetracyclin, 9-amino-6-deoxy-6-demethyl-6-methylenetetracycline,
6- deoxy-6-demethyl-6-aminomethylen-tetracyclin, 6-deoxy-6-demethyl-6-aminomethylene-tetracycline,
9-klor-6-deoxy-6-demethyl-6-amino-methylentetracyclin, 9-chloro-6-deoxy-6-demethyl-6-amino-methylenetetracycline,
9-amino-6-deoxy-6-demethyl-6-klor-methylentetracyclin, 9-amino-6-deoxy-6-demethyl-6-chloro-methylenetetracycline,
9-brom-6-deoxy-6-demethyl-6-amino-methylentetracyclin, 9-bromo-6-deoxy-6-demethyl-6-amino-methylenetetracycline,
9-amino-6-deoxy-6-demethyl-6-brom-methylentetracyclin, 9-amino-6-deoxy-6-demethyl-6-bromo-methylenetetracycline,
7- klor-6-deoxy-6-demethyl-6-amino-methylentetracyclin. 7-chloro-6-deoxy-6-demethyl-6-amino-methylenetetracycline.
Det skal angis noen eksempler på fremstilling av de nye utgangsmaterialer som anvendes ved foreliggende oppfinnelse: Eksempel 21. Some examples of the production of the new starting materials used in the present invention shall be given: Example 21.
lla- fluortetracyclin- 6, 12- hemi- ketal. lla- fluorotetracycline- 6, 12- hemiketal.
Til en suspensjon av 20 g tetracyclin-base i 800 ml vann avkjølt til 0°C settes 45 ml (2 ekvivalenter) 2N natriumhydroxyd-oppløsning. Tetracyclinet oppløses, og oppløsningens pH er omkring 11. Perklorylfluorid blir så boblet gjennom oppløsnin-gen under omøring (og under nitrogenat-mosfære) inntil blandingens pH er omkring 7. Et tungt bunnfall begynner å dannes mellom en pH på 8 og 8,5. Overskuddet av perklorylfluorid spyles ut med en nitrogen strøm, og det nesten hvite krystallinske materiale frafiltreres, vaskes med vann og tørres under vakuum ved romtemperatur, idet der erholdes 7,9—8,5 g av produktet. Ultrafiolett absorbsjon viser maksima ved 267 og 240 m|j; i det infrarøde erholdes ingen carbonylabsorpsjon under 6 mikroner. Elementaranalyse gir følgende resultater: Teoretisk: C02H2.,N2OsP . H20; To a suspension of 20 g of tetracycline base in 800 ml of water cooled to 0°C is added 45 ml (2 equivalents) of 2N sodium hydroxide solution. The tetracycline dissolves, and the pH of the solution is about 11. Perchloryl fluoride is then bubbled through the solution with stirring (and under a nitrogen atmosphere) until the pH of the mixture is about 7. A heavy precipitate begins to form between a pH of 8 and 8.5. The excess of perchloryl fluoride is flushed out with a stream of nitrogen, and the almost white crystalline material is filtered off, washed with water and dried under vacuum at room temperature, obtaining 7.9-8.5 g of the product. Ultraviolet absorption shows maxima at 267 and 240 m|j; in the infrared no carbonyl absorption is obtained below 6 microns. Elemental analysis gives the following results: Theoretical: C02H2.,N2OsP . H 2 O;
" C, 54,95, H,~5,20, N, 5,83 Funnet C, 54,97, H, 5,19, N, 5,85 " C, 54.95, H,~5.20, N, 5.83 Found C, 54.97, H, 5.19, N, 5.85
Eksempel 22. Example 22.
lla- fluor- 5- hydroxytetracyclin-6, 12- hemi- ketal. lla- fluoro- 5- hydroxytetracycline-6, 12- hemiketal.
Til en blanding av 6.9 g vannfri oxy-tetracvclin-base oppløst i 285 ml methanol avkjølt i isbad settes en ekvivalent IN natriummetoxyd-methanoloppløsning. Det sule natriumsalt utfelles. Perklorylfluorid bobles inn, og natriumsaltet går i oppløs-ning. Etter hver som pH nærmer seg 7, be-sinner et tungt bunnfall å dannes. Overskudd av perklorylfluorid spyles ut med en strøm av nitrogen, produktet frafiltreres, vaskes med kold methanol og tørres under vakuum ved romtemperatur, hvorved man får 5.1 g lysegule krystaller. Infrarød ab-sorrjsjon viser ingen carbonylabsorpsion under 6 mikroner. Ultrafiolett absorpsjon viser maksima ved 265 og 336 m\ i. Elementaranalyse gir de følgende resultater etter omkrystallisasion av produkter fra vann. To a mixture of 6.9 g of anhydrous oxy-tetracycline base dissolved in 285 ml of methanol cooled in an ice bath is added an equivalent 1N sodium methoxyd-methanol solution. The salty sodium salt is precipitated. Perchloryl fluoride is bubbled in, and the sodium salt dissolves. As the pH approaches 7, a heavy precipitate tends to form. Excess perchloryl fluoride is flushed out with a stream of nitrogen, the product is filtered off, washed with cold methanol and dried under vacuum at room temperature, whereby 5.1 g of pale yellow crystals are obtained. Infrared absorption shows no carbonyl absorption below 6 microns. Ultraviolet absorption shows maxima at 265 and 336 m\ in. Elemental analysis gives the following results after recrystallization of products from water.
Teoretisk: C2!,H3.,0.iN0F. 2H„0: Theoretical: C2!,H3.,0.iN0F. 2H„0:
C, 51,4; H, 5,25; N, 5.5 Funnet: C, 51,2; H, 5,3; N, 5,7 C, 51.4; H, 5.25; N, 5.5 Found: C, 51.2; H, 5.3; N, 5.7
Eksempel 23. Example 23.
lla- klortetracyclin- 6, 12- hemi- ketal. lla- chlorotetracycline- 6, 12- hemiketal.
Til en oppløsning av 2.2 g vannfritt tetracyclin i 25 ml monoglyme (dimethylether av ethylenglycol settes 800 mg N-klorsuccinimid under omrøring, hvorved reagenset går i oppløsning. Blandingen får stå i 7 minutter og fortynnes derpå med 25 ml vann. Produktet, 873 mg, krystalliserer som hvite nåler. Infrarød analyse viser ingen carbonyl-bånd mellom 5 og 6 mikroner. Ultrafiolett absorpsjon viser maksima ved 267 og 340—342 m^i. To a solution of 2.2 g of anhydrous tetracycline in 25 ml of monoglyme (dimethyl ether of ethylene glycol, add 800 mg of N-chlorosuccinimide while stirring, whereby the reagent dissolves. The mixture is allowed to stand for 7 minutes and then diluted with 25 ml of water. The product, 873 mg, crystallizes as white needles Infrared analysis shows no carbonyl band between 5 and 6 microns Ultraviolet absorption shows maxima at 267 and 340-342 m^i.
