NO124161B - - Google Patents
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- NO124161B NO124161B NO96671A NO96671A NO124161B NO 124161 B NO124161 B NO 124161B NO 96671 A NO96671 A NO 96671A NO 96671 A NO96671 A NO 96671A NO 124161 B NO124161 B NO 124161B
- Authority
- NO
- Norway
- Prior art keywords
- acid
- carbon atoms
- formula
- acid addition
- chloro
- Prior art date
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- 239000002253 acid Substances 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 125000001118 alkylidene group Chemical group 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- NYCVCXMSZNOGDH-UHFFFAOYSA-N pyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-N 0.000 claims 1
- 239000012458 free base Substances 0.000 description 8
- OJMMVQQUTAEWLP-UHFFFAOYSA-N Lincomycin Natural products CN1CC(CCC)CC1C(=O)NC(C(C)O)C1C(O)C(O)C(O)C(SC)O1 OJMMVQQUTAEWLP-UHFFFAOYSA-N 0.000 description 7
- 229960005287 lincomycin Drugs 0.000 description 7
- OJMMVQQUTAEWLP-KIDUDLJLSA-N lincomycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 OJMMVQQUTAEWLP-KIDUDLJLSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N thiocyanic acid Chemical compound SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000002585 base 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
- 230000000694 effects Effects 0.000 description 3
- -1 hexafluoroarsenic acid Chemical compound 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 2
- XJMMNTGIMDZPMU-UHFFFAOYSA-N 3-methylglutaric acid Chemical compound OC(=O)CC(C)CC(O)=O XJMMNTGIMDZPMU-UHFFFAOYSA-N 0.000 description 2
- AUODDLQVRAJAJM-XJQDNNTCSA-N Clindamycin hydrochloride Chemical compound Cl.CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 AUODDLQVRAJAJM-XJQDNNTCSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical class CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 239000012259 ether extract Substances 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000005649 metathesis reaction Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- PNGLEYLFMHGIQO-UHFFFAOYSA-M sodium;3-(n-ethyl-3-methoxyanilino)-2-hydroxypropane-1-sulfonate;dihydrate Chemical compound O.O.[Na+].[O-]S(=O)(=O)CC(O)CN(CC)C1=CC=CC(OC)=C1 PNGLEYLFMHGIQO-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 1
- FRPZMMHWLSIFAZ-UHFFFAOYSA-N 10-undecenoic acid Chemical compound OC(=O)CCCCCCCCC=C FRPZMMHWLSIFAZ-UHFFFAOYSA-N 0.000 description 1
- XACKAZKMZQZZDT-MDZDMXLPSA-N 2-[(e)-octadec-9-enyl]butanedioic acid Chemical compound CCCCCCCC\C=C\CCCCCCCCC(C(O)=O)CC(O)=O XACKAZKMZQZZDT-MDZDMXLPSA-N 0.000 description 1
- ZJWUEJOPKFYFQD-UHFFFAOYSA-N 2-hydroxy-3-phenylbenzoic acid Chemical compound OC(=O)C1=CC=CC(C=2C=CC=CC=2)=C1O ZJWUEJOPKFYFQD-UHFFFAOYSA-N 0.000 description 1
- LGERKUYJCZOBTB-UHFFFAOYSA-N 2-hydroxy-5-phenylbenzoic acid Chemical compound C1=C(O)C(C(=O)O)=CC(C=2C=CC=CC=2)=C1 LGERKUYJCZOBTB-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- LSPHULWDVZXLIL-UHFFFAOYSA-N Camphoric acid Natural products CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- DSLZVSRJTYRBFB-UHFFFAOYSA-N Galactaric acid Natural products OC(=O)C(O)C(O)C(O)C(O)C(O)=O DSLZVSRJTYRBFB-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 229940069428 antacid Drugs 0.000 description 1
- 239000003159 antacid agent Substances 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical compound CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 description 1
- KHAVLLBUVKBTBG-UHFFFAOYSA-N caproleic acid Natural products OC(=O)CCCCCCCC=C KHAVLLBUVKBTBG-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 229960002227 clindamycin Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- QSAWQNUELGIYBC-UHFFFAOYSA-N cyclohexane-1,2-dicarboxylic acid Chemical compound OC(=O)C1CCCCC1C(O)=O QSAWQNUELGIYBC-UHFFFAOYSA-N 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- MZGNSEAPZQGJRB-UHFFFAOYSA-N dimethyldithiocarbamic acid Chemical compound CN(C)C(S)=S MZGNSEAPZQGJRB-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- DSLZVSRJTYRBFB-DUHBMQHGSA-N galactaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O DSLZVSRJTYRBFB-DUHBMQHGSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- GOYAALBIXFNQOR-UHFFFAOYSA-N hexadecylsulfamic acid Chemical compound CCCCCCCCCCCCCCCCNS(O)(=O)=O GOYAALBIXFNQOR-UHFFFAOYSA-N 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- POUMFISTNHIPTI-BOMBIWCESA-N hydron;(2s,4r)-n-[(1r,2r)-2-hydroxy-1-[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-methylsulfanyloxan-2-yl]propyl]-1-methyl-4-propylpyrrolidine-2-carboxamide;chloride Chemical compound Cl.CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 POUMFISTNHIPTI-BOMBIWCESA-N 0.000 description 1
- KCYQMQGPYWZZNJ-BQYQJAHWSA-N hydron;2-[(e)-oct-1-enyl]butanedioate Chemical compound CCCCCC\C=C\C(C(O)=O)CC(O)=O KCYQMQGPYWZZNJ-BQYQJAHWSA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960001595 lincomycin hydrochloride Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- HHMAJEQKYRNURJ-UHFFFAOYSA-N octadecylsulfamic acid Chemical compound CCCCCCCCCCCCCCCCCC[NH2+]S([O-])(=O)=O HHMAJEQKYRNURJ-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000000590 parasiticidal effect Effects 0.000 description 1
- 239000002297 parasiticide Substances 0.000 description 1
- 238000005554 pickling Methods 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000012260 resinous material Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229920002803 thermoplastic polyurethane Polymers 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229960002703 undecylenic acid Drugs 0.000 description 1
- 150000003673 urethanes Chemical class 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
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- Saccharide Compounds (AREA)
Description
Fremgangsmåte ved fremstilling av Procedure in the manufacture of
7-klor-7-deoxy-l-thio-a-D-galacto- 7-chloro-7-deoxy-1-thio-α-D-galacto-
octopyranosider. octopyranosides.
Foreliggende oppfinnelse angår en ny fremgangsmåte ved fremstilling av nye 7-klor-7-deoxy-l-thio-<x-D-galacto-octopyranosider og syreaddisjonssalter derav fra nye utgangsmaterialer. The present invention relates to a new process for the production of new 7-chloro-7-deoxy-1-thio-<x-D-galacto-octopyranosides and acid addition salts thereof from new starting materials.
De terapeutisk aktive 7-klor-7-deoxy-l-thio-ct-D-galacto-octopyranosider som fremstilles ifolge foreliggende oppfinnelse, har formelen: hvor R er alkyl med inntil 8 carbonatomer, eventuelt alkylsubsti-tuert cycloalkyl med 3 - 8 carbonatomer eller aralkyl med inntil 12 carbonatomer og Y er acylradikalet av en ^--substituert-L-2-pyrrolidincarboxylsyre av formelen: The therapeutically active 7-chloro-7-deoxy-1-thio-ct-D-galacto-octopyranosides produced according to the present invention have the formula: where R is alkyl with up to 8 carbon atoms, optionally alkyl-substituted cycloalkyl with 3 - 8 carbon atoms or aralkyl with up to 12 carbon atoms and Y is the acyl radical of a ^--substituted-L-2-pyrrolidinecarboxylic acid of the formula:
hvor er alkyliden med inntil 8 carbonatomer, Rp er alkylen med inntil 8 carbonatomer, og R^ er hydrogen, methyl eller ethyl, og fremgangsmåten omfatter også fremstilling av syreaddisjonssaltene av disse. where is the alkylidene with up to 8 carbon atoms, Rp is the alkylene with up to 8 carbon atoms, and R^ is hydrogen, methyl or ethyl, and the method also includes preparation of the acid addition salts of these.