Det krystallinske hydroklorid av dette produkt erholdes ved at man oppløser det i et overskudd av vandig saltsyre (pH omkring 1) og frysetørrer blandingen. Eksempel 24. 7) lla- diklortetracyclin- 6, 12- hemi- ketal. The crystalline hydrochloride of this product is obtained by dissolving it in an excess of aqueous hydrochloric acid (pH around 1) and freeze-drying the mixture. Example 24. 7) lla-dichlorotetracycline-6, 12- hemiketal.
En blanding av 2,4 g vannfritt 7-klortetracyclin, 800 mg N-klorsuccinimid og 25 ml 1,2-dimethoxyethan omrøres i 2,5 mi-nutt, hvoretter der tilsettes 100 ml ether fulgt av 300 ml hexan. Det således erholdte bunnfall oppsamles ved filtrering, vaskes med hexan og tørres. A mixture of 2.4 g of anhydrous 7-chlorotetracycline, 800 mg of N-chlorosuccinimide and 25 ml of 1,2-dimethoxyethane is stirred for 2.5 minutes, after which 100 ml of ether is added, followed by 300 ml of hexane. The precipitate thus obtained is collected by filtration, washed with hexane and dried.
Eksempel 25. Example 25.
lla- klor- 5- hydroxytetracyclin- 6, 12- hemi-ketal. lla- chloro- 5- hydroxytetracycline- 6, 12- hemi-ketal.
23 g vannfritt oxytetracyclin oppløses 1 250 ml 1,2-dimethoxyethan og 8 g N-klorsuccinimid tilsettes. Blandingen omrøres i 2 minutter og helles derpå over i en liter 23 g of anhydrous oxytetracycline are dissolved in 1,250 ml of 1,2-dimethoxyethane and 8 g of N-chlorosuccinimide are added. The mixture is stirred for 2 minutes and then poured into a litre
vann under omrøring. Det produkt som utskilles, oppsamles ved filtrering, vaskes med vann og tørres. Infrarød analyse av produktet (KBr ved 1 pst. konsentrasjon) viser ingen carbonylabsorpsjon i området 5—6 microner, men viser de følgende ho-ved-maksima: 6,12; 6,35; 6,66; 6,85; 7,22; water while stirring. The product that is secreted is collected by filtration, washed with water and dried. Infrared analysis of the product (KBr at 1 per cent concentration) shows no carbonyl absorption in the range 5-6 microns, but shows the following main maxima: 6.12; 6.35; 6.66; 6.85; 7.22;
7,55; 7,75; 7,92; 8,12; 8,36; 8,78; 9,18 og 9,43 microner. 7.55; 7.75; 7.92; 8.12; 8.36; 8.78; 9.18 and 9.43 microns.
Eksempel 26. Example 26.
lla- brom- 5- hydroxytetracyclin- 6, 12-hemi- ketal. lla- bromo- 5- hydroxytetracycline- 6, 12- hemiketal.
2350 mg vannfritt oxytetracyclin opp-løses i 10,2 ml av en oppvarmet blanding av like volummengder benzen og monoglyme. Blandingen avkjøles i isbad og 0,5 ml av en IN oppløsning av brom i benzen tilsettes under omrøring. Produktet krystalliserer direkte, oppsamles og vaskes med rent opp-løsningsmiddel. 2350 mg of anhydrous oxytetracycline are dissolved in 10.2 ml of a heated mixture of equal volumes of benzene and monoglyme. The mixture is cooled in an ice bath and 0.5 ml of a 1N solution of bromine in benzene is added with stirring. The product crystallizes directly, is collected and washed with clean solvent.
Eksempel 27. Example 27.
lla- brom- tetracyclin- 6, 12- hemi- ketal. lla- bromo- tetracycline- 6, 12- hemiketal.
Fremgangsmåte ifølge eksempel 24 gjentas ved anvendelse av N-bromsuccini-mid som halogeneringsmiddel, hvorved ovennevnte produkt erholdes ut fra tetracyclin. Denne fremgangsmåte anvendes også til fremstilling av 7-klor-lla-brom-tetracyclin-6,12-hemi-ketal. The procedure according to example 24 is repeated using N-bromosuccinimide as halogenating agent, whereby the above-mentioned product is obtained from tetracycline. This method is also used for the production of 7-chloro-lla-bromo-tetracycline-6,12-hemi-ketal.
i Eksempel 28. in Example 28.
Fremgangsmåte ifølge eksempel 2<. gjentas under anvendelse av N-jodsuccinimid som halogeneringsmiddel hvorved følgende forbindelser fremstilles av passende tetracycliner: 7-klor-lla-jodtetracyclin-6,12- hemi-ketal; Method according to example 2<. is repeated using N-iodosuccinimide as the halogenating agent whereby the following compounds are prepared from the appropriate tetracyclines: 7-chloro-lla-iodotetracycline-6,12- hemi-ketal;
lla-jod-5-hydroxytetracyclin-6,12-hemi-ketal; 11a-iodo-5-hydroxytetracycline-6,12-hemi-ketal;
lla-jodtetracyclin-6,12-hemi-ketal. lla-iodotetracycline-6,12-hemi-ketal.
Eksempel 29. Example 29.
Syresalter av lla- halogentetracyclin- 6, 12-hemi- ketaler. Acid salts of lla-halotetracycline-6, 12-hemiketals.
Hydrokloridsaltene av de ovenfor beskrevne lla-halogenforbindelser fremstilles ved at man oppløser den frie base i vann inneholdende eri ekvimolar mengde hydro-genklorid og frysetørrer den resulterende oppløsning. The hydrochloride salts of the 11a halogen compounds described above are prepared by dissolving the free base in water containing an equimolar amount of hydrogen chloride and freeze-drying the resulting solution.
På lignende måte fremstilles salter med svovelsyre,; bromhydrogensyre og fosforsyre. In a similar way, salts are prepared with sulfuric acid; hydrobromic acid and phosphoric acid.