Ifolge oppfinnelsen fremstilles de nye forbindelser av formel I ved at en forbindelse av formelen: According to the invention, the new compounds of formula I are prepared by a compound of the formula:
hvor R og Y er som ovenfor angitt, eller et syreaddisjonssalt derav, behandles med vandig alkali ved pH ca. 11 og at den erholdte forbindelse overfores eventuelt til et syreaddisjonssalt på i og for seg kjent vis. where R and Y are as indicated above, or an acid addition salt thereof, is treated with aqueous alkali at pH approx. 11 and that the compound obtained is optionally transferred to an acid addition salt in a manner known per se.
Fremgangsmåteforbindelsene kan skilles i cis- og trans-isomer-ene ved motstromsfordeling eller kromatografi, eller den bnskede cis-eller trans-isomer kan fremstilles idet utgangsmaterialet anvendes i form av den tilsvarende cis- eller transisomer. The process compounds can be separated into the cis- and trans-isomers by countercurrent separation or chromatography, or the desired cis- or trans-isomer can be prepared by using the starting material in the form of the corresponding cis- or trans-isomer.
De fri baser kan overfores til stabile syreaddisjonssalter The free bases can be converted to stable acid addition salts
ved nøytralisering av den fri base med en passende syre under ca. by neutralizing the free base with a suitable acid below approx.
pH 7,0 og fortrinnsvis til ca. pH 2 til 6. Passende syrer til dette formål innbefatter saltsyre, svovelsyre, fosforsyre, thio-cyansyre, fluorkiselsyre, hexafluorarsensyre, hexafluorfosforsyre, eddiksyre, ravsyre, sitronsyre, melkesyee, maleinsyre, fumarsyre, k, ky -methylenbi.s-(3-hydroxy-2-nafthoesyre, svovelsyre, palmitinsyre, slimsyre, kamfersyre, glutarsyre, glycolsyre, fthalsyre, vinsyre, laurinsyre, stearinsyre, salicylsyre, 3-fenylsalicylsyre, 5-fenylsalicylsyre, 3-methylglutarsyre, orthosulfobenzoesyre, cyclopentan-propionsyre, 1,2-cyclohexandicarboxylsyre, ^-cyclohexancarboxylsyre, octadecenylravsyre, octenylravsyre, methansulfonsyre, benzensulfon-syre, heliantsyre, Reinecke's syre, dimethyldithiocarbaminsyre, cyclohexylsulfaminsyre, hexadecylsulfaminsyre, octadecylsulfaminsyre, sorbinsyre, monokloreddiksyre, undecylensyre, h'-hydroxyazobenzen-V-sulfonsyre, octodecylsvovelsyre, picrinsyre, benzoesyre, kanelsyre og lignende syrer. pH 7.0 and preferably to approx. pH 2 to 6. Suitable acids for this purpose include hydrochloric acid, sulfuric acid, phosphoric acid, thiocyanic acid, fluorosilicic acid, hexafluoroarsenic acid, hexafluorophosphoric acid, acetic acid, succinic acid, citric acid, lactic acid, maleic acid, fumaric acid, k,ky -methylenebi.s-(3- hydroxy-2-naphthoic acid, sulfuric acid, palmitic acid, mucic acid, camphoric acid, glutaric acid, glycolic acid, phthalic acid, tartaric acid, lauric acid, stearic acid, salicylic acid, 3-phenylsalicylic acid, 5-phenylsalicylic acid, 3-methylglutaric acid, orthosulfobenzoic acid, cyclopentane-propionic acid, 1,2- cyclohexanedicarboxylic acid, ^-cyclohexanecarboxylic acid, octadecenylsuccinic acid, octenylsuccinic acid, methanesulfonic acid, benzenesulfonic acid, heliantic acid, Reinecke's acid, dimethyldithiocarbamic acid, cyclohexylsulfamic acid, hexadecylsulfamic acid, octadecylsulfamic acid, sorbic acid, monochloroacetic acid, undecylenic acid, h'-hydroxyazobenzene-V-sulfonic acid, octodecylsulfuric acid, picric acid, benzoic acid, cinnamic acid and similar acids.