Eksempel 30. Example 30.
lla- klor- 6- deoxy- 6- demethyl- 6-methylentetracyclin. lla-chloro-6-deoxy-6-demethyl-6-methylenetetracycline.
lla-klortetr!acyclin-6,12-hemi-ketal 11a-chlorotetracycline-6,12-hemi-ketal
oppløses i flytende hydrogenfluorid (i et dissolves in liquid hydrogen fluoride (in et
forhold på 2 g pr. 15 ml) ved 0°C. Blandingen holdes på denne temperatur i 10—15 minutter, hvoretter hydrogenfluoridet avdampes. Residuet tritueres i ether, hvorved man får det faste produkt, lla-klor-6-deoxy-6-demethyl-6-methylentetracyclin, i form av hydrofluoridsaltet, som omkrystalliseres fra methanol. ratio of 2 g per 15 ml) at 0°C. The mixture is kept at this temperature for 10-15 minutes, after which the hydrogen fluoride evaporates. The residue is triturated in ether, which gives the solid product, lla-chloro-6-deoxy-6-demethyl-6-methylenetetracycline, in the form of the hydrofluoride salt, which is recrystallized from methanol.
Alternativt oppløses det urensede hydrofluoridprodukt (10 g) i 350 ml vann under oppvarmning og omrøring. Der tilsettes et like stort volum konsentrert saltsyre til den klare oppløsning, og produktet krystalliserer som hydroklorid-saltet. Elementaranalyse av dette salt gir de følgende resultater: Teoretisk: C„2H2207<N>2<C>1 ; C, 53,11; H, 4,56; Alternatively, the impure hydrofluoride product (10 g) is dissolved in 350 ml of water while heating and stirring. An equal volume of concentrated hydrochloric acid is added to the clear solution, and the product crystallizes as the hydrochloride salt. Elemental analysis of this salt gives the following results: Theoretical: C„2H2207<N>2<C>1 ; C, 53.11; H, 4.56;
N, 5,63; klor"7,13. N, 5.63; chlorine"7,13.
Funnet: C, 52,62; H, 4,63; N, 5,54; klor 6,84. Infrarød analyse av produktet som hydrokloridsaltet i en kaliumbromid-granul ved en konsentrasjon på 1 pst. viser carbonylabsorpsjon ved 5,70 ji samt de følgende karakteristiske topper: 6,1; 6,23; 6,36; 6,45 avtrapning; 6,91; 7,85; 8,14; 8,55; 10,22; 10,55 og 10,89. Ultrafiolett analyse av prøven i 0,01 N saltsyre i methanol viser meksima ved 376, 278 og 242 m\ i. Produktet viser en R,-verdi på 0,2—0,3 i det følgende system: Found: C, 52.62; H, 4.63; N, 5.54; chlorine 6.84. Infrared analysis of the product as the hydrochloride salt in a potassium bromide granule at a concentration of 1 percent shows carbonyl absorption at 5.70 ji and the following characteristic peaks: 6.1; 6.23; 6.36; 6.45 taper; 6.91; 7.85; 8.14; 8.55; 10.22; 10.55 and 10.89. Ultraviolet analysis of the sample in 0.01 N hydrochloric acid in methanol shows maxima at 376, 278 and 242 m\ in. The product shows an R, value of 0.2-0.3 in the following system:
Analyse av papiret med ultrafiolett lys viste ingen sterk fluorescens på det sted hvor produktet var. Etter dushing med vandig natriumhydrosulfit viste dette sted imid-lertid sterk fluorescens. Analysis of the paper with ultraviolet light showed no strong fluorescence at the location of the product. After showering with aqueous sodium hydrosulphite, however, this spot showed strong fluorescence.
Eksempel 31. Example 31.
lla- fluor- 6- deoxy- 6- demethyl- 6-methylentetracyclin. lla-fluoro-6-deoxy-6-demethyl-6-methylenetetracycline.
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250 mg lla-,fluortetracyclin-6,12-hemi-ketal blandes under omrøring med 2 ml 63 pst.'s vandig perklorsyre. Det faste stoff oppløses ved oppvarming til 60—65°C i 15 minutter, hvorefter blandingen avkjøles og vann tilsettes slik at der dannes lla-fluor-6-deoxy-6-demethyl-6-methylentetracyclin i form av perkloratsaltet. Produktet viser den samme absorpsjon ved ultrafiolett og infrarød analyse som produktet ifølge eksempel 30. 250 mg of lla-,fluorotetracycline-6,12-hemiketal are mixed with 2 ml of 63% aqueous perchloric acid while stirring. The solid is dissolved by heating to 60-65°C for 15 minutes, after which the mixture is cooled and water is added so that lla-fluoro-6-deoxy-6-demethyl-6-methylenetetracycline is formed in the form of the perchlorate salt. The product shows the same absorption in ultraviolet and infrared analysis as the product according to example 30.
Eksempel 32. Example 32.
lla- klor- 6- deoxy- 6- demethyl- 6-methylen- 5- oxytetracyclin. 5 g lla-klor-5-oxytetracyclin-6,12-hemi-ketal settes til 15 ml tørt, flytende hydrogenfluorid, og blandingen omrøres i 3,5 timer ved isbad-temperatur. Hydrogenfluoridet avdampes ved oppvarming under en strøm av nitrogengass, hvorved produktet erholdes som hydrofluoridsaltet. lla- chloro- 6- deoxy- 6- demethyl- 6- methylene- 5- oxytetracycline. 5 g of 11a-chloro-5-oxytetracycline-6,12-hemiketal are added to 15 ml of dry, liquid hydrogen fluoride, and the mixture is stirred for 3.5 hours at ice bath temperature. The hydrogen fluoride is evaporated by heating under a stream of nitrogen gas, whereby the product is obtained as the hydrofluoride salt.
Det rå hydrofluoridprodukt oppløses i vann, og konsentrert saltsyre eller perklorsyre (70 pst.) tilsettes dråpevis for utfelning av henholdsvis hydroklorid-perklorat-salt. Hydrojodidsaltet utfelles fra ace-tonoppløsning av det rå hydrofluoridsalt ved tilsetning av 47 pst.'s jodhydrogensyre. The crude hydrofluoride product is dissolved in water, and concentrated hydrochloric acid or perchloric acid (70 per cent) is added dropwise to precipitate the respective hydrochloride-perchlorate salt. The hydroiodide salt is precipitated from an acetone solution of the crude hydrofluoride salt by adding 47 percent hydroiodic acid.
Alternativt kan man fortynne den opprinnelige reaksjonsblanding med 6—7 volumenheter vann, og is og perklorsyre eller nafthalen-sulfonsyre (konsentrert syre) tilsettes for utfelning av det tilsvarende salt. Ved å fortynne den opprinnelige reaksjonsblanding med aceton og derpå tilsette hydrogenjodid kan man utfelle hydrojodidsaltet. Alternatively, the original reaction mixture can be diluted with 6-7 volume units of water, and ice and perchloric acid or naphthalene sulphonic acid (concentrated acid) are added to precipitate the corresponding salt. By diluting the original reaction mixture with acetone and then adding hydrogen iodide, the hydroiodide salt can be precipitated.
Ved analyse viser hydrojodidsaltet de følgende verdier: Teoretisk: C22<H>21N208C1 HI: C, 43,7; H, 3,7; N,4,6; Cl, 5,8." On analysis, the hydroiodide salt shows the following values: Theoretical: C22<H>21N208C1 HI: C, 43.7; H, 3.7; N,4,6; Cl, 5.8".
Funnet: C, 44,0; H, 4,0; N, 4,2; Cl 5,5. Ultrafiolett analyse viser de følgende maksima: 222, 270 og 372 m(.i. Found: C, 44.0; H, 4.0; N, 4.2; Cl 5.5. Ultraviolet analysis shows the following maxima: 222, 270 and 372 m(.i.
Infrarød analyse viser hovedtopper ved 3,05; 3,2; 5,7; 6,02; 6,03; 6,22; 6,4; 6,88; 7,4; 8,1; 8,9 og 9,1 microner. Ultrafiolett analyse av perklorsaltet viser maksima ved 237, 270 og 372 m\ i. Infrared analysis shows major peaks at 3.05; 3.2; 5.7; 6.02; 6.03; 6.22; 6.4; 6.88; 7.4; 8.1; 8.9 and 9.1 microns. Ultraviolet analysis of the perchlorate salt shows maxima at 237, 270 and 372 m\ i.
Eksempel 33. Example 33.
lla-fluor-6-deoxy-6-demethyl-6-methylen-5-oxytetracyclin fremstilles som angitt i eksempel 32 under anvendelse av lla-fluor-5-oxytetracyclin-6,12-hemiketal som utgangsforbindelse. 11a-fluoro-6-deoxy-6-demethyl-6-methylene-5-oxytetracycline is prepared as indicated in Example 32 using 11a-fluoro-5-oxytetracycline-6,12-hemiketal as starting compound.
Eksempel 34. 1 la- klor- 6- methylentetracyclin Utgangsforbindelse i eksempel 30 opp-løses i 94 pst.'s svovelsyre (1 gram i 10 ml) og blandingen får stå i 2 timer ved 10°C. Produktet erholdes som sulfat-saltet ved at blandingen helles over i et flere ganger større volum diethylether, hvorpå der filtreres. Example 34. 1 la-chloro-6-methylenetetracycline The starting compound in example 30 is dissolved in 94% sulfuric acid (1 gram in 10 ml) and the mixture is allowed to stand for 2 hours at 10°C. The product is obtained as the sulphate salt by pouring the mixture into a several times larger volume of diethyl ether, after which it is filtered.
Eksempel 35. Example 35.
lla- klor- 6- methylentetracyclin. lla- chloro- 6- methylenetetracycline.
Produktet ifølge eksempel 34 erholdes i form av fosfatsaltet ved anvendelse av 85 pst.'s fosforsyre istedenfor svovelsyre under de samme betingelser som beskrevet i foregående eksempel. The product according to example 34 is obtained in the form of the phosphate salt by using 85% phosphoric acid instead of sulfuric acid under the same conditions as described in the previous example.
Eksempel 36. Example 36.
Fremstilling av mineralsyresalter av lla- halogen- 6- methylentetracycliner Production of mineral acid salts of lla-halo-6-methylenetetracyclines
lla-klor-6-deoxy-6-demethyl-6-met-hylentetracyclinhydrofluorid oppløses i vann, og oppløsningen innstilles på en pH lik 5. Den resulterende amfotere forbindelse utfelles, filtreres fra og tørres. Den amfotere forbindelse oppløses i methanol inne- 11a-chloro-6-deoxy-6-demethyl-6-methylenetetracycline hydrofluoride is dissolved in water, and the solution is adjusted to a pH equal to 5. The resulting amphoteric compound is precipitated, filtered off and dried. The amphoteric compound dissolves in methanol in
holdende 1 mol ekvivalent hydrogenklo-rid, hydrokloridsaltet utfelles ved tilsetning av ether. Dette hydrokloridsalt kan også fremstilles i henhold til fremgangsmåten i eksempel 30. Andre mineralsyrér kan anvendes istedenfor saltsyre ved disse fremgangsmåter, hvorved de tilsvarende salter erholdes. containing 1 mol equivalent of hydrogen chloride, the hydrochloride salt is precipitated by the addition of ether. This hydrochloride salt can also be prepared according to the method in example 30. Other mineral acids can be used instead of hydrochloric acid in these methods, whereby the corresponding salts are obtained.
Ved hjelp av lignende fremgangsmåter fremstilles følgende syresalter av lla-halogen-methylen-tetracycliner i de foregående eksempler: hydrokloridet, hydrobromidet, sulfatet, hydrojodidet, nitratet og fosfatet. By means of similar methods, the following acid salts of 11a-halo-methylene-tetracyclines are prepared in the previous examples: the hydrochloride, the hydrobromide, the sulphate, the hydroiodide, the nitrate and the phosphate.
På lignende måte fremstilles andre salter ved hjelp av forskjellige syrer, som f. eks. organiske carboxylsyrer såsom vin-syre, sitronsyre, eplesyre, benzosyre, amino-eddiksyre, gluconsyre, gulonsyre, ravsyre, eddiksyre o. 1. Salter dannet med farma-søytisk godtagbare syrer er terapeutisk verdifulle; salter med farmasøytisk ikke godtagbare syrer kan anvendes ved rensning av produktene og ved fremstilling av farmasøytisk godtagbare salter. In a similar way, other salts are prepared using different acids, such as e.g. organic carboxylic acids such as tartaric acid, citric acid, malic acid, benzoic acid, aminoacetic acid, gluconic acid, gulonic acid, succinic acid, acetic acid, etc. 1. Salts formed with pharmaceutically acceptable acids are therapeutically valuable; salts with pharmaceutically unacceptable acids can be used in the purification of the products and in the production of pharmaceutically acceptable salts.
Eksempel 37. Example 37.
7, lla- diklor- 6- deoxy- 6- demethyl- 6-methylen- 5- hydroxytetracyclin. 7, lla- dichloro- 6- deoxy- 6- demethyl- 6- methylene- 5- hydroxytetracycline.
Fremgangsmåte A. Procedure A.