Syreaddisjonssaltene kan anvendes til samme formål som en fri base eller de kan anvendes for å rense denne. Eksempelvis kan den fri base overfores til et vannuopploselig salt, som picratet, som kan underkastes rensningsbehandling, f.eks. opplosningsmiddeleks-traksjoner og vaskninger, kromatografi, fraksjonerte vaske-væske-ekstraksjoner og krystallisasjon, og så anvendes til å regenerere den fri baseform ved behandling med alkali eller for å fremstille et annet salt ved metathese. Eller den fri base kan omdannes til et vannopploselig salt, som hydrokloridet eller sulfatet, og den vandige oppløsning av saltet kan ekstraheres med forskjellige med vann ublandbare opplbsningsmidler for regenerering av den. fri baseform ved behandling av den således ekstraherte syreopplosning eller overfores til et annet salt yed metathese. De fri baser av form-lene IA og IB kan anvendes som puffere eller antisyrer. Forbindels-ene av formel I reagerer med isocyanater under dannelse av urethaner og kan anvendes til å modifisere urethanharpikser. Thiocyansyre-addisjonssaltet danner når det kondenseres med formaldehyd harpiks-aktige materialer som er nyttige som beisningsinhibitorer ifblge US patenter 2.^-25.320 og 2.606.155. De fri baser er også gode bærere for giftige syrer. Eksempelvis er fluorkiselsyre-addisjonssalter nyttige som mbllimpregneringsmidler i henhold til US patenter I.915.33V og 2„075.359 og hexafluorarsensyre- og hexafluorfosforsyre- The acid addition salts can be used for the same purpose as a free base or they can be used to purify this. For example, the free base can be transferred to a water-insoluble salt, such as picrate, which can be subjected to purification treatment, e.g. solvent extractions and washings, chromatography, fractionated washing liquid extractions and crystallization, and then used to regenerate the free base form by treatment with alkali or to prepare another salt by metathesis. Or the free base can be converted into a water-soluble salt, such as the hydrochloride or sulfate, and the aqueous solution of the salt can be extracted with various water-immiscible solvents to regenerate it. free base form by treating the thus extracted acid solution or is transferred to another salt yed metathesis. The free bases of formulas IA and IB can be used as buffers or antacids. The compounds of formula I react with isocyanates to form urethanes and can be used to modify urethane resins. The thiocyanic acid addition salt forms, when condensed with formaldehyde, resinous materials useful as pickling inhibitors according to US patents 2,25,320 and 2,606,155. The free bases are also good carriers for toxic acids. For example, fluorosilicic acid addition salts are useful as fabric impregnating agents according to US patents I,915,33V and 2,075,359 and hexafluoroarsenic acid and hexafluorophosphoric acid
addisjonssalter er nyttige som parasittisider. addition salts are useful as parasiticides.
Nære analoger av 7-klor-7-deoxy-lincomycin, dvs. hvor -I^H er cis- eller trans-alkyl med inntil 8 carbonatomer, R^ er methyl eller ethyl, R er alkyl med inntil 8 carbonatomer, har antibakterielle egenskaper, og noen er sammenlignbare med eller overlegne over lincomycin qg kan anvendes for de samme formål som lincomycin. De tilsvarende forbindelser hvor R^ er hydrogen har lignende antibakterielle egenskaper og har dessuten forbedret gramnegativ aktivitet. Således oppviser 7-klor-6,7,8-trideoxy-6-(trans-l-ethyl-^-butyl-L-2-pyrrolidincarboxamido)-1-thio-L-threo-oc-D-galactopyranosidhydro-klorid, som er et lysebrunt, amorft fast stoff, 8 ganger aktiviteten av lincomycin mot grampositive bakterier og 16-2V ganger den for lincomycin mot gramnegative bakterier. Close analogues of 7-chloro-7-deoxy-lincomycin, i.e. where -I^H is cis- or trans-alkyl with up to 8 carbon atoms, R^ is methyl or ethyl, R is alkyl with up to 8 carbon atoms, have antibacterial properties , and some are comparable to or superior to lincomycin qg can be used for the same purposes as lincomycin. The corresponding compounds where R 1 is hydrogen have similar antibacterial properties and also have improved Gram-negative activity. Thus, 7-chloro-6,7,8-trideoxy-6-(trans-1-ethyl-^-butyl-L-2-pyrrolidinecarboxamido)-1-thio-L-threo-oc-D-galactopyranoside hydrochloride exhibits which is a light brown, amorphous solid, 8 times the activity of lincomycin against gram-positive bacteria and 16-2V times that of lincomycin against gram-negative bacteria.
Andre analoger og isomerer har lignende antibakterielle egenskaper, men i lavere grad og kan anvendes for de samme formål som lincomycin hvor storre mengder ikke er kontraindikert. Other analogues and isomers have similar antibacterial properties, but to a lesser extent and can be used for the same purposes as lincomycin where larger amounts are not contraindicated.
Det folgende eksempel illustrerer fremgangsmåten og produktene fremstilt ved denne. Deler og prosenter er angitt i vekt og opplos-ningsmiddelforhold er angitt i volum. The following example illustrates the method and the products produced by it. Parts and percentages are given by weight and solvent ratios are given by volume.
Fremgangsmåteforbindelsenes terapeutiske aktivitet er beskrevet i Antimicrobial Agents and Chemotherapy, 1966, side 727-736, og 1967, side 537-5^2. The therapeutic activity of the method compounds is described in Antimicrobial Agents and Chemotherapy, 1966, pages 727-736, and 1967, pages 537-5^2.
Fremstilling av utgangsmaterialene er beskrevet i ålment til-gjengelig norsk ansokning nr. 161.593 og i J.Med. Chem. 13_,6l8 (1970). Preparation of the starting materials is described in generally available Norwegian application no. 161,593 and in J.Med. Chem. 13_,6l8 (1970).
Eksempel Example
7-klor-7-deoxylincomycin [methyl-7-klor-6,7,8-trideoxy-6-(trans-l-methyl-1+-propyl-L-2-pyrrolidincarboxamido) -1-thio-L-threo-oc-D-galacto- octopyranosid 7-chloro-7-deoxylincomycin [methyl-7-chloro-6,7,8-trideoxy-6-(trans-1-methyl-1+-propyl-L-2-pyrrolidinecarboxamido)-1-thio-L-threo -oc-D-galacto-octopyranoside
'w 'w
A. Den fri base A. The free base
En suspensjon av 221,0 g (0,5 mol) lincomycinhydroklorid i A suspension of 221.0 g (0.5 mol) of lincomycin hydrochloride i
5 1 carbontetraklorid ble omrort godt ved 25°C under nitrogen, 5 1 carbon tetrachloride was stirred well at 25°C under nitrogen,
900 ml thionylklorid ble tilsatt på en gang og omroringen fortsatt i 2 timer. I lopet av denne tid ble det faste stoff opplost og en klar opplbsning ble dannet. Reaksjonsblandingen ble oppvarmet under tilbakelop i 2 timer, varmekilden ble så fjernet og nitrogen boblet inn i den ravfarvede oppløsning inntil temperaturen på reaksjonsblandingen falt til 25°C. Ca. h 1 væske ble fjernet ved vakuum-destillasjon ved 'en væsketemperatur på under 35°C. Det gule, faste stoff som utfeltes under denne destillasjon, ble oppsamlet og tbrret. Dette råprodukt som veiet 300 g, inneholdt både det 3,^--0-cycliske sulfit og det 3j^-O-cycliské bis-sulfit, hvorav den førstnevnte forbindelse kan isoleres som beskrevet i J. Med. Chem. 13_, 618(1970). 900 ml of thionyl chloride was added at once and stirring continued for 2 hours. During this time the solid dissolved and a clear solution was formed. The reaction mixture was heated under reflux for 2 hours, the heat source was then removed and nitrogen was bubbled into the amber solution until the temperature of the reaction mixture dropped to 25°C. About. h 1 liquid was removed by vacuum distillation at a liquid temperature below 35°C. The yellow solid that precipitated during this distillation was collected and filtered. This crude product, which weighed 300 g, contained both the 3,^--O-cyclic sulphite and the 3j^-O-cyclic bis-sulphite, from which the first-mentioned compound can be isolated as described in J. Med. Chem. 13_, 618(1970).