Til 5 g lla-klor-6-deoxy-6-demethyl-6-methylen-5-oxytetracyclin-hydrojodid i 15 ml flytende hydrogenfluorid avkjølt i isbad settes 1,5 g N-klorsuccinimid. Opp-løsningen omrøres ved isbad-temperatur i 1,5 timer. Råproduktet utfelles ved tilsetning av 500 ml ether og utvinnes ved filtrering. To 5 g of lla-chloro-6-deoxy-6-demethyl-6-methylene-5-oxytetracycline hydroiodide in 15 ml of liquid hydrogen fluoride cooled in an ice bath is added 1.5 g of N-chlorosuccinimide. The solution is stirred at ice bath temperature for 1.5 hours. The crude product is precipitated by adding 500 ml of ether and recovered by filtration.
Råproduktet taes opp i methanol ved romtemperatur, uoppløselig materiale frafiltreres, filtratet behandles med aktiv kull, filtreres og inndampes under redusert trykk. Det resulterende residuum taes opp i fortynnet saltsyre, og produktet utkrystal-liseres i form av hydrokloridet. Ultrafiolett analyse i 0,01 N saltsyre i methanol viser = 239 mn, E \% cm 352; The crude product is taken up in methanol at room temperature, insoluble material is filtered off, the filtrate is treated with activated charcoal, filtered and evaporated under reduced pressure. The resulting residue is taken up in dilute hydrochloric acid, and the product crystallizes out in the form of the hydrochloride. Ultraviolet analysis in 0.01 N hydrochloric acid in methanol shows = 239 mn, E \% cm 352;
lm. lK = 378 mn, eJ^<0>^ 60; infleksjon 258 ch. lK = 378 mn, eJ^<0>^ 60; inflection 258
m|x, E^m = 324. Infrarød analyse viser hovedbånd ved 5,7, 6,0 og 6,9 microner. m|x, E^m = 324. Infrared analysis shows main bands at 5.7, 6.0 and 6.9 microns.
Fremgangsmåte B. Procedure B.
5 g lla-klor-5-oxytetracyclin-6,12-hemi-ketal settes til 15 ml flytende hydrc-genfluorid ved isbad-temperatur. Etter om-røring i 3,5 timer ved denne temperatur følger man fremgangsmåte E etter tilsetning av samme j vekt N-klorsuccinimid, hvorved produktet erholdes. 5 g of lla-chloro-5-oxytetracycline-6,12-hemi-ketal is added to 15 ml of liquid hydrogen fluoride at ice bath temperature. After stirring for 3.5 hours at this temperature, method E is followed after adding the same weight of N-chlorosuccinimide, whereby the product is obtained.
En alternativ og noe mere bekvem fremgangsmåte ér som følger. Etter fjer-nelsen av det méste av det flytende hydrogenfluorid tilsettes 100 ml vann og derpå 5 g (3-nafthalensulfonsyre. Produktet utfelles i form av jfj-nafthalensulfonsyre-saltet og isoleres ved filtrering. An alternative and somewhat more convenient method is as follows. After the removal of most of the liquid hydrogen fluoride, 100 ml of water are added and then 5 g of (3-naphthalene sulphonic acid. The product is precipitated in the form of the jfj-naphthalene sulphonic acid salt and is isolated by filtration.
En ytterligere fremgangsmåte går ut på at man fortynner den opprinnelige reaksjonsblanding med 6—7 volumenheter vann fulgt av dråpevis tilsetning av konsentrert syre, hvorved perkloratet og (3-nafthalensulfonatet utfelles som beskrevet ovenfor. Det således erholdte rå perklorat krystalliserer fra isopropanol i form av lange nåler som ved ultrafiolett analyse viser maksima I ved 260 og 377 m\ i og en infleksjon ved 260 m^i. A further method involves diluting the original reaction mixture with 6-7 volume units of water followed by the dropwise addition of concentrated acid, whereby the perchlorate and (3-naphthalene sulphonate) are precipitated as described above. The crude perchlorate thus obtained crystallizes from isopropanol in the form of long needles which on ultraviolet analysis show maxima I at 260 and 377 m\ i and an inflection at 260 m^i.
Infrarød analyse viser topper ved 5,7; 6,0; 6,26; 6,55; 6,88; 7,2; 7,85 og 8,35 microner. Infrared analysis shows peaks at 5.7; 6.0; 6.26; 6.55; 6.88; 7.2; 7.85 and 8.35 microns.
Eksempel 38. Example 38.
lla- klor- 9- nitr^ o- 6- deoxy- 6- demethyl- 6-methylen- 5- oxy tetracyclin. lla- chloro- 9- nitro^ o- 6- deoxy- 6- demethyl- 6- methylene- 5- oxy tetracycline.
i in
Til 1 g lla-klor-6-deoxy-6-demethyl-6-methylen-5-;oxytetracyclin i 20 ml eddiksyre settes 1 Imi konsentrert salpetersyre. Blandingen får stå i 12 timer, hvorpå den inndampes til<1> en fjerdedel av det opprinnelige volum j og 200 ml ether. Produktet utskilles i form av nitratet og isoleres ved filtrering. To 1 g of lla-chloro-6-deoxy-6-demethyl-6-methylene-5-;oxytetracycline in 20 ml of acetic acid is added 1 mil of concentrated nitric acid. The mixture is allowed to stand for 12 hours, after which it is evaporated to <1> a quarter of the original volume j and 200 ml of ether. The product is excreted in the form of the nitrate and isolated by filtration.
På lignende måte fremstilles den tilsvarende lla-ffluorforbindelse. In a similar way, the corresponding 11a-fluorine compound is prepared.
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i Eksempel 39. in Example 39.
lla- klor- 6- deoxy- 6- demethyl- 6- klor-methylentetfficyclin. lla- chloro- 6- deoxy- 6- demethyl- 6- chloro-methylenetetfficycline.
iin
Til en blanding av 1,2 g av produktet ifølge eksempel 30 i 15 ml fluoreddiksyre settes 350 mg N-klorsuccinimid, og blandingen oppvarmes ved 60°C. Etter ca. 3 timer gir blandingen negativ kaliumjodid/ stivelse-prøye. Den avkjølte blanding settes dråpevis' til 500 ml kold ether under omrøring ved isbadtemperatur. Etter om-røring i 3 timer frafiltreres det utfelte produkt, oppslemmes i ether 2 ganger og tør-res, hvorved man får 1 g av produktet. 350 mg of N-chlorosuccinimide is added to a mixture of 1.2 g of the product according to example 30 in 15 ml of fluoroacetic acid, and the mixture is heated at 60°C. After approx. After 3 hours, the mixture gives a negative potassium iodide/starch stain. The cooled mixture is added dropwise to 500 ml of cold ether with stirring at ice bath temperature. After stirring for 3 hours, the precipitated product is filtered off, suspended in ether 2 times and dried, whereby 1 g of the product is obtained.