Ved dette forsbk ble imidlertid det gule, faste stoff opplost In this experiment, however, the yellow solid was dissolved
i ca. 300 ml methanol, avkjolt til 25°C, gjort basisk (pH 11) med fortynnet vandig 2N natriumhydroxydopplosning, fortynnet til ca. t 1200 ml med vann og ekstrahert godt med ether. Etherekstraktene ble forenet, vasket med en liten mengde vann, torret over vannfritt magnesiumsulfat og filtrert. Ved inndampning av en del av de for-enede etherekstrakter fikk man 7-klor-7-deoxylincomycin-fri base som et gult, amorft, fast stoff. for about. 300 ml of methanol, cooled to 25°C, made basic (pH 11) with dilute aqueous 2N sodium hydroxide solution, diluted to approx. t 1200 ml with water and extracted well with ether. The ether extracts were combined, washed with a small amount of water, dried over anhydrous magnesium sulfate and filtered. By evaporation of part of the combined ether extracts, 7-chloro-7-deoxylincomycin-free base was obtained as a yellow, amorphous, solid.
B. Hydrokloridet B. The hydrochloride
Tilsetning av hydrogenkloridgass til filtratet fra del A forte til felning av 7-klor-7-deoxylincomycinhydroklorid som ble fraskilt og omkrystallisert fra ethanol og ethylacetat. Man fikk hvitt, krystallinsk 7-klor-7-deoxylincomycin-hydroklorid inneholdende ca. Addition of hydrogen chloride gas to the filtrate from Part A precipitated 7-chloro-7-deoxylincomycin hydrochloride which was separated and recrystallized from ethanol and ethyl acetate. White, crystalline 7-chloro-7-deoxylincomycin hydrochloride containing approx.
1 molekyldel vann. 1 molecule of water.
Anal. Beregn, for C^H-^CII^O^S. HC1. R"20 Anal. Calculate, for C^H-^CII^O^S. HC1. R"20
C ^5,18, H 7,37, Cl 1^,82, N 5,86, S 6,70, H20 3,77 C 5.18, H 7.37, Cl 1^.82, N 5.86, S 6.70, H 2 O 3.77
Funnet: C Mf,70, H 7,65, Cl 1^,27, N 5,78, S 6,^5, Found: C Mf,70, H 7.65, Cl 1^,27, N 5.78, S 6,^5,
H20 3,85. H 2 O 3.85.
[a]<H>2° + 130° (C = 0,9858 g/100 ml) [a]<H>2° + 130° (C = 0.9858 g/100 ml)
D D
Aktivitet: Ca h - 8 ganger lincomycin. Activity: Ca h - 8 times lincomycin.
Antibakterielt spektrum som for lincomycin. Antibacterial spectrum as for lincomycin.
Claims (1)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NO96671A NO124161B (en) | 1965-02-08 | 1971-03-15 |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US43118465A | 1965-02-08 | 1965-02-08 | |
US51128865A | 1965-12-01 | 1965-12-01 | |
NO161593A NO123608B (en) | 1965-02-08 | 1966-02-07 | |
NO96671A NO124161B (en) | 1965-02-08 | 1971-03-15 |
Publications (1)
Publication Number | Publication Date |
---|---|
NO124161B true NO124161B (en) | 1972-03-13 |
Family
ID=27483965
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO96671A NO124161B (en) | 1965-02-08 | 1971-03-15 |
Country Status (1)
Country | Link |
---|---|
NO (1) | NO124161B (en) |
-
1971
- 1971-03-15 NO NO96671A patent/NO124161B/no unknown
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