Produktet oppløses i 300 ml varm methanol, manj filtrerer for å fjerne en liten The product is dissolved in 300 ml of hot methanol, manj filters to remove a small
mengde uoppløselig materiale og inndam-per til et volum på 100 ml. Derpå tilsettes 3 ml p-toluensulfonsyre oppløst i methanol, og blandingen får stå ved romtemperatur inntil krystalliseringen er fullført. Produktet erholdes som p-toluensulfonatet ved frafiltrering av det utfelte stoff, vas-king med methanol og tørring. quantity of insoluble material and evaporate to a volume of 100 ml. 3 ml of p-toluenesulfonic acid dissolved in methanol is then added, and the mixture is allowed to stand at room temperature until crystallization is complete. The product is obtained as the p-toluenesulfonate by filtering off the precipitated substance, washing with methanol and drying.
Infrarød analyse av produktet viser en Infrared analysis of the product shows a
klar skarp kurve nied et bånd ved 5,69 m|x. clear sharp curve below a band at 5.69 m|x.
Ultrafiolett analyse i 0,01 N methanolisk saltsyre viser maksima ved 245 og 378 m\ i. Ultraviolet analysis in 0.01 N methanolic hydrochloric acid shows maxima at 245 and 378 m\ in.
Elementar analyse gir de følgende resultater: Teoretisk: C2,,H2801(lN3 C12S (som p-toluensulfonatet) : C, 52,18; H, 4,2; N, 4,2; Cl, 10,6; Elemental analysis gives the following results: Theoretical: C2,,H2801(lN3 C12S (as the p-toluenesulfonate) : C, 52.18; H, 4.2; N, 4.2; Cl, 10.6;
S, 4,8. S, 4.8.
Funnet: C, 51,8; H, 4,3; N, 4,3; Cl, 10,3; Found: C, 51.8; H, 4.3; N, 4.3; Cl, 10.3;
S, 4,8. S, 4.8.
Eksempel 40. Example 40.
lla- klor- 6- deoxy- 6- demethyl- 6- brom-methylentetracyclin. lla- chloro- 6- deoxy- 6- demethyl- 6- bromo-methylenetetracycline.
Til en blanding av 4,8 g av produktet ifølge eksempel 30 i 40 ml trifluoreddiksyre settes en oppløsning av 0,54 ml brom i 10 ml eddiksyre. Blandingen oppvarmes ved 40—60°C i 1 time, hvorefter den får stå i 12 timer ved romtemperatur. Råproduktet erholdes på samme måte som i de foregående eksempler. Produktet krystalliseres fra methanol i form av p-toluensulfatet (3,54 g). A solution of 0.54 ml of bromine in 10 ml of acetic acid is added to a mixture of 4.8 g of the product according to example 30 in 40 ml of trifluoroacetic acid. The mixture is heated at 40-60°C for 1 hour, after which it is allowed to stand for 12 hours at room temperature. The raw product is obtained in the same way as in the previous examples. The product is crystallized from methanol in the form of the p-toluene sulfate (3.54 g).
Ultrafiolett analyse i 0,01 N methanolisk saltsyre viser maksima ved 249 og 379 mjx. Ultraviolet analysis in 0.01 N methanolic hydrochloric acid shows maxima at 249 and 379 mjx.
Eksempel 41. Example 41.
lla- klor- 9- brom- 6- deoxy- 6- demethyl- 6-brommethylentetracyclin. lla- chloro- 9- bromo- 6- deoxy- 6- demethyl- 6- bromomethylenetetracycline.
Til en blanding av 280 mg av produktet ifølge eksempel 30 i 5 ml trifluoreddiksyre settes 1,05 ml av en oppløsning av 0,53 ml brom i 10 ml eddiksyre. Et tungt orange bunnfall dannes i blandingen, som derpå omrøres og oppvarmes i to timer ved 60°C. Blandingen får derved stå i 48 timer, og produktet (287 mg) erholdes ved opparbei-delse med ether som beskrevet ovenfor. Produktet krystalliseres i form av sulfatet ved oppløsning i 5 ml methanol og tilsetning av 6 dråper konsentrert svovelsyre. Ultrafiolett analyse av produktet i 0,01 N methanolisk saltsyre viser maksima ved 251 og 348 mjx. To a mixture of 280 mg of the product according to example 30 in 5 ml of trifluoroacetic acid is added 1.05 ml of a solution of 0.53 ml of bromine in 10 ml of acetic acid. A heavy orange precipitate forms in the mixture, which is then stirred and heated for two hours at 60°C. The mixture is thereby allowed to stand for 48 hours, and the product (287 mg) is obtained by working up with ether as described above. The product is crystallized in the form of the sulphate by dissolving in 5 ml of methanol and adding 6 drops of concentrated sulfuric acid. Ultraviolet analysis of the product in 0.01 N methanolic hydrochloric acid shows maxima at 251 and 348 mjx.
Eksempel 42. Example 42.
9, lla- diklor- 6- deoxy- 6- demethyl- 6-klormethylentetracyclin. 9, lla- dichloro- 6- deoxy- 6- demethyl- 6- chloromethylenetetracycline.
Dette produkt fremstilles i henhold til fremgangsmåten i eksempel 39 ved anvendelse av 2 molekvivålenter N-klorsuccinimid. This product is prepared according to the method in example 39 using 2 mole equivalents of N-chlorosuccinimide.
Eksempel 43. Example 43.
Ved anvendelse av fremgangsmåtene ifølge de foregående eksempler fremstilles de følgende forbindelser ut fra tilsvarende 1 la-halogen-7-klor- (eller brom) -6-deoxy - 6- demethylentetracycliner: 7,lla-diklor-6-deoxy-6-demethyl-6-klor-methylentetracyclin, 7- brom-lla-klor-6-deoxy-6-demethyl-6-klormethylentetracyclin, 7,lla-diklor-6-deoxy-6-demethyl-6-brom-methylentetracyclin, 7-klor-lla-fluor-6-deoxy-6-demethyl-6-klormethylentetracyclin, 7-brom-lla-klor-6-deoxy-6-demethyl-6-j od-methylentetracyclin. By using the methods according to the preceding examples, the following compounds are prepared from the corresponding 1 la-halo-7-chloro-(or bromo)-6-deoxy-6-demethylenetetracyclines: 7,lla-dichloro-6-deoxy-6-demethyl -6-chloro-methylenetetracycline, 7-bromo-lla-chloro-6-deoxy-6-demethyl-6-chloromethylenetetracycline, 7,lla-dichloro-6-deoxy-6-demethyl-6-bromo-methylenetetracycline, 7-chloro -lla-fluoro-6-deoxy-6-demethyl-6-chloromethylenetetracycline, 7-bromo-lla-chloro-6-deoxy-6-demethyl-6-iod-methylenetetracycline.
Eksempel 44. Example 44.
lla- klor- 9- nitro- 6- deoxy- 6- demethyl- 6-methylentetracyclin. lla- chloro- 9- nitro- 6- deoxy- 6- demethyl- 6- methylenetetracycline.
En blanding av 1 g av produktet ifølge eksempel 30 i 20 ml eddiksyre inneholdende 1 ml konsentrert salpetersyre får stå i 12 timer, hvorefter tilsetning av 20 ml vann utkrystalliserer produktet i form av nitratet. Produktet isoleres ved filtrering, vaskes med vann og tørres. A mixture of 1 g of the product according to example 30 in 20 ml of acetic acid containing 1 ml of concentrated nitric acid is allowed to stand for 12 hours, after which addition of 20 ml of water crystallizes the product in the form of the nitrate. The product is isolated by filtration, washed with water and dried.
Eksempel 45. Example 45.
lla- klor- 6- deoxy- 6- demethyl- 6- nitro-methylentetracyclin. 1 g av produktet ifølge eksempel 30 oppvarmes oppslemmet i 20 ml 5 pst.'s vandig salpetersyre ved 60°C under omrøring. Produktet krystalliserer fra reaksjonsopp-løsningen i form av nitratet og isoleres ved filtrering, vaskes med vann og tørres. lla- chloro- 6- deoxy- 6- demethyl- 6- nitro-methylenetetracycline. 1 g of the product according to example 30 is heated in a slurry in 20 ml of 5% aqueous nitric acid at 60°C with stirring. The product crystallizes from the reaction solution in the form of the nitrate and is isolated by filtration, washed with water and dried.
Eksempel 46. Example 46.
9, lla- diklor- 6- deoxy- 6- demethyl- 6- nitro-methylentetracyclin. 9, lla- dichloro- 6- deoxy- 6- demethyl- 6- nitro-methylenetetracycline.
Dette produkt erholdes av produktet ifølge det foregående eksempel ved klorering under anvendelse av fremgangsmåten ifølge eksempel 39. This product is obtained from the product according to the previous example by chlorination using the method according to example 39.
Eksempel 47. Example 47.
lla- klor- 9- nitro- 6- deoxy- 6- demethyl-6- klormethylentetracyclin. lla- chloro- 9- nitro- 6- deoxy- 6- demethyl- 6- chloromethylenetetracycline.
Dette produkt erholdes av produkteu ifølge eksempel 44 ved klorering i henhold tir fremgangsmåten i eksempel 39. This product is obtained from the product according to example 44 by chlorination according to the method in example 39.
Eksempel 48. Example 48.
Ved anvendelse av fremgangsmåtene ifølge eksempler 46 og 47 erholdes de føl-gende produkter fra tilsvarende lla-halogen-nitro-forbindelser ved fremgangsmåten ifølge eksempel 40. 9-brom-lla-klor-6-deoxy-6-demethyl-6-nitromethylentetracyclin, 9-nitro-lla-fluor-6-deoxy-6-demethyl-6-brommethylentetracyclin, 7,lla-diklor-6-deoxy-6-demethyl-6-nitro-methylentetracyclin. By using the methods according to examples 46 and 47, the following products are obtained from corresponding 11a-halo-nitro compounds by the method according to example 40. 9-bromo-11a-chloro-6-deoxy-6-demethyl-6-nitromethylenetetracycline, 9-nitro-lla-fluoro-6-deoxy-6-demethyl-6-bromomethylenetetracycline, 7,lla-dichloro-6-deoxy-6-demethyl-6-nitro-methylenetetracycline.
Eksempel 49. Example 49.
9- nitro- 7, lla- diklor- 6- deoxy- 6- demethyl-6- methylen- 5- oxytetracyclin. 9- nitro- 7, lla- dichloro- 6- deoxy- 6- demethyl-6- methylene- 5- oxytetracycline.
Til en oppløsning av 600 mg 7,lla-diklor-6-deoxy-6-demethyl-6-methylen-5-oxytetracyclin-perklorat i 1,5 ml vannfritt flytende hydrogenfluorid settes 100 mg KNO.,. Blandingen omrøres ved 5°C i 15 minutter, hvorpå den helles over i 75 ml isvann og filtreres. Filtratet inndampes til tørrhet, hvorved produktet erholdes. 100 mg KNO. The mixture is stirred at 5°C for 15 minutes, after which it is poured into 75 ml of ice water and filtered. The filtrate is evaporated to dryness, whereby the product is obtained.
Eksempel 50. Example 50.
Nitrering av lla- klor- 6- deoxy- 6- demethyl- 6- methylen- 5- oxytetracyclin. Nitration of lla- chloro- 6- deoxy- 6- demethyl- 6- methylene- 5- oxytetracycline.
En oppløsning av 5 g lla-klortetracyclin-6,12-hemi-ketal i 10 ml vannfritt hydrogenfluorid får stå i 15 minutter, hvorefter der tilsettes 1,2 g KNOs under omrø-ring. Omrøringen fortsettes i 1 time ved isbadtemperatur, og blandingen settes derpå til 200 ml tørr ether, filtreres og vaskes med ether, hvorved man får 6,1 g råpro-dukt. A solution of 5 g of lla-chlorotetracycline-6,12-hemiketal in 10 ml of anhydrous hydrogen fluoride is allowed to stand for 15 minutes, after which 1.2 g of KNOs are added while stirring. Stirring is continued for 1 hour at ice bath temperature, and the mixture is then added to 200 ml of dry ether, filtered and washed with ether, whereby 6.1 g of crude product is obtained.
4 g av råproduktet oppslemmes i 60 ml vann, og 4 ml konsentrert saltsyre tilsettes under omrøring. Det krystallinske bunnfall frafiltreres og vaskes med vann (en del av stoffet oppløses). Det vann-uoppløselige produkt (1,9 g) er lla-klor-6-deoxy-6-demethyl-6-nitromethylen-tetracyclin-hydroklorid. Ved inndampning av vaskevannet erholdes 1,5 g av en nitro-genforbindelse som er isomer med oven- 4 g of the crude product is suspended in 60 ml of water, and 4 ml of concentrated hydrochloric acid is added while stirring. The crystalline precipitate is filtered off and washed with water (part of the substance dissolves). The water-insoluble product (1.9 g) is 11a-chloro-6-deoxy-6-demethyl-6-nitromethylene-tetracycline hydrochloride. By evaporating the washing water, 1.5 g of a nitrogen compound is obtained which is isomeric with the above
nevnte produkt. said product.
Claims (7)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT2107/72A IT951730B (en) | 1972-01-28 | 1972-01-28 | TRANSPORT EQUIPMENT THAT WITH HEARS THE UNLOADING OF ALL OR PART OF THE TRANSPORTED LOAD WITH ELECTROMAGNETIC COMAN DO |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NO140177B true NO140177B (en) | 1979-04-09 |
| NO140177C NO140177C (en) | 1979-07-18 |
Family
ID=11102341
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO52/73A NO140177C (en) | 1972-01-28 | 1973-01-05 | LOAD TRANSPORT CONTAINER. |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US3840148A (en) |
| JP (1) | JPS4930785A (en) |
| BR (1) | BR7300538D0 (en) |
| DE (1) | DE2302337C2 (en) |
| ES (1) | ES410940A1 (en) |
| FR (1) | FR2174561A5 (en) |
| GB (1) | GB1362353A (en) |
| IL (1) | IL41185A (en) |
| IT (1) | IT951730B (en) |
| NO (1) | NO140177C (en) |
| ZA (1) | ZA73581B (en) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5124781A (en) * | 1974-08-22 | 1976-02-28 | Fujikura Ltd | Denryokukeeburuno seizohoho |
| CH581369A5 (en) * | 1974-11-22 | 1976-10-29 | Neuhaeusser Horst | |
| SE455654B (en) * | 1985-09-13 | 1988-07-25 | Bergstedth Henri | EXHAUST DEVICE AT A VEHICLE |
| US5020965A (en) * | 1988-04-28 | 1991-06-04 | Kao Corporation | Method for shifting goods and apparatus therefor |
| DE3817853A1 (en) * | 1988-05-26 | 1989-11-30 | Honebein Horst | GOODS MAGAZINE |
| DE4209558A1 (en) * | 1992-03-21 | 1993-09-23 | Otto Versand Gmbh & Co | System for sorting out different goods for despatch - has several storage containers associated constantly with supply and delivery lines for batch time allocation |
| GB9219621D0 (en) * | 1992-09-16 | 1992-10-28 | Hagen International Uk Limited | Apparatus for dispensing golf balls |
| US5437928A (en) * | 1993-10-29 | 1995-08-01 | Ppg Industries, Inc. | Glass fiber size and mat |
| EP2154455A1 (en) * | 2008-08-05 | 2010-02-17 | F. Hoffmann-Roche AG | Convection barrier |
| US8307614B1 (en) | 2009-10-20 | 2012-11-13 | Stephen Louie | Support assembly and method |
| CN101973401B (en) * | 2010-10-21 | 2012-06-06 | 哈尔滨工程大学 | Modularized intelligent nacelle for throwing forest fire-extinguishing bomb |
| CN106043698B (en) * | 2016-06-08 | 2019-04-12 | 青海山水生态科技有限公司 | A kind of unmanned plane hanging fire extinguisher bomb dispensing cabin and method of dropping a bomb |
| CN106114862B (en) * | 2016-08-01 | 2018-06-26 | 北京理工大学 | Built-in type ammunition electromagnetic launch device on unmanned helicopter |
| CN110239714B (en) * | 2019-06-19 | 2020-10-30 | 北京理工伺服科技有限公司 | Quick automatic projectile throwing device for airborne multi-shot unlocking type fire extinguishing bomb |
| CN211751963U (en) * | 2019-12-30 | 2020-10-27 | 江苏数字鹰科技股份有限公司 | Fire extinguishing device for police unmanned aerial vehicle |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE309296C (en) * | ||||
| US505793A (en) * | 1893-09-26 | Vending-machine | ||
| US1812688A (en) * | 1929-12-13 | 1931-06-30 | Give Henry L De | Releasing device for mail bags |
| FR792140A (en) * | 1934-09-22 | 1935-12-23 | Electric token dispenser | |
| DE672525C (en) * | 1938-04-13 | 1939-03-03 | Heinrich Lilje | Device for automatically dropping leaflets or the like for hanging on a balloon |
| US2279093A (en) * | 1940-10-28 | 1942-04-07 | Peters Louis | Vending machine |
| US2608131A (en) * | 1945-01-17 | 1952-08-26 | Gen Motors Corp | Bomb release system |
| US2628701A (en) * | 1949-04-30 | 1953-02-17 | Mutual Engineering Company Inc | Conveyer |
| US2989165A (en) * | 1956-07-12 | 1961-06-20 | Robert T Cozart | Vending machine |
| CH406062A (en) * | 1963-04-09 | 1966-01-15 | Gd Spa | Mechanism for transferring objects from one machine to another, with automatic storage-buffer, particularly suitable for automatic wrapping machines |
| US3529745A (en) * | 1968-07-25 | 1970-09-22 | Us Navy | Sonobuoy dispenser |
| US3511457A (en) * | 1968-09-06 | 1970-05-12 | All American Eng Co | Aerial cargo dispenser |
-
1972
- 1972-01-28 IT IT2107/72A patent/IT951730B/en active
- 1972-12-26 IL IL41185A patent/IL41185A/en unknown
- 1972-12-29 US US00319693A patent/US3840148A/en not_active Expired - Lifetime
-
1973
- 1973-01-05 NO NO52/73A patent/NO140177C/en unknown
- 1973-01-08 GB GB103673A patent/GB1362353A/en not_active Expired
- 1973-01-18 DE DE2302337A patent/DE2302337C2/en not_active Expired
- 1973-01-23 JP JP48009822A patent/JPS4930785A/ja active Pending
- 1973-01-24 BR BR73538A patent/BR7300538D0/en unknown
- 1973-01-25 ES ES410940A patent/ES410940A1/en not_active Expired
- 1973-01-26 ZA ZA730581A patent/ZA73581B/en unknown
- 1973-01-26 FR FR7302725A patent/FR2174561A5/fr not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| JPS4930785A (en) | 1974-03-19 |
| DE2302337A1 (en) | 1973-08-02 |
| NO140177C (en) | 1979-07-18 |
| ZA73581B (en) | 1973-10-31 |
| IT951730B (en) | 1973-07-10 |
| US3840148A (en) | 1974-10-08 |
| BR7300538D0 (en) | 1973-09-27 |
| DE2302337C2 (en) | 1986-03-06 |
| GB1362353A (en) | 1974-08-07 |
| IL41185A0 (en) | 1973-02-28 |
| ES410940A1 (en) | 1976-01-01 |
| FR2174561A5 (en) | 1973-10-12 |
| IL41185A (en) | 1975-10-15 |
| AU5138173A (en) | 1974-07-25 |
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